Pharmacology, the reference

Obesity raises plasma cholinesterase activity and expands extracellular fluid, so succinylcholine needs total-weight dosing for dependable paralysis. Rocuronium on total weight delays recovery, so it and vecuronium use lean weight. Sources diverge: Miller doses cisatracurium and midazolam on total weight, while Faust puts other relaxants on lean weight; textbooks scale the propofol induction bolus to lean weight but infusions to total weight. UK obesity guidelines place only succinylcholine on total weight, propofol infusions on adjusted weight. Without succinylcholine, textbooks point to midazolam or a propofol infusion; guidelines to none.

Dexmedetomidine, total weight in one text. Dexmedetomidine tempts because Barash's obesity table does place it on total body weight. It remains the wrong pick because only one text does so, much as only Miller puts cisatracurium on total weight while Barash and guidelines put it on lean. Succinylcholine is the one drug all sources agree on.

Barash: succinylcholine on total weight, as pseudocholinesterase and extracellular fluid rise; rocuronium on lean. Miller: propofol, vecuronium and rocuronium on ideal weight; midazolam, succinylcholine, cisatracurium and fentanyl on total; boluses on lean mass, infusions total. Faust: succinylcholine total, other relaxants lean.

Sources: Barash 9eMiller 10eFaust

With age the brain becomes more sensitive to remifentanil. This pharmacodynamic change causes most of the lower requirement, and changes in drug handling play only a minor part. General texts give an overall reduction of at least 50%. Stoelting separates it by dose type: a bolus needs about half the young-adult dose, while a running infusion needs a rate of about one-third that of a young adult. So treat 50% as the smallest cut, and reduce the maintenance infusion further than the bolus.

Halving the infusion rate like the bolus dose. Half is easy to remember because it is the bolus figure and the overall 'at least 50%' figure. For an infusion, though, the books go further, to a rate of about one-third that of young adults. Halving the infusion would still overdose an older patient.

Stoelting advises roughly half the bolus and about one-third of the infusion rate in older patients. Miller's says the lower need comes mainly from greater sensitivity, and gives an overall dose reduction of at least 50%.

Sources: Stoelting 8eMiller 10e

Ageing slows the clearance of drugs that depend on hepatic blood flow or renal excretion, so vecuronium and fentanyl have longer-lasting effects in older patients. Cisatracurium is eliminated mainly through Hofmann degradation, which is independent of both organs, so its clearance is unchanged. Its elimination half-life is slightly longer, but this reflects only a modestly larger volume of distribution and does not delay recovery. Onset is slower because the drug takes longer to reach its site of action. If onset is slow, wait longer rather than giving a larger dose.

Vecuronium needs dose change in elderly patients. Vecuronium is tempting because it is also an intermediate-acting non-depolarising relaxant, so the two seem interchangeable. But it relies on organ excretion. In older patients, slower excretion makes its half-life and action longer, so its dosing needs adjusting.

Older patients clear cisatracurium as fast as younger ones; its slightly longer half-life reflects a modestly larger distribution volume, and recovery is unchanged, with only onset slower. By contrast, slower excretion prolongs vecuronium, and fentanyl clearance falls because it depends on liver blood flow.

Sources: Barash 9eMiller 10e

Stoelting states that children with cerebral palsy need less volatile agent, wake slowly, and recover slowly from neuromuscular block, so a prolonged relaxant effect is the expected default. Faust adds a branch: patients on chronic anticonvulsants may resist non-depolarisers, without the hyperkalaemic response to succinylcholine. So the condition itself slows recovery, while anticonvulsant therapy can raise the dose needed; the net requirement is unpredictable. Give relaxant in small increments to monitored effect and confirm full recovery before extubation, remembering that larger doses in resistant patients also raise residual-block risk.

Ketamine causes delayed emergence in cerebral palsy. Ketamine's tempting because a large intramuscular dose can markedly delay emergence, but that delay is dose- and route-dependent in any child, not specific to cerebral palsy. It is also proconvulsant, so best avoided in seizure-prone patients. Cerebral palsy-specific prolongation affects relaxant recovery and volatile emergence.

Stoelting: cerebral palsy lowers volatile requirement, emergence is often delayed, and relaxants need caution because block recovery is usually prolonged. Miller also records a lower MAC. Faust notes resistance to non-depolarisers in anticonvulsant-treated conditions including cerebral palsy, without succinylcholine hyperkalaemia.

Sources: Stoelting 8eFaustMiller 10e

Older patients need less hypnotic for two separate reasons. The first is pharmacokinetic: a smaller central compartment and slower redistribution mean a bolus reaches higher effect-site levels. The second is pharmacodynamic: the ageing brain responds more to the same concentration. For propofol, Miller describes sensitivity that rises with concentration, and Barash lists raised brain sensitivity. Stoelting attributes midazolam's large elderly dose cut mainly to pharmacodynamics. The sources split on etomidate: Barash lists unchanged brain sensitivity, while Stoelting reports increased sensitivity. Propofol is the agent both sources agree on.

Etomidate sensitivity unchanged with age. Etomidate is tempting because its elderly bolus is cut substantially and it is the classic induction agent for frail patients. But Barash lists its brain sensitivity as unchanged, which makes the dose cut kinetic in that source. Only Stoelting reports increased sensitivity. Propofol's increased sensitivity is not disputed.

Barash notes, by some accounts, raised propofol brain sensitivity in older patients but unchanged thiopental and etomidate sensitivity, though both need lower doses. Miller: older patients' EEG and blood pressure propofol sensitivity rises with concentration. Stoelting: older patients are markedly more midazolam-sensitive, mainly pharmacodynamically.

Sources: Miller 10eBarash 9eStoelting 8e

With age, muscle and water compartments shrink while adipose tissue grows. Water-soluble drugs therefore spread through a smaller volume, and lipid-soluble drugs spread through a larger reservoir. Serum albumin falls, so less drug is bound and more circulates free. Cardiac output, renal filtration, hepatic perfusion and liver enzyme activity all decline. Drugs are cleared more slowly, and their effects last longer.

Body fat decreases with age. Lean mass, water and most organ functions decline with age, so someone may assume fat falls too. It does the opposite: the proportion of body fat rises as lean tissue is lost. That is why lipid-soluble drugs have a larger volume of distribution in older patients.

Ageing lowers total body water, lean body mass and serum albumin, and raises total body fat. It also reduces cardiac output, glomerular filtration and hepatic blood flow and enzyme activity. Together these slow the elimination of neuromuscular blocking drugs.

Sources: Barash 9eMiller 10e

The liver takes up most rocuronium, which leaves in bile. The kidney handles only 10%-25%. In renal failure, losing that share still cuts plasma clearance by about 33% to 39%, so plasma levels fall more slowly and recovery from block is delayed. Volume of distribution barely changes, and there is no active metabolite to accumulate. Because most of the drug bypasses the kidney, the block lasts only somewhat longer. Drugs relying mainly on the kidney are affected far more.

Kidney is main elimination route for rocuronium. This looks right because the block lasts longer in renal failure, so the kidney seems to be the main exit. It is not: bile carries most of the drug. The block is prolonged because the smaller renal share is lost and clearance falls, not because the kidney dominates.

In renal failure, rocuronium clearance falls by 33% to 39%. Volume of distribution is unchanged or slightly raised, and humans form no active metabolites. Elimination is mainly hepatic and biliary, with 10%-25% renal. Renal disease is expected to slow its excretion.

Sources: Miller 10eMayo reviewStoelting 8e

Most drugs are cleared by the liver and kidneys. These organs are immature early in life, so the youngest patients usually clear drugs slowly. Remifentanil is different because non-specific esterases in plasma and tissues break it down, and these do not depend on the liver or kidneys maturing. Infants also have a larger volume of distribution than older children. Immature organs therefore do not slow its elimination, and clearance is fastest in the youngest patients. Its kinetics also vary unusually little between patients at this age.

Adults clear remifentanil fastest. Adults are tempting because their liver and kidneys are fully mature, and for most drugs that means the fastest clearance. It fails because blood and tissue esterases break remifentanil down, not those organs. Mature organs therefore give adults no advantage, and the youngest patients clear it fastest.

Miller states that, unlike most drugs, remifentanil is cleared faster by neonates than older children, attributed to breakdown by non-specific plasma and tissue esterases and a larger volume of distribution. Immature liver and kidney function does not alter its kinetics.

Sources: Miller 10e

Neostigmine only slows acetylcholine breakdown, so its effect has a ceiling and cannot outcompete a relaxant still occupying most receptors. Anticholinesterases were once given as soon as a few twitches returned. Barash now advises against any anticholinesterase for moderate or deep block; allow spontaneous recovery to four twitches first. Sugammadex binds only steroidal relaxants and cannot reverse cisatracurium. Spontaneous breathing does not exclude residual block; only quantitative monitoring confirms its resolution.

Give neostigmine at two twitches. This is the right drug, dose and antimuscarinic partner, so it looks correct. With only two twitches the block is still moderate, and neostigmine's ceiling makes full antagonism unlikely. It becomes correct only after recovery reaches four twitches, so here the dose is right but the timing is too early.

Barash no longer advises anticholinesterase reversal of moderate or deep block, and gives neostigmine 40 to 50 mcg/kg once there are four twitches (shallow block). The ASA says cisatracurium responds only to anticholinesterases and not to sugammadex. Miller describes a ceiling on the acetylcholine rise.

Sources: Barash 9eOutside our books: 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade (2023)Miller 10e

Sugammadex reverses the block by encapsulating free rocuronium, so the dose depends on how much blocker still acts at the junction. A post-tetanic response shows some receptors are already free despite a silent train-of-four. This indicates deep, not complete, block, and a medium dose reverses it within minutes. Only when post-tetanic stimulation also gives nothing is there enough blocker to need 16 mg/kg. One textbook gives a wider dose range for deep block, but its lowest dose is the labelled dose, so that is the standard answer.

Complete block needs 4mg/kg sugammadex. A train-of-four count of zero looks like 'no response', so people reach for the complete-block dose. Complete block means post-tetanic stimulation fails too. Any post-tetanic response means the block is deep, and the medium dose already reverses it fully.

Drug label and Miller both give 4 mg/kg when train-of-four twitches are absent but post-tetanic responses are present; Miller reserves 16 mg/kg for no post-tetanic response. In a trial, over 97% of patients given this dose reached a train-of-four ratio of 0.90 within 5 minutes.

Sources: Outside our books: BRIDION (sugammadex) injection, US prescribing information: sections 2, 5 and 12 (2015)Miller 10e

Sugammadex is a cyclodextrin that binds rocuronium directly, so the dose must match the drug load. Minutes after an intubating dose the block is profound: only the largest dose clears it, and anticholinesterases cannot. Faust and Barash offered this dose as a way out of cannot-intubate-cannot-ventilate. The newer DAS guidance later judged that unreliable, because reversal may provoke laryngospasm or aspiration and cannot ensure an open airway. So once waking is chosen, give the full dose while oxygenating; if oxygenation fails, go to front-of-neck access.

4 mg/kg deep-block dose. 4 mg/kg is the familiar sugammadex dose for deep block, so it looks like the right reversal. But that dose is meant for a block that still shows post-tetanic responses. Minutes after an intubating dose there are none, and too little drug leaves the patient paralysed.

Sugammadex binds rocuronium and rapidly reverses any depth of block where anticholinesterases are contraindicated. Profound block after an intubating dose, even with failed mask ventilation, needs 16 mg/kg, used to wake the patient with oxygenation maintained. DAS regards it as an unreliable rescue: the airway is not assured.

Sources: FaustBarash 9eDifficult Airway Society 2025

Neostigmine works only by slowing acetylcholine breakdown, so its effect has a ceiling. A ratio below 0.4 after its peak is shallow block, for which ASA prefers sugammadex, which binds rocuronium directly. The sources set the neostigmine limit at different levels. Barash allows repeats up to 0.1 mg/kg and warns of acetylcholine-related weakness. Faust's table tops out at 70 μg/kg. ASA caps the total at 50 μg/kg because more adds no effect. Staying within 50 μg/kg satisfies all three.

Ventilate patient another day in ICU. A day of ICU ventilation feels like the safest choice, but it treats a reversible drug effect as respiratory failure. Residual rocuronium block can be reversed now with sugammadex, or with a neostigmine top-up within its ceiling. The patient is then extubated once the ratio reaches target.

ASA requires a ratio of at least 0.9 before extubation, recommends sugammadex for rocuronium block including shallow block, and caps added neostigmine at 50 μg/kg total. Faust's table doses neostigmine at up to 70 μg/kg. Barash permits repeats short of 0.1 mg/kg.

Sources: Outside our books: 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade (2023)Barash 9eFaust

Sugammadex is a gamma-cyclodextrin: a ring-shaped sugar with a hollow core. That core wraps around the steroid skeleton of an aminosteroid relaxant and traps it, so the drug can no longer act at the receptor. Rocuronium fits best. Vecuronium binds with 2.5-fold lower affinity but is still held tightly enough to reverse clinically. Pancuronium binds too weakly to matter. Relaxants without a steroid core have nothing for the ring to encapsulate, so sugammadex has no effect on them. These include benzylisoquinoliniums such as cisatracurium, and depolarising agents.

Vecuronium binds as tightly as rocuronium. Vecuronium is also a steroidal relaxant, and sugammadex reliably reverses vecuronium block, so it looks like an equal answer. Its affinity is lower than rocuronium's, though. The drug sugammadex binds with the highest affinity is rocuronium.

The textbooks rank sugammadex affinity as rocuronium, then vecuronium, with pancuronium far behind and clinically insignificant. Vecuronium's affinity is 2.5 times lower than rocuronium's but still forms a firm complex. Sugammadex has no affinity for depolarising relaxants or for non-steroidal non-depolarising relaxants.

Sources: Barash 9eMiller 10e

MAC tracks central excitability: raised brain transmitter levels, sodium or temperature push it up; transmitter depletion and CNS depressants pull it down. Alcohol shows both: an acute dose depresses, chronic drinking raises requirement. Fever and chronic drinking both raise MAC; no source ranks them. Barash places levodopa in both its raising and lowering tables, Mayo among raisers, so it decides nothing. Cyclosporine appears in no MAC list. For pregnancy, Miller's human first-trimester figure is lower than Faust's upper bound of 40%; both are book values.

Chronic alcohol lowers or doesn't change MAC. Alcohol is a CNS depressant, so assuming chronic use lowers MAC or leaves it unchanged feels natural. It fails because only acute ingestion lowers MAC; long-term drinking raises it, so it is never a no-change factor.

Mayo lists hyperthermia, hypernatraemia and chronic ethanol abuse as raising MAC; Barash lists lithium, α2-agonists, hypothermia, barbiturates, pregnancy and acute ethanol as lowering it. For pregnancy, Miller gives 28% in humans and 40% in animals in the first trimester; Faust gives 25% to 40%.

Sources: Mayo reviewBarash 9eMiller 10eFaust

The amount of anaesthetic needed tracks how active the brain is. Anything that lowers cerebral metabolic rate lowers MAC: ageing, cooling, hypoxia, hypotension and depressant drugs. States that raise central neurotransmitter activity push MAC up. These include hyperthermia, MAO inhibitors and youth. The sources agree on the 6% figure. Barash applies it across age generally. Stoelting quotes it for volatiles after 40 and gives nitrous oxide a slightly steeper fall of 8% per decade. So use 6% per decade, and give an octogenarian noticeably less agent.

Hyperthermia lowers MAC. Temperature really does change MAC, so hyperthermia looks like a reasonable answer for a factor that lowers it. The direction is backwards. Cooling lowers cerebral metabolism and MAC. Hyperthermia raises MAC, and so do MAO inhibitors.

Barash says MAC falls by roughly 6% per decade of age. Stoelting gives the same figure for volatiles after 40, and 8% for nitrous oxide. Faust links the fall to lower cerebral metabolic rate. Hyperthermia, MAO inhibitors and younger age raise MAC.

Sources: Barash 9eFaustStoelting 8eMayo review

MAO inhibitors stop serotonin from being broken down. Pethidine, tramadol and methadone also block its reuptake. Together, serotonin builds up in the synapse and overstimulates central 5-HT1A receptors. This causes serotonin syndrome: confusion, agitation, fever, sweating, ataxia, hyperreflexia and myoclonus. Morphine has no useful reuptake-blocking action, so it is the safer choice. Fentanyl and its relatives are in the same chemical family and have been linked to toxicity in case reports. Their serotonergic effect is weak, so they can still be used with care.

Tramadol is a mild safe choice. Tramadol looks like a mild, weak opioid, so it seems a gentle and harmless choice. But it blocks serotonin reuptake, and with MAO inhibition that brings on serotonin syndrome. For that reason it is avoided along with pethidine and methadone.

