Pharmacology MCQs 2 - ANZCA Flashcards

Question

IV19 [Jul01] Propofol: A. Causes decreased hepatic blood flow to influence its own clearance B. Relatively low clearance in children C. Has a high rate of transfer from the peripheral to the central compartment on ceasing an infusion D. Has clinically significant metabolites E. Elimination halflife of 5 minutes

Answer 1

Propofol: A. Causes decreased hepatic blood flow to influence its own clearance: probably false - seems wrong to me that propofol decreases hepatic blood flow decreasing its own clearance CORRECT - Miller (see below) B. Relatively low clearance in children - False C. Has a high rate of transfer from the peripheral to the central compartment on ceasing an infusion - true: this is what gives it such a great CSHT FALSE - Miller (see below) D. Has clinically significant metabolites - false E. Elimination halflife of 5 minutes - false A: miller says may cause. B: No. Miller p 250 C: True. D: Metabolites inactive, Glucuronide and Quinol. E:Elimination half life 9 - 70 mins. Sasada. further comment I think A is correct. Propofol is metabolised by the liver, and has high hepatic extraction ratio so clearance will be limited by HBF. Propofol can decrease HBF and HER. I think C is incorrect. Propofol is released from the peripheral compartment so slowly when infusion is ceased that elimination from the central compartment can decrease the conc there. See http://www.euroanesthesia.org/education/rc_amsterdam/09rc3.HTM (paragraph below figure 2) I agree. As does Miller. A - would decrease hepatic blood flow, but also demonstrates extra-hepatic clearance, so perhaps it wouldn't influence its own elimination B - High clearance and high Vd in children (Stoelting) C - Propofol has a relatively short context sensitive half-time (40 mins after 8 hr infusion acc to Stoel), meaning that at steady-state, there would be a high transfer of drug from peripheral to central compartment, as rapid metabolism and elimination from the central compartment maintains a concentration gradient for this to occur. Prior to steady-state, drug would move the opposite direction D - probably not clinically significant given that renal failure does not change clearance, but 4-hydroxypropofol has about 1/3rd the hypnotic activity of propofol (Stoel 4th p 156) E - elimination half-life is 0.5-1.5 hrs (Stoelting) I'd go for A or C. Sitting on the fence. A - Millers: Propofol may impair its own clearance by decreasing hepatic blood flow. C - As above Hence I would sit on either A or C as well. Not the best question is it? Looks like a good question, as there's one right answer, and one answer that some candidates think is right! There is slow transfer into and out of the peripheral compartment. Re above statement: At steady state (not in the question), it doesn't matter how fast or slow transfer is, as there is no net transfer at steady state. I'd go with A as per Miller's. C - 'the longer elimination half-life indicates a deep compartment with limited perfusion, which results in a slow return of propofol back to the central compartment' (courtesy of Miller)

Answer 2

A: Ketamine - is the correct answer: Ketamine exerts its effect by binding at the phencyclidine PCP site in the NR1 subunit of the NMDA receptor channel (Faunce p264) Non-competitively inhibits glutamate in a time, concentration and stimulation frequency-dependent manner Thiopentone and Methohexitone: both are barbiturates which act at GABA receptors (p128 Stoelting): Interaction of barbiturates with GABA-A receptors decreases rate of dissociation of GABA from the receptor This extends the duration of GABA-A activated chloride channel opening Cell remains hyperpolarised (and thus in an inhibited state) for longer Propofol acts at GABA-A receptors (Stoelting p156): Decreases rate of dissociation of GABA from the receptor in a barbiturate-like fashion Propofol does not modulate other ligand-gated ion channels at clinically relevant concentrations Midazolam: Benzodiazepines selectively potentiate the effects of GABA on GABA-A receptors Benzodiazepines bind with high affinity to a specific ‘benzodiazepine site’ on the γ-subunit, distinct from the GABA binding site on the β-subunit (RDR p471, Gillman p405; Stoelting p141 states due to activation of α-subunits ?wrong) Benzodiazepine binding to its receptor enhances binding of GABA to its receptor and enhances its agonist effects

Answer 3

Answer is C - to increase the ionised portion Thiopentone undergoes keto-enol isomerism. The enol form is the predominant form in alkaline solutions. The addition of sodium carbonate raises the pH of the reconstituted solution and the Na+ replaces the H+ on the -OH group (so -O-Na+). The result is much increased water solubility (more ionised drug) which allows thiopentone to be water-soluble in solution, but then convert to the lipid soluble keto form after injection into the blood stream. All intravenous induction agents have the problem of needing to have a very high lipid solubility to be active (ie to rapidly cross the blood-brain barrier to reach the target site of action) but yet also needing to be available in a form suitable for intravenous injection (eg by being water soluble). So how can a drug be both "lipid soluble" and "water-soluble" at the same time? The answer is by having different forms of the drug present depending on the physical characteristics of the solution (eg pH). Thiopentone solubility is pH-dependent (as discussed above) because of its ability to undergo keto-enol tautomerism. Midazolam solubility is also pH-dependent because of pH-dependent ring-opening which allows conversion between the water-soluble form (in the ampoule) and lipid-soluble closed ring form after injection (due rise in pH). Carriage of significant amounts of the drug in the blood is by binding to plasma proteins. Another solution is to formulate the drug in an emulsion in the ampoule (eg propofol). 30 mg of anhydrous sodium carbonate is added to thiopentone (= 6% by weight) and the the final pH of reconstituted 2.5% Na thiopentone solution about 11. Thiopentone is a weak acid. Un-dissociated thiopentone is very H2O-insoluble. As stated above, in an alkaline environment thiopentone is more predominant in its dissociated form. Na carbonate is added to increase the water solubility of thio (so i guess the answer would be c - to increase the ionised portion). An alternative explanation to above is that the Na carbonate provides a source of OH-, which would prevents the accumulation of H+ (the H+ combines with thiopentone and leads to more of the undissociated form (H2O insoluble) which precipitates out of solution). (Refer to page 91 in Peck and Williams (the diagram explains this) For the same reason, thiopentone is stored under nitrogen, rather than air, as the CO2 in air can cause acidification. As stored, in powder form, there is no ionisation to speak of.

Answer 4

Probably C is the best answer A - increased HR is typical of thiopentone induction - related to baroreceptor function and hypotension B - true: "Cardiovascular stability is characteristic of induction of anaesthesia with 0.3mb/kg IV of etomidate. After this dose... there are minimal changes in heart rate" Stoelting p146 3rd ed. C - propofol characteristically causes a decrease in SBP without compensatory increase in HR (Comment - if anything it drops it. Certainly ablates baroreceptor reflex) D - increase in HR , increase in MAP related to SNS stimulation E - like thiopentone, see increased HR I would go for Answer C propofol as well. It is a bit of controversy as propofol causes primarily bradycardia if anything, and etomidate has always been remembered as the IV agent with best cardiovascular profile. I think maybe i would answer B = etomidate - as there are very few cardiovascular changes seen. Also propofol can, on occasion cause a profound bradycardia / asystole. Answer C - Propofol. Bradycardia is the reverse of tachycardia! From Sasada: "Etomidate is notable for its relative CVS stability. ... tachycardia is produced only by high doses of the drug." "Propofol produces a 15-25% decrease in BP and SVR without a conspensatory increase in HR; the CO decreases by 20%. ... Profound bradycardia, possibly through resetting of the baroreceptor reflex, and asystole may complicate the use of the drug." Cardiovascular System Etomidate is notable for its lack of cardiovascular effects, although the reasons for this remain obscure (Table 40–3). (54,55) At the typical induction dose of 0.3 mg/kg, it has little effect on arterial or venous vascular tone or on cardiac contractility. Following induction of general anesthesia with etomidate, usually little change in blood pressure or heart rate occurs. Cardiovascular stability usually is preserved in persons with hypovolemia or cardiac dysfunction. Etomidate does not release histamine. At the higher dose of 0.7 mg/kg needed to produce EEG burst suppression, hypotension due to vasodilatation has been reported. (56) - Longnecker's Anesthesiology, Chapter 40, section on etomidate This is not a great question; the answer could be B or C. However, etomidate has been withdrawn from the market in Australia, so you could argue that it has no effect at all on Australian patients because it's unavailable! References Smith, Scarth and Sasada - Drugs in Anaesthesia and Intensive Care, 4th ed.

Answer 5

Benzos act on GABA receptor at BDZ binding site, not glycine binding site "The benzodiazepine receptor: BZDs bind to the GABA receptor at a BZD receptor site. When doing so, BZDs allosterically increase the binding of GABA to the GABA receptor, thus augmenting the effects of GABA (Sandford, Argyropoulos, & Nutt, 2000); that is, it increases the effectiveness of GABA for opening the ion channel by changing the GARC’s shape (Carlier, 2001). The BDZ receptor is the only known receptor for which there are not only agonists (e.g., diazepam, midazolam, flurazepam), partial agonists (e.g., RO 16-6028), and antagonists (e.g., flumazenil or RO 15-1788), but also full and partial inverse agonists (e.g., respectively, RO 19-4603, and RO 15-4513) (Jackson & Nutt, 1992; Leonard, 1992). The inverse agonists are anxiogenic. Since BZD allosterically modifies the GARC, the terms ‘agonist’ and ‘inverse agonist’ have been criticised. Instead, the terms ‘positive allosteric modulator’ and ‘negative allosteric modulator’ have been proposed (Puia, Vicini, Seeburg, & Costa, 1991, as cited in Chebib & Johnston, 2000). No matter what terms are used, this complexity has generated a lot of interest in the workings of BZDs and their receptor." - from [1]

Answer 6

Rapidly absorbed from GIT but significant 1st pass metab; 50% reaches syst circulation. 80-100% bioavail imi. Elim half-life is 1-4hours. Reference (1) Midazolam oral bioavailability = 40% (Table 1) Midazolam IM bioavailability = 100%. Elimination half-life 1-4 hours. (Table 2) References (1) Benzodiazepines in epilepsy: pharmacology and pharmacokinetics, Riss et. al. Acta Neurologica Scandinavica, Volume 118, Issue 2, pages 69–86, August 2008 (2) Sasada and Smith 3rd Ed

Answer 7

A. It causes profound analgesia but insufficent hypnosis for procedure -> false - clearly is used as sole agent in field and trauma surgery B. It causes emergence phenomena in up to 30% of patients when given as an infusion -> up to 30% is true, not sure about the "as an infusion" part. Stoelting certainly lists this as ketamine's limiting feature C. It is too water soluble (or something like that) compared to proposal -> false it is more water soluble and therefore doesn't require a lipid emulsion carrier - surely and advantage D. Half life is 80 mins -> false t½β of 2.5 hours

Answer 8

Answer = A a happy reminder that the core texts on the exam list are the source of the MCQ answers: Stoelting: "Thiopental, thiamylal, and methohexital undergo maximal brain uptake within 30 seconds (rapid effect site equilibration), accounting for the prompt onset of CNS depression. The brain receives about 10% of the total dose in the first 30 to 40 seconds. This maximal brain concentration is followed by a decrease over the next 5 minutes to one-half the initial peak concentration, due to redistribution of the drug from the brain to other tissues. Indeed redistribution is the principal mechanism, accounting for early awakening after a single IV dose of these drugs. After about 30 minutes, the barbiturate has been further redistributed and as little as 10% remains in the brain." Caution, this question has recently been remembered as specifically asking for the proportion of the INITIAL dose. Reading Stoeltings paragraph, 10% of INITIAL dose reaches the brain, and after 30 minutes, only 10% remains, so 1% of INITIAL dose remains. References Stoelting (4th ed) p129

Answer 9

"small does of barbiturates seem to lower the pain threshold, accounting for the clinical impression that these drugs are anti-analgesic. Therefore barbiturates cannot be relied on to produce sedation in the presence of pain. Nevertheless, the concept that barbiturates are anti-analgesic has never been confirmed" (Stoelting 4th ed p132)

Answer 10

The rapid clearance of propofol is the key determinant in its non cumulative nature (short CSHT) and hence its usefulness as a TIVA agent. Drug t½Keo (min)for thiopentone is 1.17mins vs Propofol at 3.5 mins. hence more rapid onset time for thiopentone. a small t1/2Keo is useful, but not the source of benefit for propofol over thio, which accumulates very rapidly. A False B False C True D False

Answer 11

The truth of the following statements is listed, but beware the negative / positive wording of the question WRT which is the best answer: A. Resistance to infection thio > prop - true , propofol supports bacterial growth (soy bean oil protein and egg lecithin- yummy for bugs cf. Thio - pH 10.5) B. t½keo prop = thio - false t½keo prop = 3.5mins; thio = 1.17 (hence quicker time to sleep with thiopentone) C. Effect site conc thio faster than prop - true see answer B D. Pain on infection thio > prop - false or D. was Pain on injection prop>thio - true

Answer 12

See also IV26 which is the same question but says amount after 30 minutes. Not sure which is the correctly remembered time but there is a exact reference for the 30 min MCQ. Just a bit above the part referenced in IV26: "The brain receives about 10% of the total dose of thiopental in the first 30 to 40 seconds. This maximal brain concentration is followed by a decrease over the next 5 minutes to one-half the initial peak concentration, due to redistribution of the drug..." -Stoelting

Answer 13

See also IV26 which is the same question but says amount after 30 minutes. Not sure which is the correctly remembered time but there is a exact reference for the 30 min MCQ. Just a bit above the part referenced in IV26: "The brain receives about 10% of the total dose of thiopental in the first 30 to 40 seconds. This maximal brain concentration is followed by a decrease over the next 5 minutes to one-half the initial peak concentration, due to redistribution of the drug..." -Stoelting

Answer 14

See Stoelting 4th ed p127

Answer 15

NB:"There were two questions on it - can't recall both so I've put what I can recall from them together" See also: IV13, IV16, IV19 for related MCQs

Answer 16

A - increases B - F - nmda C - F - inc D - T ?

Answer 17

Answer D - 90% as explained below ``` !!Work in progress - not yet complete!! Henderson Hasselbach equation pH = pKa + log [A-]/[HA] pKa = pH + log[HA]/[A-] therefore pKa - pH = log [HA]/[A-] 7.9 - 6.9 = log [HA]/[A-] 1 = log [HA]/[A-] inverse log of both sides 10 = [HA] / [A-] 10 [A-] = [HA] ionised (HA) is 10 times that of ionised therefore answer should be approx 91% ionised ``` A simpler approach with easy to remember rules: Acids are predominantly ionised Above their pKa ; Bases are predominantly ionised Below their pKa Lignocaine is a base, thus predominantly ionised in the pH in question pH = pKA 50% ionised One unit away from pKa = 90% Two units away from pKa = 99%. Seemed to work for me without the pressure of the arithmetic. With these rules you can work out an approximate ionisation for any combo of pH and pKa as long as you know if acid or base. Remember most things are bases except, aspirin, paracetamol, thiopentone, propofol, penicillin and phenytoin Acidic drugs also warfarin, methotrexate, probenecid, sulphamethoxazole, chlorothiazide, levodopa and benzocaine (weak acid) Alternative rule is to draw an ionisation graph using the PISA rule. That is the axes being x-pH/pKa and y-percentage Ionised, with an S shaped graph for an Acid - the reverse graph for a base and then for unionised swap the acid/base labels. Might sound complicated but worth a try as I find with the above/below rule I run into problems when I can't remember whether or not its ionised or unionised, also its diagramatic which is always good for a viva. Try this %Ionized = 100/(1+ Anti-log(pH - pKa)) = 100/(1 + antilog -1) = 100/(1 + 10^-1) = 100/1.1 = 90.9% My personal approach of pKa type questions is this mnemonic: pH = pKa + log (proton Acceptor / proton Donor) ([AC/DC]) And then remember that acid drugs, AH: H donor A-: H acceptor hence pH = pKa + log (A-/AH) basic drugs, A: H acceptor AH+: H donor. hence pH = pKa + log (A/AH+) So this mnemonic is equally applicable for both acidic and basic drugs (save the trouble of memorising two versions). So say for this question, you need to remember that LAs are basic drugs. Using the AC/DC formula above, 7.1 = 8.1 + Log(A/AH+). Rearrangement of this shows that A/AH+ is 0.1, hence there must be 10 times more AH+ than A, i.e. AH+ 90.9% vs A 9.1%.

Answer 18

Cocaine: A. Blocks reuptake of dopamine and noradrenaline - True for both - Cocaine's "euphoric properties are due primarily to inhibition of catecholamine uptake, particularly dopamine, in the CNS." (Goodman and Gilman) B. Central effects are due to noradrenaline - False: see A C. Crosses lipid soluble membranes because its pKa is 2.8 - False pKa 8.7 D. Is not metabolised by plasma pseudocholinesterase - False "Ester-type local anesthetics are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase (pseudocholinesterase) to inactive metabolites." Katzung online ed. E. Rapidly absorbed by nasal mucosa - not sure, definitely absorbed, but rapidly? cocaine although an ester is rather resistant to plasma esterases. degredation primarily hepatic. Cocaine is a local anaesthetic ester, which is different to other esters because it is metabolised in the liver. However, it is still metabolised by plasma cholinesterase (Stoelting 4th Ed, p.187) (Sasada & Smith says "predominantly" by plasma esterases) Not sure how rapidly it is absorbed by nasal mucosa, but bioavailability of this route is 0.5% (Sasada & Smith) Cocaine is absorbed rapidly through mucous membranes, and peak plasma levels (ie, 120-474 ng/mL) are reached within 15-60 minutes. Half-life in serum is 30-90 minute (http://www.emedicine.com/ent/topic384.htm - although not strictly on the reading list I know) ------------ cocaine has a vasoconstricting property ,so i dont think rapid is correct,,(stoelting) References

Answer 19

LA03 Ropivacaine: A. Produces greater motor block than bupivacaine - False "the motor anaesthesia produced by ropivacaine is less intense and of shorter duration" (than bupivacaine) p.175 Stoelting 3rd ed B. Is prepared as the R enantiomer - FALSE "Ropivacaine has been developed as a pure S enantiomer" Stoelting p159 3rd ed. C. Is less lipid soluble than lignocaine - FALSE Both bupivacaine and ropivacaine are more lipid soluble than lignocaine D. Has the same cardiotoxicity as lignocaine - FALSE CC:CNS ratio is 5 cf lignocaine's 7

Answer 20

LA03b Ropivacaine A. Is a pure R isomer - False see above B. Is an isomer of bupivacaine - false C. Provides more motor block than bupivacaine FALSE Don't we use ropivacaine in epidurals to try to reduce the motor block?? D. Has more toxicity than bupivacaine false E. Has similar physico-chemical properties to bupivacaine - true similar protein binding and pKa CC:CNS ratio Is defined as "ratio of the dosage required for irreversible cardiovascular collapse (CC) and the dosage that produces CNS toxicity (convulsions)". As far as I can tell, the CC:CNS ratio does not tell us about the cardiac toxicity per se, but just tells us about cardiac toxicity compared to seizures. I agree that the impression is that ropivacaine is less cardiotoxic than bupivacaine, but not because of the CC:CNS ratio. Comments anyone?

Answer 21

LA03c Ropivacaine differs from bupivacaine mainly by: A. More motor blockade than bupivacaine - false B. Mainly affecting A beta rather than A delta fibres - false affects A delta and C fibres C. Lower cardiac toxicity than bupivacaine true higher CC:CNS ratio

Answer 22

A. False - Bupivacaine is an amino-amide LA B. Correct - Mepivicaine has a methyl group on the piperidine nitrogen atom, which is replaced by a butyl group in Bupivacaine (stoelting 4th pg 180 or p159 in 3rd ed) Tip/Historical note: Mepivacaine has a methyl group; (p)ropivacaine has a propyl group; bupivacaine has a butyl group C. More toxic. CNS toxicity index Bupivacaine: 2.9, Tetracaine 2.0 (p522 Evers&Maze) D. is true E. False - "Compared to bupivacaine, etidocaine produces preferential motor blockade." Goodman and Gilman Ch 14 online ed. Not sure about D. Stoelting (4th Ed, p.179) says that sodium bisulphite is added to adrenaline-containing solutions, not sodium metabisulphite. New Zealand data sheet for "0.5% marcain with adrenaline" lists sodium metabisulphite as an ingredient. Not sure about "B"... It is true that bupivacaine is the butyl derivative of mepivacaine, but is it *formed* this way? "D" is most correct. The question of equal potency of etidocaine and bupivacaine in peridural anesthesia Reg Anaesth. 1984 Apr;7(2):33-8. Diallo B, Nolte H. A double blind clinical trial was carried out on randomised groups of 20 patients each undergoing surgery for varicose veins to compare the actions of etidocaine 1% and bupivacaine 0.5% and 0.75% with adrenaline 1:200.000. Bupivacaine 0.75% and etidocaine 1% were found to be equipotent, with a rapid onset and long duration of anaesthesia, and a comparable degree of profound motor block. The latency period of Etidocaine was markedly increased in the L V and S I segments, probably due to its high fat solubility. 0.5% bupivacaine, compared to the other preparations, showed significantly less motor block and duration of analgesia. Unlike other investigators, "spotty-analgesia" was not found in this series. Miller pg 584 - Bupivacaine and etidocaine provide an interesting contrast in their differential sensory- and motor-blocking activity, although they are both potent, long-acting anesthetics.[40] Bupivacaine is widely used epidurally for obstetric analgesia and postoperative pain management because it can provide acceptable analgesia with only mild muscle weakness, particularly when used for infusions in concentrations of 0.125% or less (also see Chapter 43 Chapter 44 Chapter 45 and Chapter 58 ). When given by epidural bolus dosing, bupivacaine produces more effective sensory than motor blockade over a concentration range from 0.25% to 0.75%, whereas etidocaine produces almost equal effective sensory and motor blockade over this concentration range.

Answer 23

Molecular weights for the above local anaesthetics are as follows: Cinochocaine: MW 379.9 (C20.H3.0.Cl.N3.O2) Bupivacaine: MW 288.4 (C18.H28.N2.O) Lignocaine: MW 234.3 (C14.H22.N2.O) Prilocaine: MW 220.3 (C13.H20.N2.O) Hence the correct answer is [A] - Cinochocaine > Bupivacaine > Lignocaine > Prilocaine I have just noticed it goes with the number of letters in the name. Hope it helps! How good is your spelling? It also goes with potency - except that I don't really know the potency of cinochocaine or dibucane It goes with the number of letters because Cinchocaine was misspelt.

Answer 24

A correct Lignocaine acts by selectively binding to Na channel in the inactivated states,local anaesthestics molecule stablize these channels in this configuration and prevents there changes to rested closed and active open. It also bind to specificed sites located in the inner portion of Na channels(H gates)and well as physically obstruct the external opening of the channel & maintain them inactive closed state Comments In addition to the above, frequency-dependent blockade occurs (a phenomenon which comes in handy in its use as a Class I anti-arrhythmic. In this situation, the lignocaine molecule is able to gain access to receptors only when the voltage-gated sodium channels are in the activated-open state. "In addition to sodium ion channels, local anesthetics block voltage-dependant potassium ion channels. Compared with sodium ion channels, local anesthetics exhibit a much lower affinity........Considering the structural similarity between voltage-dependant calcium ion channels and sodium ion channels, it is not surprising that calcium ion channels (L-type most sensitive) may also be blocked by local anesthetics. (Stoelting 4th Ed. Pg 182). He goes on to say on pg 191 that "Effects of local anesthetics on calcium ion and potassium ion channels and local anesthetic-induced inhibition of cyclic adenosine monophosphate production may also contribute to cardiac toxicity"

Answer 25

``` Lung Uptake: Alfentanil 80% Fentanyl 75% Propranolol 75% Pethidine 65% Lignocaine 60% Thiopentone 14% Morphine 3-5% Lignocaine is 25% UNionized at physiologic pH ```

Answer 26

Lignocaine: A. Has active metabolites - TRUE: they are responsible for preventing cardiac arrhythmias when the infusion of lignocaine is stopped B. Metabolism faster in females because of progesterone C. Metabolism is independent of liver blood flow - FALSE "hepatic disease or decreases in hepatic blood flow... can decrease the rate of metabolism" Stoelting p 164 3rd ed D. ? E. ? Does have active metabolites ->A correct Amides as a class are affected by liver blood flow ->so C wrong B) EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS Volume 30, Number 4, 231-234 The effects of gender and menopause on serum lidocaine levels in smokers (Sermin Oztekin, Omur Mavioglu, Zahide Elar, Hulya Guven, Şule Kalkan and Tugba Gurpinar) "These results suggest that gender and menopause may have no significant effect on serum lidocaine levels in smokers."

Answer 27

Answer: B ``` Percentage protein binding Bupivacaine 95% Lignocaine 70% Prilocaine 55% Procaine 6% ``` This question can be answered by remembering that Bupivacaine is the most protein bound (apart from levobupivacaine), and that procaine is the least protein bound. Reference Stoelting and Hillier. Pharmacology and physiology in anaesthetic practice. 4th edition, Lippincott Williams and Wilkins. Page 181.

Answer 28

It depends on how this is measured - is it clearance? Ester LA's are generally rapidly metabolised by plasma esterases, but there is no value in Stoelting for the clearance of procaine - it does say that "compared with that of ester anaesthetics, the metabolism of amides is more complex and slower" Prilocaine is the most rapidly metabolised amide LA, followed by lignocaine, bupivacaine, and ropivacaine (going by clearance) Therefore, I think Procaine > Prilocaine > Lignocaine > Bupivacaine > Ropivacaine Peck and Williams (page 172) says ropivacaine has greater clearance than bupivacaine. Thus, I would go (assuming there was an option): Procaine > Prilocaine > Lignocaine > Ropivacaine > Bupivacaine I'd go by t1/2 beta where longest to shortest is bupivacaine, ropivacaine, lignocaine, prilocaine and procaine... no specific reference as stoelting does not have value for prilocaine while Peck + Williams says lignocain = prilocaine References Stoelting 4th Ed. p. 181, 185

Answer 29

Poorly remembered question... Saxitoxin site on sodium channel is: A. Inside channel - FALSE B. Outside channel - Perhaps True (see below) C. On membrane outside - Perhaps true (see below) D. ? E. ? Of tetrodotoxin and saxotoxin: "Both toxins, in nanomolar concentrations, specifically block the outer mouth of the pore of Na+ channels in the membranes of excitable cells." From Goodman and Gilman Ch 14 online ed. Saxitoxin and tetrotoxin are bio-toxins which both block the neural voltage-gated sodium channel by binding to a specific site at the extracellular side of the channel. It binds to "site 1" [1] near the extracellular pore opening. Saxitoxin has been evaluated to see whether it would be useful for producing long-lasting local anaesthesia (eg [2] & [3]) saxitoxin2.gif Saxitoxin In contrast, the active form of the clinically available local anaesthetics (LAs) is the charged form (BH+) which blocks the channel from the inside (ie intracellular end of the channel). Consequently, LAs applied outside the nerve diffuse through the ECF in the charged form but diffuse through the cell membrane in the uncharged form, before finally re-equilibrating within the ICF so that both charged and uncharged forms are present. ( B BH+) Benzocaine is different as it is uncharged and seems to block the channel as a consequence of dissolving in the lipid cell membrane. (See LA12) Humans can be poisoned by saxitoxin or by tetrotoxin. The algae that produce saxitoxin can in certain conditions multiply to produce large 'algal blooms' in the ocean which produce characteristic 'red tides'[4]. Other References Saxitoxin details Saxitoxin: Essential Information Tetrotoxin article in Wikipedia (useful) Information about fugu (pufferfish that contain tetrodotoxin) [5] "The Australian Research Network for Algal Toxins" (ARNAT) (would you believe).

Answer 30

Option "E In the cell membrane" would be the best answer. Benzocaine is an ester local anaesthetic which is a secondary amine. It is unique among clinically useful LA's. As a weak base with a low pKa (3.5) - therefore at physiological pH exists primarily in an unionized form rendering it lipid soluble (& water-insoluble). Because of this it is suitable for topical anaesthesia of mucus membranes (in concentrations up to 20%). Its systemic toxicity is also diminished because of rapid hydrolysis. It has a very rapid onset Mechanism of action "Certain local anaesthetics (eg benzocaine) are only present in the body as uncharged, tertiary bases, and must therefore act in a different way. They are believed to cause conduction blockade by "membrane expansion" (ie by causing swelling of the lipoprotein matrix of the Na+ channel. To some extent, other local anaesthetics, which are partly present in the neurilemma as the uncharged base may act in this manner." - from Calvey & Williams "Principles and Practice of Pharmacology for Anaesthetists" 4th ed 2001, p152-3 So option "E In the cell membrane" would be the best answer. Benzocaine is a weak base Potential problems with benzocaine 1. Allergic reactions Metabolism to produce para-amino benzoic acid (PABA) so potential for allergic reactions (like other ester LAs) 2. Methaemoglobinaemia Benzocaine can cause methaemoglobinaemia [1](so dose is limited to 200-300mg in adults). Babies are at higher risk [2] because of their smaller weight (easier to give a high dose) and because of lower levels of the enzymes which convert met-HbF back to Hb. Treatment of symptomatic methaemoglobinaemia is IV 1% methylene blue at a dose of 1-2mg/kg over 20 minutes. Note that with concentrations of 20%, one ml will contain 200mg! Regarding methaemoglobinaemia "Of 198 reported adverse events of all types reported with benzocaine, 132 cases (66.7%) involved definite or probable methemoglobinemia, including 107 serious adverse events (81.1%) and two deaths (1.5%). The formulation implicated was a spray in 123 cases (93.2%), a benzocaine-containing lozenge in two cases (1.5%), and a gel in one case. Of the 69 cases that specified a dose, 37 (53.6%) indicated that a single spray was applied, which is approximately the recommended amount. "Health professionals involved in endoscopy, intubation, bronchoscopy, or similar invasive procedures using benzocaine-containing sprays should know that (1) administration may cause MHb with potentially serious consequences, (2) identifying the reaction to benzocaine usually requires cooximetry (although it can be implied by symptoms), and (3) treatment involves immediate intravenous administration of 1 to 2 mg/kg of methylene blue." - from [3]

Answer 31

EMLA cream contains: A. Soluble in water at >16 degrees C - FALSE: looks like a trick answer; melting point for the eutectic mixture of lignocaine and prilocaine is 17 degrees (cf lignocaine 67 and prilocaine 37 individually) B. 20% ionised at pH ?? - perhaps true; the mixture is buffered with NaOH to a high pH of ~9.6 to increase the non-ionised fraction to over 90% (sorry, no reference apart from a medal winner's model answers!) C. 80% ionised at pH ??.. OR: Base contains 80% local anaesthetic D. ?? amount of ionised drug E. All of the above Are there no correct answers in the above options? Considering how widely this cream is now used, it is surprising that there is only one MCQ about it. Its use is not without risk. EMLA = Eutectic Mixture of Local Anaesthetic 5% EMLA is a mixture of crystalline bases of 2.5% lignocaine and 2.5% prilocaine in an emulsion of white oil:water. One of the metabolites of prilocaine, o-toludine may cause methaemoglobinaemia. Therefore its use should be avoided in patients with methaemaglobinaemia (congenital or idiopathic) or in those taking other drugs associated with an increased risk of methaemoglobinaemia (eg sulphonamides or phenytoin). In contrast to the eutectic mixture, I understand that AnGel cream (Royal Children's Hospital Formulation) is 4% amethocaine, an ester local anaesthetic used for topical anaesthesia. Some paediatric departments appear to be favouring this over EMLA, perhaps due to its lack of association with methaemoglobinaemia? Topical amethocaine has a faster onset of action, producing good topical anaesthesia in 30mins, unlike EMLA which needs to be on for one hour. The extra speed is great when attempting to canulate a sick child! COMMENT: Additional advantage of Amethocaine over EMLA is local vasodilation and erythema that may assist venous cannulation. EMLA is noted to cause skin blanching and vasoconstriction. References Some of the information came from the following article: General anaesthesia or conscious sedation for painful procedures in childhood cancer: the family‘s perspective Archives of Disease in Childhood 2003;88:253-257 See EMLA

Answer 32

What factor (?does not) influence the peak plasma levels after epidural injection of local anaesthetic? A. Vasoconstrictor - TRUE: reduces systemic absorption B. Natural vasoconstrictor activity of the drug - TRUE: reduces systemic absorption C. Hepatic clearance - TRUE: higher clearance will result in lower peak concentrations D. Renal clearance - TRUE: higher clearances will result in lower peak concentrations So obviously the answer forgotten is the odd one out and probably the correct answer I think the answer is D. Stoelting says "clearance values... for amide local anaesthetics probably mainly represent hepatic metabolism, because renal excretion of unchanged drug is minimal (

Answer 33

LA15 [Mar99] [Mar03] Which ONE of the following is an amide? A. Tetracaine - ESTER B. Procainamide - AMIDE (class Ia antiarrhythmic as well) C. Procaine - ESTER D. Prilocaine - AMIDE E. Cinchocaine (Dibucaine) - AMIDE Amides have an i followed by caine. Tetracaine is an ester local anaesthetic. Prilocaine, Etidocaine and Cinchocaine (Dibucaine) are amide local anaesthetics. Structure of local anaesthetics Lipophilic and hydrophilic portions connected by hydrocarbon chain. In most cases the amide or ester linkage occurs between the lipophilic portion and the hydrocarbon chain. Ester bond (-(C=O)O-) Amide bond (-NH(C=O)-) Metabolic differences Ester local anaesthetics are hydrolysed by cholinesterase enzyme, mostly in plasma (also in liver) Amide local anaesthetics are metabolised by microsomal liver enzymes (more complex and slower process than for esters) References Stoelting and Hillier. Pharmacology and physiology in anaesthetic practice. 4th edition, Lippiincott Williams and Wilkins, 2006. Or alternatively, 2 "i" in the name = amide. One "i" = ester

Answer 34

