Antiepileptic Drugs (PDF)

‫بسم هللا الرحمن الرحيم‬ Antiepileptic Drugs (Antiseizure Drugs)  Epilepsy  Epilepsy is a very common disorder, affecting 0.5 - 1% of the population.  The characteristic event in epilepsy is the seizure, which is associated with the episodic high- frequency discharge of impulses by a...

‫بسم هللا الرحمن الرحيم‬ Antiepileptic Drugs (Antiseizure Drugs)  Epilepsy  Epilepsy is a very common disorder, affecting 0.5 - 1% of the population.  The characteristic event in epilepsy is the seizure, which is associated with the episodic high- frequency discharge of impulses by a group of neurons in the brain.  The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or 2 abnormal electrical properties of the affected cells.  Epilepsy  Usually there is no recognizable cause of epilepsy, although it often develops after brain damage, such as trauma, infection or tumor growth, or other kinds of neurologic disease.  Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm and often interfering with education and employment.  The symptoms produced depend on the function of the region of the brain that is 3 affected. Epilepsy  Involvement of the motor cortex causes convulsions.  Involvement of the hypothalamus causes peripheral autonomic discharge.  Involvement of the reticular formation in the upper brainstem leads to loss of consciousness. 4  EEG recorded from frontal (F), temporal (T) and occipital (O) sites Abnormal electrical activity during a seizure can be detected by electroencephalograph (EEG) recording 5 from electrodes distributed over the surface of the scalp.  Types of epilepsy Partial seizure: Generalized seizure: A. Simple partial A. Generalized tonic- seizures. clonic (grand mal) B. Complex partial seizures. seizure B. Absence (petit mal) C. Secondary seizures generalized C. Myoclonic jerking. D. Atonic seizures. 6  Partial seizures  Partial seizures are those in which the discharge begins locally, and often remains localized.  There are three types of partial seizures: A. Simple partial seizures (least complicated) (minimal spread of the abnormal discharge) normal consciousness and awareness are preserved. B. The complex partial seizure: Has a localized onset, but the discharge becomes more widespread (usually bilateral). C. Secondarily generalized attack: In which a partial seizure immediately precedes a 7 generalized tonic-clonic (grand mal) seizure.  Generalized seizures  There is no evidence of localized onset.  Generalized seizures involve the whole brain, immediate loss of consciousness is characteristic of generalized seizures.  The main categories of generalized seizures are: A. Generalized tonic-clonic (grand mal) seizures (They are most dramatic of all epileptic seizures and are characterized by tonic rigidity of all extremities) 8  Generalized seizures A. Generalized tonic-clonic (grand mal) seizures  Loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases.  May be followed by a period of confusion and exhaustion due to the depletion of glucose and 9 energy stores.  Generalized seizures B. The absence (petit mal) seizures: Characterized by both sudden onset and abrupt cessation. 10  Antiepileptic drugs  Therapy is symptomatic in which available drugs inhibit seizures, but neither effective prophylaxis nor cure is available.  Compliance with medication is a major problem because of the need for long-term therapy together with unwanted effects of many drugs.  Three main mechanisms appear to be important in the action of antiepileptic drugs: 1. Enhancement of GABA action. 2. Inhibition of sodium channel function. 11 3. Inhibition of calcium channel function.  Enhancement of GABA action A. Drugs that potentiate GABA action "benzodiazepines, barbiturates". B. GABA reuptake inhibitors e.g. guvacine, nipecotic acid and tiagabine. C. Drugs that inhibit GABA metabolism e.g. vigabatrin. (inhibit GABA 12 transaminase)  Inhibition of sodium channel function  This is principal mechanism of action of: phenytoin, carbamazepine, and lamotrigine; it may also contribute to the effects of phenobarbital, valproate, and topiramate. 13  Inhibition of voltage-activated Ca2+channel  This is principal mechanism of action of ethosuximide and dimethadione "used for absence seizures". 14  A. Drugs used in partial seizures and generalized tonic-clonic seizures  The major drugs for partial and generalized tonic-clonic seizures are:  Phenytoin, carbamazepine, valproate, and the barbiturates, and the newer drugs: lamotrigine, gabapentin, oxcarbazepine, topiramate and vigabatrin. 