Antiepileptic drugs

Central nervous system

Dr . Shadab Khan

The brain

The spinal cord

Anatomical classification Cerebral hemispheres Diencephalon

Thalamus Hypothalamus

Brain stem Midbrain Pons Medulla

Cerebellum

Spinal cord

Cerebrum

hypothalamus

thalamus

mid-brain

pons varolii

medulla oblongata

cerebellum

spinal cord

cerebral cortex

cerebrum

Acknowledgement: Picture of model from Mentone Educational Centre C15

The functional areas of the cerebrum sensory areas interpret impulses

from receptors. motor areas control muscular

movements. association areas are involved with

intellectual and emotional processes.

Functional areas of the cerebral cortex

Motor area for speech

Primary auditory area

Auditory association area

Primary sensory area

Primary motor area

Speech

Primary visual areaVisual

association area


functions of cerebrum

thinking reasoning learning memory intelligence sense of responsibility perception of the senses initiation and control of voluntary

muscle contraction

simplified…

Back of brain: perception Top of brain: movement Front of brain: thinking

Hypothalamus

hypothalamus

thalamus

mid-brain

pons varolii

medulla oblongata

cerebellum

spinal cord

cerebral cortex

cerebrum


The hypothalamus regulates: heart rate body temperature movement of food through the alimentary

canal food and water intake patterns of waking and sleeping contraction of the urinary bladder sexual cycles sensory information from internal organs associated with fear and anger the release of hormones from the pituitary

gland

BASAL GANGLIA

Include:• Caudate nucleus• Globus pallidus• Putamen• Amygdaloid

ClaustrumPartly

• Substancia nigra• Subthalamic nucleus

Brain Stem

Midbrain Pons Medulla

oblongata

The medulla oblongata regulates: heartbeat through its

cardiovascular centre

breathing rhythm through its respiratory centre

the diameter of blood vessels through its vasomotor centre

Cerebellum Two major hemispheres: three lobes each

• Anterior• Posterior• Floculonodular

Vermis: midline lobe connecting hemispheresSeparated from brain stem by 4th ventricle

Functions of cerebellum

Smooths, coordinates & fine tunes bodily movements

Helps maintain body posture Helps maintain equilibrium Also some role in cognition

Damage: ataxia, incoordination, wide-based gait, overshooting, proprioception problems

Spinal cord

http://www.apparelyzed.com/spinalcord.html

Spinal nerves

Divided based on vertebral locations 8 cervical 12 thoracic 5 lumbar 5 sacral 1 coccygeal Cauda equina (“horse’s tail”): collection

of nerve roots at inferior end of vertebral canal

The action of the spinal cordSensory neurons pick up signals from

theskin and transfer that information toconnector neurons in the spinal cord

and/orbrain.This information is relayed on to the

motorneurons in the spinal cord to illicit aresponse.

Major fiber tracts in white matter of spinal cord

Damage: to motor areas – paralysis

sensory motor

Ascending pathways:

sensory information by multi-neuron chains from body up to more rostral regions of CNS Dorsal column Spinothalamic tracts Spinocerebellar tracts

Descending pathways: motor instructions from brain to more caudal

regions of the CNS Pyramidal (corticospinal) most important to

know All others (“extrapyramidal”)

Blood-Brain Barrier

Tight junctions between endothelial cells of brain capillaries, instead of the usual permeability

Highly selective transport mechanisms Allows nutrients, O2, CO2 Not a barrier against uncharged and

lipid soluble molecules; allows alcohol, nicotine, and some drugs including anesthetics

Drugs Acting on the Central nervous System

ANTIEPILEPTIC DRUGS

Dr Shadab Khan

What is Epilepsy?

Epilepsy is a collective term for a group of disorders characterised by paroxysmal cerebral dysrthmia, menifesting as brief episodes (seizures) of loss or disturbance of conciousness with or without characteristic body movements(convulsions)sensory or psychiatric phenomina

Convulsion – Involuntary spasmodic contractions of any or all voluntary muscles throughout the body, including skeletal and facial muscles.

Seizures – Brief episode of abnormal electrical activity in the nerve cells of the brain -- detected on EEG

Epilepsy – Chronic, recurrent pattern of seizures

• Generalized

• Partial

Classification

1.Generalised tonic clonic seizures (GTCS) Grand mal epilepsy• Major epilepsy1-2 min• Commonest• Aura –cry –unconciousness –tonic

spasm of all body muscles-tonic jerking

• Prolongrd sleep and depression of all CNS functions

Generalised seizures

2.Absence SeizuresMinor epilepsy, petit mal •½ minute•Children•Apparent freezing•EEG: 3 cycle per second spike and wave pattern

3. Atonic SeizuresAkinetic Epilepsy ,Drop Attack

•Sudden loss of postural tone •Unconciousness•Excessive inhibitory discharges

4.Myoclonic seizures

Shock like momentary contraction of muscles of a limb or the whole body

5. Infantile Spasms

Hypsarrhythmias

Partial seizures

1.Simple partial seizures

2.Complex Partial seizures

3. Simple Partial or complex partial seizures secondarily generalized

Classification:

