Antiepileptic Drugs PDF

Antiepileptic Drugs LAWRENCE MICAH-AMUAH  Epilepsy Epilepsy is a syndrome of central nervous system (CNS) dysfunction that can cause symptoms ranging from momentary sensory disturbances to convulsive seizures. It is the most common chronic neurologic illn...

Antiepileptic Drugs LAWRENCE MICAH-AMUAH  Epilepsy Epilepsy is a syndrome of central nervous system (CNS) dysfunction that can cause symptoms ranging from momentary sensory disturbances to convulsive seizures. It is the most common chronic neurologic illness, affecting about 50 million people worldwide. It results from excessive electrical activity of neurons (nerve cells) located in the superficial area of the brain known as the cerebral cortex or gray matter. Seizure – is a brief episode of abnormal electrical activity in the nerve cells of the brain, which may or may not lead to a convulsion. Convulsion – is a more severe seizure characterized by involuntary spasmodic contractions of any or all voluntary muscles throughout the body. Commonly reported symptoms include abnormal motor function, loss of consciousness, altered sensory awareness, and psychic changes. Epilepsy – is a chronic, recurrent pattern of seizures. Excessive electrical discharges can often be detected by an electroencephalogram (EEG), which is obtained to help diagnose epilepsy. Types of Epilepsy 1. Primary or idiopathic epilepsy Epilepsy without an identifiable cause. accounts for roughly 50% of cases. Evidence indicates genetic predispositions. 2. Secondary or symptomatic epilepsy that has a distinct cause, such as trauma, infection, cerebrovascular disorder, or other illness. In children and infants, the chief causes of secondary epilepsy are developmental defects, metabolic disease, and injury at birth. Febrile seizures occur in children 6 months to 5 years of age, and by definition are caused by fever. Children usually outgrow these seizures and thus febrile seizures do not constitute a chronic illness. Antipyretic drugs (e.g., acetaminophen) are normally adequate for acute treatment. CLASSIFICATION OF SEIZURES (ILAE) Seizures are classified into different categories based on their presenting features. The three major classifications of seizures include: 1. Generalized onset 2. Focal onset 3. Unknown onset.  Generalized onset seizures – formerly called grand mal seizures, are characterized by neuronal activity that originates simultaneously in the gray matter of both hemispheres. There are several subtypes of generalized seizures. ✓Tonic-clonic seizures begin with muscular contraction throughout the body (tonic phase) and progress to alternating contraction and relaxation (clonic phase). ✓Tonic seizures involve spasms of the upper trunk with flexion of the arms. ✓Clonic seizures are the same as tonic-clonic seizures but without the tonic phase. ✓Absence seizures involve a brief loss of awareness that commonly occurs with repetitive spasmodic eye blinking for up to 30 seconds. This type occurs primarily in childhood and rarely after 14 years of age. Focal onset seizures originate in a localized or focal region (e.g., one lobe) of the brain. They are further subdivided based on level of awareness and motor or non-motor onset. Unknown onset seizures are seizures which do not clearly fit into any of the other categories. NB: Status epilepticus is a medical emergency when multiple seizures occur with no recovery between them. If appropriate therapy is not started promptly, hypotension, hypoxia, brain damage, and death can quickly ensue. Thus, status epilepticus is considered a true medical emergency Drugs and other substances that can cause Seizures Drugs of Abuse Amphetamine Psychotropics Cocaine Antidepressants Phencyclidine Antipsychotics Methylphenidate Sedative-hypnotic drug Anesthetics and Analgesics withdrawal Pethidine (Meperidine) Barbiturates Tramadol Benzodiazepines Local Anesthetics Alcohol Antiepileptic Drugs Antiepileptic drugs are also called anticonvulsants. The goal of antiepileptic drug therapy is to control or prevent seizures while maintaining a reasonable quality of life. Approximately 70% of patients can expect to become seizure free while taking only one drug. The remaining 30% of cases are more complicated and often require multiple medications. Antiepileptic drugs have many adverse effects, and it is often difficult to achieve seizure control while avoiding adverse effects. Abrupt discontinuation of these drugs can result in withdrawal seizures. SELECTION OF ANTIEPILEPTIC MEDICATIONS 1. known efficacy of a drug for a certain type of seizure 2. adverse effects and drug interaction profile 3. Cost 4. ease of use 5. availability of pediatric dosage forms. Patients are normally started on a single antiepileptic drug, and the dosage is slowly increased until the seizures are controlled or until clinical toxicity occurs. If the first antiepileptic drug is not effective, the drug is tapered slowly while a second drug is