4. Pharmaco Flashcards
Seizure
a paroxysmal (unexpected) event due to abnormal, hypersynchronous discharge from a mass of CNS neurons
manifestation of seizure
Diverse manifestation: convulsion (observable) to an experience (subjective)
is a single seizure due to correctable or avoidable circumstance (ie provoked) considered an epilepsy?
not an epilepsy (eg due to alcohol, hypoglycaemia, pyrexia, sleep deprivation)
epilepsy pathophysiology
a seizure occurs when there is excessive synchronous depolarisation due to unbalanced excitatory and inhibitory receptor/ ion channel function which favours depolarisation → dysregulated/ unregulated discharge
types of seziure
- generalised (both hemisphere affected, consciousness affected) -> tonic clonic, absence
- partial seizures (half hemisphere affected) -> simple (consciousness not impaired), complex (consciousness impaired)
- status epilepticus
rationale for anti-epileptics
- decrease membrane excitability by altering Na+ and Ca2+ conductance during action potential
- enhanced effects of inhibitory GABA NT (GABA when bind to receptor opens Cl- channels allowing Cl- ions to enter)
- drugs should be individualised and started on monotherapy initially
phenytoin MOA
block voltage-dependent Na+ channels → decreases Na+ entry → decrease AP discharge → decrease excitation of neuron
phenytoin indication
for all types of seizures except absence seizures
characteristics of phenytoin
- relative narrow therapeutic range
- teratogenic
- non-linear saturation kinetics profile (need TDM)
MOA of carbamazepine
blockade of voltage-dependent Na+ channels (similar to phenytoin)
Indiction of carbamazepine
for all types of seizures except absence seizures
characteristics of carbamazepine
Autoinduction: hepatic CYP450 enzyme inducer, T1/2 shortens with repeated/increasing doses → accelerate metabolism of carbamazepine and other drugs
carbamazepine pgx
HLA-B*1502 positive - increased risk of SJS/ TEN (require PGx testing before drug initiation)
MOA of valproate
- blockade of voltage-dependent Na+ and Ca2+ channels
- inhibit GABA transaminase (enzyme that breakdown GABA) → increase GABA (inhibitory NT)
indication for valproate
for all types of seizures including absence seizures
characteristics of valproate
strongly bound to plasma proteins, displaces other antiepileptics/ drugs (ie DDI)
Adverse effects of antiepileptics (dose related)
drowsiness, confusion, nystagmus (shifty eyes), ataxia (unable to keep balance), slurred speech, nausea, unusual behaviour, mental changes, coma
Adverse effects of antiepileptics (non dose related)
hirsutism, acne, gingival hyperplasia (swollen gums), folate deficiency, osteomalacia (softening of bone), hypersensitivity (eg SJS)
MOA of benzodiazepines
bind to regulatory site of of GABA receptors (different binding site from GABA) → increase GABA mediated Cl- ions influx → hyperpolarisation → neurons not firing
- potentiates inhibitory effect of GABA (only works when GABA is present)
acute toxicity/overdose of benzodiazepines
acute toxicity/ overdose - cause severe respiratory depression, especially when used concurrently with alcohol
tx of benzodiazepine overdose
flumazenil (benzodiazepine competitive antagonist)
SE of benzodiazepine
drowsiness, confusion, amnesia (memory loss), impaired muscle coordination, tolerance and dependence
MOA of phenobarbital
potentiates GABA mediated Cl- ions entry (inhibitory effects) but different site from benzodiazepines (flumazenil not effective for overdose of barbiturate)
SE of phenobarbital
Severe withdrawal symptoms (more severe than benzodiazepines), greater risk of causing CNS effects especially at higher doses as compared to benzodiazepines
Levetiracetam indication
- adjunctive tx
- can be used as monotherapy for partial onset seizures
- not effective for absence seizures
PK characteristics of levetiracetam
- highly soluble and permeable
