Pharmacology and pharmacokinetics: exam questions
Discuss the neuromuscular junction (motorische eindplaat), give all the drugs that affect it
and their indications
- Neuromuscular junction only nicotinic acetylcholine receptors present
- nAChR = ligand-activated ion channel pentamer with 5 extracellular ligand binding
domains + cation selective ion pore = ionotropic (excitatory synaptic transmission)
fast electrochemical transduction (< 100 ms)
- heteropentamer: alfa4-beta2-alfa4-beta2-beta2
Agonists of nAChR:
- Normal dose: no effect in healthy individuals, but increase in muscle tone in patients
with myasthenia gravis
- Higher dose: fasciculation (uncontrolled contraction of individual muscle fibres =
“twitch”) or jerking (contraction of whole muscle)
- Extremely high dose: depolarizing block with muscle paralysis = “cholinergic crisis”
Drugs:
- Nicotine = nAChR agonist indication = quit smoking
- Varenicline = nAChR partial agonist (lower efficacy, never reach 100% receptor activation) but
higher affinity; competitively inhibits nicotine binding indication = quit smoking
- Bupropion = non-competitive nAChR antagonist + NA and DA reuptake inhibitor indication =
smoking cessation
These don’t work on neuromuscular junction !!!
- Edrophonium = competitive antagonist AChE indication = myasthenia gravis (not
used anymore)
- Neostigmine & pyridostigmine = reversible AChE inhibitor indication = myasthenia
gravis (often together with atropine = mAChR antagonist, to restrict the effect to the
neuromuscular junction), neutralization of pachycurare-induced neuromuscular block,
postoperative stomach, intestinal and bladder atony
- Physostigmine = reversible AChE inhibitor (can cross BBB) indication =
neutralization of pachycurare-induced neuromuscular block, antidote for intoxication
with atropine; induction of miosis in closed-angle glaucoma (local administration via
eye drops)
- Side effects:
- NMJ- related: muscle cramps, muscle fasciculations, muscle weakness
(if overdose), cholinergic crisis (paradoxical paralysis)
- Systemic: bradycardia, bronchoconstriction, excess salivation,
diarrhoea, abdominal cramps, sweating, urinary urgency
,- Parathoin, sarin, soman tabun = irreversible AChE inhibitors (chemical warfare) no
clinical indications
- Pachycurares (real competitive antagonists of nAChR; non-depolarizing): d-
tubocurarine & pancuronium = nAChR antagonist causes limp muscle paralysis
indication = induction of muscle paralysis during anaesthesia to prevent spinal reflexes
with muscle contractions during surgery or electroconvulsive therapy (ECT); after the
operation the effect of pachycurares is neutralized by a cholinesterase inhibitor;
atropine is added to avoid the unwanted effects from the muscarinic receptors
- Side effects: flaccid paralysis, hypotension, tachycardia, histamine release
(flushing, bronchospasm)
- Leptocurares (depolarizing blocker antagonists of nAChR): suxamethonium,
atracurium, decamethonium cause depolarizing block (continuous depolarization)
indication = induction of muscle paralysis during anaesthesia to prevent spinal
reflexes with muscle contractions during surgery or electroconvulsive therapy (ECT);
atropine is added to avoid the unwanted effects from the muscarinic receptors
- Side effects: muscle fasciculations, post-operative muscle pain, prolonged
paralysis, hyperkalaemia, hyperthermia, bradycardia
- Botulinum toxin: inhibition of ACh-release (presynaptic effect) indication = muscle
spasms
,Can these drugs be the cause of these side effects?
● codeine blurred vision
○ YES (causes CNS depression and miosis)
● aspirin black stools (melena)
○ YES (inhibits COX-1 less prostaglandin synthesis gastric mucosal
damage and bleeding black stools)
● rosuvastatin myalgia
○ YES (rosuvastatin = statin can cause myopathy with rhabdomyolysis)
● methylphenidate insomnia
○ YES (CNS stimulant: increases dopamine and noradrenaline
increases alertness and delays sleep onset)
● propranolol hypoglycaemia
○ YES (non-selective beta blocker: blocks b1 and b2 b2 blockade: lower
hepatic glycogenolysis and gluconeogenesis increased risk of
hypoglycaemia, especially in diabetics)
DE HOON Formulas:
- Elimination half life: t(1/2) = 0,693 * Vd/ Cl(body)
- Fick’s law of diffusion:
V = P * (A/d) * D * (C0 – C1)
Velocity = partition coefficient * (surface area / membrane thickness) * diffusion
constant * delta C
(with delta C = concentration at t0 – concentration at ti)
- Michaelis Menten: V = (C * Vmax) / (Km + C)
= rate of uptake by carrier mediated active transport
, TRUE / FALSE (and why?)
