Drugs

Question 1

Describe the A-E effects of propofol

Answer 1

A - loss of laryngeal reflexes and airway muscle tone

B - respiratory depression, reduced response to hypoxia/ hypercapnia, bronchodilator by attenuating vagal bronchoconstriction

C - balanced arterial and venous vasodilation. Not a negative inotrope at clinically relevant doses, unclear whether it reduces cardiac output - traditional stance is that it does.

D - Sedation, anti-epileptic, reduces cerebral metabolic demand and ICP, anti-emetic (D2 receptor antagonism), can cause myoclonus/ opisthonus induction/ emergence phenomena

E - heat loss due to vasodilation

Question 2

Describe the structure of propofol

Answer 2

A phenol ring with two propyl groups attached to 2nd and 6th carbons (2,6-diisopropylphenol)

Question 3

Describe the pharmacodynamics and kinetics of propofol

Answer 3

Comes in a soybean emulsion for two reasons: raw propofol freezes at 19 degrees, and it is very insoluble in water

pKA 11.1, highly lipophillic, a weak acid

Its bolus VoD is 4L/kg, and steady state VoD is 2-10L/kg

It is highly protein-bound in plasma, but is even more lipophillic and so the vast majority of it distributed to fatty tissues such as the brain.

Clearance is hepatic via CYP450, at a rate of 30-60ml/kg/min. All metabolites are inactive and excreted renally

Question 4

Why is the half-life of propofol from bolus so much shorter than from steady state (and what are the half-lives)

Answer 4

2 minutes from bolus, 5-12 hours from steady state

Initial half-life is small because of extremely rapid distribution paired with rapid elimination. However following a steady state infusion, large propofol reserves re-distribute from fat into plasma meaning the half-life is significantly prolonged.

NB: offset of effects is still fast after prolonged infusions because elimination is much faster than re-distribution with propofol

Question 5

What is the mechanism of action of propofol?

Answer 5

GABA-A agonist, activating the cell membrane channels which allows chloride influx and hyperpolarizes the membrane

Question 6

Describe the direct vs. indirect cardiovascular effects of propofol

Answer 6

Propofol mainly acts indirectly through sympathetic inhibition, in-keeping with its role as a GABA-agonist. Veno/vasodilation affects preload and afterload roughly equally. The traditional stance is that propofol is a negative inotrope and reduces cardiac output but this is disputed and unclear.

Question 7

Describe the mechanism of PRIS

Answer 7

Propofol inhibits cytochrome C and co-enzyme Q, inhibiting oxidative phosphorylation. This leads to anaerobic respiration and lacatataemia, and hyperlipidaemia as fat metabolism is inhibited. This usually presents after prolonged high-dose infusions.

Question 8

Describe the effects of opioids on respiration

Answer 8

There are three main effects:

1) Direct blunting of inherent respiratory drive by action at Bötzinger’s complex in the ventral medulla

2) Blunting of response at medullary chemoceptors to acid-base changes caused by hypercapnia

3) Blunting of response at carotid/aortic chemoceptors to hypoxia

Question 9

What is the generic receptor action of opioids?

Answer 9

They activate G-protein coupled receptors (mostly Mu) which inhibits adequate cyclase, reducing cAMP. This closes voltage-gated calcium channels and open potassium channels to cause potassium efflux and hyperpolarisation. The overall effect is inhibitory

Question 10

Why is the initial half-life of fentanyl low, but the context-sensitive half-life high?

Answer 10

Elimination half-life after low doses is ~13 minutes. Elimination half-life after prolonged infusion is 3-4 hours.

This is because fentanyl is highly lipophillic and redistributed very rapidly, causing plasma concentration to drop. However after a steady state has been reached, it relies on elimination which is comparatively slow.