``` LA15b [Jul01] The following are all amides except: A. Bupivacaine - AMIDE B. Prilocaine - AMIDE C. Etidocaine - AMIDE D. Tetracaine - ESTER E. Dibucaine - AMIDE ``` Amides have an i followed by caine. Tetracaine is an ester local anaesthetic. Prilocaine, Etidocaine and Cinchocaine (Dibucaine) are amide local anaesthetics. Structure of local anaesthetics Lipophilic and hydrophilic portions connected by hydrocarbon chain. In most cases the amide or ester linkage occurs between the lipophilic portion and the hydrocarbon chain. Ester bond (-(C=O)O-) Amide bond (-NH(C=O)-) Metabolic differences Ester local anaesthetics are hydrolysed by cholinesterase enzyme, mostly in plasma (also in liver) Amide local anaesthetics are metabolised by microsomal liver enzymes (more complex and slower process than for esters) References Stoelting and Hillier. Pharmacology and physiology in anaesthetic practice. 4th edition, Lippiincott Williams and Wilkins, 2006. Or alternatively, 2 "i" in the name = amide. One "i" = ester

Answer 35

``` LA15c [Feb12] Which of the following is not an esther local anaesthetic? A Prilocaine - amide B Procaine - ester C Amethocaine - ester Other wrong answers' ``` Amides have an i followed by caine. Tetracaine is an ester local anaesthetic. Prilocaine, Etidocaine and Cinchocaine (Dibucaine) are amide local anaesthetics. Structure of local anaesthetics Lipophilic and hydrophilic portions connected by hydrocarbon chain. In most cases the amide or ester linkage occurs between the lipophilic portion and the hydrocarbon chain. Ester bond (-(C=O)O-) Amide bond (-NH(C=O)-) Metabolic differences Ester local anaesthetics are hydrolysed by cholinesterase enzyme, mostly in plasma (also in liver) Amide local anaesthetics are metabolised by microsomal liver enzymes (more complex and slower process than for esters) References Stoelting and Hillier. Pharmacology and physiology in anaesthetic practice. 4th edition, Lippiincott Williams and Wilkins, 2006. Or alternatively, 2 "i" in the name = amide. One "i" = ester

Answer 36

``` Lignocaine: A. Anti-arrhythmic effect - ??Na channel /open & inactivated state; perhaps TRUE as lignocaine works on cells in the activated open and inactivated closed but not resting closed B. Prolongs QRS ; FALSE see below C. ? D. ? E. ? ``` "Lignocaine delays the rate of spontaneous phase 4 depolarisation by preventing or diminishing the gradual decrease in potassium ion permeability that normally occurs during this phase... In usual thereputic doses, lignocaine administered as an antidysrhythmic drug has no significant effect on QRS, QT interval on the ECG or on AV conduction" Stoelting 3rd ed p336 It depends what the question is talking about. Stoelting (4th Ed, p.191) says "excessive plasma concentrations of lidocaine may conduction of cardiac impulses through the heart, manifesting as prolongation of the P-R interval and QRS complex on the ECG". Also, what is the reference for lignocaine working on both inactivated-closed and activated-open channels? From what I can see - They only bind to channels in the inactivated-closed state, which prevents their change to the resting-closed or activated-open states (Stoelting 4th Ed, p.182) Stoelting handbook p185: "By selectively binding to sodium channels in the inactive-closed states, LA molecules stabilize these channels in this configuration and prevent their change to the rested-closed and activated-open states in response to nerve impulses" Stoelting handbook p 186: "Local anaesthetic molecules can gain to receptors only when sodium channels are in activated-open states" Peck p164: "In this ionised form it binds to the internal surface of a Na+ channel, preventing it from leaving the inactive state." Do these details have any relevance to what we do clinically? Like much of what we are expected to know, not in the slightest.

Answer 37

Answer is C - 10 mcg/ml Alt answer is A - 5mcg/mL 1:100 = 1% = 10 mg/mL; 1:1000 = 0.1% = 1 mg/mL; 1:10000 = 0.01% = 0.1 mg/mL = 100 mcg/mL; 1:100000 = 0.001% = 0.01 mg/mL = 10 mcg/mL Percentage refers to concentration rather than amount added Disagree - they are interchangeable (if you take % to mean w/v) ``` An easy way to work this out for any example is: 1 in 100 000 = 1g in 100 000 g As it is in solution, this is approx: 1g in 100 000ml 1000mg in 100 000ml 1mg in 100ml 1000 mcg in 100ml 10 mcg in 1ml Think about how much you add to your LA mix! ``` It may be helpful to start with the adrenaline ampoule you're most familiar with: 1: 1000 adrenaline = 1 mg in 1 mL 1: 10,000 adrenaline = 1 mg in 10 mL = 100 mcg / mL 1: 100,000 adrenaline = 1 mg in 100 mL = 10 mcg / mL

Answer 38

Answer is C - 10 mcg/ml Alt answer is A - 5mcg/mL 1:100 = 1% = 10 mg/mL; 1:1000 = 0.1% = 1 mg/mL; 1:10000 = 0.01% = 0.1 mg/mL = 100 mcg/mL; 1:100000 = 0.001% = 0.01 mg/mL = 10 mcg/mL Percentage refers to concentration rather than amount added Disagree - they are interchangeable (if you take % to mean w/v) ``` An easy way to work this out for any example is: 1 in 100 000 = 1g in 100 000 g As it is in solution, this is approx: 1g in 100 000ml 1000mg in 100 000ml 1mg in 100ml 1000 mcg in 100ml 10 mcg in 1ml Think about how much you add to your LA mix! ``` It may be helpful to start with the adrenaline ampoule you're most familiar with: 1: 1000 adrenaline = 1 mg in 1 mL 1: 10,000 adrenaline = 1 mg in 10 mL = 100 mcg / mL 1: 100,000 adrenaline = 1 mg in 100 mL = 10 mcg / mL

Answer 39

A is correct (see clarification below) A - ?true and hence INCORRECT; bupivicaine is highly lipid soluble but the addition of adrenaline is known to decrease its systemic absorption, and presumably increase its duration of action B - potentially true and hence INCORRECT; adrenaline can cause intense vasospasm and local hypoxia resulting in local acidosis C - true and hence INCORRECT; adrenaline is a vasoconstrictor Intresting: I think it does increase the duration of action but not the time of onset, and the effect is more pronounced with lignocaine than with bupivacaine In relation to vasoconstrictors effect on spinal anaesthesia Stoelting 4th Ed pg 200 states "whereas the effect on bupivacaine spinal anaesthesia remains controversial and is, at best, minimal." Therefore A is probably true. Comment: Time of onset is related to degree of ionisation, duration of action is related to protein binding, LA's intrinsic vasodilator activity, and presence of vasoconstrictor like adrenaline. Comment no.2: well if you extrapolate answer 2, producing a local area of acidosis would then reducing the non-ionised portion of the drug which slow the onset of action, yeah? bloody complicated why can't we just keep it simple :S Clarification This question is about epidural, and not spinal, administration. Hence, Stoelting 4th ed p 198 is where the money is: "The addition of epinephrine 1:200,000 to 0.5% or 0.75% bupivacaine or ropivacaine does not appear to offer an advantage in terms of duration of action." Hence, it definitely doesn't significantly prolong duration of action!

Answer 40

Regarding local anaesthetic plasma protein binding A. Is predominantly by albumin - probably also correct but maybe less than B B. Is predominantly by alpha-1 acid glycoprotein - most correct C. Is greater for tetracaine than for bupivacaine - False (76% vs >90%) D. Neonates have a greater number of binding sites - No idea E. Plasma binding is directly proportional to local anaesthetic concentration. - no idea B is true. AAG Alpha1 acid glycoprotein is responsible for the binding of basic drugs.The percentage of local aneasthetic bound to protein is INVERSELY related to plasma concentration of drug. Bupivacaine has 95% protein binding % compared to 76% for Tetracaine. Peck and Williams (p 155) states that "alpha1 acid glycoprotein binds local anaesthetics with high affinity although albumin binds a greater quantity due to its relative abundance." This would make A correct. = regarding option d - INCORRECT "Piafsy and Mpamugo showed significant reductions in both alpha-1-acidglycoprotein levels and in binding of basic drugs lidocaine and propranolol in cord blood when compared with adult controls. When the a-1-acidglycoprotein levels were increased to adult levels, the protein binding of lidocaine and propranolol approached adult levels, suggesting reduced a-1-acidglycoprotein levels as the reason for reduced protein binding." p152 Neonatal and Pediatric Pharmacology By Sumner J. Yaffe, Jacob V. Aranda

Answer 41

A - unsure B - true; LAs cause a frequency dependent blockade from memory C - false; ionised form is effective at blocking the channel. It is non-ionised to get to the channel but the ionised form blocks it, on the cytoplasmic side of the membrane (internal or H gate) D - true; blocks Na channel in activated-open and inactive-closed but not resting-closed state E - unsure D - Stoelting 4th Ed pg 182 states that "By selectively binding to Na channels in in inactivated-closed states, local anesthetic molecules stabilize these channels in this configuration and prevent their change to the rested-closed and activated-open states in response to nerve impulses." E I think is false - a more negative membrane potential means more Na channels are in the resting state (and this state has less affinity for LAs). Hyperkalaemia, on the other hand, will make the RMP more positive (ie partially depolarise the cell) and favour the inactive state thus enhancing the effect of LAs D is also false, effect is predominantly via occluded inactivated channels - "occlusion of OPEN (ie ACTIVE) sodium channels by local anaesthetics contributes little to overall inhibition of sodium permeability" (Stoelting 4th Ed page 181) - COMMENT: P&H pg 164 "the degree of blockade in vitro is proportional to the rate of stimulation due to atraction of local anaesthetic to 'OPEN' Na+ channel." References Stoelting handbook p185: "By selectively binding to sodium channels in the inactive-closed states, LA molecules stabilize these channels in this configuration and prevent their change to the rested-closed and activated-open states in response to nerve impulses" Stoelting handbook p 186: "Local anaesthetic molecules can gain to receptors only when sodium channels are in activated-open states" Peck p164: "In this ionised form it binds to the internal surface of a Na+ channel, preventing it from leaving the inactive state." Do these details have any relevance to what we do clinically? Like much of what we are expected to know, not in the slightest.

Answer 42

LA21 [Feb04] Lignocaine | A. Over 50% UNIONISED at pH 7.4 ?? - FALSE; at pH 7.9, 50% will be ionised; bases are ionised BELOW their pKA so at a pH

Answer 43

A and B wrong - As an enantiomer of bupivacaine, it must be one of the two mirror images of the molecule, therefore there would be no difference in hydrophobicity or hydrophilicity, correct? C wrong - Bupivacaine is different to ROPIVACAINE by the addition of one methyl group. Perhaps the question was recalled wrongly, and should have been Levobupivacaine compared to ropivacaine? Reading Recent Advances in Anaesthesia and Intensive Care 22 (Adams et. al) Levobupivacaine compared with bupivacaine has same pKa (8.1), essentially the same protein binding (95 vs 95.5), a smaller Vd (73L vs 54L) and shorter T1/2 (210min vs 157min), and almost 50% clearance value (0.58L/min vs 0.32 L/min). They unfortunately don't comment on other physical characteristics, but this did challenge (my own) assumption that the physical properties should be the same. The only time chirality doesn't matter is when the molecule is in an achiral environment. Eg. pKa, hexanol partition coefficient. However in the INTENSELY chiral environment of the body the chirality of the molecule has a big impact, thus it is not at all surprising that Vd, clearance etc are different, they are a consequence of the interaction of the molecule with a chiral environment.

Answer 44

I would say D. Airway, breathing, circulation. I would have agreed up until a couple of weeks ago - the new ILCOR and now endorsed by the Australian Resusc Council guidelines are all about compressions. http://www.resus.org.au/public/arc_adult_cardiorespiratory_arrest.pdf Making E the correct answer. Although adrenaline may be indicated before amiodarone. Any thoughts? COMMENT: Miller 7th edition pg 933 says "It is not recommended that bupivacaine induced ventricular arrhythmias be treated with lidocaine or amiodarone" On D, we just wait as we untangle and attach the defib pads and defib before we can start CPR? On E, we just wait for the Amiodarone to be found, drawn up and given before we can proceed to ventilate? Ok, so the examiner says it's about conceptual priorities, not practical priorities of doing the actual resus. So then, conceptually, to get the heart going, we need to do both defib and CPR - whichever can be done quicker, why then, make a distinction between defib before CPR or CPR before defib in D and E? So it's not about conceptual priority? It's about what actually happens? Circle back to my first statement then. For witnessed, in-hospital arrests you should shock first (even stack 3 shocks). The thinking being that the biochemical environment is more likely to be conducive to cardioversion (as less time has passed) rather than an unwitnessed arrest for whom CPR may deliver oxygen to the myocardium and improve chances of a shock being successful. I write this from memory of my ALS course, 3 yrs ago, recommendations may have changed - any comments? Comment: The question asks about priorities, not actual sequence of action. Defib is a higher priority than CPR - although but you may have CPR as your only option for 2 minutes, this is not the question. I agree: D. I also would point out that a dead person's seizure will end without benzos pretty quickly. E is wrong because it uses amiodarone. JB 2012 E is correct. Check the Australian Resus Guidelines - there is a link regarding the Summary of changes which states that the priority is cardiac compressions. Basically brain perfusion above all else is important and from memory you are less likely to Defib to a perfusing rhythm when your coronaries have rendered the heart muscle hypoxic. 3 stacked shocks are no longer a priority unless you are in a cath lab and the patient is on the table having an MI or it is post CABG. Also Amiodarone is very much indicated with this patient's VF. From "Current Concepts in Resuscitation of Patient's with Local Anaesthetic Cardiac Toxicity" Reg Anaes Pain Med Vol 27(6) pp 568-575 "amiodarone is a potent inhibitor of ion channels that are mechanistically implicated in bupivacaine toxicity." Also from the review article in treatment of LAST - Regional Anesthesia and Pain Medicine & Volume 35, Number 2, March-April 2010 - check Table 1 -- it clearly states that "If cardiac arrest occurs... recommend standard ALS... and Amiodarone!!!" It does have other things like airway management or seizures -- but that I am using my commonsense and assuming that the patient still has a perfusing rhythm. -- drfpc 2012 References I think the answer was probably D for 2009 prior to the ARC update which now emphasizes early effective CPR above all else in all BLS/ALS scenarios. So D is NOW no longer correct, however if it was me with the LA toxicity I'll have 100% oxygen straight out of the wall with a BM straight after you start compressions please, because I know it will be at least 2 minutes before you get the AED out, 5 minutes before MET arrive, draw up the amiodarone and give it to me (imagine all the while saying "no, no, don't worry about that 100% O2 - ARC says don't worry!!!). ARC emphasizes effective early CPR and that it shouldn't be interrupted for prolonged periods for ETT/IVC/defib pads etc, it doesn't anywhere suggest that Airway/Breathing/100% O2 is superceded by amiodarone administration. This is from ARC "ALS for special circumstances - LA Toxicity" "Local anaesthetic agents Local anaesthetic toxicity typically occurs in the setting of regional anaesthesia, when a bolus of local anaesthetic inadvertently enters the arterial or venous system, leading to refractory seizures, dysrhythmias or rapid cardiovascular collapse. There are no RCTs evaluating conventional versus alternative therapies for the treatment of cardiac arrest caused by local anaesthetics. Evidence is limited to case reports involving cardiac arrest and severe cardiovascular toxicity and animal studies. Five single-case reports describe patients in cardiac arrest attributed to local anaesthetic intoxication, who were refractory to advanced life support conventional treatment, but who obtained ROSC soon after treatment with IV lipid emulsion. Five single-case reports describe patients with acute, life-threatening cardiovascular toxicity from local anaesthetic intoxication, but who were not pulseless at the time of lipid administration. In three cases severe cardiovascular toxicity resolved rapidly following IV lipid, but in two other cases the patient’s condition deteriorated to cardiac arrest after IV lipid, although the patients were resuscitated and survived to hospital discharge. [Deakin 2010][Morley 2011] Recommendations There is insufficient clinical evidence to suggest any change to cardiac arrest resuscitation treatment algorithms for patients with cardiac arrest caused by local anaesthetics. Animal studies and case reports suggest severe cardiovascular toxicity or cardiac arrest attributable to local anaesthetic intoxication may respond to treatment with intravenous lipid emulsion. [Class B, LOE IV/Expert Consensus Opinion]"

Answer 45

A - Wrong - convulsions are common B - Correct - but increased 5HT and Noradrenalin also important, so if D has a better option... C - Wrong - Primarily metabolised in liver D - Source: Wikipedia (yeah, I know...) I disagree with C - I think this is TRUE. Stoelting (4th, p 186-187) - Ester Local Anaesthetics undergo hydrolysis by cholinesterases, principally in the plasma and to a lesser extent in the liver. Cocaine is an Ester LA. And cocaine use in plasma cholinesterase deficiency can be fatal via sudden cardiac arrest (Medscape online reference under pseudocholinesterase deficiency). True but I think you will find cocaine is the exception to the above... C is wrong Yes, seriously, read the whole paragraph next time: "The exception to hydrolysis of ester local anaesthetics in the plasma is cocaine, which undergoes significant metabolism in the liver". So although it is metabolised by pseudocholinesterase, it is not the best answer.

Answer 46

``` A. G-protein mediated - truish B. Voltage gated K channels- truish C. Voltage gated Na channels - Very True! D. Voltage gated Ca channels - truish E. Voltage gated Mg channels - false ``` A,B,C,D all blocked pp Stoelting 4th ed p182, although clearly the principal site of action is the "H" gate of the voltage gated sodium channel

Answer 47

A - true - pKa 7.9 - see below B - false - pKa 8.1 - slow onset (stoeting 4th ed p181 table 7.1) C - false - pKa 8.6 - slowish onset D - false - pKa 8.1 - slow onset (stoeting 4th ed p181 table 7.1) E - false - pKa 8.1 - slow onset (stoeting 4th ed p181 table 7.1) speed of onset is related to the degree of ionisation of the drug. As weak bases, the nearer to physiological pH the drugs pKa is, the more unionised it will be and therefore the quicker the absorption into the axoplasm for protonation and binding to the H unit of the voltage gated Na+ channel

Answer 48

A- F - oil at room temp B- TRUE - see P&H (4th ed) p162: "...contains a mixture of crystalline bases of 2.5% lidocaine and 2.5% prilocaine in a white oil:water emulsion" C- F ? D- F - EMLA causes skin blanching and vasoconstriction E- F - ? 2 hours max ? P&H (4th ed) p162: "It should be applied to intact skin under an occlusive dressing for at least 60 minutes to ensure adequate anaesthesia" Duration of anaesthesia is said to be 2 hours after removal of the dressing.

Answer 49

With regard to tetanic stimulation by a nerve stimulator: A. Used to determine residual curarisation - FALSE: tetanic stimulation is used to assess response when there is no TOF count, i.e. when you have a very dense paralysis, not residual paralysis see below B. Degree of fade is independent of stimulus duration - FALSE: the degree of fade will be dependent on the stimulus duration, i.e. if the stimulus duration is short, then the degree of fade seen will be less than with a prolonged stimulus. With the prolonged stimulus, there will be more fade due to depletion of ACh vesicles. (See Miller Fig 39-3) "The degree of fade depends primarily on the degree of neuromuscular blockade. Fade also depends on the frequency (Hz) and the length (seconds) of stimulation and on how often tetanic stimuli are applied. Unless these variables are kept constant, results from different studies using tetanic stimulation cannot be compared." - Miller Ch 39 C. Degree of fade is dependent on stimulus intensity - wording not great but probably the best answer; see comment for B D. Used to check depth of anaesthesia - checks the depth on NMB but not really anaesthesia (e.g. BIS) E. ? Degree of fade from tetanic stimulation is dependent on the duration (seconds) and frequency (Hz) of the stimuli. Increased frequency results in a greater degree of fade. Fade refers to the gradual reduction in muscle strength (or twitch height) during a tetanic stimulation due to depletion of the readily available ACh stores in the nerve terminal. It is exaggerated by non-depolarising neuromuscular blockade. ???Is intensity related to frequency?? A is wrong. TOF or even better DBS is used to check residual block. B is wrong. It is dependent. C. Possible? It is dependent on intensity... but is that the point? D is wrong. Depth of block of depth NOT anaesthesia (I'd hope you weren't using it for that!) I think A is correct. see Morgan Mikhail and Murray 4th edition p 209: "The occurrence of fade...during prolonged or repeated nerve stimulation is indicative of a non-depolarising block." I also think A is correct. Aitkenhead + Smith (5th ed p93) says that tetanic stimulation "is the most sensitive... and can detect minor degrees of residual NM block... when twitch response is normal". It is not as useful as TOF/DBS because it is very painful (pts may feel discomfort after waking up), muscle may fatigue if high frequencies used (100-200Hz), and can't be repeated within 6 min (otherwise will see post-tetanic potentiation). The post-tetanic count is used for assessing deep paralysis when there is no response to TOF. Check out the review article below. PTC is useful when there is no TOF b/c of heavy blockade. In someone with minimal paralysis- then PTC will be 100% So a tetanic stimulation won't give you the depth of blockade - it's the POST-tetanic potentiation that yields the useful data = A wrong A. True: Tetanic stimulus can be used to determine small degrees of residual curarisation (i.e. residual block) B. False: Fade can only be observed with sufficient duration of tetanic stimulus e.g. 5 seconds. See first answer above for explanatory quote from Miller. C. False: Intensity = amplitude of signal i.e. voltage. If a higher than supramaximal stimulus is used, fade can still occur, it will just take longer to occur. D. False: "Depth of anaesthesia" is not measured in this way. This is a word substitution used to test our proofreading skills rather than our knowledge E. Supplied answer was: '?' This is likely correct as I often feel like "?" when I am faced with this type of difficult MCQ

Answer 50

Hyperkalaemia with suxamethonium is associated with: A. Abdominal infection - true; "severe abdominal infections have been associated with SCH-induced potassium release" (Stoelting 3rd ed. p.192) B. Parkinson's disease - false; "no evidence... with Parkinson's disease, cerebral palsy or myelomeningocele" (Stoelting p.192) C. Meningomyelocoele - false; see above D. Cerebral palsy - false; see above E. Myotonic dystrophy - 90% sure true; definitely correct if the answer states "muscular dystrophy". According to Mason, there is a case report of a patient with Parkinson's disease who had had their levodopa withheld for five days developing hyperkalaemia after suxamethonium. In patients have been getting their medication, there is no evidence that suxamethonium is unsafe. Miller 4th ed p490 states suxamethonium with abdominal infection can lead to hyperkalaemia. Stoelting and Hillier 4th ed p220 has a list of diseases where Sch-induced hyperkalaemia can follow: 1) clinically unrecognised muscular dystrophy 2) unhealed third degree burns 3) denervation leading to skeletal muscle atrophy 4) severe skeletal muscle trauma 5) upper motor neurone lesions. Stoelting then states "Severe abdominal infections have been associated with Sch-induced potassium release.....There is no evidence of Sch-induced hyperkalaemia in patients with Parkinson's disease, cerebral palsy, myelomeningocele or those undergoing cerebral aneurysm surgery." I'd go for myotonic dystrophy - it also happens to be one of the absolute contraindications to sux, as abnormal muscle means that contractions will persist, making ventilation difficult if not impossible. I don't think myotonic dystrophy is right because this question is asking about hyperkalaemia. The section in Miller states that the problem is due to muscle contract and difficulty in ventilation due to the myotonia and not due to hyperkalaemia that depolarising muscle relaxant is not to be used. Abdominal infection has been mentioned in Miller and Stoelting to cause hyperkalaemia with sux. A is correct (HE821) Sch-induced rhabdomyolysis, hyperkalemia and cardiac arrest may occur with... undiagnosed myopathy (Stoelting) I would go for A and E. According to Stoelting 4th Ed., p 220, hyperkalaemia could occur with administration of SCh to patients with clinically unrecognized muscular dystrophy. Also severe abdominal infections have been associated with SCh-induced potassium release. Indeed myotonic dystrophy is a form of muscular dystophy (from Tally O'Connor, 4th Ed., p 428), so that explains my choice for E.

Answer 51

``` A F B - false - although major metabolic process is hepatic cholinesterase C - true - hepatic D - false E - true - red cell esterase F False ```

Answer 52

``` A F B T C F D? E F ```

Answer 53

``` A F B F C T D F E F ```

Answer 54

A- false - esmolol - red cell esterase's B - true C - false - both metabolised by esterases D - false - esmolol - red cell esteras E - false - remi metabolised by non specify tissue and plasma esterase's

Answer 55

``` A F B F C F D T- true - tissue and non specific esterases E F Comments ``` This page has been edited significantly for ease of reading and to clarify the following information: There are 3 esterase groups at play here: Acetylcholinesterase - in synaptic cleft Plasma / pseudo / butyrylcholinesterase - in the plasma and breakdown Sux, mivacurium, and ester local anaesthetics and who's action is inhibited by both dibucaine and fluoride Plasma, tissue and red cell esterase's / non specific esterases (no choline) - break down esmolol (red cell esterase's) and remifentanil (non specific tissue and plasma esterase's) References Esterase Substrates Atracurium "Atracurium undergoes spontaneous nonezymatic degredation at normal body temperature and pH by a base-catalyzed reaction termed Hoffman elimination. A Second and simultaneously occurring route of metabolism is hydrolysis by non specific plasma esterase's" (Stoelting 4th ed p 232) Esmolol "Plasma esterase's responsible for the hydrolysis of esmolol are distinct from plasma cholinesterase, and the duration of action of sux is not predictably prolonged in patients treated with esmolol" (Stoelting 4th ed p 330) "Esmolol is rapidly hydrolysed by the esterase's in the cytosol of red blood cells. Plasma cholinesterases and red cell membrane acetylcholinesterase do not have any action." (Peck and Williams p157,) "Esmolol is biodegraded by esterases in the cytosol of red blood cells, so their effects are not prolonged in patients with abnormal or absent renal function." (Miller Ch 54) Remifentanil "Remifentanil is unique among the opioids in undergoing metabolism by nonspecific plasma and tissue esterase's" (Stoelting 4th ed p.114) "Remifentanil does not appear to be a substrate for butyrylcholinesterases (pseudocholinesterase), and thus its clearance should not be affected by cholinesterase deficiency or anticholinergics" Stoelting 4th ed p 114 "Remifentanil is cleared by nonspecific esterases located primarily in muscle and intestines, but the lungs, liver, kidneys, and blood contribute minimally to remifentanil clearance." (Miller Chapter 3) Hepatic Metabolism Dibucaine "This local anaesthetic is metabolised in the liver..." (Stoelting 4th ed. p.186) Cholinesterase Substrates Cocaine "Cocaine is metabolised by plasma and liver cholinesterases..." (Stoelting 4th Ed p 187) also "Ester local anaesthetics undergo hydrolysis by cholinesterase enzyme principally in the plasma and to a lesser extent in the liver... The exception of hydrolysis of ester local anaesthetics in the plasma is cocaine, which undergoes significant metabolism in the liver." (Stoelting 4th ed. p.186 Ester Local Anaesthetics in General "Ester local anaesthetics undergo hydrolysis by cholinesterase enzyme principally in the plasma and to a lesser extent in the liver... The exception of hydrolysis of ester local anaesthetics in the plasma is cocaine, which undergoes significant metabolism in the liver." (Stoelting 4th ed. p.186 Mivacurium "The cis-trans and trans-trans isomers of mivacurium are hydrolysed by plasma cholinesterase" (Stoelting 4th ed. p.242); Procaine "Ester local anaesthetics undergo hydrolysis by cholinesterase enzyme, principly in the plasma" (Stoelting 4th ed. p.186) Pyridostigmine "neostigmine and pyridostigmine inhibit the breakdown of acetylcholine by virtue of their being hydrolysed by ACETYLcholinesterase." (Stoelting 4th ed. p.251) wrt major mechanisms of clearance for anticholinestersases:"Anticholinesterase drugs are actively secreted into the lumens of the renal tubules. Renal Clearance accounts for... approximately 75% of the elimination of edrophonium and pyrdiostigmine... In the absence of renal function hepatic metabolism accounts for... 25% of the dose of pyridostimine" (Stoelting 4th ed. p.255-6) also see this paper reporting that pyridostigmine is metabolised by PLASMA cholinesterases. http://www.ualberta.ca/~csps/JPPS9(1)/Zhao.B/review.htm" Suxamethonium "Succinylcholine, mivacurium, and 2-chloroprocaine are metabolized by plasma butyrylcholinesterases (formerly designated pseudocholinesterases)" (Miller Chapter 3) "the brief duration of action of SCh (3 - 5 minutes) is principally due to its hydrolysis by plasma cholinesterase (pseudocholinesterase) enzyme)" (Stoelting 4th ed. p.218)

Answer 56