1. Drugs used to abolish seizures(anticonvulsants)

2. Drugs to prevent seizures (prophylaxis)

Classification:

1. Drugs used to abolish seizures(anticonvulsants)

2. Drugs to prevent seizures (prophylaxis)

Chemical Classification1. Barbiturate: phenobaritone2. Deoxybarbiturate : Primidone3. Hydantoin: Phenytoin4. Iminostillbene : Carbama zepine5. Succinimide: Ethosuximide6. Aliphatic Carboxylic acid: Valproic acid7. Benzodiazepines: Clonazepam , Diazepam8. Phenyltriazine : Lamotrigine9. Cyclic GABA analogue: Gabapentine 10.Newer Drugs: vigabatrine ,Zonisamide

ION Theory – movement of K+, Na+, Ca+, Mg+:

Stabilizes neurons: from becoming hyperexcited prevents excessive impulses to adjacent neurons

1. Increase threshold of activity in the motor cortexMakes it more difficult to excite; reduces response

2. Depress the seizure discharge from its originSuppress transmission of impulses from one nerve to the next

3. Decrease the speed of nerve impulse conduction within a given neuron

Mechanism of Action

•Prevention or control of seizure activity•Long-term maintenance treatment of epilepsy•Acute treatment of convulsions and status epilepticus

Status epilepticus: common seizure disorder –

life-threatening emergency characterized by tonic-clonic convulsions that occur in succession. Loss of consciousness, hypotension, hypoxia, cardiac dysrhythmias – brain damage and death may quickly resultOnce controlled, long term therapy is begun to prevent future seizures

•Brain Surgery - Head injuries = prophylactic AED Therapy

Indications

First efficatious antiepileptic 1912 Mechanism: GABA receptor mediated synaptic

inhibition Raises seizure threshold as well as limits spread

and suppresses kindled seizures Long plasma t1/2 (80-120 hrs)

Drawback :

• Sedative action

• Behaviouralar abnormalities

• Diminution of intelligence

• Impairment of learning

• Hyperactivity in children

• Mental confusion in older people

Phenobarbitone

Uses:

Generalised tonic Clonic seizuresSimple partial Seizures Complex partial Seizures

Gardinal ,syr Luminal

Phenytoin (Diphenylhydantoin)Synthesised in 1908 as a barbiturate analogue

Mechanism of Action•The drug slows the recovery of voltage-dependent sodium channels(stabilising effect) on all neuronal membranes including the peripheral nerves as well as on all non-excitable & excitable membranes •It inhibits the spread of seizure discharges in the brain & shortens the duration of after discharge•It reduces the neuronal sodium concentration leading to a reduction in PDS•Decreases post tetanic potentiation which is responsible for the spread of seizure activity

Pharmacokinetics

•Slowly absorbed from the gut •Plasma peak level 3-12 hrs after ingestion•70-95% albumin bound•Metabolised mainly by parahydroxylation in the liver•About 94% of a single dose is excreted in urine in 48 hrs•The dose increments must be smaller with increasing dosage since plasma concentration rises dispropotionately to the dose increment

Adverse Effects

At therapeutic level:

a) Gum Hypertrophy:Commonestb) Hirsutism,Acne,coarsening of facial

hairc) Hypersensitivity reactionsd) Megaloblastic Anemiae) Osteomalaciaf) Hyperglycemiag) During pregnancy: fetal hydantoin

syndromeHypoplastic phalangesCleft palate Hare lipMicrocephaly

At High plasma levels

a)Cerebellar & vestibular menifestationsb)Drowsiness, behavioral alterations,mental

confiusion,hallucinations,disorientations and rigidity

c) Epigastric pain,nausea and vomitingd)IV injections – local vascular injury• Intimal damage ang thrombosis of vein• Edema and discoloration of the injected limb• Rate of injection should not exceed 50mg/min • Fall in BP and cardiac arrhythmias

Interactionsa. Phenobarbitone inhibits phenytoin metabolismb. Carbamazepine and phenytoin increase each

others metabolismc. Valproate decreases its metabolismd. Chloramphenicol,

isoniazid,cemitidine,dicumaroland warfarin inhibit phenytoin metabolism

e. It inhibits warfarin metabilismf. Inceases degradation of

steroids,digitixin,doxycycline,theophyllineg. Sucralfate decrease it absorption

Uses

a) Generalised tonic-clonic,simple and complex partial seizure 100 mg BD max 400mg /day 5-8 mg /kg/day for children b) Status epilepticusc) Trigeminal neuralgia

DILACTIN ,EPTON,EPSOLIN , SYR FENTOIN –ER

Fosphentoin:

• Water soluble prodrug of phenytoin• To overcome the difficulties in I.V administration of

phenytoin in status epilepticus• Few vascular complications• Can be injected at a faster rate• Can be injected with both saline and glucose