Giving pethidine with an MAO inhibitor can cause serotonin syndrome. Pethidine, methadone and tramadol should be avoided in these patients, and morphine is safer. Phenylpiperidine opioids are weak serotonin reuptake inhibitors. Selegiline, used in Parkinson's disease, is an MAO inhibitor.

Sources: Miller 10eFaustBarash 9eMayo review

MAO normally breaks down noradrenaline inside sympathetic nerve endings, so blocking it leaves those stores enlarged. Indirect-acting agents such as ephedrine work mainly by releasing that stored noradrenaline. The surge is unpredictable and can cause a hypertensive crisis. Direct-acting agents act on the receptors themselves and do not depend on the stores, so you can predict and titrate their effect. The receptor response may still be exaggerated, so start with a reduced dose and titrate carefully.

Ephedrine is the first choice here. Ephedrine is the usual first choice for hypotension after induction because it is familiar and raises both heart rate and pressure. It fails here because it acts mostly by releasing stored noradrenaline. Under MAO inhibition those stores are enlarged, so the release risks a hypertensive crisis.

One text advises small, carefully titrated doses of direct-acting agents (phenylephrine, noradrenaline, vasopressin, dopamine) and avoiding indirect agents, above all ephedrine, which can provoke hypertensive crisis. The other recommends phenylephrine, at a reduced dose to limit excessive pressor response.

Sources: Stoelting 8eFaust

Tramadol is not a pure opioid. It also has strong serotonergic effects and can cause fits even when given on its own. Tricyclics and SSRIs lower the seizure threshold too, so the two risks add together. Their combined serotonergic effect can also cause serotonin syndrome: confusion, autonomic instability and neuromuscular excitability. Ondansetron works differently. It is a serotonin antagonist, and its known interaction is to weaken part of tramadol's pain relief.

Ondansetron interacts with tramadol seizure threshold. Ondansetron is tempting because it is the drug best known for interacting with tramadol through serotonin. But it blocks serotonin receptors, and the sources link it only to reduced analgesia, not to fits. The drug that lowers the seizure threshold here is the tricyclic.

Tramadol has caused fits when given by itself. It needs care alongside agents that lower the threshold for fits, such as tricyclics and SSRIs. With serotonergic antidepressants it risks serotonin syndrome, and it is barred with MAO inhibitors. Ondansetron partly blunts its analgesia.

Sources: Mayo reviewBarash 9e

The cyclosporine label, a source outside the textbooks, keeps two separate interaction lists. The first names drugs whose own kidney effects add to cyclosporine's. Its gastrointestinal agents are ranitidine and cimetidine, so creatinine should be watched and doses cut if function falls. The second covers drugs that change cyclosporine concentration. Metoclopramide speeds delivery into the small bowel, where more cyclosporine is absorbed and levels rise, so doses are adjusted to measured concentrations. So the drug that worsens kidney function alongside cyclosporine comes from the first list.

Metoclopramide potentiates renal dysfunction. Metoclopramide is a real cyclosporine interaction, so it feels right. But the label puts it among drugs that raise cyclosporine concentration through better small-bowel absorption, not on the list of drugs that potentiate renal dysfunction. That list's gastrointestinal agents are ranitidine and cimetidine.

Cimetidine and ranitidine may add to renal dysfunction. With cyclosporine plus drugs with additive or synergistic renal effects, monitor renal function closely, especially serum creatinine. Small-bowel absorption may increase; adjust Sandimmune dose to achieve intended concentrations when other drugs substantially alter levels.

Sources: Outside our books: SANDIMMUNE (cyclosporine) capsule, liquid filled / SANDIMMUNE (cyclosporine) injection - FDA-approved prescribing information (2026)Outside our books: METOCLOPRAMIDE tablet - FDA-approved prescribing information (2010)

Both calcineurin inhibitors are broken down in the liver by CYP3A4. Inducers such as phenytoin, phenobarbital or carbamazepine make the liver produce more of this enzyme and its reductase partner. Every CYP3A4 substrate is then cleared faster, so plasma levels and immunosuppression fall, which risks graft rejection. Inhibitors do the opposite: clearance slows, the parent drug builds up, and toxicity such as renal dysfunction and hypertension appears. The same enzyme also handles benzodiazepines, fentanyl and propofol, so these interactions work in both directions.

Erythromycin reduces cyclosporine effect. Erythromycin is one of the best-known ciclosporin interactions, so it feels like the answer. But it is a macrolide that inhibits CYP3A4. It slows ciclosporin breakdown, so levels and toxicity rise. It does not reduce the drug's effect.

Both calcineurin inhibitors are metabolised by CYP3A4. Phenytoin, carbamazepine, phenobarbital and rifampin are listed as hepatic enzyme inducers, and macrolides and azoles as inhibitors. Induction speeds breakdown of every CYP3A4 substrate and usually lowers efficacy. Inhibition increases the parent drug's activity.

Sources: Barash 9eMiller 10e

This comes from the manufacturer's label, which is outside the textbook corpus. The label warns that hydroxychloroquine lengthens the QT interval and that torsades and other ventricular arrhythmias have occurred in treated patients. Its risk adds to that of other QT-lengthening or pro-arrhythmic drugs, so the label advises against giving them together. In overdose the cardiac toxicity gets worse: QRS and QTc widening, ventricular tachycardia or fibrillation, heart block, arrest and death.

Remdesivir prolongs QT interval. Remdesivir is the best-known coronavirus antiviral, so people may assume it carries the arrhythmia warning. In these sources the QT and torsades warning belongs to hydroxychloroquine, an antimalarial that was repurposed early in the pandemic. Nothing here links remdesivir to QT lengthening.

The only source, the hydroxychloroquine prescribing label (outside the textbook corpus), lists QT prolongation and torsades among its warnings and cardiac adverse effects, advises against co-prescribing other QT-prolonging drugs, and describes QRS and QTc widening and cardiac arrest in overdose.

Sources: Outside our books: PLAQUENIL (hydroxychloroquine sulfate) tablets, for oral use - FDA-approved prescribing information (2026)

Feverfew is taken to prevent migraine and inhibits platelets; abrupt withdrawal provokes rebound headache. Valerian's two entries answer different questions: the herbal appendix names it a sedative that potentiates barbiturates and anaesthetics, which is its effect; the preoperative supplement table grades that sedation mild and advises continuing, which is the stopping decision. St John's wort sits among CYP3A inducers, altering metabolism of co-administered drugs, and the supplement table separately warns it may prolong anaesthesia; both converge on holding it 2 wk before surgery.

Feverfew mainly affects clotting. Feverfew is known to act on platelets, so someone who remembers only a coagulation effect may pick clotting. The effect runs the other way: it inhibits platelet activity and raises bleeding risk. The distinctive feverfew answer is headache rebounding after abrupt cessation.

The preoperative supplement table: feverfew impairs platelets and gives rebound headache on sudden cessation, hold 2 wk; St John's wort may prolong anaesthesia, hold 2 wk; valerian, mild sedative, continue. The herbal appendix: valerian potentiates barbiturates and anaesthetics. St John's wort induces CYP3A.

Sources: Barash 9e

Oxidising agents change haem iron from the ferrous to the ferric form. This creates methaemoglobin, which can build up to dangerous levels and does not carry oxygen to the tissues. Arterial oxygen tension can look adequate while oxygen delivery fails and lactate rises, so giving more inspired oxygen cannot correct the blue colour. Co-oximetry confirms the diagnosis. The acquired, drug-induced form is reversed by removing the cause, supporting the patient and giving methylene blue. Only the inherited haemoglobin M variant fails to respond.

Stop oxygen to prevent CO2 retention. Stopping oxygen is tempting because a drowsy patient on two high-flow sources suggests oxygen-induced carbon dioxide retention. But the blue colour comes from methaemoglobin, which no amount of inspired oxygen reverses. Removing oxygen takes away supportive care without treating the cause. The patient needs the specific antidote.

Oxidising chemicals can cause life-threatening acquired methaemoglobinaemia. Suspect it when oxygen delivery fails despite adequate arterial oxygen. Withdraw the agent, give supportive care; once co-oximetry confirms, first-choice methylene blue 1 to 2 mg/kg over 3 to 5 minutes.

Sources: Stoelting 8eFaust

Methylene blue is the usual antidote for methaemoglobinaemia. In G6PD-deficient patients it does not work, and it is also on the list of drugs that provoke haemolysis. The patient's oxygen delivery is already reduced by methaemoglobin. Giving methylene blue fails to fix that and adds red-cell destruction, which can be lethal. Ordinary anaesthetic drugs are not oxidant triggers in the same way, so the ban applies to the antidote, not to routine sedatives or analgesics.

Codeine is contraindicated in G6PD. Codeine is tempting because some analgesics, such as high-dose aspirin, appear on haemolysis lists, so it seems plausible that another analgesic would be banned too. It is wrong because codeine is named outright as safe in G6PD deficiency, along with ketamine and midazolam.

Methylene blue is ineffective in G6PD deficiency and may be fatal; it is potentially life-threatening when methaemoglobinaemia coexists, and haematology tables list it as causing haemolysis. Midazolam, codeine and ketamine are safe.

Sources: Mayo reviewStoelting 8eBarash 9e

Suxamethonium depolarises the muscle and causes fasciculation. In myotonic disorders this sets off a sustained contracture inside the muscle. Deeper anaesthesia or a nondepolarising blocker cannot release it, and the spasm may stop ventilation. In other myopathies it can cause rhabdomyolysis and hyperkalaemic arrest. Stoelting says to avoid it outright. Faust limits the contraindication to severe disease and says it has no malignant hyperthermia link. Avoiding it is safe under both views. Myasthenia is the opposite: resistance and a tendency to phase II block.

Myasthenia gravis is a contraindication. Myasthenia gravis is a neuromuscular disease, so it looks like a suxamethonium contraindication. In fact these patients resist suxamethonium and tend towards phase II block. The issue is changed dosing and duration, not an uncontrollable contracture or hyperkalaemia.

Stoelting advises against suxamethonium in myotonic dystrophy because the myotonia it provokes cannot be reversed by anaesthesia or nondepolarising relaxants. Faust calls it possibly contraindicated in severe disease. Barash avoids it in any suspected myopathy. Myasthenia shows resistance and phase II block.

Sources: Stoelting 8eBarash 9eFaust

Burns, like denervation and immobility, make acetylcholine receptors multiply across the muscle membrane. Succinylcholine depolarises all of them and releases potassium that can stop the heart. This multiplication takes days, so the first day is safe and risk rises after. The extra receptors also bind non-depolarisers, so resistance tracks burn size and time since injury. Children's vagal response lets a single dose slow the heart, hence atropine pretreatment. If the burn's age is not given, bradycardia in a child is true regardless; hyperkalaemia applies once past the first day.

Succinylcholine best intubating drug for burns. Succinylcholine is the classic rapid-sequence drug, so people assume it gives better intubating conditions. It does not beat high-dose rocuronium, which the burns literature names the drug of choice when rapid paralysis is needed and succinylcholine is contraindicated.

The first 24 hours after a burn are deemed safe; hyperkalaemia risk may start by 2 days and peaks at 7 to 10 days. A single dose can cause bradycardia, mainly in the very young. Non-depolariser resistance tracks burn size and time; rocuronium is preferred.

Sources: Mayo reviewBarash 9eMiller 10eFaust

Plasma cholinesterase, also called butyrylcholinesterase, is made in the liver. It hydrolyses suxamethonium, mivacurium and the ester local anaesthetics. Mivacurium is short-acting only because this enzyme clears it so fast. If a patient carries an atypical form of the enzyme, especially two copies, that clearance fails. The block can then last for hours instead of minutes. A past episode of slow waking after an ester-cleared drug marks the patient as at risk, so drugs from this pathway should not be given again.

Cisatracurium prolonged by esterase deficiency. Cisatracurium sounds like the answer because the atracurium family is partly broken down by ester hydrolysis, so people link it to esterases. That hydrolysis is not done by plasma cholinesterase, and Hofmann elimination does most of the work. Enzyme deficiency therefore does not prolong its block.

Plasma cholinesterase breaks down suxamethonium, mivacurium and ester local anaesthetics. The main anaesthetic danger of deficiency is prolonged apnoea after either relaxant. Mivacurium is short-acting because the enzyme clears it rapidly, but patients homozygous for the atypical enzyme can stay blocked for several hours.

Sources: Barash 9eMiller 10e

Sugammadex encapsulates only steroidal relaxants, so molecules still circulating can trap fresh rocuronium or vecuronium; succinylcholine and benzylisoquinolinium drugs escape it. Barash offers either; Mayo notes succinylcholine is essentially unaffected, which suits an urgent, full-stomach rapid sequence. Miller is most conservative, advising a benzylisoquinolinium such as cisatracurium for 24 hours to cover the longest clearance. The US label is most permissive: standard steroidal doses after 4 hours, or rocuronium 1.2 mg/kg from 5 minutes, accepting onset delayed by up to about 4 minutes. So urgency decides the drug.

Vecuronium safe alternative after sugammadex. Vecuronium looks like a neutral alternative to repeating rocuronium, since it is a different familiar relaxant. It is still steroidal, so residual sugammadex binds it; at standard dose it must wait 4 hours, and the label offers no early high-dose route for it.

Barash offers succinylcholine or a benzylisoquinolinium; Mayo says succinylcholine is unlikely to be affected; Miller conservatively advises a benzylisoquinolinium within 24 hours; the US label permits rocuronium 1.2 mg/kg from 5 minutes, standard steroidal doses after 4 hours, onset delayed up to about 4 minutes.

Sources: Barash 9eMiller 10eOutside our books: BRIDION (sugammadex) injection, US prescribing information: sections 2, 5 and 12 (2015)Mayo review

Pressure rises within 1 minute, peaks at 2 to 4 minutes and resolves by 6 minutes. The cause is not fully understood; contraction of tonic extraocular muscle fibres, brief choroidal vasodilatation, or both, are thought responsible. Being brief, it does not threaten an intact eye, even with glaucoma. Miller cautions only against an open anterior chamber. Barash accepts it in open-eye injury, provided anaesthesia is deep and block is complete. Coughing or straining at laryngoscopy raises pressure significantly.

Glaucoma as a contraindication. Raised intraocular pressure in a patient with uncontrolled glaucoma feels like an obvious bar. It is not. The rise is brief and harmless to an intact globe. Only an open globe was ever flagged, and even that is now accepted within a controlled rapid sequence induction.

Miller: the rise starts within a minute, peaks at 2 to 4 minutes, and is gone by 6; mechanism muscular and/or choroidal vascular; only an open anterior chamber bars it. Barash accepts it in open-eye injury when adequate anaesthesia and block prevent coughing.

Sources: Miller 10eBarash 9e

Succinylcholine raises intraocular pressure because tonic myofibrils in the extraocular muscles contract and choroidal vessels briefly dilate. Tracheal intubation adds its own rise. Anaesthetic drugs, opioids included, lower intraocular pressure by depressing the central ocular centres, which relaxes extraocular muscle tone. Remifentanil given with propofol or thiopental adds enough of this central depression to offset both causes of the rise. Fentanyl lowers the pressure too, but in comparative data the fall was smaller.

Fentanyl prevents IOP rise after intubation. Fentanyl is the usual induction opioid and does lower intraocular pressure at induction, so it looks like a safe pick. But the evidence for preventing the rise after succinylcholine and intubation is for remifentanil. In a direct comparison, fentanyl lowered the pressure less.

Remifentanil 1 mcg/kg, given with propofol or thiopental, was reported to prevent the pressure change after succinylcholine and intubation. In non-ophthalmic surgery, pressure fell from 13.6 to 7.1 mm Hg with remifentanil and from 13.7 to 9.7 with fentanyl.

Sources: Miller 10e

Succinylcholine resembles acetylcholine and acts on the autonomic pathways to the sinus node. Children have high resting vagal tone, so even the first dose can slow the heart. Adults have less vagal tone and more often become tachycardic with the first dose. A second dose given soon after the first adds its breakdown products, succinylmonocholine and choline. These stimulate the same receptors further and can cause sinus bradycardia, junctional rhythm or arrest. An anticholinergic given beforehand blunts this. Overall, the most frequent effects are fasciculations, followed by postoperative myalgia.

Large propofol dose causes this bradycardia. A large induction dose of propofol can lower heart rate, but the infant's high vagal tone, the repeat dose of relaxant and the response to atropine point instead to the muscarinic effect of succinylcholine and its metabolites.

Succinylcholine can cause bradycardia or asystole. The risk is higher in children and after repeat doses, where accumulated metabolites are blamed, and anticholinergic pretreatment lowers it. Fasciculations occur in 80% to 90% of patients and myalgias in 50% to 60%.

Sources: Barash 9eFaust

The sources do not conflict: they rank the options. Barash rates NSAID pretreatment best: about one case is prevented for every 2.5 patients treated. Miller shows that rocuronium pretreatment cut myalgia well below placebo. Faust agrees that a small defasciculating dose of a non-depolariser works, but warns it can cause double vision, ptosis, dysphagia and breathing difficulty. Dose works against intuition: bigger succinylcholine doses, not smaller ones, were tied to less myalgia. If only one answer is allowed, choose the NSAID.