15  Phenytoin  It is highly effective in reducing the intensity and duration of electrically induced convulsions in mice, but it is ineffective against leptazol induced convulsions.  At therapeutic concentrations, the major action of phenytoin is to block sodium channels and inhibit the generation of repetitive action potential. 16  Phenytoin  Pharmacokinetics: Phenytoin is metabolized by the hepatic mixed function oxidase system (to in active) and excreted mainly as glucuronide in the urine.  Its metabolism shows the characteristic of saturation, which means that quickly can develop symptoms of toxicity.  Clinical use: Phenytoin is one of the most effective drugs against partial seizures and generalized tonic-clonic seizures.  "The drug is not effective against absence 17 seizures, which may even get worse".  Phenytoin Unwanted effects  The milder side-effects include vertigo, ataxia, headache and nystagmus, sedation and hyperplasia of the gums often develops gradually.  Hirsutism (probably results from increased androgen secretion).  Fetal malformations (cleft palate).  Severe idiosyncratic reactions, including hepatitis and skin reactions. 18  Carbamazepine Tegretol®  Pharmacologically and clinically its actions resemble those of phenytoin, it appears to be particularly effective in treating complex partial seizures.  Mechanism of action:  Carbamazepine blocks sodium channels at therapeutic concentrations and inhibits high- frequency repetitive firing in neurons. 19  Carbamazepine  Clinical use:  Carbamazepine is considered the drug of choice for partial seizures, and many physicians also use it first for generalized tonic-clonic seizures.  It can be used with phenytoin in many patients who are difficult to control.  The drug is also very effective in some patients with trigeminal neuralgia.  The drug is also useful in some patients with mania (bipolar disorder). 20  Carbamazepine  Pharmacokinetics:  Carbamazepine is well absorbed. Peak levels are usually achieved 6-8 hours after administration.  Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses.  Unwanted effects: The most common dose- related adverse effects are diplopia and ataxia. Other dose-related complaints include mild gastrointestinal upsets and drowsiness. 21  Phenobarbital  The antiepileptic effect of phenobarbital is activity profile closely resembling phenytoin, it is ineffective in treating absence seizures. Mechanism of action: Like phenytoin, phenobarbital suppress high-frequency repetitive firing in neurons in culture through action on Na+ conductance, but only at high concentrations. Clinical use: Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures.  Phenobarbital may worsen certain patients with 22 absence seizures and atonic attacks.  Phenobarbital Unwanted effects  The main unwanted effect of phenobarbital is sedation, others include megaloblastic anemia (like that caused by phenytoin), mild hypersensitivity reactions and osteomalacia.  Like other barbiturates it must not be given to patients with porphyria.  In overdose, phenobarbital produces coma and respiratory and circulatory failure, as do all barbiturates. 23  Lamotrigine  Lamotrigine principal mechanism of action, like that of phenytoin, it also inhibit the release of excitatory amino acids.  Lamotrigine is almost completely absorbed. Protein binding is only about 55%. Its plasma half-life is about 24 hours. Clinical use: Most controlled studies have evaluated lamotrigine as add-on therapy; some also suggest that the drug is effective as monotherapy for partial seizures.  The drug also active against absence and myoclonic seizures in children. Adverse effects: Dizziness, headache, diplopia, nausea, 24 somnolence (sleeping), and skin rash.  Gabapentin and Pregabalin  Their main mechanism of action appears to be on T-type calcium channel function and they also inhibit the release of various neurotransmitters and modulators, but the details remain unclear.  They are effective as an adjunct against partial seizure and tonic-clonic seizures.  They have also been found effective in the treatment of neuropathic pain.  Side effects: Their side effects (mainly sedation and ataxia) are less severe than with many antiepileptic drugs. 25  Pregabalin extensively abused Lyrica®.  Topiramate  Topiramate appears to do a little of everything (pleiotropic), blocking sodium channels, enhancing the action of GABA, blocking AMPA receptors and weakly inhibiting carbonic anhydrase.  Its spectrum of action resembles that of phenytoin.  