``` A - false, remi isn't B - false, esmolol isn't C assuming there was only one true answer the other agent not recalled here must not have been metabolised by cholinesterase, although mivacurium is. D - hurrah! Comments ``` This page has been edited significantly for ease of reading and to clarify the following information: There are 3 esterase groups at play here: Acetylcholinesterase - in synaptic cleft Plasma / pseudo / butyrylcholinesterase - in the plasma and breakdown Sux, mivacurium, and ester local anaesthetics and who's action is inhibited by both dibucaine and fluoride Plasma, tissue and red cell esterase's / non specific esterases (no choline) - break down esmolol (red cell esterase's) and remifentanil (non specific tissue and plasma esterase's) References Esterase Substrates Atracurium "Atracurium undergoes spontaneous nonezymatic degredation at normal body temperature and pH by a base-catalyzed reaction termed Hoffman elimination. A Second and simultaneously occurring route of metabolism is hydrolysis by non specific plasma esterase's" (Stoelting 4th ed p 232) Esmolol "Plasma esterase's responsible for the hydrolysis of esmolol are distinct from plasma cholinesterase, and the duration of action of sux is not predictably prolonged in patients treated with esmolol" (Stoelting 4th ed p 330) "Esmolol is rapidly hydrolysed by the esterase's in the cytosol of red blood cells. Plasma cholinesterases and red cell membrane acetylcholinesterase do not have any action." (Peck and Williams p157,) "Esmolol is biodegraded by esterases in the cytosol of red blood cells, so their effects are not prolonged in patients with abnormal or absent renal function." (Miller Ch 54) Remifentanil "Remifentanil is unique among the opioids in undergoing metabolism by nonspecific plasma and tissue esterase's" (Stoelting 4th ed p.114) "Remifentanil does not appear to be a substrate for butyrylcholinesterases (pseudocholinesterase), and thus its clearance should not be affected by cholinesterase deficiency or anticholinergics" Stoelting 4th ed p 114 "Remifentanil is cleared by nonspecific esterases located primarily in muscle and intestines, but the lungs, liver, kidneys, and blood contribute minimally to remifentanil clearance." (Miller Chapter 3) Hepatic Metabolism Dibucaine "This local anaesthetic is metabolised in the liver..." (Stoelting 4th ed. p.186) Cholinesterase Substrates Cocaine "Cocaine is metabolised by plasma and liver cholinesterases..." (Stoelting 4th Ed p 187) also "Ester local anaesthetics undergo hydrolysis by cholinesterase enzyme principally in the plasma and to a lesser extent in the liver... The exception of hydrolysis of ester local anaesthetics in the plasma is cocaine, which undergoes significant metabolism in the liver." (Stoelting 4th ed. p.186 Ester Local Anaesthetics in General "Ester local anaesthetics undergo hydrolysis by cholinesterase enzyme principally in the plasma and to a lesser extent in the liver... The exception of hydrolysis of ester local anaesthetics in the plasma is cocaine, which undergoes significant metabolism in the liver." (Stoelting 4th ed. p.186 Mivacurium "The cis-trans and trans-trans isomers of mivacurium are hydrolysed by plasma cholinesterase" (Stoelting 4th ed. p.242); Procaine "Ester local anaesthetics undergo hydrolysis by cholinesterase enzyme, principly in the plasma" (Stoelting 4th ed. p.186) Pyridostigmine "neostigmine and pyridostigmine inhibit the breakdown of acetylcholine by virtue of their being hydrolysed by ACETYLcholinesterase." (Stoelting 4th ed. p.251) wrt major mechanisms of clearance for anticholinestersases:"Anticholinesterase drugs are actively secreted into the lumens of the renal tubules. Renal Clearance accounts for... approximately 75% of the elimination of edrophonium and pyrdiostigmine... In the absence of renal function hepatic metabolism accounts for... 25% of the dose of pyridostimine" (Stoelting 4th ed. p.255-6) also see this paper reporting that pyridostigmine is metabolised by PLASMA cholinesterases. http://www.ualberta.ca/~csps/JPPS9(1)/Zhao.B/review.htm" Suxamethonium "Succinylcholine, mivacurium, and 2-chloroprocaine are metabolized by plasma butyrylcholinesterases (formerly designated pseudocholinesterases)" (Miller Chapter 3) "the brief duration of action of SCh (3 - 5 minutes) is principally due to its hydrolysis by plasma cholinesterase (pseudocholinesterase) enzyme)" (Stoelting 4th ed. p.218)

Answer 57

MB04 [Mar96] [Jul02] The action of nondepolarising neuromuscular blocking agents is PROLONGED by: A. Respiratory acidosis - true; "Respiratory acidosis enhances pancuronium-induced NMB and opposes its antagonism with neostigmine" (Stoelting p202 3rd ed) "prolonged in most, but reduced in gallamine" (Peck Hill and Williams p.173) B. Increased temperature - false; HYPOthermia prolongs action (Table 12.3 in Peck Hill and Williams p.173) C. Increased calcium - false; calcium channel antagonists prolong duration (Table 12.3 as above) so increased calcium levels will presumably oppose this effect D. Increased potassium - false; has an antagonistic effect with non-depolarising agents (Table 12.3 as above) E. Decreased magnesium - false; hypermagnesaemia causes prolonged action (Table 12.3) Respiratory acidosis prolongs all NDNMBDs except gallamine where it shortens the duration. Atracurium is metabolised by ester hydrololysis (2/3) which is increased by acidosis, and Hoffman elimination (1/3) which is reduced by acidosis, although it is unlikely that those changes seen clinically would alter the rate significantly. a)Respiratoy acidosis. [true - for all currently used non-depolarising blockers. Alcuronium (diallyl-nortoxiferine, dANT) was the odd one out in that the duration of blockade was little influenced by acidosis, however it has now been withdrawn from clinical use in Aust] b)Increased temperature. [Mostly False. The effects of temperature on characteristics of blockade appear to be biphasic, depending on when the patient's temperature rises. A - if the patient is febrile before the relaxant is given, as temp rises there is increased sensitivity of neuromuscular junction to block, and increased block intensity. B - BUT...block duration is shorter and reversal easier when patients become hyperthermic after having received the drug] c) Increased serum calcium [False - Non-depolarising neuromuscular blockade is potentiated by serum ionised hypOcalceamia] d) Increased serum potassium [False - hyperkalaemia diminishes resting membrane potential and antagonises the effect of the blockade] e: Decreased serum magnesium [False: Non-depolarising neuromuscular blockade is potentiated by serum ionised hypERmagnesaemia ref: Cass and Cass, "Pharmacology for Anaesthetists"

Answer 58

MB05 [Mar96] Agents prolonging nondepolarising NMBA by desensitising the post-junctional membrane : A. Phenytoin - false; "patients treated chronically with phenytoin are resistant to the... effects of NDMB drugs" (Stoelting p.199) B. Halothane - false; "Volatile anaesthetics most likely enhance the effects... by virtue of anaesthetic depression of the CNS" (Stoelting 3rd ed. p.196) C. Lignocaine - Best answer; "depending on the dose, local anaesthetics... stablise the post-junctional membrane" (Stoelting 3rd ed. p.197) D. Verapamil - partly true; CCBs work by reducing Ca2+ influx and preventing ACh release thus working pre-synaptically Best answer is C - lignocaine Verapamil may prolong NMB via blockade of calcium channels on the presynaptic membrane, reducing Ach release. Whilst Halothane does reduce the excitability of the post-synaptic membrane it does so less than other potent inhaled anaesthetics (enflurane, isoflurane, then sevo/desflurane). Phenytoin can prolong NMB after an acute loading dose via membrane stabilisation but lignocaine is the best answer due to sodium channle blockade.

Answer 59

``` [Mar96] [Jul98] Which drugs (?competitively) inhibit acetylcholinesterase? A. Neostigmine B. Pyridostigmine C. Physostigmine D. Edrophonium E. All of the above - TRUE ``` Cyclophosphamide is a pseudocholines- terase inhibitor and may prolong the effects of succinylcholine for up to 4 weeks following its use. [Evers and Maze] Metoclopramide also inhibits pseudocholinesterase [ Evers and Maze] Mag may inhibit pseudocholinesterase Phenytoin reduces ACHE in chick embryos [google] Frusemide potentiates NMBD but does it inhibit acetylcholinesterase? Neostigmine, pyridostigmine and physostigmine form carbamyl ester complexes at the esteratic site of acetylcholinesterase producing reversible inhibition. They act as competitive substrates for the enzymes normal binding site with acetylcholine. Edrophonium does not have a carbamyl group and produces reversible acetylcholinesterase inhibition by electrostatic attachment to the anionic site and hydrogen bonding to the esteratic site. There is no covalent bond making it easy for acetylcholine to compete. The answer is therefore E. All of the above. Reference Stoelting and Hillier 4th ed page 252

Answer 60

``` MB06b [Jul00] [Apr01] The activity of plasma cholinesterase is decreased by the following drugs except: A. Neostigmine - WRONG B. Organophosphates - WRONG C. THA D. Metoclopramide - WRONG E. Cimetidine - ? CORRECT ANSWER ``` Cimetidine does not alter plasma cholinesterase activity. Reference: Stoelting and Hillier 4th ed page 440.

Answer 61

MB06c [Jul04] Which decrease plasmacholinesterase activity? (remembered options from 2 questions) A. Hepatic disease - TRUE (See Stoelting p191 3rd ed) B. Cyclophosphamide -TRUE C. 6 weeks post partum - TRUE if still increased oestrogen levels D. Hyperthyroidism - ?FALSE/?True, would this increase cholinesterase activity, but also note Peck and Hill list below E. Obesity - FALSE "In obese patients there is an increase in plasma cholinesterase activity" Stoelting p191 3rd ed F. Cytotoxic drugs - TRUE G. Pregnancy - TRUE H. Dibucaine number of 20 - TRUE version c "Aquired factors associated with reduced plasma cholinesterase activity include: pregnancy liver disease renal failure cardiac failure thyrotoxicosis cancer drugs - either directly or by acting as a substrate or inhibitor to AChE. Ecothipate, metoclopramide, ketamine, the OCP, lithium, lignocaine, ester local anaesthetics, cytotoxic drugs, edrophonium, neostigmine and trimetaphan" (Peck Hill and Williams pp.170-171) Decreased plasma cholinesterase activity: - Severe hepatic disease - Atypical plasma cholinesterase (dibucaine number 20 greatly prolongs the action of suxamethonium) - Drugs - Neostigmine - Organophosphates - Chemotherapeutics - Nitrogen mustard and cyclophosphamide - Metoclopramide - High oestrogen - Parturients at term Increased plasma cholinesterase activity: - Obesity Resistance to suxamethonium: - Myasthenia gravis - Juvenile hyaline fibromatosis Q: What is THA? A: Tacrine is a weak acetylcholinesterase inhibitor.

Answer 62

MB06d [Aug2014] Which drug does NOT potentiate the action of non-depolarising neuromuscular blockers by inhibiting the action of acetylcholinesterase: A. Cyclophosphamide [does] B. Magnesium [does] C. Metoclopramide [does] D. frusemide ? [?answer] E. phenytoin ? [does] version d Cyclophosphamide is a pseudocholines- terase inhibitor and may prolong the effects of succinylcholine for up to 4 weeks following its use. [Evers and Maze] Metoclopramide also inhibits pseudocholinesterase [ Evers and Maze] Mag may inhibit pseudocholinesterase Phenytoin reduces ACHE in chick embryos [google] Frusemide potentiates NMBD but does it inhibit acetylcholinesterase? -- For version D, several notes: Magnesium's MOA should not involve pseudocholinesterases, it works by decreases ACh release by competition with Ca2+ (Peck and Hill 4th Ed pg177 Table 12.3). Frusemide's MOA also should not involve pseudocholinesterases. At low doses potentiates the effects of NMBs by inhibiting protein kinases. At high doses it inhibits phosphodiesterase, and thus increases cAMP dependent ACh release presynaptically, antagonizing NMB effect. See [1] and Dr Finnis ICU Adelaide notes

Answer 63

MB07 [Mar97] [Jul98] [Jul99] [Feb00] [Apr01] Regarding vecuronium: A. It accumulates in renal failure - correct; see table 8-2 in Stoelting 3rd ed. p.185. Both vecuronium and rocuronium are dependent on renal and hepatic function where atracurium and cisatrurium are not B. Is a benzylisoquinolinium - false; it is an aminosteroidal compound. The benzylisoquinolonium compounds are the "curiums" such as tubocuraine, atracurium and mivacurium C. Is a bisquaternary amine - false; it has a "monoquaternary structure" (Stoelting 3rd ed. p.210) D. Is more lipid soluble than pancuronium - correct; "the monoquaternary structure... increases its lipid solubility compared with pancuronium" (Stoelting 3rd ed. p.210) E. Is predominantly renally excreted - false; renal excretion 15-25% and biliary excretion 40-75% in Table 8-2 from Stoelting 3rd ed. p185) Most correct answer D - "The monoquaternary structure of vecuronium increases its lipid solubility compared with pancuronium" (Stoelting 3rd ed p.210) Vecuronium is an aminosteroid, monoquaternary NMB that is protonated at physiological pH. It is more lipd soluble than pancuronium. 80% is eliminated unchanged (60% bile; 20% urine) but Stoelting and Hillier 4th ed p236 state "Despite the presumption that the liver is the main organ of elimination, the elimination half-time of vecuronium and 3-desacetylvecuronium is prolonged in patients with renal failure. ......may contribute to persistent skeletal muscle paralysis after prolonged infusion of vecuronium in patients with renal failure." That quote actually reads "Increased plasma levels of 3-desacetylvecuronium may contribute...". That doesn't convince me that "Vecuronium accumulates in renal failure". Stoelting 4th p235 "The monoquaternary structure of vecuronium increases its lipid solubility compared with pancuronium." D is undeniably correct References Miller 4th edition

Answer 64

``` Best answer C Onset of action Edrophonium 1-2 minutes Neostigmine 7-11 minutes Pyridostigmine 16 minutes Atropine 1 minute Glycopyrrolate 2-3 minutes References ``` Stoelting and Hillier 4th ed page 254&268

Answer 65

Most correct answer - ??C A. Dibucaine is an amide local anaesthetic used to inhibit normal plasma cholinesterase when testing for deficiency of this enzyme. A normal person will have 80% of the enzyme blocked in the presence of dibucaine ie. a dibucaine number of 80. Dibucaine is an amide local and is metabolised by microsomal enzymes in the liver - is the most slowly eliminated of all the amide derivatives (Stoelting & Hillier 4th ed. p186, 219) B. Esmolol is metabolised by RBC esterases and is independant of plasma cholinesterase activity. It's T1/2 is 9.3 minutes. Metabolites are methanol and a primary acid metabolite (major) which has minimal adrenoceptor antagonist activity but a T1/2 of 3.5 hours. The metabolites are mainly renally excreted and acumulate in renal failure, so despite esmolol's rapid hydrolysis, caution needs to be taken with dosing in patients with severe renal failure. (stoelting 4th p330). C. Mivacurium is hydrolysed by plasma cholinesterase at 88% of the rate of hydrolysis of Suxamethonium. (Stoelting 4th ed. p242) D. Neostigmine reduces plasma cholinesterase activity by 50%. This effect may last 30 minutes. (Stoelting 4th ed. p 218)

Answer 66

MB09b [Jul01] [Jul04] Suxamethonium A. Bigger molecule than vecuronium - false B. Needs to occupy 80% of nicotinic receptors to get effect - false -- why is this false? Peck says you need 75% of receptors to be blocked before twitch height is reduced. Do we ever quibble over 5% in medicine? C. Resistant to hydrolysis by acetylcholinesterase - correct D. Is an antagonist at nicotinic receptors - false; it is an agonist at the nicotinic receptors (but is longer acting than Ach due to resistance to metabolism by acetylcholinesterase in the synaptic cleft) E. Increasing dose produces similar block - false Plasma cholinesterase is inhibited by dibucaine. Plasma cholinesterase hydrolyses mivacurium at 88% rate of sux (according to Stoelting). It is inhibted by neostigmine. Esmolol is metabolised by red blood cell esterases MB09b: Suxamethonium is metabolised by plasma pseudocholinesterase and is resistant to hydrolysis by acetylcholinesterase. Answer C Re: '5% quibble" Depolarising MR (agonists) ie sux only req 20% receptor occupancy Non-depol MR (antagonists) req 80% receptor occupancy

Answer 67

Fade in response to tetanic stimulation is dependant on degree of NMB, frequency of stimulation, length of stimulation and how often tetanic stimuli applied (ref: Miller) TOF ratio is a better indicator of adequate reversal with figures between 0.7-0.9 quoted (see Millers section on neuromuscular monitoring). TOF count indicates whether reversal is safe (some say 1 twitch needed, some say 2).

Answer 68

MB11 [Jul97] Anticholinesterase agents: A. Carbamates duration of action is related to the time required for dissociation from the anionic site. - Half true; time required is for dissociation from esteratic site -- half true? not true! B. Carbamates act by acetylation of the esteratic site. - true C. ? (See also MD28) Carbamylation or acetylation? I think both are wrong- carbamates don't dissociate, it is hydrated. Alcohols (e.g. edrophonium) dissociates because it binds electrostatically and by hydrogen bonds (Katzung p101, 10th Ed) And Carbamates carbamylates, not acetylates- Acetylcholine acetylates the esteratic site.

Answer 69

MB11b [Jul00] [Apr01] [Jul02] [Jul04] Carbamylation of acetylcholinesterase: (Jul02: Phosphorylation of acetylcholinesterase: ) A. Ionic bonding at anionic site B. Ionic bonding at esteratic site C. Covalent bonding at anionic site D. Covalent bonding at esteratic site - TRUE E. None of above Covalent bonding at esteratic site

Answer 70

Mivacurium: A. Is metabolised at 80% the rate of suxamethonium TRUE Stoelting says 88% B. Takes 15 mins from ED95 dose to recovery of 95% twitch height ?TRUE - "has an onset of NMB in 2-3 mins lasting 12-20 mins" (Stoelting p216) ""clinically insignificant prolongation of mivacurium in the anaphoric patients" There appears to be no clear cut answer as A, B and E are all potentially correct depending on the wording - I disagree. A the best answer. I think the offset of 12-20 minutes is more likely after a 2-3x ED95 dose given the "vibe" of Stoelting's comparisons. E is least correct of the three. JB2012

Answer 71

July 2000 version: Mivacurium: A. Twice the ED95 dose is 1.5mg/kg (False ED95 0.067mg/kg) B. is metabolised at 80 to 90% the rate of suxamethonium - ALMOST TRUE C. After 2 x ED95 dose 95% return of twitch height after 15mins - ED95 will give a block lasting 12-20 mins... will 2ED95 give a longer block?? also note that "the rate of hydrolysis of mivacurium by plasma cholinesterase depends on the concentration of mivacurium in the plasma" Was there an "all of the above"? - I would take it! JB20120 July 2002]] version included the following options: C. Does not usually require reversal CONTROVERSIAL "Spontaneous recovery from the NMB effects of mivacurium is rapid and the need for pharmacologic antagonism has been questioned" Stoelting p217 3rd ed D. Duration of action may be prolonged by anti-cholinesterases - ?TRUE - Stoelting says "...nevertheless, moderate levels // are antagonised readily by anticholinesterases such as neostimine".

Answer 72

July 2006 Mivacurium A. Is not made up of different isomers - False "Mivacurium consists of three stereoisomers" Miller Ch 13 B. Metabolised at 75-85% rate of suxamethonium - True "occurs at about 70% to 88% of the rate of succinylcholine in vitro" Miller Fig 13-22 C. Has a Half life of 30 minutes - False D. Is antagonised less by edrophonium than neostigmine - FALSE "Edrophonium provides more rapid antagonism of deep mivacurium-induced NMB than does neostigmine" Stoelting p217

Answer 73

MB12b [Jul00] Mivacurium administered at a dose of 2 times the ED95 dose produces relaxation for: A. 10 mins B. 15 mins C. 20 mins D. 25 mins E. None of the above Mivacurium metabolised at 70-88% the rate of suxamethonium invitro Template:Miller pge 508 fig 13.22. Mivacurium ED95 60-80mcg/kg. Intubating dose 0.07-0.15mg/kg - 0.1-0.2mg/kg for children 2-12yo; Intubating conditions within 2.5min; single dose lasts 10-20min. Renal Failure increases the clinical duration by a factor of 1.5; Hepatic failure increases it by a factor of 3 (Sasada) (?by decreased plasma cholinesterase activity) Duration of action is 10-20 minutes (which Stoelting says corresponds to return to >25% control twitch height) However, for return of twitch height to 95% the time would be longer (given that 25% twitch height corresponds to a TOF of 3, and that 95% twitch height corresponds to a TOF ratio of about 0.75 - according to Peck, Hill and Williams). The FDA info for Mivacurium says that 95% recovery from 2 x ED95 (about 0.15mg/kg) takes 25 mins (and duration of relaxation is 15 mins). (Stoelting says the duration for return to a TOF ratio of >0.9 is 25-40 mins.)

Answer 74

``` Mean Recovery index Mivacurium: 6.6 mins. Vecuronium: 14-30 mins according to dose. Rocuronium: 8-17 mins. Duration of Return to TOF > 0.9 Mivacurium - 25-40 mins Vecuronium - 50-80 mins Atracurium - 55-80 mims Rocuronium - 55-80 mins (Ref Stoelting 4th Ed table 8-3, p212) So in 7 mins a normal TOF ratio could only occur with Sux! (TOFR would always be 1.0 unless phase II block had occurred - unlikely if dose was twice ED95) - can´t be Sux, since if TOF ratio stays normal (with 2xED95) then it can´t RETURN to normal - must be the wording References ``` Sasada & Smith

Answer 75

``` Mean Recovery index Mivacurium: 6.6 mins. Vecuronium: 14-30 mins according to dose. Rocuronium: 8-17 mins. Duration of Return to TOF > 0.9 Mivacurium - 25-40 mins Vecuronium - 50-80 mins Atracurium - 55-80 mims Rocuronium - 55-80 mins (Ref Stoelting 4th Ed table 8-3, p212) So in 7 mins a normal TOF ratio could only occur with Sux! (TOFR would always be 1.0 unless phase II block had occurred - unlikely if dose was twice ED95) - can´t be Sux, since if TOF ratio stays normal (with 2xED95) then it can´t RETURN to normal - must be the wording References ``` Sasada & Smith

Answer 76

Aminoglycosides prolong NMB by decreasing ACh release (probably by competing with calcium). Motor nerve action potential evoked ACh release is dependant on calcium. However,spontaneous ACh release does occur and this produces MEPPs (miniature end plate potentials) Gentamicin inhibits release of presynaptic Ach and also stabilises post-synaptic membrane. (1. Stoelting 2. Sasada) Botulinum toxin blocks Ach release by cleaving enzymes that help Ach containing vesicles fuse with the nerve cell wall in the pre-synaptic nerve end. (Rang & Dale p 154) Hemichlinium interferes with synthesis of Ach by blocking transport of choline into the nerve end. This is the rate limiting step of Ach production. (Rand and Dale p 154) Action potential is only one mechanism for Ach release at end plate. Random minature end plate potentials (MEPP) occur continuously (Stoelting 4th ed. p 214) Calcium dependant process - yep. (Rang and Dale 154 and Stoelting 214) Always causes action potential - not necessarily. As above, small quanta released

Answer 77

Aminoglycosides prolong NMB by decreasing ACh release (probably by competing with calcium). Motor nerve action potential evoked ACh release is dependant on calcium. However,spontaneous ACh release does occur and this produces MEPPs (miniature end plate potentials) Gentamicin inhibits release of presynaptic Ach and also stabilises post-synaptic membrane. (1. Stoelting 2. Sasada) Botulinum toxin blocks Ach release by cleaving enzymes that help Ach containing vesicles fuse with the nerve cell wall in the pre-synaptic nerve end. (Rang & Dale p 154) Hemichlinium interferes with synthesis of Ach by blocking transport of choline into the nerve end. This is the rate limiting step of Ach production. (Rand and Dale p 154) Action potential is only one mechanism for Ach release at end plate. Random minature end plate potentials (MEPP) occur continuously (Stoelting 4th ed. p 214) Calcium dependant process - yep. (Rang and Dale 154 and Stoelting 214) Always causes action potential - not necessarily. As above, small quanta released

Answer 78

Aminoglycosides prolong NMJ block by competing with calcium which reduces acetylcholine release

Answer 79

Rocuronium: A. Monoquaternary at physiological pH - definitely monoquaternary, but at physiological pH? B. More lipid soluble than pancuronium - presumably given it is only monoquaternary as opposed to pancuronium which is bisquaternary, or are they all simply poorly lipid soluble? C. 30% metabolised (?deacetylated) in the liver - FALSE "Animal studies have suggested that rocuronium is largely excreted unchanged in the bile. Deacetylation of rocuronium does not occur" Stoelting p213 D. Rapid onset is due to its high potency - false due to low potency E. Fastest onset is with 2 times ED95 dose - probably false as you can give 3-4 ED95 for sux like speed of onset F. Is bisquaternary - false see above Rocuronium is a monoquaternary aminosteroid, nondepolarising, neuromuscular blocking drug. Its rapid onset is due to its low potency. It is eliminated in the bile 55%(mostly unchanged) and 35% urine. There is very little hepatic metabolism of rocuronium. Pancuronium is bisquaternary Most appropriate answer A - it is also more lipid soluble than pancuronium isn't it? (pancuronium being bisquaternary)...

Answer 80

Dibucaine at this concentration inhibits the normal (Eu) variant of palsma cholinesterase by 80%, which would probably be the case in pregnancy ie, pregnancy causes an acquired defect in plasma cholinesterase - so it is still genetically the Eu variant and will be inhibited by 80%

Answer 81

A. Volatile anaesthetics wrong - will cause a dose dependant enhancement of the magnitude and duration of NMBD. (Stoelting) B. Antibiotics - wrong - aminoglycosides block the influx of Calcium into the pre-synaptic nerve preventing Ach release thus prolonging effects of NMBD. (Stoelting) C. Phenytoin - correct - phenytoin and carbamazepine both speed up the recovery from NMBD perhaps due to enzyme induction. (Stoelting) D. Beta-blockers - perhaps wrong - Esmolol prior to Rocuronium will decrease cardiac output (20% reduction - Sasada & Smith, Drugs in Anaesthesia and Intensive Care) which delays delivery to tissues and delay onset time by 26%. I'm not sure this translates to a prolonged duration of action though. Ephedrine alternatively enhaces cardiac output and speeds up onset by 22%. (Stoelting); Alpha & Beta adrenergic antagonists prolong NDNMB action (Sasada) E. Hyperthermia - correct - Mild hypothermia doubles the duration of vecuronium. Reduced hepatic flow in hypothermia as well as reduced enzyme activity in liver and tissue/RBC/Plasma esterases and reduced spontaneous Hoffman degradation prolong block by all NMBD in hypothermia. (Stoelting); Hyperthermia will increase enzyme activity -> increase clearance of drugs. ``` Ref. 1. Stoelting & Hillier 4th ed. pp224-6. 2. Sasada & Smith, Drugs in Anaesthesia and Intensive Care handbook. Prolonged neuromuscular blockade Volatile anaesthetics Aminoglycoside antibiotics Local anaesthetics Cardiac antidysrhythmic drugs (quinidine) Frusemide (1mg/kg) Magnesium Lithium Cyclosporin Hypothermia Hypokalaemia Females Dantrolene Decreased neuromuscular blockade Anticonvulsants (phenytoin, carbamazepine) Frusemide (high doses) Hyperkalaemia Hypercalcaemia Burns Paresis or hemiplegia Steroids Azathioprine References ``` Stoelting and Hillier 4th ed page 224-228 Miller 6th ed page 518

Answer 82

Answer B. See links above. Really? Whole body rigidity certainly not universal, plus exam technique would warn against the word "whole" in the same way as you'd be nervous about the word "always". I wonder if D was the best option...

Answer 83

MB20 [Jul99] [Jul01] Edrophonium: A. Longer halflife than neostigmine - true; t1/2 is 110 cf 77 min for neostigmine (Stoetling 3rd ed. Table 9-1 p.226) B. Onset slower than neostigmine - false; rapid speed of onset compared to intermediate for neostigmine (Table 9-1) C. ?Pyridostigmine D. Binds to anionic site of cholinesterase - partly true, partly false; "produces reversible inhibition of ACh by electrostatic attachment to the anionic site and hydrogen bonding at the esteratic site" (Stoelting 3rd ed. p225 Fig 9-2) both of those things constitute "binding", so true E. Relieves symptoms of myaesthenia gravis - false; used to diagnose myaesthenia gravis see below F. ? Is reliable in reversing a Phase 2 block - unsure Edrophonium can be used for reversal of non-depolarising neuro-muscular block BUT a sufficient dose needs to be used (eg 0.5-1.0 mg/kg) to get a duration comparable to that with neostigmine. The onset of reversal is quicker than with neostigmine and the duration is almost as long. If you only use small doses of edrophonium ('Tensilon')(eg 5-10mg) then termination of action is due to redistribution and duration is VERY short. The use of low doses of edrophopnium is used as a test for myaesthenia. At one time, pyridostigmine was recommended for reversal as an alternative to neostigmine, and indeed it can be successfully used for this purpose. However, the argument for its use was that it had a longer duration of action than neostigmine so would be less likely to be associated with "re-curarisation". Now, its true that it lasts longer (hence its use in myaesthenia in preference to neostigmine), but this is rarely if ever clinically advantageous. Neostigmine lasts long enough. The reason it didn't catch on though was that it had a slow onset and that was a problem! Reversal of phase 2 block? Well it might work. Or it might not. A bit unpredictable. The preferred technique is to ventilate the patient until sufficient spontaneous recovery has occurred. Nowdays, insufficient suxamethonium is used to make clinically recognised phase-2 block a problem. Most anaesthetists would never see a case in their careers, because to be in the situation where you get it, means you have to be pretty incompetent. Re: option E - used to diagnose myasthenia gravis because it temporarily relieves the symptoms, so shouldn't this be true?

Answer 84

MB20 [Jul99] [Jul01] Edrophonium: A. Longer halflife than neostigmine - true; t1/2 is 110 cf 77 min for neostigmine (Stoetling 3rd ed. Table 9-1 p.226) B. Onset slower than neostigmine - false; rapid speed of onset compared to intermediate for neostigmine (Table 9-1) C. ?Pyridostigmine D. Binds to anionic site of cholinesterase - partly true, partly false; "produces reversible inhibition of ACh by electrostatic attachment to the anionic site and hydrogen bonding at the esteratic site" (Stoelting 3rd ed. p225 Fig 9-2) both of those things constitute "binding", so true E. Relieves symptoms of myaesthenia gravis - false; used to diagnose myaesthenia gravis see below F. ? Is reliable in reversing a Phase 2 block - unsure Edrophonium can be used for reversal of non-depolarising neuro-muscular block BUT a sufficient dose needs to be used (eg 0.5-1.0 mg/kg) to get a duration comparable to that with neostigmine. The onset of reversal is quicker than with neostigmine and the duration is almost as long. If you only use small doses of edrophonium ('Tensilon')(eg 5-10mg) then termination of action is due to redistribution and duration is VERY short. The use of low doses of edrophopnium is used as a test for myaesthenia. At one time, pyridostigmine was recommended for reversal as an alternative to neostigmine, and indeed it can be successfully used for this purpose. However, the argument for its use was that it had a longer duration of action than neostigmine so would be less likely to be associated with "re-curarisation". Now, its true that it lasts longer (hence its use in myaesthenia in preference to neostigmine), but this is rarely if ever clinically advantageous. Neostigmine lasts long enough. The reason it didn't catch on though was that it had a slow onset and that was a problem! Reversal of phase 2 block? Well it might work. Or it might not. A bit unpredictable. The preferred technique is to ventilate the patient until sufficient spontaneous recovery has occurred. Nowdays, insufficient suxamethonium is used to make clinically recognised phase-2 block a problem. Most anaesthetists would never see a case in their careers, because to be in the situation where you get it, means you have to be pretty incompetent. Re: option E - used to diagnose myasthenia gravis because it temporarily relieves the symptoms, so shouldn't this be true?

Answer 85

E is true (Spot the prizewinner!) "The effect of neostigmine 0.05mg kg–1 or pyridostigmine 0.25mg kg–1 on serum cholinesterase activity was investigated in 20 adult patients undergoing elective surgery. Both drugs produced marked depression of enzymatic activity. The maximal depression was observed in samples taken 5mm after injection." - Reference (1) E is true From Stoelting 4th, p244: "Neostigmine profoundly decreases plasma cholinesterase activity and could thus interfere with the normal rapid spontaneous recovery from mivacurium-induced NMB." References Effect of Neostigmine and Pyridostigmine on The Plasma Cholinesterase Activity, A. BARAKA et. al. BJA Volume 53, Issue 8Pp. 849-851. [1]

Answer 86

A - incorrect; laudanosine has "no neuromuscular-blocking properties" but may cause seizures (Peck Hill and Williams p.177) B - incorrect; ester metabolism is the major pathway for elimination I agree, Peck, Hill and Williams & Stoelting both say this - however, Sasada & Smith says the opposite C - partly correct; 1/3 of metabolism is by Hoffman elimination. Atracurium is stable at a pH of 4 and at 4 degrees, but readily breaks down at physiological pH and temperature.

Answer 87

MB23 [Feb00] [Jul04] What muscle relaxant has an active metabolite with a half-life twice that of the parent compound? A. Rocuronium - false B. Vecuronium - the metabolite 3desacetylvecuronium has a short half life C. Pancuronium - most likely D. Atracurium or Cisatracurium - false E. None of the above F. Mivacurium - false I disagree with above: http://jpet.aspetjournals.org/cgi/content/abstract/270/3/1216: "The pharmacology of 3-desacetylvecuronium, the principal metabolite of vecuronium, was investigated...3- Desacetylvecuronium, compared with vecuronium (median, range in parentheses), had a smaller plasma clearance, 3.51 (2.11-6.57) vs. 5.39 (5.04-7.19) ml.kg-1.min-1; a larger steady-state distribution volume, 254 (215-410) vs. 152 (111-170) ml.kg-1; a longer terminal elimination half-life 116 (44-672) vs. 34 (25-61) min and a longer mean residence time, 67 (42-145) vs. 26 (18-32) min (P 2 x duration Pancuronium has active metabolite 50% to 2/3 (66%) as active, with similar elimination half life to pancuronium The correct answer is B.

Answer 88

MB23b [Jul04] Which of these NDNMB has a metabolite that’s 50-70% as active as its parent drug A. Atracurium - false; metabolite laudanosine B. Vecuronium - true; " The ...metabolite is approximately half as potent as the parent compound" (SToelting 3rd ed. p.210) C. Rocuronium - false D. dTC E. None of the above Both pancuronium (though 80% is excreted unchanged) and vecuronium have active metabolites that are more than 50% active at the NMJ. Miller says pancuronium metabolite 50% as active then on table on same page says 2/3 as active - which means 50-66% as active - very similar to the figure quoted in the question, while vec's metabolite activity is 80%; Stoelting actually says both has metabolite that are 50% as active. I'd go for pancuronium for this one if pancuronium is an option, otherwise vec seems to be the best choice. (NB quoted figures from page 210 3rd edition stoelting; page 507 miller electronic edition - which I presume is the same as the newest paper edition)

Answer 89

