Pharmacology MCQs 2 - ANZCA Flashcards
IV01 [Mar96] [Mar97] [Jul97] Propofol: A. Has a pKa of 7 B. Has a pH of 11 C. Causes hypotension due to myocardial depression D. Has 98% protein binding E. ?
Answer D is correct.
Propofol has pH 6.5-8 and pKa 11. Hypotension is secondary to reduction in SVR.
According to Goodman & Gilman
p227 Table 13-2:
% Protein binding of propofol is 98
p228 under Cardiovascular:
Propofol produces a dose-dependent decrease in blood pressure that is significantly
greater than that produced by thiopental; the effect is explained by vasodilation and
mild depression of myocardial contractility
Thus although propofol has direct alpha and beta blocking properties, answer D is more correct as the hypotension is due more to vasodilation than myocardial depression.
IV02 [Mar96] [Jul97] [Apr01] [Jul06]
Thiopentone causes a decrease in BP by:
A. Direct decrease in myocardial contractility
B. Fall in systemic vascular resistance
C. Decrease in venous tone
D. Does not usually cause an increase in heart rate
E. ?
IV02 [Mar96] [Jul97] [Apr01] [Jul06]
Thiopentone causes a decrease in BP by:
A. Direct decrease in myocardial contractility - incorrect “…thiopental produces minimal minimal to no evidence of myocardial depression” (Stoelting 3rd ed. p.120)
Conversely, Stoelting (4th ed p.134) also says “in the absence of compensatory increases in SNS activity… a negative inotrope effect is readily demonstrated”, and (Sasada & Smith) also back it up by saying “Thiopentone is a negative inotrope”
B. Fall in systemic vascular resistance probablycorrect
C. Decrease in venous tone correct “the resulting dilatation of peripheral capacitance vessels lead to pooling of blood, decreased venous return, and the potential for deceases in cardiac output and blood pressure” (Stoelting 3rd ed. p.120)
D. Does not usually cause an increase in heart rate - incorrect “most likely explanation for compensatory tachycardia and unchanged myocardial contractility associated with IV administration of thiopental is a carotid sinus baroreceptor mediated increase in peripheral sympathetic nervous system activity” and “In normovolaemic subjects, thiopental… produces a transient… decrease in blood pressure that is offset by a compensatory… increase in heart rate” (Stoelting 3rd ed. p.120)
E. ?
The predominant cardiovascular effect of thiopentone is venodilation.
Other effects include:
SVR is usually unchanged
Pulmonary vessels are dilated
Myocardial contractility is depressed (but to a lesser extent than with volatile agents)
Only slight baroreceptor reflex suppression
Cerebral vasoconstriction (decreasing CBF & ICP) due to decreased cerebral metabolism
“Thiopentone directly depresses the contractile force of the heart, it increases heart rate,
coronary blood flow, and the oxygen demand of the heart. Thiopentone also causes a decrease
in venous tone, causing pooling of blood in the peripheral veins; this can cause hypotension
in patients who are hypovolaemic (eg following haemorrhage).
[1]
“Heart rate generally rises slightly on injection but there is vasodilation and a drop in
cardiac output. This is clinically significant in hypovolaemic patients and those with
intercurrent medical conditions but in otherwise healthy patients, is well tolerated.
Cardiovascular compromise is less marked than with propofol.
[2]
THIO DROPS BLOOD PRESSURE BY DEPRESSIon of medullary vasomotor center & sympathetic outflow
Seems to me, that every answer except D is correct to some extent
IV03 [Mar96] [Jul96] [Jul97] [Mar99] Ketamine: A. Is a direct inotrope B. Causes bronchodilatation C. Less likely to see emergence delirium (?psychotomimetic effects) in ?older/?younger females D. Reduces pharyngeal secretions E. Leaves airway reflexes reliably intact
A: NO - the positive sympathomimetic effects of ketamine are INDIRECT due to stimulation in the brain stem centres. The ‘direct’ effect of ketamine on the heart is a negative inotrophic effect (This is now ‘standard knowledge’ but I remember the point was made in the review of Ketamine that was in Anesthesiology in the 1980s.)
B: Bronchodilation. Yes - good drug for asthmatics (but not ‘routine’ therapy).
C: Emergence delirium is more likely in females aged >16, pre existing psych illness, rapid admin/high dose. Less likely if age >65 yrs, benzodiazepine pre-med, children, repeated doses.
D: Totally wrong: ketamine increases secretions and depending on the circumstances in which you use it, may need to use an anti-cholinergic (ie atropine or scopolamine) for its anti-sialogogue effect.
E: not “reliably”, thank you
The phrase that was often used when referring to ketamine was “relative sparing of airway reflexes”. The “relative” meant compared to other agents, and yes, there have been cases of aspiration associated with the use of ketamine. In practice, this phrase was part of the justification that was given as to why ketamine was “safer” in less skilled hands, but in reality this was wrong.
IV04 [Mar96] [Apr01] With regards the action of midazolam: A. Ring closure occurs immediately on injection B. ? C. ?
the ph 3.5 its ring structure is open and it’s ionised. >4 ring structure closes and it becomes unionised answer a
does it occur immediately then? Given that it’s 5ml of pH 3.5 solution, into 5L of pH 7.4 solution I’d think it would.
IV05 [Jul97] [Mar99] [Jul99] [Apr01]
Propofol depresses cardiac output predominantly by:
A. Direct depression of myocardial contractility
B. Decreased SVR
C. ?
D. ?
Most correct answer A - “A negative inotropic effect of propofol may result from a decrease in intracellular calcium availability secondary to inhibition of transsarcolemmal calcium influx” (Stoelting 3rd Ed. p.143)
A- because CO = HR x SV and determinants of SV are Preload and Contractility and a decrease in Afterload should cause an increase in CO, but a negative inotrope will drop contractility thus CO.
Would be interesting to see other options for this stem. I believe A is incorrect. Propofol has similar venodilation and negative inotropy to thiopentone. It also causes decreased SVR, increased vagal tone and inhibition of baroceptor reflex.
B - Decreased SVR : correct
No mention about direct cardiac depression on Peck & Hill’s – the likely answer will be B.
B - decreased SVR - is a correct statement in of itself, but not in answer to the question. Decreased SVR does NOT directly reduce CO (it possibly after several beats if pooling begins to develop)
stoelting 159 These decreases in blood pressure are often accompanied by corresponding changes in cardiac output and systemic vascular resistance - I vote B
I could propose a summary of the statements above. 1. Propofol causes both direct myocardial depression and vasodilation causing decreased SVR 2. Propofol has beta blocking properties; thus a reflex tachycardia is not seen 3. The decreased blood pressure is thus caused by vasodilation 4. The reduction in cardiac output, on the other hand, is caused by direct myocardial depression
Thus A would be the correct answer in this case. If the query were regarding reduced MAP, B would be the correct answer.
