Drugs Flashcards

Question

How does mivacurium differ from atracurium/ cisatracurium?

Answer 1

MIvacurium is the most potent of the three and so has the slowest onset, while also having a very rapid offset. This is because its metabolised by plasma cholinesterases, similarly to suxamethonium

Answer 2

E) Co-administration of nitrous oxide Speed of onset of volatiles is related to how quickly an alveolar:plasma concentration gradient can be built up, as a higher concentration gradient is the most influential factor causing fast diffusion. High CO will delay build-up of volatile in the alveoli, and a high FRFC provides a large reservoir into which volatile distributes thereby diluting its alveolar concentration. A high blood:gas partition coefficient reflects higher water-solubility essentially. This leads to slower diffusion into target site as less of a concentration gradient builds up.

Answer 3

blood:gas partition coefficient - describes the solubility of a particular gas in blood, which is essentialy hydrophilicity oil:gas coefficient - essentially just lipophilicity which, for volatile anaesthetics, equates to potency

Answer 4

Physical properties: Liquid at room temperature Stable and inert Cheap Environmentally safe Pharmacological properties: No airway irritation or respiratory depression No cardiovascular instability Analgesic, not epileptogenic, doesn't increase ICP Low blood:gas partition coefficient High oil:gas coefficient/ potency Not metabolised

Answer 5

Latent heat of vaporisation - the energy required for a molecule to transition from liquid to gas without an increase in temperature Sustained vapour pressure - the pressure at which (for a given temperature) a vapour will be in equilibirum of movement between states with its liquid form Critical temperature - the temperature at which a substance is completey gaseoues irrespective of pressure

Answer 6

MH is an autosomal dominant condition with variable penetrance that causes mass metabolic activation and muscle breakdown leading invariably to death in the absence of treatment. Incidence is 1 in 10,000, and the mechanism is activation of the ryanodine receptor leading to uncontrolled calcium release from the sarcoplasmic reticulum of myocytes. This can be triggered by any volatile anaesthetic agent, or suxamethonium. Initial signs are rising EtCO2 and tachycardia with muscle rigidity. The patient will develop an oxygen requirement from the increased metabolic demand, and will eventually develop pyrexia and a mixed acidosis Treatment is: Stopping the causative agent and hyperventilate with high flow pure oxygen via a clean circuit. Maintain anaesthesia with TIVA and end the surgery ASAP, achieve muscle relaxation with a non-depolarising NMB. Actively cool, treat electrolyte abnormalities/ arrhythmias. Bolus dantrolene at 2.5mg/kg (9 vials for the average 70kg male). Each vial of 20mg should be reconstituted in 60ml sterile water. Repeat boluses at 1mg/kg up to a maximum of 10mg/kg NB previous uneventful anaesthesia doesn't rule out MH.

Answer 7

Sevo: 0.65 - 47 Iso: 1.4 - 91 Des: 0.45 - 26

Answer 8

A - preservation of airway reflexes, hypersalivation so may provoke laryngospasm especially in children B - broadly preserves respiratory drive though may cause transient apnoea on induction, Useful as a bronchodilator e.g in I&V asthma exacerbations C - increase in sympathetic drive leads to increased preload, SVR, BP, and cardiac output. Is a direct negative inotrope but its dose-dependent sympathomimetic properties almost always outweigh this. D - produces dissociative anaesthesia and is an excellent analgesic. Increases cerebral blood flow and metabolic rate. Traditionally considered to increase ICP - this is now believed to be untrue or a small rough effect as to be irrelevant. Causes emergence phenomenae in ~20% of patients.

Answer 9

It reduces down regulation of opioid receptors, and so reduces opioid tolerance and hyperalgesia. This is accomplished by disrupting interactions between NMDAr and PSD-93 & 95 scaffolding proteins, which are part of a NOS synthase->protein kinase C pathway that further up-regulates NMDAr and leads to opioid tolerance.

