VIVA: Pharmacology - Nervous system Flashcards
What is the mechanism of action of benzodiazepines?
- Binds to molecular components of GABA(A) receptor* in neuronal membranes in CNS* (gamma subunit of pentamer)
- This receptor is a chloride ion channel* and causes hyperpolarisation of the membrane
- The benzodiazepines do not substitute for GABA (major inhibitory neurotransmitter in the CNS), but appear to potentiate GABA’s effects without directly activating GABA(A) receptors or opening the chloride channels
- Causes an increase in the frequency (but not duration) of channel-opening events
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What are the organ level effects of diazepam?
- CNS:
- Sedation*
- Anxiolysis*
- Amnesia and psychomotor and cognitive depression at lower doses
- Hypnosis*
- Anaesthesia* at higher doses
- Anticonvulsant effect*
- Muscle relaxation* - Respiratory depression*
- Cardiovascular depression* (at higher doses and when hypovolaemic/CCF/chronic heart disease)
*3 to pass
What are the clinical uses of diazepam in the ED?
2 to pass:
- Anticonvulsant
- Sedation of agitated patient
- EtOH or benzodiazepine withdrawal
- Various toxidromes
What receptors do carbamazepine effect?
- Sodium channel blocker*
- Adenosine receptors antagonist
- Anticholinergic (antimuscarinic)
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What are the most common dose-related adverse effects of carbamazepine?
- CNS effects:
- Cerebellar effects: nystagmus, diplopia, ataxia
- Drowsiness - Anticholinergic effects:
- Dry mouth
- Tachycardia
- Blurred vision
- Delirium - Cardiovascular effects:
- Hypotension - GIT:
- GIT upset (nausea, vomiting)
- Hepatic dysfunction - Metabolic:
- Hyponatraemia, water intoxication - Haematological:
- Blood dyscrasias, including leukopaenia commonly
- Aplastic anaemic and agranulocytosis rarely - Dermatological:
- Erythematous skin rash
What important drug interactions does carbamazepine have?
- Induces CYP450 enzymes / hepatic drug metabolising enzymes* and P-glycoprotein, resulting in increased clearance of some drugs and reducing their therapeutic blood levels (e.g. OCP, warfarin, phenytoin, valproate, lamotrigine, diazepam, phenobarbitone, carbamazepine itself)
- As it induces its own metabolism, can result in breakthrough seizures
- Valproate and phenytoin may inhibit carbamazepine elimination
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Outline the clinical uses of carbamazepine
- Anticonvulsant (partial and generalised tonic-clonic seizures)*
- Treatment of bipolar mood disorder
- Trigeminal neuralgia
Describe the mechanism of action of carbamazepine’s anticonvulsant activity
Blocks sodium channels:
- Inhibits high-frequency repetitive firing of neurons
- Presynaptic blocker of synaptic transmission (similar to phenytoin)
What are the pharmacokinetics of midazolam?
- Absorption:
- Water-soluble*
- Can be given PO, intranasal, buccal, PR, IV/IM/subcut
- Poor oral bioavailability* - Distribution:
- Highly protein bound*
- Crosses BBB easily at body pH - Metabolism:
- Hepatic metabolism
- Short elimination half-life* 1.5-2.5hrs - Excretion:
- Renal excretion
*2/4 to pass
What are the clinical effects of midazolam?
- Strong amnestic effect
- Anticonvulsant*
- Anxiolytic
- Sedative-hypnotic
- Antiemetic
- Reduced sensitivity to CO2 (respiratory depression)
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What are the clinical indications for the use of midazolam?
- Anxiolysis
- Sedation*
- Anticonvulsant*
- Antiemetic
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What are the adverse effects of midazolam?
- Excess sedation*
- Respiratory depression*
- Decreased motor skills
- Impaired judgement
- Hypotension (particularly in hypovolaemic/CCF/chronic heart disease patients)
- Occasionally rash
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What is the mechanism of action of phenytoin?
- Sodium channel blockade* / reduced neuronal sodium conductance and prolongation of inactivated state of the sodium channel
- Reduces Ca2+ influx into cells to decrease glutamate release
- Enhances GABA release
- Inhibits generation of rapidly repetitive action potentials
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Describe the elimination pharmacokinetics of phenytoin and how it affects toxicity
- Phenytoin has dose-dependent elimination*
- At low serum concentration it has first order kinetics*
- Elimination becomes zero-order as serum concentration rises* with prolonged elimination and greater chance of toxicity with recurrent dosing and with even small increases in dose
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What are the adverse effects of phenytoin?