Reduce succinylcholine dose to prevent myalgia. Cutting the dose seems logical: less drug should mean fewer fasciculations and less pain. The evidence points the other way. Larger succinylcholine doses were associated with less myalgia, so reducing the dose gives no protection.

Barash names NSAID pretreatment as the most effective prophylaxis. Miller found rocuronium pretreatment clearly reduced myalgia compared with vecuronium and placebo. Faust lists larger succinylcholine doses, lidocaine, NSAIDs and a defasciculating non-depolariser as reducing it, and warns of weakness-type side effects.

Sources: Barash 9eMiller 10eFaust

Parkinson's disease is a loss of dopamine signalling in the extrapyramidal motor system. Treatment works by restoring that signalling. Any antiemetic that blocks dopamine receptors in the brain works against this. It can bring on or worsen rigidity, slowness of movement and tremor. Ondansetron controls nausea by blocking serotonin receptors, not dopamine receptors, so it spares the extrapyramidal pathway.

Promethazine lacks dopamine-blocking effects. Promethazine is usually thought of as a sedating antihistamine, so it looks safe from dopamine side effects. It also blocks dopamine receptors. The sources list it with droperidol as a drug that causes extrapyramidal effects, so it is contraindicated in Parkinson's disease.

Drugs that block dopamine should be avoided in Parkinson's disease because they cause extrapyramidal effects. The sources name droperidol, promethazine, thiethylperazine and metoclopramide, and list haloperidol in the same dopamine-blocking group. Ondansetron is the preferred antiemetic.

Sources: Mayo reviewFaust

Droperidol acts like most antipsychotics. It slows how heart muscle repolarises. That lengthens the QT interval. In a heart already slow to repolarise, the extra delay can set off torsades de pointes. The risk seems to grow with dose. Fainting spells with a long QT suggest arrhythmia is already happening. So this patient faces the most added danger. Regulators responded with warnings. Some countries withdrew the drug. In the US it is now used only against sickness after surgery.

Morphine prolongs QT interval. Morphine can seem risky in a child who has fainted. But it is not an antipsychotic. The texts link delayed repolarisation and torsades to droperidol only. Nothing here names morphine as the drug to avoid.

Droperidol can lengthen QT by slowing repolarisation. It may trigger torsades de pointes. The effect seems dose dependent. An FDA warning followed in 2001. Several countries withdrew it. The US gives it a black box warning.

Sources: Miller 10eBarash 9e

The chemoreceptor trigger zone in the medulla carries opioid, serotonin 5HT3, histamine, D2 and muscarinic receptors. Dopamine acting on this zone causes nausea and vomiting. Blocking its D2 receptors with a butyrophenone such as droperidol or haloperidol stops that drive. Metoclopramide belongs to the same D2-antagonist class, and 5HT3 antagonists also bind in the zone. The deciding feature is antagonism: the natural transmitter or an agonist excites the zone and causes emesis, while the drug that blocks the receptor is the antiemetic.

Dopamine blocks the chemoreceptor trigger zone. Dopamine is tempting because it really does act on the trigger zone, and the concept is built around dopamine. But dopamine stimulates the zone and causes vomiting. The antiemetic is the drug that blocks dopamine's D2 receptors, such as droperidol.

The texts say that central dopamine stimulates the medullary trigger zone and causes vomiting, and that haloperidol and droperidol counter this. The zone holds 5HT3, histamine, D2 and other receptors. 5HT3 antagonists bind there too, and metoclopramide is grouped with the D2 antagonists.

Sources: Barash 9eFaustMayo review

It is a highly selective alpha-two agonist. It gives sedation that is calm, sleep-like and easy to rouse, together with anxiolysis, some analgesia and sympatholysis, while barely depressing breathing. That profile suits a ventilated patient who needs to stay settled, cooperative and ready for weaning. In a trial against lorazepam it gave more days free of delirium or coma and more time at the target sedation level. Because it spares breathing, its use later spread to procedures and the operating theatre, but these grew out of the intensive care role.

Dexmedetomidine used as general anaesthetic. This is tempting because dexmedetomidine is famous for preserving spontaneous breathing. That property makes it useful for procedural sedation. It is still used as a sedative, though, not as a general anaesthetic, and its licensed main use remains sedation of ventilated intensive care patients.

Miller states it was approved only for short-term (<24 hours) sedation of ventilated adult ICU patients, with other settings added later. Barash places ICU sedation of ventilated patients first among its key uses and stresses minimal respiratory depression.

Sources: Miller 10eBarash 9e

Shivering usually comes with postoperative hypothermia. Forced-air warming corrects the low temperature, and drugs damp down the shivering response itself. Pethidine is the usual adult choice. Several non-opioid drugs also suppress shivering: ondansetron, clonidine and ketamine, plus dexmedetomidine given as an intraoperative infusion to prevent it. Tramadol worked as well as pethidine in parturients shivering after epidural anaesthesia. Not all shivering is caused by cold: remifentanil increases postanaesthetic shivering whether or not the patient became hypothermic during surgery.

Midazolam, because it settles shaking. Midazolam tempts because it settles a restless, shaking patient in recovery. But it is not on the textbook list of antishivering drugs, and unlike propofol or alfentanil it barely shifts the thermoregulatory thresholds; small trials show a modest preventive effect. Ondansetron is on that list, with opioids, clonidine and ketamine.

Opioids, ondansetron, clonidine and ketamine all prevent or treat shivering, and pethidine 12.5–25 mg IV is the commonest adult choice. An intraoperative dexmedetomidine infusion works as prevention. Tramadol matched pethidine after epidural anaesthesia in parturients. Remifentanil causes shivering unrelated to hypothermia.

Sources: Miller 10e

To cannulate the papilla, the endoscopist needs a still duodenal wall. Spasm and peristalsis keep moving the target. Antispasmodics relax the smooth muscle of the duodenum, which quietens the bowel and gives the endoscopist better working conditions. Glucagon is the standard agent. Hyoscyamine works the same way through an anticholinergic effect. Both can speed the heart, so expect sinus tachycardia after giving them and do not mistake it for light anaesthesia or hypovolaemia.

Metoclopramide relaxes duodenum for ERCP. Metoclopramide is a familiar gut drug, so it looks like the right kind of answer when the problem is duodenal motility. But it is a prokinetic. It increases upper gut motility and would make the duodenum harder to cannulate. The procedure needs the gut relaxed, not stimulated.

Endoscopists often give antispasmodics such as glucagon or intravenous hyoscyamine to damp duodenal motility and improve conditions during the procedure. Sinus tachycardia is a recognised side effect.

Sources: Barash 9e

Propranolol blocks beta-one and beta-two receptors. Losing beta-two bronchodilation can provoke bronchospasm in asthma and blunts salbutamol, so the airway disease decides the choice. Caution for conduction starts only beyond first-degree block. Antiepileptics avoid both problems, and valproate and topiramate prevent migraine about equally. Valproate is teratogenic and harms neurodevelopment, so regulators contraindicate it in women able to conceive unless a pregnancy prevention programme is followed. Topiramate also needs contraception but is safer for them. Where valproate is the only antiepileptic available, it is still the right class.

Propranolol as standard beta-blocker. Propranolol is the standard beta-blocker for migraine prevention, so it is the reflex pick. But it is non-selective, and blocking beta-two receptors can trigger dangerous bronchospasm in an asthmatic who relies on inhaled bronchodilators. Asthma therefore rules it out.

Beta-blockers have an established role in preventing migraine, but non-selective agents need caution in obstructive airway disease, heart failure and conduction block beyond first degree. Oral valproate is widely used to prevent migraine, and topiramate works about as well as divalproex.

Sources: Miller 10eBarash 9e

The electrical stimulus sets off a generalised tonic–clonic seizure. The violent contraction of skeletal muscle during that seizure can break bones or dislocate joints. Suxamethonium given straight after the induction agent acts at the neuromuscular junction and blunts those contractions. It does nothing to the brain's seizure threshold. The teeth and tongue need a separate measure, a soft bite block placed for the seizure. So the relaxant is there to prevent orthopaedic injury, not oral injury.

Succinylcholine prevents tongue and dental injury. Tongue and dental injury during the fit is real and easy to picture, so it feels like the reason for paralysis. But the texts give that job to a soft bite block. The relaxant is listed for fractures and dislocations.

One text says suxamethonium given right after induction is meant to blunt dangerous seizure contractions and the fractures they cause. Another says it prevents musculoskeletal injury. A third lists fractures and dislocations as the relaxant's target, with a soft bite block for teeth and tongue.

Sources: Stoelting 8eBarash 9eFaust

Propofol raises the seizure threshold, so the seizure triggered by the electrical stimulus is shorter. With propofol or methohexital, this suppression deepens as the dose rises. Etomidate behaves differently: at usual induction doses, 0.15 to 0.3 mg/kg, it shows no dose-related inhibition and gives longer, better-quality seizures. Faust rejects propofol for ECT outright. Stoelting accepts it as an alternative that blunts the haemodynamic response. The two fit together: propofol suits many patients, but once a seizure proves inadequate, change to etomidate.

Increase propofol to prolong seizure. More propofol can look like simply deepening the anaesthetic to get a cleaner treatment. It fails because propofol's anticonvulsant effect grows with the dose. A bigger dose suppresses the seizure further and shortens it again. The fix is to change the hypnotic, not to give more of it.

Propofol's anticonvulsant action shortens ECT seizures, while etomidate improves both how long they last and their quality. Across 0.15 to 0.3 mg/kg, etomidate does not inhibit seizures in proportion to dose, unlike propofol or methohexital. Propofol raises the seizure threshold.

Sources: Stoelting 8eMiller 10eFaust

Elimination half-life is how fast the plasma level falls once distribution is complete. It sets how long sedation lasts after a dose. Midazolam's is short. That, plus fewer drug interactions, makes it the preferred benzodiazepine for premedication and procedural anxiolysis. Do not confuse it with equilibration half-time, which is the delay before the drug reaches its site of action and controls onset. For midazolam this is about 0.9 minutes, so leave a few minutes between repeat doses.

Alprazolam is shortest-acting benzodiazepine. Alprazolam is prescribed for anxiety and is often called short-acting, so it seems to fit an anxious-patient question. But its half-life is several times midazolam's and close to lorazepam's. Being a good anxiolytic does not make it the shortest-acting.

A comparison table gives midazolam a half-life of 2.5, against 8.8 for temazepam, 11.2–16.3 for alprazolam and 14 for lorazepam. Its short elimination half-life and fewer interactions make it the benzodiazepine of choice for procedural anxiolysis.

Sources: FaustBarash 9e

These hypnotics reduce neuronal electrical activity more as the dose rises. Once the EEG reaches burst suppression, brain oxygen use has fallen by about 60%. Flow–metabolism coupling stays intact, so cerebral blood flow falls with it. Any drug that can produce burst suppression reaches the same ceiling, so thiopental and propofol are equal at maximal dose. Opioids hardly change cerebral metabolism. Benzodiazepines cause a significant fall only at doses that induce general anaesthesia.

Midazolam lowers cerebral metabolic rate. Midazolam is a GABA-ergic hypnotic that does lower cerebral flow and metabolism as the dose rises, so it looks like a peer of propofol. At sedative doses the effect is minor, and it is not among the drugs described as driving the EEG to burst suppression.

Barbiturates, etomidate and propofol can produce EEG burst suppression, reducing cerebral metabolism by roughly 60% with matching falls in blood flow. Opioids cause only minor falls. Benzodiazepines have little effect at sedative doses, significant only at anaesthetic doses.

Sources: Miller 10eBarash 9e

An antimuscarinic has central effects, such as sedation or the central anticholinergic syndrome, only if it crosses the blood-brain barrier. Scopolamine crosses most readily, atropine less so, and glycopyrrolate does not cross, so it neither sedates nor causes the central syndrome. The eye follows the same order. Scopolamine dilates the pupil and paralyses accommodation more than atropine does, especially when put on the eye. Each drug has a different profile: atropine is the stronger blocker at the heart, and scopolamine is stronger for sedation and the eye.

Atropine most sedating antimuscarinic. Atropine is the standard antimuscarinic and the textbook cause of dilated pupils, so people pick it by reflex. Its strength is blocking the heart's muscarinic receptors. For the eye, and for sedation, scopolamine has the greater effect, so atropine is not the best answer.

Both atropine and scopolamine affect the eye, dilating the pupil and paralysing accommodation. Scopolamine does this more strongly. Sedation needs the drug to enter the brain, so it is marked with scopolamine, weaker with atropine and absent with glycopyrrolate. Atropine is the best cardiac blocker.

Sources: Mayo review

Atropine, scopolamine and glycopyrrolate all block muscarinic receptors on salivary and airway glands. None of them favours a particular receptor subtype, so they differ mainly in potency and in how strongly they act on the heart. Glycopyrrolate gives the deepest and longest-lasting drying of the three, and it raises heart rate less than atropine. This makes it the drug of choice when a dry airway is the aim, for example before fibreoptic intubation.

Scopolamine most potent antisialagogue. Scopolamine is famous as a powerful anticholinergic that also sedates, so it feels like the heavyweight choice. But the sources rank glycopyrrolate above both atropine and scopolamine for drying potency, and its drying effect also lasts longer.

Barash calls glycopyrrolate the most potent antisialagogue, with less tachycardia than atropine, and says drying for fibreoptic intubation is a major indication. Faust ranks it above atropine and scopolamine, with drying lasting up to 7 h.

Sources: Barash 9eFaust

Systemic fentanyl does not raise vasopressin, renin or aldosterone. The hormonal drive to hold on to salt and water is therefore not switched on, and any renal change during opioid anaesthesia comes second-hand from haemodynamics. Volatile agents depress the myocardium and dilate vessels, which lowers renal blood flow and filtration. Any technique that causes hypotension also cuts urine flow, because it changes the hydrostatic forces around the peritubular capillaries even when autoregulation still holds.

Halothane preserves urine output through renal perfusion. Halothane is tempting because renal blood flow is reported to be maintained with it, which suggests a kidney-friendly agent. But keeping flow is not the same as keeping output. Volatile agents still reduce filtration through myocardial depression and vasodilation, so urine output falls.

Systemic fentanyl-type opioids leave vasopressin, renin and aldosterone unchanged and preserve renal function. Volatile agents cause mild to moderate falls in renal blood flow and GFR, although blood flow may be preserved with halothane. Hypotension from any technique reduces urine flow.

Sources: Miller 10e

Glucocorticoid potency is expressed against cortisol, which is fixed at 1.0. A higher figure means a smaller dose in milligrams gives the same anti-inflammatory effect. Prednisone and methylprednisolone are only a few times stronger than cortisol, at four and five times respectively. Betamethasone rates 25, which puts it far above both. So when betamethasone is offered alongside those two for an injection, it is the choice with the greatest anti-inflammatory potency.

Methylprednisolone is most potent corticosteroid. Methylprednisolone is a familiar injectable steroid and is a little stronger than prednisone, so it can look like the strongest option. On the cortisol-referenced scale, though, it sits just above prednisone and well below betamethasone.

Betamethasone's potency is 25. On the anti-inflammatory scale, with cortisol as the 1.0 reference, methylprednisolone scores one more than prednisone, which scores between three and five (exclusive).

Sources: Mayo reviewBarash 9e

The daily ceiling exists to prevent liver injury. A healthy adult can safely take up to 4 g in 24 hours, and more than that counts as a toxic dose. If the liver is diseased or the kidneys are impaired, the margin shrinks, so the ceiling drops to 2 g or less. Paracetamol is also hidden in many combined oral opioid tablets. Count every source towards the daily total. Giving it intravenously avoids first-pass hepatic exposure and lowers the risk of liver injury.

Two grams daily ceiling for all adults. 2 g/day is a real ceiling, so it looks like the safe, cautious choice. But it applies only to patients with impaired liver or kidney function. A young patient with acute pain and no stated organ disease gets the full adult ceiling.

Adults: 4 g a day at most; above 4 g in 24 hours is toxic, so count paracetamol hidden in combined opioid tablets. Impaired liver or kidney function: 2 g or less. Children: under 90 mg/kg in 24 hours.

Sources: Miller 10eBarash 9eFaust

Equianalgesic tables compare every opioid with morphine, so do the conversion in two steps rather than one. First, change the route: 10 mg IV morphine matches 30 mg oral morphine, which triples the dose. Second, change the drug: 30 mg oral morphine matches 20 mg oral oxycodone, which is two-thirds of that. Together, the oral oxycodone dose is twice the IV morphine dose. Barash also lists a parenteral oxycodone dose. That dose is for injection, not tablets.