Answer 10

Chronic benzo use Epilepsy/ propensity to seizures Possible mixed overdose with TCAs, as this increases risk of cardiac dysrhythmia with flumazenil

Answer 11

They bind to a site on the GABA receptor adjacent to GABA. This increases the affinity of GABA for its receptor, leading to more activation and an increased frequency of opening of the chloride channel

Answer 12

A - reduces upper airway tone and suppresses reflexes B - respiratory depression and blunted response to hypercarbia C - obtunds hypertensive response to laryngoscopy, arterial and venous dilatation, reduced cardiac output D - anxiolysis->sedation->hypnosis, anterograde amnesia, anticonvulsant, muscle relaxation (effect on dorsal horn of spinal cord), reduced REM sleep E - reduces hepatic and renal flow

Answer 13

Ketamine is presented as a colourless solution available as 1%, 5%, or 10%. It contains a mixture of S and R optical stereoisomers. It has poor oral bioavilaibilty (20-25%) but can be given orally. It is used IV and IM for anaesthesia, sedation, and analgesia. The dose for anaesthesia is 0.5-2mg/kg IV or 4-10mg/kg IM. The dose for analgesia is 0.25mg/kg IV, and the dose for sedation is up to 0.75mg/kg IV Ketamine is a non competitive NMDA receptor antagonist. Its VoD is reasonably large as 3L/kg. It is very rapid in onset owing to reasonable lipophilicity, pKA of 7.5, and small molecule size. Metabolism is hepatic to active metabolites, which are then conjugated and excreted in urine. Distribution half life is 10 minutes but elimination half life is 2-3 hours.

Answer 14

A - laryngeal reflexes are generally not suppressed, so there is a risk of laryngospasm when using SADs B - causes apnoea and the standard suppression of response to hypoxia and hypercarbia. However patients will breathe more quickly after thiopentone than propofol, making it more ideal for RSI in the event of failure. C - mostly causes venodilation and reduced preload -> reduced cardiac output. SVR is generally preserved, and at high doses it is a direct negative inotrope. Will cause a reflex tachycardia, and negative inotropy is more common with high rapid doses in the elderly, critically unwell, hypovolaemic, hypoalbuminaemic, and those with ischaemic/valvular heart disease. D - provides extremely quick anaesthesia (one arm brain circulation time). It is less protein bound than propofol which contributes to it having faster onset because concentration between central compartment and effect site equilibrates faster. Reduced ICP and cerebral metabolic rate. Cerebal blood flow and CO2 is preserved by autoregulation. Anticonvulsant and proven neuroprotective in focal ischaemia. E - causes enzyme induction after just one dose. Can cause tissue damage if it extravasates due to alkaline pH, and is catastrophic if given arterially.

Answer 15

A lipophillic anaesthetic agent given IV at a dose of anywhere from 3-7mg/kg. 80% protein bound so lower doses needed in hypoalbuminaemia. It has a VoD of 2L/kg and acts as a GABA agonist and non-NMDA glutamate receptor antagonist. Its pKA is 7.6 and is the fastest acting induction agent. Offset of action is due to redistribution to fatty tissue, and metabolism is actually very slow as the responsible enzymes are quickly saturated and it starts to obey zero order kinetics. After a single bolus the offset time is 5-10 minutes. Metabolism is hepatic, to inactive metabolites. Induction of CYP450 occurs after a single dose

Answer 16

A - preservation of laryngeal reflexes B - brief hyperventilation followed by brief apnoea - minimal net effect. No histamine release so no bronchospasm C - famously cardiostable, may produce slight tachycardia and hypertension D - produces sedation/anaesthesia in 30-60 seconds, reduces cerebral blood flow and metabolic rate, however reduces ICP by 50% so maintains or increases cerebral perfusion pressure. Causes myoclonus on induction and prolongs seizures (hence is useful in potentiation ECT) E - dose dependent reversible inhibition of 11B hydroxylase leading to reduced cortisol production. Unclear how significant this is after one dose, and whether its more significant in the critically ill

Answer 17

Action is positive modulation of the GABA A receptor at low doses, and independent agonism at higher doses. Dose is 0.2-0.6mg/kg

Answer 18

N&V Sedation Bradycardia and hypotension Respiratory depression Constipation Urinary retention Delirium Dysphoria & hallucinations Itching Tolerance & addiction

Answer 19

C) It has an oral bioavialibility of ~25% Morphine is an opioid used for acute and chronic pain. It has 25% oral bioavailability, and is used IV as a slow-onset agent (~10 minutes) at a dose of 0.1-0,2mg/kg. VoD is 3.5L/kg, pKa is 7.9, and metabolism is mostly through glucoronidation in the liver and gut excretion. The main metabolite (70%) is M3G which is inactive, but M6G is also produced which is more potent and accumulates in renal failure; in chronic use M6G is even responsible for the majority of activity. Elimination half-life is very variable, 3 hours is an average estimate.

