Anticonvulsants

Pharmacology of anticonvulsant drugs

1. Anticonvulsants By: Tandzile Simelane Year of study: MBBS V Medicine Rotation 2017

2. Presentation Outline Introduction Anticonvulsants Indications MOA Dosage Side effects Contraindications

3. Introduction Convulsion- medical condition where body  muscles  contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body Seizure- any clinical event caused by abnormal electrical discharge in the brain. Epilepsy- Epilepsy is a central nervous system disorder (neurological disorder) in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behaviour, sensations and sometimes loss of consciousness. Status epilepticus- prolonged, sustained unconsciousness with persistent convulsive activity in a seizing patient.

4. Categories of antiepileptic drugs: Enhancement of GABA action Inhibition of Sodium channel function Inhibition of Calcium channel function

5. Carbamazepine focal and generalized seizures bipolar disorder and chronic pain syndromes ( trigeminal neuralgia) CBZ binds to voltage-dependent sodium channels . This binding extends the inactivated phase and inhibits the generation of rapid action potentials when the cell is experiencing incoming depolarizing trains. 70 percent protein bound. It is metabolized in the liver by cytochrome P450 (CYP) 3A4 and is a potent and broad spectrum inducer The main metabolite, carbamazepine 10,11-epoxide

6. Carbamezapine initial starting dose is 2 to 3 mg/kg PO BD, TDS/QID the dose is increased every five days to 10 mg/kg daily side effects:nausea , vomiting, diarrhea , hyponatremia , rash, pruritus , and fluid retention, drowsiness, dizziness, blurred or double vision, lethargy, and headache CBZ-induced leukopenia or neutropenia

7. Phenytoin focal and generalized seizures,status epilepticus second-line agent:mixed seizures ( myoclonic and tonic- clonic )  it blocks voltage-dependent neuronal sodium channels and reduces synaptic transmission, limiting fluctuation of neuronal ionic gradients via Na/K ATPase , and affecting second messenger systems by inhibiting calcium- calmodulin protein phosphorylation .  metabolized in the liver and is a potent and broad spectrum inducer of CYP and UGT- glucuronidation The initial oral dose:15  mg/kg in three divided doses, maintenance dose of 5 mg/kg daily in one or two divided doses.

8. Phenytoin Side effects: Gingival hypertrophy, rash, gingival hypertrophy, body hair increase, rash, folic acid  depletion, and decreased bone density, sexual dysfunction Neurotoxic side effects include confusion, slurred speech, double vision, ataxia, and neuropathy (with long-term use)

9. Lamotrigine focal epilepsy, idiopathic generalized epilepsy and mixed seizure disorders newly diagnosed absence seizures in children blocks the repetitive firing of neurons by inactivating voltage-dependent sodium channels and selectively influence neurons that synthesize glutamate and aspartate , since it diminishes the release of these excitatory neurotransmitters 55% percent bound to plasma proteins, and the liver metabolizes LTG to inactive glucuronide conjugates excreted in the urine  the initial dose is 25 mg/day , increasing to 50 mg/day after two weeks, titrating upward by 50 mg per day every one to two weeks to maintenance dose of 225 to 375 mg per day (in two divided doses ). Side effects: Dizziness , tremor, diplopia

10.   Ethosuximide Absence seizures no activity against generalized tonic- clonic or focal seizures . diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized The recommended dose 20 to 40 mg/kg per day in one to three divided doses. Blood levels should be checked initially after one to three weeks, with a goal therapeutic concentration of 40 to 100 mcg/ mL  (280 to 700 micromole/L). Contraindications: hypersensitivity S ide effects: nausea , vomiting, sleep disturbance, drowsiness, Steven Johnsons

11. Phenobarbital  G eneralized and focal seizures. However, its clinical utility is limited by its sedating effects Binds to the GABA(A) receptor, extends the duration of GABA-mediated chloride channel openings. This process permits an increasing flow of chloride ions across the membrane, causing neuronal hyperpolarization M etabolized primarily in the liver by the CYP system and 25 percent is excreted renally as unchanged drug. It is a potent and broad spectrum inducer of CYP and UGT- glucuronidation . The oral dose of  1 to 5 mg/kg per day; it may also be administered intravenously. goal therapeutic level of 10 to 40 mcg/ mL  (43 to 172  micromole/L Side effects: Alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence

12. Valproate Partial or generalised, absence seizures It causes an increase in the GABA content in the brain and a weak inhibitor of enzyme systems that inactivate GABA (GABA transaminase and succinic semialdehyde dehydrogenase ). Enhances postsynaptic GABA action Inhibits the T-type calcium channels. 10-15mg/kg/d PO; increase incrementally until therapeutic dose to max of 60mg/kg/d Contraindication: hypersensitivity, urea cycle disorder Side effects: Hepatotoxicity , neural tube defect, alopecia, diarrhea , tremor, diplopia , thrombocytopenia

13. Benzodiazepines Diazepam bind to the GABA(A) receptor and facilitate the attachment of GABA to its binding site on the receptor. The inhibitory action of endogenous GABA is magnified because benzodiazepines increase the occurrence of chloride channel openings Seizures : Adjunctive maintenance therapy: Oral:  2 to 10 mg BD to QID. Intermittent management of seizures: Rectal gel ( Diastat ):  0.2 mg/kg; may be repeated in 4 to 12 hours if needed; Status epilepticus: IV : 0.15 to 0.2 mg/kg (maximum dose: 10 mg); may repeat once(American Epilepsy Society recommendations) 

14. Side effects: sedation, irritability, ataxia, and depression,withdrawal seizures

15. Thank you

16. REFERENCES Davidson's Principles and Practise of Medicine, 21 st Edition Rang and Dale’s Pharmacology, 7 th Edition Step Up to Medicine, 3 rd Edition Uptodate