One-fifty milligrams complete oxycodone conversion. 150 mg is the oral morphine equivalent, so it looks like a finished answer. It only covers the route change. It leaves out the second step, from morphine to oxycodone, which reduces the dose to two-thirds. The correct tablet dose is double the IV morphine dose.

Barash's text and Miller's consensus table both say 10 mg IV morphine equals 30 mg oral morphine and 20 mg oral oxycodone. Barash lists parenteral oxycodone as 10–15 mg and says its table is only a general guide.

Sources: Barash 9eMiller 10e

The ratio is grams of drug per millilitres of solution, so 1:1000 means 1 mg in every mL. Concentration is the total drug divided by the final volume. Drawing up 1 mL (1 mg) and making it up to 10 mL spreads that 1 mg through the larger volume, giving 0.1 mg/mL, which is 100 mcg/mL or 1:10,000. Diluting again by the same factor gives 10 mcg/mL (1:100,000). Taking a smaller amount out of a well-mixed bag never changes its concentration.

One milligram in ten makes required concentration. It is a real bedside recipe, so it looks familiar. But it makes the weaker push-dose strength of 10 mcg/mL (1:100,000). Drawing 10 mL out of the bag does not concentrate it. To reach 0.1 mg/mL, the 1 mg must sit in a final volume of only 10 mL.

The textbooks label 1:1000 adrenaline as 1 mg/mL, the intramuscular anaphylaxis strength. They label 1:10,000 as 100 mcg/mL, used for arrest and unstable bradycardia doses. A further dilution to 1:100,000 gives 10 mcg/mL, used for small incremental boluses.

Sources: Miller 10eBarash 9e

ED95 is shorthand for the dose that produces a 95% twitch reduction in 50% of patients. It measures potency: the smaller the ED95, the more potent the drug. Rocuronium is a weak blocker at 0.3 mg/kg, while vecuronium's ED95 is 0.05, so vecuronium is the more potent drug. A single ED95 is not enough for reliable intubating conditions, so doses are given as multiples of it. Because rocuronium is weak, a large dose delivers many molecules, and this shortens onset.

Zero point six rocuronium ED95. 0.6 mg/kg is the rocuronium figure people remember best, because it is the standard intubating dose. But that dose is twice the ED95, deliberately set above the potency figure so that intubating conditions are reliable. The ED95 itself is half of it.

Barash lists the ED95 of rocuronium and succinylcholine as 0.3 mg/kg, and that of vecuronium and cisatracurium as 0.05. Routine intubation uses 2× or 3× the ED95, which is 0.6 mg/kg for rocuronium. A 4× dose, 1.2 mg/kg, brings onset to about 1 minute.

Sources: Barash 9e

A median effective dose makes only half of patients respond. A working induction dose has to put nearly everyone to sleep, so it sits above the median. Age also changes requirements. Children have a larger volume of distribution because the drug redistributes quickly, so their induction needs rise as age falls. In infants aged 1–6 months, the median dose for losing the eyelash reflex is 3 mg/kg, roughly double the adult figure.

Two-point-five milligrams kilogramme is median. It is tempting because 2.5 mg/kg is the induction dose most people remember, and it is quoted alongside propofol's rapid onset. It fails because a clinical dose is chosen to work in almost every patient. The median dose, which works in only half, is lower.

In adults, the median bolus dose for loss of consciousness is 1–1.5 mg/kg. Hypnosis lasts 5–10 minutes after 2–2.5 mg/kg. Younger patients need more: infants aged 1–6 months need a median of 3 mg/kg to lose the eyelash reflex.

Sources: Miller 10e

Laryngeal and diaphragmatic muscles are actually more resistant to non-depolarising drugs than the thumb. However, they get more blood flow per gram, so a higher peak drug level reaches them before the drug redistributes. Their plasma-to-effect-site equilibration half-life is therefore shorter: 2.7 versus 4.4 minutes at the thumb. Their resistance only shows during recovery, when these central muscles move again before the thumb does. So the thumb, the muscle we usually monitor, lags the larynx both at onset and at offset.

Laryngeal muscles block before adductor pollicis. It sounds like the adductor pollicis or the foot monitoring site, so it feels like the textbook reference muscle. But it is a peripheral limb muscle with less blood flow and slower drug equilibration. Peripheral muscles are among the last to block, not the first.

The laryngeal adductors and diaphragm block faster than the thumb, even though they are relatively resistant. The larynx equilibrates faster (2.7 versus 4.4 minutes). This is put down to greater central blood flow. Their resistance appears only as earlier recovery.

Sources: Miller 10eBarash 9e

Felt or seen fade shows only while blockade is marked: Miller puts the tactile ceiling near 0.31, and elsewhere says estimation is reliable only below 0.4. Between 0.4 and 0.9 no fade is felt, so only a measured ratio closes that gap. Awake patients are tested clinically, but these tests are insensitive too. The classic 5-second head lift is passed at a ratio of about 0.6; clenching a tongue depressor needs about 0.85; grip may still be only about 60% of control at 0.7 to 0.75, so it recovers last.

Normal tidal volume taken as recovery. Good breathing after extubation looks like recovery, and tidal volume is usually the first thing checked. But ventilation returns while much of the receptor pool is still blocked, so a normal tidal volume can sit alongside a weak grip and says little about residual paralysis.

Miller says felt fade is missed above an average ratio near 0.31 and is accurate only below 0.4, so between 0.4 and 0.9 a measured ratio is needed. At 0.7 to 0.75 grip may be about 60% of control; tongue-depressor clenching outperforms head lift.

Sources: Miller 10e

Fingers and eyes cannot reliably compare the fourth twitch with the first when the difference is modest, so manual assessment overestimates recovery. Double-burst replaces the train with short tetanic bursts, each felt as one movement, making a weaker second response easier to notice. The gain is modest. Weakness persists at a ratio of 0.7, and the pharynx does not recover until the ratio exceeds 0.9. Both lie beyond what either pattern can show, so finding no fade proves nothing. Fade you can feel confirms inadequate recovery.

Point-seven ratio indicates complete recovery. 0.7 was once the accepted recovery benchmark, so the number feels familiar. But clinical weakness persists at that ratio, and pharyngeal function is not normal until the ratio exceeds 0.9. A ratio of 0.7 is residual block, not good recovery.

Miller says touch or sight judges fade accurately only below a ratio of 0.4, so it overestimates recovery. The European guideline puts the limit of detectable fade at 0.4 for train-of-four and 0.6 for double-burst. Barash calls double-burst a slight improvement.

Sources: Miller 10eOutside our books: Peri-operative management of neuromuscular blockade: a guideline from the European Society of Anaesthesiology and Intensive Care (2023)Barash 9e

Depth indices read the EEG patterns of GABA-ergic hypnotics well. Ketamine's EEG changes are different, so the index misreads them. It climbs falsely even as antinociception deepens: from 40 to 63 after 0.5 mg/kg on a propofol–fentanyl background. Nitrous oxide also acts differently from GABA-ergic drugs, and given alone it rarely produces full unconsciousness. Its EEG changes are small and inconsistent, so its contribution barely moves the number.

Fentanyl explains ketamine raising BIS. Opioids add analgesia with little hypnotic effect, so someone may expect fentanyl to leave the index high. But fentanyl was part of the background regimen that held BIS low until ketamine raised it. The drug whose effect the index misses is nitrous oxide.

Barash reports that a higher dose of ketamine added to propofol–fentanyl anaesthesia raises BIS markedly. Miller says ketamine's EEG changes falsely raise depth indices despite better antinociception. Miller also says nitrous oxide's minimal, subtle EEG effects make its contribution hard for indices to detect.

Sources: Barash 9eMiller 10e

Isoflurane depresses cortical electrical activity more as the dose rises. As the level deepens, the EEG slows. It then shows bursts separated by flat periods at about 1.5 MAC, and it becomes isoelectric between 1.5 and 2 MAC. Cerebral oxygen consumption falls alongside this and reaches its lowest point at the same moment the EEG goes silent. Giving more isoflurane, even up to 6% end-tidal, lowers metabolism no further and shows no metabolic toxicity.

Burst suppression starts above two MAC. Burst suppression feels like very deep anaesthesia, so a high figure is tempting. But isoflurane already produces bursts at about 1.5 MAC and is fully isoelectric by 2 MAC. At a higher concentration, beyond 2 MAC, the EEG is past complete suppression, not at the point where burst suppression starts.

The textbook puts the isoflurane burst-suppression pattern at about 1.5 MAC. It says EEG suppression, together with the largest fall in cerebral oxygen consumption, happens at 1.5 to 2 MAC in humans. Extra isoflurane up to 6% end-tidal gives no further metabolic reduction.

Sources: Miller 10e

The classical ether scheme sorts depth by what the patient shows. In the first stage the patient still answers to voice, breathes normally and keeps airway reflexes. In the second stage consciousness is lost, but higher control is not yet suppressed. Breathing becomes erratic, sometimes with overbreathing, and there may be purposeless movement and dangerous reflexes such as laryngospasm, vomiting and arrhythmias. Only in the third, surgical stage does breathing settle into a regular rhythm. So erratic breathing without responsiveness points to the second stage.

Irregular breathing defines surgical anaesthetic stage. A breathing rate this slow looks like deep anaesthesia, so the surgical stage seems likely. But the surgical stage is defined by breathing that has become regular again. Irregular, unpredictable breaths in an unresponsive patient belong to the excitement stage, not the surgical one.

In the classical stages, the first stage keeps verbal response and normal breathing. The second (delirium or excitement) stage brings unconsciousness, erratic breathing, purposeless movement and reflex risks. The third stage marks the return of regular breathing and is where MAC is reached.

Sources: Mayo review

Scopolamine, and atropine in large doses, pass into the brain. Central muscarinic blockade then causes restlessness, confusion, delirium or stupor. Peripheral signs such as dry mouth and blurred vision appear too. Reversal needs an anticholinesterase that reaches the brain. Physostigmine is a tertiary amine, so it crosses into the brain. Neostigmine and edrophonium are quaternary, so they cannot act centrally.

Neostigmine reverses central anticholinergic syndrome. Neostigmine is the anticholinesterase used daily to reverse neuromuscular block. So it feels like the natural antidote. But it is quaternary and cannot cross into the brain. The central muscarinic blockade driving the delirium is left untouched.

It follows scopolamine most often, and sometimes high-dose atropine. Features include delirium, confusion or obtundation, with dry mouth and blurred vision. Physostigmine, a tertiary amine, crosses into the brain and treats it. Quaternary anticholinesterases cannot.

Sources: Mayo reviewBarash 9e

PRIS is a dose- and duration-dependent injury: heart and skeletal muscle break down, producing refractory bradycardia progressing to asystole, myocardial failure, rhabdomyolysis, hyperkalaemia, lactic acidosis and lipaemia. Because the drug drives the injury, the remedy is removal, not dose reduction or buffering: discontinue propofol and consider continuous haemofiltration. Long infusions can turn urine green through a phenolic or quinol metabolite; this is benign and signals nothing about PRIS. Dark brown urine would fit the myoglobinuria of rhabdomyolysis, but that is an inference; no book names a PRIS urine colour.

Rate reduction stops propofol syndrome. Turning the rate down feels proportionate, because the syndrome tracks dose and many drug side effects settle with titration. But once muscle and myocardial injury is under way, any continued exposure keeps driving it. The sources direct stopping the drug, not running it at a lower rate.

The syndrome follows infusions of 4 mg/kg/h or more lasting 48 hours, and refractory bradycardia leads it. Lactic acidosis, lipaemia, rhabdomyolysis and myocardial failure follow. Propofol should be stopped and haemofiltration considered. Green urine after long infusions has no clinical significance.

Sources: Stoelting 8eBarash 9eFaust

Ketamine uncouples thalamocortical activity from the limbic system, and the EEG shows the two falling out of synchrony. So the patient can be anaesthetised and pain-free while looking awake. The eyelids stay open, the gaze drifts with nystagmus and the pupils widen moderately. Corneal, cough and swallow reflexes may still be present, but they cannot be trusted to protect the airway. This awake look is the drug working as expected. It is not a sign of light anaesthesia or of a new neurological event.

Eyes open nystagmus indicates seizure. Open, roving eyes with nystagmus in an unresponsive patient can look like seizure activity. But this is exactly the dissociative state ketamine is described as producing, so reading it as a convulsion treats a normal drug effect as a disease.

The textbooks describe ketamine's dissociative state as one where the eyes stay open with a nystagmic gaze and the pupils dilate moderately. The EEG shows the thalamus uncoupled from limbic structures. Some airway reflexes may persist but should not be relied on for protection.

Sources: Barash 9eMiller 10eFaust

The cause is too much serotonin in the central nervous system. It builds up when several serotonergic agents are given together: antidepressants, MAOIs, some antibiotics and antiemetics, and the phenylpiperidine opioids such as tramadol and pethidine, which weakly block serotonin reuptake. The excess drives three systems. Neuromuscular: clonus, myoclonus, hyperreflexia and tremor. Autonomic: sweating, tachycardia and fever. Mental: agitation and confusion. Onset is within 12 hours. The dopamine-antagonist syndrome develops more slowly, with rigidity, bradykinesia and stupor.

Metoclopramide causes serotonin syndrome. It is tempting because it also causes fever, autonomic instability and altered mentation, and antiemetics such as metoclopramide can trigger it. But it follows dopamine blockade, develops over days, and shows rigidity, bradykinesia and stupor rather than clonus and brisk reflexes.

Textbooks list antidepressants, MAOIs, opioids, antibiotics and antiemetics as culprits, and pethidine, tramadol and methadone act as weak reuptake inhibitors. Hallmarks are clonus, myoclonus, hyperreflexia, agitation, sweating and fever, usually starting within 12 hours, unlike the slower, rigid, stuporous neuroleptic syndrome.

Sources: Stoelting 8eMiller 10eMayo review

Parkinson's disease destroys dopaminergic neurons that drive the extrapyramidal motor system. The resulting imbalance between neurotransmitters causes slow movement, rigidity and tremor. Metoclopramide blocks dopamine receptors (and serotonin receptors), so it shuts down what dopaminergic signalling is left. This deepens the functional dopamine deficit and can bring out or worsen rigidity. The same reasoning rules out other antidopaminergic antiemetics, such as droperidol, haloperidol and prochlorperazine, in these patients.

Anticholinergic toxicity causes dopamine blockade. Anticholinergic syndrome is a well-known postoperative diagnosis, and some antiemetics also have anticholinergic activity. But metoclopramide works by blocking dopamine receptors, not muscarinic ones. The sources link it to worse parkinsonian rigidity through that dopamine blockade, and anticholinergic toxicity does not explain new extrapyramidal rigidity.

The texts list metoclopramide as a dopamine receptor antagonist antiemetic. They say dopamine antagonism can make parkinsonian features, including muscular rigidity, worse. They also say it is contraindicated in Parkinson's disease, along with other drugs that provoke extrapyramidal effects.

Sources: Barash 9eMayo review

Droperidol is a butyrophenone that blocks dopamine receptors, including those in the basal ganglia. There, dopamine normally balances cholinergic signalling. When dopamine is blocked, cholinergic tone goes unopposed, and the result is sudden sustained muscle contraction: oculogyric crisis, torticollis and a spasming tongue or jaw. The treatment has to reach the brain and restore that balance. Diphenhydramine crosses the blood-brain barrier and has anticholinergic activity as well as blocking histamine, so it reverses the reaction, usually quickly.

Midazolam fixes droperidol dystonia. A distressed, rigid child after anaesthesia makes you think of a benzodiazepine for sedation or muscle relaxation. Midazolam may calm the child, but it does not correct the loss of dopamine-cholinergic balance that causes the dystonia. The sources name diphenhydramine as the treatment.

Drugs that block dopamine receptors can cause acute dystonic reactions, and this happens in about 1% of patients given droperidol. Treatment is an agent that gets into the brain. Intravenous diphenhydramine 25 to 50 mg resolves acute dystonia.

Sources: Stoelting 8eMayo review

Some opioids set off skin mast cells directly. This is not IgE-mediated and is not a mu-receptor effect: fentanyl and sufentanil are very potent mu agonists yet release no histamine in skin. Morphine does it through a mast-cell receptor called MRGPRX2. The histamine released widens terminal arterioles, so vascular resistance and blood pressure fall while heart rate and contractility rise. The skin reacts too, so the picture looks like allergy even though true opioid allergy is rare. This is why intravenous codeine is not used.

Codeine is main histamine-releasing opioid. It is an intravenous opioid and its name echoes morphine, so it looks like the obvious histamine releaser. But these texts name only morphine, codeine and pethidine as opioids that release histamine. Potency at the mu receptor does not predict mast-cell release.

Stoelting names morphine, codeine and pethidine as opioids that release histamine straight from mast cells and basophils, mimicking allergy. Miller says intravenous codeine causes profound hypotension and is not recommended. Barash says fentanyl and sufentanil release no histamine in skin.