introduced. Antiepileptic drugs are never to be stopped abruptly unless a severe adverse effect occurs. NURSING CONSIDERATIONS Antiepileptic drugs have many adverse effects, and it is often difficult to achieve seizure control while avoiding adverse effects. Constant counselling on adherence is key to achieving therapeutic goals Abrupt discontinuation of these drugs can result in withdrawal seizures. Antiepileptic drugs are never to be stopped abruptly unless a severe adverse effect occurs. ANTIEPILEPTICS AND PREGNANCY Seizure is very harmful for pregnant women Monotherapy usually better than drug combinations Folic acid supplementation is recommended to be given for every pregnant woman with epilepsy. At best start folic acid 5mg daily for 2 months before conception to reduce the risk of fetal malformation Phenytoin, Sodium valproate are absolutely contraindicated. Carbamazepine and oxcarbamazepine are better options  Mechanism of Action and Drug Effects Epilepsy is due to the imbalance between excitatory (Glutamate) and the inhibitory (GABA) at the post synaptic Antiepileptics alter the movement of sodium, potassium, calcium and chloride ions. The changes in the movement of these ions result in more stabilized and less excitable cell membranes. The major pharmacologic effects of antiepileptics are threefold. 1. They increase the threshold of activity in the motor cortex 2. They act to limit the spread of a seizure discharge from its origin 3. They can decrease the speed of nerve impulse conduction within a given neuron. ASSIGNMENT What is the management Status Epilepticus? Medications Supportive therapy ADVERSE EFFECTS COMMONLY USED ANTIEPILEPTICS PHENYTOIN Belongs to the class called HYDANTOINS A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use; this phosphate ester compound is rapidly converted to phenytoin in the plasma. MECH OF ACTION It alters Na+, K+, and Ca2+ conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine, acetylcholine, and g-aminobutyric acid (GABA). This leads to membrane stabilization The major action of phenytoin is to block sodium channels and inhibit the generation of rapidly repetitive action potentials. It also inhibits the release of excitatory amino acids (e.g. glutamate) via inhibition of Calcium influx  Phenytoin Clinical Use Phenytoin is effective against partial seizures and generalized tonic-clonic seizures Not effective for absence seizures Can also be used for treatment of ventricular fibrillation (cardiac arrhythmic condition) ADVERSE EFFECTS GI upset Neurological like headache, vertigo, ataxia, diplopia, etc. Sedation Venous tissue damage Gingival hyperplasia Hirsutism Hypotension Cardiac arrythmia Megaloblastic anaemia Phenytoin NURSING CONSIDERATIONS Phenytoin cannot be injected in a drip of glucose solution because it gets precipitated. It is only injected in a drip of saline solution Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration. Loading dose is often administered in emergencies because of the long half life of the drug (12 – 36 hours) Drug has a narrow therapeutic window so careful dosage and drug administration is key in achieving therapeutic plasma levels whiles minimizing the adverse effects It can cause venous tissue phlebitis so ensure maximum rate of administration is not exceeded – 50mg/min for phenytoin and 150mg/min for fosphenytoin Hypotension and arrythmias may occur from rapid infusion (esp rate above 50mg/min) Folic acid supplementation especially for pregnant women to avoid NTD FOSPHENYTOIN Water soluble prodrug of Phenytoin Introduced to overcome the difficulties in IV administration of Phenytoin esp in status epilecticus On IV injection it is less damaging to the intima of the veins Can be injected with both Saline and Glucose. NB: Phenytoin cannot be injected in a drip of glucose solution because it gets precipitated CARBAMAZEPINE Carbamazepine is available only in oral form Oxcarbazepine is closely related to carbamazepine and useful in the same seizure types, but it may have an improved toxicity profile Mechanism of Action blocks sodium channels at therapeutic concentrations and inhibits high- frequency repetitive firing in neurons. It also acts pre-synaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine Clinical Use Partial seizures and generalized tonic-clonic seizures. Trigeminal neuralgia Mania (bipolar disorder). CARBAMAZEPINE ADVERSE EFFECTS GI upsets Drowsiness, ataxia and headache, diplopia Hepatotoxicity (rare) Congenital malformation (Craniofacial anomalies and NTDs) Hyponatremia Blood Dyscrasias (aplastic anaemia, mild leukopenia, etc) NURSING CONSIDERATIONS To be taken with meals to lessen side effects. Food slows absorption and prevents the rapid build up of plasma concentrations SODIUM VALPROATE (VALPROIC ACID) MECH OF ACTION Phenytoin-like frequency dependent prolongation of NA channel inactivation Weak attenuation of Ca mediated T-current Inhibition of the degradation of GABA by GABA transaminase