IV06 [Jul97] [Apr01] Methohexitone: A. Has a molecular weight of 285 B. Has a melting point of 158 degrees C. A 2.5% solution is isotonic D. Is yellow E. Has 4 isomers
V06 [Jul97] [Apr01]
Methohexitone:
A. Has a molecular weight of 285 (False; 262)
B. Has a melting point of 158 degrees (Can’t find data, but unlikely)
C. A 2.5% solution is isotonic
D. Is yellow - false - ‘white crystalline powder dissolved to yield clear, colourless solution’ Sasada + Smith
E. Has 4 isomers - true
IV06b [Mar02]
Methohexitone
A. Is a oxythiobarbiturate
B. Breakdown is principally by splitting of ring
C. “Longer duration than thio/ or maybe greater protein binding compared to thio??”
D. ?
E. ?
IV06b [Mar02]
Methohexitone
A. Is a oxythiobarbiturate - false
B. Breakdown is principally by splitting of ring
C. “Longer duration than thio/ or maybe greater protein binding compared to thio??” - shorter acting than thiopentone
D. ?
E. ?
Not sure about answer A is memorised correctly, it may actually be oxybarbiturate and thiobarbiturate as tehre is no such thing as oxythiobarbiturate. The answer would be correct if it was oxybarbiturate.
C is wrong because thio has longer duration AND greater protein binding
IV06c [Jul06]
Methohexitone
A. is an oxythiobarbiturate
B. is painful when injected into small veins
C. has a longer onset of action than thiopentone
D. is metabolised by opening of the ring
E. has a MWt of 285
F. Is no longer in the syllabus but they asked it anyway!
IV06c
Option F is most correct, but this has never stopped them before!
Option B is the best answer
A: oxybarbiturate -
B: more significant pain on injection than thiopentone
C: false
D: side chain modification occurs first
E: MWT = 257
see “Basic & Clinical Pharmacology”, B. G. Katzung, 10th ed., McGraw-Hill, 2006.
Methohexitone is a methylated oxybarbiturate (No sulphur so NOT a thiobarbiturate). It is presented as a white crystalline powder. It has a shorter duration of action than thiopentone
Has 4 optically active isomers but clincally used as racemic mixture (see Peck, Williams)
From Qld Short Cse 2007: Structure activity relationships of Barbiturates - double or triple bonds in the alkyl side chains increase lipid soluability and speed of onset…see diagram below.
IV07 [Mar98] Benzodiazepine binding site on GABA receptor is: A. Near Cl- channel B. Inside the channel C. Outside the channel D. On the alpha subunit E. ?
Answer is D - “Benzodiazepines attach selectively to alpha subunits” (Fig 5-2 Stoelting 3rd ed. p.127)
Benzodiazepines bind on the interface of the alpha and gamma subunits (see diagrams below). D is the closest answer.
figura_4_4.jpg
fig10.32.gif
Gamma-Aminobutyric acid (GABA) is:
the most common inhibitory neurotransmitter in the brain, and is
present at about 40% of brain synapses.
There are three classes of GABA-receptors: A, B, and C.
The GABAA receptor is a pentameric, ligand-gated chloride channel which has sites which can bind GABA, benzodiazepines, barbiturates, and steroid anaesthetics. The GABAA receptor belongs to a superfamily of ligand-gated ionotropic receptors, including the nicotinic acetylcholine receptor, which the GABAA receptor evolved from.
In mammals, seven classes of subunits of this receptor have been identified, and most subunits have several isoforms: α1-6, β1-4, γ1-3, δ, ε, θ, and ρ1-2.
GABA-receptor.jpg
Subunits from only one class (α) or two classes (α and β) can form functional GABA receptors under experimental conditions, but subunits from three classes (α, β, and γ) are needed for full receptor function; these three subunits also compose most of the GABAA receptors in the mammalian brain. With the use of these three, the most common isoform in the mammalian brain is (α1)2 (β2)2 (γ1).
http://www.kerrybrandis.com/wiki/mcqwiki/index.php?title=IV07
IV08 [Mar98] [Jul01] The drug with the largest volume of distribution at steady state is: A. Propofol B. Midazolam C. Etomidate D. Thiopentone E. Methohexitone
a) Propofol 4.5 l/kg
b)Midazolam - 1-1.5 l/kg (t1/2 1-4 hrs)
c)Etomidate - lipid sol than thio ??lower vd (t1/2 - 1.5 hrs plasma and liver esterases)
d)Thiopentone - 2.5 l/kg (t1/2 - 11.6 hrs)
e)Methohexitone - 2.2 l/kg (t1/2 - 3.9 hrs)
Additional: Etomidate Vd 3 l/kg P&H 109
The information sheet in Diprivan actually says that the “Propofol has a steady state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults”
IV09 [Jul98] [Jul04]
GABA:
A. Is the principal inhibitory neurotransmitter in the spinal cord
B. Barbiturates decrease the dissociation time between GABA and its receptor
C. ??A & B types??
D. ?
A incorrect - “Glycine is the principle inhibitory neurotransmitter in the spinal cord” Stoelting 3rd ed p 603.
B correct - “The interaction of barbiturates (and propofol) with specific membrane components of GABA receptor appears to decrease the rate of dissociation of GABA from its receptor” (Stoelting 3rd ed p 113)
“Electrophysiologic studies have shown that benzodiazepines potentiate GABAergic inhibition at all levels of the neuraxis, including the spinal cord” (Katzung 9th ed. pp.356-7). Also “GABA is the major inhibitory neurotransmitter in the CNS, being present in diverse areas including the… spinal cord” (Stoelting 3rd ed. p.602) In response to the answer below the line, if there are other major inhibitory neurotransmitters in the spinal cord, what are they?
Answer to above-glycine is major inhibitory neutro transmitter in Spinal cord.
B false - “The interaction of barbiturates (and propofol) with specific membrane components of the GABA receptor appears to decrease the rate of dissociation of GABA from its receptor, thereby increasing the duration of the GABA-activated opening of the chloride-ion channel” (Stoelting 3rd ed. p 114)
GABA IS the major inhibitory neurotansmitter in the brain; present at 40% of brain synapses.
Other: Tricky wording of option B - decreases the dissociation rate (but would increase association time). Barbiturates thought to act by decreasing the rate of dissociation of GABA with its receptor (thereby ‘potentiating’ the effect of GABA).
I think (and Stoelting agrees) A is wrong - "glycine is principal inhibitory neurotransmitter in the spinal cord". Stoelting eth ed p675 - hint look up the index for the word GLYCINE...the only page number is 675. Easy. I think B is correct - by decreasing the dissociation time they must increase the association time of GABA and its receptor. That's exactly how they work. BZD increase the frequency of the association and barbiturates increase the time of association. Am I missing something here?? Stoelting 4th ed p128 describes it as "decrease the rate of dissociation of GABA from it's receptor, thereby increasing the duration of the GABAa-activated opening of chloride channels." Wow, that's confusing! But doesn't the phrase 'decreasing the dissociation time' really mean the same thing as 'decreasing the association time'? Because don't we mean 'decreasing the time TO dissociaton' and 'decreasing the time OF association'...?