Answer 20

E) It is much more lipid soluble than morphine Diamorphine is a very lipid soluble prodrug with no inherent activity at opioid receptors. It is 3,6-diacetyl morphine and is rapidly converted to the active metabolite 6-MAM, then to morphine by plasma and tissue esterases. Both it and 6-MAM are much more lipid soluble than morphine and crosses the blood-brain barrier quickly. Because of these differences, diamorphine, in clinical use, has twice the potency of morphine despite having no inherent action at opioid receptors.

Answer 21

D) It can produce lethal bradycardia and hypotension if bolused Remifentanil has a similar potency and speed of onset to fentanyl, but is metabolised by tissue esterases (not plasma cholinesterases so not affected by anti-cholinergic drugs, and not subject to genetic variation in metabolism). It produces an active metbaolite but it only has 0.1% the potency so is clinically irrelevant. In response to C), a Cet of 5ng/ml in the setting of Cet propofol 4mg/ml will obtund the pressor response to larngoscopy.

Answer 22

A) It forms a racemic mixture with different stereoisomers activiating differen receptors One stereoisomer activates opioid receotors and inhitibs serotonin reuptake , the other inibits noradrenaline reputake presynaptically. This variety of action explains why tramadol is only partly reversed by naloxone. Tramadol is more dangerous than other opioids in overdose, causing seizures in 15% of cases, though it does produce less respiratory depression. It produces active metabolites that accumulate in renal failure similarly to codeine and morphine. It is classed as a phenylpiperidine. It is a nicotinic and muscarinic antagonist.

Answer 23

Alfentanil - 6.5 Remifentanil - 7.1 Morphine - 7.9 Fentanyl - 8.4

Answer 24

B) 1% of people have an absent CYP2D6 resulting in codeine inefficacy ~10% of people have an absence of this enzyme, resulting in codeine inefficacy.

Answer 25

A) Buprenorphine can precipitate withdrawal if given to a patient on opioids Buprenorphine is a partial agonist with very high affinity for mu opioid receptors. Consequently it out-competes other opioids while not stimulating the receptor much, which can cause acute withdrawal. The high affinity for its receptor also explains why naloxone can be ineffective against higher doses of buprenorphine. Buprenoprhine undergoes hepatic metabolism to an active 'nor' metabolite which is excreted in bile. Nalozone is a competitive opioid antagonist, but only has a short duration of action (30-45 minutes) and so may need repeat doses or an infusion. Initial dose is often 100-400mcg, but may need more like 2mg in some cases, and can be repeated up to 10mg total. Nalaxone increases sympathetic tone which can cause hypertension, arrhythmia, and rarely pulmonary oedema.

Answer 26

D) Prilocaine metabolites ionise iron in haemoglobin to increase its avidity for oxygen This change ion affinity means the oxygen does not unload oxygen in hypoxic tissues - causing methaemoglobinaemia

Answer 27

B) Ametop cream contains an amide LA Ametop contains tetracaine (amethocaine) which is an ester LA along with cocaine, procaine, and benzocaine.

Answer 28

Isoprenaline is very beta-selective, so its chronotropy is not offset by reflex from vasoconstriction. However dobutamine stimulates both beta1 and alpha1 so its vasoconstriction offsets some of its chronotropy.

Answer 29

Milrinone is a PDE III inhibitor. phosphodiesterases are enzymes that break down cAMP and so are part of the de-coupling of beta adrenergic reeptors that occurs with sustained stimulation. Inhibiting this breakdown potentiates beta receptors and so is particularly useful in chronically sick hearts, which will exhibit this de-coupling. Milrinone also binds to calcium channels on the sarcoplasmic reticulum, and so potentiate CICR to provide another mechanism for inotropy.

Answer 30

B) Most norad released is taken up post synaptically and metabolised by COMT Norad is recycled pre synaptically due to very high affinity of NET for norad, where it is recycled into vesicles by VMAT or metabolised by MAO. COMT also metabolises catecholamines but is less important for norad.

Answer 31

Because it has a comparatively poor blood supply as it is peripheral, so will recover from block later than central sites such as the diaphragm. Hence this provides a margin of safety, especially as the larynx and pharynx recover more slowly than the diaphragm.

Answer 32

Concentration effect: large volumes of a non-potent carrier gas are given alongside sevo. The carrier gas is more soluble than the other gases in the mix and so rapidly diffuses into the bloodstream. This causes loss of volume within the lungs and an increase in concentration of other gases within the mix as N2O is disproportionately absorbed and distributed. Second gas effect: almost the same thing. It refers to the augmented ventilation i.e. creation of a concentration/ pressure gradient which the anaesthetic and carrier gases then diffuse down into the alveoli. This increases the anaesthetic gradient at the alveolus:capillary interface and so speeds up diffusion.