- Neurological (dose-related)*:
- Ataxia
- Drowsiness
- Dizziness
- Blurred vision
- Hallucinations
- Slurred speech and confusion
- Peripheral neuropathy (idiosyncratic) - Skin/soft tissue:
- Hirsutism
- Gingival hypertrophy
- Acne
- Facial coarsening - Cardiovascular*:
- Hypotension and arrhythmias with rapid IV administration
*1 of each to pass
Describe the pharmacokinetics of phenytoin
- Absorption:
- High oral bioavailability (90%), poor IMI
- Peak serum concentration 3-12hrs - Distribution:
- Highly plasma protein bound (90%)*
- Vd 45L/70kg and widely distributed (brain, liver, skeletal muscle, fat) - Metabolism:
- Metabolised to inactive metabolites by the liver*
- Dose-dependent: first order kinetics at low concentrations, zero order kinetics at higher concentrations due to saturation of hepatic enzymes (slows elimination)*
- Half-life variable (12-36hrs) dependent on serum concentration as above - Excretion:
- Renal (<2% unchanged)
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What is the rationale for using a loading dose of phenytoin?
Reaches target concentration dose more quickly (otherwise it takes 4 half-lives to get to steady state)
What are the risks associated with IV phenytoin administration?
- Hypotension and bradycardia with rapid infusion* (due to diluent):
- Limit rate of infusion to 50g/min maximum (30-60mins for full dose)
- Less likely with fosphenytoin - Allergic reactions
- Local necrosis if extravasation
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Describe the pharmacokinetics of valproate
4 to pass:
- Absorption:
- Can be administered IV or PO
- Well-absorbed orally with bioavailability >80%
- Peak blood levels within 2hrs - Distribution:
- Highly protein bound
- Low volume of distribution 0.15L/kg - Metabolism:
- Extensively metabolised in the liver
- Long half-life 9-18hrs - Excretion:
- Excreted as glucuronide conjugate in urine (30-50% of dose)
What are the adverse effects of sodium valproate?
- GIT*:
- Nausea, vomiting
- Abdominal pain
- Reflux
- Asymptomatic LFT derangement
- Weight gain, increased appetite (less commonly)
- Idiosyncratic hepatic failure (rare; risk highest <2yrs old)
- Pancreatitis - CNS*:
- Fine tremor
- Ataxia
- Sedation
- Fatal encephalopathy if there is also a genetic abnormality of urea metabolism - Skin/soft tissue:
- Alopecia
- Rash - Haematological:
- Idiosyncratic thrombocytopaenia - Metabolic:
- Hypernatraemia - Reproductive:
- Teratogenic if given in 1st trimester (e.g. neural tube defects, cardiovascular/facial/digital abnormalities) - Hypersensitivity reactions
*1 of each to pass + 2 others
Sodium valproate exhibits capacity-limited protein-binding kinetics. What is this?
- Sodium valproate is highly bound to plasma proteins (90%) at lower concentrations (75mg/L)
- This mechanism is saturated at higher concentrations (150mg/L) leading to an increase in free drug (70% protein bound)
- Results in apparent increased clearance of drug at higher doses and reduction in half-life: variable clearance
- Thus dosage is preferred as a sustained release preparation
What are the possible pharmacodynamic mechanisms of sodium valproate?
- GABA increased presynaptically by reduced GABA breakdown to succinate (ABAT/GAT1), possibly increased production (GAD)
- Direct inhibitory actions on post-synaptic sodium channel, particularly high frequency gates, and Ca2+ (membrane-stabilisation - reduced voltage-gated outflow)
- Possible blocked NMDA receptor activation effects
Describe the pharmacodynamics of amitriptyline
- Blocks reuptake of serotonin and noradrenaline*
- Blocks muscarinic, sympathetic a1, GABA(A), Na+ channel and histamine receptors
- Monoamine vs neurotrophic vs neuroendocrine theories
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What are the toxic effects of amitriptyline and how are they mediated?
3 effects + receptor responsible:
1. Anticholinergic:
- Blurred vision
- Dry mouth
- Tachycardia
- Urinary retention
- Delirium
2. Antihistamine:
- Sedation
3. Alpha adrenergic blockade:
- Hypotension
4. Na+ channel blockade:
- Widened QRS
- Bradycardia
5. Direct central effects:
- Seizures
What are the adverse and/or toxic effects of lithium?