IV10 [Mar96] Propofol is structurally related to: A. Althesin B. Etomidate C. Ketamine D. ? E. None of the above
Option E is the best answer
Propofol is a 2,6 - diisopropyl phenol - an alkyl phenol derivative It is structurally unrelated to any of the above agents
althesin = alphalaxone and alphadolone in cremophor EL (= propylene glycol, castor oil and parabenz) —- both water insoluble steroids
etomidate = imidazole derivative , unrelated to any other IV anaesthetic
ketamine = arylcyclohexylamine structurally related to phencyclidine
clove oil = eugenol derivative , called propanidid
IV11 [Mar99] [Feb00] Midazolam: A. Water soluble at physiological pH B. Undergoes oxidative metabolism C. More lipophilic than lorazepam D. Causes hypotension E. Has a pKa of 7.4 (or ? 8.1) F. Causes retrograde amnesia
Midazolam:
A. Water soluble at physiological pH -> false: at physiologic pH midazolam is a “highly lipid-soluble drug” (Stoelting 3rd ed. p.128)
B. Undergoes oxidative metabolism -> true: “undergoes extensive hydroxylation by hepatic microsomal oxidative mechanisms” (Stoelting p. 129)
C. More lipophilic than lorazepam -> unsure. Lorazepam is less lipophilic than diazepam (Stoelting p.136)
D. Causes hypotension -> true: “produces a greater decrease in systemic blood pressure and increase in heart rate than does diazepam” (Stoelting p. 130)
E. Has a pKa of 7.4 (or ? 8.1) - false: pK is 6.15 (Stoelting p.128)
F. Causes retrograde amnesia -> false (trust me, but no reference!!) [anterograde amnesia only, somewhere in Ch5 Stoelting 4ed.
Its commonly stated that no drugs cause retrograde amnesia, and that the only thing that causes retrograde amnesia is a head injury. I’ve never seen the evidence for this sweeping generalisation but its such “common knowledge” that you would be foolish to think otherwise when in exam context.
Midazolam: Correct answer D? (B)
1. not water soluble at physiological pH as it is lipophilic and binds to proteins in plasma.
2. Undergoes hydroxylation and conjugation, not oxidation (???? see below)
3. Midazolam is MORE lipophilic than lorazepam (Miller)
4. CAN CAUSE HYPOTENSION AT PREAAESTHETIC DOSES (secondary to decrease in peripheral vascular resistance) - BUT This is not a serious issue with midazolam which is more associated with CVS stability, so I think this is UNLIKELY to be the correct answer.
5. pKa is 6.5 - (Peck Hill and Williams)
6. causes anterograde amnesia NOT retrograde
Hydroxylation is a form of oxidative metabolism; it is due to the mixed function oxidases in the liver (cytochrome p450 3A4 - benzos, barbiturates, macrolides, paracetamol, fentanyl)
I think I would go with mida more lipophillic than lorazepam. seems to be the most clear cut true option. Ive always thought that oxidation and hydroxylation are two different things and along with reduction are classified as phase 1 reactions in liver metabolism as opposed to glucoronidation, sulphation et al which is phase 2. the other options are all clear false statements
A common Phase I oxidation involves conversion of a C-H bond to a C-OH. [1]
IV12 [Jul98]
Thiopentone:
A. Is the sulphur analogue of phenobarbitone
B. Has higher protein binding than its oxy analogue
C. ? 6% sodium bicarbonate
D. Isotonic at 2.5% concentration
IV12 - Jul98
A - FALSE - thiopentone is the sulphur analogue of PENTObarbitone. (easy to remember - it’s thioPENTOne not thioPHENOne)
B - TRUE - protein binding of barbiturates parallels lipid solubility, thiobarbiturates are bound to greater extent than oxybarbiturates Stoelting 4th ed p128
C - FALSE - it’s 6% sodium CARBONATE
D - FALSE - 2.5% is not isotonic, just less chance of necrosis/tissue damage if extravasation
Commercial Preparations
Ref: Stoelting 4th page 127
prepared from highly alkaline solutions as sodium salts that are readily soluble in water or saline.
pH of 2.5% Thio is 10.5
incompatible for mixture with opiois, catecholamines and NMB drugs (which are acidic in solution)
bacteriostatic - due to high pH
contains 6% anhydrous calcium carbonate to prevent precipitation of the insoluble acid form of barbiturate by atmospheric CO2 - for same reason stored under N2 not air
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IV12b [Feb12] Thiopentone contents A Commercial preparation contains sodium carbonate B 2.5% solution has a pH of 11.5 C Preparation contains CO2 D It is presented as sodium salt E ?
IV12b - Feb12
A - Commercial preparation contains sodium carbonate - true - to prevent precipitation of the acidic salt with CO2
B - 2.5% solution has a pH of 11.5 - false 10.5 (stoelting 4th ed p127) or 10.8 (sassada and smith 4th ed p634)
C - Preparation contains CO2 - false - CO2 would potentially cause precipitation of the acidic salt of thiopentone - stored under nitrogen not air containing CO2
D - It is presented as sodium salt - true
E - ?
Commercial Preparations
Ref: Stoelting 4th page 127
prepared from highly alkaline solutions as sodium salts that are readily soluble in water or saline.
pH of 2.5% Thio is 10.5
incompatible for mixture with opiois, catecholamines and NMB drugs (which are acidic in solution)
bacteriostatic - due to high pH
contains 6% anhydrous calcium carbonate to prevent precipitation of the insoluble acid form of barbiturate by atmospheric CO2 - for same reason stored under N2 not air
IV13 [Jul98] Propofol clearance is significantly increased in: A. Elderly B. Metabolic acidosis C. Pregnancy D. ? E. ?
Propofol clearance is significantly increased in:
A. Elderly - FALSE: decreased in elderly
B. Metabolic acidosis - probably false: no justification for this though!
C. Pregnancy - probably TRUE: pregnancy is a high cardiac output state; propofol has a high hepatic extraction ratio (in fact clearance is greater than hepatic blood flow), so in this situation, propofol would probably have a higher than normal clearance
D. ?
E. ?
Stoelting 4th edn 156-7 has no mention of any condition with a marked increase in propofol clearance.
A: False - Stoelting states age >60yrs is associated with decreased clearance.
? look for E: none of the above.
Factors increasing clearance of propofol:
Fever, Hyperthyroidism, Anaemia (increase hepatic blood flow)
Hypoproteinaemia (increase free drug available for hepatic clearance)
http://www.anesthesia-analgesia.org/cgi/reprint/87/1/195.pdf
In Pregnancy there is a relative hypoproteinuria, physiologic anaemia and an increased hepatic blood flow, therefore, theoretically there would be an increased propofol clearance. However, propofol is not widely used in anaesthesia as it has a pregnancy category C whereas thiopentone has a category A.
Best Answer would be C. Pregnancy
Regarding option C:
I have read in a few places that pregnancy does not affect hepatic blood flow (despite it being a high cardiac output state). Hepatic enzymes are more active causing increased metabolism of drugs with low HER (but not influencing propofol which has high HER).
I have found a study where propofol pharmacokinetics were compared between pregnant women having LSCS and non-pregnant women having lap sterilisation following an IV bolus dose. They found that clearance was increased in the pregnant women (40ml/min/kg vs 30ml/min/kg) which they thought may be due to blood loss, delivery of foetus/placenta or increased extra-hepatic clearance.
So C seems to be true, at least for women having C-section, but nothing to do with the liver.
References
Laurence, Bennett and Brown 8th Ed p115
Pharmacokinetics of Propofol in Women Undergoing Elective Caesarean Section British Journal of Anaesthesia, 1990, Vol. 64, No. 2 148-153
Additional Comment: OK this question has been repeated in MULTIPLE RECENT EXAMS (2006-2008) in various forms and with quite annoying varied answers from everybody. The problem is the definition of “significant” change –> anyway, when all else fails, go to MILLER.
