Drugs Flashcards
Describe the A-E effects of propofol
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
Describe the structure of propofol
A phenol ring with two propyl groups attached to 2nd and 6th carbons (2,6-diisopropylphenol)
Describe the pharmacodynamics and kinetics of propofol
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
Why is the half-life of propofol from bolus so much shorter than from steady state (and what are the half-lives)
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
What is the mechanism of action of propofol?
GABA-A agonist, activating the cell membrane channels which allows chloride influx and hyperpolarizes the membrane
Describe the direct vs. indirect cardiovascular effects of propofol
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.
Describe the mechanism of PRIS
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.
Describe the effects of opioids on respiration
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
What is the generic receptor action of opioids?
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
Describe the adverse effects of suxamethonium
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)
What effect does neostigmine reversal have on suxamethonium?
It potentiates the block
What is the structure of suxamethonium?
Two molecules of acetylcholine joined together by their acetyl groups
What are the two structural classifications of neuromuscular blockers?
Aminosteroids/ “curonium”drugs
Benzylisoquinolinium diesters/ “curium” drugs
Compare rocuronium reversal with neo/glyo and sugammadex
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
Why do more potent agents have slower onset of action?
The effective dose is lower, hence the concentration gradient between plasma and effector site is lower and diffusion slower.
List 3 factors that would prolong neuromuscular blockade
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
At what ToF ratio (ratio of strength of contraction between first and fourth twitch) is fade visually appreciable?
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
Why is suxamethonium dangerous in patients with: burns, severe trauma, prolonged immobility/ ICU stay, spinal cord transection, and neuropathies?
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.
What is the risk of anaphylaxis with NMB drugs?
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)
Compare the following characteristics of neuromuscular block between depolarising and non-depolarising agents:
ToF ratio
Post-tetanic potentiation
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
Summarise the key pharmacodynamic differences between fentanyl and alfentanil
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. Fentanyl is the most potent opioid, and is five times more potent than alfentanil.
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.
Summarise the general pharmacokinetics of aminosteroid NMBs
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%
Describe the mechanism of action of non-depolarising NMBs
Aminosteroid NMBAs compete with acetylcholine for binding to the alpha-subunit of the nicotinic receptor
Describe the degree of active metabolites for roc, vec, and pancuronium
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
Which aminosteroid NMB causes vagal suppression and sympathetic stimulation?
Pancuronium
it inhibits noradrenaline reuptake post-synaptically, and suppresses vagal post-ganglionic fibres
What is the intubating dose and half-life of atracurium?
0.5mg/kg
Onset ~2 minutes, though peak may be more like 3
Half-life is 50 minutes
What is the unique feature of atracurium’s elimination?
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
How does cisatracurium differ from atracurium?
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
Why do patients with significant liver failure require higher doses of non-depolarising NMBs?
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
How does mivacurium differ from atracurium/ cisatracurium?
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
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
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.
What is the difference between blood:gas partition coefficient and oil:gas coefficient?
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
What are the properties of an ideal volatile anaesthetic agent?
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
Define the following terms:
Latent heat of vaporisation
Sustained vapour pressure
Critical temperature
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
Summarise malignant hyperthermia
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.
Give the blood:gas partition coefficient and oil:gas coefficient for each of: sevofluorane, isofluorane, and desflurane
Sevo: 0.65 - 47
Iso: 1.4 - 91
Des: 0.45 - 26
Describe the A-E effects of ketamine
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.
Describe the effects of ketamine in chronic opioid users
It reduces down regulation of opioid receptors, and so reduces opioid tolerance and hyperalgesia
Give 3 contraindications to flumazenil
Chronic benzo use
Epilepsy/ propensity to seizures
Possible mixed overdose with TCAs, as this increases risk of cardiac dysrhythmia with flumazenil
Describe the mechanism of action of benzodiazepines
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
Describe the A-E effects of midazolam
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
Describe the pharmacokinetics of ketamine
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.
