25 Antiepileptic drugs Flashcards
25.01 SODIUM CHANNEL INHIBITORS
Carbamazepine, oxcarbazepine, phenytoin - actions
anticonvulsant
relieves neuropathic pain
25.01 SODIUM CHANNEL INHIBITORS
Carbamazepine, oxcarbazepine, phenytoin - MOA
blocks Na+ channels to inhibit action potential initiation and propagation
use-dependence of block means that action is preferentially on rapidly firing neurons in the epileptic focus
25.01 SODIUM CHANNEL INHIBITORS
Carbamazepine, oxcarbazepine, phenytoin - abs/distrib/elim
these drugs are metabolised by P450 and are potent enzyme inducers, thus associated with many serious drug interactions
phenytoin half-life 20h, but increases with dose due to saturation kinetics
monitoring of plasma concentrations required due to narrow therapeutic range
25.01 SODIUM CHANNEL INHIBITORS
Carbamazepine, oxcarbazepine, phenytoin - clinical use
partial and generalised (tonic-clonic) seizures
also neuropathic pain and bipolar disorder
phenytoin use is decreasing due to poor pharmacokinetic and toxicity profile, although still used in status epilepticus
25.01 SODIUM CHANNEL INHIBITORS
Carbamazepine, oxcarbazepine, phenytoin - adverse effects
drowsiness, dizziness, ataxia, mental disorientation
rare, but serious skin reactions with carbamazepine
phenytoin may cause thickening of the gums and hirsutism
25.02 T-TYPE CALCIUM CHANNEL BLOCKERS
Ethosuximide - actions
anticonvulsant with specific action on absence seizures
25.02 T-TYPE CALCIUM CHANNEL BLOCKERS
Ethosuximide - MOA
blocks T-type Ca2+ channels in thalamic neurons to counteract the slow (3 Hz), spike-and-wave firing pattern thought to be important in absence epilepsy
25.02 T-TYPE CALCIUM CHANNEL BLOCKERS
Ethosuximide - abs/distrib/elim
given orally
oxidised by cytochrome P450 system
half-life 60h
25.02 T-TYPE CALCIUM CHANNEL BLOCKERS
Ethosuximide - clinical use
drug of choice for absence seizures (not effective against partial or tonic-clonic seizures)
25.02 T-TYPE CALCIUM CHANNEL BLOCKERS
Ethosuximide - adverse effects
anorexia, GIT upset, pancytopaenia
rash, drowsiness, fatigue
overdose can cause coma and respiratory depression
25.03 BROAD-SPECTRUM ANTIEPILEPTIC
Valproate - actions
anticonvulsant
mood stabiliser
25.03 BROAD-SPECTRUM ANTIEPILEPTIC
Valproate - MOA
several actions may contribute to the antiepileptic action
blocks voltage-gated Na+ channels to inhibit action potential initiation and propagation
inhibits GABA transaminase to reduce GABA breakdown
may also affect T-type calcium channels
25.03 BROAD-SPECTRUM ANTIEPILEPTIC
Valproate - abs/distrib/elim
given orally
subject to glucuronidation and mitochondrial oxidation
half-life 9-16h
25.03 BROAD-SPECTRUM ANTIEPILEPTIC
Valproate - clinical use
broad coverage of most forms of epilepsy, but appears particularly useful in generalised seizures and absence seizures
manic phase of bipolar disorder
migraine
contraindicated in women of reproductive age due to risk of teratogenicity
25.03 BROAD-SPECTRUM ANTIEPILEPTIC
Valproate - adverse effects
nausea and vomiting
tremor
weight gain
reproductive dysfunction
hepatotoxicity
teratogenic effects (e.g. neural tube defects, including spina bifida)
25.04 BENZODIAZEPINES
Lorazepam, midazolam, diazepam, clonazepam, clobazam - actions
anticonvulsant
also hypnotic and anxiolytic