- Neurological:
- Tremor
- Choreoathetosis
- Ataxia*
- Dysarthria
- Hyperactivity
- Confusion*
- Withdrawal - Endocrine:
- Reversible hypothyroidism* - Renal:
- Nephrogenic diabetes insipidus (polyuria, polydipsia)*
- Chronic interstitial nephritis
- Nephrotic syndrome - Cardiovascular:
- Oedema
- Worsening of sick sinus syndrome
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Describe the pharmacokinetics of lithium
- Absorption:
- Oral absorption* peaks at 0.5-2hrs, complete at 6-8hrs - Distribution:
- Distributes in TBW*
- Therapeutic concentration 0.6-1.4mmol/L - Metabolism:
- Half-life 20hrs* - Excretion:
- Unchanged in urine*
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How can you assess lithium toxicity and how is it treated?
- Measure levels 10-12hrs post last dose*
- > 2mmol/L should be considered toxic
- Treatment is supportive and haemodialysis
What is the mechanism of action of tricyclic antidepressants?
- Inhibition of serotonin and noradrenaline reuptake*:
- Increases amount of serotonin and noradrenaline in certain parts of the brain (cortex and limbus; “monoamine hypothesis” for depression”) and spinal cord (ascending corticospinal tract - useful in neuropathic pain) - Also blocks:
- Na+ channels
- K+ channels
- Muscarinic (M1) receptors (anticholinergic)
- Histaminic (H1) receptors
- Alpha-1 adrenergic receptors (peripheral post-synaptic)
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What clinical manifestations would be seen in an overdose of tricyclic antidepressants?
- Cardiovascular*:
- Tachycardia
- Hypotension (due to alpha blockade, impaired contractility)
- ECG changes: PR prolongation, QRS widening (Na+ blockade), prolonged QT (K+ blockade), VT, VF - CNS*:
- Drowsiness
- Delirium (anticholinergic)
- Seizures
- Coma - Anticholinergic*:
- Agitation, delirium
- Mydriasis
- Dry, warm, flushed skin
- Urinary retention
- Ileus
- 1 example from each
What factors determine the volume of distribution of a drug?
- Drug factors*:
- Lipid solubility
- pKa
- pH
- Protein binding - Patient factors*:
- Age
- Gender
- Comorbid disease (e.g. oedema, ascites)
- Body fat
- Blood flow to tissues
- 2 from each group
What therapies for tricyclic toxicity might reduce their tissue distribution?
Alkalinisation (e.g. with bicarbonate or hyperventilation) increases plasma protein binding of free drug, removing it from the tissues and reducing its toxicity
Describe the volume of distribution of tricyclic antidepressants. What factors contribute to this, and how does their volume of distribution influence their toxicity?
TCAs have a large Vd* (5-30L/kg), with high lipid solubility and high tissue protein binding
Tissue concentrations are high* in toxicity especially in well-perfused organs such as the brain and heart*
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By what routes can olanzapine be administered?
- PO*, sublingual
- Parenteral* (IV, IM, depot IM)
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What dose and what route of olanzapine would you use for sedation in an agitated patient?
Dose 10-20mg regardless of route
What are the advantages of olanzapine over older “typical” antipsychotics?
- Less extrapyramidal effects*
- Less hypotension
- Less tachycardia
- Less effect on prolactin
- More effective for both negative and positive psychotic symptoms, and cognition
- Multiple routes of administration
- High clinical potency
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What are the some of the clinical disadvantages of olanzapine?
2 to pass:
- Anticholinergic effects
- Lowered seizure threshold
- Weight gain
- Diabetes mellitus
- Hyperlipidaemia
- Expense
What are the pharmacodynamics of haloperidol?
Butyrophenone:
- High potency D2 receptor effects (dopamine antagonist)*
- High extra-pyramidal side effects*
- Low sedative effects*
- Minimal anticholinergic effects
- Minimal 5HT and H1 blockade effects
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How do the pharmacodynamics of olanzapine differ from haloperidol?
