Anti Epileptics I

‫بسم ال الرحمن الرحيم‬ Drugs for Epilepsies & Migraine-I 1

Introduction • • • • • • • •

Epilepsy: Chronic paroxysmal brain disorder due to excessive neuronal discharge associated with changes in behavior, consciousness and/or convulsions (jerky movements) Seizure: Any abnormal clinical event, due to electrical discharge in brain, may be epileptic or non-epileptic Non-epileptic seizures: evoked in normal brain by electroshock, fever, chemical convulsants, etc Drugs that control seizures, also used in epilepsies 2

Epileptic seizures & drug treatment A. Partial seizures Simple partial seizures (20-60 sec)

Minimal spread Patient is conscious Features related to site of activation

Carbamazepine, Phenytoin, Valproate, Phenobarbitone Gabapentin , Lamotrigine, Topiramate, Tiagabine

Complex Moderate spread partial Transient loss of seizures consciousness (20-60 sec)

Carbamazepine, Phenytoin, Valproate, Phenobarbitone Gabapentin , Lamotrigine Topiramate, Tiagabine

Partial seizures secondarily generalized (1-2 min)

Carbamazepine, Phenytoin, Valproate, Phenobarbitone Gabapentin , Lamotrigine, Topiramate, Tiagabine

Partial seizures evolve to tonic and then clonic seizures Loss of consciousness

3

Epileptic seizures & drug treatment (Cont.) B. Generalized seizures Tonicclonic Seizures (1-2 min)

Loss of consciousness Carbamazepine, Phenytoin, Sustained contraction Valproate, Phenobarbitone of muscles all over & Lamotrigine, Topiramate clonic contractions

Absence seizures (< 30 sec)

Abrupt loss of Ethosuccimide, Valproate consciousness, staring Clonazepam Loss of activity Lamotrigine, Topiramate

Myoclonic seizures (one sec)

Brief contractions of muscles, part of limb or whole body

Valproate,Nitrazepam Lamotrigine, Topiramate

Status epilepticus

Many forms; mostly Tonic-clonic seizures

Diazepam, Lorazepam

Phenytoin • •

• • •

Mechanism of action: Blocks Na+- channels, inhibits generation of repetitive action potentials Inhibits Ca++ induced release of hormones & chemical mediators: serotonin, nor-adrenaline, acetylcholine & GABA Uses: Partial seizures Generalized tonic-clonic seizures Cardiac arrhythmias 5

• • • • • • • • • •

Phenytoin (Cont.) Pharmacokinetics: Phenytoin Na is given orally or IV Oral absorption is good, but variable Time to peak plasma concen. varies from 3-12 hours Metabolized in liver to inactive metabolites that are excreted in urine Plasma level rises when metabolic enzymes saturate Plasma half-life varies from 12-36 hours Therapeutic plasma level in most cases is 10-20 µg/ml Therapeutic drug monitoring is important Induces liver microsomal enzymes & can cause drug interactions 6

Phenytoin (Cont.) • Adverse effects: • • • • • • • •

Nystagmus, diplopia & ataxia (dose related) Hirsutism in women Gingival hyperplasia & coarsening of facial features Peripheral neuropathy: diminished deep tendon reflexes Osteomalacia: altered Vit. D metabolism & ↓ GI absorp. Megaloblastic anemia: altered folate metabolism Hypersensitivity: skin rash, exfoliative dermatitis, fever Sedation & depression 7

Carbamazepine • • • • • • • • •

Related to tri-cyclic anti-depressants Mechanism of action: Blocks Na - channels & inhibit repetitive neuron firing Acts pre-synaptically & ↓ synaptic transmission, mainly that of nor-adrenaline Potenciates post-synaptic action of GABA Uses: Mostly first choice in generalized tonic-clonic seizures & partial seizures Mania (bipolar depression) Trigeminal neuralgia 8