List the A-E effects of thiopentone
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.
Summarise the pharmacokinetics of thiopentone
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
Describe the A-E effects of etomidate
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
Describe the dose and mechanism of action of etomidate
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
Give 5 side effects of opiates
N&V
Sedation
Bradycardia and hypotension
Respiratory depression
Constipation
Urinary retention
Delirium
Dysphoria & hallucinations
Itching
Tolerance & addiction
Which of the following statements is true of morphine?
A) VoD is ~0.5L/kg
B) M3G accumulates in renal failure leading to toxicity
C) It has an oral bioavialibility of ~25%
D) It has a lower pKa than alfentanil
E) It is a histamine receptor agonist
C) It has an oral bioavialibility of ~25%
Morphine is an opioid used for acute and chronic pain. It has 25% oral bioavailability, and is used IV as a slow-onset agent (~10 minutes) at a dose of 0.1-0,2mg/kg. VoD is 3.5L/kg, pKa is 7.9, and metabolism is mostly through glucoronidation in the liver and gut excretion. The main metabolite (70%) is M3G which is inactive, but M6G is also produced which is more potent and accumulates in renal failure; in chronic use M6G is even responsible for the majority of activity. Elimination half-life is very variable, 3 hours is an average estimate.
Which is the following is true of diamorphine?
A) It has higher affinity for mu receptors than morphine
B) It is metabolised to M6G
C) It is a prodrug metabolised in the liver
D) It has a similar onset time to morphine
E) It is much more lipid soluble than morphine
E) It is much more lipid soluble than morphine
Diamorphine is a very lipid soluble prodrug with no inherent activity at opioid receptors. It is 3,6-diacetyl mohprine and is rapidly converted to the active metabolite 6-MAM, then to morphine by plasma and tissue esterases. Both it and 6-MAM are much more lipid soluble than morphine and crosses the blood-brain barrier quickly. Because of these differences, diamorphine, in clinical use, has twice the potency of morphine despite having no inherent action at opioid receptors.
Which of the following is true of remifentanil?
A) It is twice as potent as fentanyl
B) It depends on plasma cholinesterase metabolism
C) A Cet of 2ng/ml in combination with propofol will obtund the pressor response to larngoscopy
D) It can produce lethal bradycardia and hypotension if bolused
E) It produces active metabolites with 10% potency
D) It can produce lethal bradycardia and hypotension if bolused
Remifentanil has a similar potency and speed of onset to fentanyl, but is metabolised by tissue esterases (not plasma cholinesterases so not affected by anti-cholinergic drugs, and not subject to genetic variation in metabolism). It produces an active metbaolite but it only has 0.1% the potency so is clinically irrelevant. In response to C), a Cet of 5ng/ml in the setting of Cet propofol 4mg/ml will obtund the pressor response to larngoscopy.
Which of the following is true of tramadol?
A) It forms a racemic mixture with different stereoisomers activiating different receptors
B) It has a similar profile to other opioids in overdose
C) It is safer in renal impairment than codeine
D) It is a diphenylpropylamine
E) It has cholinergic effects
A) It forms a racemic mixture with different stereoisomers activiating differen receptors
One stereoisomer activates opioid receotors and inhitibs serotonin reuptake , the other inibits noradrenaline reputake presynaptically. This variety of action explains why tramadol is only partly reversed by naloxone.
Tramadol is more dangerous than other opioids in overdose, causing seizures in 15% of cases, though it does produce less respiratory depression. It produces active metabolites that accumulate in renal failure similarly to codeine and morphine. It is classed as a phenylpiperidine. It is a nicotinic and muscarinic antagonist.
Arrange the following opioids in order of pKA (ascending):
Alfentanil, fentanyl, morphine, remifentanil
Alfentanil - 6.5
Remifentanil - 7.1
Morphine - 7.9
Fentanyl - 8.4
Which of the following statements on opioids is false?