It produces less severe side effects. Its main drawback is that (like many antiepileptic drugs) it is teratogenic in animals.  It is recommended for use as add-on therapy in refractory cases of epilepsy. 26  B. Drugs used in generalized seizures  The major drugs for generalized seizures are ethosuximide, valproic acid and oxazolidinediones (trimethadione, paramethadione, and dimethadione)  "Trimethadione, the first drug found to be effective in absence seizures, has now been supplanted by ethosuximide, which has fewer unwanted effects, especially sedation and hypersensitive reactions".  Oxazolidinediones inhibit Ca2+ currents as 27 ethosuximide (T-type calcium).  Ethosuximide  The main effect described is inhibition of a calcium channel subtype (T-channel).  Ethosuximide is particularly effective against absence seizures.  The most common adverse effects are gastric distress, including pain, nausea, and vomiting (can be avoided by starting therapy at a low dose, with gradual increases to therapeutic range“).  Other dose-related adverse effects include transient fatigue and, much less commonly, 28 headache, dizziness, hiccup, and euphoria.  Valproic acid (sodium valproate)  Valproate has many effects, and probably works by several mechanism (pleiotropic): 1. It causes a significant increase in the GABA content of the brain and is a weak inhibitor of GABA- transaminase. 2. It facilitates glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. 3. It inhibits GABA transporter (GAT-1). 4. It inhibits sodium channels, (weaker than those of phenytoin). 29  Valproic acid (sodium valproate) Clinical uses  Valproate is effective against absence seizures.  “Although ethosuximide is the drug of choice when absence seizures occur alone, valproate is preferred if the patient has concomitant generalized tonic-clonic attacks.  Valproate is unique in its ability to control certain types of myoclonic seizures.  Other uses of valproate include management of bipolar disorder and migraine prophylaxis. 30  Valproic acid (sodium valproate) Side effects and toxicity  The most common dose-related adverse effects of valproate are nausea, vomiting, abdominal pain and heartburn.  A fine tremor is frequently seen at higher levels.  Reversible adverse effects include weight gain, increased appetite, and hair loss.  The most serious side-effect is hepatotoxicity. but proven cases are rare.  Valproate is teratogenic, causing spina bifida 31 and other neural tube defects.  Other drugs used in management of epilepsy Benzodiazepines  Diazepam, given intravenously, is used to treat status epilepticus, a life-threatening condition in which epileptic seizures occur almost without a break.  Its advantage in this situation is that it acts very rapidly compared with other antiepileptic drugs. 32  Benzodiazepines  Clonazepam, be relatively selective as antiepileptic drugs.  Sedation is the main side-effect of benzodiazepines (an added problem) may be the withdrawal syndrome, which results in an exacerbation of seizures if the drug is stopped. 33  Acetazolamide  The depolarizing action of bicarbonate ions moving out of neurons via GABA receptor ion channels will be diminished by carbonic anhydrase inhibition.  Acetazolamide has been used for all types of seizures but is severely limited by the rapid development of tolerance, with return of seizures usually within a few weeks.  The drug may have a special role in epileptic women who experience seizure exacerbations at the time of menses; tolerance may not develop 34 because the drug is not administered continuously.  Management of status epilepticus  There are many forms of status epilepticus. The most common, generalized tonic-clonic status epilepticus, a life-threatening emergency. 1. Diazepam is the most effective drug in most patients for stopping the attacks and is given directly by intravenous push to a maximum total dose of 20-30 mg in adults. 2. Phenytoin should be given as a loading dose of 13-18 mg/kg in adults. A ministration should be at a maximum rate of 50 mg/min. careful monitoring of cardiac rhythm and blood pressure 35 is necessary, especially in elderly people.  Management of status epilepticus 3. For patients who do not respond to phenytoin, Phenobarbital can be given in large doses: 100 -200 mg intravenously to a total of 400 -800 mg. Respiratory depression is a common complication, especially if benzodiazepines have already been given, and there should be no hesitation in instituting intubation and ventilation. 36 37