Answer 33

Renal dysfunction is common in the critically unwell population. Atracurium's metabolism relies 45% on Hoffman elimination (depends only on pH and temp) and 45% on non-specific ester hydrolysis. Therefore it is eliminated normally even in organ dysfunction. Variations in temp and pH do affect its elimination, but not at values within a realistic clinical range. Concerns over laudanosine accumulation and seizures are purely theoretical and don't seem to have ever been substantiated. Even if this was a concern, Cisatracurium could be used as it produces 90% less laudanosine, and is 75% metabolised by Hoffman elimination with 15% urinary excretion.

Answer 34

D) Midazolam is highly bioavailable and quickly cleared This is half true - midazolam is cleared much faster than diagram or lorazepam. However midazolam has oral bioavailability of 44%, much lower than diazepam or lorazepam. Benzos are positive allosteric modulators of the GABAa receptor. They bind to one of two receptor subtypes (BLZ1 or 2) at a site between the alpha and gama subunits of the GABAa receptor. This increases the affinity of GABA receptors for GABA, and leads to increased frequency of opening of the central chloride channel and inhibitory hyperpolarisation of the cell membrane. Benzos are unsafe in pregnant women as they can cause cleft palate, respiratory distress, and in breastfeeding women they are secreted in breast milk and may sedate the baby. Most benzos have active metabolites, the longer acting ones (diazepam and chlordiazepoxide) produce a series of active metabolites that partly explains their long duration of action.

Answer 35

As an intermediate-duration acetylcholinesterase inhibitor, it binds to both the anionic and esteratic enzyme sites. This prevents ACh from binding and being cleaved. The enzyme is not available to clear ACh until the neostigmine-AChE complex has been hydrolysed.

Answer 36

D) Untreated Alzheimer's There is a link between Alzheimer's and increased AChE and plasma cholinesterase activity, hence the duration of action of sux would be less. This doesn't necessarily hold true if the patient is taking treatment, which for Alzheimer's can consist of AChE +/- BChE (butyrylcholinesterase). Factors that would prolong a suxamethonium block include wasting states (cancer, malnutrition, chronic infection), hepatic dysfunction (reduced cholinesterase manufacture), and renal disease. However a 75% decrease in AChE activity is required to be clinically significant, so this is not commonly clinically significant.

Answer 37

Sux apnoea describes a markedly prolonged action of suxamethonium from 15 minutes to ~8 hours. It is the result of an autosomal recessive condition resulting in deficiency of plasma cholinesterases which metabolise suxamethonium, mivacurium, and ester local anaesthetics.

Answer 38

E) A heterozygous EuEa genotype at position 3q26.1-2 Sux apnoea generally requires two dysfunctional alleles for sufficient impairment. Phenotypically: Eu is the normal allele, Ea and Ef produce altered enzymes, and Es produces an inactive enzyme. Being homozygous for the k-variant is one of the most common genotypes in sux apnoea, along with presence of two of the Dib variants. ToF fade and post tetanic potentiation are features of either non-depolarising block or phase 2 depolarising block. In sux apnoea, suxamethonium lingers at the synapse and so causes the same phase 2 block that would be expected with repeated doses/ infusions. As sux apnoea is autosomal recessive, there may well be no family history. EsEs is the most severe phenotype in sux apnoea and is more likely in cases where recovery is more prolonged.

Answer 39

A-3 B-5 C-4 D-1 E-2 It's important to remember that adrenaline is a little more potent at A1 and a little less at B1 than norad despite classic teaching. The difference in effect between the two is explained by adrenaline having a significantly greater affinity for B2 giving it inodilator properties.

Answer 40

C) It competes at glutamate and glycine binding sites Ketamine is a non competitive antagonist, and acts at NMDA receptors by binding at phenylcyclidine binding sites sites situated within the ion channel. Ketamine is presented as a racemic mixture, and the S enantiomer is three times more potent than the R. Due to its antagonism of a wide range of receptors (monoamine, adrenergic, cholinergic, muscarinic, nicotinic, neuronal sodium channels, purinic, and in the thalamo-neocortical projection system) it has a range of clinical effects. It also seems to be an opioid agonist.

Answer 41

E) Action would be prolonged by phenytoin Ketamine is metabolised by cytochrome P450 and one of its metabolites (norketamine) is active with 20% potency. Phenytoin is a CYP450 inducer and so would shorten ketamine's duration of action. Ketamine does disrupt interactions between NMDAr and PSD proteins, and through this inhibits a pathway involving nitric oxide synthase and protein kinase C that is involved in opioid tolerance. 4mg/kg IM is the top end of the sedation range (2mg/kg-4mg/kg) and the bottom end of the anaesthetic range (4mg/kg-10mg/kg). Clearance is rapid, and elimination half life is likely only as long as it is because of the large volume of distribution.

