ANTI-EPILEPTICS DRUGS- LECTURE 5 KANS.pptx

ANTI-EPILEPTICS DRUGS- LECTURE 5 KANS.pptx

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  ANTI-EPILEPTICS DRUGS
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  Epilepsy is agroup of long term neurological disorder characterized by epileptic seizures. These seizures are episodes which vary from brief and nearly undetectable to long periods of vigorous shaking. • Seizures due to epilepsy tend to recur and have no immediate cause while seizures that occur right around a specific cause are not deemed to be epilepsy.
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  • The causein most cases is unknown, while some are the result of brain trauma, stroke, brain cancer, and drug and alcohol misuse among others. Epileptic seizures are the result of excessive and abnormal cortical nerve cell activity in the brain. • The diagnosis typically involves ruling out other conditions that might cause similar symptoms (such as syncope-Loss of consciousness and postural tone caused by diminished cerebral blood flow) as well as figuring out if any immediate causes are present. Epilepsy can sometimes be confirmed with an electroencephalogram.
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  • Epilepsy iscontrollable, but not cured, with medication in about 70% of cases.[5] In those who do not get control surgery, neurostimulation or dietary changes may be considered. Not all epilepsy syndromes are lifelong, and a substantial number of people improve to the point that medication is no longer needed.
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  • About 1%of people worldwide (65 million) have epilepsy,and nearly 80% of cases occur in developing countries. • Epilepsy becomes more common as people age. Onset of new cases occurs most frequently in infants and the elderly in the developed worldand in older children and young adults in the developing world. • About 5–10% of all people will have an unprovoked seizure by the age of 80,and the chance of experiencing a second seizure is between 40% and 50%.
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  Signs and symptoms 1.Seizures • The most common type (60%) of seizures are convulsive. Of these, two-thirds begin as focal seizures (which may then become generalized) while one-third begin as generalized seizures.The remaining 40% of seizures are non-convulsive. An example of this type is the absence seizure, which presents as a decreased level of consciousness and usually lasts about 10 seconds. • About 6% of those with epilepsy have seizures that are often triggered by specific events and are known as reflex seizures. Those with reflex epilepsy have seizures that are only triggered by specific stimuli .Common triggers include flashing lights and sudden noises. In certain types of epilepsy, seizures happen more often during sleep, and in other types they occur almost only when sleeping. 2. Physical • Loss of bowel or bladder control may occur. The tongue may be bitten at either the tip or on the sides during a seizure. In tonic-clonic seizure, bites to the sides are more common. Tongue bites are also relatively common in psychogenic non-epileptic seizures.
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  3. Psychosocial • Epilepsycan have adverse effects on social and psychological well-being. These effects may include social isolation, stigmatization, or disability. They may result in lower educational achievement and worse employment outcomes. Learning difficulties are common in those with the condition, and especially among children with epilepsy. The stigma of epilepsy can also affect the families of those with the disease. 4. Associated conditions • Certain disorders occur more often in people with epilepsy, depending partly on the epilepsy syndrome present. These include: depression, anxiety disorders, and migraines.Attention-deficit hyperactivity disorder affects three to five times more children with epilepsy than children in the general population. ADHD and epilepsy have significant consequences on a child's behavioral, learning, and social development. Epilepsy is also more common in those with autism.
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  Causes 1. Genetics • Geneticsis believed to be involved in the majority of cases, either directly or indirectly. Some epilepsies are due to a single gene defect (1-2%); most are due to the interaction of multiple genes and environmental factors. Some of the genes involved affect ion channels, enzymes, GABA, and G protein-coupled receptors. • In identical twins, if one is affected there is a 50-60% chance that the other will also be affected. In non-identical twins the risk is 15%. These risks are greater in those with generalized than focal seizures. If both twins are affected, most of the time they have the same epileptic syndrome (70- 90%). • Close relatives have a risk five times that of the general population. Between 1-10% of those with Down syndrome and 90% of those with Angelman syndrome have epilepsy.
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  2. Secondary • Epilepsymay occur as a result of a number of other conditions including: tumors, strokes, head trauma, infections of the central nervous system, genetic abnormalities, and as a result of brain damage around the time of birth. • The risk of epilepsy following meningitis is less than 10%; that disease more commonly causes seizures during the infection itself. In herpes simplex encephalitis the risk of a seizure is around 50%. Infection with the port tapeworm, which can result in neurocysticercosis, is the cause of up to half of epilepsy cases in areas of the world where the parasite is common. As well, epilepsy may occur after other brain infections such as cerebral malaria, toxoplasmosis, and toxocariasis. Chronic alcohol use increases the risk of epilepsy: those who drink six drinks per day have a two and a half fold increase in risk. • Other risks include Alzheimer's disease, multiple sclerosis, tuberous sclerosis, and autoimmune encephalitis. Getting vaccinated does not increase the risk of epilepsy.Malnutrition is a risk factor seen mostly in the developing world.
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  CLASSIFICATION OF SEIZURETYPES 1. Partial seizures • Simple partial seizures • Complex partial seizures • Partial seizures secondarily generalized 2. Generalized seizures • Generalized tonic-clonic (grand mal) seizures • Absence (petit mal) seizures • Tonic seizures • Atonic seizures • Clonic and myoclonic seizures • Infantile spasms1
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  Drugs Used inPartial Seizures & Generalized Tonic-Clonic Seizures HYDANTOINS 1. PHENYTOIN • The oldest nonsedative antiseizure drug. (a) Mechanism of Action • Phenytoin has major effects on several physiologic systems. It alters Na+ , K+ , and Ca2+ conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine, acetylcholine, and -aminobutyric acid (GABA).