``` Succinylcholine can cause: A. Bradycardia - true; it can mimick the effect of ACh and thus mimick vagal stimulation of the heart B. Histamine release - true C. Tachycardia - false D. Hypertension - false E. All of the above - likely false ``` Bradycardia can occur. It is MOSTLY related to administration of a second dose of sux. In this situation, the bradycardia can be severe, and asystole can occur. The bradycardia is prevented by a sufficient dose of IV atropine but this may cause tachycardia. Anaphylactic reactions with release of histamine are well described. Tachycardia & hypertension are not caused by sux, but may occur with the sympathetic stimulation of laryngoscopy and intubation. --- Stoelting (Ed 4, p.220) says sux can cause bradycardia via action on cardiac muscarinic receptors (more likely in children and with a 2nd dose of sux). Also says that can cause tachycardia and hypertension via action on autonomic ganglia. He does not say anything about histamine release, but given it is one of the more common causes of anaphylaxis in anaesthesia, it is possible. Actually Stoelting does mention histamine release with sux (4th edn, pg 223 table 8.6), describing it as "slight". I disagree with the above, as I have said, Stoelting says it can cause all those things - therefore E would be my guess. I concurr with E being the right answer: just check MIMs! " The following adverse reactions have been reported following administration of suxamethonium. Neuromuscular. Postoperative muscle pain, muscle fasciculation, rhabdomyolysis, myoglobinuria, myoglobinaemia, elevated creatine phosphokinase, hypertonia. Cardiovascular. Bradycardia, tachycardia, arrhythmias, cardiac arrest, hypertension, hypotension, tachyphylaxis, ventricular fibrillation as a result of hyperkalaemia. Respiratory. Apnoea, prolonged respiratory failure, bronchospasm, increased bronchial secretions, pulmonary oedema in infants. Endocrine/ metabolic. Malignant hyperthermia, porphyria, hyperkalaemia, excessive salivation. Gastrointestinal. Increased intragastric pressure, increased bowel movements, increased gastric secretions, possible aspiration. Special senses. Increased intraocular pressure. Other. Rise in intracranial pressure, renal failure, precipitation or exacerbation of myasthenia gravis. Hypersensitivity reactions including circulatory collapse, flushing, rash, urticaria, bronchospasm and shock, which may lead to death. "

Answer 90

A - incorrect - Relaxation due to NDMR is potentiated by most volatile anaesthetic agents. Halothane has the LEAST effect of the current halogenated agents. B - probably true; how much you give will depend on whether the patient has been paralysed with an infusion or bolus - think CSHT C - probably incorrect; I think it would be affected by age

Answer 91

MB26 [Feb00] Which of the following is associated with a decrease in duration or effect of nondepolarising neuromuscular blocking drugs: A. Volatile anaesthetic alkanes B. Volatile anaesthetic ethers - FALSE will prolong C. Aminoglycoside antibiotics - FALSE, will prolong D. Aminopyridine derivatives - TRUE will shorten: "In patients with LEMS, neostigmine is ineffective as an antagonist for residual neuromuscular block.[1076] It has been suggested that a combination of an anticholinesterase and 4-aminopyridine might be of value in these patients." Miller Ch 13 E. Local anaesthetic esters - FALSE will prolong (see also MB18) MB26 [Feb00] Which of the following is associated with a decrease in duration or effect of nondepolarising neuromuscular blocking drugs: A. Volatile anaesthetic alkanes B. Volatile anaesthetic ethers C. Aminoglycoside antibiotics D. Aminopyridine derivatives - true; aminopyridine "prolongs action potentials thereby increasing transmitter release at the neuromuscular junction and elsewhere."[1] E. Local anaesthetic esters

Answer 92

Alt version: Which of the following decreases the duration/depth of neuromuscular blockade? A. Enflurane at 2 MAC -FALSE increases depth B. Aminoglycosides - FALSE increases depth C. Bolus doses versus infusion - ? D. Aminopyridines - true decreases depth ``` Alt version: Which of the following decreases the duration/depth of neuromuscular blockade? A. Enflurane at 2 MAC B. Aminoglycosides C. Bolus doses versus infusion D. Aminopyridines - true ``` 4-Aminopyridine or 4-pyridinamine is a potassium channel blocker. It is used primarily as a research tool and is helpful in characterizing subtypes of potassium channels. It has been used clinically in Lambert-Eaton myasthenic syndrome and multiple sclerosis because by blocking potassium channels it prolongs action potentials thereby increasing transmitter release at the neuromuscular junction and elsewhere. Hypothermia prolongs blockade by decreasing metabolism of NDNMB or delaying excretion of NDNMB

Answer 93

``` MB26b [Jul01] Neuromuscular blockade is NOT prolonged by: A. Hyperthermia - true B. Gentamicin - False C. Volatile agents - false D. Hypothermia - false E. ? ``` ``` MB26b [Jul01] Neuromuscular blockade NOT prolonged by: A. Hyperthermia - correct B. Gentamicin C. Volatile agents D. Hypothermia E. ? ``` 4-Aminopyridine or 4-pyridinamine is a potassium channel blocker. It is used primarily as a research tool and is helpful in characterizing subtypes of potassium channels. It has been used clinically in Lambert-Eaton myasthenic syndrome and multiple sclerosis because by blocking potassium channels it prolongs action potentials thereby increasing transmitter release at the neuromuscular junction and elsewhere. Hypothermia prolongs blockade by decreasing metabolism of NDNMB or delaying excretion of NDNMB

Answer 94

MB27 [Jul00] [Apr01] [Jul04] Neostigmine's mechanism of action: A. Binds covalently to esteric site on AChEsterase - true; produces "reversible inhibition of AChE by formation of a carbamyl ester complex at the esteratic site of the enzyme" (Stoelting 3rd ed. p 225) B. Binds electrostatically to esteric site on AChEsterase - false C. Binds to anionic site - false D. Forms complex with AChEsterase with a shorter halflife than acetylcholine - false E. (“Some other long winded explanation requiring 30 seconds to read and impossible to remember.”) Neostigmine binds to the anionic site, but is then transferred to the esteratic site and hydrolysed. This is a much slower process with neostigmine (minutes) than with acetylcholine (milliseconds). Neostigmine is an ester. Most binding between a drug and its receptor is non-covalent. Neostigmine binds non-covalently. For those few drugs that react with and bind covalently to their receptor, the effect is often permanent and requires synthesis of new protein to restore normal activity. Contrary perspective: I think the bond *is* covalent - see (eg): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=223706 While technically Neostigmine is attracted to the anionic site (in a similar fashion to ACh) via an ionic "bond" for proper orientation, the actual binding is more properly at the esteratic site where a covalent bond forms. Addit: Tertiary NH3+ attracted to anoinic site...aligning carbmyl group with the esteratic site. Carbamylation of the esteratic site prolongs the duration of action but is competitive. (Stoeling) COMMENT: Miller (6th Ed. p519) states, "Neostigmine and pyridostigmine transfer a carbamate group to the acetylcholinesterase, which forms a COVALENT BOND AT THE ESTERATIC SITE"......Answer = A References Article by Nair (see p166) - You will need to logon via the ANZCA library page to get access to the the full-text article. This article has a simple diagram of the binding sites on the enzyme.

Answer 95

With depolarising neuromuscular blocker: must be C or D (could be A) A: Is competitively antagonised by NDMR - FALSE: "The prior administration of SCh... enhances the... twitch response suppression produced by subsequently administered NDNMB adrug" Stoelting 3rd ed p200 B: ("Something about tetany & fade") C. ? D. ? E. Shows post tetanic potentiation - DEFINITELY FALSE, no potentiation for sux in phase I although with phase II...? Option A - I think this is true. Question is about effect of NDMR on DMR ie pre-curarisation - the comment above seems to be referring to the other way around. Evers + Maze Anaesthetic Pharmacology states that "the efficacy of precurarisation is undisputed... the basis for this effect is the antagonism of the depolarizing effect of succinylcholine by the blocking effect of nondepolarizing muscle relaxant... to overcome these effects an increased dose of succinylcholine... is recommended" Option A is correct: "[pre-curarization] can increase the amount of succinylcholine required for relaxation" - Katzung References

Answer 96

2ED95 dose is the intubating dose of rocuronium - it has a rapid onset and an intermediate duration of action Rapid onset Intermediate duration Rocuronium has an ED95 dose of 0.3mg/kg At an intubating dose of 0.6mg/kg, has an onset of 1-2 mins, and a duration of action of 20-35 mins. At 3-4x ED95 dose, the onset resembles the onset of suxamethonium (approx 60 secs), but has a duration of action resembling pancuronium (60-90 mins Stoelting 4th Ed, P.238

Answer 97

The clinical uses of anticholinesterase drugs are: 1. Antagonist - assisted reversal of neuromuscular blockade produced by non depolarising neuromuscular blocking agents. In addition treatment of: 2. myasthenia gravis 3. glaucoma 4. paralytic ileus and atony of the urinary bladder 5. CNS effects of certain drugs 6. May be useful in alzheimers disease. Reference: Page 231 Stoelting, Pharmacology and physiology in Anaesthetic practice 3rd edition

Answer 98

Neostigmine: A. Tertiary ammonium compound - false; "quaternary ammonium group" Stoelting p 227 3rd ed B. ? no, quaternary - true C. ? It is possible to have a quarternay ammonium compound, but not a tertiary (would be an "amine"). Neostigmine is a quarternay ammonium compound, meaning it is less lipid soluble and unable to cross the BBB. Physostigmine is one of the lipid soluble anticholinesterases (as well as the organophophates), and it is able to cross the BBB due to having a tertiary amine group rather than a quarternay ammonium group. It can therefore be used to treat central anticholinergic syndrome produced by atropine or scopolamine (Stoelting, 4th 260.)

Answer 99

MB32 [Jul01] [Jul04] The dibucaine number for a normal person is: A. 20 B. 40 C. 60 D. 80 - true dibucaine number of 80 is normal for a person with normal plasma cholinesterase E. 100. Dibucaine (aka cinchocaine) is an amide local anaesthetic that inhibits normal plasma cholinesterase. It tends to inhibit variant forms of plasma cholinesterase less effectively. The dibucaine number is the percentage of inhibition and indicates the genetic makeup for an individual but makes no assessment of the quantity of enzyme in the plasma. There are four alleles - usual (normal), atypical (dibucaine resistant), silent (absent), fluoride resistant - which have been identified on a single locus on chromosome 3 See table http://www.kerrybrandis.com/wiki/mcqwiki/index.php?title=MB32.

Answer 100

``` MB32b [Aug 2011] The dibucaine number in a patient with Ea:Ea genotype is: *repeat* A. 0 B. 20 - true C. 35 D. 50 E. 60 ``` Dibucaine (aka cinchocaine) is an amide local anaesthetic that inhibits normal plasma cholinesterase. It tends to inhibit variant forms of plasma cholinesterase less effectively. The dibucaine number is the percentage of inhibition and indicates the genetic makeup for an individual but makes no assessment of the quantity of enzyme in the plasma. There are four alleles - usual (normal), atypical (dibucaine resistant), silent (absent), fluoride resistant - which have been identified on a single locus on chromosome 3. See table http://www.kerrybrandis.com/wiki/mcqwiki/index.php?title=MB32

Answer 101

Muscle relaxants are less likely to cause anaphylaxis if: A. Injected slowly - False: anaphylaxis occurs whether fast or slow injected B. Suxamethonium is the most common cause depending upon where you live - ?? C. H1 and H2 blockers prevent anaphylaxis - FALSE: histamine blockers can reduce the symptoms of anaphylaxis but cannot prevent it. Recall that anaphylaxis is a Type I hypersensitivity reaction involving the binding of IgE to an antigen. It causes mast cell and basophil activation which is common to both it and anaphylactoid reactions D. Always fatal - FALSE: anaphylaxis is not always fatal E. ?

Answer 102

Laudanosine is a breakdown product of atracurium and cisatracurium's Hofmann elimination. Has been associated with CNS excitation and precipitation of seizures.Toxicity probably only relevant with extremely high dose and hepatic failure. Is metabolised by liver and excreted in urine and bile. Laudanosine is a metabolite of BOTH pathways of atracurium metabolism. For every molecule of atracurium, Hofmann elimination produces two molecules of laudanosine and ester hydrolysis produces one. [Stoelting 4e p.232]

Answer 103

A - false; hypokalaemia potentiates the effect on NDMBs B - true; "the subsequent duration of action of neuromuscular blockade produced by atracurium or vecuronium is not prolonged by the prior administration of SCh." Stoelting 3rd ed. p.200 Sux prior to Vec will enhance the magnitude of response to Vec but will not prolong the subsequent duration of action. See page 228-228 in Stoelting. Option A presumably does by producing hypokalaemia.

Answer 104

Post-suxamethonium myalgia: A. Preceeded by transient myoglobinuria - FALSE B. More common in the elderly - FALSE; more common in young adults C. Can be prevented by pre-treatment with 0.04 mg/kg of D-tubocurarine - true, "pre-curarisation" D. Is invariably associated with increased intra-ocular pressure - FALSE E. Is associated with hypokalaemia - FALSE, sux is associated with hyperkalaemia Answer - C Stoelting 4th edn pg 221 pre treatment with a nonparalyzing dose of dTc prevents or attenuates the incidence of myalgia post sux.

Answer 105

MB37 [Feb04] Regarding anticholinesterases: A. Pyridostigmine is a tertiary amine - false B. Quaternary ammonium anticholinesterases have a larger volume of distribution than non-depolarising muscle relaxants - correct; "large Vd of quaternary ammonium anticholinesterase drugs compared with nondepolarising NMBD" (Stoelting 3rd ed p.227) C. Edrophonium has a slower onset of action than neostigmine - false; faster onset D. Neostigmine has a longer duration of action than pyridostigmine - false E. Edrophonium binds covalently to the esteratic site of acetylcholine - false; edrophonium has electrostatic bonds

Answer 106

MB37b [Jul04] Regarding Antiacetylcholinesterase A. Given orally to treat glaucoma - false; used topically B. Edrophonium is a long acting AChE inhibitor - false; shorter acting C. Physostigmine is quarternary ammonium - false; physiostigmine is a tertiary amine; neostigmine, edrophonium and pyridostigmine are quaternary amines D. ? Re MB37: B is true according to Stoelting 4th ed p254. (3rd ed p227). It is speculated that the larger Vd may be due to extensive tissue storage in the liver It could be argued that edrophonium is relatively long-acting (Stoelting says it has the same duration of action as the other acetylcholinesterases, and a longer half-life than neostigmine, 110 vs 77 mins). comments? "Although edrophonium in the past has been considered a short acting drug, controlled studies in anaesthetised paths have documented that the duration of action of edophonium does not differ from that of neostigmine (Cronnelly etal, 1982)" Stoelting 4th Ed. Page 255.

Answer 107

MB38 [Jul04] Which is the best indicator of adequate reversal? A. TOF count of 4 - FALSE; TOF count can be 4 but ratio can be low B. No fade on DBS - TRUE C. No fade to 200 Hz tetanus - FALSE; tetany not a good indication D. Head lift?? - reasonable clinical indicator I guess E. Evidence of post-tetanic facilitation - FALSE; NO WAY

Answer 108

MB38b [Jul04] Residual curarization is best evaluated with: A. TOF 1:4 > 50% - FALSE B. Equal twitch height on DBS if you have no access to TOFR when ratio was classically >0.7 but many now suggest >0.9 - TRUE C. ?Degree of fade is independent on stimulus intensity D. ?Used to check depth of anaesthesia E. ? A TOF count of 4 can occur with receptor blockade of 85-90% (depending on which text you read). Double burst stimulation consists of two short tetanic stimuli separated by a gap of 750ms, each consisting of 3 square waves of 0.2ms duration, at frequency 50Hz. It was introduced as it is easier to detect fade clinically compared to TOF ratio and mechanically it correlates well with TOF ratio. No detectable fade of double burst stimulation indicates the absence of clinically significant residual neuromuscular blockade (Refs: Peck and Williams, Miller 4th Ed). Answer: D I disagree. TOF of over 90% can still be associated with around 70% receptor occupancy. The most sensitive test is response to tetanic stimulation at 200hz which if there is no fade during the 5 seconds correlates with less than 30% receptor occupancy. Good article is: Indian J of Anaesthesia, Aug 2002, p279. The question asked was what is the best indictor of adequate reversal?.From my understanding it has to be DBS coz it is usual indicated the magnitude of block, if the block has been reversed adequately then the DBS should be the same height, as per Miller. I agree - the reasoning is that humans are notoriously poor at picking a difference between TOF ratio of 0.7 and 0.9, which does make a significant difference clinically. However, if DBS is perceived to have no fade, then you're pretty sure that TOF is >0.9. DBS is t1-t3, t4-6 at 50Hz separated by 750ms - I think it may be DBS for both. For the 1st question, TOF of 4 may still exhibit significant fade (and a low TOF ratio for example) equal twitch height on DBS is comparable to no fade on TOF (in Peck, Hill, Williams) No fade to a tetanic stimulus is very sensitive, and can elicit minor neuromuscular block (According to article referenced below). However, it also says that at higher frequencies (100-200hz) that muscle fatigue may occur which interferes with the response, so this could be a trick. Head lift is a crude test of blockade according to the article by McGrath and Hunter post-tetanic facilitation is for monitoring profound block I think the best reponse for the 2nd question is double burst stimulation (equal twitch height means no fade).

Answer 109

Answer is B. Rocuronium | Sugammadex will also adequately reverse vecuronium and may partly reverse pancuronium

Answer 110

C Stoelting, 5th ed, p338 Dr mitta 11:12, 18 November 2015 (CST)

