Anticonvulsants 2nd Medical Year 2006/07 JC3-NS8 Prof John Waddington

Issues of selectivity Neuronal selectivity : drugs may act at more than one site; e.g. inhibition of reuptake and receptor antagonism CNS selectivity : drugs act in the periphery as well as in the brain; e.g. action on brain function may give therapeutic effects, while these same actions peripherally may cause side effects

Neuronal selectivity : drugs may act at more than one site; e.g. inhibition of reuptake and receptor antagonism

CNS selectivity : drugs act in the periphery as well as in the brain; e.g. action on brain function may give therapeutic effects, while these same actions peripherally may cause side effects

Epilepsy 2nd most common neurological disorder after stroke; 0.5-1.0% of population Seizure : sudden abnormal discharge of impulses from a group of neurons Symptoms determined by site [ focus ] and spread [ localised/generalised ] of discharge as well as amplitude

2nd most common neurological disorder after stroke; 0.5-1.0% of population

Seizure : sudden abnormal discharge of impulses from a group of neurons

Symptoms determined by site [ focus ] and spread [ localised/generalised ] of discharge as well as amplitude

Classification of epilepsy 1. Partial (focal) seizures Discharge begins and remains localised, often in cortex; site determines symptoms (a) Simple seizures No loss of consciousness (b) Complex seizures Some loss of consciousness

1. Partial (focal) seizures

Discharge begins and remains localised, often in cortex; site determines symptoms

(a) Simple seizures

No loss of consciousness

(b) Complex seizures

Some loss of consciousness

(a) Absence (Petit mal): 3 Hz discharge Brief, sudden loss of consciousness (b)Tonic-clonic (Grand mal): Widespread, polyphasic Repetitive contraction/ relaxation Unconsciousness 2. Generalised seizures Discharge from focus with rapid spread to other areas of brain ( c) Myoclonus Brief, jerking movements (d) Status epilepticus Repeated seizures No recovery of consciousness Potentially life threatening

(a) Absence (Petit mal):

3 Hz discharge

Brief, sudden loss of consciousness

(b)Tonic-clonic (Grand mal):

Widespread, polyphasic

Repetitive contraction/ relaxation

Unconsciousness

( c) Myoclonus

Brief, jerking movements

(d) Status epilepticus

Repeated seizures

No recovery of consciousness

Potentially life threatening

Anticonvulsants Mechanisms of anticonvulsant activity General Action at focus to reduce discharge Reduction of propagation from focus Specific Prolong inactivation state of Na + channels Reduce Ca 2+ channel entry Enhance GABA A -mediated inhibition Reduce glutamate-NMDA-mediated excitation

General

Action at focus to reduce discharge

Reduction of propagation from focus

Specific

Prolong inactivation state of Na + channels

Reduce Ca 2+ channel entry

Enhance GABA A -mediated inhibition

Reduce glutamate-NMDA-mediated excitation

3. Enhance GABA A -mediated inhibition Increase in Cl - channel opening through GABA A -benzodiazepine receptor complex Inhibition of GABA-T [ T ransaminase] Inhibition of GABA uptake 4. Reduce glutamate-NMDA-mediated excitation Reduction in release of glutamate

Increase in Cl - channel opening through GABA A -benzodiazepine receptor complex

Inhibition of GABA-T [ T ransaminase]

Inhibition of GABA uptake

4. Reduce glutamate-NMDA-mediated excitation

Reduction in release of glutamate

Classical anticonvulsants Phenobarbitone Mechanism Na + and Ca 2+ channels Enhances GABA A  glutamate release Use Gen. tonic-clonic>partial Enzyme inducer S/Es Highly sedative Behavioural changes Enzyme inducer No longer front-line agent

Phenobarbitone

Mechanism

Na + and Ca 2+ channels

Enhances GABA A

 glutamate release

Use

Gen. tonic-clonic>partial

Enzyme inducer

S/Es

Highly sedative

Behavioural changes

Enzyme inducer

No longer front-line agent

Typical agents Phenytoin Mechanism Prolongs inactivation state of Na + channels, reducing likelihood of repetitive discharge Use Gen. tonic-clonic, partial [status epilepticus] S/Es Occular, ataxia [sedation], gingival hyperplasia, hirsuitism dysmorphogenic-cleft palate