There is a dissociation between pharmacokinetics and pharmacodynamics in coumarins,
omeprazole and aspirin.
- TRUE (in all 3 cases, the effect outlasts the presence of the drug in the plasma)
- Coumarin (e.g. warfarin) = competitive vitamin K antagonist (inhibits new synthesis of vit
K dependent coagulation factors); takes several hours before anticoagulant function
starts (because takes time for existing coagulation factors to degrade) but the effect
lasts 4-5 days after cessation (because these factors have to be produced again).
- Omeprazole (= PPI): irreversible inhibition of H+/K+-ATPase (because covalent bond)
so even though they have a short half-life (out of plasma within 6 hours), the acid
secretion only recovers after new pumps are synthesised (acid suppression lasts 24-
48h; so only take once a day)
- Aspirin (irreversible COX inhibition): at low doses a bit more selective for COX-1 in
platelets permanent effect of aspirin on platelets (covalent bond) so only new
synthesis of platelets after 7-10 days (while aspirin itself is cleared quickly; short half-
life)
Extra question: What is TDM and when is it used?
- Therapeutic drug monitoring measurement of drug concentration in plasma to
individualize dosing (especially in drugs where the effect correlates more with the
plasma concentration than with the dose)
- Used for:
- Drugs with a narrow therapeutic window = MED (minimal effective dose) and
MTD (maximal tolerated dose) are close to each other (e.g. lithium, digoxin,
phenytoin last has non-linear kinetics)
- If there is a large inter-individual pharmacokinetic variability (e.g. liver or renal
disease)
Extra question: How is VKA monitored?
- INR = international normalized ratio
- Normal coagulation: INR = 1
- Higher INR means that blood clots more slowly higher bleeding risk
- For CVT, PE, AF: INR needs to be 2 - 3
- For artificial valves: INR needs to be 2,5 - 3,5
- Lower INR means that there is insufficient anticoagulation higher thrombosis risk
- INR = PT (sec.) of patient divided by PT of average control patient
Discuss the neuromuscular junction (motorische eindplaat), give all the drugs that affect it
and their indications
- Neuromuscular junction only nicotinic acetylcholine receptors present
- nAChR = ligand-activated ion channel pentamer with 5 extracellular ligand binding
domains + cation selective ion pore = ionotropic (excitatory synaptic transmission)
fast electrochemical transduction (< 100 ms)
- heteropentamer: alfa4-beta2-alfa4-beta2-beta2
Agonists of nAChR:
- Normal dose: no effect in healthy individuals, but increase in muscle tone in patients
with myasthenia gravis
- Higher dose: fasciculation (uncontrolled contraction of individual muscle fibres =
“twitch”) or jerking (contraction of whole muscle)
- Extremely high dose: depolarizing block with muscle paralysis = “cholinergic crisis”
Drugs:
- Nicotine = nAChR agonist indication = quit smoking
- Varenicline = nAChR partial agonist (lower efficacy, never reach 100% receptor activation) but
higher affinity; competitively inhibits nicotine binding indication = quit smoking
- Bupropion = non-competitive nAChR antagonist + NA and DA reuptake inhibitor indication =
smoking cessation
These don’t work on neuromuscular junction !!!