25.04 BENZODIAZEPINES
Lorazepam, midazolam, diazepam, clonazepam, clobazam - MOA
bind to benzodiazepine binding site on GABAA receptor to enhance channel opening by GABA
increased Cl− permeability reduces electrical excitability
clonazepam and clobazam are said to be more selective anticonvulsants with less sedation
25.04 BENZODIAZEPINES
Lorazepam, midazolam, diazepam, clonazepam, clobazam - abs/distrib/elim
given orally for chronic use (IV for status epilepticus)
if no IV access, IM/buccal midazolam or rectal diazepam
metabolised by P450 system and glucuronide conjugation
25.04 BENZODIAZEPINES
Lorazepam, midazolam, diazepam, clonazepam, clobazam - clinical use
lorazepam, diazepam or clonazepam can be given IV for status epilepticus
oral clonazepam is used for tonic-clonic and absence seizures
clobazam is used as an add-on anticonvulsant to existing therapy
25.04 BENZODIAZEPINES
Lorazepam, midazolam, diazepam, clonazepam, clobazam - adverse effects
unwanted effect in treating epilepsy is sedation
severe respiratory depression when used IV or in combination with other CNS depressants (e.g. ethanol)
25.05 BARBITURATES
Phenobarbital - actions
anticonvulsant
hypnotic (at higher doses)
25.05 BARBITURATES
Phenobarbital - MOA
binds to barbiturate binding site on GABAA receptor to enhance Cl− channel opening by GABA
this reduces neuronal excitability and action potential frequency at the epileptic focus
effects on Na+ and Ca2+ channels may contribute to the anticonvulsant activity
25.05 BARBITURATES
Phenobarbital - abs/distrib/elim
given orally
some drug is excreted unchanged, but the majority is oxidised in the liver
half-life 50-100h
25.05 BARBITURATES
Phenobarbital - clinical use
tonic-clonic and simple partial seizures, but less frequently used in clinical practice nowadays due to toxicity and unfavourable pharmacokinetics related to liver enzyme induction
25.05 BARBITURATES
Phenobarbital - adverse effects
highly sedative
megaloblastic anaemia, hypersensitivity reactions
in overdose - coma, respiratory and circulatory failure
induces dependence
25.06 BROAD-SPECTRUM ANTIEPILEPTIC
Gabapentin (similar: pregabalin) - actions
anticonvulsant, analgesic, anxiolytic
25.06 BROAD-SPECTRUM ANTIEPILEPTIC
Gabapentin (similar: pregabalin) - MOA
action is attributed to binding to the α2-δ-1 and α2-δ-2 subunits of voltage-activated Ca2+ channels (P/Q or N-type) to block Ca2+ entry and exocytosis of transmitter (glutamate) from nerve endings
(enhanced release of GABA has also been suggested)
25.06 BROAD-SPECTRUM ANTIEPILEPTIC
Gabapentin (similar: pregabalin) - abs/distrib/elim
given orally
excreted unchanged
half-life 6h (longer with renal impairment)
25.06 BROAD-SPECTRUM ANTIEPILEPTIC
Gabapentin (similar: pregabalin) - clinical use
adjunctive treatment for partial seizures
widely used to treat neuropathic pain
anxiolytic used in generalised anxiety disorders
25.06 BROAD-SPECTRUM ANTIEPILEPTIC
Gabapentin (similar: pregabalin) - adverse effects
sedation, dizziness and unsteadiness
both gabapentin and pregabalin have become drugs of abuse because they potentiate the effects of opioids
25.07 BROAD-SPECTRUM ANTIEPILEPTIC
Lamotrigine - actions
anticonvulsant
reduces frequency of mood episodes in bipolar disorder
25.07 BROAD-SPECTRUM ANTIEPILEPTIC