Miller : Electronic Edition, page 320 “ The pharmacokinetics of propofol may be altered by a variety of factors (e.g., gender, weight, preexisting disease, age, concomitant medication).14,15,18,48,49 Propofol may impair its own clearance by decreasing hepatic blood flow.50 Of clinical significance is that propofol may alter its own intercompartmental clearance because of its effects on cardiac output. Changes in cardiac output alter propofol concentrations after a bolus dose and during constant infusion. Increasing cardiac output leads to a decrease in propofol plasma concentration and vice versa.51,52 In a hemorrhagic shock model, propofol concentrations increase up to 20% until uncompensated shock occurs, at which point a rapid and marked increase in propofol concentration occurs.53 Women have a higher volume of distribution and higher clearance rates, but the elimination half-life is similar for males and females.14,18 The elderly have decreased clearance rates but a smaller central compartment volume.15,18 In addition, patients presenting for coronary artery bypass surgery seem to have different pharmacokinetic parameters than other adult populations do. When a patient is placed on a cardiopulmonary bypass machine, the resulting increase in central volume and initial clearance necessitates higher initial infusion rates to maintain the same propofol plasma concentration.54 Children have a larger central compartment volume (50%) and more rapid clearance (25%).55 In children older than 3 years, volumes and clearances should be adjusted by weight.56 Children younger than 3 years also demonstrate weight-proportional pharmacokinetic parameters, but with greater central compartment and systemic clearance values than in adults or older children.56 This finding explains the higher dosing requirements in this age group.57 Hepatic disease appears to result in larger steady-state and central compartment volumes; clearance is unchanged, but the elimination half-life is slightly prolonged.48 The effect of fentanyl administration on the pharmacokinetic parameters of propofol is controversial. Some studies suggest that fentanyl may reduce intercompartmental and total-body clearance rates, as well as volumes of distribution.58 When propofol was administered with alfentanil at similar infusion rates, the measured propofol concentrations were 22% greater than when propofol was administered alone.59 A separate study found that fentanyl did not alter propofol pharmacokinetics after a single dose of both drugs.60 Some of these differences in propofol pharmacokinetics when given with an opioid may be explained by studies in cats in which it was shown that pulmonary uptake of propofol is reduced by 30% when propofol is administered immediately after fentanyl, but not if administered 3 minutes later.61 In addition, in vitro studies on human hepatocytes have demonstrated that propofol inhibits the enzymatic degradation of both sufentanil and alfentanil in a dose-dependent manner.62 Propofol kinetics is unaltered by renal disease.49”
As per miller: (1) propofol reduces its own metabolism by decreasng hepatic flow. (2) propofol clearanc is higher in women but with larger Vd t1/2 beta is unchanged (3) propofol clearance is lower in elderly but with smaller Vd (4) propofol clearance and Vd is greatest in children 3years, > adults (5) Propofol clearance is unchanged in hepatic disease but with larger Vd t1/2 beta is prolonged (6) Propofol clearance is unaltered by renal disease.
IV14 [Feb00] [Jul04] Thiopentone: A. 100% reabsorbed in renal tubule B. Does not cross the placenta in significant amounts due to high plasma protein binding C. ??accumulate in the foetus D. ? E. ?
Thiopentone:
A. 100% reabsorbed in renal tubule
B. Does not cross the placenta in significant amounts due to high plasma protein binding - sounds incorrect. Although high protein binding, it is also lipid soluble meaning relatively easy placental transfer
C. ??accumulate in the foetus
D. ?
E. ?
Seems to be completely reabsorbed in kidney as highly lipophilic. Crosses placenta, but processed by fetal liver so concentrations not as high as for mother, so does not accumulate. So, going for A unless you’ve got a better idea!?
Not sure if this helps but: Stoelting 4th ed p128 - “Protein binding of thiopental in neonatal plasma (placental blood) is about half that measured in adults, suggesting a possible increased sensitivity to thiopental in neonates. This unbound fraction of thiopental could be increased further by foetal acidosis that may accompany a stressful delivery.”
- the “100%” wording is worrying and reminds me of “always” or “never” which are flags for a wrong answer.
-
IV15 [Jul00] Thiopentone: A. ? Tachyphylaxis if multiple administration in short period B. ? C. ?
The time frame here is quite vague. Barbiturates induce hepatic enzymes after 2-7 days of continuous infusion (and therefore increase tolerance). However, you can see acute tolerance to barbiturates before the enzyme induction (mechanism?). from Stoelting.
Stoelting 4th ed p137 - “Acute tolerance to barbiturates occurs earlier than does barbiturate-induced induction of microsomal enzymes.”
IV16 [Jul00] Propofol: A. 10% eliminated unchanged B. Undergoes oxidative metabolism C. Clearance depends on hepatic blood flow D. No effect / chronic liver disease E. ?
This is a difficult question
Propofol:
A. 10% eliminated unchanged - FALSE: “less than 0.3%… excreted unchanged” (Stoelting p.140)
B. Undergoes oxidative metabolism - ?false: “Hepatic metabolism is rapid and extensive” (Stoelting p.140) via conjugation to glucuronide and sulphates.
C. Clearance depends on hepatic blood flow - ?false “clearance of propofol… exceeds hepatic blood flow” (Stoelting p.140) but if you had no blood flow would clearance be impaired -> answer is probably
D. No effect / chronic liver disease - ?correct “no evidence of impaired elimination in patients with cirrhosis of the liver” (Stoelting p.140) and it’s used frequently in liver patients at a liver centre I’ve worked in…
E. ?
0.3% excreted unchanged in urine
Metablolism in liver is by hydroxylation then glucuronide conjugation (isn’t this oxidative??)
Clearance greater than hepatic blood flow (25-30ml/kg/min)
Clearance continues independent of liver and renal function
?option E
Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes
“Oxidation of propofol to 4-hydroxypropofol represents a significant pathway in the metabolism of this anesthetic agent in humans”. (Anesthesiology. 2001 Jan;94(1):110-9).
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=11135730&dopt=Abstract
Stoelting page 156: hepatic oxidative metabolism by cytochrome P-450 is important in removal of propofol (sic) from the plasma
REferences
“Drugs in Anaesthesia and Intensive Care”, M. Sasada & S. Smith, 3rd ed, Oxford Medical, 2003.
IV17 [Apr01] Ketamine: A. Direct acting negative isotope (“It did say this”) B. ?Indirectly acts on SNS peripherally C. Directly on the sympathetic ganglia D. ? E. ?
Comments:
[1] Both independently submitted versions of this MCQ contained a comment that one of the options was ‘negative isotope’.
[2] Using the information contained in these 2 submitted versions, we can attempt to reconstruct the whole question as below. However, the question still does not look right: for example 3 options say ‘directly’ and only one says ‘indirect’ & the other does not use either term, so by ‘frequency analysis’, this suggests that one of A, C or E is correct. The problem with this is the College has in recent times been going through their whole MCQ Bank trying to eliminate this type of “design problem” where you can guess or narrow in towards the answer by looking at the frequency of numbers or words in the different options.
Reconstructed IV17:
Alt version: Ketamine:
A. Is a negative isotope (“it was isotope and not inotrope”)
B. ?
C. Directly stimulates autonomic ganglia
D. Is a competitive antagonist at NMDA receptors
E. Directly stimulates alpha and beta receptors?
Comments:
[1] Both independently submitted versions of this MCQ contained a comment that one of the options was ‘negative isotope’.