Thienobenzodiazepine:
- Less D2 receptor effects
- High 5HT receptor blockade effects*
- Low extra-pyramidal side effects*
- Medium sedative effects*
- Low hypotensive and anticholinergic effects
- Low H1 blockade effects
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Describe the pharmacokinetics of adrenaline
3 to pass:
1. Absorption:
- Poorly absorbed orally
- Routes of administration: subcut, IM, IV, nebulised
2. Distribution:
- 50% protein bound
- Does not cross BBB but crosses placenta
- Onset in seconds, duration of action 2mins
3. Metabolism:
- Terminated in synaptic nerve terminals, metabolised by catechol-O-methyltransferase and MAO with metabolites of VMA/MOPEG
4. Excretion:
- Metabolites in urine
What are the pharmacodynamic effects of adrenaline?
- Agonist effects for both alpha and beta receptor to the same degree
- Low dose mainly beta, higher dose more alpha
- Alpha*: vasoconstriction
- B1*: positive inotropy and chronotropy
- B2*: smooth muscle relaxation -> bronchodilatation, skeletal muscle vasodilatation (this may cause fall in TPR reflected in fall in diastolic BP sometimes seen)
*1 alpha and 1 beta effect to pass
Describe the effects of adrenaline on other organs besides the heart
3 effects (from different systems) to pass:
1. Respiratory:
- Bronchodilation
2. Neurological:
- Pupillary dilatation
- Decreased IOP
3. GIT:
- Relaxation of gastric smooth muscle
- Increased glycogenolysis in the liver
4. Genitourinary:
- Uterine smooth muscle relaxation
- Bladder relaxation
- Bladder sphincter contraction
5. Salivary glands:
- Dry mouth
6. Metabolic:
- Metabolic acidosis
- Lipolysis (increased FA and glycerol in circulation)
What is the mechanism of action of atropine?
- Competitive reversible muscarinic ACh receptor antagonist*
- Binds to muscarinic receptors, preventing the release of IP3 (inositol triphosphate), DAG (diacylglycerol) and inhibition of adenylyl cyclase caused by muscarinic agonists
- Anticholinergic agent, equipotent at M1/M2/M3 receptors
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Describe the organ effects of atropine
3 organ systems with an example of each to pass:
1. CNS:
- Delirium
- Decreased tremor in Parkinson’s disease
- Mydriasis
- Cycloplegia
2. Cardiovascular:
- Tachycardia
3. Respiratory:
- Bronchodilation
- Decreased secretions
4. GIT:
- Decreased saliva secretion
- Decreased gastric acid secretion
- Decreased mucin production
- Decreased gastric emptying and gut motility (increased intestinal transit time)
5. Genitourinary:
- Relaxes ureteric and bladder wall smooth muscle
- Urinary retention
6. Skin:
- Decreased sweating
What is atropine used for clinically?
- Symptomatic bradyarrhythmias/bradycardia*
- Ophthalmology (used as mydriatic and cycloplegic)
- Occasionally in paediatric RSI using suxamethonium, especially 2nd dose
- Drying of secretions (e.g. in cholinergic nerve agent / organophosphate poisoning, or in palliative care)
- Traveler’s diarrhoea
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Describe the pharmacokinetics of atropine
- Absorption:
- Route of administration: IV, PO, nebulised, topical
- Well absorbed orally - Distribution:
- Wide Vd (including CNS) - Metabolism:
- 40% undergoes phase I and phase II hepatic metabolism
- Half-life 2hrs - Excretion:
- Renal (60% unchanged)
How does metoclopramide cause a dystonic reaction?
Metoclopramide is a dopamine antagonist* and causes an imbalance in the anticholinergic/dopamine transmission in the basal ganglia
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What is the mechanism of action of benztropine in the treatment of dystonia?
Blocks muscarinic cholinergic receptors
What are the potential side effects of benztropine?
3 to pass:
- Tachycardia
- Sedation
- Mydriasis
- Urinary retention
- Dry mouth
What is the mechanism of action of metaraminol?
Direct a1 receptor agonist
Some indirect effect through increased noradrenaline
What are the effects of metaraminol on the cardiovascular system?
- Vasoconstriction (increased BP)
- HR slows due to vagal feedback
- CO unchanged or slightly decreased
- Direct cardiac effects less important
What role do sympathomimetics have in management of shock?
- Temporising only* while other treatment instituted (fluids, etc)
- Efficacy not proven
- Useful in “failure” of sympathetic nervous system (e.g. in spinal injury or anaesthesia)
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What receptors does noradrenaline act on?