Question 11

Describe the adverse effects of suxamethonium

Answer 11

Fasiculations/ post-op muscle pain
Relatively high risk of anaphylaxis
Malignant hyperthermia
Bradycardia
Raised compartmental pressure (eye, cranium but only 2-3mmHg, and abdomen which is more concerning for patients with reflux risk)
Hyperkalaemia (mass efflux of potassium due to synapse depolarisation)

Question 12

What effect does neostigmine reversal have on suxamethonium?

Answer 12

It potentiates the block

Question 13

What is the structure of suxamethonium?

Answer 13

Two molecules of acetylcholine joined together by their acetyl groups

Question 14

What are the two structural classifications of neuromuscular blockers?

Answer 14

Aminosteroids/ “curonium”drugs

Benzylisoquinolinium diesters/ “curium” drugs

Question 14

Summarise the dosing for sugammadex

Answer 14

Partial residual block - 2mg/kg
Full reversal of rocuronium standard dose (0.6mg/kg) - 4mg/kg
Full reversal of rocuronium RSI dose (1.2mg/kg) - 16mg/kg

Question 14

Compare rocuronium reversal with neo/glyo and sugammadex

Answer 14

Glyco/neo can’t reverse a high grade block, and if longer acting NMBs are used there is a risk the still-circulating NMB will re-block
Sugammadex is rapid onset, able to reverse any degree of block
There is a risk of anaphylaxis (0.3%) and a small chance of bradycardia but sugammadex is otherwise free of side-effects. Glyco/neo causes tachycardia in addition to anti-muscarinic side effects, and takes a few minutes to work. However its risk of anaphylaxis is negligible
It effectively prevents use of rocuronium again if re-paralysis is required within a short time

Question 15

Why do more potent agents have slower onset of action?

Answer 15

The effective dose is lower, hence the concentration gradient between plasma and effector site is lower and diffusion slower.

Question 16

Which neuromuscular blocker would be contraindicated in each of the following?

• Ocular trauma
• CKD 3
• Epilepsy

Answer 16

Glaucoma - suxamethonium

CKD 3 - pancuronium

Epilepsy - atracurium (metabolised to laudanosine which lowers seizure threshold). NB this has only been shown in animal studies and at very high doses so it’s generally felt to be safe.

Question 17

List 3 factors that would prolong neuromuscular blockade

Answer 17

Advanced age (for rocuronium this could equate to 50 minutes for block to wear off instead of 25)
Hepatic impairment (renal impairment for pancuronium)
Myasthenia gravis
Aminoglycosides, furosemide, volatile anaesthetics, calcium channel blockers (all decrease acetylcholine concentration at synapse, and therefore decrease competition with blocker)
Hypermagnasaemia, hypocalcaemia, and hypokalaemia all prolong the block
Acidaemia and hypothermia

Question 18

At what ToF ratio (ratio of strength of contraction between first and fourth twitch) is fade visually appreciable?

Answer 18

0.4

For reference - 0.9 should be the aim pre-extubation

https://pubs.asahq.org/anesthesiology/article/63/4/440/28715/Tactile-and-Visual-Evaluation-of-the-Response-to

Question 19

Why is suxamethonium dangerous in patients with: burns, severe trauma, prolonged immobility/ ICU stay, spinal cord transection, and neuropathies?

Answer 19

These conditions feature up-regulation of ACh receptors, therefore when sux is given and there is potassium efflux, it may be more pronounced in these populations so the risk of cardiac events is increased.

Question 20

What is the risk of anaphylaxis with NMB drugs?

Answer 20

1 in 6000-20,000

Suxamethonium is generally accepted to have the highest risk at 1:9000 (for context the risk of sux apnoea is 1:1800)
Rocuronium has the highest risk of the non-depolarising NMBs, some large studies even have it as higher risk than sux (NAP6 said 1:17,000)

Question 21

Compare the following characteristics of neuromuscular block between depolarising and non-depolarising agents:

ToF ratio
Post-tetanic potentiation

Answer 21

ToF ratio for a one-off dose of suxamethonium should be >0.7/ there should be no fade. Fade and post-tetanic potentiation are features of phase 2 depolarising block which occurs after prolonged or repeated use. However both of these features occur after one-off doses of non-depolarising blockers

Question 22

Summarise the key pharmacodynamic differences between fentanyl and alfentanil

Answer 22

Fentanyl is a highly lipophilic synthetic opioid with a rapid onset and offset after single bolus (due to redistribution rather than elimination). Context-sensitive half-life is significantly higher due to relatively slow elimination paired with redistribution.

