ANS&CNS

ANTI EPILEPTIC DRUGS

Epilepsy: sudden excessive and synchronous discharge of cerebral neurons. (loss of consciousness, abnormal movements, Atypical or odd behavior or distorted perception)

1. Blockage of Voltage-Gated channels (Na+ or Ca+2 )2. Enhancement of inhibitory GABAergic impulses. 3. Interference with excitatory glutamate transmission.
Mechanism of Action of Anti Epileptic Drugs:

a. Partial seizures involve only a portion of the brain (localized area) typically part of one lobe of one hemisphere b. Generalized seizures abnormal electrical discharges through out both hemispheres of the brain
Classification of Seizures

Partial &/or secondary generalized

Characteristic
Treatment
• Simple
• 2. Complex
• 3.Secondary generalized
Localized, jerking of the limb or the face, stiffness of one part of the body.


Automatic behavior, plucking of the clothes, fidding with various objects, chewing movement, grimacing.

Partial , simple and complex could lead or converted to secondary generalized similar to the generalized seizure.
For all types Lamotrigine,
Carbamazepine,
Valproic acid
(Divalproex)

Primary generalized

Characteristic
Treatment
• 1.Tonic-clonic (Grand mal)
• 2. Absence (petit mal)
• 3.Atonic convulsion
• 4.Myoclonic convulsion
• 5.Status epilepticus
Commonest of all epileptic seizure without warning, patient suddenly has epilepsy abnormal breathing, stiffness, salivation, cyanosis, tongue bite, loss of consciousness.

It is rare, usually in children and adolescent, stares, rapid eye blinking which last 3-5 seconds, flopping of head may occur.

Sudden loss of muscle tone causing the person to collapse, the EEG normal

Brief involuntary shock like jerks involve body, head, arms . It occur after waking in the morning

2-3 seizers recur without recovery of full consciousness between them

Divalproex (valproic acid)
Lamotrigine
Carbamazepine
Clonazepam

Divalproex

Lamotrigine
Ethosuximide

Valproic acid

Clonazepam

• Divalproex

Benzodiazepines
• Lamotrigine

It is emergency

• Benzodiazepines
Diazepam
Lorazepam


Carbamazepine
It reduce the propagation of abnormal impulses by blockage Na+ channels.
Pharmacokinetics the t1/2 of carbamazepine falls from 35-20 hrs over the 1st few weeks of therapy due to induction of hepatic enzymes that metabolize it as well as other drugs including corticosteroids(adrenal &contraceptive), theophylline & warfarin. Cimetidine &valproate inhibit its metabolism raze the plasma level of carbamazepine,not use in absence seizure,the condition increase.
Uses :
• Partial ,secondary and primary generalized seizures.
• Trigeminal neuralgia .
• Peripheral neuritis .

Adverse effects:

Blurred vision, diplopia, ataxia, dizziness, depression of cardiac AV conduction, skin rash, osteomalacia, blood disorder(a plastic anemia, leukopenia), kidney &liver dysfunction,hypo natremia.

Oxcarbazepine

Its analogue carbamazepine act by blocking Na+ channels. Its apro drug, its use in partial &secondary generalized, it’s a selective inducer that metabolizes oral contraceptive.
Side effect:
Hyponatraemia, nausea, vomiting, headache &visual disturbance.

Sodium valproate (valproic acid)

Acts by inhibiting GABA transaminase, the enzyme that break down the inhibitory neurotransmitter GABA so increasing its concentration at GABA receptors. Its used in all cases of convulsion(partial &primary generalized)
Side effect:
Weight gain, teratogenicity, polycystic ovary syndrome, hair loss but reversible, nausea be problem, rise in liver enzyme transient, metabolic inhibition by valproate prolong the action of co administered Anti epileptic drugs .


Divalproex
Combination of sodium valproate and valproic acid it acts by block Na+ channels, block GABA transaminase and act at T type Ca+2 channels, its broad spectrum Anti epileptic drugs used in all type of epilepsy,it developed to improveGIT tolerance of valproic acid. Affect cognition,birth defect so use other drug during pregnancy teratogenic ,take folic acid prior to conception,
Hepatotoxic cause rise in liver enzyme so monitor frequently.

PHENYTOIN(Diphenyl Hydantoin)

The mechanism of action: It act by inhibition of voltage dependent Na+ channels.
Pharmacokinetics: It follow zero order kinetic (saturation kinetic) small dose of phenytoin follows 1st order kinetic, but the therapeutic dose will follow zero order kinetic also phenytoin cause enzyme induction that metabolize other drugs like carbamazepine, warfarine, vitamin D & phenytoin it self, also drugs that cause enzyme inhibition raise the level of phenytoin.

PHENYTOIN(Diphenyl Hydantoin)

Its used in partial and generalized, status epilepticus, cardiac arrhythmia, resistant pain in trigeminal neuralgia.
Side effects:(FOLATES) Folic acid deficiency, Osteomalacia, Pseudo Lymphoma, Anemia, Teratogenicity, Enzyme induction, sedation, impair cognitive function, gum hyperplasia, hirsutism, coarsening feature. Saturation (zero order kinetics) not used now because of many side effects.Ataxia,nystagmus . Phenytoin never give as IV,IM Injection it cause tissue damage and necrosis ,Fosphenytoin pro drug give as IV,IM injection.

Succinamide

Ethosuximide it act by inhibiting T-type Ca+2 channels. It effective in treatment of absence seizures.
Adverse effect: Drowsiness, nausea GIT upset, weight gain, SLE, rash, blood dyscrasias can occur, abrupt (discontinuation of drugs may cause seizure).not use carbamazepine in absence seizure because it may increase in seizure.

Lamotrigine

It act to stabilize presynaptic neuronal membrane by blocking Na+ channels as well as Ca+2 channels, it reduce the release of excitatory amino acid (Glutamate & Aspartate) it has long duration of action its effective as mono therapy and adjuvant for primary generalized &partial generalized, absence seizures, its well tolerated but may cause serious adverse effect on skin and toxic epidermal necrolysis.

Gabapentin

Its an analogue of GABA, is sufficiently lipid soluble cross (BBB) but its mechanism of action is unknown, is effective in partial, generalized seizures, it used in neuropathic pain it may cause dizziness, unsteadiness and fatigue.


Barbiturates
Phenobarbital it act by enhancement of inhibitory effect of GABA mediated neurons, it long acting barbiturate, it used in primary generalized seizures, status epilepticus and febrile convulsion in children, T1/2 100 hours.
Adverse effect: Sedation, cognitive impairment, osteoporosis.
Primidone is pro drug of phenobarbitone.

Benzodiazepines

It bind to GABA inhibitory receptors.
Diazepam, lorazepam,Clonazepam: used as second line for treatment of primary generalized and status epilepticus.

Topiramate

It block sodium channels ,reduce high-voltage calcium currents,is a carbonic anhydrase inhibitor,it act at glutamate sites.it used in partial & primary generalised epilepsy,used for prevention of migraine.
Adverse effects: somnolence,weight loss &paresthesias,renal stone,oligohydrosis decrease sweating &hyperthermia.