Sources: Stoelting 8eMiller 10eBarash 9e

Most opioids make the pupils small, so pinpoint pupils with drowsiness is the classic sign of opioid excess. Pethidine is the exception because its structure resembles atropine and it has some anticholinergic activity. Anticholinergic drugs widen the pupil, so pethidine does not produce the usual small pupils. That is why an opioid-poisoned patient with wide pupils suggests pethidine and not a typical opioid.

Morphine dilates pupils. Morphine is the standard opioid, and drowsiness after a wrong prescription looks like opioid overdose, so it is the reflex choice. But morphine constricts the pupils. Wide, fixed pupils argue against it and point to the one opioid with atropine-like action.

A toxicology table lists opioids among drugs that cause small pupils but names pethidine as the exception. Anticholinergics head its list of drugs that dilate the pupils. A review text says pethidine resembles atropine in structure and has mild anticholinergic effects.

Sources: Miller 10eMayo review

All volatile agents depress the sinoatrial node's firing rate and slow conduction through the His–Purkinje system. Sevoflurane is the agent used for inhalational induction in children, so this nodal depression shows up at induction. Children with trisomy 21, and those with congenital heart disease, are especially prone. Severe slowing occurs in up to 50% of children with Down syndrome. Reducing the agent and correcting hypoxia often restore the rate. If drugs are needed, give atropine or adrenaline.

Desflurane bradycardia trisomy 21 induction. Desflurane is tempting because it is the other modern volatile, and its pungency can cause laryngospasm with hypoxic slowing. But it is not used for inhalational induction. It is also not the agent the sources single out for bradycardia in trisomy 21: that agent is sevoflurane.

The texts list sevoflurane among the commonest drug causes of bradycardia in children, particularly in trisomy 21 and congenital heart disease. Severe slowing affects up to 50% of children with Down syndrome at sevoflurane induction. Volatiles slow sinoatrial discharge and conduction.

Sources: Stoelting 8eBarash 9e

Cancer is already prothrombotic because tumours release procoagulants such as tissue factor, and some anticancer drugs add to that risk. Stoelting names tamoxifen as a thrombogenic drug in its text, in its drug-toxicity table and in its breast cancer section, where the listed events are deep vein thrombosis, pulmonary embolism and stroke. The drugs with the highest risk are thalidomide and lenalidomide, and cisplatin is also implicated. Doxorubicin appears only as a co-drug that increases the risk from thalidomide, not as a cause in its own right.

Doxorubicin independently causes thromboembolism. Doxorubicin is tempting because the text lists it beside thalidomide, which carries a high venous thrombosis risk. It is mentioned only because it adds to thalidomide's risk. Alone, it is not listed as a cause of thromboembolism, so without thalidomide it is unlikely to be responsible.

Stoelting says tumours create a hypercoagulable state that some chemotherapies make worse. Thalidomide and lenalidomide carry especially high risk, more so with glucocorticoids and doxorubicin. Cisplatin and tamoxifen also raise risk, and tamoxifen specifically causes DVT, PE and stroke.

Sources: Stoelting 8e

Bleomycin kills cells by oxidative damage that breaks DNA, and lung tissue bears the same oxidant injury; hence its gravest, dose-related effect is pneumonitis that can scar into fibrosis, even though skin and mucosal effects are commoner. Risk rises beyond 250 mg total, over 40 years, and with creatinine clearance under 80 mL/min. High inspired oxygen was long blamed for worsening this injury; Stoelting notes newer evidence questions that but still advises the least oxygen needed, so titrate oxygen rather than withhold it.

Fluorouracil causes pulmonary fibrosis. The patient has colon cancer, and fluorouracil is the backbone of colorectal chemotherapy, so it feels like the drug being tested. Its usual toxicities are gut, mucosal and marrow, not lung. Whatever the patient's tumour, the chemotherapy drug known for pneumonitis and fibrosis is bleomycin.

Review texts list pneumonitis and fibrosis after bleomycin, calling dose-related lung toxicity its most serious effect. Risk rises beyond 250 mg total, over 40 years, and with creatinine clearance under 80 mL/min. Keeping inspired oxygen low is still advised despite newer contrary evidence.

Sources: Mayo reviewStoelting 8e

Insulin does not excite neurones itself. It lowers blood glucose, and the brain needs a steady glucose supply. As glucose falls, the EEG slows. At very low levels the EEG goes flat, and if this lasts, seizures and hippocampal damage follow. The risk rises when patients fast around surgery. Patients who have had many hypoglycaemic episodes can lose their warning symptoms, so a seizure may be the first sign that glucose is low.

Gabapentin provokes seizures normally. Gabapentin is tempting because it is the only neuroactive drug in the list, and stopping it suddenly can cause fits. At normal doses, though, it is an anticonvulsant and protects against seizures. The drug that actively provokes seizures is insulin, through hypoglycaemia.

Insulin carries a risk of hypoglycaemia. Severe hypoglycaemia (below 54 mg/dL) causes neuroglycopenia with confusion and seizures. Below 20 mg/dL the EEG goes flat, and if that level persists, seizures and hippocampal injury follow. Patients with repeated episodes may not notice symptoms.

Sources: Miller 10e

Phenylephrine acts only on alpha-1 receptors and has no beta-1 activity, so it does not stimulate the heart directly. Applied to the nasal mucosa, it is absorbed into the circulation. There it constricts arterioles and blood pressure rises sharply. The heart slows as a reflex response to that pressure rise, not because the drug acts on the heart. Uncounted drops in a small child can therefore cause severe hypertension together with bradycardia.

Pseudoephedrine hypertension nose drops. Pseudoephedrine is a familiar decongestant, so it looks like the obvious culprit. But it is a mixed-acting sympathomimetic with beta effects, so it tends to speed the heart up rather than slow it. The slow rate points to a pure alpha agonist.

Phenylephrine, an alpha-agonist topical vasoconstrictor sometimes mixed with lidocaine, should have a first dose of 500 mcg or less, and below 20 mcg/kg in children of 25 kg or less. It can cause severe hypertension; adverse effects include bradycardia.

Sources: Miller 10eFaust

Succinylcholine breaks down in solution. It does so faster when warm or alkaline and in stronger solutions, so its label demands refrigeration and Miller lists it among relaxants that lose potency with heat. Rocuronium and pancuronium are sturdier: rocuronium keeps at room temperature for 60 days and pancuronium for 6 months. A later stability study found succinylcholine's real room-temperature loss is slow, taking months before potency falls 10%. So the refrigeration rule is conservative, but it still marks succinylcholine as the relaxant most sensitive to warmth.

Rocuronium degrades most from heat. Rocuronium is tempting because its room-temperature allowance is shorter than pancuronium's and its label also calls for refrigeration. But that limit comes from breakdown caused by terminal sterilisation during manufacture, and it is a defined allowance. Succinylcholine is the relaxant whose potency is directly heat-labile.

Outside the textbooks, the succinylcholine label requires refrigeration to keep potency, and a stability study found 10% loss takes months. Miller notes it loses potency with heat, and gives rocuronium 60 days and pancuronium 6 months at room temperature.

Sources: Outside our books: ANECTINE (succinylcholine chloride injection, USP) and QUELICIN (succinylcholine chloride injection, solution) - FDA-approved prescribing information (2010)Miller 10eOutside our books: Stability of succinylcholine solutions stored at room temperature studied by nuclear magnetic resonance spectroscopy (2007)

Ketamine suppresses the relay nuclei that pass visual and auditory signals up to the cortex. On waking, the patient misreads what they see and hear. This produces illusions, vivid dreams, dysphoria, fear, excitement or euphoria. These psychic reactions appear early after emergence and usually settle within hours. Larger doses make them more likely. They also occur with a postoperative ketamine infusion for pain, not only after a ketamine anaesthetic. Midazolam given beforehand blunts them.

Morphine causes vivid emergence hallucinations. Opioids are the usual suspects for postoperative confusion and sedation, so morphine feels like the safe pick. But hallucinations, dysphoria and vivid dreams are the side effects the texts list for ketamine used as a pain adjunct. That dissociative picture belongs to ketamine, not to the opioid.

The texts list hallucinations, dysphoria and vivid dreams as side effects of postoperative ketamine infusion. The emergence reactions come from depressed visual and auditory relay nuclei and are dose dependent. Midazolam given beforehand may lessen them.

Sources: FaustMiller 10eMayo review

Dibucaine is an amide local anaesthetic that strongly suppresses normal plasma cholinesterase but has little effect on the common atypical variant. The laboratory reports the percentage of enzyme activity suppressed: about 80% for normal enzyme and about 20% for atypical. A heterozygote carries one allele of each, so the value falls between them. Barash gives 40–60 and the Mayo review 50–60; 50–60 lies within both, so it is the safe answer. The test reflects enzyme quality, not quantity.

Atypical dibucaine number near zero. The atypical enzyme is called dibucaine-resistant, so people imagine almost no inhibition and a near-zero number. But the atypical homozygote's enzyme is still inhibited by roughly a fifth. That puts its value below 30, in the 20–30 band, not close to zero.

Barash gives normal enzyme a value of 70–80 and the homozygote for the common abnormal allele a value below 30. Dibucaine inhibits normal enzyme by 80% and atypical by 20%. Barash puts heterozygotes at 40–60; the Mayo review puts them at 50–60.

Sources: Barash 9eMayo review

How long suxamethonium lasts depends mainly on plasma cholinesterase activity and on the extracellular volume the drug spreads into. When enzyme activity falls, as in pregnancy, hepatic disease, plasmapheresis or glucocorticoid therapy, the drug stays longer. When activity rises, as in obesity, the drug is cleared faster. The two obstetric sources agree that activity falls in pregnancy and differ only in size: Barash gives 20–30% and Faust gives 25% to 30%. The ranges overlap, so a fall of about a quarter fits both, and the resulting prolongation is clinically trivial.

Cholinesterase activity rises during pregnancy. This is tempting because so much goes up in pregnancy, including plasma volume, cardiac output and oxygen consumption, so people assume every value rises. Cholinesterase goes the other way. Its activity falls, so suxamethonium lasts slightly longer, not shorter.

Barash reports serum cholinesterase activity falls 20–30% at term; Faust reports a 25–30% fall from early pregnancy to the puerperium, clinically insignificant. Miller lists hepatic disease, plasmapheresis and glucocorticoids as causes of reduced activity. Activity is increased in obesity.

Sources: Barash 9eFaustMiller 10e

Phenylephrine is a pure alpha agonist. Drops absorbed through the conjunctiva, the nasal mucosa or venous channels opened at surgery tighten the arteries and raise the pressure sharply. The slow heart rate is the baroreceptor reflex responding to that pressure. It is not the primary problem. Blocking alpha receptors, or relaxing vascular smooth muscle directly, reverses the vasoconstriction, and the reflex bradycardia then settles. A beta-blocker leaves the vasoconstriction in place and removes what cardiac drive remains. That deepens the bradycardia against a high afterload.

Esmolol manages phenylephrine hypertension safely. Esmolol is short-acting and easy to titrate, so it looks like a safe way to bring down a crisis pressure. But alpha-mediated vasoconstriction is driving the pressure. Beta-blockade does not relax the vessels, and with the heart already reflexively slowed it risks profound bradycardia or failure against high afterload.

Treatment works best with a direct vasodilator or an alpha-antagonist such as phentolamine. Topical 10% drops can provoke dysrhythmias and myocardial ischaemia in coronary disease. Drops should not be instilled once surgery has opened venous channels, and 2.5% suits infants and the elderly.

Sources: Mayo reviewBarash 9e

Noradrenaline stops acting mainly because it is pumped back into the nerve terminal. Cocaine blocks this pump, and so do amphetamines. Transmitter builds up at the receptor and the response is exaggerated, with faster heart rate, higher pressure, arrhythmia and ischaemia. Stoelting puts this picture in acute intoxication, when more anaesthetic is needed. With long-term abuse the catecholamine stores run down, so less anaesthetic is needed and hypotension may resist treatment. Across both phases, Miller lists stroke, cardiomyopathy and arrhythmia as lasting cardiovascular risks.

Hypotension from chronic stimulant resistance. Hypotension is tempting because long-term stimulant users can become resistant to vasopressors once their catecholamine stores are used up. But that belongs to chronic depletion and is not the defining risk of cocaine. The sources consistently name stroke, cardiomyopathy and arrhythmia for these users.

Miller says cocaine and amphetamine users risk stroke, cardiomyopathy and arrhythmias, with uptake blockade causing hypertension, tachycardia and ischaemia. Stoelting links acute amphetamine intoxication to hypertension, tachycardia, hyperthermia and increased anaesthetic requirement; long-term abuse lowers requirement and causes refractory hypotension.

Sources: Miller 10eStoelting 8eBarash 9e

Clonidine is an alpha2-adrenoceptor agonist that holds sympathetic tone down while it is taken regularly. If it is stopped suddenly, that restraint is lost and noradrenaline surges out. The result is hypertension with a sympathetic picture: tachycardia, headache, anxiety, tremor and sweating. The risk is highest after high chronic doses, above 1.2 mg/day. A hypertensive patient who omits a drug the day before surgery and arrives with a crisis-level pressure should therefore make you suspect clonidine withdrawal first.

Verapamil rebound hypertension withdrawal. Verapamil is tempting because, like beta-blockers, it slows the heart, and people carry over the idea that rate-controlling drugs rebound when stopped. None of these sources describe a withdrawal crisis for it. The noradrenaline-surge rebound belongs to the alpha2 agonist.

Barash describes severe rebound hypertension with sympathetic symptoms after abrupt withdrawal. The ACC/AHA guideline attributes it to a noradrenaline surge. The Mayo review times it at 8 to 36 hours, worse above 1.2 mg/day, and advises continuing clonidine before surgery.

Sources: Barash 9eAHA/ACC 2024 · §7.4Mayo review

Several agents make a competitive blocker work harder. Volatiles, aminoglycosides, magnesium and dantrolene all enhance it, so the same dose gives a deeper, longer block. Calcium works the other way and counters magnesium. A high calcium, as in hyperparathyroidism, therefore leaves the junction less sensitive, and the block wears off sooner. Older adults show longer-lasting block and need smaller maintenance doses. Absorbed echothiophate inhibits cholinesterase, so the drugs that enzyme breaks down, succinylcholine and mivacurium, last longer.

Hypercalcaemia shortens depolarising blockade. Succinylcholine tempts because it is the relaxant most linked to electrolyte hazards, so any calcium disturbance seems to point at it. But the shortened, less sensitive block that hypercalcaemia produces is described for non-depolarising agents such as the atracurium family, not for the depolarising drug.

A review lists volatiles, aminoglycosides, magnesium and dantrolene among drugs that enhance non-depolarising block. It says the hypercalcaemia of hyperparathyroidism lowers sensitivity and shortens action. A major textbook reports longer duration and lower maintenance needs in older adults. Absorbed echothiophate prolongs succinylcholine and mivacurium.

Sources: Miller 10eMayo review

Magnesium is a divalent cation that competes with calcium. At the motor nerve terminal it blocks the calcium entry that triggers acetylcholine release, so less transmitter reaches the endplate. It also dampens postsynaptic calcium-dependent function. With less acetylcholine to compete, the same relaxant dose gives a deeper, longer-lasting block. Neostigmine only works by letting more acetylcholine build up at the junction, so when release is suppressed it has less to work with and recovery is slower.

Floppy neonate expected magnesium effect. It is tempting because magnesium reaches the fetus and can weaken muscle. But the effect an anaesthetist must predict and plan for at therapeutic maternal levels is potentiated, prolonged relaxant block in the mother. A floppy neonate is a possible effect, not the routine expected finding.

Miller describes clear potentiation of any non-depolarising relaxant, with longer recovery. It advises smaller doses guided by monitoring, because magnesium enhances both relaxant classes. Recovery with neostigmine is blunted. Barash attributes the potentiation to magnesium blocking calcium channels before and after the synapse.

Sources: Miller 10eBarash 9e

All sources agree that a raised CO2 blunts neostigmine. Barash reasons that hypercarbia creates acidosis, which interferes with anticholinesterase action, and Miller's laboratory work found reversal needed nearly twice the neostigmine dose during respiratory acidosis. The books part company on metabolic disturbances. Barash extends the harm to acidosis of any cause; Miller's measurements showed metabolic acidosis made no difference while metabolic alkalosis impaired reversal. So treat hypoventilation first, accept metabolic alkalosis as a Miller-correct answer, and never let a metabolic-acidosis option decide a question.

Hyperkalaemia opposes neostigmine reversal. Hyperkalaemia tempts because potassium disturbances do alter reversal, but the books name the opposite direction: low potassium deepens block and weakens neostigmine. Raised potassium is not listed as opposing antagonism, so someone who remembers only 'potassium' picks the wrong disturbance.

Barash says acidosis hinders anticholinesterases and that hypercarbia acts through acidosis. Miller cites laboratory data in which respiratory acidosis and metabolic alkalosis nearly doubled the neostigmine requirement, while respiratory alkalosis and metabolic acidosis left it unchanged. Barash adds that hypokalaemia makes neostigmine less effective.