Answer 111

``` This seems likely to have been mis-remembered as there is more than 1 correct answer A - true B - true, this would also be a cause of a small VD, although [[rocuronium] is only 30% protein bound. C - also true: As per Brandis p1: In a 70kg man: TBW 42 litres ICF 55% (23 litres) ECF 45% (19 litres) made up of: Interstitial fluid 20 % Intravascular fluid 7.5% Water in dense CT 7.5% Water in bone 7.5% Transcellular fluid 2.5% therefore: TBW is 42/70 = 0.6L/kg ICF is 23/70 = 0.32L/kg ECF is 19/70 = 0.27L/kg ```

Answer 112

A. Hoffman elimination - false, missing the and... B. Hoffman elimination and plasma esterases - true C. Hoffman elimination and excretion of metabolites in the urine - false, missing esterase and then its hepatic clearance D. Hoffman elimination and plasma esterases and excretion of metabolites in the urine - false, laudanosine depends on hepatic clearance E. ?

Answer 113

A. Pancuronium - true - 32-40% renally excreted unchanged (sassada and smith - 40-50% renal excretion (80% unchanged). B. Atracurium - false - extensively if not completely metabolised - hoffman degradation + esterase hydrolysis C. Mivacurium - false - extensivley metabolised by plasma cholinesterases (only 7% is excreted as unchanged drug - steeling 4th ed page 243) NB If Vecuronium is an option, 20% is excreted unchanged in bile and 25-30% unchanged in urine = total 45-50% excreted unchanged. Rocuronium is NOT metabolised.

Answer 114

A - Dose required to cause twitch height depression TO 95% of control value - false B - Dose required to cause twitch height depression OF 95% of control value - true - "Equal Potency between neuromuscular blocking drugs is determined by measuring the dose needed to produce 95% supression of the single-twitch response (ED95)." (Stoelting 4th Ed page 208) C - 95% of patients will be paralysed at this dose - false

Answer 115

A. Accumulation of 3-OH vecuronium metabolite - true if actually says 3-desacetylvecuronium B. Long term steroid use - true, it might be a steroid associated polymyoneuropathy / critical illness myopathy - nerve conduction studies show pure axonal degeneration affecting motor rather than sensory fibres - slow recovery as new axons are required to grow C. Hyperthermia - false D. Hypomagnesaemia - false E. Hyperkalaemia - false The metabolite it said was 3 acetyl o-des vecuronium or something weird and wrong I remembered it as being 1,3 des acetyl vecuronium - which is still wrong according to Peck who says it is only 3 des acetyl vecuronium - sneaky to add in the 1,3 rather than 3 I thought! Hi, I remembered option A is "accumulation of 3,17-dihydroxy-vecuronium". Miller (electronic edition, page 508): "The principal metabolite of vecuronium, 3-desacetylvecuronium, is a potent (≈80% of vecuronium) neuromuscular blocking drug in its own right. The metabolite, though, has lower plasma clearance and a longer duration of action than vecuronium does. " Stoelting also agrees noting that "Vecuronium has a large volume of distribution, reflecting its tissue uptake. After single dose of vecuronium, the plasma concentration decreases rapidly because of redistribution from central to peripheral compartments. With subsequent doses, any vecuronium present in various peripheral tissues will limit the distribution phase and thus also the rate of decrease of the plasma concentration of vecuronium. As a result, vecuronium can be demonstrated to have a cumulative effect that is less than for pancuronium and greater than for atracurium... Accumulation of the 3-desacetylvecuronium metabolite of vecuronium may contribute to prolonged effects of this drug, expecially with repeated doses of vecuronium administered to patients with renal failure ``` Sasada and Smith 4ed p375 notes that: The duration of action of vecuronium, in common with other noon-depolarising relaxants, is prolonged by: hypokalaemia, hypocalcaemia, hypermagnesaemia, hypoproteinaemia, dehydration, acidosis, hypercapnia. The following drugs when co-administered with Vecuronium increase the effect of the latter: volatiles, induction agents including ketamine, fentanyl, sux, diuretics, calcium channel blockers, alpha and beta antagonists, protamine, lidocaine, metronidazole amino glycosides. Patients with burns may develop resistance to vecuronium. Onset and duration of neuromuscular blockade is shortened in patients receiving chronic anticonvulstant therapy ```

Answer 116

See also OP07 Answer Octanol coeff 40, pka 8.5, phenylpiperidine, vd 4.5l.kg, 60% protein bound (Faunce 244)

Answer 117

Answer is E See table 10-11, page 300, Miller 5th edition Factors predisposing to bradycardia/asystole during opioid induction presence of beta and/or calcium channel blockade premedication or concomitant use of benzodiazepines rapid administration muscle relaxants with little or no vagolytic properties vagotonic muscle relaxants (e.g. suxamethonium) added vagal stimuli (e.g. laryngoscopy)

Answer 118

OP3 A - ? incorrect; naloxone as a competitive antagonist should antagonise partial agonists (agonist/antagonists) at a high enough dose as long as they are not irreversible B - partially correct/partially incorrect; "Naloxone is a pure opioid antagonist and will reverse opioid effects at mu, kappa and delta receptors" (Peck, Hill and Williams p. 135); as for sigma receptors, "they are not reversed by naloxone" and are no longer considered opioid receptors. (Peck, Hill and Williams p. 125) C - correct; may precipitate pulmonary oedema (morphine is used to treat, therefore naloxone can potentially precipitate) D - incorrect; naloxone has previously been tried in shock states to reverse hypotension E - correct; will increase sympathetic tone depending on circumstance as opioid receptors decrease sympathetic tone.

Answer 119

OP3B A - ?incorrect; see OP3 answer A B - correct; see OP3 answer B Naloxone CAN cause pulmonary oedema, but the mechanism is not by acting the 'opposite of morphine'. Morphine reduces the subjective sensation of increased work of breathing by increasing the volume threshold of the pulmonary stretch receptors, thus allowing patients to take deeper breaths, improve their oxygenation, and feel better. Naloxone, according to Stoelting, can cause pulmonary oedema from increased sympathetic nervous system activity (I suppose a decompensated tachycardia).

Answer 120

A. N17 substitution does give anatagonist activity. E.g. naloxone has CH2CHCH2 (as opposed to the CH3 in morphine. Naloxone is an oxymorphone derivative. B. C3 O-methylation produces codeine. C. Glucuronidation occurs at C3 and C6 (hence Morphine-3-glucuronide is the major metabolite, M6G the minor metabolite). D. Diacetylation (as in C3 and C6 for diacetylmorphine = heroin) increases lipid solubility.

Answer 121

A. N17 substitution does give anatagonist activity. E.g. naloxone has CH2CHCH2 (as opposed to the CH3 in morphine. Naloxone is an oxymorphone derivative. B. C3 O-methylation produces codeine. C. Glucuronidation occurs at C3 and C6 (hence Morphine-3-glucuronide is the major metabolite, M6G the minor metabolite). D. Diacetylation (as in C3 and C6 for diacetylmorphine = heroin) increases lipid solubility.

Answer 122

A is correct answer - pethidine was discovered by the Nazi's looking for a synthetic supply of atropine; thus it has anticholinergic effects and causes tachycardia NOT bradycardia. (No reference) A. Pethidine has an antimuscarinic action which may cause tachycardia. This is one of the opioid group's few cardiovascular side effects. Most opioid medications have no significant direct effects on the heart and cardiac rhythm -bradycardia excepted. Katzung, Basic and clinical pharmacology, 2004, p505. B. Therapeutic doses of morphine-like opioids in therapeutic doses produce vasodilation, decreased peripheral resistance, and inhibition of baroreceptor reflexes (therefore orthostatic hypotension can occur). - from Goodman & Gilman, Pharmacological Basis of Therapeutics,1996, p531. C. In supine position and at therapeutic dose, opioids have no major effect on BP, HR, rhythm. When the patient sits up, however orthostatic hypotension can occur. Goodman & Gilman, Pharmacological basis of therapeutics, 1996, p531. BP is usually well maintained unless there is undue cardiac strain, when hypotension may develop (possibly due to peripheral arterial and venous depression secondary to histamine release and/or depression of vasomotor stabilising mechanisms). Katzung, 2004, p505. D. There is no great demonstrated effect on cardiac output by pethidine. Pethidine can cause tachycardia, in which case if stroke volume is constant, cardiac output could increase, however this has not been demonstrated (that I can find). For opioids generally where there is not consistent effect on cardiac output or ECG. Katzung, 2004, p505. However, I did find a comment in Clinical Anaesthesiology by ?Morris? that "with the exception of pethidine there is not decreased cardiac output by opioids" pethidine is unique among opioids in decreasing cardiac output by depressing myocardial contractility as per Stoelting pg no 104

Answer 123

A - false; "Renal metabolism makes a significant contribution to the total metabolism of morphine, which offers a possible explanation for the absence of any decrease in systemic clearance of morphine in patient with hepatic cirrhosis or during the anhepatic phase of orthotopic liver transplantation" (Stoelting 3rd ed. pp84-85) B - true; morphine "undergoes extensive first-pass metabolism and only 25-30% reaches the systemic circulation" (Peck Hill and Williams p.127) suggesting high hepatic extraction ratio Morphine hepatic extraction ratio 0.6-0.8 (Miller) C - false; as above

Answer 124

OP07 [Jul97] [Mar99] [Jul99] [Jul00] [Feb04] [Jul04] Fentanyl: A. With pKa 8.4 is 90% ionised at physiological pH - true; pKa is around 8.4 and thus at physiological pH 90% will be ionised (I could do the maths, but can't be bothered) B. Has an octanol coefficient of 10 - false C. Is 1,000 times more potent than morphine - false; 10mcg fentanyl=1mg morphine so it is 100 times more potent D. Has first-pass lung uptake reduced to 20% by propranolol - unsure E. Has up to 50% uptake in the lung - false; "an estimated 75% of the initial fentanyl dose undering first-pass pulmonary uptake" (Stoelting 3rd ed. p.93) F. Elimination half-life

Answer 125

OP08 [Jul97] An opioid which can not be used for TIVA: A. Morphine - true; half life too long B. Pethidine - True; problem with norpethidine metabolite C. Fentanyl - probably true; long CSHT with long infusion time D. Sufentanil - probably false; sufentanil has predictable pharmacokinetics and as short half time E. Alfentanil - probably true; high individual variability in metabolism makes infusion prediction difficult Ideal characteristics for TIVA medications are: short time to onset of action short half life (therefore decreased accumulation and faster recovery). Of the above choices all can theoretically be used, however pethidine would be the worst choice due to complications of accumulation. Accumulation of a demethylated metabolite of pethidine with multiple doses of the drug or in renal impairment can cause CNS disturbance (hallucinations, seizures). Katzung, Basic & Clinical Pharmacology, 2004, p500. Remifentanil is a newer drug and has ideal properties for TIVA. See following articles: [1]TIVA tutorial I [2]TIVA tutorial II [3]TIVA tutorial III Addition: Faunce also states that Pethidine should not be used in TIVA due to neg inotropism and histamine release, although this is not stated in MIMS Metabolite of pethidine is norpethidine which has long half-life. So it should not be used as a continous infusion.

Answer 126

Nalbuphine is a mu antagonist, low potency kappa agonist, moderate potency delta partial agonist. Similar profile to pentazocine - only difference is moderate 'delta agonist'. Therefore best answer is B. Ref. Table in Rang, Dale and Ritter. I don't think B is right either. Stoelting says nalbuphine gives less dysphoria than pentaz, doesn't raise BP, PAP, HR or atrial filling pressures as pentaz does, and produces a more severe withdrawal than pentaz. am I missing the part where this drug is on the curriculum? Maybe it was 13 years ago!

Answer 127

A. 75-100mg pethidine IM is an equivalent dose to 10mg IM/SC morphine (based on single dose studies on opioid naive patients), however the effects of each drug are not identical. Aust Medicines Handbook (AMH), 2004, p45. Katzung, Basic and Clinical Pharmacology, 2004, p499. B. Yes. Pethidine has an antimuscarinic action which may cause tachycardia. This is one of the opioid group's few cardiovascular side effects. Most opioid medications have no significant direct effects on the heart and cardiac rhythm -bradycardia excepted. In supine position and at therapeutic dose, opioids have no major effect on BP, HR, rhythm. When the patient sits up, however orthostatic hypotension can occur. Katzung, 2004, p 504. Goodman & Gilman, Pharmacological basis of therapeutics, 1996, p531. C. There is no great demonstrated effect on cardiac output by pethidine. Pethidine can cause tachycardia, in which case if stroke volume is constant, cardiac output could increase, however this has not been demonstrated (that I can find). For opioids generally where there is not consistent effect on cardiac output or ECG. Katzung, 2004, p505. However, I did find a comment in Clinical Anaesthesiology by ?Morris? that "with the exception of pethidine there is not decreased cardiac output by opioids" Addition: Stoelting notes big doses gives decreased contractility. D. No. Morphine is widely used for acute and chronic pain, and more commonly than pethidine. Pethidine is not suitable for long term use due to accumulation of toxic metabolities which can effect the CNS. AMH, 2004, p53. Pethidine is used in preference to other opioids in childbirth and the neonatal period due to it's shorter half life and low conjugating capacity in neonates. OP10b [Mar98] Pethidine produces: A. Miosis B. More severe hypotension with comparable dose of morphine C. More biliary spasm than morphine D. ? Comments Summary: B is best answer: "In fact, hypotension after meperidine [sic!] injection is more frequent and more profound than after comparable doses of morphine". Further, pethidine causes mydriasis due to atropine-like structure, and less biliary constriction (all from Stoelting 4Ed pp104) JB2012 A. Pethidine can produce miosis. Pethidine has moderate agonist selectvitiy for mu receptors which are associated with the following effects: spinal and supraspinal analgesia, respiratory depression, pupil constriction, decr gut motility, euphoria, sedation and physical dependence). Constriction of pupils is seen with virtually all opioid agonists. Miosis is an effect to which little or no tolerance develops (therefore this sign is useful in overdose). However, Stoelting actually states that pethidine "does not cause miosis but rather tends to cause mydriasis" (4th edition, p104) B. No. Morphine is associated with a drop in BP; pethidine is associated with tacycardia due to its anti-cholinergic properties Contrary View: Hypotension more profound and frequent than with morphine (Stoelting, 3rd Ed, p92). C. Opioids can constrict biliary smooth muscle and the sphincter of oddi, which may result in biliary colic, reflux of biliary/ pancreatic secretions, and elevation of lipase/ amylase. Pethidine and fentanyl seem to produce less pronounced increases in biliary pressure. Katzung, 2004, p505. Goodman & Gilman, 1996, p532. Comment: I think Pethidine can produce mydriasis as well. Not that there is a better option here. Comment: Pethidine has some antimuscarinic properties (responsible for tachycardia) and hence may also result in mydriasis (Peck Hill and Williams 2nd Ed. p 131). Pethidine is less used now in labour as it crosses the placenta readily and neonates metabolise it more slowly due to enzymatic immaturity, so that it may have prolonged (several days) sedative effects. Pharmacodynamics - Pethidine CNS Analgaesic – 1/10th the potency of morphine More euphoria cf morphine No miosis but may cause mydriasis secondary to atropine like effects at Kappa receptors May precipitate seizures – due to norpethidine Interacts with MAO → reduced uptake of NA and 5H-T3 therefore can precipitate Serotonin syndrome in pts on SSRI or MAOI Due to LA activity – has bee used as sole agent in spinal anaesthetic CVS Decreased myocardial contractility – only opioid to do so significantly Greater reduction in SVR cf morphine → greater levels of hypotension and more prone to postural hypotension Atropine like activity → increased HR Less histamine release cf morphine Respiratory More potent respiratory depressant cf morphine TV reduced >> RR Blunt response to hypoxia and hypercapnia Chest wall rigidity can occur Little antitussive action GIT Effects less when cf with morphine decreased motility Minimal biliary spasm Causes N&V Renal Increased ureteric peristalsis but to lesser extent than morphine Dependence – greater addicitve potential cf morphine Withdrawal – as per morphine

Answer 128

A. Morphine usually causes miosis in humans (although caused mydriasis in animals eg. rats). Oral morphine OD can however cause mydriasis " Morphine causes miosis, even in total darkness, and little tolerance develops to this effect. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia in the setting of KADIAN® overdose" Reference http://www.kadian.com/pages/getfile.aspx?id=1C6197AB-8F83-43E7-B239-D4615293989B B. Morphine can cause muscle rigidity in high doses c. Morphine can cause respiratory depression

Answer 129

Stoelting 4th edn pg 115 A. Substitution of a methyl group for the hydroxyl group on C3 of morphine. B. 10% is metabolised via demethylation in the liver to morphine. (note question asks about diacetylmorphine i.e. heroin, not morphine C. IM 120mg of codeine is equivalent in analgesic effect to 10 mg of morphine d. see a e. IV codeine not reccommended because of histamine release - hypotension, angioedema, pul oedema f. Presence of methyl group on C3 limits first pass hepatic metabolism. ? not sure if this answers the question or have I missed something? (no, you got it!) -- So, in summary, best answer is C.

Answer 130

A. Morphine is primarily conjugated to morphine-3-glucuronide (which has neuroexcitatory properties). Approximately 10% is metabolised to morphine-6-glucuronide (an active metabolite with a much greater analgesic potency than morphine, especially when the blood brain barrier is bypassed -eg. for intrathecal of intraventricular administration in animal models there is 100 times greater potency for M6G). Katzung, Basic & Clinical Pharmacology, 2002, p400 Goodman & Gilman, Pharmacologic Basis of Therapeutics, 1996, p535 B. Half Life of Various opioids: Opioid Plasma Half Life Heroin 0.5 hours Morphine 2 hours Hydromorphone 2-3 hours Oxymorphone 2-3 hours Codeine 2-4 hours Fentanyl 3-4 hours Pethidine 3-4 hours Methadone 15-40 hours Goodman & Gilman, Pharmacological Basis of Therapeutics, 1996, p535 The question refers to the half-lives of the metabolites, which are longer than morphine. Stoelting appears to suggest that M-6-G, and M-3-G hang around for days C. Morphine-6-glucuronide is renally excreted (therefore can accumulate in renal impairment). Elimination by glomerular filtration primarily as morphine-3-glucuronide. Enterohepatic circulation of morphine and it's glucuronides occurs, therefore small amounts can be found in faeces and urine for several days after the last dose. Goodman & Gilman, Pharmacological Basis of Therapeutics, 1996, p535 Hepatic oxidative metabolism is primary route of degredation for fentanyl/ alfentanil/ sufentanil and eventually leaves only small quantities for excretion. Codeine, oxycodone, hydrocodone all undergo metabolism in the liver. Katzung, Basic and Clinical Pharmacology, 2004, p499 "Stoelting says that morphine is metabolised principally by conjugation to glucuronic acid, in hepatic and extrahepatic sites, primarily the kidney" also says "renal metabolism makes a significant contribution" D. Morphine-3 + Morphine-6 glucuronide both have limited ability to cross the blood brain barrier. Katzung, Basic and Clinical Pharmacology, 2004, p499 E. Morphine-6 accounts for a significant proportion of morphine's analgesic actions due to higher potency and higher concentrations. Goodman & Gilman, Pharmacological Basis of Therapeutics, 1996, p535 M-3-G has no analgesic properties however F. "Sulfation is an important pathway for the elimination of acetaminophen and of morphine in neonates." Evers and Maze 2004 p.69 G. See A above. H Is correct. Comment: re option E, Evers and Maze (2004) have this to say about morphine 6 glucuronide "It is not clear from clinical studies whether M6G contributes significantly to the opioid effect of a single dose of morphine." but it probably "...accumulates over time." (p465)

Answer 131

Not effective orally as high hepatic first pass metabolism | Oral bioavailability

Answer 132

5-10 times as potent as fentanyl. Less than 1% excreted unchanged in the urine Protein binding - 93%, fentanyl - 84%. Elimination half-life - Sufentanil - 2.2-4.6 hours, fentanyl - 3.1-6.6 hours, alfentanil - 1.4-1.5 hours Bound to alpha-1-acid glycoprotein References Stoelting and Hillier 4th ed page 93 and 109

Answer 133

``` A. Incorrect ... it does. B. C. Causes less neonatal depression D. Incorrect ... it does. E. Answer C "Meperidine is the most commonly used parenteral opioid analgesic during labor. Meperidine is thought to cause less respiratory depression in the neonate than morphine does; therefore, it is more commonly used.[73] It may, however, cause loss of beat-to-beat variability of FHR tracings." - Miller's Anesthesia, 6th Ed, chapter 58 (under Anesthesia for spontaneous vaginal delivery) Reference 73: Way WL, Costley EC, Way EL: Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965; 6:454-461. ``` - don;t know if it was a trick, but I think E is correct, not C. (respiratory depression as opposed to feeling a bit down).

Answer 134

Codeine has 60-70%

Answer 135

Norpethidine is a major metabolite which contributes to pethidine's toxicity. (see wikipedia) Option B is presumably meant to confuse those thinking of morphine metabolism.

Answer 136

Correct answer appears to be B Miller (2000) is a good reference for this question. Alfentanil's most unique physiochemical feature is that at physiological pH it is mostly (90%) unionised because of its relatively low pKa (6.5). Thus, despite more intense protein binding, the diffusible fraction of alfentanil is higher than fentanyl. This explains (in part) its short latency to peak effect after IV injection. Although not proven, it may be that alfentanil's lower lipid solubility compared with fentanyl makes for less uptake of alfentanil by lipid rich brain tissue. This may also contribute to alfentanil's rapid onset and offset of effect" A - Miller gives data for fentanyl (84%) alfentanil (92%) plasma protein bound. however this should have little effect on speed of onset of action B - Miller suggests comparable potency data of fentanyl 4x as potent as alfentanil. again unrelated to speed of onset of action C - Miller octanol/water partition coefficient data fentanyl (813) has greater lipid solubility than alfentanil (145) D - from first principles, the drug which is less ionised at body pH should be more capable of rapid diffusion. Miller gives data fentanyl (

Answer 137

(B. Seems correct...as Alfentanyl 90% unionised and 8% unbound = 7.2% unbound and unionised vs Fentanyl 10% unionised and 16% unbound = 1.6% unbound and unionised.....or have i missed something???)) Correct answer appears to be B Miller (2000) is a good reference for this question. Alfentanil's most unique physiochemical feature is that at physiological pH it is mostly (90%) unionised because of its relatively low pKa (6.5). Thus, despite more intense protein binding, the diffusible fraction of alfentanil is higher than fentanyl. This explains (in part) its short latency to peak effect after IV injection. Although not proven, it may be that alfentanil's lower lipid solubility compared with fentanyl makes for less uptake of alfentanil by lipid rich brain tissue. This may also contribute to alfentanil's rapid onset and offset of effect" A - Miller gives data for fentanyl (84%) alfentanil (92%) plasma protein bound. however this should have little effect on speed of onset of action B - Miller suggests comparable potency data of fentanyl 4x as potent as alfentanil. again unrelated to speed of onset of action C - Miller octanol/water partition coefficient data fentanyl (813) has greater lipid solubility than alfentanil (145) D - from first principles, the drug which is less ionised at body pH should be more capable of rapid diffusion. Miller gives data fentanyl (

Answer 138

Option C seems to be single best answer ``` A - false. See Katzung. Methadone is a potent synthetic opiate agonist of the phenylheptylamine class and is structurally unrelated to morphine. Phenanthrenes consist of morphine, hydromorphone, oxymorphone and codeine and its relations. C - See martindales table. time from admin to peak plasma conc : epidural 15-20mins, intrathecal 30mins, nasal inhalation .12 hours, oral 2-4 hours D - false. Significant incidence of dependence and addiction with definite withdrawal reaction E - methadone is marketed as the racemic mixture. l-isomer is responsible for analgesic effects and d-isomer has less analgesic, resp depression activity or addiction, but does have antitussive effects Depends on what the question asked - the l isomer has most of the opioid activity, while the d isomer is a weak opioid agonist but also an NMDA antagonist. Alternatively, " Methadone has been proposed as an alternative to slow release formulations for treatment of chronic pain because of its low abuse potential."- Stoelting p.116 4th edition ```

Answer 139

rom Stoelting 4th edn page 117 : tramadol is a racemic mixture of 2 enantiomers - 1 is responsible for the inhibition of NAD reuptake and the other is responsible for inhibition of 5HT reuptake and facilitation of its release plus the action of this drug at mu receptors. In this regard tramadol may be the exception to the argument that chiral mixtures should be avoided when technology exists to prepare a single pure isomer. This question is awful!!! There is a rat research paper about psychological effects of tramadol as an antidepressant (Rojas-Corrales et al, Life Sci 1998 63(12) 175-80) - mentions antidepressant effects of racemic mixture are inhibited by yohimbine. Hence both B and D are true. (-) isomer blocks NAD uptake (+) tramadol has opioid agonist properties and inhibits 5HT reuptake . Most likely answer is option B I disagree with option D as Yohimbine is an a2 blocker so is not a direct inhibitor of the multitude of actions of Tramadol. It could be said it partially antagonises the effects of Tramadol, acting indirectly. According to G+G Yohimbine is an alpha2 and 5-HT blocker. So I agree - tramadol is not directly inhibited.

Answer 140

I would say dependence is least likely to occur in recovery... Given that the recovery period is minimum 30 minutes, maximum 3-4 hours, and physical dependence takes 3-4 weeks to develop (intermittent dosing) (Ref: Stoelting) but may also occur after intravenous infusion for 48 hours - Stoelting It would seem, therefore, that dependence is "least likely". A few doses of morphine in recovery, could definitely constipate a patient, even if this would not be apparant for some days.

Answer 141

Most correct appears to be option A Remifentanil is metabolised by non-specific plasma and tissue esterases (?which are also present in rbc?) It is not metabolised by plasma cholinesterase (so not option B) Option D is wrong as remifentanil has a mean CL of 40-60ml/kg/min (>2.8Lmin for 70kg) Option E is wrong as inactive metabolites are produced Cannot find a reference for "incubated blood" (option C) (See 4th Edition Stoelting P112) Additional In the paper "In Vitro Remifentanil Metabolism: The Effects of Whole Blood Constituents and Plasma Butyrylcholinesterase" it suggests that hydrolysis does not occur in vitro in whole blood and plasma. They hypothesise that the prolonged half life of remifentanil in both whole blood and plasma in vitro may be due to protein binding that protects remifentanil from hydrolysis. This could make C partially correct, I'm not sure if this is a definitive answer. Alternative view Administration of FFP is a recognised treatment for suxamethonium apnoea as the infusion contains pseudocholinesterase. Might FFP also contain non-specific plasma esterases which are not inactivated by processing of blood products? In addition, remifentanil is hydrolysed to remifentanil acid which is 300 - 4600 fold less potent than remifentanil. Therefore it is still technically an active metabolite. Re-read the reference you quoted! It says that the half-life of remi was prolonged when added to FFP and whole blood groups when compared to a red cell mixture. Therefore, it is very likely to be metabolised in RBCs. References In Vitro Remifentanil Metabolism: The Effects of Whole Blood Constituents and Plasma Butyrylcholinesterase by Peter J. Davis, MD, Richard L. Stiller, PhD, Annette S. Wilson, PhD, Francis X. McGowan, MD, Talmage D. Egan, MD, and Keith T. Muir, PhD

Answer 142

``` CORRECT ANSWER E Morphine-3-glucuronide - 75-85% Morphine-6-glucuronide - 5-10% Normorphine - 5% Codeine - Small amount References ``` Stoelting and Hillier 4th ed page 95

Answer 143

A - false; fentanyl has a "lack of direct myocardial depressant effects" (Stoelting 3rd ed. p.94) B - false; all opioids can cause chest wall rigidity C - true; elimination half-time 3.1-6.6hr (longer than morphine)[Stoelting 3rd ed. p.83 Table 3-5] but has a shorter duration of action due to redistribution D - false; causes "suppression of the stress responses to surgery." (Stoelting 3rd ed. p.94) E - false; whilst it may lack direct myocardial depressant effects, it will cause veno and vasodilation which will cause a fall in cardiac output. Large doses are used in cardiac surgery (for example, the high dose group in this study [1] was 50 mcg/kg.) Large doses of fentanyl can be used without causing cardiovascular depression. In contrast, pethidine cannot be used in high doses because of marked cardiovascular toxicity. High dose fentanyl, and indeed high doses of all potent opioids (eg remifentanil) cause muscle rigidity. Comments from Bulletin Board Feb 06 From Stoelting 3rd ed p94 (under Fentanyl: Clinical Uses): "Large doses of fentanyl, 50 to 150 mcg/kg IV, have been used alone to produce surgical anesthesia. Large doses of fentanyl as the sole anesthetic have the advantage of stable hemodynamics due principally to the: (a) lack of direct myocardial depressant effects, (b) absence of histamine release, and (c) suppression of the stress responses to surgery. Disadvantages of using fentanyl as the sole anesthetic include (a) failure to prevent sympathetic nervous system responses to painful surgical stimulation at any dose, especially in patients with good left ventricular function, (b) possible patient awareness, and (c) postoperative depression of ventilation" It just seems strange to me, but do (c) from the first list and (a) from the second list contradictory? Aren't the stress responses sympathetically mediated? Is there any way to resolve this that anyone else can see? Responses (in order of posting): C) From the table in Stoelting (4th Ed) The elimination half time is 3.3 + hours, making C the most correct. It also has a comment about the cardiac output dropping in the text. C,D and E are all correct. i don't know how you would decide which is the most correct D Correct - The sort of dose that it's talking about here (say 3500 micrograms for a 70kg patient) is the sort of dose given in cardiac, which is enough to abolish the stress response to intubation at least. D Incorrect - Stoelting does say that 50-150ug/kg is enough to supress the stress response. So D is not correct. E incorrect - these doses are likely to cause bradycardia and if heart rate falls significantly then so will cardiac output Seriously, how many quotes do we need to state the obvious: of course fentanyl RELIEVES stress response, it does so even in boluses of 10-20 mcg... it just doesn't obliterate it. It WILL decrease sympathetic tone and therefore WILL affect either heart rate, contractility, or both, and as such, cardiac output most likely, will decrease (NB: demand decreased, pump function decreased!). So, directly or indirectly, it will affect cardiac output. The only correct answer in all of these situations is that its elimination half life is > 3 hours!

Answer 144

Option B is the best answer See Katzung. (More information than this would be useful, eg edition & page no, relevant quote etc -KB) Camu, F Pharmacology of systemic analgesics. Best Practice and Research Clinical Anaesthesiology 16:4 475-488 2002 Hepatic metabolism of opioids may produce pharmacologically active metabolites. M6G is 20-40 times more potent than morphine. M6G excretion by the kidney is directly related to calculated creatinine clearance. In patients with impaired renal function, M6G may accumulate in blood and CSF,

Answer 145

Morphine causes miosis not mydriasis; answer is therefore B Can morphine cause seizures? Answer could also be A as no EEG evidence of seizure activity with morphine. Seizure activity has been described following rapid iv admin of fentanyl, sufentanil and alfentanil - again no EEG changes with fentanyl, but may be a form of myoclonus (4th Edition of Stoelting P99 & 108) I agree - Stoelting says that "clonic skeletal muscle activity resembling grand mal seizure" has been observed, with no EEG changes. Also, that morphine causes miosis (due to stimulation of the Edinger-Westphal nucleus in the brainstem), but that severe respiratory depression and "profound arterial hypoxaemia can still result in mydriasis" MIMS: "Seizures. High doses of morphine may cause seizures; therefore, patients with known seizure disorders should be carefully observed, especially if doses are increased in response to tolerance to the drug." - Morphine tartrate injection "Morphine may lower the seizure threshold in patients with a history of epilepsy." - MS contin "A potentially lethal interaction between cimetidine and morphine, in which the patient exhibited apnoea, a significantly reduced respiratory rate and suffered a grand mal seizure, has been reported. Administration of naloxone increased the respiratory rate; however, confusion, disorientation, generalised twitching and periods of apnoea persisted for 80 hours." - morphine sulphate injection How many percent of patients with drug related seizures get an EEG? And how many un-substantiated case reports do we need to believe that it does cause seizures? "and profound arterial hypoxaemia can still result in mydriasis"... how's that counted as an effect of morphine? It's like saying metaraminol causes tachycardia because we give it with atropine... Morphine as a cause of mydriasis following "profound arterial hypoxaemia"? Sounds fairly close to brain death to me! Following that logic, many drugs used in anaesthesia (iv and volatile agents, muscle relaxants, opioids) should have mydriasis listed as a potential side effect with the proviso "BUT ONLY IF YOUR ANAESTHETIST IS A DINGBAT AND FORGETS ABOUT OXYGENATION"... -- hahaha lovin' it; by the way, sasada/smith on morphine:"seizures and muscular rigidity may occur with the use of high dose morphine" Bingo. Never thought I would get a laugh during last minute cramming - but this cracked me up! While you are confirming absent heart/breath sounds and no pulses, flip the lids and check out the fixed dilated pupils! References Stoelting, Ed 4, page 99

Answer 146

A. Supraspinal Effect - false - not for a peripheral nerve block or in fact any block see (Steolting 4th ed. p.242) B. Spinal effect - false - not for a peripheral nerve block C. Effect on primary afferent nerves at the site - True? by elimination of the others D. Clonidine has no effect in peripheral nerve blocks - false see (Steolting 4th ed. p.242) E. Can cause neurotoxicity - false see Gordh A - "activation of post synaptic α2 receptors in the substantial gelatinosa of the spinal cords the presumed mechanism by which clonidine produces analgesia" (Steolting 4th ed. p.241) D - "addition of 0.5mg/kg clonidine to 1% mepivacaine-containing solution prolongs the duration of brachial plexus block performed via the axially approach." (Steolting 4th ed. p.242) E - :"Additives to Local Anesthetics for Peripheral Nerve Blockade", Brummet/Williams, International Anesthesiology Clinics, Vol 4,4, pp104-116.)" "Clonidine is not neurotoxic" Anders Tamsen , Torsten Gordh - The Lancet, Volume 324, Issue 8407, Page 876, 13 October 1984) always nice when the title includes the conclusion! & (GORDH T ]r, POST C, OLSSON Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine, and a substance P-antagonist. Light and electron microscopic observations after chronic intrathecal administration. Anesth Analg 1986;65:1303-11.) F - "Clonidine has comparable effects on spontaneous sympathetic activity and afferent A delta and C-fiber-mediated somatosympathetic reflexes in dogs." (Wang C, Knowles MG, Chakrabarti MK, Whitwam JG. Anesthesiology. 1994 Sep;81(3):710-7.) NYSORA Textbook of Regional Anesthesia suggests: C - ?True, Clonidine inhibits "...action potentials of C fibers greater then A-alpha fibers in rat sciatic nerve" (Chapter 9, Alpha2 Agonists & Clonidine) However these are possibly efferent pain fibres and not afferent as the option above says F - ?False; "Inhibits A-delta/C fibres" could possibly be incorrect (inhibits C and A-alpha fibres - does this imply not A-delta fibres? Not sure.) Thus "none of the above" may actually be the correct answer for this question.

Answer 147

A. Oxycodone - metabolised to α and β oxycodol and then oxymorphone - clearly very active B. Morphine - hepatic metabolism to morphine-3-gluconuride, morphine-6-gluconuride (active) and normorphine C. Pethidine - n-methylation to norpethidine (50%potency of pethidine) and hydrolysis to pethidinic acid. D. Methadone - undergoes extensive biotransformation in the liver primarily to two inactive metabolites, 2-ethylidene-1.5-dimethyl-3.3diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), through N-demethylation and cyclization. E. Codeine. - extensively metabolised in the liver: 10-20% to codeine-6-glucuronide; 10-20% to norcodeine; 5-15% to morphine (active)

Answer 148

C- false: poor oral bioavailability - effective at antagaonism at GI mu-receptors - this is the basis of Targin's purported prevention of opioid constipation. E - definitely true, especially with high dose opioid or long acting opioids Comment - My understanding was that Naloxone is well absorbed, but has poor bioavailability due to first pass. So if the answer is "well absorbed orally" then this isn't incorrect - Not sure I get the concept of naloxone causing refractory respiratory depression. It is used to treat respiratory depression, which may persist despite a single dose of naloxone...

Answer 149

Buprenorphine: A - Transdermal is used as an effect acute pain stategy - not so much - slow onset, difficult to titrate as half life of 96 hours Aa - option A may have read "has been used in the treatment of acute pain - yes, but not transdermally B - Plasma concentration rises rapidly when injected IV - by definition yes - this applies to everything that is injected IV C - Maybe an option to do with its pKa - it definitely has a pka D - semisynthetic derivative of thebaine - it is derrived from thebaine, but stoelting 4th ed page 119 makes no mention of it being semisynthetic. - Dr Wiki describes it as semi-synthetic[1]

Answer 150

Which is most true regarding Pethidine: A Pethidine affects serotonin reuptake - true B Pethidine causes less nausea and vomiting than morphine - false in fact it causes more nausea[1]

Answer 151

Naltrexone: A - Partial mu antagonist - false - highly effective antagonist (Stoelting 4th ed page 121) B - Reverses the effect of a heroin o/d for 72 hours - false - 24 hours (Stoelting 4th ed page 121) C - One isomer only - false, although only one may be active (this is true of naloxone) D - absorbed well across small intestine into portal vein - true - 96% absorbed, extensive 1st pass metabolism - bioavailability 5-40% E - Is only effective for the treatment of opioid addiction. - false, useful in alcoholism and bizarrely kleptomania![1] "Naltrexone hydrochloride is rapidly and almost completely (about 96%) absorbed from the GI tract following oral administration, but the drug undergoes extensive first-pass metabolism in the liver. Only 5-40% of an orally administered dose reaches systemic circulation unchanged. Considerable interindividual variation in absorption of the drug during the first 24 hours after a single dose has been reported. The bioavailability of naltrexone hydrochloride tablets is reportedly similar to that of an oral solution of the drug (not commercially available in the US).

Answer 152

Decreased effect of a dose of opioid in a chronic narcotic abuser would be best described as: A. Tolerance - true - hyporeactivity due to chronic exposure to a drug e.g. alochol, opioids & barbiturates. Cross tolerance may develop between drugs of different classes that produce similar pharmacodynamic effects (e.g. alcohol and inhaled anesthetics. The most important mechanism is neuronal adaptation, aka cellular tolerance. Other mechanisms of tolerance may include: hepatic enxzyme induction depletion of neurotransmitters caused by sustained stimulation. If mediated by antibody formation it is referrec to as immunity. B. Tachyphylaxis - false - this is decreased sensitivity that develops acutely within only a few doses of a drug (e.g. thiopental C. Addiction - false - psychological compulsion to seek reward (seek effect of drug)(may be associated with physical withdrawl syndromes as a result of physical dependance)

Answer 153

P&H 144 A- F - longer, 14-21 hrs and accumulates in RF B- T - accumulation leads to hallucinations and grand mal seizures C - F - half the analgesic effect of pethidine D - F E - F - norpethidine, pethidinic acid and small amounts unchanged pethidine excreted unchanged in urine

Answer 154

P&H 144 A- F - longer, 14-21 hrs and accumulates in RF B- T - accumulation leads to hallucinations and grand mal seizures C - F - half the analgesic effect of pethidine D - F E - F - norpethidine, pethidinic acid and small amounts unchanged pethidine excreted unchanged in urine

Answer 155

``` A- false - reduced B- T - P&H 146 C- ? D- false - liver metabolism E- F - metabolism by N-demethylation to noralfentanil ```

Answer 156

Henbane is a plant that has anti-cholinergic alkaloids e.g. scopolamine. Maybe option A really said "thebaine" (which is a natural opioid alkaloid) BUT of course henbane could have been used to exploit the verbal similarity between 'henbane' and 'thebaine' Thebaine was an option in OP32, another recent MCQ about buprenorphine P&H p149: A - ? B - ? - has high PB , would guess it also has high lipid solubility ? C - T - high affinity D - F - high first pass, hence not given orally E - F - more potent than morphine

Answer 157

4 hours = 240 mins -- Graph http://www.kerrybrandis.com/wiki/mcqwiki/index.php?title=OP40

Answer 158

A - F - no... B - F - Morphine = M3G , Tramadol = o-desmethyltramadol , hydromorphone but INACTIVE = H3G C - T - all CYP2D6 to active metabolites D - F - no seizure activity for endone

Answer 159

Glycopyrrolate is a synthetic anticholinergic which contains mandelic acid contrasting with atropine and scopolamine which contain tropic acid. It is a competitive antagonist of acetylcholine at post ganglionic muscarinic receptors. Glycopyrrolate is a quaternary ammonium compound. It is poorly lipid soluble and has minimal central effects as it does not readily cross the blood brain barrier. (as per its charged structure)

Answer 160

Not quaternary Crosses blood-brain barrier so can cause central effects (such as amnesia, anti-emesis, confusion esp in the elderly) It can cause mydrasis also can't it??? being anti muscarinic and all... This may be the difference between may cause and will cause.... It may cause confusion It will cause mydriasis Really? If I attempt to topically administer hyoscine by pouring it on the examiner, do you think he will get mydriasis or confused?