[2] Using the information contained in these 2 submitted versions, we can attempt to reconstruct the whole question as below. However, the question still does not look right: for example 3 options say ‘directly’ and only one says ‘indirect’ & the other does not use either term, so by ‘frequency analysis’, this suggests that one of A, C or E is correct. The problem with this is the College has in recent times been going through their whole MCQ Bank trying to eliminate this type of “design problem” where you can guess or narrow in towards the answer by looking at the frequency of numbers or words in the different options.
Reconstructed IV17:
Ketamine:
A. Direct acting negative isotope
B. ?Indirectly acts on sympathetic nervous system peripherally
C. Directly on the sympathetic ganglia
D. Is a competitive antagonist at NMDA receptors
E. Directly stimulates alpha and beta receptors
Ketamine:
A. Direct acting negative isotope - yes, no, maybe
B. ?Indirectly acts on sympathetic nervous system peripherally - true: indirect sympathomimetic
C. Directly on the sympathetic ganglia - probably false: thought to act centrally
D. Is a competitive antagonist at NMDA receptors - false: non-competitive antagonist
E. Directly stimulates alpha and beta receptors - false: indirect sympathomimetic
IV17a [Jul04] -Aug15
Ketamine:
A. Is a NON-competitive antagonist at NMDA receptors
B. ?Direct acting negative inotrope
C. ?Indirectly acts on sympathetic nervous system peripherally
D. ?Directly on the sympathetic ganglia
E. ?Directly stimulates alpha and beta receptors
Re version IV17a [Jul04] Ketamine:
A. Is a NON-competitive antagonist at NMDA receptors - True
B. ?Direct acting negative inotrope - False
C. ?Indirectly acts on sympathetic nervous system peripherally - sort of true
D. ?Directly on the sympathetic ganglia - false
E. ?Directly stimulates alpha and beta receptors - false
A TRUE. Ketamine is a noncompetitive antagonist of the NMDA receptor.
B TRUE. Ketamine has a direct negative cardiac inotropic effect, causing direct myocardial depression invitro. The direct negative effect is usually overshadowed by ketamines central sympathetic stimulation but can be seen when halothane is given (depresses sympathetic NS outflow from CNS)or in cases of critically ill patients whose endogenous catecholamine stores are depleted.
C D E FALSE Ketamine increases sympathetic nervous system outflow by direct stimulation of the central nervous system (inhaled anaesthetics, ganglionic blockade, cervical epidural anaesthesia, spinal cord transaction prevent ketamine induced increases in BP, HR)
Actually, I believe the answer would be “Indirectly acts on SNS peripherally”. Goodman and Gilman 11th ed. - “CVS effects are indirect and are most likely mediated by inhibition of both central and peripheral catecholamine reuptake. Ketamine has direct negative inotropic and vasodilating activiy, but these effects usually are overwhelmed by the indirect sympathomimetic action.”
It is likely that ketamine’s action is to inhibit norepinephrine uptake at the neuroeffector
junction rather than to augment norepinephrine release.
- Mechanism of the positive inotropic effect of ketamine in isolated ferret ventricular papillary muscle
Cook et. al. Anesthesiology [1991, 74(5):880-8]
IV18 [Jul01]
With regard to GABA receptors: (OR: Which of the following is INCORRECT about
GABA neurotransmission?
A. GABA-A found all over the body
B. Is an excitatory transmitter in 20% of CNS synapses
C. GABA-B is predominately post-synaptic
D. GABA receptor located in spinal cord, medulla and rest in cortex.
E. Is metabolised by deamination
F. Is metabolised by transamination by ?GABA transaminase
G. Stimulated by benzodiazepines
H. Opposes action of glycine
With regard to GABA receptors: (OR: Which of the following is INCORRECT about GABA neurotransmission?
A. GABA-A found all over the body - probably false: mostly in CNS
B. Is an excitatory transmitter in 20% of CNS synapses - false: inhibitory neurotransmitter
C. GABA-B is predominately post-synaptic - false: mainly presynaptic
D. GABA receptor located in spinal cord, medulla and rest in cortex. - probably true
E. Is metabolised by deamination - likely false (is it possible to deaminate an amino acid??)
F. Is metabolised by transamination by ?GABA transaminase - true
G. Stimulated by benzodiazepines - yes and no: increased frequency of opening in the presence of GABA
H. Opposes action of glycine - false: glycine is also an inhibitory neurotransmitter
GABA-B is both pre-synatpic and post-synaptic.
Benzodiazepines increase the freq of Chloride channel opening
Dissenting comment: “In contrast (to GABA A), GABA B mechanisms may be preferentially involved in presynaptic inhibition through suppression of excitatory amino acid release from primary afferent terminals.” Power and Kam 2001 p.341
“GABA B receptors can mediate both postsynaptic and presynaptic inhibition.” (1)
GABA is metabolised by GABA transaminase also
[1] GABA metabolism: note: GABA –> GABA transaminase –> succinic semialdehyde
is it possible to transaminate a GABA receptor by ? GABA transaminase …the original question does say GABA receptors
References
(1) Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Siegel GJ, Agranoff BW, Albers RW, et al., editors. Philadelphia: Lippincott-Raven; 1999.
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
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)
IV20 [Mar02] Which one of the following induction agents does NOT exert its main effect via the GABA receptor? A. Ketamine B. Thiopentone C. Propofol D. Midazolam E. Methohexitone
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
IV21 [Feb04] [Aug11] Sodium carbonate is added to thiopentone: A. As a bacteriostatic agent B. To neutralise Thiopentones acidity C. To increase ionised portion D. Enhances activity E. ?
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.
IV22 [Jul04] Which agent does NOT cause increased heart rate on induction of anaesthesia? A. Thiopentone B. Etomidate C. Propofol D. Ketamine E. Methohexitone
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.
IV23 [Jul04] Benzodiazepine receptor has A. Two glycine binding sites B. ? C. ? D. ? E. ?
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]
IV24 [Jul04] Midazolam: A. Bioavailability 10% B. Bioavailability 50% C. Elimination t1/2 30 min D. Elimination t1/2 30 hours E. ?
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
Ketamine is not usually used as a sole TIVA agent because repeat
A. It causes profound analgesia but insufficent hypnosis for procedure
B. It causes emergence phenomena in up to 30% of patients when given as an infusion
C. It is too water soluble (or something like that) compared to propofol
D. Half life is 80 mins
E. ?
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
IV26 The amount of thiopentone remaining in brain 30 mins after administration: A. 10% B. 20% C. 30% D. E. 40%
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
IV27 Thiopentone is A. anti-analgesic in sub-therapeutic doses B. ? C. ? D. ? E. ?
“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)
IV28 Propofol is preferred to thiopentone in TIVA because: A Low therapeutic index B T1/2 keo C high clearance D. ? something about lipid solubility
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
IV29 Comparing thiopentone to propofol: A. Resistance to infection thio > prop B. t½keo prop = thio C. Effect site conc thio faster than prop D. Pain on infection thio > prop or D. was Pain on injection prop>thio
I’m pretty sure the question was “which selection was false” and options
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
IV30 [Feb13] Propofol: A. Has a chiral centre B. Does NOT need a dose reduction in the elderly C. Has active metabolites D. Clearance affected in cirrhosis E. ?