Sources: Barash 9eMiller 10e

Anything that prolongs relaxant action or increases the dose given raises risk. Older adults, and those with renal or hepatic dysfunction, handle non-depolarisers less well, so younger patients sit at the low-risk end. Volatile agents relax skeletal muscle themselves and cut relaxant requirement, so they add to residual weakness; TIVA lacks this effect. Chronic antiseizure therapy causes resistance, so larger doses are given, which is why these drugs appear on the risk list. Postoperative hypothermia and respiratory acidosis also raise risk.

Antiseizure drugs lower residual block. Chronic antiseizure therapy really does cause resistance to non-depolarisers, so it sounds protective. Because of that resistance, clinicians give larger doses. The extra drug is why these medications are listed among factors that raise residual block risk, not lower it.

The patient factors listed as raising residual block are older age, renal or liver dysfunction and antiseizure medication. Inhalational maintenance carries more risk than TIVA, and postoperative hypothermia and respiratory acidosis add risk. Volatiles lower the relaxant dose needed.

Sources: Miller 10eStoelting 8e

Codeine has little effect itself; analgesia comes from morphine produced by the liver enzyme CYP2D6, which is the binding site in question, not an opioid receptor. The gene is polymorphic. Ultra-rapid metabolisers convert codeine quickly, so a standard dose produces excess morphine, causing sedation and respiratory depression. Children after adenotonsillectomy are already at risk, making codeine especially dangerous for them. An ultra-rapid-metabolising mother exposes her breastfed baby to excess morphine. Slow metabolisers make little morphine and get poor analgesia.

Extensive metabolisers convert codeine fastest. 'Extensive' sounds like the busiest enzyme, and one passage loosely links extensive metabolisers to making large amounts of morphine. In the four-group scheme, though, extensive means normal activity. The group with abnormally high conversion, and the one behind the reported neonatal harm, is ultra-rapid.

CYP2D6 turns inactive codeine into active morphine. Slow metabolisers get weak analgesia and rapid metabolisers risk morphine toxicity. In children, the ultra-rapid phenotype and adenotonsillectomy are both named risks for opioid respiratory depression. Case reports include a lethargic breastfed neonate.

Sources: Mayo reviewBarash 9e

Codeine is an inactive prodrug. CYP2D6 demethylates it to morphine, which binds the mu receptor far more avidly, so ultra-rapid metabolisers make excess morphine and depress breathing. Fentanyl uses a different isoform, CYP3A4, so inhibitors such as protease inhibitors keep it high for longer. For methadone, Barash names CYP2B6; the product label lists CYP3A4 alongside CYP2B6, and newer work ranks CYP2B6 first, so say mainly CYP2B6. Fentanyl added to methadone causes apnoea because two opioids sum, not through an enzyme; the enzyme belonging to fentanyl is CYP3A4.

CYP3A4 because of the fentanyl patch. CYP3A4 tempts because the patient wears a fentanyl patch and fentanyl is its substrate. But the patch dose was unchanged and no CYP3A4 inhibitor was added. The new drug was codeine, whose CYP2D6 conversion to morphine explains the drowsiness and slow breathing.

Barash calls codeine an inactive prodrug converted to morphine by CYP2D6, lists ultra-rapid CYP2D6 metabolism among causes of opioid respiratory depression, and places methadone metabolism on CYP2B6. The Mayo review says protease inhibitors raise fentanyl levels through CYP3A4.

Sources: Barash 9eMayo review

Fentanyl is a basic drug binding mainly to α1-acid glycoprotein and albumin. The preterm liver makes little of either, so more fentanyl stays unbound. Raised bilirubin occupies the remaining binding sites, freeing still more. Free drug crosses an immature blood–brain barrier easily, and immature hepatic and renal handling slows elimination. All these effects act together: a standard weight-based dose produces a high brain concentration and apnoea. Any explanation based on more protein, faster clearance or a barrier excluding the drug has the physiology backwards.

Immature barrier reduces fentanyl penetration. It names a real preterm feature, the immature blood–brain barrier, so it feels correct. But it gets the direction wrong. An immature barrier lets more fentanyl into the brain, not less, and a drug kept out of the central nervous system could not cause apnoea.

Barash attributes preterm drug sensitivity to scarce binding protein, bilirubin competing for binding sites, a poorly formed blood–brain barrier admitting more drug, and reduced metabolism and excretion. Low protein raises free synthetic opioid. Miller adds that neonatal opioid respiratory depression reflects easy brain entry.

Sources: Barash 9eMiller 10e

A fentanyl patch delivers drug through the skin, so release depends on local conditions. Warming the skin raises permeation several-fold, and other perioperative changes can lower it unpredictably. Barash treats the patch as the baseline and usually continues it into theatre. Miller refines this for major surgery: because uptake is unpredictable, convert the patch dose to an equivalent intravenous background infusion, starting on arrival in theatre. Either way, the baseline continues. Heat over the patch is the reason for the swap.

Heat warming patch negligible absorption. It is tempting because the patch is a slow, constant-rate system and its analgesic effect builds over hours, so brief warming seems irrelevant. But delivery depends on skin conditions. Heat over the patch raises fentanyl permeation several-fold, so plasma levels can climb unexpectedly.

Miller warns that warming blankets or heat packs on the patch multiply skin permeation several-fold. It advises removing patches in major surgery and converting to an intravenous morphine background infusion started on arrival in theatre. Barash notes patients usually keep the patch as their baseline.

Sources: Miller 10eBarash 9e

A charged molecule cannot cross the lipid bilayer. Only the uncharged fraction diffuses across cell membranes, the blood–brain barrier and the placenta. Being lipid soluble, un-ionised drug filtered by the kidney is also reabsorbed by the renal tubule, so the body must convert it into polar metabolites to clear it. Drugs that remain ionised at body pH are excreted unchanged in urine. The ionised fraction depends on pKa relative to pH. When pKa equals pH, the drug is split evenly between both forms; this is the midpoint, not un-ionised.

Un-ionised drugs pass urine unchanged. Renal excretion sounds like a general drug property, so people tick it. It actually describes the opposite group. The tubule reabsorbs lipid-soluble un-ionised drug. Muscle relaxants and other drugs that are highly ionised at body pH are the ones passed unchanged in urine.

Anaesthetic drugs are lipid soluble when un-ionised and are largely reabsorbed in the tubule; highly ionised drugs are cleared unchanged in urine. Only the un-ionised form crosses the placenta. pKa is the pH at which base and acid are equal.

Sources: Miller 10eBarash 9e

Most drugs cross the placenta by simple passive diffusion. Fick's law sets the rate from the exchange area, the free-drug gradient between mother and fetus, the drug's own diffusion constant and the barrier thickness. Area and gradient add to flux. Thickness is the distance a molecule must travel, so a thinner barrier lets it cross faster. The diffusion constant reflects the drug's chemistry. Lipid-soluble, un-ionised molecules pass through membrane lipid easily. Water-soluble or charged molecules are held back.

Inverse relationship between surface area and transfer. It is a Fick variable written the same way as the right answer, so someone who knows the equation but mixes up which terms go on top can pick it. Surface area is directly proportional to diffusion. Making it smaller reduces transfer.

Barash says simple diffusion is the main route of placental drug transfer. The rate is directly proportional to exchange area, and barrier thickness is one of the equation's terms. The Mayo review says high lipid solubility, low ionisation and a large gradient all favour transfer.

Sources: Barash 9eMayo review

A nerve is blocked only by the unbound drug that can cross the axonal membrane. Plasma and tissue proteins such as alpha-1 acid glycoprotein hold anaesthetic near the injection site and release it slowly. This keeps a supply of free drug available to the nerve for longer. Removal of drug from the site also limits duration: the faster it is taken away, the shorter the block. Agents that bind protein strongly therefore give longer blocks.

PKa determines local anaesthetic block duration. PKa is the property most often linked to local anaesthetic behaviour, so people pick it for every question. It controls how much drug is non-ionised at body pH, and so how quickly the block begins. It does not control how long the block lasts.

Faust says that binding to alpha-1 acid glycoprotein and clearance from the injection site both affect duration. The block depends on how much free drug can diffuse into the nerve. A pKa near physiological pH speeds onset.

Sources: Faust

Phase I reactions, mostly driven by cytochrome P450, change the molecule itself by oxidising or reducing it, which often exposes a polar group. Phase II then attaches a hydrophilic endogenous group to that site. Glucuronic acid is the commonest, and the result is water-soluble and easier to excrete. Phase II is also called 'synthetic' because something is added to the molecule rather than its structure being rearranged. A drug that is already polar can skip Phase I and go straight to conjugation.

Oxidation is hepatic Phase II metabolism. Oxidation is the best-known hepatic reaction because of cytochrome P450 and its drug interactions, so people link it with liver metabolism in general. But oxidation changes the drug's own structure, which makes it a Phase I reaction, not a conjugation step.

Textbooks call Phase II conjugation or synthetic reactions, which attach hydrophilic endogenous groups, most often glucuronic acid, to make the product water-soluble. Phase I covers oxidative and reductive reactions catalysed by cytochrome P450. A polar drug may be conjugated without Phase I first.

Sources: Barash 9eMiller 10e

Drugs are eliminated by enzymes or transport carriers, which have limited capacity. At low concentrations spare capacity exists, so the elimination rate rises with concentration and the body clears the same fraction per unit time. Once concentration exceeds this capacity, the enzymes are saturated and the rate stops rising, so a fixed quantity is cleared per unit time. Clearance and half-life then change with dose. If the dosing rate exceeds the liver's clearance capacity, plasma levels keep climbing and never reach steady state.

Renal excretion capacity determines enzyme saturation. This option sounds right because it also describes elimination being overwhelmed, and 'excretion' is a familiar pharmacokinetic word. It fails because the step that saturates is enzyme-driven metabolism, which depends on the liver's metabolic capacity. Comparing a concentration with renal excretion does not describe saturation of the eliminating system.

Elimination depends on saturable enzymes or carriers. At high doses, removal shifts from a constant fraction to a constant amount per unit time (phenytoin is classic). If hepatic capacity is below the dosing rate, plasma levels keep rising and no steady state is reached.

Sources: Barash 9eFaust

A lipophilic bolus reaches the brain first. Muscle and fat receive less blood flow, so they keep taking up drug for longer, and plasma levels fall below brain levels. The gradient then reverses. Propofol diffuses out of the brain into blood and moves on to those slower tissues, so the brain concentration falls below the hypnotic level quickly. Hepatic and extrahepatic metabolism act later. They control final elimination from the body, not the moment the patient wakes.

Propofol metabolism enables rapid brain clearance. It is tempting because propofol is known for quick, clear-headed recovery, which sounds like fast clearance. After one bolus, though, the brain level falls because drug shifts into other tissues well before metabolism removes much of it. Metabolism follows redistribution.

The sources agree that propofol's quick offset after a bolus comes from redistribution, not fast metabolism. The drug moves into poorly perfused muscle and fat. A reversed brain-to-blood gradient drives it out of the brain, and hepatic and extrahepatic metabolism come afterwards.

Sources: FaustMayo reviewBarash 9e

Potency tells you how much drug you need to reach half the maximal response. A curve shifted left gets there at a lower dose. Efficacy is how much effect the drug can produce once it occupies its receptors, and that sets the plateau. The two vary independently. A less potent full agonist still reaches the full maximum if you give enough. A partial agonist levels off below the maximum however much you give, because a bigger dose cannot overcome its limited intrinsic effect.

Potency determines peak drug effect plateau. The usual mistake is to think a more potent drug produces a bigger maximal effect. Potency only moves the curve left or right. It says nothing about the height of the plateau. A weaker full agonist can match a stronger one's peak, and a partial agonist can never reach it.

Potency is expressed as the dose that produces an effect in 50% of subjects, the ED50. Efficacy is the maximum effect. A left-shifted curve with a small C50 means greater potency. A less potent full agonist still reaches Emax, but a partial agonist does not.

Sources: Barash 9eMiller 10e

Both books describe two routes to tolerance, and neither ranks one above the other overall. What decides between them is where the change happens. At the neurone, receptors desensitise, uncouple from G proteins and are internalised, and NMDA signalling becomes more sensitive, so the same concentration at the site does less. Opioid adaptation starts here, and this is the route that operates within an anaesthetic. In the liver, induced CYP450 enzymes speed up metabolism, so less drug reaches its target. That reflects the patient's earlier exposure, not the anaesthetic itself.

Enzyme induction causes acute anaesthetic tolerance. Enzyme induction is a genuine textbook cause of tolerance, so it looks like an equal contender. But it is pharmacokinetic: faster metabolism lowers how much drug reaches the target. Tolerance that arises during the anaesthetic is driven by adaptation that begins at the receptor, on the neurone.

Barash names both enzyme induction and receptor desensitisation as causes of opioid tolerance. It defines kinetic tolerance as faster CYP450 metabolism, and dynamic tolerance as neuroadaptation through receptor downregulation, internalisation and G-protein uncoupling. Miller says opioid adaptation starts with direct modulation of receptor signalling.

Sources: Miller 10eBarash 9e

A swallowed drug is absorbed from the small bowel into portal blood. It meets gut-wall enzymes and then the liver before any of it reaches the systemic circulation. When the liver extracts a drug avidly (extraction ratio above 0.7), much of the dose is removed on that single pass, so oral bioavailability falls. For morphine it drops to about 20–30%. An IV dose enters the systemic circulation directly and avoids this loss. Sublingual nitrates escape the first pass, so they need far smaller doses than oral ones.

Hepatic clearance creates first-pass effect orally. It is tempting because the liver drives both. But hepatic clearance acts on drug that is already in the systemic circulation, whatever route was used, so it removes IV and oral doses alike. Only the presystemic pass through gut and liver separates oral from IV.

Oral absorption sends drug through gut mucosa and portal blood before reaching the systemic circulation, lowering bioavailability. High-extraction drugs (ratio above 0.7) lose much of an oral dose this way: oral morphine bioavailability is 20–30%, and oral nitrates need higher doses than sublingual.

Sources: Barash 9eMiller 10eFaust

Rectal venous drainage splits by level. The upper rectum drains through the superior rectal vein into the portal system, so drug absorbed there crosses the liver before it reaches the body. The middle and inferior rectal veins drain the lower rectum into the inferior vena cava, so drug absorbed there goes straight into the systemic circulation. Absorption is shared between the two beds, so the route escapes first-pass metabolism only in part. This is how the anaesthesia textbook explains rectal morphine's higher bioavailability than oral morphine.

Lower rectum drains into portal circulation. It is tempting because 'systemic circulation' and 'first pass' sound like correct rectal-route words. It reverses the anatomy, though. The lower rectum drains by the middle and inferior rectal veins to the vena cava, so the drug reaches the systemic circulation without going through the liver.

A pharmacology review and an anatomy reference, both outside the core textbooks, put the upper rectum on portal drainage and the lower rectum on caval drainage. The anaesthesia textbook says rectal morphine's greater bioavailability may come from partly avoiding hepatic metabolism.

Sources: Outside our books: Rectal Drug Delivery in Children (review) — Frontiers in Pharmacology (2019)Miller 10e

An intramuscular dose enters the circulation without meeting the liver first, so nearly all of it survives; the product label reports over 90%. A concentrated nasal spray reached 74-76% in Schrier's study, placing intranasal second. Swallowed tablets face high hepatic extraction, so Heizmann measured only 31-72%. Rectal absorption partly escapes that loss; Clausen found 40-65%, mean 52%. Rectal beats oral only on adult means: the ranges overlap, and a paediatric study reversed them. All of these figures come from outside the textbooks.

Intranasal first, oral above rectal. Intranasal acts fastest and oral is the usual premedication route, so people put intranasal first and oral above rectal. Measured bioavailability is highest after intramuscular injection, and intranasal comes second. On adult means rectal sits above oral, but the ranges overlap and paediatric data reverse it.

These figures come from outside sources, not textbooks. The product label gives intramuscular bioavailability above 90%. Schrier's concentrated nasal spray gave 74-76%. Clausen found rectal bioavailability of 40-65%, mean 52%. Heizmann's tablets gave 31-72%, limited by high liver extraction.

Sources: Outside our books: MIDAZOLAM HYDROCHLORIDE injection, solution - FDA-approved prescribing information (2026)Outside our books: Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation (2017)Outside our books: Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration (1988)Outside our books: Pharmacokinetics and bioavailability of midazolam in man (1983)

Context-sensitive half-time lengthens when a lipid-soluble drug builds up in poorly perfused tissue during a long infusion, then leaks back into plasma after it stops. Remifentanil has an ester link. Nonspecific esterases in blood and tissue hydrolyse it quickly, so any drug returning from tissue stores is removed almost at once. One text says the half-time rises minimally with duration; the others call it independent of duration. Both describe the same result: in practice it barely changes.