- Predominantly a1 receptor* to induce vascular smooth muscle constriction
- Also active at a2 receptor (presynaptic), inhibiting noradrenaline release via negative feedback
- Some effect on B1 and B2 receptors (more potent effect on B1)
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How does noradrenaline increase blood pressure?
- Increased a1 activity -> vasoconstriction -> increased TPR* -> increased DBP
- Increased B1 activity -> increased myocardial contractility* -> increased SBP
- Overall rise in both SBP and DBP
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How does noradrenaline affect the heart rate?
- B1 activity increases HR
- However compensatory baroreflex causes reflex bradycardia -> therefore minimal change in HR*
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Describe the pharmacokinetics of ethanol
- Absorption:
- Rapid from GIT, with peak levels in 30mins - Distribution:
- Rapid
- Volume of distribution approximates TBW (0.5-0.7L/kg) - Metabolism:
- Predominantly hepatic*
- Mainly by alcohol dehydrogenase* and less by microsomal ethanol oxidising system (MEOS)
- Zero-order kinetics* - Excretion:
- Lungs, urine (small amounts)
What does zero-order kinetics mean?
Elimination occurs at a constant rate independent of drug concentration
What drugs other than ethanol have zero order kinetic metabolism?
1 to pass:
- Phenytoin
- Theophylline
- Warfarin
- Salicylate
- Heparin
- Paracetamol
What are the pharmacodynamic effects of ethanol?
- CNS*:
- Sedation
- Disinhibition
- Impaired judgement
- Impaired motor skills
- Ataxia
- Slurred speech
- Respiratory depression
- Coma - Cardiovascular:
- Depressed contractility - Smooth muscle:
- Vasodilator -> hypothermia
- Uterine smooth muscle relaxation
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Describe the pharmacodynamics of ketamine
- Complex, but major effect is probably produced through the inhibition of the NMDA receptor complex* (with blockade of excitatory neurotransmitter glutamate)
- Inhibits reuptake of catecholamine and serotonin
- Potent short-acting sedative, amnestic, analgesic and anaesthetic
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What are the systemic effects of ketamine?
- CNS:
- Dissociative anaesthesia* (cataleptic state)
- Profound analgesia*
- Cerebral vasodilator and increases cerebral blood flow and cerebral metabolic rate (increases ICP, but not clinically significant)
- May have anticonvulsant properties
- Myoclonus - Cardiovascular:
- Haemodynamically stable*
- Increases HR, BP and CO
- Increases cardiac workload and myocardial oxygen consumption - Respiratory:
- Intact airway reflexes*
- Minimal respiratory depression
- Causes lacrimation and salivation that may cause laryngospasm in children
- Bronchodilator - Ocular:
- Nystagmus
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What are the adverse effects of ketamine?
1 to pass:
1. CNS:
- Emergence phenomena (dysphoria)
- Hallucinations
- Seizures
2. GIT:
- Vomiting
3. Respiratory:
- Laryngospasm
- Increased salivation
Besides the anaesthetic effect, what are the other indications for ketamine?
2 to pass:
- Analgesia
- Bronchodilator effect in asthma
- Acute behavioural disturbance
- Procedural sedation
In what conditions might you avoid using ketamine?
1 to pass (excluding allergy):
- Allergy
- Raised ICP
- Raised IOP
- Recent or current URTI
- Shock
Describe the pharmacokinetics of ketamine
- Absorption:
- Highly lipid soluble, hence rapid onset* - Distribution:
- Low protein binding (12%)
- Effect terminated by redistribution to inactive tissue sites* - Metabolism:
- Metabolised in liver* (N-demethylation by cytochrome P450) to norketamine, which has 1/3-1/5th the potency of ketamine
- Norketamine then hydroxylated and conjugated into water-soluble inactive metabolites - Excretion:
- Metabolites excreted in urine*
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Give an appropriate route and dose for ketamine for use in procedural sedation of a child
Either to pass:
- 1-2mg/kg IV
- 4-10mg/kg IMI
Please describe the pharmacokinetics of propofol
- Absorption:
- IV administration only - Distribution:
- Distribution half-life 2-4mins*
- Rapid onset and recovery due to redistribution* from brain to skeletal muscle and fat, rather than metabolism - Metabolism:
- Duration of action 3-8mins, elimination half-life 4-23mins
- Metabolised rapidly in the liver, some extra-hepatic metabolism (lung) when total body plasma clearance exceeds hepatic blood flow - Excretion:
- Urinary as glucuronides and sulphates, <1% unchanged
*needed to pass with reasonable understanding of drug distribution
What are the adverse effects of propofol?