Answer 161

Scopolamine (otherwise known as hyoscine) derived from belladona plant laevorotatory (active) isomer is a tertiary amine and thus crosses the blood brain barrier provided as racemic mixture but only L-hyoscine is active (Peck +Hill p289 2nd ed)

Answer 162

True - "The resulting relaxation of bronchial smooth muscle decreases airway resistance and increases dead space" (Stoelting 3rd ed. p243) [ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13242494&dopt=Abstract ] Dissenting comment: Bronchodilation of any cause will increase anatomical deadspace, but I can't see how it would increase alveolar deadspace. i agree ,even tachycardia can potentially result in increasing cardiac output ,this will decrease alveolar dead space. A recent study which suggests this might be the case.. [1]

Answer 163

Glycopyrrolate: synthetic, with mandelic rather than tropic acid is quaternary ammonium compound so doesnt cross BBB, thus very unlikely to cause direct CNS side effects. Scopolamine is the anti-cholinergic drug most likely to cause confusion, particularly in elderly, because it crosses the BBB more easily. Mar09 Version Atropine & glycopyrrolate: A. Both are naturally occurring B. Both can cause initial bradycardia after IV administration C. Glycopyrrolate increases oxidative metabolism Answer: B: Page 268 Stoelting 4Ed: "...similar heart rate slowing in response to the administration of glycopyrrolate..."

Answer 164

Answer - C: hyperthermia "Thermoregulatory sweating is suppressed by atropine. In adults, body temperature is elevated by this effect only if large doses are administered, but in infants and children even ordinary doses may cause 'atropine fever'". Katzung, Basic and Clinical Pharmacology. 5th Ed. 1992 "The increase in body temperature largely reflects inhibition of sweating by anticholinergic drugs, emphasizing that innervation of sweat glands is by sympathetic nervous system nerves that release acetylcholine as the neurotransmitter. Small children are particularly vulnerable to drug-induced increases in body temperature, with "atropine fever" occuring occasionally in this age group after administration of even a therapeutic dose of anticholinergic drug." Stoelting, Pharmacology and Physiology in Anesthetic Practice. 3rd Ed. 1999 p245

Answer 165

AH07 [Apr07] The nerve agent sarin: A. should not be treated with anticholinesterase if there is tachycardia - TRUE; sarin is an organophosphate compound with anticholinesterase effect. Why should you treat with another anticholinesterase?? Suggest that this answer is remembered incorrectly B. something about pyridostigmine - pyridostigmine, like neostigmine is an anticholinesterase. Unlikely to be true C. symptoms can include fasciculations and paralysis - TRUE D. something about pralidoxime unblocking the receptor (a red herring teaser) - MAYBE Pralidoxime "effectively regenerates ChE after poisoning by nerve agents. It acts by breaking the nerve agent–ChE bond, thereby displacing the nerve agent. Displacement of nerve agents by PAM occurs only if the enzyme has not yet aged" From The Bioterrorism Handbook accessed through Access Medicine website E. ? From Wikepedia it looks like Pralidoxime (OPTION D) may be the correct answer: Mechanism of action Organophosphates inhibit cholinesterase by phosphorylation of the enzyme. Pralidoxime reactivates the cholinesterase by removing the phosphoryl group that is bound to the ester group. In this reaction both the organophosphate and the pralidoxime are mutually inactivated. These products undergo rapid metabolism, leading to the removal of the organophosphate. Paradoxically, pralidoxime in doses above the optimal dose is itself an inhibitor of cholinesterase, and therefore can also produce the same symptoms as the toxins themselves. However, unlike organophosphates, pralidoxime binding is reversible, hence some protection is extended to the cholinesterase enzyme, this although has a negligible effect on the pharmacology of pralidoxime COMMMENT: Am I missing something here? Sarin is an anticholinesterase (an organophosphate). Hence: A - should not be treated with anticholinesterase.....TRUE!!! (regardless of HR; why exacerbate the problem?!) B - who knows C - symptoms can include fasciculations and paralysis....TRUE!!! D - depends on what the actual question was, but pralidoxime would be an excellent treatment - better early. Pralidoxime is a 'cholinesterase reactivator', and all of the above comments seem correct enough. The actual answers may have included "E - all of the above", which therefore may have been the right answer. Re: Option B - obviously hard to know what the option actually said, but pyridostigmine has been used as prophylaxis when risk of exposure to sarin is high eg during Gulf War 1 - pyridostigmine (or other -stigmines) occupy cholinesterase and prevent sarin from binding and doing its thing. Ref: Toxicology Volume 134, Issues 2-3, p169-178 Additional comment: The option D provided says something about pralidoxime unblocking the receptor. Pralidoxime reactivates cholinesterase, thus reducing ACh. AChE is an enzyme. Is 'receptor' simply thrown in to mislead us?

Answer 166

Answer A false - quaternary ammonium - doesn't easily cross BBB B false - quaternary ammonium - doesn't easily cross BBB C True - lipid soluble teritary amine - crosses BBB Stoelting suggests slow IV 0.4mg/kg as a diagnostic / therapeutic measure D false - used in cases of anti cholinesterase toxicity and therefore excess of ACh rather than lack of ACh activity. - E false - likely to have been the cause. Hyoscine (aka scopolamine) is the other. --- References Stoelting 4th ed p 273 Mnemonics Physostigmine fixes atropine overdose.

Answer 167

``` A ?false (midazolam water soluble in ampoule [but lipid soluble at physiological pH - they all must be to have any central effects]) B false - some metabolised in liver (remember to beware abolutes such as "all" and "never") C false anterograde amnesia "Stored information (retrograde amnesia) is not altered by benzodiazepines" (Stoelting 3rd ed. p.126) D false(hence slower onset of Lorazepam into CNS) E false - they actually facilitate GABA binding at the GABAa receptor, increasing the frequency of chloride channel opening (Stoelting 3rd ed. p.127) F ?True - They have a "greater magin of safety after an overdose, and elicit fewer and less serious drug interactions" compared to barbiturates. (Stoelting 3rd ed. p.126) This is relative, not absolute... ```

Answer 168

A - False. Old advice. Now considered risk is greater from rebound depression. Also unknown whether 2 weeks would be sufficient to restore MAO levels from irreversible block. B- False. Due to pethidine's inhibition of 5HT uptake, causes excitatory phenomena and hypertension with MAOIs. C- False, ephedrine and metaraminol activity enhanced. D- True. MAO in gut metabolises ingested bioactive amines such as tyramine which would otherwise cause hypertension via indirect sympathomimetic effects. E- False, these are TCAs. MAOIs include phenelzine, moclobamide and selegiline. I think B is true as well Type II response with pethidine Ref : STOELTING p407

Answer 169

Answers: A. False: usually occurs at 2 weeks; can be on 1st dose. (per UpToDate) B. False: mortality is 10-20%. (per UpToDate) C. Can be treated with dantrolene. D. True. E. True. NMS is a life threatening disorder (with 10% mortality) which is characterised by altered mental status, rigidity, fever and autonomic instability in response to the use of a neuroleptic agent. It usually occurs within the first two weeks of neuroleptic use but can be precipitated by a rapid rise in dose, parenteral therapy, or an acute illness. It can also occur on withdrawal or reduction of L-Dopa or Dopamine agonist therapy in patients with Parkinson's Disease. Excessive rapid postsynaptic dopamine receptor blockade is thought to be responsible. Investigations may reveal elevated CK (from muscle damage)and leukocytosis (acute stress). Treatment involves stopping the neuroleptic agent and immediate supportive care. Extrapyramidal symptoms can be treated with antiparkinsonian medications and muscle relaxation achieved with Diazepam. Dantrolene (a direct-acting skeletal muscle relaxant), and bromocriptine (a dopamine agonist) are also helpful. References Basic and Clinical Pharmacology (9th ed) 2004

Answer 170

MAO enzymes come in two forms MAO-A and MAO-B which are distributed around the body. They are responsible for the metabolisation of neurotrnasmitters including serotonin, NAdr, Adr and dopamine thus MAO enzyme inhibition increases the synaptic concentrations of these neurotransmitters resulting in antidepressive effects. Inhibition of GIT MAO-A prevents the sympathomimetic tyramine (contained in aged cheeses and other foods) from being metabolized and thus allows it to be absorbed into circulation resulting in a hypertensive crisis called the "Cheese Reaction".

Answer 171

Answer - A (I think) "Benzodiazepines are drugs that exert, in slightly varying degrees, five principle pharmacologic effects: sedation, anxiolysis, anticonvulsant actions, spinal cord-mediated skeletal muscle relaxation, and anterograde amnesia" (Stoelting 3rd ed. p.126) Note: I was always taught BZD all have antanalgesic properties at low dose. I have tried to find a reliable reference for this in one of the recommended text books...and bugger me they don't seem to support the thought. Sasada and Smith even say Diazepam has "anticonvulsant and analgesic properties..". I feel so strongly about it that I still might go for antanalgesic. I refuse to be taught new things damn them all!!! Option D allows me the grace to bow out with some dignity...unless I wear my pyjamas to the exam...just like in my dreams!!! Stoelting 4e p.142: "...the analgesic actions of opioids are reduced by bzd. Indeed, antagonism of bzd effects with flumazenil results in enhanced analgesic effects of opioids." Therefore I am torn between A and B. Counterview - Midazolam and diazepam have kappa opioid activity in vitro, and this may explain their antinociceptive effects when administered neuroaxially (Sasada and Smith) - indeed a consultant I have worked with sometimes uses midazolam via an intrathecal catheter (as part of a cocktail of several agents) for analgesia in difficult to treat pain in palliative patients - therefore C may be correct. Counter-counterview - a 1997 study of patients who received benzos pre-op and morphine post-op found that benzos made post-op pain worse, and that giving flumazenil made pain better. The authors concluded that benzos antagonise the analgesic effects of morphine - whether that means they are antanalgesic in their own right or that they interfere with opioids I don't know. Pain 1997 71:25-9 Note that this question is from as early as 2000 and the below study is from 2008. "Intrathecal midazolam binds with gamma aminobutyric acid-A receptors in the spinal cord leading to an analgesic effect." "Based on the limited data available, intrathecal midazolam appears to improve perioperative analgesia and reduce nausea and vomiting during caesarean delivery." - Use of intrathecal midazolam to improve perioperative analgesia: a meta-analysis. Anaesthesia and intensive care 2008;36(3):365-73. [1] Personally I would be inclined towards C; the term "antanalgesic" is extremely dated and the only reference I could find in the literature was in the BJA, in 1963. Digging through Medline with the terms "benzodiazepine" and "pain", there are references to benzodiazepines being "pain modulators" and reducing the total doses of opioids needed. Alt approach 1. Have you ever administered BZD for pain? 2. Have you ever NOT administered BZD because you are concerned you may precipitate pain? 3. What does Stoelting say? therefore Answer is A I think.

Answer 172

``` Answer: Diazepam Elimination Half lifes: Diazepam 20-80 hours Oxazepam 10-20 hours Temazepam 10-40 hours Midazolam 2-4 hours Lorazepam 10-20 hours Flunitrazepam 20-30 hours References ``` Basic and Clinical Pharmacology, Katzung 9th Edition Pharmacology Rang and Dale, 5th Edition

Answer 173

fluoxetine is an SSRI. therefore they selectively inhibit the neuronal re-uptake of 5-HT (=serotonin). References Pharmacology for anaesthesia and Intensive care Peck, TE. Williams, M.

Answer 174

Alternative answers to option D would seem most correct as it should still work in the presence of hypoxia and hypercarbia (if these are secondary to respiratory depression caused by decreased respiratory drive) AND it is quite reliable in reversing the effects of BZDs and as its duration of action is "30-60 mins" (Stoelting 3rd ed. p 138) compared with much longer durations of actions with longer acting BZDs, so respiratory depression may still occur. In their absence suggest that B is the next best answer as it has "weak intrinsic agonist activity" Stoeting 3rd ed. p.138. [Stoelting] 4th p152 Exclusive benxodiazepine antagonist with a high affinity for benzodiazepine receptors where it exerts minimal agonist activity. It prevents or reverses all the agonist effects of benzodiazepines. Duration of action - 30 -60 mins. Mims states: Active. Flumazenil. Inactive. Disodium edetate, acetic acid, sodium chloride, sodium hydroxide in water for injections adjusted to pH 4.0. Also, flumazenil DOES have some agonist activity...according to other texts It also has some inverse agonist activity to explain precipitating seizures in some people... In support of preceeding statements, Peck & Williams says that flumazenil acts as: Competitive BZ antagonist. Some agonist activity. Inverse agonist activity. (See also Goodman & Gillman). Also, note the drug monograph states "While flumazenil reverses benzodiazepine-induced sedation, it has no proven effectiveness in the treatment of hypoventilation induced by benzodiazepines" From Goodman & Gilman "...effects resembling those of inverse agonists sometimes have been detected at low doses" "...slight benzodiazepine-like effects often have been evident at high doses" I think to then go all out and call it an "inverse agonist" would be less correct than the alternative options for D.

Answer 175

STOELTING: Diazepam primarily metabolised by hepatic microsomal enzymes involving an oxidative pwy of D-methylation. Two principal metabolites are oxazepam and desmethyldiazepam and a lesser amount is metabolised to temazepam. T1/2 more like 20-100 hrs

Answer 176

ALL ANSWERS WRONG A - Like haloperidol, it is a butyrophenone (and NOT a phenothiazine) B - "are less effective against anxiety" (Stoelting 3rd Ed. p.373) C - Very effective anti-emetic acts on dopamine receptors in CTZ D - Hypotension with larger doses E - "Alpha rhythm persists on the EEG" (Stoelting 3rd ed. pp.373-374) Dissenting comment: "Droperidol is a butyrophenone, a fluorinated derivative of the phenothiazines". Miller, Sixth edition, page 359. Answer = A Additional Comment: Miller (6th edn, p.360) states that "The EEG....shows some reduction in frequency, with occasional slowing". Stoelting states that alpha rhythm PERSISTS (as quoted above), but does not say that the frequency is constant. Also - regarding option A: A substitution is not a whole rearrangement of the molecule. Sure, the butyrophenones may be derivatives of phenothiazines, but check out the structure of basic phenothiazines and then compare the structure of droperidol. More than a mere substitution if you ask me!....Option A = WRONG I'm going for option E According to Lange Clinical Anesthesiology 4e, Chapter 8 Droperidol has mild alpha-adrenergic blocking properties that reduce MAP through vasodilation The EEG is not significantly changed So it either slows the alpha rhythm, or is related to phenothiazines in an intimate and important way. References Butyrophenones Butyrophenones & related drugs (diagram)

Answer 177

Moclobemide is a reversible inhibitor of monoamine oxidase A A single 300mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition on any of the neurotransmitters occurs. PS11 A - TRUE B - TRUE - prevents breakdown of tyramine --> hypertensive crisis C - FALSE - causes hyperthermia Typo above for B? It doesn't interact with tyramine to cause hypertension, it does so and prevents hypertension.

Answer 178

PS11b A - FALSE - type A (RIMA) B - TRUE - "dietary tyramine is destroyed by MAO in the gut wall and liver before reaching the systemic circulation. When MAO is inhibited, this is prevented..." Rang, Dale and Ritter 5th Ed p178

Answer 179

The main metabolic pathway for diazepam is diazepam -> desmethyldiazepam (active with long half-life) -> oxazepam (active) -> glucuronide conjugate (inactive, excreted). There is also a minor pathway diazepam -> temazepam (active, short half-life) -> glucuronide conjugate (inactive, excreted). Lorazepam is NOT a metabolite of diazepam.

Answer 180

A - wrong; GABA A receptor B - wrong; increases frequency of opening C - wrong; barbiturates and BZDs have separate binding sites D - correct; cimetidine inhibits cytochrome p450 E - wrong; increases chloride conductance F - wrong; acts at the alpha subunit Stoelting p142 The elimination half time is increased in elderly reflecting age related decreases in hepatic blood flow and possibly enzyme activity Answering the question: Midazolam: 1. Not affected by H2 anatagonists (incl cimetidine). 2. Acts on GABA-A 3. Increases freq of opening of Cl channel (barbiturates increase duration) 4. Interacts with alpha subunit. 5. Uses different receptor site than barbiturates. So, they all seem wrong!!! BUT Cimetidine inhibits cytochrome p450 enzymes. Midaz undergoes phase 1 metabolism in the liver. Poss prolongs action of Midaz. Agree-Metab is decreased by cimetidine. See Goodman and Gilman. Chap16: "Cimetidine and oral contraceptives inhibit N-dealkylation and 3-hydroxylation of benzodiazepines. Ethanol, isoniazid, and phenytoin are less effective in this regard. These reactions usually are reduced to a greater extent in elderly patients and in patients with chronic liver disease than are those involving conjugation." Stoelting 4e p.144: "Metabolism of midaz is slowed in the presence of drugs (cimetidine, erythromycin, Ca channel blockers, antifungal drugs) that inhibit cytochrome P450 enzymes..." References

Answer 181

Best Answer is D - all depend on hepatic metabolism "Midazolam is rapidly metabolised ... to active and inactive metabolites. The principal metabolite of midazolam , 1-hydroxymidazolam, has approximately half the activity of the parent compound." This metabolite is then glucuronated and has activity in high concentrations. " The other active metabolite 4-hydoxymidazolam, ... not present in detectable concentrations in plasma following IV administration" TEMAZEPAM, which is one of the BDZs, is 80% excreted in urine unchanged (P&H). But S&S says 80% of orally administered dose appears in urine as inactive conjugates. Confusing argghhhh. Lange Clin. Anesth. 4e. Ch8: Benzos rely on the liver for metabolism into soluble glucuronide products Goodman & Gilman. Ch 17: Temazepam's preferred pathway for metabolism is conjugation because it is faster than conversion to oxazepam References Stoelting "Pharmacology and physiology in Anaesthetic practice" 4th ed, p144

Answer 182

A: False. Sedation is one of the most common side effects. B. True: Tricyclic antidepressants are closely related in structure to phenothiazines. They differ from phenothiazines due to the incorporation of an extra atom into the central ring. C. False. Tricyclic cause anticholinergic effects such as dry mouth, blurred vision, constipation and urinary retention. D. False. Mechanism of action is block the amine (noradrenalinse or serotonin) reuptake pumps which terminate amine neurotransmission. E. False. Mechanism of action is to block uptake of amines by nerve terminals hence increasing amine levels. References Basic and clinical pharmacology, Katzung 9th Edition Pharmacology, Rang and Dale 5th Edition Drugs in Anaesthesia and Intensive Care, Sasada and Smith, 3rd edition

Answer 183

"The bioavailability after oral admministration is 100 percent, and 90 percent after rectal administration." ([1]) "Based on areas under the oral versus intravenous plasma concentration curve, bioavailability of diazepam averaged 97%." [2] Diazepam is absorbed rapidly following oral administration; with peak plasma concentrations generally being achieved within 1.0 hour (range 0.08 to 2.5 hours). (Greenblatt,1988). The absorption rate is slowed by food and antacids. Absorption is almost complete with bioavailability close to 1.0. (Mandelli et al., 1978). Goodman & Gilman Ch. 17 The benzodiazepines are absorbed completely

Answer 184

All of the above. From Stoelting pages 135 - 136

Answer 185

A - False - open and ionised under pH4 B - True C - False - has twice the affinity References Sassada & Smith 3rd ed Stoelting 4th p142

Answer 186

A - false - Ephedrine has indirect and direct sympathomimetic actions - potential to cause hypertensive crisis B - false - Tramadol has serotenergic actions - potential to cause serotonin syndrome C - false - Etomidate is associated with epileptiform EEG ? bad - used for ECT in patients on MAOI D - True - Phenyleprhine has direct actions only therefore "no" risk of a hypertensive crisis E - false - Metaraminol has indirect and direct sympathomimetic actions - potential to cause hypertensive crisis ?F - false - Pethidine - potential to cause serotonin syndrome Smith & Sasada 4E 2011 p 285: "Excessive hypertension may occur when phenylephrine is administered to patients... receiving monoamine oxidase inhibitors." I would argue that etomidate is probably the least problematic thus C.

Answer 187

A - F - Selegiline is a MAO B for parkinsons B - F - irreversibly C - F D - F - Mocolobeminde is a selective reversible inhibitor of MAO A Wikipedia: "Selegiline is a substituted phenethylamine used for the treatment of early-stage Parkinson's disease, depression and dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor. However, in larger doses it loses its specificity and also inhibits MAO-A. Dietary restrictions are common for MAOI treatments, but special dietary restrictions for lower doses have been found to be unnecessary, and dietary restrictions appear to be unnecessary at standard doses when selegiline is taken as Emsam, the transdermal patch form, as no adverse events due to diet have ever been reported with Emsam." The main use of selegiline is in the treatment of Parkinson's disease. It can be used on its own or in a combination with another agent, most often L-DOPA. For newly diagnosed Parkinson's patients, some claim that selegiline slows the progression of the disease, although this claim has not been widely accepted and the methodology has been rejected by the Food and Drug Administration (FDA)." "Selegiline delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months after diagnosis, which is beneficial despite not being definitive evidence of neuroprotection. The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the motor complications of levodopa therapy." Wikipedia Moclobemide is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety.