- Edrophonium = competitive antagonist AChE indication = myasthenia gravis (not
used anymore)
- Neostigmine & pyridostigmine = reversible AChE inhibitor indication = myasthenia
gravis (often together with atropine = mAChR antagonist, to restrict the effect to the
neuromuscular junction), neutralization of pachycurare-induced neuromuscular block,
postoperative stomach, intestinal and bladder atony
- Physostigmine = reversible AChE inhibitor (can cross BBB) indication =
neutralization of pachycurare-induced neuromuscular block, antidote for intoxication
with atropine; induction of miosis in closed-angle glaucoma (local administration via
eye drops)
- Side effects:
- NMJ- related: muscle cramps, muscle fasciculations, muscle weakness
(if overdose), cholinergic crisis (paradoxical paralysis)
- Systemic: bradycardia, bronchoconstriction, excess salivation,
diarrhoea, abdominal cramps, sweating, urinary urgency
,- Parathoin, sarin, soman tabun = irreversible AChE inhibitors (chemical warfare) no
clinical indications
- Pachycurares (real competitive antagonists of nAChR; non-depolarizing): d-
tubocurarine & pancuronium = nAChR antagonist causes limp muscle paralysis
indication = induction of muscle paralysis during anaesthesia to prevent spinal reflexes
with muscle contractions during surgery or electroconvulsive therapy (ECT); after the
operation the effect of pachycurares is neutralized by a cholinesterase inhibitor;
atropine is added to avoid the unwanted effects from the muscarinic receptors
- Side effects: flaccid paralysis, hypotension, tachycardia, histamine release
(flushing, bronchospasm)
- Leptocurares (depolarizing blocker antagonists of nAChR): suxamethonium,
atracurium, decamethonium cause depolarizing block (continuous depolarization)
indication = induction of muscle paralysis during anaesthesia to prevent spinal
reflexes with muscle contractions during surgery or electroconvulsive therapy (ECT);
atropine is added to avoid the unwanted effects from the muscarinic receptors
- Side effects: muscle fasciculations, post-operative muscle pain, prolonged
paralysis, hyperkalaemia, hyperthermia, bradycardia
- Botulinum toxin: inhibition of ACh-release (presynaptic effect) indication = muscle
spasms
,Can these drugs be the cause of these side effects?
● codeine blurred vision
○ YES (causes CNS depression and miosis)
● aspirin black stools (melena)
○ YES (inhibits COX-1 less prostaglandin synthesis gastric mucosal
damage and bleeding black stools)
● rosuvastatin myalgia
○ YES (rosuvastatin = statin can cause myopathy with rhabdomyolysis)
● methylphenidate insomnia
○ YES (CNS stimulant: increases dopamine and noradrenaline
increases alertness and delays sleep onset)
● propranolol hypoglycaemia
○ YES (non-selective beta blocker: blocks b1 and b2 b2 blockade: lower
hepatic glycogenolysis and gluconeogenesis increased risk of
hypoglycaemia, especially in diabetics)
DE HOON Formulas:
- Elimination half life: t(1/2) = 0,693 * Vd/ Cl(body)
- Fick’s law of diffusion:
V = P * (A/d) * D * (C0 – C1)
Velocity = partition coefficient * (surface area / membrane thickness) * diffusion
constant * delta C
(with delta C = concentration at t0 – concentration at ti)
- Michaelis Menten: V = (C * Vmax) / (Km + C)
= rate of uptake by carrier mediated active transport
, TRUE / FALSE (and why?)
There is a dissociation between pharmacokinetics and pharmacodynamics in coumarins,
omeprazole and aspirin.
- TRUE (in all 3 cases, the effect outlasts the presence of the drug in the plasma)
- Coumarin (e.g. warfarin) = competitive vitamin K antagonist (inhibits new synthesis of vit
K dependent coagulation factors); takes several hours before anticoagulant function
starts (because takes time for existing coagulation factors to degrade) but the effect
lasts 4-5 days after cessation (because these factors have to be produced again).
- Omeprazole (= PPI): irreversible inhibition of H+/K+-ATPase (because covalent bond)
so even though they have a short half-life (out of plasma within 6 hours), the acid
secretion only recovers after new pumps are synthesised (acid suppression lasts 24-
48h; so only take once a day)
- Aspirin (irreversible COX inhibition): at low doses a bit more selective for COX-1 in
platelets permanent effect of aspirin on platelets (covalent bond) so only new
synthesis of platelets after 7-10 days (while aspirin itself is cleared quickly; short half-
life)
Extra question: What is TDM and when is it used?
- Therapeutic drug monitoring measurement of drug concentration in plasma to
individualize dosing (especially in drugs where the effect correlates more with the
plasma concentration than with the dose)
- Used for:
- Drugs with a narrow therapeutic window = MED (minimal effective dose) and
MTD (maximal tolerated dose) are close to each other (e.g. lithium, digoxin,
phenytoin last has non-linear kinetics)
- If there is a large inter-individual pharmacokinetic variability (e.g. liver or renal
disease)
Extra question: How is VKA monitored?
- INR = international normalized ratio
- Normal coagulation: INR = 1
- Higher INR means that blood clots more slowly higher bleeding risk
- For CVT, PE, AF: INR needs to be 2 - 3
- For artificial valves: INR needs to be 2,5 - 3,5
- Lower INR means that there is insufficient anticoagulation higher thrombosis risk
- INR = PT (sec.) of patient divided by PT of average control patient