- Cardiovascular:
- Hypotension* (due to vaso- and veno-dilation)
- Negative inotropy - Respiratory:
- Apnoea*
- Dose-related central depression of respiratory drive - Pain on injection
- Hypersensitivity:
- Allergy (due to soy/egg constituents)
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How can you limit adverse effects when using propofol?
2 to pass:
- Caution with simultaneous co-administration of opiates/benzodiazepines
- Titrate small doses (10-20mg aliquots) slowly to effect
- Reduce doses in the elderly or with poor cardiovascular reserve
- Caution with haemodynamically unstable patients
- Give IV fluid bolus alongside
What dose of propofol is used for induction of general anaesthesia? How does this differ from a procedural sedation dose?
Induction dose: 1-2.5mg/kg* (adults), 2.5-3.5mg/kg (children)
Procedural sedation: 0.5-1.0mg/kg single bolus dose or titrate in 10-20mg aliquots particularly in conjunction with morphine
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What clinical effects should be anticipated when using propofol?
- CNS:
- Anaesthesia
- Sedation
- NO analgesia - Cardiovascular:
- Hypotension* (due to vaso- and veno-dilation)
- Negative inotropy - Respiratory:
- Apnoea*
- Dose-related central depression of respiratory drive - GIT:
- Antiemetic properties - Pain on injection
- Hypersensitivity:
- Allergy (due to soy/egg constituents) - Metabolic:
- Metabolic acidosis when given as an infusion - Propofol-related Infusion Syndrome
- Acute refractory bradycardia progressing to asystole
- Metabolic acidosis
- Rhabdomyolysis
- Hyperlipidaemia
- Fatty or enlarged liver
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What type of drug is rocuronium?
- Non-depolarising* muscle relaxant
- Steroid derivative
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What are the pharmacokinetics of rocuronium?
- Absorption:
- Given IV
- Onset 45-60secs
- Dose 1.2mg/kg - Distribution:
- Duration of action 20-75mins - Metabolism:
- Hepatic - Excretion:
- 75-90% enterohepatic, the rest renal
How does suxamethonium differ from rocuronium?
- Duration of action is much shorter* (suxamethonium 5-10mins)
- Different side effects and contraindications
- Suxamethonium is metabolised by plasma pseudocholinesterase
- Suxamethonium is a depolarising muscle relaxant with two phases of action: phase I is augmented by cholinesterase inhibitors
- Rocuronium has an antidote (sugammadex)
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What is the mechanism of action of suxamethonium?
Depolarising neuromuscular blocker*
Phase I (depolarising):
- Binds to nicotinic receptor and opens channel, causing depolarisation of motor end plate
- Spreads to adjacent membranes causing contractions of muscle motor units (fasciculations)
- Depolarised membrane remains depolarised (and unresponsive to subsequent impulses) causing flaccid paralysis*
Phase II (desensitising):
- With continued or repeated exposure to suxamethonium, the initial endplate depolarisation decreases and membrane becomes repolarised
- Membrane cannot be depolarised
again as it is desensitised (mechanism unclear, however ? due to channel block becoming more important than agonist action at receptor)
*needed to pass + understanding of concept
What are the pharmacokinetic properties of suxamethonium?
- Absorption:
- Rapid onset (30-60secs)* - Metabolism:
- Short duration of action (2-8mins)
- Hydrolysed rapidly by plasma pseudocholinesterase
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What are the adverse effects of suxamethonium?
- Musculoskeletal:
- Muscle pain from fasciculation
- Malignant hyperthermia
- Prolonged paralysis (due to reduced or absent pseudocholinesterase) - Cardiovascular:
- Bradycardia* (especially with repeated doses)
- Other cardiac arrhythmias (e.g. if given with halothane) - Metabolic:
- Hyperkalaemia* (risk increased with burns, closed head injury, trauma, stroke) - CNS:
- Raised IOP - GIT:
- Raised intragastric pressure
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What is suxamethonium?
- Depolarising neuromuscular blocker* producing rapid neuromuscular blockade at motor endplate nicotinic receptors
- Structurally two acetylcholine molecules linked end to end
What is the mechanism of action of vecuronium?