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  • Studies withneurons in cell culture show that phenytoin blocks sustained high-frequency repetitive firing of action potentials. This effect is seen at therapeutically relevant concentrations. (b) Clinical Use • Phenytoin is effective against partial seizures and generalized tonic-clonic seizures. In the latter, it appears to be effective against attacks that are either primary or secondary to another seizure type.
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  (c) Pharmacokinetics • Absorptionof phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 hours to 12 hours. • Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended for phenytoin.
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  • Phenytoin ishighly bound to plasma proteins. The total plasma level decreases when the percentage that is bound decreases, as in uremia or hypoalbuminemia, but correlation of free levels with clinical states remains uncertain. • Drug concentration in cerebrospinal fluid is proportionate to the free plasma level. Phenytoin accumulates in brain, liver, muscle, and fat. Phenytoin is metabolized to inactive metabolites that are excreted in the urine. Only a very small proportion of phenytoin is excreted unchanged. • The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached
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  (d) Toxicity • Thetoxic effects of phenytoin depend on the route of administration, the duration of exposure, and the dosage. • cardiac arrhythmias with or without hypotension, CNS depression, Gingival hyperplasia, cerebellar atrophy etc.
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  (e) Therapeutic Uses. •Phenytoin is one of the more widely used antiseizure agents, and it is effective against partial and tonic-clonic but not absence seizures.
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  2. MEPHENYTOIN, ETHOTOIN,& PHENACEMIDE • Many congeners of phenytoin have been synthesized, but only three have been marketed recently in the USA, and one of these (phenacemide) has been withdrawn from the market. The other two congeners, mephenytoin and ethotoin, like phenytoin, appear to be most effective against generalized tonic-clonic seizures and partial seizures. • The incidence of severe reactions such as dermatitis, agranulocytosis, or hepatitis is higher for mephenytoin than for phenytoin. • Ethotoin may be recommended for patients hypersensitive to phenytoin, but larger doses are required. The adverse effects and toxicity are generally less severe than those associated with phenytoin, but the drug appears to be less effective.
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  BARBITURATES 1. Phenobarbital • Mostbarbiturates have antiseizure properties. However, only some of these agents, such as phenobarbital, exert maximal antiseizure action at doses below those required for hypnosis, which determines their clinical utility as antiseizure agents. Phenobarbital is active in most antiseizure tests in animals but is relatively nonselective. It inhibits tonic hindlimb extension in the maximal electroshock model, clonic seizures evoked by pentylenetetrazol, and kindled seizures. (a) Mechanism of Action • The mechanism by which phenobarbital inhibits seizures likely involves potentiation of synaptic inhibition through an action on the GABAA receptor. • At levels exceeding therapeutic concentrations, phenobarbital also limits sustained repetitive firing; this may underlie some of the antiseizure effects of higher concentrations of phenobarbital achieved during therapy of status epilepticus. (b) Pharmacokinetic Properties. • Oral absorption of phenobarbital is complete but somewhat slow; peak concentrations in plasma occur several hours after a single dose.
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  (c) Toxicity. Sedation,Nystagmus and ataxia occur at excessive dosage, irritability and hyperactivity in children, agitation and confusion in the elderly, Scarlatiniform or morbilliform rash, Hypoprothrombinemia with hemorrhage has been observed in the newborns of mothers who have received phenobarbital during pregnancy-vitamin K is effective for treatment or prophylaxis.
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  (d) Clinical Use •Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug is often tried for virtually every seizure type, especially when attacks are difficult to control. There is little evidence for its effectiveness in generalized seizures such as absence, atonic attacks, and infantile spasms; it may worsen certain patients with these seizure types. • Some physicians prefer either metharbital or mephobarbital— especially the latter—to phenobarbital because of supposed decreased adverse effects. Only anecdotal data are available to support such comparisons.
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  IMINOSTILBENES 1. Carbamazepine (TEGRETOL,CARBATROL, others) • Was initially approved in the United States for use as an antiseizure agent in 1974. It has been employed since the 1960s for the treatment of trigeminal neuralgia. It is now considered to be a primary drug for the treatment of partial and tonic-clonic seizures. (a) Mechanism of Action. • The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture. • It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known.
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  (b) Therapeutic Uses. •Carbamazepine is useful in patients with generalized tonic-clonic and both simple and complex partial seizures. When it is used, renal and hepatic function and hematological parameters should be monitored. (c) Drug Interactions. • Phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4; carbamazepine may enhance the biotransformation of phenytoin. Concurrent administration of carbamazepine may lower concentrations of valproate, lamotrigine, tiagabine, and topiramate. Carbamazepine reduces both the plasma concentration and therapeutic effect of haloperidol. The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid.
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  2. Oxcarbazepine • Oxcarbazepineis closely related to carbamazepine and useful in the same seizure types, but it may have an improved toxicity profile. • It is less potent than carbamazepine
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  SUCCINIMIDES 1. Ethosuximide (ZARONTIN) •is a primary agent for the treatment of absence seizures. • Acts by reducing low threshold Ca2+ currents (T currents) in thalamic neurons. • It is effective against absence seizures but not tonic-clonic seizures.
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  VALPROIC ACID • Itis strikingly different from phenytoin or ethosuximide in that it is effective in inhibiting seizures in a variety of models. • produces effects on isolated neurons similar to those of phenytoin and ethosuximide. At therapeutically relevant concentrations, valproate inhibits sustained repetitive firing induced by depolarization of mouse cortical or spinal cord neurons. • It is effective in the treatment of absence, myoclonic, partial, and tonic-clonic seizures.