?
IV31 [Feb13] Five minutes after giving thiopentone, the amount remaining in brain is: A. 5% B. 10% C. 30% D. 50% E. 100%
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
IV31b [Alt Version] [Feb13] Percentage of thiopentone dose remaining in the brain FIVE minutes after a bolus dose: (definitely 5 not 30 mins as previously recalled/asked) A. 0.2% B. 0.5% C. 20% D. 35% E. 50%
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
IV32 [Feb13] Addition of sodium carbonate to thiopentone: A - Confers a yellow colour B - Increases lipophilicity?? C - provides CO2 D - E - Bacteriostatic
?
IV33 [Feb13]
With regards to the structure of barbiturate drugs:
A. ?
B. Oxygen substitution at the 1- position increases (?)half-life
C. Phenol substitution at the 5- position increases anticonvulsant activity
D. ?
E. ?
See Stoelting 4th ed p127
IV34 [Feb13] Propofol clearance A. Decreased in hepatic failure B. Decreased in renal failure C. Increased in children D. Decreased in cirrhosis E. ?
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
IV35 [Feb13] Ketamine: A. Decreases ICP / CBF B. Acts via opioid receptors C. Decreases salivation D. Airway reflexes E. ?
A - increases
B - F - nmda
C - F - inc
D - T ?
LA01 [Mar96] [Mar97] [Jul97] [Mar99] [Jul01]
Lignocaine has a pKa of 7.9 At pH 6.9, the percentage ionised is:
A. 1% (or 5%)
B. 10%
C. 50%
D. 90%
E. 99%
.
(Also remembered as: With a pKa of 7.9, what percent of lignocaine is ionised at intracellular pH?)
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%.
LA02 [Mar96] [Jul04]
Cocaine:
A. Blocks reuptake of dopamine and noradrenaline
B. Central effects are due to noradrenaline
C. Crosses lipid soluble membranes because its pKa is 2.8
D. Is not metabolised by plasma pseudocholinesterase
E. Rapidly absorbed by nasal mucosa
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
LA03 [Mar96] [Mar03]
Ropivacaine:
A. Produces greater motor block than bupivacaine
B. Is prepared as the R enantiomer
C. Is less lipid soluble than lignocaine
D. Has the same cardiotoxicity as lignocaine
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
LA03b [Mar97] [Feb00] Aug15
Ropivacaine
A. Is a pure R isomer
B. Is an isomer of bupivacaine
C. Provides more motor block than bupivacaine
D. Has more toxicity than bupivacaine
E. Has similar physico-chemical properties to bupivacaine
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?
LA03c [Mar98] [Jul98]
Ropivacaine differs from bupivacaine mainly by:
A. More motor blockade than bupivacaine
B. Mainly affecting A beta rather than A delta fibres
C. Lower cardiac toxicity than bupivacaine
D. ?
E. None of the above
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
LA04 [Mar96] [Mar99]
Bupivacaine:
A. Is an aminoester local anaesthetic
B. Is formed by substituting butyl for methyl on amino group of mepivacaine
C. ?Less/more toxic than tetracaine
D. Adrenaline solution contains sodium metabisulphite
E. Equipotent to etidocaine in causing motor block
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.
LA05 [Jul97]
With regard to molecular weight of local anaesthetics, which is the correct sequence?
A. Cinchocaine > bupivacaine > lignocaine > prilocaine
B. Bupivacaine > lignocaine > cinchocaine > prilocaine
C. Bupivacaine > lignocaine > prilocaine > cinchocaine
D. Prilocaine > bupivacaine > cinchocaine > lignocaine
E. Lignocaine>bupivacaine>prilocaine>cinchocaine
.
(see also LA09, LA10)
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.
LA06 [Jul97] [Jul04] Lignocaine works by: A. Altering Na+ permeability B. Altering membrane structure C. Reduced Ca++ permeability D. Increased K+ permeability E. Ca++ binding to tropomyosin
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”
LA07 [Jul97] Lignocaine: A. Has ?% uptake in lung B. Is 24% ionised at physiological pH C. Reduces Na+ conductance (?) D. ? E. ?
Lung Uptake: Alfentanil 80% Fentanyl 75% Propranolol 75% Pethidine 65% Lignocaine 60% Thiopentone 14% Morphine 3-5% Lignocaine is 25% UNionized at physiologic pH
LA08 [Jul97]
Lignocaine:
A. Has active metabolites
B. Metabolism faster in females because of progesterone
C. Metabolism is independent of liver blood flow
D. ?
E. ?
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.”
LA09 [Mar98] [Feb00]
Protein binding of local anaesthetics (in decreasing order):
A. Procaine > bupivacaine > lignocaine > prilocaine
B. Bupivacaine > lignocaine > prilocaine > procaine
C. Prilocaine > bupivacaine > lignocaine > prilocaine
D. Lignocaine > bupivacaine > prilocaine > procaine
E. Bupivacaine > lignocaine > procaine > prilocaine
F. Bupivacaine > procaine > lignocaine > prilocaine
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.
LA10 [Mar98]
Local anaesthetics are metabolized in the following order:
A. Bupivacaine > ropivacaine > lignocaine > prilocaine > procaine
B to E. (The above in different orders)
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
LA11[Mar98] Saxitoxin site on sodium channel is: A. Inside channel B. Outside channel C. On membrane outside D. ? E. ?
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).
LA12 [Jul98] The site of action of benzocaine is: A. Same site as saxitoxin (alt option: At the channel mouth ) B. Inside Na+ channel C. At axoplasmic end of Na+ channel D. At Ca++ channel E. In the cell membrane
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. 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]
LA13 [Jul98] EMLA cream contains: A. Soluble in water at >16 degrees C B. 20% ionised at pH ?? C. 80% ionised at pH ??.. OR: Base contains 80% local anaesthetic D. ?? amount of ionised drug E. All of the above
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
LA14 [Mar99] [Mar03]
What factor (?does not) influence the peak plasma levels after epidural injection of local anaesthetic?
A. Vasoconstrictor
B. Natural vasoconstrictor activity of the drug
C. Hepatic clearance
D. Renal clearance
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 (
LA15 [Mar99] [Mar03] Which ONE of the following is an amide? A. Tetracaine B. Procainamide C. Procaine D. Prilocaine E. Cinchocaine
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
LA15b [Jul01] The following are all amides except: A. Bupivacaine B. Prilocaine C. Etidocaine D. Tetracaine E. Dibucaine
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
LA15c Which of the following is not an esther local anaesthetic? A Prilocaine B Procaine C Amethocaine Other wrong answers'
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
LA16 [Jul99] Lignocaine: A. Anti-arrhythmic effect - ??Na channel /open & inactivated state B. Prolongs QRS C. ? D. ? E. ?
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.
LA17 [Jul99] [Feb00] [Jul00] [Jul01] [Jul03] [Jul07]
A solution of local anaesthetic contains 1:100,000 adrenaline. How much adrenaline has been added?
A. 0.01%
B. 0.1%
C. 10 mcg/ml
D. 100 mcg/ml
E. 1000 mcg/ml
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
Alt Jul07
A solution of LA contains 1:200000 adrenaline. How much adrenaline has been added?