Plasma cholinesterase deficiency prolongs remifentanil action. The word ester makes people think of suxamethonium and its prolonged block when plasma cholinesterase is deficient. Remifentanil is broken down by nonspecific plasma and tissue esterases instead, so that deficiency does not lengthen its offset.

The sources describe remifentanil's half-time as consistently short, 3 to 5 minutes, and barely affected by how long the infusion runs. They attribute this to rapid breakdown by nonspecific plasma esterases, which clears drug returning from tissues quickly.

Sources: Barash 9eMayo review

Context-sensitive half-time is how long plasma concentration takes to halve after an infusion stops, and the elimination half-life does not predict it. During a long fentanyl infusion the peripheral tissues fill with drug. Once the infusion stops, those stores keep replacing whatever the liver clears, so plasma levels fall slowly, more so after longer infusions. Barash's pharmacokinetics chapter gives fentanyl the shorter elimination half-life; its opioid chapter gives sufentanil the shorter. Either way, sufentanil's level halves sooner after an infusion. Remifentanil's value stays the same however long it runs.

Sufentanil, from longer elimination half-life. Sufentanil looks like the drug that should linger, since one widely quoted table gives it the longer elimination half-life. But elimination half-life does not predict offset after an infusion. Of these opioids, fentanyl shows the greatest context-sensitive half-time, since continued return from peripheral stores keeps topping up plasma, even once the infusion has run for just one hour.

Modelled curves plot this half-time against infusion duration. Fentanyl's rises markedly as peripheral stores replace hepatically cleared drug, despite one chapter giving it a shorter elimination half-life than sufentanil. After a 1-hour infusion it is nearly 6 times alfentanil's or sufentanil's; remifentanil's is duration-independent.

Sources: Mayo reviewBarash 9eMiller 10e

Half-time is a simulated figure: the time plasma concentration takes to halve once the infusion stops. After a short infusion, peripheral tissues hold little drug, so redistribution brings plasma levels down quickly. With longer infusions those tissues fill up and redistribution does less of the work. The fall then depends more and more on elimination, so the half-time climbs towards a plateau at steady state. The terminal elimination half-life is a separate, fixed figure. Do not confuse the two.

Context-sensitive half-time equals elimination half-life. Two hours is tempting because it matches the familiar elimination half-life of about 2 hours. But half-time measures something else. It is the time for plasma levels to halve after stopping, and it changes with how long the infusion ran, from minutes to hours.

Dexmedetomidine's half-time is quoted as about 4 minutes when the infusion lasted 10 minutes, rising to 250 minutes when it lasted 8 hours. Its terminal elimination half-life is about 2 hours. Half-time grows with infusion length and levels off at steady state.

Sources: Miller 10eBarash 9e

When an infusion stops, drug stored in peripheral tissues moves back into plasma and can keep the concentration up. With propofol, that returning drug is metabolised quickly, so plasma levels still fall fast. As a result the half-time grows only slightly with longer infusions, and recovery is quick and predictable. Thiopental does not behave this way: its half-time rises sharply after anything but a very short infusion. Propofol's long elimination half-life measures slow terminal washout, which is a different quantity.

Propofol context-sensitive half-time increases with infusions. It is tempting to give the elimination half-life, which runs to many hours, or to expect the half-time to grow with infusion length as thiopental's does. Neither is right. However long the infusion ran, propofol's plasma level halves quickly once it stops.

One text says propofol's context-sensitive half-time stays below 40 minutes even after infusions lasting several hours, while its terminal half-life is 4 to 23.5 hours. Another says the reason is fast metabolism of drug coming back from tissues. Thiopental's half-time, by contrast, rises steeply.

Sources: Miller 10eBarash 9e

Elimination half-life is the time for plasma level to halve once distribution is complete. Clearance is the plasma volume cleared of drug per unit time. Neither accounts for redistribution. After a long infusion, drug returning from peripheral tissues delays the fall in plasma level, increasingly with longer infusions. Context-sensitive half-time captures this and best predicts recovery, though waking also depends on how far the level must fall. Effect-site equilibration time is how fast brain level catches up with blood, governing response onset.

Context-sensitive half-time predicts drug onset speed. Context-sensitive half-time is known as the better predictor, so it seems right for any question about prediction. But it describes how the level falls after an infusion stops, which is recovery. How quickly a dose takes effect depends on how fast blood and brain equilibrate, not on offset.

Context-sensitive half-time is the time for plasma level to halve, the context being infusion duration. It lengthens with longer infusions, which elimination half-life cannot show. It is not the sole determinant of waking; effect-site equilibration half-time describes blood–brain equilibration.

Sources: Barash 9e

The alveolar fraction lags behind the inspired fraction because blood keeps removing agent from the alveoli. How much blood removes depends on how soluble the agent is and how much blood passes through the lungs. A soluble agent is removed in large amounts, so more ventilation or less pulmonary blood flow changes its alveolar level a lot. An insoluble agent is barely taken up, so its FA/FI rises quickly anyway. Changing ventilation or cardiac output then has little room left to speed it up.

Isoflurane resists ventilation-induced FA/FI changes. Isoflurane is less soluble than halothane or enflurane and is seen as a modern agent, so it seems a likely pick. But it is still much more soluble in blood than desflurane. Its uptake stays large enough for ventilation and cardiac output to change its FA/FI noticeably.

Barash says ventilation and cardiac output change the wash-in of poorly soluble agents less than that of soluble ones. Faust says poorly soluble agents rise fast whatever the cardiac output, and soluble agents are affected most. Mayo explains that more ventilation offsets uptake into blood.

Sources: Barash 9eFaustMayo review

Blood solubility sets how much agent the blood takes up from the alveoli before partial pressure can rise. A poorly soluble agent fills the blood quickly, so the alveolar concentration soon approaches the inspired one. That gives fast induction and fast wash-out. A highly soluble agent builds a large store in blood, which slows both. Different books quote slightly different decimals. Every table still puts desflurane just below nitrous oxide, and isoflurane between sevoflurane and halothane.

Nitrous oxide has lowest blood solubility. Nitrous oxide is the classic example of an insoluble, fast-onset gas, so people reach for it. Its blood:gas coefficient is almost the same as desflurane's. However, every source lists it slightly higher, so desflurane is the lowest.

At body temperature, desflurane has the lowest coefficient (0.45) and nitrous oxide is next (0.47). Sevoflurane (0.65), isoflurane (1.4) and halothane (2.5) follow. Isoflurane's blood solubility lies between sevoflurane's and halothane's. The alveolar fraction rises faster with less soluble agents.

Sources: Mayo reviewMiller 10e

Potency is judged by MAC, the alveolar concentration preventing movement in half of patients. An agent that dissolves readily in fat reaches an effective concentration at its site of action at a lower alveolar concentration, so it needs less to work. This holds for many chemically unrelated agents across a 70,000-fold range of potency, and was once taken as proof that membrane lipids are the target. Later work found potency also tracks inhibition of a protein enzyme. The rule therefore predicts potency but does not identify where anaesthetics act.

Meyer-Overton lipid rule predicts effect type. Meyer–Overton is often described as a theory of how anaesthetics act, so 'effect' sounds right. The rule is quantitative, though. It links lipid solubility to how much agent is needed, which is MAC or potency. It does not describe the kind or size of the effect produced.

MAC falls as lipid solubility rises, so potency increases with the oil:gas coefficient over a 70,000-fold range. Potency also correlates with inhibition of a protein enzyme, which supports protein targets rather than lipids.

Sources: FaustBarash 9eMayo review

Halothane depresses the heart muscle directly. Each rise in dose weakens contraction further, so output falls clearly. Isoflurane, sevoflurane and desflurane lower blood pressure mainly by reducing vascular resistance, so output tends to hold. Both statements are true. Miller says volatiles as a class reduce pressure and output with dose. Mayo notes that halothane is the agent whose output falls clearly. So the class effect is real, but it matters clinically mostly with halothane: 'halothane most', not 'halothane only'.

Isoflurane reduces cardiac output dose-dependently. Isoflurane is tempting because it causes dose-related hypotension and is named as a strong arterial dilator. But that hypotension comes from lower vascular resistance, not a weaker heart. Cardiac output tends to be maintained, unlike with halothane's direct depression of the heart muscle.

Miller names halothane as the inhaled agent with the largest fall in cardiac output, and says volatiles as a class lower pressure and output with dose. Mayo says the three newer agents tend to preserve output and lower pressure mainly through reduced vascular resistance.

Sources: Miller 10eMayo review

Fluorine forms very strong bonds with carbon, and heat or chemical attack cannot easily break them. A fluorinated anaesthetic molecule therefore does not burn. Cyclopropane, like ether and the other potent agents of its era (except chloroform), formed explosive mixtures in the operating theatre. Every spark from static electricity was a risk to the patient and the anaesthetist. Replacing these agents with fluorinated ones removed that danger. This is why the fluorinated agents are described as having transformed inhalational anaesthesia.

Potency improvement distinguished fluorinated volatile agents. Newer drugs feel like they should simply be stronger, so potency is an easy guess. But the history describes cyclopropane itself as a potent anaesthetic. What set the fluorinated agents apart, and changed practice, was that they would not burn. Potency was never the defining advance.

Every potent anaesthetic of the cyclopropane era except chloroform was explosive. Fire in the operating room was first a concern because of flammable volatile agents such as cyclopropane and ether. Fluorinated hydrocarbons were non-flammable and transformed inhalational anaesthesia.

Sources: Barash 9e

Oxidative metabolism of a volatile agent produces a reactive trifluoroacetyl metabolite, which binds hepatocyte proteins and makes them foreign antigens. Antibodies form against these altered proteins and attack the liver, sometimes fulminantly. Rash, eosinophilia and the link with repeated exposure indicate an immune process. Risk rises with the extent of oxidation: halothane is oxidised most, then enflurane, isoflurane and desflurane in falling order. Sevoflurane is metabolised by a different route and forms no such antigen.

Isoflurane causes hepatitis like halothane does. Isoflurane produces the same kind of trifluoroacetyl metabolite and has rare case reports of liver failure, so it can look like the answer. But very little of it is metabolised. That makes the immune hepatitis minimal with isoflurane, while halothane is the classic cause.

Patients with halothane hepatitis have IgG antibodies against liver proteins altered by halothane's trifluoroacetyl metabolite. The expected incidence is greatest after halothane and falls with enflurane and then isoflurane. Sevoflurane forms none of these oxidative metabolites.

Sources: Barash 9eMiller 10eStoelting 8e

Nitrous oxide directly dilates cerebral vessels while barely changing cerebral oxygen consumption, so flow rises beyond metabolic need. The rise is greatest when N2O is given alone and smallest with opioids, propofol or benzodiazepines. Inhaled agents do not abolish arteriolar reactivity to carbon dioxide: low CO2 still constricts and high CO2 still dilates. N2O does depress the brainstem's ventilatory response to CO2 and hypoxia, but this is a respiratory effect, not a cerebrovascular one.

Nitrous oxide causes no cerebral vasodilation. Nitrous oxide seems weak and inert, so a sedation dose feels unlikely to change blood flow in the brain. In fact it directly widens cerebral vessels, and the effect is largest exactly when it is given alone, with no intravenous agent to reduce it.

Textbooks describe nitrous oxide as a direct cerebral vasodilator with little effect on cerebral oxygen consumption, most marked when used alone. Inhaled agents preserve cerebral CO2 responsiveness, whereas N2O blunts the ventilatory response to CO2 and hypoxia.

Sources: FaustBarash 9eMiller 10e

Faust says volatile agents as a class may raise heart rate slightly from about 1 MAC. It adds a separate transient tachycardia with desflurane and, less so, isoflurane: their pungency irritates airway receptors when the concentration climbs quickly, which raises sympathetic tone. Faust does not name sevoflurane for this. Barash's volunteer data are specific to sevoflurane, which barely changed heart rate below 1.5 MAC. The figure for the individual agent takes priority over the general class statement, so with sevoflurane a rise in heart rate belongs above 1.5 MAC.

Sevoflurane raises heart rate above 1 MAC. That figure looks appealing because it exceeds roughly 1 MAC, where volatile anaesthetics may slightly raise heart rate. However, Barash's volunteer data show little or no heart rate change with sevoflurane below 1.5 MAC, so this figure remains within the stable range.

Inhaled anaesthetics can slightly raise heart rate from about 1 MAC. Desflurane causes a short, pronounced tachycardia through airway irritation, isoflurane less so. In volunteers, sevoflurane produced little or no heart rate change below 1.5 MAC.

Sources: Barash 9eFaust

Carbon monoxide comes from the breakdown of ethers that carry a difluoromethyl group, and only when the absorbent is almost completely dry. Desflurane, enflurane and isoflurane all have this group, and the amount of carbon monoxide rises with the agent's concentration in the circuit. Desflurane heads the list. Sevoflurane and halothane also break down in strong base, but they form other products, not carbon monoxide. Sevoflurane's absorbent hazards are compound A and heat.

Sevoflurane forms most carbon monoxide with absorbent. Sevoflurane is the agent most linked with absorbent reactions. It forms compound A and gives the hottest reaction with dry absorbent, which has caused fires. It has no difluoromethyl group, though, so it forms little or no carbon monoxide. Heat and carbon monoxide are separate hazards.

Barash ranks carbon monoxide output for equal MAC multiples as desflurane, then enflurane, then isoflurane, with halothane and sevoflurane least. Miller's says only difluoromethyl ethers form it and that nearly dry absorbent is required. Halothane and sevoflurane form none, although sevoflurane generates the most heat.

Sources: Barash 9eMiller 10e

During recovery, a large volume of dissolved nitrous oxide leaves the blood and floods the alveoli. Because it was given at high concentrations, this outflow dilutes alveolar oxygen and carbon dioxide. The low alveolar oxygen causes hypoxaemia. The low alveolar carbon dioxide weakens the drive to breathe, so ventilation falls and the hypoxaemia gets worse. Breathing 100% oxygen for a short time during this washout keeps alveolar oxygen high while the dilution is at its greatest.

Desflurane causes diffusion hypoxia on emergence. Desflurane's rapid washout on emergence tempts people to link it with diffusion hypoxia. However, that effect requires a very large volume of gas flooding the alveoli. Only nitrous oxide does this, as it is given at concentrations high enough to dilute alveolar oxygen.

During recovery, high-concentration nitrous oxide washing out of the blood lowers alveolar oxygen and carbon dioxide. Low oxygen can cause hypoxaemia; low carbon dioxide can depress breathing. Give brief 100% oxygen before stepping down to a lower oxygen fraction or room air.

Sources: Barash 9e

Class I drugs slow the phase 0 sodium upstroke, widening QRS. Potency runs Ic above Ia above Ib, so Ic markedly widens QRS while Ib barely affects normal tissue. Ia also lengthens the action potential, raising QT. Class II blunts sympathetic drive to the nodes, slowing rate and AV conduction. Class III delays repolarisation through potassium blockade, prolonging QT; sotalol also blocks beta-receptors yet is filed as III. Class IV slows the AV node, lengthening PR. Adenosine, digoxin and magnesium sit outside the scheme.

Sotalol is Class II antiarrhythmic agent. The '-olol' ending really does mark a beta-blocker, and sotalol does block beta-receptors, so class II feels automatic. But its defining action is potassium-channel blockade, which lengthens repolarisation and QT. That is why it is grouped with amiodarone and dofetilide as class III.

Outside the local books, a pharmacology review, a reclassification paper and the drug-name stem list give the sodium-block potency order, sotalol's beta and potassium blockade within class III, and the name stems '-cain-' and '-ilide'; a local textbook confirms verapamil as class IV, prolonging PR.

Sources: Outside our books: Antiarrhythmic Medications (2024)Outside our books: Modernized Classification of Cardiac Antiarrhythmic Drugs (2018)Outside our books: USAN stem list (cumulative) and WHO INN Stem Book 2018: drug-name stems (2018)Barash 9e

Each class names a drug's main target. Esmolol is a short-acting β1-selective blocker, and Lei's modernised scheme keeps beta-blockers such as carvedilol in class II. Amiodarone chiefly blocks potassium channels, lengthening repolarisation and refractoriness, so it sits in class III although it also blocks sodium and calcium channels and β-receptors; peer-reviewed sources outside these books place bretylium in class III as well. Diltiazem and verapamil block slow calcium channels at the sinoatrial and atrioventricular nodes, slowing nodal conduction, which defines class IV.

Amiodarone is Class II antiarrhythmic. Amiodarone is tempting for class II because it also blocks β-receptors and acts across every class. Its dominant action, though, is potassium-channel blockade that prolongs repolarisation, so it is filed as class III; class II is reserved for drugs whose main action is β-blockade, such as esmolol.

Jooma describes esmolol as an ultra-short-acting β1-selective blocker; Lei's revised scheme labels carvedilol class IIa; Stoelting calls amiodarone a class 3 antidysrhythmic; StatPearls lists diltiazem and verapamil as class IV non-dihydropyridine calcium-channel blockers that slow atrioventricular nodal conduction.