Alfentanil is a synthetic opioid with the fastest speed of onset of all opioids due to its low pKA - i.e. even though it’s not as lipophillic as fentanyl, it is 90% unionised at pH 7.4 and so it crosses the BBB faster. It’s half life is also very short, but this is due to rapid clearance rather than redistribution as its VoD is roughly 10% that of fentanyl. Even after prolonged infusion it’s half-life plateaus at around 50 minutes.

Question 23

Summarise the general pharmacokinetics of aminosteroid NMBs

Answer 23

Nil oral absorption

All have poor lipid solubility, the bisquaternary more than the mono quaternary, and so a small volume of distribution (essentially just the extracellular fluid) and don’t cross the BBB or placenta.

There isn’t much metabolism, but what little there is is hepatic. Excretion is biliary for monoquaternary compounds and urinary for bisquaternary (due to the reduced lipophilicity). Generally roc and vec have 30% excreted unchanged in urine, and pancuronium has 60%

Question 24

Describe the mechanism of action of non-depolarising NMBs

Answer 24

Aminosteroid NMBAs compete with acetylcholine for binding to the alpha-subunit of the nicotinic receptor

Question 25

Describe the degree of active metabolites for roc, vec, and pancuronium

Answer 25

Rocuronium is converted to a small amount of metabolite, 5% as potent as roc

Vecuronium is converted to a small amount of metabolite, about 80% as potent as vector

Pancuronium is converted to a small amount (5-10% injected dose) of metabolite about 50% as potent as panc

Question 26

Which aminosteroid NMB causes vagal suppression and sympathetic stimulation?

Answer 26

Pancuronium

it inhibits noradrenaline reuptake post-synaptically, and suppresses vagal post-ganglionic fibres

Question 27

Describe the dosing ranges for rocuronium, vecuronium, and suxamethonium

Answer 27

Rocuronium is 0.6mg/kg standard and 1.2mg/kg RSI

Vecuronium is 0.1mg/kg standard. RSI dosing schedules have been suggested but aren’t commonly used

Suxamethonium is 1mg/kg standard and 1.5mg/kg RSI

Question 28

What is the intubating dose and half-life of atracurium?

Answer 28

0.5mg/kg
Onset ~2 minutes, though peak may be more like 3

Half-life is 50 minutes

Question 29

What is the unique feature of atracurium’s elimination?

Answer 29

Its metabolism is split 45:45 (10% is renally ectreted unchanged):

45% spontaneously degrades to inactive metabolites at normal body temperature and pH (Hoffman elimination)

45% undergoes hydrolysis by tissue esterases

Question 30

How does cisatracurium differ from atracurium?

Answer 30

More potent so slower onset but produces only 10% as much laudonasine metabolite
Similar half-life
75% undergoes Hoffman elimination, 15% renally excreted, minimal hydrolysis

Question 31

Why do patients with significant liver failure require higher doses of non-depolarising NMBs?

Answer 31

Hepatic failure causes fuild retention which increases the volume of distribution of NMBs

These patients are also at risk of prolonged block when using NMBs that are metabolised by plasma cholinesterases as these are produced in the liver

Question 32

How does mivacurium differ from atracurium/ cisatracurium?

Answer 32

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

Question 33

Which of the following would increase the speed of onset of a volatile anaesthetic agent?

A) High cardiac output
B) High functional residual capacity
C) High blood:gas partition coefficient
D) High potency
E) Low oil:gas coefficient

Answer 33

E) Low oil:gas coefficient

Oil:gas partition coefficient is essentially lipid-solubility and so is almost analagous to potency in volatiles. Accordingly, lower potency induction agents have faster onset.