FOSOLIN 50mg /ml in 2ml, 10 ml injection

Carbamazepine1960 mechanism of action similar to that of phenytoinPharmacological actions

Specific for trigeminal neuralgiaEffective in differentiation pain in diabetic neuropathy,cancer and multiple sclerosis

Pharmarmacokinetic:

Oral absorption slowMetabolised by liver (98%)Potent hepatic microsomal enzyme inducer

Adverse Effects

1. Nausea, sedation,dizziness,vertigo,diplopia anorexia2. Coma, convulsions and cardiovascular collapse3. Hypersensitivity reactions4. Agranulocytosis and aplastic anemia5. Water retention and hyponatremia in elderly6. Minor fetal malformations

Interactions

a)Reduces efficacy of haloperidol,oral contraceptives,lamotrigine and topiramate

b)Metabolism of carbamazepines induced by phenobarbitone,phenytoin,valproate and vice versa.

c) Erythromycin, flouxetine,isoniazid inhibit metabolism of carbamazepines

Uses

1.Grand mal & petit mal seizures2.Trigeminal and related neuralgias 3.Manic depressive illness and acute mania

Dose : 200-400mgTDS 15-30mg /kg/day

TEGRATOL,MAZETOL

OXCARBAZEPINE

•Newer congener of carbamazepine• better tolerated

OXETOL, OXCARB,OXEP 150,300,600MG TABS

ETHOSUCCIMIDE most frequently used succinimide Mechanism of ActionThe drug reduces the low threshold calcium currents in the thalamic neurones which are responsible for the generation of the absence seizures

Pharmacological actionsEffective only in petit mal epilepsy , does not induce liver enzymes

Pharmacokinetics

•Completely absorbed from GIT •20% excreted unchanged in urine •Rest metabolised by liver

Adverse Reactions:Anorexia, Nausea, Vomiting, Drowsiness, dizziness, skin rashes etc

Uses

Drug of Choice in petit mal epilepsy Dose 20-30mg /kg/day

ZARONTIN 250mg/5ml syr

Valproic Acid : Sodium Valproate Mechanism of Action •It’s a broad spectrum antiepileptic which probably acts at multiple sites •Actions similar to that of ethosuccimide and phenytoin•Inhibits the T type Ca++ current and also delays the recovery of the inactivated Na++ channels •It also inhibits GABA transaminase thus increasing the GABA

Pharmacokinetics•Rapidly and completely absorbed from the GI •More than 90% is metabolised in liver

Adverse Reactions

•Nausea, vomiting•Increases apetite and causes weight gain•Dose related hair loss•Hypoalbunemia•Hepatotoxicity with death

Uses

•Petit mal •Combined grand mal and petit mal•Myoclonic epilepsy•Partial epilepsy•Mania and bipolar illnesses

DIPROEX, VALANCE 125,250,500mg tabs

Clonazepam Benzodiazepine with prominent anticonvulsant properties Potentiate GABA induced Cl- influx to produce sedation and anticonvulsant properties

Pharmacokinetics Good oral absorptionCompletely metabolised in liver t1/2 24 hrs

Uses

Absence seizuresAdjuvant in myoclonic and akinetic epilepsyInfantile spasm Dose: A0.5-5mg tdsChildren: 0.02-0.2mg/kg/day

LONAZEP, CLONAPAX,RIVOTRIL 0.5, 1.0,2.0mg tab

CLOBAZAM 1,5 benzodiazepine

Uses

Adjuvant to other antiepileptic drugs

FRISIUM, LOBAZAM, CLOZAM 5,10,20,mg capsules

Diazepam

Drug of choice for emergency control of convulsions

•Status epilepticus•Tetanus •Eclampsia•Convulsant drug poisoning

Dose0.2-0.5mg/kg injected i.v slowly Maximum 100mg/day

Febrile convulsions in children : rectal instillation

Lorazepam :alternative to diazepam

Gabapentine

Lipophyllic GABA derivative

Mechanism of action

Crosses to the brain and enhances GABA release

Dose : start with 300mg OD & increase to 300-600 mg tds as required

NEURONTIN , GABANTIN

Uses

•Reduces seizurepartial seizures with or without generalization

•First line drug for pain due to diabetic neuropathy and post herpetic neuralgia• frequency in refractory Prophylactic effect in migraine

Vigabatrin

Inhibitor of GABA transaminase

•Anticonvulsant activity due to increase in synaptic GABA concentration •Effective in many cases of refractory epilepsy•Adjuvant medication

Adverse effects

•Behavioral changes•Depression •Psychosis

Dose : 2-4g daily

Children : 40-100mg /kg/day

Conclusion

Choice of drug and dose according to type of seizures and need of individual patients

Initiate treatment early starting with low dose and gradually increasing it

Treatment should be as simple as possible

All drug withdrawal should be gradual except in case of toxicity

Thank you