Answer 42

The unusual feature is that it is both ligand and voltage gated - it requires both to activate. The ligand opens the channel, but magnesium and zinc ions block the channel and are only dislodged when the neuron depolarises.

Answer 43

C) It has the largest VoD and most protein-binding of any of the induction agents Thiopentone has the lowest VoD of the induction agents at 2.2, though is reasonably heavily protein-bound at 80% (propofol is 96%). Thiopentone will precipitate in combination with acidic or oxidised solutions including roc, vec, calcium chloride, morphine, and lidocaine. Thiopentone is contraindicated in respiratory disease because it triggers histamine release which could cause bronchospasm and worsen the respiratory failure. Thiopentone causes venodilation which reduces cardiac output, without decreasing afterload. These effects are more concerning in patients with hypovolaemia, pre-existing cardiac disease, or who are frail or critically unwell

Answer 44

Action sites for opioid-mediated analgesia can be divided into three: 1) Central inhibition of ascending pain pathways - Takes place in the substantia gelatinosa of the dorsal horn of the spinal cord - Opioid receptors activation reduces calcium influx and neurotransmitter release pre-synaptically, and causes potassium efflux and membrane hyperpolarisation post-synaptically 2) Central enhancement of descending inhibitory pathways - These pathways run from the periaqueductal grey matter in the pons, via the nucleus raphe magnus in the medulla, down the spinal cord as far as the dorsal horn - Opioid act on GABA-ergic interneurons in the periaqueductal grey matter. They act pre-synpatically to inhibit these neurons. This disinhibits the descending inhibitory pathway, which then releases noradrenaline and serotonin to inhibit nociceptive transmission. 3) Peripheral - Inflammation triggers up regulation of opioid receptors locally, and hence provides a non-CNS site of action for opioids.

Answer 45

A) Most morphine is metabolised by demethylation at the 'N' site Most morphine (70%) undergoes glucoronidation in the liver to M3G, an inactive metabolite. Some undergoes glucoronidation to M6G which is more potent than morphine. A small amount is demthylated to normorphine at the 'N' site.

Answer 46

D) It may cause hypercalcaemia Hypercalcaemia is a feature of thiazides, loop diuretics cause hypocalcaemia. Furosemide is a loop diuretics which blocks the co-transporter of sodium/ potassium/ chloride on the apical membrane of the thick ascending limb in the Loop of Henle. It is heavily protein bound and 80% is excreted unchanged, with the other 20% undergoing glucoronidation in the kidney.

Answer 47

D) Chlordiazepoxide, diazepam, and tempazepam are all metabolised to oxazepam Long-acting benzodiazepines are partly long-acting because they produce a series of active metabolites. Benzodiazepines are positive modulators of the GABA A receptor. They bind at their receptor (BZ1 and BZ2) between the alpha and gama subunits of the receptor, whereas GABA binds between the alpha and beta subunits. However the GABA receptors is ligand gated rather than voltage gated. Flumazenil is an imidazobenzodiazepine that acts as a competitive benzo antagonist. It is 40-50% protein bound, has a half life of 50 minutes, and is metabolised in the liver to inactive metabolites. Midazolam is presented in a solution with pH 3.0 which makes it ionised and water-soluble. Once it is in a solution with pH >4 then it becomes unionised and lipid-soluble. Diaz, loraz, and midaz all have similar protein binding and VoD. However midazolam is half as bioavailable orally as the others.

Answer 48

A) Hypoalbuminaemia increases the effect of furosemide Furosemide is heavily protein bound, so you would expect this to be the case. However experiments have shown that low albumin reduces furosemide delivery to the PCT. Furthermore, Co-administration of albumin has no effect to counter this.

Answer 49

C) Reabsorption of Na via ENaC channels is responsible for hypokalaemia Furosemide inhibits absorption of potassium, sodium, and chloride from the tubular lumen. The sodium is then reabsorbed in the distal nephron via ENaC channels (RAAS mediated). This creates a charge gradient down which potassium exits the cell into the tubule. Furosemide does cause urinary excretion of sodium, however there is enough reabsorption via ENaC channels plus concentration due to water loss that it will generally cause hypernatraemia.

Answer 50

Oxazepam, temazepam, lorazepam