A. 5 mcg/mL B. 50 mcg/mL C. 500 mcg/mL D. 0.5 mcg/mL E. 0.05 mcg/mL
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
LA18 [Feb00]
Regarding the addition of adrenaline to a local anaesthetic administered epidurally,
which of the following is NOT true?
A. Significantly prolongs the duration of action of bupivacaine
B. Causes tissue acidosis at the site of injection
C. Causes vasoconstriction
D. ?
E. ?
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!
LA19 [Jul00] [Jul01]
Regarding local anaesthetic plasma protein binding
A. Is predominantly by albumin
B. Is predominantly by alpha-1 acid glycoprotein
C. Is greater for tetracaine than for bupivacaine
D. Neonates have a greater number of binding sites
E. Plasma binding is directly proportional to local anaesthetic concentration.
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
[Jul01] For a local anaesthetic agent at a given concentration:
A. Effect is NOT dependent on resting membrane potential
B. Faster onset with increasing frequency of stimulation of nerve
C. Unionised form blocks the surface receptor
D. Agent blocks the channel in the activated state
E. Faster onset with more negative resting membrane potential.
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.
LA21 [Feb04] Lignocaine: A. Over 50% unionised at pH 7.4 ?? B. Decreased metabolism with GA ?? C. ? D. ? E. ?
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
LA22 Mar09
Levobupivacaine is different from bupivacaine in:
A. Increased hydrophobicity of the aromatic ring
B. Increased hydrophilicity of amine group
C. Addition of a methyl group to the hydrophilic amine ring
D. ?
E. ?
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.
LA23 Mar09
A toxic dose of bupivacaine is given and results in seizure and ventricular fibrillation. Which is most correct in order of priority:
A. Amiodarone, diazepam, ventilate with 100% O2, defibrillation
B. Ventilate with 100% O2, external cardiac compressions, diazepam, defibrillation
C. Diazepam, defibrillation, vetilate with 100% oxygen, cardiac compression
D. Ventilate with 100% oxygen, defibrillate, external cardiac compressions, adrenaline
E. External cardiac compressions, defibrillation, amiodarone, ventilate with 100% oxygen
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]”
LA24 [Mar09]
Cocaine
A. Overdose rarely causes convulsions
B. Central effects are due to high dopamine levels
C. Metabolism is dependent on plasma pseudocholinesterase
D. ?
E. ?
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.
LA25 Something about lignocaine blocking certain channels... A. G-prot mediated B. Voltage gated K channels C. Voltage gated Na channels D. Voltage gated Ca channels E. Voltage gated Mg channels
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
LA26 Which local anaesthetic has the FASTEST onset time? A. Lignocaine B. Bupivacaine C. Cocaine D. Levobupivacaine E. Ropivacaine
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
LA27 - 15A
EMLA is a local anaesthetic solution that
A. Consists of a mixture of local anaesthetics that are water soluble above room temperature
B. Consists of a base and its respective local anaesthetics in an emulsion
C. 20% ionisation of prilocaine and lignocaine
D. causes vasodilation
E. should not be left on longer than 1 hour
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.
LA28 11A
EMLA:
A. Contains lignocaine + procaine
B. The total local anaesthetic concentration is 2.5%
C. At 60 minutes, skin penetration is 10mm
D. Is more effective in caucasians
E. It causes vasoconstriction
?
MB01 [Mar96] [Jul97]
With regard to tetanic stimulation by a nerve stimulator:
A. Used to determine residual curarisation
B. Degree of fade is independent of stimulus duration
C. Degree of fade is dependent on stimulus intensity
D. Used to check depth of anaesthesia
E. ?
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
MB02 [Mar96] [Apr01] Hyperkalaemia with suxamethonium is associated with: A. Abdominal infection B. Parkinson's disease C. Meningomyelocoele D. Cerebral palsy E. Myotonic dystrophy
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.
MB03 [Mar96] [Jul96] [Jul97] [Mar98] [Mar99] [Jul99] [Feb00][Jul06x2] Which of the following is NOT metabolised by plasma cholinesterase? A. Procaine B. Cocaine C. Dibucaine D. Suxamethonium E. Esmolol F. Mivacurium
A F B - false - although major metabolic process is hepatic cholinesterase C - true - hepatic D - false E - true - red cell esterase F False
MB03b [Mar98] [Apr01] Which of the following is metabolised by plasma cholinesterase? A. Remifentanil B. Procaine C. Esmolol D. ? E. All of the above
A F B T C F D? E F
MB03c [Jul98] [Feb00]
Esterases metabolise all EXCEPT:
A. Remifentanil
B. Dibucaine - true - hepatic
C. Pyridostigmine - true - metabolised by CHOLINEsterases (also has significant renal clearance)
D. ?
i suggest that this has been remembered incorrectly
?
MB03 [Feb04] Which drug has a significantly prolonged duration of action in plasma cholinesterase deficiency? A. Remifentanil B. Procaine C. Mivacurium D. Rocuronium E. Cocaine
A F B F C T D F E F
MB03d [Aug 2011] In pseudo (plasma) cholinesterase deficiency which of these two drugs will have a prolonged effect? A. Mivacurium and Esmolol B. Suxamethonium and Procaine C. Remifentanil and Esmolol D. Suxamethonium and Esmolol E. Remifentanil and Mivacurium
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
MB03e [July 2012] Which of the following is NOT metabolised by plasma cholinesterase? (new) A. Heroin B. Mivacurium C. Suxamethonium D. Remifentanil E. Procaine
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)
MB03f Which of the following 2 drugs are metabolised by Plasma cholinesterase:
A Remifentanil and Procaine
B Esmolol and suxamethonium
C mivacurium and … -
D procaine and suxamethonium - hurrah! true
E…
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)
MR04 [Mar96] [Jul02] The action of nondepolarising neuromuscular blocking agents is PROLONGED by: A. Respiratory acidosis B. Increased temperature C. Increased calcium D. Increased potassium E. Decreased magnesium
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”
MB05 [Mar96] Agents prolonging nondepolarising NMBA by desensitising the post-junctional membrane : A. Phenytoin B. Halothane C. Lignocaine D. Verapamil
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.
MB06a [Mar96] [Jul98] Which drugs (?competitively) inhibit acetylcholinesterase? A. Neostigmine B. Pyridostigmine C. Physostigmine D. Edrophonium E. All of the above
[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
MB06b [Jul00] [Apr01] The activity of plasma cholinesterase is decreased by the following drugs except: A. Neostigmine B. Organophosphates C. THA D. Metoclopramide E. Cimetidine
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.
MB06c [Jul04] Which decrease plasmacholinesterase activity? (remembered options from 2 questions) A. Hepatic disease B. Cyclophosphamide C. 6 weeks post partum D. Hyperthyroidism E. Obesity F. Cytotoxic drugs G. Pregnancy E. Dibucaine number of 20
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.
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]
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
MB07 [Mar97] [Jul98] [Jul99] [Feb00] [Apr01]
Regarding vecuronium:
A. It accumulates in renal failure
B. Is a benzylisoquinolinium
C. Is a bisquaternary amine
D. Is more lipid soluble than pancuronium
E. Is predominantly renally excreted
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
MB08 [Jul97] [Jul98] [Mar99] [Jul02] [Mar03]
In reversing neuromuscular blockade, which of the following drug combinations
is best matched with respect to time of onset?