- PK profile is linear with low and intra and inter subject variability (different from phenytoin)
route of administration for levetiracetam
IV infusionor PO
SE of levetiracetam
- common: headache, vertigo, cough, depression, insomnia
- rare: agranulocytosis, suicide, delirium, dyskinesia (involuntary movement)
MOA of lamotrigine
- blocks voltage-gated sodium channels
- inhibit release of glutamate
indication of lamotrigine
- adjunctive/ monotherapy tx
- can be used as monotherapy for absence seizures (alternative to valproate)
PK of lamotrigine
- linear PK, oral route (chewable)
- shorter half-life in children
- half-life reduced with co-administration with carbamazepine and phenytoin and increased with valproate
SE of lamotrigine
- common: headache, irritability/ aggression, tiredness
- rare: agranulocytosis, hallucination, movement disorders, SJS/TEN, hepatic failure
indication of topiramate
- monotherapy for partial seizures and generalised seizures (tonic clonic)
- Prophylaxis of migraine headaches in adults (not for acute tx)
PK characteristics of topiramate
- linear PK, oral route, long plasma half life
- renal clearance
- not a potent inducer of drug-metabolising enzymes
SE of topiramate
- common: depression, somnolence, fatigue, nausea, weight change
- rare: neutropenia, mania, tremor, transient blindness, SJS/TEN, hepatic failure
when are TDM needed?
- Assess compliance
- Assess symptoms due to ASM toxicity
- Titration of phenytoin dose (phenytoin needs TDM)
headache/migraine pathophysiology
vasodilation of intracranial extracerebral blood vessels → activation of perivascular trigeminal nerves → release vasoactive neuropeptides → neurogenic inflammation
sx of headache/migraine
nausea, vomiting, photophobia, phonophobia (scared of loud noises)
role of serotonin in migraine
serotonin is an important mediator of migraine
- Serotonin agonist for vascular and neuronal 5HT1 receptor cause vasoconstriction of meningeal blood vessels and inhibit vasoactive neuropeptide release and pain signal transmission.
MOA of cafergot
tonic action on vascular smooth muscles in the intracranial extracerebral blood vessels → vasoconstriction by stimulating alpha-adrenergic and 5HT (1B & 1D) receptors
indication of cafergot
for ACUTE tx of migraine
PK of cafergot
- oral/rectal, rapidly absorbed (max plasma conc in 1.5-2hr)
- high plasma protein binding, low F
- inhibit CYP3A4 (avoid use with other 3A inhibitors like macrolides → can elevate ergot toxicity causing vasospasm and tissue ischemia)
SE of cafergot
- common: nausea and vomiting
- rare: hypersensitivity, MI, ergotism (vascular ischemia)
DDI
Should not be used with other vasoconstrictor agents (eg ergot derivatives, sumatriptan, 5HT1 agonists)
MOA of sumatriptan
- selective 5HT 1B/1D receptor agonist → selectively constricts carotid arterial circulation (does not affect cerebral blood flow)
- inhibit trigeminal nerve activity (eg vasoactive peptides and inflammatory mediators)
Indication of sumatriptan
acute tx of migraine with or without aura
PK of sumatriptan
- oral, nasal, IV
- rapidly absorbed, low plasma binding, eliminated primarily by MAO (type A)
CI of sumatriptan
hypersensitivity to triptans, concomitant use with MAOi, MI
SE of sumatriptan
- common: dysgeusia (unpleasant taste), transient BP rise, flushing, cold, pressure, tightness, serotonin syndrome
- rare: minor disturbances in liver function tests
MOA of erenumab
is a monoclonal antibody that inhibits CGRP receptors
- CGRP are nociceptive neuropeptide at the trigeminal ganglion, a vasodilator
- CGRP increase with migraine
indication of erenumab
prophylaxis of migraine in adults who have at least 4 migraine days per mth
PK characteristics of erenumab
- SC q monthly, benefit seen within 3mths
- linear kinetics at therapeutic doses (CGRP receptor binding is saturated)
SE of erenumab
hypersensitivity reactions, injection site reactions, constipation, prutitis
