Anticonvulsants - JU Medicine

Anticonvulsants Epilepsy and Seizures - Epilepsy is a chronic disorder characterized by recurrent seizures that happen because of sudden, abnormal electrical activity in the brain. - Epilepsy is the most prevalent neurological disorder affecting more than 0.5% of the world’s population. - The etiology of epilepsy is largely unknown even though recent evidence suggests that it may have a genetic component associated with its disease development. - Seizures: are symptoms of disturbed electrical activity in the brain characterized by episodes of abnormal, excessive, and synchronous discharge of a group of neurons within the brain that cause involuntary movement, sensation, or thought. - Seizures may result from primary or acquired neurological disturbances of brain function as a result of an imbalance between excitatory and inhibitory processes in the brain. - There are many possible causes of seizures including brain tumors or infections, head trauma, neurological diseases, systemic or metabolic disorders, alcohol abuse, drug overdose, or toxicities. - Table 11.1 describes the different seizure types. (Table 11.1) Types of Seizures Seizure Type Partial seizures (focal, local) Features Simple Complex Motor, somatosensory, autonomic, or psychic symptoms, with loss of consciousness Impaired consciousness at the onset, or simple partial seizure followed by impaired consciousness. Absence Generalized seizures (convulsive or nonconvulsive) - Typical Sudden brief lapses of consciousness with loss of posture Atypical Typical form brief motor activity or loss of muscle tone Myoclonic Isolated jerking movements Clonic Repetitive jerking movements without muscle rigidity Tonic Muscle rigidity without jerking movements Muscle rigidity followed by rhythmic jerking movements. Tonic-clonic Atonic Note: Partial seizures can evolve to generalized tonic-clonic. Loss of muscle tone Unclassified epileptic seizures, including some neonatal seizures. Status epilepticus - Status epilepticus is the term used to describe prolonged seizures (usually lasting 30 minutes or more) or multiple seizures that occur without recovery of consciousness. - Status epilepticus constitutes a medical emergency, as the risk of death or brain damage increases the longer the seizures continue. - Treatment involves maintaining the patient's airway and giving oxygen, a bolus of glucose (as the brain is a huge consumer of glucose), and intravenous (IV) or rectal diazepam to terminate the seizure. - IV diazepam is given in the form of an emulsion to prevent thrombophlebitis (inflammation of a vein due to a blood clot).

Febrile convulsions - Febrile seizures (seizures associated with elevated body temperature) are the most common type in children, affecting 2 to 5% between the ages of 6 months and 5 years, with the peak incidence at 18 months. These seizures are not associated with trauma, infection, metabolic disturbances, or a history of seizures, and most last less than 10 minutes. - More serious illnesses must be ruled out, but the treatment of simple febrile seizures with anticonvulsants is generally not recommended, as the potential drug toxicities associated with these medications outweigh the relatively minor risks associated with the convulsion. - There is also no need to specifically cool the child in a cooling bath or to administer an antipyretic drug, e.g., acetaminophen, to reduce the fever. Most febrile convulsions will stop on their own after a few minutes. Lennox-Gastaut syndrome - Lennox-Gastaut syndrome is a disorder of childhood characterized by multiple difficult-totreat seizure types. It is usually accompanied by some form of cognitive impairment. - Antiepileptic drugs may control seizures for a time, but tolerance frequently develops. Non-pharmacologic Therapy a. Surgery is the treatment approach with the greatest probability of eliminating seizures. The most common surgical approach is temporal lobectomy. b. Ketogenic diet, it can be extremely effective, resulting in complete seizure control and reduction of AEDs. c. Vagal nerve stimulation to treat all types of epilepsy, usually reserved for patients who do not respond to several drugs and are not surgical candidates. A deep brain stimulation device has been approved for individuals with seizures refractory to other treatments. Some AED therapy is usually continued in patients with devices. Mechanism of action of anticonvulsants Antiepileptic drugs act at many neuronal sites to inhibit the excitation of the neuron. A- Modulation of voltage-gated sodium channels. In the presynaptic nerve terminal of excitatory glutamate receptors, some drugs inactivate Na channels – which can inhibit the release of the excitatory neurotransmitter glutamate. Example: Phenytoin, Carbamazepine, Oxcarbazepine, and Lamotrigine. B- Interaction with GABAA receptors, which are ligand-gated chloride ion channels; enhancing inhibitory neurotransmission. Example: Barbiturates, Picrotoxin, Steroids, and Benzodiazepines. C- Interaction with Glutamate receptors; attenuating excitatory neurotransmission. D- Other drugs block the N-methyl-d-aspartate (NMDA) glutamate receptor or T-type Ca2 channels.