Phenytoin

Mechanism

Prolongs inactivation state of Na + channels, reducing likelihood of repetitive discharge

Use

Gen. tonic-clonic, partial [status epilepticus]

S/Es

Occular, ataxia [sedation], gingival hyperplasia, hirsuitism

dysmorphogenic-cleft palate

Carbamazepine Mechanism Na + channels Use Partial-complex, gen. tonic-clonic Mood stabiliser S/Es Occular, ataxia, GIT Aplastic anaemia, agranulocytosis, Enzyme inducer Valproate Mechanism Na + channels [+Ca 2+ channels, enhances GABA A ] Use Gen. tonic-clonic, absence, myoclonus Mood stabiliser S/Es GIT, tremor, hepatotoxicity Enzyme inhibitor Dysmorphogenic-spina bifida

Carbamazepine

Mechanism

Na + channels

Use

Partial-complex, gen. tonic-clonic

Mood stabiliser

S/Es

Occular, ataxia, GIT

Aplastic anaemia, agranulocytosis,

Enzyme inducer

Valproate

Mechanism

Na + channels [+Ca 2+ channels, enhances GABA A ]

Use

Gen. tonic-clonic, absence, myoclonus

Mood stabiliser

S/Es

GIT, tremor, hepatotoxicity

Enzyme inhibitor

Dysmorphogenic-spina bifida

Ethosuximide Mechanism T-type Ca 2+ channels [distinct from L-type Ca 2+ channel blockers] Use Absence seizures S/Es GIT Benzodiazepines Mechanism Enhance GABA A Use Diazepam: status epilepticus Clonazepam: absence, myoclonus S/Es Sedation, tolerance

Ethosuximide

Mechanism

T-type Ca 2+ channels [distinct from L-type Ca 2+ channel blockers]

Use

Absence seizures

S/Es

GIT

Benzodiazepines

Mechanism

Enhance GABA A

Use

Diazepam: status epilepticus

Clonazepam: absence, myoclonus

S/Es

Sedation, tolerance

Drug interactions 1. Induction of hepatic microsomal enzymes E.g. by phenobarbitone, carbamazepine: increases clearance of itself, phenytoin [and other drugs] 2. Inhibition of hepatic microsomal enzymes E.g. by valproate: decreases clearance of phenytoin, phenobarbitone, to give toxicity 3. Interactions with other drugs E.g. enzyme inhibitors such as cimetidine decrease clearance of phenytoin to give toxicity

1. Induction of hepatic microsomal enzymes

E.g. by phenobarbitone, carbamazepine: increases clearance of itself, phenytoin [and other drugs]

2. Inhibition of hepatic microsomal enzymes

E.g. by valproate: decreases clearance of phenytoin, phenobarbitone, to give toxicity

3. Interactions with other drugs

E.g. enzyme inhibitors such as cimetidine decrease clearance of phenytoin to give toxicity

Pharmacokinetics Phenytoin Lower doses: normal, 1st order kinetics , i.e. constant fraction cleared/unit time Higher doses: elimination mechanisms saturated; change to zero order kinetics , i.e. constant amount cleared/unit time -  small increase in dose gives large increase in concentration, hence toxicity

Phenytoin

Lower doses: normal, 1st order kinetics , i.e. constant fraction cleared/unit time

Higher doses: elimination mechanisms saturated; change to zero order kinetics , i.e. constant amount cleared/unit time -

 small increase in dose gives large increase in concentration, hence toxicity

Newer agents Vigabatrin Mechanism Inhibition of GABA-T, elevating brain GABA Use Add-on therapy for refractory partial seizures Monotherapy? S/Es Sedation, occular, mental Minimal drug interactions Lamotrigine Mechanism Na + channels  glutamate release Use Add-on therapy for refractory partial seizures Monotherapy? S/Es Sedation, occular, GIT, rash Minimal drug interactions

Vigabatrin

Mechanism

Inhibition of GABA-T, elevating brain GABA

Use

Add-on therapy for refractory partial seizures

Monotherapy?

S/Es

Sedation, occular, mental

Minimal drug interactions

Lamotrigine

Mechanism

Na + channels

 glutamate release

Use

Add-on therapy for refractory partial seizures

Monotherapy?

S/Es

Sedation, occular, GIT, rash

Minimal drug interactions