Lamotrigine - MOA
inhibition of glutamate release decreases postsynaptic neuronal excitation
this may be due to Na+ (and perhaps Ca2+) channel inhibition in the nerve ending
25.07 BROAD-SPECTRUM ANTIEPILEPTIC
Lamotrigine - abs/distrib/elim
given orally
subject to hepatic glucuronidation
half-life 24-36h
25.07 BROAD-SPECTRUM ANTIEPILEPTIC
Lamotrigine - clinical use
broad-spectrum anticonvulsant, covering partial and generalised seizures, including absence
bipolar disorder
25.07 BROAD-SPECTRUM ANTIEPILEPTIC
Lamotrigine - adverse effects
dizziness, headache, double vision, sedation
serious skin rashes may occur in a small percentage of patients, particularly children
25.08 AMPA RECEPTOR BLOCKERS
Topiramate (similar: perampanel) - actions
anticonvulsant
25.08 AMPA RECEPTOR BLOCKERS
Topiramate (similar: perampanel) - MOA
topiramate most likely blocks AMPA/kainate receptors for glutamate, but also blocks voltage-dependent Na+ channels and potentiates GABA action on GABAA receptors
perampanel is a non-competitive blocker of the AMPA receptor on postsynaptic neurons
25.08 AMPA RECEPTOR BLOCKERS
Topiramate (similar: perampanel) - abs/distrib/elim
given orally
25.08 AMPA RECEPTOR BLOCKERS
Topiramate (similar: perampanel) - clinical use
generalised tonic-clonic and partial seizures (usually as adjuncts)
also used for migraine prophylaxis
25.08 AMPA RECEPTOR BLOCKERS
Topiramate (similar: perampanel) - adverse effects
psychomotor slowing, motor incoordination, memory impairment, paraesthesia, sedation, fatigue, confusion
visual disturbances
25.09 BROAD-SPECTRUM ANTIEPILEPTIC
Levetiracetam (similar: brivaracetam) - actions
anticonvulsant
25.09 BROAD-SPECTRUM ANTIEPILEPTIC
Levetiracetam (similar: brivaracetam) - MOA
activity is thought to be due to binding to synaptic vesicle protein SV2A - how this modifies the release of neurotransmitter (e.g. glutamate) is not established
25.09 BROAD-SPECTRUM ANTIEPILEPTIC
Levetiracetam (similar: brivaracetam) - abs/distrib/elim
given orally or IV
mostly excreted unchanged
half-life 7h
25.09 BROAD-SPECTRUM ANTIEPILEPTIC
Levetiracetam (similar: brivaracetam) - clinical use
broad-spectrum anticonvulsant
monotherapy for partial seizures in newly diagnosed epilepsy
as an adjunct to other anticonvulsants in the treatment of partial, generalised or myoclonic seizures
25.09 BROAD-SPECTRUM ANTIEPILEPTIC
Levetiracetam (similar: brivaracetam) - adverse effects
dizziness, headache, fatigue, sedation
few drug interactions
25.10 OTHER ANTIEPILEPTIC AND ANTI-SPASTICITY DRUGS
Vigabatrin
irreversible inhibition of GABA transaminase in GABAergic nerves increases the GABA concentration
restricted clinical use because vigabatrin causes visual field defects
25.10 OTHER ANTIEPILEPTIC AND ANTI-SPASTICITY DRUGS
Tiagabine
inhibits GABA reuptake (by GAT-1) into GABAergic nerve endings and glia, thus raising synaptic GABA concentration and inhibiting neuronal activity
adjunct use in partial seizures
25.10 OTHER ANTIEPILEPTIC AND ANTI-SPASTICITY DRUGS
Zonisamide, lacosamide
act on Na+ channels
mainly used in partial seizures
25.10 OTHER ANTIEPILEPTIC AND ANTI-SPASTICITY DRUGS
Baclofen
selective agonist at GABA receptor
acts mainly on spinal cord for muscle spasticity from multiple sclerosis or spine trauma
not used in epilepsy