Carbamazepine (Cont.) • Pharmacokinetics: • Given orally. Gradual & variable absorption • Completely metabolized in liver to active metabolite (10, 11-epoxide) & many inactive metabolites • Therapeutic level is mostly 4 - 8 ug/ml • Induces liver microsomal enzymes & can cause drug interactions • Toxicity: • Diplopia, ataxia, drowziness, GI upset & hyponatremia (dose related) • Aplastic anemia & agranulocytosis 9

Phenobarbital • Mechansm of action: • In therapeutic concentration: • ↑ GABA mediated inhibition by prolonging opening of Cl - channels • ↓ glutamate mediated excitation by blocking AMPA (aminohydroxy-methylisoxazole-propionate) or nonNMDA receptors • In higher doses: • Block Na & Ca channels (L & N) • Uses: • Generalized tonic-clonic & partial seizures, probably more effective in children 10

Phenobarbital (Cont.) • • • • • • • • •

Pharmacokinetics Give orally, IM & IV. Well absorbed & easily cross blood brain barrier Mostly metabolized in liver & partially (20-30%) excreted unchanged. Excretion is ↑ in alkaline urine Therapeutic levels 15 - 40 ug/ml Can induce liver enzymes & cause drug interactions Toxicity: Sedation, ataxia, respiratory depression, stupor, coma Tolerance, dependence & abuse 11

Valproic acid & sodium valproate • • • • •

Mechanism of action: In therapeutic concentration: ↓ Na-channels & block ↑ frequency repititive firing Blocks NMDA receptor-mediated excitation ↑ GABA levels in brain by activating glutamic acid decarboxylase enzyme • At high concentrations: • ↑ K-conductance • ↓ GABA degradation by ↓ in GABA-T enzyme 12

Valproic acid & sodium valproate (Cont.) • Uses: • Valproic acid & Na valproate both are useful against partial & generalized seizures, including: Generalized tonic-clonic seizures, absence seizures, myoclonic seizures & some partial seizures • Bipolar affective disorder & prophylaxis of migraine

13

Valproic acid & sodium valproate (Cont.) • Adverse effects: • GI: nausea, vomiting, heart burn, abdominal pain, ↑ appetite, weight gain • Liver: hepato-toxicity, usually reversible after withdrawal of drug. In few cases fatal • Hair loss • Teratogenecity: spina bifida, cleft palate & digital abnormalities in offspring 14

Ethosuccimide • • • • •

Use: 1st choice in absence seizures (Petit mal epilepsy) Mechanism: ↓ low-threshold (T - type) Ca - currents These currents provide pacemaker in thalamus for attack of absence seizures • Pharmacokinetics: • Given orally, well absorbed, distributed equally, completely metabolized by hydroxylation, plasma half life = 40 hrs, therapeutic level = 60 - 100 ug/ml

Ethosuccimide (Cont.) • • • •

Adverse effects: GI: nausea, vomiting, gastric pain CNS: euphoria, headache, dizziness, hiccup Rare: skin rash (Stevens-Johnson syndrome), pancytopenia • Drug interaction: • Valproic acid can inhibit its metabolism

Benzodiazepines • Diazepam, lorazepam, clonazepam & nitrazepam • Mechanism of action: • Benzodiazepines bind to specific sites (BZ receptor) on GABA-A receptor & facilitate GABA inhibition by increasing the frequency of Cl - channel opening • Differences in the effects of various benzodiazepines & differences between benzodiazepines & other sedative hypnotics are related to selective binding to & distribution of sub-types of GABA-A receptors. • e.g. α-1 subtype mediate seizures control & sedation; while α-2 involve anxiolytic & muscle relaxation

Benzodiazepines (Cont.) • Diazepam: Used for continuous seizures, e.g. generalize tonic-clonic status epilepticus • Lorazepam: More effective & longer acting than diazepam in controlling status epilepticus • Clonazepam: Longer acting & used for absence seizures • Nitrazepam: Used for infantile spasms & myoclonic seizures

Benzodiazepines (Cont.) • Adverse effects: • Amnesia, drowsiness, dizziness & ataxia • May result in tolerance, psychological & physical dependence; & abuse • Toxic doses cause coma, respiratory depression & cardiovascular collapse • Wide margin of safety as compared to barbiturates & phenytoin