Answer 188

``` OTHER version A - T B - F C - T D - F ``` Wikipedia: "Selegiline is a substituted phenethylamine used for the treatment of early-stage Parkinson's disease, depression and dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor. However, in larger doses it loses its specificity and also inhibits MAO-A. Dietary restrictions are common for MAOI treatments, but special dietary restrictions for lower doses have been found to be unnecessary, and dietary restrictions appear to be unnecessary at standard doses when selegiline is taken as Emsam, the transdermal patch form, as no adverse events due to diet have ever been reported with Emsam." The main use of selegiline is in the treatment of Parkinson's disease. It can be used on its own or in a combination with another agent, most often L-DOPA. For newly diagnosed Parkinson's patients, some claim that selegiline slows the progression of the disease, although this claim has not been widely accepted and the methodology has been rejected by the Food and Drug Administration (FDA)." "Selegiline delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months after diagnosis, which is beneficial despite not being definitive evidence of neuroprotection. The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the motor complications of levodopa therapy." Wikipedia Moclobemide is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety.

Answer 189

CD01 [Mar96] [Mar98] [Mar99] [Jul01] Milrinone: A. Decreases pulmonary vascular resistance - true; milrinone is a vasodilator. "In the peripheral vasculature, the result is dilation of both resistance and capacitance vessels, leading to reduction of both afterload and preload." Goodman and Gilman Ch 33 B. Increases systemic vascular resistance - false; see above C. Is poorly absorbed when given orally - false; Milrinone has been investigated as an oral inotrope but was found to cause an increase in mortality. "Several oral inotropic agents have been developed and subsequently investigated in clinical trials. Some of these agents, particularly those of the PDE inhibitor class, have vasodilator actions in addition to their inotropic effects. While improvement in symptoms, functional status, and hemodynamic profile have been reported, the impact of these drugs on mortality during longer-term therapy has been disappointing. The dopaminergic agonist ibopamine, PDE inhibitors milrinone, inamrinone, and vesnarinone, and the benzimidazoline PDE inhibitor with calcium-sensitizing properties, pimobendan, have been associated with increased mortality" Goodman and Gilman Ch 33 D. Chronic use causes thrombocytopaenia - false; "Clinically significant thrombocytopenia occurs in 10% of patients receiving inamrinone but is rare with milrinone." Goodman and Gilman Ch 33

Answer 190

CD01c [Feb00] Milrinone Was this a pick the false answer question?? A. Is structurally related to thyroid hormone - False; milrinone is a bipyridine. I don't think it's related to thyroid hormone although I cannot see any books stating this categorically. B. Is arrhythmogenic - true; "Milrinone appears less likely to cause bone marrow and liver toxicity than inamrinone, but it does cause arrhythmias." Katzung Ch 13 C. Has its effects via cAMP mediated increase in intracellular Ca2+ - true; "The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum. They also have an important vasodilating effect. Inhibition of phosphodiesterase results in an increase in cAMP and the increase in contractility and vasodilation" Katzung Ch 13 D. Increases myocardial oxygen consumption - maybe true; milrinone acts to increase cardiac contractility and therefore O2 demand, but it also decreases preload and afterload. "The O2 consumption by the heart is determined primarily by the intramyocardial tension, the contractile state of the myocardium, and the heart rate." Ganong Ch 29 Regarding option D in CD01c: MIMS: "Use of inotropic agents such as milrinone during the acute phases of a myocardial infarction may lead to an undesirable increase in myocardial oxygen consumption (MVO2). Milrinone has not increased MVO2 in patients with chronic heart failure, however, until further clinical experience with this class of drugs is gained, Primacor is not recommended during the acute phase of post-myocardial infarction"

Answer 191

CD01c [Feb00] Milrinone Was this a pick the false answer question?? A. Is structurally related to thyroid hormone - False; milrinone is a bipyridine. I don't think it's related to thyroid hormone although I cannot see any books stating this categorically. B. Is arrhythmogenic - true; "Milrinone appears less likely to cause bone marrow and liver toxicity than inamrinone, but it does cause arrhythmias." Katzung Ch 13 C. Has its effects via cAMP mediated increase in intracellular Ca2+ - true; "The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum. They also have an important vasodilating effect. Inhibition of phosphodiesterase results in an increase in cAMP and the increase in contractility and vasodilation" Katzung Ch 13 D. Increases myocardial oxygen consumption - maybe true; milrinone acts to increase cardiac contractility and therefore O2 demand, but it also decreases preload and afterload. "The O2 consumption by the heart is determined primarily by the intramyocardial tension, the contractile state of the myocardium, and the heart rate." Ganong Ch 29 Regarding option D in CD01c: MIMS: "Use of inotropic agents such as milrinone during the acute phases of a myocardial infarction may lead to an undesirable increase in myocardial oxygen consumption (MVO2). Milrinone has not increased MVO2 in patients with chronic heart failure, however, until further clinical experience with this class of drugs is gained, Primacor is not recommended during the acute phase of post-myocardial infarction"

Answer 192

The best text for this MCQ was Stoelting 3rd edition page 318. Based on this text, A. Correct, converts Hb to Meth-Hb which acts as antidote by converting cyanide to cyanometh-Hb B. Incorrect, Na-Thiosulphate does this: sulfur donor C. Incorrect, incr. cyano-meth-Hb but can give hydroxycobalamine which binds cyanide to form cyanocobalamine. D. Incorrect, converts Hb to Meth-Hb which binds cyanide to form cyanometh-HB E. correct, as reversal of cyanide toxicity should improve the impaired oxidative phosphorlylation I don't agree with E - you are correct in that the treatment of cyanide toxicity will lead to improvements in oxidative phosphorylation, but this is not a direct action of sodium nitrite.

Answer 193

(Stoelting 4th ed, p302-3) A. Ephedrine is resistant to metabolism by MAO in the GIT, but some ephedrine is deaminated by MAO in the liver (synthetic noncatecholamines without a 3-hydroxyl group cannot be metabolised by catechol-o-methyltransferase (COMT) therefore depend on metabolism by MAO. Ephedrine has no hydroxyl group at the 3 position). ... If you are going to talk about structure-activity relationship, Ephedrine has a methyl substitution on the alpha C blocking Oxidation by MAO. Hence A is the most correct answer. Ephedrine is 65% excreted unchanged in urine. "Hepatic metabolism is through oxidative metabolism, demethylation and and aromatic hydroxylation with subsequent conjugation." (Goodman and Gilman, Sasada and Smith p.135) B. False- see above C. False- has both direct and indirect actions D. Best answer Acts via direct and indirect beta AND alpha effects ... Not "The Best Answer" as does not mention alpha effects. E. False- see above

Answer 194

E. True- see above

Answer 195

A. Increases skeletal muscle blood flow (also increases coronary blood flow, but decreases renal and splanchnic blood flows) B. False- see above C. RESISTANT to GIT MAO- not sure whether this means it doesn't happen at all D. True E. False- see above ... ? Best answer is A (assume increase muscle flow).

Answer 196

All true! but only B gives a complete picture.

Answer 197

The principal (?urinary) metabolite of adrenaline is: A. Normetanephrine B. Metanephrine C. 3,4-dihydroxy-mandelic acid D. 3-methoxy, 4-hydroxymandelic acid - true; See Goodman and Gilman Figure 6-6. For those interested in the chemistry, COMT acts at the 3-hydroxy to make it 3-methoxy while hydroxyl group on 4 remains the same. Therefore C is automatically wrong. E. 3-Methoxy 4-hydroxy phenylalanine Actually according to G&G, 3,4-dihydroxymandelic acid (DOMA) is a product of adrenaline metabolism via MAO. MAO converts adrenaline into a short-lived intermediate (DOPGAL) and then aldehyde dehydrogenase converts DOPGAL into 3,4-dihydroxymandelic acid. So C is just an intermediary in the pathway to VMA, rather than a chemistry fail. (Reference: 2) Answer is D For both adrenaline and noradrenaline, the principal urinary metabolite is 3-methoxy, 4-hydroxymandelic acid (otherwise known as vanillylmandelic acid, or VMA). Both MAO and COMT are involved in the pathway. But more important in ceasing activity of adrenaline and noradrenaline is reuptake, mostly at postganglionic sympathetic nerve endings. Also, the lungs clear areound 25% of circulating noradrenaline (but not adrenaline). References Stoelting, 4th ed, p700-701, p296-7 Goodman & Gilman, 12th Edition, Figure 8-7 (accessed online)

Answer 198

Thiazide diuretics: A. Work mainly on PCT - False; Work "principly in the cortical portions of the ascending loops of Henle and to a lesser extent, in the proximal renal tubules and distal renal tubules" (Stoelting 3rd ed. p. 435) B. Not effective if severely sodium depleted C. Action is independent of acid-base balance - True; "The diuretic effect of thiazide diuretics is independent of acid-base balance" (Stoelting 3rd ed. p.435) D. Increase GFR immediately - false; "In general, inhibitors of Na+–Cl– symport (i.e. thiazide diuretics) do not affect RBF and only variably reduce GFR owing to increases in intratubular pressure." Goodman and Gilman Ch 28 E. Decrease BP by decreasing contractility - false; "Thiazide diuretics decrease blood pressure in hypertensive patients by increasing the slope of the renal pressure–natriuresis relationship (Saito and Kimura, 1996), and thiazide diuretics are used widely for the treatment of hypertension either alone or in combination with other antihypertensive drugs" Goodman and Gilman Ch 28. Also "The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. Initially, the drugs decrease extracellular volume by interacting with a thiazide-sensitive Na-Cl cotransporter in the kidney, leading to a fall in cardiac output. However, the hypotensive effect is maintained during long-term therapy because of reduced vascular resistance; cardiac output returns to pretreatment values and extracellular volume returns almost to normal due to compensatory responses such as activation of the renin-angiotensin system. How this occurs is unknown; however, thiazides promote vasodilation in isolated vessels from laboratory animals and humans." Goodman and Gilman Ch 32 F. Cause hypoglycaemia - false; "Thiazide diuretics also decrease glucose tolerance, and latent diabetes mellitus may be unmasked during therapy. The mechanism of the impaired glucose tolerance is not completely understood but appears to involve reduced insulin secretion and alterations in glucose metabolism." Goodman and Gilman Ch 28 G. Interferes with kidney concentrating mechanisms - false; "Since inhibitors of Na+–Cl– symport inhibit transport in the cortical diluting segment, thiazide diuretics attenuate the ability of the kidney to excrete a dilute urine during water diuresis. However, since the DCT is not involved in the mechanism that generates a hypertonic medullary interstitium, thiazide diuretics do not alter the kidney's ability to concentrate urine during hydropenia." Goodman and Gilman Ch 28 H. Causes hypocalcaemia - false; "These adverse effects include extracellular volume depletion, hypotension, hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, and hyperuricemia... Thiazide diuretics, which reduce urinary excretion of Ca2+, sometimes are employed to treat calcium nephrolithiasis and may be useful for the treatment of osteoporosis" Goodman and Gilman Ch 28 I. Used to treat hypercalcaemia - false; see above J. Potentiate hyperglycaemia - true; see above K. Are effective as antihypertensives by decreasing cardiac output - false see above L. Cause hypernatraemia - false; see H. M. Washes out the medullary concentration gradient - false; "the DCT is not involved in the mechanism that generates a hypertonic medullary interstitium" Goodman and Gilman Ch 28 -- Yes, it says that. But the reabsorption of Urea in the collecting duct depends on a relatively concentrated urine, which is now not as concentrated. And that urea is responsible for some of the medullary hypertonicity. (Multiple options remembered so possibly an amalgam of 2 or more questions)

Answer 199

MCQ no.17 on the July 2001 paper: Thiazide diuretics:- A. Increase calcium excretion in the urine. - false B. Decreased efficacy in sodium depletion. - C. Main site of action is the proximal tubule. - false; "The DCT expresses thiazide binding sites and is accepted as the primary site of action of thiazide diuretics; the proximal tubule may represent a secondary site of action." Goodman and Gilman Ch 28 D. Cause equivalent amount of diuresis to frusemide - false; "However, thiazides are only moderately efficacious (i.e., maximum excretion of filtered load of Na+ is only 5%) because approximately 90% of the filtered Na+ load is reabsorbed before reaching the DCT." Goodman and Gilman Ch 28 E. ? Regarding sodium depletion... " In cases of advanced kidney and liver disease, where depletion of sodium and potassium may exist, aggravation can be expected to occur with thiazides" - this implies that they will exaccerbate a low Na+, rather than be ineffective. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849092/pdf/canmedaj00946-0026.pdf

Answer 200

A)Incorrect, "SNP produces direct venous and arterial vasodilation" (Stoelting 3rd ed. p.319). GTN however at low doses up to 2mcg/ kg/ min can preferentially dilate veins over arterioles. B)Incorrect, "In the setting of LVF, SNP decreases SVR, pulmonary vascular resistance" (Stoelting p.319) C)Incorrect, leads to "increased cerebral blood flow and cerebral blood volume" (Stoelting p.319) D is true: "sodium nitroprusside inhibit(s) the spontaneous contractions of the non-pregnant human uterus through a cGMP independent pathway." (P. Hoffmann1, F. Stanke-Labesque2, R. Fanchin3, N. Dilaï1, J.C. Pons1 and J.M. Ayoubi, Effects of L-arginine and sodium nitroprusside on the spontaneous contractility of human non-pregnant uterus) E)Incorrect(very obviously!), see Stoelting p.319. SNP Inhibits HPV leading to red. in Pao2(via incr. shunting) hence requirements for higher Fi02/ PEEP if SNP infusion used. References The best text for answering this question was Stoelting(3rd edition) pg 319, 324 Also A-Z(3rd edition) p527

Answer 201

A - wrong, decreases MAC requirements (Stoelting 3rd ed. p306) B - ?right, causes transient hypertension (Goodman & Gilman) C - ?right clonidine has some (minimal) alpha 1 activity which is postulated to explain the transient increase in BP sometimes seen with iv bolus. D - wrong, see above E - wrong, it is available in a patch formulation (Stoelting 3rd ed. p.305) Best answer is C. "...the transient vasoconstriction is followed by a more prolonged hypotensive response..." (Goodman and Gilman).

Answer 202

Best Answer - A Structurally, cardiac glycosides consist of 2 parts: aglycone (or 'genin')- this is the steroid and the lactone ring glycone - the attached sugar residues Both are required for the drug to be useful clinically. It is said that the the intrinsic cardiac activity resides in the aglycone portion (see below for structure-activity), but that the glycone (sugar) portion is responsible for pharmacokinetic factors (eg uptake into tissues). Digoxin consists of 3 molecules of beta(1,4)-D glycoside linked digitoxose linked to digoxigenin. ('genin' is a suffix used to indicate the aglycone. The cardiac activity of cardiac glycosides is a consequence of inhibition of the cell membrane Na+-K+ ATPase ('sodium pump'). Structure - Activity Relationships * "The sugar moiety appears to be important only for the partitioning and kinetics of action. It possesses no biological activity. For example, elimination of the aglycone moiety eliminates the activity of alleviating symptoms associated with cardiac failure. * The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive. * Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important. * The 14b-OH groups is now believed to be dispensible. A skeleton without 14b-OH group but retaining the C/D cis ring fusion was found to retain activity. * Lactones alone, when not attached to the steroid skeleton, are not active. Thus the activity rests in the steroid skeleton. * The unsaturated 17-lactone plays an important role in receptor binding. Saturation of the lactone ring dramatically reduced the biological activity. * The lactone ring is not absolutely required. For example, using a,b-unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity." (from [1])

Answer 203

A is ?right. (very poorly worded option) "Enhanced parasympathetic nervous system activity produced by ... digitalis decreases activity of the SA node and prolongs the effective refractory period, and thus the time for conduction of cardiac impulses through the AV node" (Stoelting p.279) B false - Digoxin's direct effect is to bind and inhibit the Na/K/ATPase pump, leading to increased intracellular calcium therefore causing a positive inotropic effect. ***Recall that both entry of calcium and removal of calcium from the cell uses energy. Only levosimendan does not increase myocardial oxygen consumption. C false - Shortens QT interval (Stoelting p.281) D true - see above

Answer 204

``` CD10 A is correct - increases PR interval "Atrial tachycardia with block is the most common cardiac dysrhythmia attributed to digitalis toxicity" (Stoelting p.282) B wrong - QT decreased C wrong - flattened or inverted T waves D wrong - ST depression (scooped) E wrong - no idea ``` Addit: I think E is correct because resting membrane potential is increased (less negative). higher tendency for bigeminy because after depolarization may itself trigger depolarization at toxic levels. Answers to B-E from Stoelting p.281 (ECG effects [therapeutic] of digoxin)

Answer 205

July 2000: B is the answer Addit 2: I disagree with either answer. ECG changes such as reversed tick, prolonged PR, T wave flattening, shortened QT are not signs of toxicity but merely ECG changes associated with digoxin treatment. True cardiac toxicity is manifested as arrhythmias such as PVCs, bigeminis, all forms of AV block, and atrial or ventricular tachycardias (peck/hill). --- Digoxin toxicity Any arrhythmia can occur with digoxin toxicity. Most common is atriventricular conduction delay, followed by ventricular ectopic beats and sinus bradycardia. Note that the 'reversed tick' sign on ECG is merely a sign of digoxin therapy and not toxicity. Other toxic effects are yellow vision (xanthopsia), anorexia, n+v, diarrhoea serum levels >2.5 ng/ml diagnose toxicity (kumar & Clark 3rd Ed P.575) [Is this close enough to 2.1?] electrolyte imbalances predisposing to toxicity include hypokalaemia, hypomagnesaemia and hyperkalaemia amiodarone may cause toxicity by displacing from tissue binding sites, whereas quinine / calcium antagonists may do so by intefering with tubular clearance Rx - correct electrolytes, atropine for bradycardia, avoid cardioversion except for VF, give Digibind, never give calcium as it will cause lethal arrhythmias refs. K&C 3rd ed, Katzung 3rd ed P.1021, Revision Notes for MRCP (Kalra) Digoxin toxicity cases Increased PR interval, flattened / inverse T waves, ST depression (in reverse tick pattern) Disagree with above-they are signs of digoxin treatment not toxicity. (See Peck & Williams "The ECG signs of prolonged PR interval, characteristic ST segment depression, T wave flattening, and shortened QT interval are not signs of toxicity".) ``` From Wikipedia (soft I know) The pharmacological actions of digoxin usually results in electrocardiogram (ECG) changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca2+ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia or fibrillation. The combination of increased (atrial) arrhythmogenesis and inhibited atrio-ventricular conduction (for example paroxysmal atrial tachycardia with A-V block - so-called "PAT with block") is said to be pathognomonic (i.e. diagnostic) of digoxin toxicity. An often described but rarely seen adverse effect of digoxin is a disturbance of colour vision (mostly yellow and green colour) called xanthopsia. ``` Is it possible that the answers are actually E and C? PHW states that prolonged PR interval is not a sign of toxicity, whereas ventricular extrasystoles and xanthopsia could both be signs of toxicity Stoelting puts prolonged PR under both "ECG effects" and under toxicity

Answer 206

July 2000: B is the answer Addit 2: I disagree with either answer. ECG changes such as reversed tick, prolonged PR, T wave flattening, shortened QT are not signs of toxicity but merely ECG changes associated with digoxin treatment. True cardiac toxicity is manifested as arrhythmias such as PVCs, bigeminis, all forms of AV block, and atrial or ventricular tachycardias (peck/hill). --- Digoxin toxicity Any arrhythmia can occur with digoxin toxicity. Most common is atriventricular conduction delay, followed by ventricular ectopic beats and sinus bradycardia. Note that the 'reversed tick' sign on ECG is merely a sign of digoxin therapy and not toxicity. Other toxic effects are yellow vision (xanthopsia), anorexia, n+v, diarrhoea serum levels >2.5 ng/ml diagnose toxicity (kumar & Clark 3rd Ed P.575) [Is this close enough to 2.1?] electrolyte imbalances predisposing to toxicity include hypokalaemia, hypomagnesaemia and hyperkalaemia amiodarone may cause toxicity by displacing from tissue binding sites, whereas quinine / calcium antagonists may do so by intefering with tubular clearance Rx - correct electrolytes, atropine for bradycardia, avoid cardioversion except for VF, give Digibind, never give calcium as it will cause lethal arrhythmias refs. K&C 3rd ed, Katzung 3rd ed P.1021, Revision Notes for MRCP (Kalra) Digoxin toxicity cases Increased PR interval, flattened / inverse T waves, ST depression (in reverse tick pattern) Disagree with above-they are signs of digoxin treatment not toxicity. (See Peck & Williams "The ECG signs of prolonged PR interval, characteristic ST segment depression, T wave flattening, and shortened QT interval are not signs of toxicity".) ``` From Wikipedia (soft I know) The pharmacological actions of digoxin usually results in electrocardiogram (ECG) changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca2+ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia or fibrillation. The combination of increased (atrial) arrhythmogenesis and inhibited atrio-ventricular conduction (for example paroxysmal atrial tachycardia with A-V block - so-called "PAT with block") is said to be pathognomonic (i.e. diagnostic) of digoxin toxicity. An often described but rarely seen adverse effect of digoxin is a disturbance of colour vision (mostly yellow and green colour) called xanthopsia. ``` Is it possible that the answers are actually E and C? PHW states that prolonged PR interval is not a sign of toxicity, whereas ventricular extrasystoles and xanthopsia could both be signs of toxicity Stoelting puts prolonged PR under both "ECG effects" and under toxicity

Answer 207

A: "Plasma concentrations between 0.5 and 2.5ng/mL are usually considered therapeutic, and levels >3ng/mL are definitely in a toxic range" (A incorrect) ... Goodman and Gilman state therapeutic range 0.5 - 2.0 ng/ml. A is most correct. C: "..delayed conduction of impulses through the AV node (prolonged PR interval on the ECG)" (C correct) D: Xanthopsia is form of chromatopsia, a visual defect in which objects appear as if they have been overpainted with an unnatural color - yellow. (medicinenet.com). Is a SIDE-EFFECT, but not due to overdose. ... Xanthopsia is a manifestation of toxicity. (Goodman and Gilman). (Although still think A is most correct). E: Stoelting states that "conduction of cardiac impulses through specialised conducting tissues of the ventricles is not altered, as evidenced by failure of even toxic plasma concentrations ... to alter duration of QRS complex on ECG". Although many textbooks state bigeminy I could not specifically find 'long QT interval' as a complication. A. Serum level > 2.1 ng/ml is toxic -- yes and no; peck/hill defines level > 2.5 as toxic B. C. Causes a long PR interval -- no; it is a non-toxic ECG feature of digoxin treatment D. Causes xanthopsia (OR: 'causes yellow vision') -- no; again, it is a S/E of digoxin rather than feature of toxicity E. Causes a long QT interval and bigeminy -- yes and no; can certainly cause bigeminy at toxic level but could not find any evidence about QT prolongation. Shortened QT is a non-toxic ECG feature of digoxin treatment References Stoelting, Pharmacology and physiology in Anaesthetic practice 4th edition p314-315 Peck, Hill, Williams, Pharmacology for anaesthesia and intensive care 3rd edition pg 232 Royal Australian College of Pathology website - digoxin toxic levels > 2.6 nmol/L (> 2 mcg/L). http://www.rcpamanual.edu.au/index.php?option=com_pttests&task=show_test&id=484&Itemid=27 Plus if you think about it clinically, at levels of 2, I'd probably think about reducing the dose but I've never seen anyone get particularly excited about it either in medicine or ICU.

Answer 208

A: Incorrect elimination half life 6-23 hours (Katzung p160: 8-12 hours) B: True Katzung (7th ed p160): "About half the drug is eliminated unchanged in the urine" Peck and Williams say that 50% is excreted unchanged in the urine Stoelting (4th ed p343): "approximately 50% metabolized in the liver whereas the rest is excreted unchanged in urine" C: Incorrect 100% oral bioavailabilty. Katzung says: the bioavailability of clonidine averages 75%" (p160) D: Incorrect can be absorbed topically (eg see [1]) E: Incorrect 20% protein bound "Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours" (from [2]) " Clonidine is well absorbed orally, and is nearly 100% bioavailable. The mean half life of the drug in plasma is about 12 hours. It is excreted in an unchanged form by the kidney, and its half life can increase dramatically in the presence of impaired renal function. A transdermal delivery system is available in which the drug is released at a constant rate for about a week. Three or four days are required to achieve steady state concentrations. (from [3])

Answer 209

A - most likely correct: adenosine slows AV conduction, hence its use to treat SVT. Not sure about it's effect on the refractory period. Adenosine's mechanism of action is to open potassium channels and hence hyperpolarise the cell, thus affecting ?phase 3 and phase 4 of the cardiac action potential? "Adenosine has a direct effect on atrial tissue causing a shortening of the refractory period" wikipedia. B - incorrect. It's taken up via a specific nucleoside transporter by RBCs and is metabolised by enzymes on the lumenal surface of the vascular endothelium (Rang D&R 5th Ed P.278) C - incorrect: "Uric acid levels may increase 10% to 20% when adenosine is used" (Stoelting 1999 p329) D - incorrect: methylxanthines such as theophylline block A1 receptors (Rang Dale and Ritter 1995 p188), so likely to be incorrect. However, lower doses of adenosine are required when the patient is receiving concommitant dipyramidole treatment (Stoelting 1999 p328) Peck Hill and Williams say that refractory period is shortened by adenosine, and consequently it may induce AF or flutter. They also say that deamination occurs in the plasma then uptake by RBCs (2nd edition, p.227) - B correct ... Goodman and Gilman disagree, "Adenosine is eliminated with a half-life of seconds by carrier-mediated uptake, which occurs in most cell types, including the endothelium, and subsequent metabolism by adenosine deaminase." Definitely not metabolised in plasma, B incorrect. Agree A most likely correct. ... wikipedia "When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red cells and the vessel wall. Dipyridamole, an inhibitor of adenosine deaminase, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation." not the best source but I guess if the answer B was 'metabolised in the circulation' it will be the best answer; alternately answer A should be "shortening/decreasing refractory period", otherwise there will be no correct answer for this question. ....Katzung 10e Pg 231 "..adenosine directly inhibits AV nodal conduction and INCREASES the AV nodal refractory period"

Answer 210

Don't think the question was remembered correctly. A incorrect. alpha carbon CH3 substitution blocks metabolism by MAO, and increases indirect activity. B possibly correct as beta -OH substitution gives increased potency of direct actions C correct if discussing actions at a1 receptor. levo dobutamine potent alpha 1 agonist dextro dobutamine alpha 1 antagonist, beta 1 agonist; hence the combination of the two gives selective b1 agonist activity.

Answer 211

CD16a A: esmolol is beta 1 selective B: t1/2 is about 10 min C: true D: metabolised by esterases in RBCs (not plasma cholinesterases) E: see above F: partly true - see A above Esmolol has neither ISA nor membrane stabilising properties F is false is it not? A. Active at beta-1 & beta-2 receptors - Yes and No; esmolol is highly cardiac selective but still exerts some beta-2 effect at high dose B. Half-life

Answer 212

CD16b A. Is a non-selective beta antagonist - False B. Has intrinsic sympathomimetic activity - False C. Does not have membrane stabilising activity - Never heard of, hence false; but don't quote on me! --- correction, no membrane stabilising activity as per P&H table 13.2, hence make this answer "True" D. ?

Answer 213

CD16c A. False: - broken down by red cell esterase's (N.B. esterases[1] are not the same as cholinesterases[2] B. False:- Has no membrane stabilising activity as per P&H table 13.2 C. True: - is metabolised into methanol and a major acid metabolite that is weakly active but with a long elimination half life. D. False E. False:- β1 selective

Answer 214

CD 17 A Incorrect. More delivered at a lower concentration. B Incorrect. Isotonic. C Correct D Incorrect. Their osmolalities will be the same. E Incorrect. Decreases sodium resorption. F Incorrect. MW 182.17 G Correct. That's how it works! 'Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle's loop...presence of a nonreabsorbable solute such as mannitol prevents the normla absorption of water by interposing a countervailing osmotic force. ..The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na as well as water reabsorption' (Katzung 10th ed. pg 248) But regarding the change in the medulla, haven't seen anything that states if it becomes hypo- or iso-tonic, but, really, as long as it isn't the usual hypertonic medulla, it would still work, right? Diuretics abolish the kidney's ability to concentrate urine by washing out the hypertonic medulla. They do this either by an osmotic effect that prevents water reabsorption (e.g mannitol) or by inhibition of active NaCl transport in the thick ascending loop (e.g furosemide) or the first part of the distal tubule (e.g hydrochlorothiazide)..(Miller 7th ed, page 450) hold on, frusemide acting on Na/K/Cl symporter abolishes hypertonic interstitium. This is not a general property of all diuretics. Mannitol, HCT, amiloride, spironolactone have NO effect on the hypertonic medullary gradient -> That is only true if they work proximally. Thiazide words on the distal tubule (cortical) where only 5% of Na is normally reabsorbed and therefore has little effect on medullary concentration gradient

Answer 215

``` July 2001 A Incorrect. Mannitol and urea B Correct C Incorrect. Causes sodium loss. D Hmm... E MW 182.17 comment I thought that mannitol induced diuresis by preventing the reabsorption of water from the collecting ducts (?) ``` 'Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle's loop...presence of a nonreabsorbable solute such as mannitol prevents the normla absorption of water by interposing a countervailing osmotic force. ..The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na as well as water reabsorption' (Katzung 10th ed. pg 248) But regarding the change in the medulla, haven't seen anything that states if it becomes hypo- or iso-tonic, but, really, as long as it isn't the usual hypertonic medulla, it would still work, right? Diuretics abolish the kidney's ability to concentrate urine by washing out the hypertonic medulla. They do this either by an osmotic effect that prevents water reabsorption (e.g mannitol) or by inhibition of active NaCl transport in the thick ascending loop (e.g furosemide) or the first part of the distal tubule (e.g hydrochlorothiazide)..(Miller 7th ed, page 450) hold on, frusemide acting on Na/K/Cl symporter abolishes hypertonic interstitium. This is not a general property of all diuretics. Mannitol, HCT, amiloride, spironolactone have NO effect on the hypertonic medullary gradient -> That is only true if they work proximally. Thiazide words on the distal tubule (cortical) where only 5% of Na is normally reabsorbed and therefore has little effect on medullary concentration gradient

Answer 216

CD18 A. ?doesn't cross BB barrier B. BEST ANSWER - "Therapeutic use of guanethidine is often associated with symptomatic postural hypotension" (Katzung 9th ed p.169) C. False - Appears to have multiple mechanisms of actions. "Guanethidine inhibits the release of NA from sympathetic nerve endings" (Katzung 9th ed. p.169)

Answer 217

``` CD18b A. see above B. True - see above C. Probably false if A is false D. doesn't cross BBB E. see B above Background Guanethidine is one of those useless drugs which is no longer used. "Can produce profound sympathoplegia... can produce all of the toxicities expectrf from "pharmacologic sympathectomy", including marked postural hypotension, diarrhoea, and impaired ejaculation" - Katzung 9th ed p.168 ```

Answer 218

From Katzung 9th ed. p.171 "Labetalol is formulated as a recemic mixture of four isomers... Two ...are inactive, a third (S,R) is a potent alpha-blockers, and the last (R,R) is a potent beta-blocker... Labetalol has 3:1 ratio of beta:alpha antagonism" Labetolol is both alphablocker and betablocker, but the alpha blocking properties are relatively weak. Only C is correct Excerpt from G&G for educational purposes Labetalol has two optical centers, and the formulation used clinically contains equal amounts of the four diastereomers. The pharmacological properties of the drug are complex, because each isomer displays different relative activities. The properties of the mixture include selective blockade of a1 receptors (as compared with the a2 subtype), blockade of b1 and b2 receptors, partial agonist activity at b2 receptors , and inhibition of neuronal uptake of norepinephrine (cocaine-like effect). The potency of the mixture for b receptor blockade is fivefold to tenfold that for a1 receptor blockade.

Answer 219

CD20 A false - 95% protein bound and excreted unchanged in urine (p305 Peck and Hill) B ? - Sassada and Smith: 60-70% absorption after oral administration, the bioavailability by this route is 43-71% C true - "The elimination half-time is

Answer 220

April 2001 | B is the answer

Answer 221

CD20B C true - "As with thiazine diuretics, loop diuretics may cause hyperuricaemia, but this is rarely clinically significant." (Stoelting p. 439) C is the correct answer (Peck) - remember how lasix is a precipitant for gout? Regarding C, it is true that frusemide doesn't cause hypouricaemia. Lange Clinical Anesthesiology 4e describes hyperuricaemia caused by frusemide as involving increased urate reabsorption and competitive inhibition of urate secretion in the proximal tubule. Stoelting 4th pg488 Frusemide also evokes renal production of prostaglandins resulting in renal vasodilation and increased renal blood flow.'

Answer 222

A. Does increase refractoriness but main efect is slowing of phase 4 depolarisation due to blockage of sodium channels. B. 2-5 micrograms/ml not nanograms Addition: Class 1b drug (Vaughan-Williams): blocks fast sodium channels in Phase 0; state-dependent as more likely to block when open or inactivated rather than depolarised; additionally slows sodium window currents which decreases APD duration. Don't know about this Phase 4 bit on the slow pacemakers... Phase 4 bit in Stoelting (p378) - doesn't talk at all about phase 0 here - too many conflicting stories!!! PECK, HILL & WILLIAMS Just a note, Peck, Hill, Williams says that lignocaine is a class Ib anti-arrythmic, which shortens action potential duration and refractory period "Lignocaine reduces the rate of rise of phase 0 of the AP by blocking inactivated Na+ channels and raising the threshold potential. The duration of the AP and the eRP are decreased as the repolarization phase 3 (not 4) is shortened." Quinidine (class Ia) reduces the rate of rise of Phase 0 of the AP, raises the threshold potential and prolongs the eRP without affecting duration of AP. Flecainide (class Ic) reduces the rate of rise of Phase 0 of the AP with no effect on eRP or duration of AP.

Answer 223

A. beta 2 stimulation (salbutamol) relaxes uterine smooth muscle, so presumably this is false B. slows AV conduction so.. answer is true C. inhibits lipolysis (adrenergic agonists stimulate), so false D. incorrect, so true E. they do, so false F. they do, so false G. false? (agonists oppose insulin) H. see C above Query re:D With chronic use of B Blockers you get a decrease in MAP, sure. Acutely however,(if it was not a Labetolol type which blocks alpha1 also) would you not get an initial increase in SVR due to B2 block leaving unopposed Alpha1 vasoconstriction. What do you think? I agree - eg with non-selective B-Blocker (eg propranolol) would see initial increase in SVR due to B2 block. Comments Propranolol actually decreases uterine tone (Sasada & Smith), so A is true - Salbutamol relaxes the gravid uterus due (?due to increased beta2 receptors towards term) SVR is increased, due to an element of beta 2 blockade (which is why beta blockers cause poor peripheral circulation and cold hands - Peck, Hill, Williams) (so D is true) That's odd, my P,H,W says "due to antagonism of peripheral B2 receptors there will be an element of vasoconstriction, which appears to have little hypertensive effect but may result in poor peripheral circulation and cold hands" P223 3rd ed. Hypotensive effect is due to decreased cardiac output, and possibly blockade of renin release Regarding beta blockers in pregnancy: " Blockade of myometrial beta2 adrenergic receptors of the uterus induced by a nonselective beta-blocker, may stimulate uterine contractions and induce premature labor." From www.hmc.org.qa/heartviews/VOL1NO4/PDF/CONTROVER_CARDIO.pdf "The influence of propranolol, isoprenaline, papaverine and caffeine on basal tone and contractile responses to spasmogens (oxytocin, KCl) was investigated in the presence and the absence of external calcium in estrogen-treated rat uterus. Isoprenaline, papaverine and caffeine relaxed precontracted uterus and caffeine also decreased the basal tone of uterine muscle in calcium-containing or calcium-free solution. Propranolol had a dual activity in calcium-free medium: lower concentrations contracted the sustained contraction elicited by oxytocin, whereas the highest concentration partially relaxed it. In calcium-containing solution the highest dose of propranolol partially inhibited KCl-induced contractions" from: http://cat.inist.fr/?aModele=afficheN&cpsidt=3451797 How do beta blockers MASK hypoglycaemia? if they inhibit lipolysis wouldn't that potentially CAUSE hypoglycaemia? Or possibly mask hyperglycaemia Why so many NOT true questions. They are testing your processing of double negatives not the material. B-blockers do NOT relax uterine muscle, they cause contraction therefore the statement is NOT true which makes the answer TRUE... seriously!! Seriously! So clinically irrelevant. Next thing patients will be saying "Doc, I don't not have an allergy, and I refuse to not tell you what it isn't that I'm not allergic to."

Answer 224

Phentolamine is a non-selective alpha antagonist. Acts at alpha 1 and 2 It does not bind covalently (phenoxybenzamine does). It is competitive (reversible) antagonist. It decreases systemic blood pressure and causes reflex TACHYCARDIA (via baroreceptor reflex) Also causes tachycardia via its alpha 2 effects - enhanced neural release of noradrenaline. Increase in noradrenaline release also INCREASES CARDIAC OUTPUT. E. is Correct

Answer 225

CD24 A non-selective beta-blocker with low extraction ratio, long half-life and ISA Difficult to answer - your guess is as good as mine!! Atenolol is selective for beta-1 Propranolol is non-selective but "lacks intrinsic sympathomimetic activity" (Stoelting p.290) Metoprolol is beta-1 selective Labetalol is non-selective for both beta and alpha, does have some intrinsic beta-2 agonist properties, don't know about its extraction ratio (oral bioavailability 100%) Could the answer be nadolol which is non-selective, has a long duration of action with no metabolism (=> ?low extraction ratio), but unsure of ISA

Answer 226

CD 24b Which ONE of the following is water soluble, half life 6-8hrs, (“and something else”)? A - Esmolol HL = 10 minutes B - Metoprolol HL 3-7 hrs depending on whether pt is fast or slow hydroxylators, clearance is hepatic suggesting more likely to be lipid soluble? C - half life 2-3 hours according to Stoelting p.292 ? E - Atenolol's half life 6-7 hours according to Stoelting, also renally excreted, therefore more likely to be water soluble?

Answer 227

``` CD24c Which one of the following selective beta blockers has a low extraction ratio and is predominantly excreted in urine? A. Propranolol B. Esmolol C. Atenolol D. Metoprolol C. Atenolol ```

Answer 228

``` CD24d A beta 1 selective antagonist, predominantly excreted in urine and with a halflife of 6-8 hours, would be... A. Sotalol B. Esmolol C. Atenolol D. Propranolol E. Metoprolol ``` Bingo - atenolol fits this question like a hand in a glove Of these only labetolol has ISA. Atenolol and Sotalol are the most hydrophilic. Sotalol and propranolol are non selective. Esmolol is metabolised by red cell esterases. Metoprolol is metabolised mainly in the liver. C is correct.