- Non-depolarising neuromuscular blockade*
- Competitive antagonist for acetylcholine at nicotinic receptors of neuromuscular junction*
- Large doses will enter ion channel’s pore directly to produce more intense blockade
- Also blocks pre-junctional Na+ channels to interfere with acetylcholine mobilisation at nerve endings
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Describe the pharmacokinetics of vecuronium
- Absorption:
- Highly polar
- Poorly absorbed from GIT
- Given IV
- Onset within 1min, maximum effect at 3-5mins - Distribution:
- Rapidly distributed to extracellular space
- Small volume of distribution (approximates blood volume)
- Plasma protein 60-90% - Metabolism:
- Duration of action 20-35mins
- Short half-life - Excretion:
- 75-90% by liver, rest by kidney
Describe the mechanism of action of bupivacaine
Amide local anaesthetic:
- Blocks voltage-gated Na+ channels* in nerve
- Threshold for excitation increases, conduction slows, action potential rise declines, and action potential generation is abolished
- If Na+ current is blocked over the length of the nerve, propagation is ceased
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Describe the pharmacokinetics of bupivacaine
- Distribution:
- Distribution half-life 28mins
- Large Vd (72L)
- 95% protein bound
- Lipophilic - Metabolism:
- Metabolised by the liver*
- Duration of action 4-8hrs* (longer than lignocaine or ropivacaine)
- Elimination half-life 3.5hrs
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Give examples of clinical uses of bupivacaine
Nerve block (in low concentration 0.25%) for local infiltration*:
- Digital ring block
- Femoral
- Intercostal
- Intrapleural
- Epidural (post-op)
- Brachial plexus
- Sciatic nerve
- Intra-articular
*2 to pass
List some toxic effects of bupivacaine
- Cardiovascular:
- Cardiac arrhythmia*
- Hypotension
- Cardiac arrest - CNS:
- Sedation
- Visual and auditory disturbance
- Seizure*
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How long will a bupivacaine block last?
3-6hrs
What are the potential adverse effects of bupivacaine?
- Neurological*:
- Sedation
- Light-headedness
- Visual and auditory disturbance
- Tongue and mouth numbness
- Metallic taste
- Nystagmus
- Restlessness
- Muscle twitches
- Seizure - Respiratory:
- Respiratory depression - Cardiovascular*:
- Arrhythmias
- Cardiovascular collapse
- Cardiac arrest - Local toxicity:
- Trauma
- Neurotoxicity - Allergy
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How can the risk of the adverse effects of bupivacaine be minimised in the ED?
- Ask about Hx of allergy
- Use safe maximum dose (<2mg/kg)
- Withdraw pre-injection
- Avoid vessels (anatomical consideration, e.g. above rib below in intrapleural block)
- Use US guidance
- Ask patient to flag symptoms (e.g. metallic taste, tongue numbness)
- Avoid hypoxia/acidosis
What is the maximum safe dose of lignocaine for local anaesthesia?
Plain: 3mg/kg* (to maximum 300mg)
With adrenaline: 5mg/kg* (to maximum 500mg)
*needed to pass
What factors affect absorption of lignocaine after local infiltration?
3 to pass:
- Dose
- Site of injection
- Drug-tissue binding
- Tissue blood flow
- Vasoconstrictors (combined preparation)
What are the toxic effects of lignocaine?
- CNS*:
- Early/mild: circumoral/tongue numbness, metallic taste, paraesthesia, sedation
- Moderate: nystagmus, muscle twitching, nausea and vomiting, tinnitus, visual disturbance
- Severe: seizures, sedation - Cardiovascular*:
- Cardiovascular collapse
- Hypotension
- Bradycardia
- Rarely other arrhythmias
- Worsen CCF or conduction blocks - GIT:
- Anorexia
- Nausea and vomiting (through CNS effects) - Haematological:
- Methaemoglobinaemia - Allergy:
- Rare with amides
*2 of each to pass
Describe the mechanism of action of lignocaine
- Na+ channel blocker, class 1b (fast dissociation)
- Blocks activated and inactivated Na+ channels to block nerve conduction
- Less effect in infected tissue
Describe the pharmacokinetics of sodium valproate
4 to pass:
- Can be administered IV or orally
- Well-absorbed orally with bioavailability of >80%
- Peak blood levels within 2hrs
- Highly protein bound and low volume of distribution 0.15L/kg
- Extensively metabolised in liver and excreted as glucuronide conjugate in urine (30-50% of dose)
- Long half-life 9-18hrs