A. Atropine & neostigmine
B. Atropine & glycopyrrolate
C. Atropine & edrophonium
D. Atropine & physostigmine
E. Glycopyrrolate and edrophonium
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
MB09 [Jul97] [Jul98] [Mar99] [Jul99] [Jul00] [Mar03]
Plasma cholinesterase:
A. Metabolises dibucaine
B. Metabolises esmolol
C. Hydrolyses mivacurium at 80% the rate of suxamethonium
D. Is unaffected by neostigmine
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)
MB09b [Jul01] [Jul04]
Suxamethonium:
A. Bigger molecule than vecuronium
B. Needs to occupy 80% of nicotinic receptors to get effect
C. Resistant to hydrolysis by acetylcholinesterase
D. ??Is an antagonist at nicotinic receptors
E. Increasing dose produces similar block
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
MB10 [Jul97] [Jul98]
With regard to the nerve stimulator in competitive blockade:
A. Fade is dependent on stimulating frequency
B. TOFC of four is a sign of adequate reversal
C. ?
D. ?
E. ?
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).
MB11 [Jul97]
Anticholinesterase agents:
A. Carbamates duration of action is related to the time required for dissociation from the anionic site.
B. Carbamates act by acetylation of the esteratic site.
C. ?
(See also MD28)
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.
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 E. None of above
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
MB12 [dgj] [Jul00] [Jul02] [Jul04]
Mivacurium:
A. Is metabolised at 80% the rate of suxamethonium
B. Takes 15 mins from ED95 dose to recovery of 95% twitch height
C. Has an ED95 of 1.5 mg/kg
D. Trigger for malignant hyperthermia
E. ? Duration of action is increased in renal failure
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
July 2000 version:
Mivacurium:
A. Twice the ED95 dose is 1.5mg/kg
B. is metabolised at 80 to 90% the rate of suxamethonium
C. After 2 x ED95 dose 95% return of twitch height after 15mins
July 2002 version included the following options:
C. Does not usually require reversal
D. Duration of action may be prolonged by anti-cholinesterases
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”.
July 2006
Mivacurium
A. Is not made up of different isomers
B. Metabolised at 75-85% rate of suxamethonium
C. Has a Half life of 30 minutes
D. Is antagonised less by edrophonium than nestigmine
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
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
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.)
MB13 [Mar98] [Jul99] [Jul01] The Recovery Index 25% to 75% is 7 minutes for which drug? A. Vecuronium B. Rocuronium C. Mivacurium D. Suxamethonium
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
Also recalled as: A muscle relaxant is administered at twice ED95 for a short dental
case. Return of normal TOF ratio occurred at 7minutes. The muscle relaxant used was:
A. Suxamethonium
B. Vecuronium
C. Atracurium
D. Rocuronium
E. Mivacurium
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
MB14 [Mar98] [Jul00] [Mar03] Release of acetylcholine at the motor endplate: A. ?? gentamicin B. Botulinum toxin works by ?? C. ? D. ?
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
July 2000 version: Release of acetylcholine at motor endplate:
A. Hemicholinium directly interferes with releae
B. Only in response to action potential
C. Decreased by aminoglycosides / ?? prejunctional effect
D. Is Ca++ dependent process
E. Always causes an action potential
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
MB15 [Mar98]
Gentamicin potentiates non-depolarising neuromuscular block by:
A. Interfere with Ca++ influx for exocytosis
B. ?
C. ?
Aminoglycosides prolong NMJ block by competing with calcium which reduces acetylcholine release
MB16 [Jul98] [Mar99] [Feb00] [Jul01] [Mar03]
Rocuronium:
A. Monoquaternary at physiological pH
B. More lipid soluble than pancuronium
C. 30% metabolised (?deacetylated) in the liver
D. Rapid onset is due to its high potency
E. Fastest onset is with 2 times ED95 dose
F. Is bisquaternary
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)…
MB17 [Mar96] Plasma cholinesterase is inhibited 80% by 10 -5 molar dibucaine: A. In late pregnancy B. ? C. ?
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%
MB18 [Mar99] Which of the following do NOT prolong neuromuscular blockade? A. Volatile anaesthetics B. Antibiotics C. Phenytoin D. Beta-blockers E. Hyperthermia
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
MB19 [Jul98] Malignant hyperthermia causes: A. Hypertension B. Whole body rigidity C. Tachyphylaxis with a suxamethonium infusion D. ?
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…
MB20 [Jul99] [Jul01]
Edrophonium:
A. Longer half-life than neostigmine t1/2 110min vs 80min
B. Onset slower than neostigmine
C. ?Pyridostigmine
D. Binds to anionic site of cholinesterase
E. Relieves symptoms of myasthenia gravis - hence ‘Tensilon’ test
F. ? Is reliable in reversing a Phase 2 block
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?
(“Edrophonium Q about elimination half times and metabolism”)
A. ?
B. ?
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?
. .? . . with return of ¾ TOF ratio: A. ? B. ? C. ? D. ? E. Neostigmine may prolong the action of mivacurium
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]
MB22 [Jul99] [Apr01]
Atracurium:
A. Has an active metabolite
B. Ester metabolism is a minor pathway of elimination
C. Metabolism is by Hofmann elimination which is pH dependent (‘Did not include temperature’)
D. ?
E. ?
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.
MB23 [Feb00] [Jul04] What muscle relaxant has an active metabolite with a half-life twice that of the parent compound? A. Rocuronium B. Vecuronium C. Pancuronium D. Atracurium or Cisatracurium E. None of the above F. Mivacurium
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.
MB23b [Jul04] Which of these NDNMB has a metabolite that’s 50-70% as active as its parent drug A. Atracurium B. Vecuronium C. Rocuronium D. dTC E. None of the above
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)
MB24 [Feb00] Succinylcholine can cause: A. Bradycardia B. Histamine release C. Tachycardia D. Hypertension E. All of the above
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. “
MB25 [Feb00]
Neostigmine reversal of nondepolarising neuromuscular block
A. Not affected by enflurane at 2 MAC
B. Varies depending on use of NDMR by bolus or infusion if only response giving option of dose
C. Is (or Isn’t) affected by age
D. ?
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
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 E. Local anaesthetic esters
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
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
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
MB26b [Jul01] Neuromuscular blockade is NOT prolonged by: A. Hyperthermia B. Gentamicin C. Volatile agents D. Hypothermia E. ?
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
MB27 [Jul00] [Apr01] [Jul04]
Regarding neostigmine’s mechanism of action:
A. Binds covalently to esteric site on AChEsterase
B. Binds electrostatically to esteric site on AChEsterase
C. Binds to anionic site
D. Forms complex with AChEsterase with a shorter halflife than acetylcholine
E. (“Some other long winded explanation requiring 30 seconds to read and
impossible to remember.”)
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.
MB28 [Jul00]
With depolarising neuromuscular blocker: must be C or D (could be A)
A: Is competitively antagonised by NDMR
B: ("Something about tetany & fade")
C. ?
D. ?
E. Shows post tetanic potentiationWith 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
MB29 [Jul00] Rocuronium administered in 2 times the ED95 dose: A. Rapid onset, short duration B. Rapid onset, Intermediate duration C. Slow onset, intermediate duration D. Slow onset, long duration E. (“some other combination.”)
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