Sources: Outside our books: Antiarrhythmic drugs (2023)Outside our books: Modernized Classification of Cardiac Antiarrhythmic Drugs (2018)Stoelting 8eOutside our books: Antiarrhythmic Medications (2024)

Diuretics are classed by how they act, not by chemical family. Ethacrynic acid belongs with furosemide, bumetanide and torsemide. Its product label applies loop-diuretic precautions to it, such as magnesium wasting. It does not work by blocking carbonic anhydrase; it acts through sulfhydryl binding. Its structure sets it apart because it has no sulfonamide. That makes it the alternative loop agent when a non-sulfonamide drug is needed.

Indapamide is a loop diuretic. Indapamide is a familiar sulfonamide-type diuretic used for hypertension, and its chemistry looks like furosemide's, so it feels like the loop answer. It is actually a thiazide-like agent that acts further along the nephron. The loop agent here is the odd, sulfonamide-free acid.

This comes from outside the anaesthesia textbooks. A paediatric pharmacotherapy paper calls ethacrynic acid a loop diuretic that differs from the others by having no sulfonamide group. Its product label says it does not act through carbonic anhydrase and warns of loop-diuretic magnesium loss.

Sources: Outside our books: Ethacrynic Acid Continuous Infusions in Critically Ill Pediatric Patients (2014)Outside our books: EDECRIN (ethacrynic acid) tablet / SODIUM EDECRIN (ethacrynate sodium) powder, for solution - FDA-approved prescribing information (2020)

Nalbuphine has the same basic structure as naloxone and oxymorphone. At the μ-receptor it binds without activating it, which blocks other opioids there. At the κ-receptor it acts as an agonist, and that produces analgesia. Because the μ route is blocked, both pain relief and breathing depression level off as the dose rises. The same μ blockade lets small doses undo μ-agonist side effects, such as respiratory depression or itch from neuraxial opioids, while some κ-driven analgesia remains. Buprenorphine, butorphanol and pentazocine belong to the same class.

Tramadol is mixed opioid agonist-antagonist. Tramadol is tempting because it is an atypical opioid with a second, non-opioid action. That second action is inhibition of monoamine reuptake, not receptor blockade. At opioid receptors tramadol only acts as an agonist, so it cannot antagonise μ effects.

A major textbook calls nalbuphine an agonist–antagonist that is related to naloxone, blocks μ-receptors and stimulates κ-receptors. Review texts note that its analgesia and respiratory depression both reach a ceiling. It is used to reverse opioid respiratory depression and to treat pruritus from neuraxial opioids.

Sources: Miller 10eMayo review

The type III phosphodiesterase isoenzyme is found in heart muscle and vascular smooth muscle, where it breaks cAMP down to AMP. When milrinone blocks this enzyme, cAMP builds up inside the cell. In the heart, this changes intracellular calcium handling, so the muscle contracts more strongly. In vessels, the smooth muscle relaxes. Milrinone works on the enzyme, downstream of the receptor. It does not release catecholamines or stimulate alpha or beta receptors, and it does not raise myocardial oxygen consumption.

Milrinone works through adrenergic receptors. This option tempts because milrinone is grouped with dobutamine and adrenaline as an inotrope, so people assume it works through adrenoceptors. It does not. It acts on the enzyme that breaks down cAMP, so it has no alpha or beta activity. It also dilates vessels, which rules out direct vasoconstriction.

The textbooks call milrinone a selective PDE III inhibitor that stops cAMP being broken down. This gives both inotropy and vasodilation without acting on alpha or beta receptors. The enzyme sits in cardiac and vascular smooth muscle and converts cAMP to AMP.

Sources: Miller 10eBarash 9e

Hydralazine relaxes vascular smooth muscle directly. It does not work through adrenergic receptors. As pressure falls, the baroreceptor reflex activates the sympathetic system. The heart-rate rise is often bigger than that reflex alone would produce, perhaps because the drug also acts on central cardiovascular control. A faster heart needs more oxygen. When a coronary narrowing fixes the supply, that extra demand cannot be met and acute ischaemia can follow. Its onset is also slow compared with labetalol, so it is not an agent that works within a minute.

Hydralazine safe for ischaemic heart disease. Hydralazine lowers pressure reliably and is a familiar choice for postoperative hypertension, so it can seem safe for any hypertensive patient. It fails here because its reflex tachycardia, amplified centrally, raises oxygen demand. That can push a heart with a flow-limiting coronary lesion into acute ischaemia.

Barash says hydralazine tachycardia often exceeds baroreflex expectations, possibly via a central effect, and can raise oxygen demand enough to cause acute ischaemia beyond flow-limiting coronary lesions. Mayo classes it as a direct smooth muscle relaxant. Faust notes onset is slower than labetalol's.

Sources: Barash 9eMayo reviewFaust

Normally, acetylcholinesterase in the synaptic cleft breaks down acetylcholine almost at once, which ends each signal. Organophosphates such as sarin bind this enzyme permanently. Neostigmine, by contrast, binds it only reversibly. Acetylcholine therefore piles up and keeps firing every cholinergic receptor. Too much muscarinic activity gives bradycardia, hypotension, miosis, salivation, rhinorrhoea, heavy airway secretions and bronchospasm. Nicotinic receptors are overdriven as well. So 'cholinergic' correctly names the effect, and enzyme inhibition names the mechanism and the site of action.

Sarin acts directly on muscarinic receptors. Every listed sign is parasympathetic, so 'muscarinic' feels right. But sarin never acts on the receptor. It disables the enzyme, and the extra acetylcholine then overstimulates nicotinic receptors too. The muscarinic receptors are where the symptoms show up, not where the drug acts.

The texts class sarin and other nerve agents as acetylcholinesterase inhibitors that cause cholinergic overstimulation. Acetylcholine then accumulates at both muscarinic and nicotinic receptors. Organophosphates block the enzyme irreversibly, whereas neostigmine blocks it reversibly.

Sources: Miller 10eStoelting 8eBarash 9e

The class is set by the chemical backbone, and the backbone decides how the drug behaves. Aminosteroids carry their charged nitrogen on a steroid skeleton. Sugammadex was built to wrap around that skeleton, so it reverses only aminosteroids and does nothing to benzylisoquinoliniums. Benzylisoquinoliniums are more likely to trigger mast cells directly and release histamine, especially atracurium given quickly. Aminosteroids at clinical doses mostly do not. Tubocurarine belongs with the benzylisoquinoliniums even though its name lacks the usual ending.

Tubocurarine is a steroidal neuromuscular blocker. Tubocurarine does not end in -curium, so someone relying on the suffix may place it with the steroids. It is actually a curare alkaloid in the benzylisoquinolinium class. It sits alongside mivacurium and atracurium, releases histamine readily and is not reversed by sugammadex.

Classification tables list mivacurium, atracurium, cisatracurium, tubocurarine, metocurine and doxacurium as benzylisoquinoliniums, and vecuronium, rocuronium and pancuronium as aminosteroids. Sugammadex reverses only the steroidal group. The benzylisoquinolinium group causes direct histamine release more often.

Sources: FaustMayo reviewStoelting 8e

Phenylephrine binds alpha-1 receptors directly and has almost no beta activity. It therefore raises arterial and venous tone without meaningful beta stimulation. Ephedrine works largely by displacing noradrenaline from nerve terminals, so its effect depends on those stores being present. On receptor grading tables, isoprenaline carries top-grade beta activity. Noradrenaline scores higher than adrenaline at both alpha-1 and alpha-2, which makes it the stronger alpha agent of the two natural catecholamines.

Adrenaline has strongest alpha-2 and beta-2 affinity. Adrenaline feels like the all-round strongest catecholamine, so people choose it for both alpha-2 affinity and beta-2 potency. On the grading table it sits below noradrenaline at alpha-2 and below isoprenaline at beta-2. Acting on many receptors does not make it the strongest at any single one.

Grading tables give noradrenaline more alpha-1 and alpha-2 activity than adrenaline, and give isoprenaline top-grade beta activity. Phenylephrine is described as acting almost only, and directly, on alpha-1 receptors, whereas ephedrine relies on displacing stored noradrenaline.

Sources: FaustBarash 9e

Nicotinic receptors move back and forth between resting and desensitised shapes all the time, whether or not an agonist is present. Agonists push receptors towards the desensitised shape. Because they bind tightly to that shape, they can also hold a receptor in it. A wide range of unrelated drugs also promote this state: volatile agents, alcohols, barbiturates, local anaesthetics, cocaine and anticholinesterases. The junction may then look normal, but it responds differently to both agonists and antagonists. This can mislead interpretation of neuromuscular block.

Fentanyl desensitises nicotinic receptors at junction. Fentanyl is given with relaxants at almost every induction, so it seems relevant to the junction. It is not on the list of desensitising drugs. Ethanol (an alcohol) and lidocaine (a local anaesthetic) are both on that list, so picking only one of them misses the other.

The textbook lists drugs that cause or promote desensitisation of muscle nicotinic receptors. They include volatile agents, polymyxin B, cocaine, alcohols including ethanol, barbiturates, agonists such as succinylcholine, anticholinesterases, local anaesthetics including lidocaine, phenothiazines, phencyclidine and verapamil.

Sources: Miller 10e

Gabapentin binds the alpha-2-delta subunit, an accessory part of the dorsal horn P/Q-type calcium channel. This changes how the channel works and how it is moved within the neurone. As a result, sensitised nociceptors release less glutamate and other excitatory transmitters when calcium enters. Pain signalling and central sensitisation are damped, which explains the benefit in neuropathic pain. The drug does not plug the channel pore. It modulates the channel through the accessory subunit, so an option worded as calcium-channel modulation or calcium-channel antagonism points to the same answer.

Gabapentin acts on GABA receptors. The drug's name and structure resemble GABA, so people assume it acts on a GABA receptor. In fact it binds no GABA receptor subtype and no allosteric GABA site, so it is not GABAergic. Blocking GABA receptors would also increase neuronal excitability, not relieve pain.

The textbook says gabapentinoids bind the alpha-2-delta subunit of voltage-gated calcium channels. This alters channel function and trafficking and reduces release of excitatory transmitters from nociceptors. They are grouped with anticonvulsants acting on alpha-2-delta, and they bind no GABA receptor site.

Sources: Barash 9e

Ketamine blocks the NMDA receptor rather than activating it. This leaves the patient in a cataleptic trance, looking detached rather than asleep. Its anticholinergic and adrenergic actions open the airways and push heart rate and blood pressure up, so a slow heart and airway spasm are not expected. The two books agree on breathing. Barash lists only mild depression, with hypoxia that oxygen corrects. Faust says ketamine alone keeps ventilation and airway patency. Marked depression or obstruction happens only when benzodiazepines or opioids are added.

Ketamine significantly depresses spontaneous ventilation. Most induction agents depress ventilation, and one table even lists mild depression, so this seems safe. But ketamine by itself keeps the patient breathing with an open airway. Significant depression comes from added benzodiazepines or opioids, so it is not a defining feature of the drug.

Barash lists ketamine as an NMDA antagonist that gives dissociative anaesthesia and bronchodilation and raises heart rate and blood pressure. Increased salivation is among its side effects. Both texts say spontaneous breathing is kept, and depression arises when other respiratory depressants are combined.

Sources: Barash 9eFaust

Blocking conversion to angiotensin II removes a strong arterial constrictor. Afterload falls, arteries become more compliant, arterial pressure drops and the heart ejects more. More blood reaches the kidneys, so they excrete more sodium and intravascular volume falls. The drug does not act on the tubule the way a true diuretic does. The sodium loss comes from these haemodynamic and renal changes, so it is indirect. As pressure and volume normalise, the chronically raised sympathetic drive eases. The net result is lower pressure, not higher.

ACE inhibitors cause hypokalaemia from natriuresis. Natriuresis makes people think of loop and thiazide diuretics, which waste potassium, so hypokalaemia seems to follow. It does not. ACE inhibitors are not tubular diuretics. They only make sodium loss easier through haemodynamic and renal effects, so the potassium-wasting pattern of diuretics does not apply.

Barash lists the effects of ACE inhibition as reduced left ventricular afterload, better arterial compliance, lower arterial pressure, higher cardiac output, more renal blood flow and easier natriuresis. These changes lower sympathetic tone, and the renal effects shrink intravascular volume.

Sources: Barash 9e

Fenoldopam stimulates first-subtype dopamine receptors, which selectively dilates arteries and lowers blood pressure. That is the same job a nitroprusside infusion does, so the two are interchangeable. The kidney is where they differ. Nitroprusside reduces renal blood flow. Fenoldopam maintains or increases it, which causes a diuresis and sodium loss. Trials of it as a kidney protector remain equivocal. Severe hypertension needs larger doses, and these can cause an unwanted tachycardia. For that reason, fenoldopam is seldom the first choice after surgery.

Dopamine is fenoldopam's appropriate haemodynamic substitute. The names and receptors overlap, so dopamine looks like the natural counterpart. But using the same receptor does not make one drug a substitute for the other. Fenoldopam only dilates arteries to lower pressure. Its counterpart is therefore another vasodilator, not a catecholamine given to support the circulation.

Miller describes fenoldopam as a short-acting, arterial-selective dopamine-receptor agonist of the D-one type. Unlike nitroprusside, it can produce deliberate hypotension without reducing renal blood flow. Higher doses can raise the heart rate, which limits its use as a first-line drug after surgery.

Sources: Miller 10e

Nitroprusside, like nitroglycerin, is a nitric oxide donor. These drugs reduce platelet aggregation and secretion, weakening primary haemostasis and lengthening bleeding time. Cerebral vasodilation raises intracranial pressure. Pulmonary vasodilation undoes hypoxic vasoconstriction, increasing shunt. Metabolism releases cyanide, which accumulates with large, rapid or prolonged dosing, and more readily in hepatic dysfunction, malnourishment or hypothermia. Watch for metabolic acidosis, tachyphylaxis, arrhythmias, rising mixed venous saturation and confusion.

Nitroprusside has maximum infusion rate limit. Nitroprusside does have a well-known dose ceiling, so a maximum-rate option looks familiar. But the textbooks state its safety limit as a cumulative dose over hours, set by how much cyanide builds up. They don't give it as a brief high-rate burst, and they don't support this figure.

The books state that nitroprusside reversibly impairs platelet aggregation, that it raises intracranial pressure, and that toxic cyanide levels follow more than 1.0 mg/kg within 2 hours or more than 0.5 mg/kg/hr within 24 hours.

Sources: FaustBarash 9eStoelting 8eMiller 10e

How much transmitter is released depends on how much and for how long the terminal membrane stays depolarised. An anticholinesterase reversibly lengthens the terminal action potential, so the nerve keeps releasing acetylcholine for longer after each impulse. The enzyme is also inhibited, so this extra acetylcholine is broken down more slowly. End-plate potentials therefore last longer and muscle fibres discharge repeatedly. With no blocking drug present, this repeated firing shows up as spontaneous contractions, which is evidence of a prejunctional action.

Anticholinesterases only act postsynaptically at junction. People learn anticholinesterases only as inhibitors of the enzyme in the cleft. They then assume the twitching comes from acetylcholine building up at the end-plate alone. That misses the nerve terminal. Its depolarisation and release period are prolonged, and the textbook links spontaneous contractions without relaxant to these prejunctional effects.

Reversible lengthening of the nerve-terminal action potential and refractory period prolongs depolarisation-dependent release per impulse. With slower hydrolysis, this prolongs end-plate potentials and causes repetitive fibre firing. The textbook credits this for contractions seen without relaxant.

Sources: Miller 10e

Both autonomic divisions use acetylcholine on nicotinic receptors at the ganglion. The sympathetic postganglionic neurone then releases noradrenaline onto target adrenoceptors. It also acts on presynaptic α2 receptors on its own terminal, which damps further release. Sweat glands and some skeletal muscle vessels are the cholinergic exceptions. The adrenal medulla is driven by the same preganglionic acetylcholine and sends adrenaline into the blood as a hormone. Vagal postganglionic fibres release acetylcholine onto cardiac M2 muscarinic receptors, which lowers rate, conduction and contractility.

Adrenaline is postganglionic sympathetic nerve transmitter. Adrenaline sounds like the sympathetic transmitter, it surges under stress, and some texts group it with noradrenaline as a sympathetic mediator. But the adrenal medulla secretes it into the blood as a circulating hormone. The sympathetic nerve endings themselves release noradrenaline.

Acetylcholine stimulates nicotinic receptors in sympathetic ganglia and the adrenal medulla. Noradrenaline is the main postganglionic transmitter, with cholinergic exceptions for sweat glands and muscle vessels. Adrenaline is an adrenal hormone. Presynaptic α2 receptors limit release, and cardiac depression acts via M2.

Sources: FaustBarash 9e