Answer 229

``` Sotalol is a non-selective beta-blocker with both class II & III activity. It causes prolonged QT interval & precipitates torsades in about 4% of those on it. The class 3 activity is due to K channel block in the myocardium. Major use is for treating ventricular arrhythmias (not torsades) and for atrial fibrillation. ```

Answer 230

Trimetaphan camsylate Ganglion blocking drug, used in hypotensive anaesthesia. Does not cross blood brain barrier. Is incompatible with Thio Faunce pg 331 I reckon "incompatible with thio" is usually a safe bet for anything - agree I know I've never used the two together, and there has to be a reason for that. There are mentions in the literature of the incompatibility of trimetaphan with sodium thiopental in the same syringe - this is also true with other NaOH containing/highly basic medications. However the exact mechanism wasn't described. Given this is a 13 year old question about a drug that has been obsolete for 30 years, that is probably more than enough information! "For many years, the ganglionic blocker trimethaphan had been touted as an antihypertensive with little or no cerebral vascular effects. This is probably untrue—or at least the drug is not remarkably "better" than nitroprusside.474 However, because this agent is now effectively obsolete, we do not discuss it further." - Longnecker Anesthesiology. Too obsolete for a core anaesthesia text, but not too obscure for the exam!

Answer 231

A - False: "Unlike thiazide diuretics, diazoxide causes sodium and water retention" (Stoelting p327) B - True: Diazoxide opens potassium channels (Katzung p 175) C - False: given orally to treat hypoglycaemia (increases catecholamine release) at a dose of 5mg/kg/day. From Yentis A-Z.

Answer 232

A - False: "Because it is not a catechol derivative, (phenylephrine) is not inactivated by COMT" (Katzung p134) B - True: "It is an effective mydriatic" (Katzung p134) C - True: "metabolised by MAO" (Rang Dale and Ritter p168) D - True if longer than: Phenylephrine "has a much longer duration of action than the catecholamines" (Katzung p134) E - False: "It acts directly on the receptors" (Katzung p135) Addition: Knowledge of the structure-activity relationships of phenylephrine would allow some of these options to be answered, viz: Catechol O-methyl transferase (COMT) requires a catechol (ie both 3-OH and 4-OH groups on the benzene ring) to work (so doesn't work on phenylephrine as only has 3-OH group) Monoamine oxidase (MAO) does not work if alpha carbon has substitutes (not in this case, so MAO works), etc.

Answer 233

A - Probably true: rapid acetylators have much lower bioavailability and acetylation appears to be the major form of metabolism (Stoelting p310) C - False: Slow acetylators will increase half-life D - False: Causes sodium and water retention, a property common to most vasodilators E - Probably false: "After IV administration

Answer 234

Table | http://www.kerrybrandis.com/wiki/mcqwiki/index.php?title=CD31

Answer 235

A - False: has a direct relaxant effect; do not confuse with phenylephrine which DOES have a direct alpha-1 effect E - most correct out of the two choices but not really all that correct: "elimination half-time averages 3 hours"; "effect begins within 10 to 20 minutes after IV administration and lasts 3 to 6 hours" (Stoelting p310)

Answer 236

None of the above answers are correct. The levo (-) isomer has alpha agonist effects which opposes the Dextro (+) isomer which has alpha antagonist and beta 1 agonist effects. (also in Katzung p.135) Thus leaving it a selective beta 1 agonist. The (-) isomer of dobutamine is a potent agonist at alpha-1 receptors. The (+)-dobutamine is a potent a1 receptor antagonist, which can block the effects of (-)-dobutamine. The effects of these two isomers are mediated via beta receptors. The (+) isomer is a more potent beta receptor agonist than the (-) isomer (approximately tenfold). Both isomers appear to be full agonists

Answer 237

A - Correct: Adenosine causes "block of cardiac AV conduction (A1)" (Rang, Dale and Ritter 1995 p189) B - Incorrect: Bronchoconstriction occurs via A1 receptors (Rang Dale and Ritter 1995 p189) C - Incorrect: Adenosine causes renal vasoconstriction but vasodilation of most other systems including the coronary vessels (Rang Dale and Ritter 1995 p189) D - Incorrect: Adenosine "has lesser effects on the sinoatrial node" (Katzung 2004 p236) E - Correct but I think A is more correct: "Decreases AV transmission" is a quite imprecise term. (However, the exact wording is not important as this is just what people remember, thats where the imprecision probably arises. The actual question will be different.) This question appears to relate straight to the dot points in Rang, Dale and Ritter 1995 p189. Here the authors discuss the role of adenosine receptors (A1 and A2 which inhibit and stimulate cAMP respectively). However, both Katzung and Stoelting propose that adenosine works via stimulating adenosine-sensitive K+ channels in the myocytes of the atria which cause hyperpolarisation of the cells and do not mention the adenosine receptors. Stoelting also mentions that "ventricular myocytes do not possess these adenosine-sensitive potassium channels". Interestingly, on p277 of Rang et al 2003 they say that the A1 receptor is responsible for adenosine's effect on the AV node and that these receptors are linked to the KACh potassium channel causing hyperpolarisation of the cardiac conducting tissue, but don't make any reference on this page to adenylate cyclase or cAMP From Goodman & Gilman 12e states that: Mechanism is via interaction with G-protein coupled adenosine receptors Activates ACh-sensitive K+ current in atrium and SA/AV nodes Effect: shorter AP, hyperpolarisation, slower automaticity Also inhibits effects of inc. cAMP that occurs after SNS stim. Thus, by reducing Ca++ currents is antiarrhythmic and increases AV nodal refractoriness This of course is referring to the A1 receptor which is found in the heart. Thus the best answer is A. Answer A (Pharmacological Reviews December 1, 2001 vol. 53 no. 4 527-552)

Answer 238

A - Most true: "Vasodilatory effects are more pronounced on the coronary, cerebral, renal and splanchnic circulations" (Stoelting p310) B - False: hydralazine has a direct relaxant effect via inhibition of calcium entry into VSMC or Ca release from internal stores C - Probably false if A is true I disagree - vasodilatory effects may be more pronounced in those circulations, but I don't know if that is enough to make it a 'selective' vasodilator. I think it causes generalised vasodilation - no reference for this, but I doubt that selective vasodilation in those circulations would really be enough to cause the fall in SVR and BP that is seen clinically. I would go for A being false and C being true (depending on the other options).] Hydralazine is a general vasodilator (arterioles) which reduces TPR causing a compensatory increase in HR -> increase in CO and blood flow to brain, heart, kidneys especially (but not exclusively - also get skin flushing due to increase skin blood flow) Hence C (which is probably D) I loved how C is none of the above. Why bother with D. Also of note is the comment that if A is true, C is 'probably' false. Brilliant deductive reasoning

Answer 239

CD36 A false - causes a decrease in HR B true - "there is a decrease in sympathetic nervous system outflow from CNS to peripheral tissues... manifested as decreases in systemic BP, HR and CO" (Stoelting 3rd ed. p.306) C false - "rapidly absorbed after oral administration and reaches peak plasma concentrations within 60-90min" (Stoelting 3rd ed. p. 306) D false - "Clonidine will decrease the plasma concentration of catecholamines in normal patients but not in the presence of phaeochromocytoma" (Stoelting 3rd ed. p.305)

Answer 240

CD36B A - incorrect answer: see above B - correct answer: clonidine NOT known to cause apnoea C - incorrect answer: clonidine causes sedation Clonidine may cause a transient initial rise in BP, but not tachycardia (fall in HR is more common). 100% oral bioavailability. Unlike opioids, clonidine does not affect respiratory drive. Alpha 1 and 2 antagonist would be much more useful in phaeo (phentolamine or phenoxybenzamine). Well known for its sedating effect.

Answer 241

i think the answer is tachyphylaxis A. I understand SNP toxicity is cyanide toxicity B. Tachyphylaxis is a sign of toxicity C. Hypotension is false as a sign of toxicity is when the pt BP does not fall despite maximal therapy. Other signs of toxicity: a. Increased mixed venous PO2 indicating paralysis of cytochrome oxidase and inability of tissues to use O2 b. metabolic acidosis (secondary to anaerobic metabolism). Monitor blood lactate, which correlates well with increasing blood cyanide concentrations. c. CNS dysfunction in awake pts From: Anesthesia Secrets 4th Ed. "The presence of tachyphylaxis with administration of sodium nitroprusside suggests a therapeutic ceiling and ensuing cyanide toxicity and is usually associated with prolonged infusions of more than 2mcg/kg/min or when sulfur donors and methemoglobin stores are exhausted." Goodman & Gilman doesn't list incidence of signs, but the first mentioned is lactic acidosis. Tachyphylaxis is an indication that toxic levels may have been reached. Technically cyanide toxicity is not a 'sign' so if that was the wording of option A, I'd say it is less correct than B. As mentioned above, hypotension is an effect, not a sign of toxicity. Reference: page 317 Stoelting, Pharmacolgy and physiology in anaesthetic practice 3rd edition.

Answer 242

A - false: it is mainly an alpha-2 agonist C - true: see BJA 1992;68:570 - single dose of dexmedetomidine prior to cataract surgery under GA - 34% reduction in IOP in dexmedetomidine group D - false: "dexmedetomine is considered a full agonist at the alpha2 receptor" (Stoelting p307) E - false: "Compared with clonidine, dexmedetomine is seven times more selective for alpha2 receptors" (Stoelting p307)

Answer 243

A- False. Potassium sparing diuretic, blocks sodium channels which have been inserted in response to aldosterone. B- True. Amiloride antagonises the "effects of aldosterone at the late distal tubule and cortical collecting tubule" amd works by "inhibition of Na+ influx through ion channels in the luminal membrane" (Katzung 9th ed. p.250) C- False. It is a potassium SPARING diuretic D- False. "Excreted unchanged in urine" (Katzung 9th ed. p.250) E- False. 18-24 hours. Reference- Sasada and Smith.

Answer 244

A is correct (Peck and Hill p244)

Answer 245

A - unclear B - unclear C - correct: methylxanthines "are A1 receptor antagonists; however they also increase cAMP by inhibiting phosphodiesterase, which probably accounts for most of their pharmacological actions independently of adenosine receptor antagonism" (Rang Dale and Ritter 1995 pp188-189) D - unsure - i can't find any specific references but I would expect BSL to go up given that its actions are generally sympathomimetic E - unsure; "The methyxanthines are weak diuretics... may involve both increased glomerular filtration and reduced tubular sodium reabsorption" (Katzung 9th ed. p.327) F - true Background "The three important methylxanthines are theophylline, theobromine and caffeine" (Katzung 9th ed. p.325) Their exact mechanism of action is still unclear and "none have been firmly established". (Katzung p.326). Proposed is that they inhibit phosphodiesterases or inhibit cell surface receptors of adenosine. Addition : Caffeine inhibits ADH secretion -> diuresis (possibly an action of all methylxanthines?) Peck+Hill says that aminophylline inhibits Na reabsorption in tubules --> natriuresis - supports E being true Regarding D - Methyxanthines decrease plasma glucose level: false "In conclusion, the results of this study show that the administration of caffeine results in a significant decrease in insulin-mediated glucose uptake in resting humans. Carbohydrate storage is also significantly reduced after caffeine ingestion compared with placebo ingestion." - "Caffeine Ingestion Decreases Glucose Disposal..." [1] Regarding E - Methylxanthines cause diuresis by acting on renal tubules: true "pharmacological blockade of A1 receptors can induce diuresis and natriuresis by inhibition of proximal tubular reabsorption" - Requirement of Intact Adenosine A1 Receptors for the Diuretic and Natriuretic Action of the Methylxanthines Theophylline and Caffeine [2]

Answer 246

Sequence in guidelines (Feb 2006) Adrenaline --then-> amiodarone --then-> lignocaine --then-> consider others eg, Mg, K with electricity and CPR obviously C correct NB: On searching through the current (2010) guidelines I could not see where the drug sequence above is listed. This may have been in an earlier version I guess. This MCQ of course completely misses the point in an important clinically relevant sense: In VF, defibrillation is the way to go; not to argue over which 'drug' is the 'best'. Very interesting question. I assume most people would choose C as the correct answer. However, is there any evidence for this? Here are some interesting excerpts from the Dec 2010 (latest as of June 2012) ARC guidelines: "There are no studies that addressed the order of drug administration. (4)" "There is inadequate evidence to define the optimal timing or order for drug administration. An incomplete review of animal studies suggests that timing of vasopressor administration may affect circulation and further investigations are important to help guide the timing of drug administration. (4)" "...there is evidence that vasopressors (adrenaline or vasopressin) may improve return of spontaneous circulation and short-term survival..." "There is no convincing evidence that the routine use of other drugs (atropine, amiodarone, lidocaine, procainamide, bretylium, magnesium, buffers, calcium, hormones or fibrinolytics) during human CPR increases survival to hospital discharge. (4)" The first drug to give in a cardiac arrest is and always has been adrenaline. There is no evidence that anything improves outcome in VF arrest except effective CPR and early defibrillation (from ARC). Nevertheless this is a pharmacology question and the answer is clearly C. References Australian Resus Guidelines (now available free on-line) Reference 4 referred to is: Deakin CD, Morrison LJ, Morley PT, Callaway CW, Kerber RE, Kronick SL, et al. Part 8: Advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. [doi: DOI: 10.1016/j.resuscitation.2010.08.027]. 2010;81(1, Supplement 1):e93-e174.

Answer 247

CD43 B is correct Bendrofluazide can precipitate pancreatitis (Peck P.304)

Answer 248

CD43b A - True - thiazides do NOT lower serum calcium. they increase renal reabsorption & can lead to hypercalcaemia by reducing renal compensation of other causes of hypercalcaemia (e.g. Ca, hyperparathyroidism, sarcoidosis.) B - False - thiazides do cause hypomagnesaemia C - False - thiazides do cause hyponatraemia D - False - thiazides do cause hypokalaemia E - False - thiazides do cause metabolic alkaloses (increased K+ & H+ excretion References Complications[edit] Hyperglycemia Hyperlipidemia Hyperuricemia Hypercalcemia Hypokalemia Hyponatremia Hypomagnesemia From Wikipedia!!!

Answer 249

B, then may need infusion after reverts for stunning From December 2010 ARC Guideline: "Adrenaline: This is a naturally occurring catecholamine with alpha and beta effects. It is administered in cardiac arrest to cause peripheral vasoconstriction via its alpha-adrenergic action (directing available cardiac output to myocardium and brain). It may facilitate defibrillation by improving myocardial blood flow during CPR."

Answer 250

Dicobalt edetate: chelates CN- ions Sodium thiosulfate: provides sulfhydryl groups to facilitate conversion of CN- to SCN (which is 100 times less toxic than CN- but still toxic esp if it accumulates) Nitrites (sodium nitrite/amyl nitrite): conversion of oxyHb to metHb, which has a higher affinity for CN- than cytochrome oxidase Vitamin B12 can be used as prophylaxis (but not in acute setting), complexes CN- to cyanocobalamin [Peck 3e pp248-249]

Answer 251

Answer is A - tachyphylaxis "Clinical evidence of cyanide toxicity may occur when the rate of IV SNP infusion is >2mcg/kg/kin or when sulphur donors and methaemoglobin are exhausted... Regardless of SNP infusion rate or total administered dose, cyanide toxicity shuld be suspected in any patient who is resistnant to the hypotensive effects of the drug despite maximim infusion rates... or in a previously responsive patient who becomes unresponsive to the systemic blood pressure-lowering effect of SNP (tachyphylaxis). Mixed venous PO2 is increased in the presence of cyanide toxicity" (Stoelting 3rd ed. p.317) Symptoms include hypotension, vomiting, hyperventilation, tachycardia, muscular twitching, hypothyroidism, cyanide or thiocyanate toxicity. Thiocyanate toxicity includes psychosis, hyper-reflexia, confusion, weakness, tinnitus, seizures, and coma. Cyanide toxicity includes acidosis (decreased HCO3, decreased pH, increased lactate), increase in mixed venous blood oxygen tension, tachycardia, altered consciousness, coma, convulsions, and almond smell on breath. Nitroprusside has been shown to release cyanide in vivo with hemoglobin. Cyanide toxicity does not usually occur because of the rapid uptake of cyanide by erythrocytes and its eventual incorporation into cyanocobalamin. However, prolonged administration of nitroprusside or its reduced elimination can lead to cyanide intoxication. In these situations, airway support with oxygen therapy is germane, followed closely with antidotal therapy of amyl nitrate perles, sodium nitrate 300 mg I.V. for adults (range based on hemoglobin concentration: 6-12 mg/kg for children), and sodium thiosulfate 12.5 g I.V. for adults (range based on hemoglobin concentration: 0.95-1.95 mL/kg of the 25% solution for children). Nitrates should not be administered to neonates and small children. Thiocyanate is dialyzable. May be mixed with sodium thiosulfate in I.V. to prevent cyanide toxicity. Re answer: Get increased mixed venous pO2 as tissues unable to use oxygen as cyanide blocking oxidative phosphorylation. Would not get decrease arterial pO2. Using SNP for hypotensive effect. Stoelting/Peck say toxicity should be suspected in anyone resistant to hypotensive effect of the drug either at the start or during the infusion (ie tachyphylaxis develops).

Answer 252

"in chronic use the dihydropyridines often cause ankle swelling, related to arteriolar dilatation and increased permeability of postcapillary venules" (Rang D&R 5th ed p284) This makes A the best answer listed here "Despite having an intrinsic diuretic effect, the dihydropyridines cause peripheral oedema. The oedema represents a redistribution of extra cellular fluid rather than a net retention of salt and water and hence does not respond to diuretics" - Calcium channel antagonists (L.M.H. Wing, Professor and Director of Clinical Pharmacology, Flinders Medical Centre, Adelaide - Aust Prescr 1997;20:5-8) Background Calcium channel blockers can be classed structurally as dihydropyridines (nifedipine, amlodipine, any-other-ipine) and others (verapamil and diltiazem). The difference between the two classes is that the dihydropyridines have an affinity for peripheral arterioles while the others have a more central effect and are used for treatment of supraventricular tachydysrhythmias. Dihydropyridines end with -dipine

Answer 253

Isoprenaline cannot be used as a substitute for metaraminol as it DECREASES systemic vascular resistance. Not used in ischaemic heart disease as it decreases diastolic BP and therefore coronary blood flow and causes increased contractility and tachycardia (increases O2 requirements) Does decrease SVR Causes TACHYCARDIA.

Answer 254

Answer is D. A. incorrect- this is the most important adverse effect, incidence 5-15%, mortality 5-10% B. incorrect- photosensitivity and rash in up to 10% patients C. incorrect- present in almost all patients after a few weeks of treatment D. correct- can cause bradycardia/heart block/arrhythmias but not known to cause cardiomyopathy E. incorrect- can cause BOTH hyper- & hypo-thyroidism References Stoelting p381-382 Katzung p233-234

Answer 255

ANSWER ? C Bioavailablity Atenolol 50% Metoprolol 10% Sotalol 100% Labetalol 90% Carvedilol 30% Propanolol 12% Taken from Wiki From Katzung's 11th ed, page 157 Bioavailability Atenolol 40% Metoprolol 50% Sotalol 90% Labetalol 30% Carvedilol 25-35% Propranolol 30% Esmolol 0% References ``` Sotalol is officially Class III antiarrhythmic, does it leave Labetalol as the best answer? It's not 'officially' anything, its effects include a non-selective antagonist action at beta-adrenoceptors (i.e. it is a beta-blocker), and antagonist activity at potassium channels (class III antiarrhythmic). The Vaughan-Williams classification system is not perfect and some drugs to not fit neatly into its categories. ```

Answer 256

A. false decrease MAC for Iso 35% with plasma level 0.3ng/ml, and 48% with plasma level 0.6ng/ml B. true C. not sure - peripheral vasodilation -> hypotension -> ?decrease CBF C. false Dexmedetomidine decreases cerebral blood flow. Mechanisms could include a2R smooth muscle relaxation or reduction in CMRO2. (1) References Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow. [1] Stoelting p344 4th ed.

Answer 257

ANSWER C A: maximum urine pH occurs 2 post oral ingestion B: false . max safe dose inhibitions 85% HCO3 reabsorption at PCT C:true. max safe dose 45% inhibition for whole kidney as there is continued HCO3 reabsoption via CA independant mechanism D: false, causes hyperchloremic metabolic acidosis E: false, distal tubules excrete K in exchange for Na Goodman & Gilman 12e, Ch 25, section on Inhibitors of Carbonic Anhydrase, Effects on Urinary Excretion agrees: Carbonic anhydrase inhibition causes a rapid rise to excretion of ~35% filtered HCO3- load Even with a "high degree" of inhibition, ~65% of filtered load reabsorbed by unknown, downstream, non-carbonic anhydrase related mechanisms

Answer 258

Procainamide (4-amino-N-(2-diethylaminoethyl) benzamide) is a benzamide antiarrhythmic. Acetazolamide (N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide) is a non-bacteriostatic sulfonamide. It has weak anti-epileptic properties but not antiarrhythmic. It is not metabolised and is excreted unchanged in the urine.

Answer 259

A - false - "poor absorption and wide inter-patient variability of absorption" (datasheet) B - false - "modification of the dose is not required in the presence of renal impairment" (S+S) although "should be used with extreme caution in patients with hepatic disease" (datasheet) C - false - very long half life so a missed dose or two shouldn't make much difference overall D - possibly true depending on actual question - "The principal metabolite of amiodarone... is desethylamiodarone" (datasheet). Note that it says desETHYLamiodarone, as does S+S but Stoelting refers to it as desMETHYLamiodarone. Not sure of the significance of this. E - possibly true depending on actual question - "prolongs the effective refractory period in all cardiac tissues" (Stoelting) Amiodarone metabolism: (goodman & gilman) Hepatic via CYP3A4 Metabolite is desethyl-amiodarone (I'm going to assume that Stoelting is wrong here) Metabolite is active and has similar effects to amiodarone t1/2 in patient on years of Rx is from weeks to months Elimination of amiodarone and metabolite not well understood Regarding D: CYP3A4 is a monooxygenase; these enzymes function by hydroxylating substrates I would hazard a guess that hydroxylation would be correct, whereas demethylation appears to be incorrect.

Answer 260

A. True - ish... acts only on alpha-1 receptors. So D option D might be 'more' correct B. False - "stimulates alpha- and beta- receptors by indirect and direct effects" (Stoelting) C. False - "beta adrenergic receptor stimulation is absent" (Stoelting), 4th ed: 'large doses ... have an inhibitory effect on beta-receptors and may produce bradycardia" - p. 306. Will it make it True? D. True - "Pseudoephedrine...is a stereoisomer of ephedrine" (datasheet) How a normal person thinks: A, C and D are all possibly true How an ANZCA examiner probably thinks: A is 50% true, C is 20% true and D is 75% true, therefore the answer is D

Answer 261

A. False - "rapidly destroyed in the liver and kidneys" (datasheet) B. False - "should not be used in patients with vascular disease, especially disease of the coronary arteries" (datasheet) C. True - hence its use in management of variceal haemorrhage D. True - V2 receptors are essential for plasma volume and osmolality control. Their presence on endothelial cells induces the release of Von Willebrand Factor (VWF) and Factor VIII:coagulant (FVIII:c). (Contin Educ Anaesth Crit Care Pain (2008) 8 (4): 134-137. doi: 10.1093/bjaceaccp/mkn021) E. ________________________________________________________________ I thought it was terlipressin that was used in variceal haemorrhage? Or is it implied that terlipressin is an ADH analogue, and so is also avp? COMMENT Circulating t1/2 15 minutes, with renal and hepatic metabolism via the reduction of disulfide bond and peptide clevage. Extrarenal V2 like receptors regulate the release of coagulation factor 8 and von Willebrand factor. Vasopressin infusion is effective in some cases of oesophageal variceal bleeding and colonic diverticular bleeding. Reference: Katzung's 11th edition page 658

Answer 262

(A) Probably incorrect. Drowsiness and dry mouth in up to 50% of patients (however incidence of agitation only 3% on further searching so common but not very common) (B) Incorrect Elimination t1/2 6-23 hrs. (Sassada and smith) (C) (D) True - Rapid Removal of the drug (clonidine) may lead to life threatening rebound hypertension and tachycardia (Sassada and Smith) (E) Incorrect. Therapeutic dose is 50-600ug 8hrly PO, with corresponding IV dose of 0.15-0.3mg. Epidural route 0.15mg

Answer 263

Answer:B "Non-selective beta blockade may obtund the normal blood sugar response to exercise and hypoglycemia..." Peck & Hill 3rd edition p 223.

Answer 264

B. True Labetolol is specific alpha1 and non-specific beta blocker (P & H page 226) Addit: it is a non-specific partial agonist at beta, not alpha, receptors (Goodman & Gilman 12e Ch. 27) addit #2: stoelting pg 335 states alpha1 plus non-selective beta blocker, with b2 agonist activity. will the real labetalol please stand up?

Answer 265

e CD60a: A. True B. False Methaemoglobinaemia is not helpful for myocardial infarction..... Sodium Nitroprusside(SNP)--> MetHb C. False Dilates large arterioles

Answer 266

e CD60a: A. True B. False Methaemoglobinaemia is not helpful for myocardial infarction..... Sodium Nitroprusside(SNP)--> MetHb C. False Dilates large arterioles

Answer 267

e CD60a: A. True B. False Methaemoglobinaemia is not helpful for myocardial infarction..... Sodium Nitroprusside(SNP)--> MetHb C. False Dilates large arterioles

Answer 268

none of the above. selegilline is a selective MAO-b inhibitor Mmmm I can't agree. While impulsively E does looks correct, if you spend more than 5 minutes looking into it you'll find you are probably off base there... DRUG INTERACTIONS: Selegiline is a monoamine oxidase inhibitor. Although at LOW DOSES selegiline is selective for MAO type B, in doses above 30-40 mg/day, this SELECTIVITY IS LOST. Selegiline, despite its selectivity, can provoke serious CNS reactions in patients receiving either tricyclic antidepressants (clomipramine, desipramine, etc.) or fluoxetine. Other catecholamine-releasing or indirect sympathomimetic agents (e.g., EPHEDRINE, phenylpropanolamine) may induce drug interactions with selegiline at higher doses. (The P-I-E-N-O Parkinsn's List Drug Database Index) (I then found this article: A 57-year-old white man presented with hypertensive crisis apparently as a result from an interaction between ephedrine and selegiline. ... www.theannals.com/cgi/content/full/37/3/438 Note- Despite Sassada suggesting that ephedrine is MAO resistant... Stoelting p303 states that while "Ephedrine is resistant to metabolism by MAO in the gastrointestinal tract........ Some ephedrine is deaminated by MAO in the liver, and conjugation also occurs"... Continuing the conversation with myself.... Peck (p277/78) states Those taking MAOI's ... should not be given pethidine or any INDIRECTLY acting sympathomimetics (eg ephedrine). If CVS support is required the DIRECT acting agents should be used but with extremet caution as they may also precipitate exaggerated Hypertension. The directly acting symapthomimetic amines should also be used in caution although they are highly metanolised by COMT and therefore not subject to the same degree of exaggerated response. Peck page 205: (Dopamine)... despite being a direct acting sympathomimetic amine the effects of dopamine may be significantly exaggerated and prolonged during MAO therapy In summary; I'd gor for EPHEDRINE; It acts indirectly, has some MAO metabolism in liver as above and is linked in literature to a hypertensive crises. My second choice would possibly be Dopamine as the question doesn't state selegiline in high doses. Re other options: metaraminol has both direct and indirect sympathomimetic actions but predominately direct actions. Phenlynephrine is direct acting. Feel free to add anything. I'm so done with this one....

Answer 269

COMMENT Diuretics abolish the kidney's ability to concentrate urine by washing out the hypertonic medulla. They do this either by an osmotic effect that prevents water reabsorption (e.g mannitol) or by inhibition of active NaCl transport in the thick ascending loop (e.g furosemide) or the first part of the distal tubule (e.g hydrochlorothiazide)..(Miller 7th ed, page 450) Agreed - A best answer

Answer 270

A - True - produces thiocyanate which is >100x less toxic B - False - no brainer really C - False - releases 5 CN- ions not 4 D - False sodium nitrate is used to generate methaemaglobin and then Cyanomethaemaglobin in turn. A different treatment strategy than sodium thiosulphate. The last treatment strategy is to administer Vit B12a (hydroxycobalamin) which binds cyanide to form cyanocobalamin (Vit B12) - it is both expensive and leads to red skin and mucous membranes Tachyphylaxis is the first sign along with a metabolic acidosis and raised mixed venous pO2 References Stoelting 4th Ed p357

Answer 271

A. Potassium sparing - false - Triamterene directly blocks the epithelial sodium channel (ENaC) on the lumen side of the kidney collecting tubule. may cause hyperkalaemia and minimal hyponatraemia B. Thiazide - false - likely to cause hyponatraemia and hypokalaemia C. Loop - false - likely to cause hypernatraemia and hypokalaemia D. Thiazide - false - likely to cause hyponatraemia and hypokalaemia E. Aldosterone Antagonist (potassium sparing) - True - best answer as more likely to cause significant hyponatraemia than a potassium sparing diuretic like tiamterene or amiloride

Answer 272

A - False - "Vasopressin may serve as an adjunct in the control of oesophageal varicose... effect is due to marked splanchnic vasoconstriction" (Stoelting 4th e. p.472) B - False - "Vasopressin is an alternative to epinephrine for vasopressor therapy during CPR. (Stoelting 4th e. p.472) C - True - "This drug [vasopressin] is not effective in the management of patients with nephrogenic diabetes insidious" (Stoelting 4th e. p.472) D - False - "Vasopressin infusion is effective in reversing systemic hypotension in catecholamine-resistant septic shock" (Stoelting 4th e. p.472) References Stoelting 4th ed. p472)

Answer 273

A. - False - synthetic non-catecholamine B. - True - increased CNS norad and dopamine -> hypertensive crisis and vasoconstriction + tachycardia and dysrthymias at high doses. (katsung 11th ed. p.565) C. - True - "tachyphylaxis is prominent and drug dependence is predictable" (Stoelting 4th ed. p.304) D. E. - likely false - "CNS stimulant effects, as well as appetite suppressant actions reflect release of norepinephrine from storage sites in the CNS." (Stoelting 4th e.d p.304)

Answer 274

A false - electricity is the first line B false - it does not C false - no improvement D true - v1 action increases svr and therefore MAP. No improvement in mortality. E false - amiodarone is indicatd in VF and has a survival benefit. Amiodarone is contraindicated in Tosrsades as it will increase the QTc and potentially worsen the dysrhythmia.

Answer 275

``` Adenosine class 5 There are five main classes in the Singh Vaughan Williams classification of antiarrhythmic agents: Class I agents interfere with the sodium (Na+) channel. Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers. Class III agents affect potassium (K+) efflux. Class IV agents affect calcium channels and the AV node. Class V agents work by other or unknown mechanisms. ``` Answer: D