A) Fentanyl and morphine have a similar elimination half-life
B) 1% of people have an absent CYP2D6 resulting in codeine inefficacy
C) Pethidine belongs to the same structural group as alfentanil
D) Tramadol produces less respiratory depression
E) De-methylation produces the active metabolite of codeine
B) 1% of people have an absent CYP2D6 resulting in codeine inefficacy
~10% of people have an absence of this enzyme, resulting in codeine inefficacy.
Which of the following is true of opioid partial agonists/ antagonists?
A) Buprenorphine can precipitate withdrawal if given to a patient on opioids
B) Buprenorphine should be used with caution in renal failure
C) Naloxone has a duration of action of ~4 hours
D) Buprenorphine overdose can be reliably reversed using naloxone
E) Naloxone reduces sympathetic tone
A) Buprenorphine can precipitate withdrawal if given to a patient on opioids
Buprenorphine is a partial agonist with very high affinity for mu opioid receptors. Consequently it out-competes other opioids while not stimulating the receptor much, which can cause acute withdrawal. The high affinity for its receptor also explains why naloxone can be ineffective against higher doses of buprenorphine.
Buprenoprhine undergoes hepatic metabolism to an active ‘nor’ metabolite which is excreted in bile.
Nalozone is a competitive opioid antagonist, but only has a short duration of action (30-45 minutes) and so may need repeat doses or an infusion. Initial dose is often 100-400mcg, but may need more like 2mg in some cases, and can be repeated up to 10mg total. Nalaxone increases sympathetic tone which can cause hypertension, arrhythmia, and rarely pulmonary oedema.
Which of the following is true of local anaesthetics?
A) An amide linkage makes local anaesthetics shorter-acting
B) Cocaine triggers catecholamine release from pre-synpatic vesicles
C) Bupivicaine can be used as a treatment for VT
D) Prilocaine metabolites ionise iron in haemoglobin to increase its avidity for oxygen
E) Levobupivicaine was developed to be less reno-toxic
D) Prilocaine metabolites ionise iron in haemoglobin to increase its avidity for oxygen
This change ion affinity means the oxygen does not unload oxygen in hypoxic tissues - causing methaemoglobinaemia
Which of the following is false of local anaesthetics?
A) LAs cause conformational change to block Na channels
B) Ametop cream contains an amide LA
C) Ropivicaine is quick onset and long action
D) LAs are mostly ionised at pH 7.4
E) Altered taste, perioral tingling, and tinnitus are early signs of LA toxicity
B) Ametop cream contains an amide LA
Ametop contains tetracaine (amethocaine) which is an ester LA along with cocaine, procaine, and benzocaine.
Explain why isoprenaline is a better chronotrope than dobutamine
Isoprenaline is very beta-selective, so its chronotropy is not offset by reflex from vasoconstriction. However dobutamine stimulates both beta1 and alpha1 so its vasoconstriction offsets some of its chronotropy.
Describe the mechanism of action of milrinone
Milrinone is a PDE III inhibitor. phosphodiesterases are enzymes that break down cAMP and so are part of the de-coupling of beta adrenergic reeptors that occurs with sustained stimulation. Inhibiting this breakdown potentiates beta receptors and so is particularly useful in chronically sick hearts, which will exhibit this de-coupling.
Milrinone also binds to calcium channels on the sarcoplasmic reticulum, and so potentiate CICR to provide another mechanism for inotropy.
Which of the following is false of ephedrine & catecholamines?
A) Alpha 2 receptors also inhibit ACh release
B) Most norad released is taken up post synaptically and metabolised by COMT
C) Ephedrine’s efficacy is reduced by cocaine & amitryptilline
D) Tachyphylaxis is a result of norad store depletion
B) Most norad released is taken up post synaptically and metabolised by COMT
Norad is recycled pre synaptically due to very high affinity of NET for norad, where it is recycled into vesicles by VMAT or metabolised by MAO. COMT also metabolises catecholamines but is less important for norad.