Speed of onset of volatiles is related to how quickly an alveolar:plasma concentration gradient can be built up, as a higher concentration gradient is the most influential factor causing fast diffusion.

High CO will delay build-up of volatile in the alveoli, and a high FRFC provides a large reservoir into which volatile distributes thereby diluting its alveolar concentration.

A high blood:gas partition coefficient reflects higher water-solubility essentially. This leads to slower diffusion into target site - I’m struggling to find the reason. High potency means a lower mass of drug is used and the concentration gradient is less steep, as with IV medications.

Question 34

What is the difference between blood:gas partition coefficient and oil:gas coefficient?

Answer 34

blood:gas partition coefficient - describes the solubility of a particular gas in blood, which is essentialy hydrophilicity

oil:gas coefficient - essentially just lipophilicity which, for volatile anaesthetics, equates to potency

Question 35

What are the properties of an ideal volatile anaesthetic agent?

Answer 35

Physical properties:
Liquid at room temperature
Stable and inert
Cheap
Environmentally safe

Pharmacological properties:
No airway irritation or respiratory depression
No cardiovascular instability
Analgesic, not epileptogenic, doesn’t increase ICP
Low blood:gas partition coefficient
High oil:gas coefficient/ potency
Not metabolised

Question 36

Define the following terms:

Latent heat of vaporisation

Sustained vapour pressure

Critical temperature

Answer 36

Latent heat of vaporisation - the energy required for a molecule to transition from liquid to gas without an increase in temperature

Sustained vapour pressure - the pressure at which (for a given temperature) a vapour will be in equilibirum of movement between states with its liquid form

Critical temperature - the temperature at which a substance is completey gaseoues irrespective of pressure

Question 37

Summarise malignant hyperthermia

Answer 37

MH is an autosomal dominant condition with variable penetrance that causes mass metabolic activation and muscle breakdown leading invariably to death in the absence of treatment.

Incidence is 1 in 10,000, and the mechanism is activation of the ryanodine receptor leading to uncontrolled calcium release from the sarcoplasmic reticulum of myocytes. This can be triggered by any volatile anaesthetic agent, or suxamethonium.

Initial signs are rising EtCO2 and tachycardia with muscle rigidity. The patient will develop an oxygen requirement from the increased metabolic demand, and will eventually develop pyrexia and a mixed acidosis

Treatment is:
Stopping the causative agent and hyperventilate with high flow pure oxygen via a clean circuit. Maintain anaesthesia with TIVA and end the surgery ASAP, achieve muscle relaxation with a non-depolarising NMB. Actively cool, treat electrolyte abnormalities/ arrhythmias.

Bolus dantrolene at 2.5mg/kg (9 vials for the average 70kg male). Each vial of 20mg should be reconstituted in 60ml sterile water. Repeat boluses at 1mg/kg up to a maximum of 10mg/kg

NB previous uneventful anaesthesia doesn’t rule out MH.

Question 38

Give the blood:gas partition coefficient and oil:gas coefficient for each of: sevofluorane, isofluorane, and desflurane

Answer 38

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

Question 39

Describe the A-E effects of ketamine

Answer 39

A - preservation of airway reflexes, hypersalivation so may provoke laryngospasm

B - broadly preserves respiratory drive though may cause transient apnoea on induction, Useful as a bronchodilator e.g in I&V asthma exacerbations

C - increase in sympathetic drive leads to increased preload, SVR, BP, and cardiac output.

D - produces dissociative anaesthesia and is an excellent analgesic. Increases cerebral blood flow and metabolic rate. Traditionally considered to increase ICP - this is now believed to be untrue or a small rough effect as to be irrelevant.