Drug Mechanism Phenytoin - Limits action potentials in the brain by slowing the rate of recovery of voltage- Na channels from inactivation. - Slow, unpredictable absorption. Pharmacokinetics Uses - 90% bound to plasma proteins. - Metabolized in the liver; may induce hepatic enzymes. - Effective in all types of epilepsy except absence, myoclonic, and atonic seizures. - Trigeminal neuralgia. Carbamazepine - Same as Phenytoin; slows the recovery of Na channels from inactivation. Valproic Acid - Increases Na channel inactivation and GABA mediated inhibition. Inhibits Ttype Ca2 channel activation. - Its anticonvulsant action continues after the drug has been withdrawn. - Slow and erratic absorption. - 90% bound to plasma proteins. - Metabolized in the liver; may induce hepatic enzymes. - Metabolized by the cyt P-450 enzymes, but it does not induce these enzymes. - Generalized tonic-clonic seizures. - Absence seizures (myoclonic types) that are difficult to treat with other drugs. - Complex partial seizures. - It appears to have an equivalent effect as ethosuximide for absence seizures. - Trigeminal neuralgia. - It is ineffective for absence and myoclonic seizures - Combination therapy in the treatment of generalized tonic-clonic seizures and for complex partial seizures. Relatively safe, but the following may occur: - Gingival hyperplasia is the most common side effect in children. Infections are minimized by good oral hygiene. Side Effects - GI upset. - Vertigo, diplopia, and blurred - Nausea, vomiting, insomnia, agitation; sedation, vision, drowsiness, ataxia, confusion, behavioural disturbances, impaired learning dizziness, headache (all dose related). (dose-related). Nystagmus, ataxia, vertigo, and diplopia. - Hematological disorders: - Hirsutism - Hyperglycemia, osteomalacia, lymphadenopathy, rashes (SJS; erythema multiform bullous), and hematological reactions (leukopenia, megaloblastic anemia, thrombocytopenia, agranulocytosis, and aplastic anemia). These are allergic reactions that require cessation of therapy. - Cardiovascular collapse can occur after IV phenytoin. aplastic anemia, thrombocytopenia, agranulocytosis, and leukopenia. - Hypersensitivity. - Rash, dry mouth, abdominal pain, nausea, vomiting, anorexia, diarrhea, constipation, asymptomatic hyponatremia. - Alopecia (reversible) in 5% of patients. - Transient GI effects in 16% of patients. - Mild behavioral effects, ataxia, and tremor; not a CNS depressant. - Hepatic failure (rare). - Teratogenic. - Common: nausea, vomiting, increased appetite, weight gain, paresthesia, drowsiness, elevated liver transaminase concentrations.

Special consideration (cautions) Diabetes: risk of hyperglycemia Hepatic impairment: may require dosage reduction. Pregnancy: can cause fetal hydantoin syndrome Breastfeeding: may be used - Metabolism of phenytoin is affected by agents that can induce or inhibit cytochrome P-450 enzymes. Drug interactions - Reduces the plasma concentration of warfarin, oral contraceptives, carbamazepine, and some antibiotics. - Drugs that bind to plasma proteins will displace phenytoin, which could result in toxicity. Pregnancy: Increased risk of congenital malformations. Breastfeeding: Safe to use; monitor infant for drowsiness. - Metabolism of phenytoin is affected by agents that can induce or inhibit cytochrome P450 enzymes. - Reduces the plasma concentration of warfarin, oral contraceptives, and some antibiotics. Surgery: Check platelet count and INR before surgery. Pregnancy: ADEC category D. Breastfeeding: Safe to use at low dosage. Contraindicated in Pancreatic dysfunction, Porphyria; Urea cycle disorders. - Increases blood levels of phenobarbital and primidone by inhibiting their metabolism. - It lowers phenytoin levels.

Drug Mechanism Pharmacokinetics Phenobarbital - Phenobarbital is a long-acting barbiturate that potentiates and mimics GABA. - It increases the threshold for action potential firing and inhibits the spread of activity from focus. - Effective orally. - Induces hepatic enzymes - Generalized tonic-clonic epilepsy. Uses - Partial seizures. - Prophylaxis or treatment of febrile convulsions. Primidone Benzodiazepine - The mechanism is similar to that of phenobarbital. - Increases the action of GABA. - Metabolized in the liver to phenobarbital phenylethylmalonamide (PEMA). - - Complex partial seizures (primidones are more effective than phenobarbital). - Generalized tonic-clonic seizures and simple partial seizures. - Frequently combined with phenytoin in refractory cases. - Chronic treatment of epilepsy (clonazepam and clorazepate). - Status epilepticus (lorazepam or diazepam IV). - Atonic (akinetic) seizures, especially as adjuncts. - Absence seizures, but not preferred because of CNS depression. - Benzodiazepines do not prevent generalized tonic-clonic seizures. - Sedation (tolerance develops). - Rashes (e.g. scarlatiniform) are seen in 1 to 2% of patients. Side Effects - Nystagmus (a rapid, involuntary, oscillatory motion of the eyeball) and ataxia (the inability to coordinate voluntary muscular movement) at excessive doses. - Sedation is the most common side effect. - Rashes, leukopenia, thrombocytopenia, and systemic lupus erythematosus. - CNS depression. - Respiratory depression is not seen with this longacting barbiturate given orally, but it may be observed after IV injection. Drug interactions - Reduces the plasma concentration of warfarin, oral contraceptives, carbamazepine, and some antibiotics. - Ataxia - Behavioral problems, such as aggression, anxiety, and restlessness. - Amnesia - Valproic acid increases phenobarbital blood levels. - Rashes, leukopenia, thrombocytopenia, and systemic lupus erythematosus. - Additive effects with other CNS depressants. - CNS depression. -