thereby increasing the action of GABA at receptor site Blockade of excitatory NMDA type of glutamate receptor SODIUM VALPROATE (VALPROIC ACID) USES Drug of choice for Generalized tonic clonic seizures Absence seizures Myoclonic seizures Atonic seizures Alternative/adjuvant drug for focal seizures Mania and bipolar illness. As an alternative to Lithium SODIUM VALPROATE (VALPROIC ACID) ADVERSE EFFECTS Vomiting Alopecia Liver toxicity Pancreatitis Rash Obesity Anaemia Agranulocytosis Increased bleeding tendencies Teratogenic (congenital malformations e.g. spine bifida, cleft palate, heart defects ,etc). Recommend the oral intake of Folic acid LAMOTRIGINE Broad spectrum antiepileptic MECH OF ACTION. Blocks voltage sensitive Na channels USES Generalized tonic-clonic seizures Absence seizures Myoclonic seizures Atonic seizures Focal seizures LAMOTRIGINE ADVERSE EFFECTS Drowsiness Dizziness Diplopia Ataxia Vomiting Rash PHENOBARBITAL (PHENOBARBITONE) Drug of choice for seizures in infants. The four derivatives of barbiturates clinically useful as anti-seizure drugs are phenobarbital, mephobarbital, metharbital, and primidone Mechanism of Action Binds to an allosteric regulatory site on the GABAA receptor, and it enhances the GABA receptor-mediated current by prolonging the openings of the chloride channels. Also blocks excitatory responses induced by glutamate, principally those mediated by activation of the AMPA receptor. Both the enhancement of GABA-mediated inhibition and the reduction of glutamate-mediated excitation contribute significantly to membrane stabilization and abortion of seizures PHENOBARBITAL (PHENOBARBITONE) Clinical Use Treatment of partial seizures and generalized tonic-clonic and myoclonic seizures Treatment of Status Epilepticus (usually when benzodiazepines and phenytoin fails to abort seizures Insomnia (sedative-hypnotic) Benzodiazepine and alcohol withdrawal PHENOBARBITAL (PHENOBARBITONE) ADVERSE EFFECTS GI upsets (nausea, vomiting, constipation) Apnoea, hypoventilation Hypotension, bradycardia, syncope Exfoliative dermatitis Stevens-Johnson syndrome (rare) Dizziness Hallucination, nightmares, nervousness, ataxia,etc PRIMIDONE Primidone (2-desoxyphenobarbital) is metabolized to phenobarbital and phenylethylmalonamide (PEMA). All three compounds (Primidone and its metabolites) are active anticonvulsants. Mechanism of Action Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin. Clinical Uses Partial seizures Generalized tonic-clonic seizures Complex partial seizures PRIMIDONE CONTRAINDICATIONS Hypersensitivity to phenobarbitone Porphyria ADVERSE EFFECTS Sedation Ataxia Diplopia Vertigo Epigastric pain Megaloblastic anaemia Respiratory depression VIGABATRIN Mechanism of Action Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for the degradation of GABA. Acts by increasing the amount of GABA released at synaptic sites, thereby enhancing inhibitory effects. A decrease in brain glutamine synthetase activity is probably secondary to the increased GABA concentrations. It is effective in a wide range of seizure models. Clinical Use Treatment of partial seizures and West's syndrome ADVERSE EFFECTS drowsiness, dizziness, and weight gain. Less common but more troublesome adverse reactions are agitation, confusion, and psychosis; preexisting mental illness is a relative contraindication. GABAPENTIN & PREGABALIN Gabapentin (an amino acid) and Pregabalin are analogs of GABA Mechanism of Action Gabapentin and pregabalin do not act directly on GABA receptors. They modify the synaptic or non-synaptic release of GABA. Gabapentin and pregabalin also act pre-synaptically to decrease the release of glutamate; this effect is probably dependent on reduced presynaptic entry of Ca2+ via voltage-activated channels. Clinical Use & Dosage Gabapentin and Pregabalin are effective as adjuncts against partial seizures and generalized tonic-clonic seizures Pregabalin is also used for management of neuropathic pain (diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, etc.) TOPIRAMATE Broad spectrum antiepileptic agent 1st line drug in atypical absence, myoclonic and atonic seizures 2nd line drug in generalized tonic-clonic seizures and focal seizures Approved for prophylaxis of migraine ( when beta blockers/ other prophylactics are contraindicated or ineffective) MECH OF ACTION Prolongation of Na channel inactivation Suppression of repetitive neuronal firing GABA potentiation Antagonism of certain glutamate receptors Neuronal hyperpolarization through K channels conductance TOPIRAMATE ADVERSE EFFECTS Impairment of attention Sedation Ataxia Poor memories Weight loss Renal stones LEVETIRACETAM (KEPPRA) 1ST LINE DRUG for Focal seizures 2ND LINE DRUG for Generalized tonic clonic seizures and typical absence seizures MECH OF ACTION Bind selectively to a synaptic vesicular protein SV2A and this may alter the release of glutamate and / or GABA across the synapse ADVERSE EFFECTS Dizziness Drowsiness weakness