Question 40

Match each of these pharmacological profiles to the drug:

VoD 3L/kg

VoD 1L/kg, active metabolites

Question 41

Describe the effects of ketamine in chronic opioid users

Answer 41

It reduces down regulation of opioid receptors, and so reduces opioid tolerance and hyperalgesia

Question 42

Give 3 contraindications to flumazenil

Answer 42

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

Question 43

Describe the mechanism of action of benzodiazepines

Answer 43

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

Question 44

Describe the A-E effects of midazolam

Answer 44

A - reduces upper airway tone and suppresses reflexes

B - respiratory depression and blunted response to hypercarbia

C - obtunds hypertensive response to laryngoscopy, arterial and venous dilatation, reduced cardiac output

D - anxiolysis->sedation->hypnosis, anterograde amnesia, anticonvulsant, muscle relaxation (effect on dorsal horn of spinal cord), reduced REM sleep

E - reduces hepatic and renal flow

Question 45

Describe the pharmacokinetics of ketamine

Answer 45

Ketamine is presented as a colourless solution available as 1%, 5%, or 10%. It contains a mixture of S and R stereoisomers. It has poor oral bioavilaibilty but can be given orally. It is used IV and IM for anaesthesia, sedation, and analgesia. The dose for anaesthesia is 0.5-2mg/kg IV, and for sedation/ analgesia is 0.2-0.75mg/kg.

Ketamine is a non competitive NMDA receptor antagonist. Its VoD is reasonably large as 3L/kg. It is very rapid in onset owing to reasonable lipophilicity, pKA of 7.5, and small molecule size. Metabolism is hepatic to active metabolites, which are then conjugated and excreted in urine. Distribution half life is 10 minutes but elimination half life is 2-3 hours.

Question 46

List the RSI dose ranges for a standard modified RSI

Answer 46

Fentanyl 2-5mcg/kg
Propofol 1-2.5mg/kg
Rocuronium 1.2mg/kg

Question 47

List the A-E effects of thiopentone

Answer 47

A - laryngeal reflexes are generally not suppressed

B - causes apnoea and the standard suppression of response to hypoxia and hypercarbia. However patients will breathe more quickly after thiopentone than propofol

C - mostly causes venodilation and reduced preload -> reduced cardiac output. SVR is generally preserved, and at high doses it is a direct negative inotrope.

D - provides extremely quick anaesthesia (one arm brain circulation time). Reduced ICP and cerebral metabolic rate. Anticonvulsant.

E - causes enzyme induction after just one dose. Can cause tissue damage if it extravasates due to alkaline pH, and is catastrophic if given arterially.

Question 48

Summarise the pharmacokinetics of thiopentone

Answer 48

A lipophillic anaesthetic agent given IV at a dose of anywhere from 3-7mg/kg. 80% protein bound so lower doses needed in hypoalbuminaemia. It has a VoD of 2L/kg and acts as a GABA agonist and non-NMDA glutamate receptor antagonist. Its pKA is 7.6 and is the fastest acting induction agent.

Offset of action is due to redistribution to fatty tissue, and metabolism is actually very slow as the responsible enzymes are quickly saturated and it starts to obey zero order kinetics. After a single bolus the offset time is 5-10 minutes. Metabolism is hepatic, to inactive metabolites. Induction of CYP450 occurs after a single dose

Question 49

Describe the A-E effects of etomidate

Answer 49

A - preservation of laryngeal reflexes

B - brief hyperventilation followed by brief apnoea - minimal net effect. No histamine release so no bronchospasm

C - famously cardiostable, may produce slight tachycardia and hypertension

D - produces sedation/anaesthesia in 30-60 seconds, reduces cerebral blood flow and metabolic rate, however reduces ICP by 50% so maintains or increases cerebral perfusion pressure. Causes myoclonus on induction and prolongs seizures (hence is useful in potentiation ECT)

E - dose dependent reversible inhibition of 11B hydroxylase leading to reduced cortisol production. Unclear how significant this is after one dose, and whether its more significant in the critically ill

Question 50

Describe the dose and mechanism of action of etomidate

Answer 50

Action is positive modulation of the GABA A receptor at low doses, and independent agonism at higher doses.

Dose is 0.2-0.6mg/kg