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Anti convulsants
- 2. INTRODUCTION • Group of disorders characterized by chronic, recurrent, paroxysmal changes in neuralgic function caused by abnormalities in electrical activity of the brain. • They are one of the common neuralgic disorders, estimated to affect 0.52% of the population and can occur at any age. • Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. • Anticonvulsants also prevent the spread of the seizure within the brain. • Conventional antiepileptic drugs may block sodium channels or enhance γ- aminobutyric acid (GABA) function.
- 3. TYPES OF EPILEPSY • Grand Mal – Most common – 2 to 5 minutes – Person often experiences an aura (sounds, fear discomfort) immediately before a seizure. – Loss consciousness and has tonic-clonic convulsions.. • Petit Mal – Mostly found in children. – 1 to 30 seconds – Person stops what he is doing and after the seizure resumes what he was doing before the seizure. (persons may not aware of seizure). • Jacksonian (Focal) – Rare – 1 to 2 minutes – It is usually associated with lesion of a certain part of the brain (cerebral cortex). – Focal or local clonic type convulsions of localized muscle. • Psychomotor – Rare – It is characterized by periods of abnormal types of behavior. – The individual experience an aura with perceptual alterations (hallucinations or sense of fear).
- 4. MECHANISM OF ACTION • Seizures are caused by abnormal stimulation of nerves in the brain by other nerves. • Generally, anticonvulsants reduce the excitability of the neurons (nerve cells) of the brain. When neuron excitability is decreased, seizures are theoretically reduced in intensity and frequency of occurrence or, in some instances, are virtually eliminated. • However, it is believed that the anticonvulsants suppress seizures by depressing the cerebral (motor) cortex of the brain, thereby raising the threshold of the central nervous system (CNS) to convulsive stimuli. Therefore, the person is less likely to undergo seizures.
- 5. BARBITURATRES • Barbiturates are central nervous system (CNS) depressants (medicines that cause drowsiness). • Barbiturates produce a wide spectrum of CNS depression, from mild sedation to coma, and have been used as sedatives, hypnotics, anesthetics and anticonvulsants. But, they can be addictive and abused. • Excessive doses can cause depression, slurred speech, slowed reflexes and confusion. • SAR : – Hypnotic activity. Side chains at position 5 (especially if one of them is branched) is essential for activity. – Potency and duration of action. Length of side chain at position 5 influences potency and duration of action. Ex: Secobarbital and thiamylal are slightly more potent than pentobarbital and thiopental, respectively.
- 6. • Sulfur instead of oxygen atom at postion 2 has more rapid onset of action but shorter duration. Ex: thiamylal and thiopental have more rapid onset and shorter duration of action than secobarbital and pentobarbital, respectively. • Increased incidence of excitatory side effects. Methylation at position 1 (methohexital) enhances excitatory side effects. • Generally an increase in the lipophilicity of the compound results in more rapid onset of action accompanied with an increase in potency. • Introduction of polar groups (hydroxyl, keto, amino, or carboxyl) into C-5- alkyl side chain makes the compound more hydrophilic in nature. Due to the polar nature, hydrophilic barbiturates do not dissolve in microsomal membranes of liver and are excreted. • Branched, cyclic or unsaturated side chain at C-5 position generally reduce the duration of action due to an increased ease of metabolic conversion to a more polar, inactive metabolite. 1 3 2 4 5 6
- 7. • Phenobarbitone – White, crystalline powder – Hygroscopic substance – Freely soluble in water and also soluble in alcohol. – Used as sedative, hypnotic and antiepileptic (drug of choice in the treatment of grandmal and petitmal epilepsy). It is useful in nervous and related tension states. An overdose of it can result in coma, severe r hypotension leading to cardiovascular collapse, and renal failure. • Methabarbital – White, crystalline powder – odourless, with a bitter taste – Soluble in water, alcohol, chloroform, and in solutions of alkali hydroxides or carbonates. – Mephobarbitone is a strong sedative with anticonvulsant action, but a relatively mild hypnotic. Hence, it is used for the relief of anxiety, tension, and apprehension, and is an antiepileptic in the management of generalized tonic clonic and absence seizures.
- 8. HYDANTOINS • Hydantoins prevent repetitive detonation of normal brain cells during depolarization shift. This is achieved by prolonging the inactived state of voltage gate sensitive sodium channels and governs the refractory period of specific neurons, moreover, reduces the calcium infl ux and inhibits the glutamate activity. Intracellular storation of Na+ leads to the prevention of repetitive firing. • SAR: – 5-phenyl or other aromatic substitution is essential for activity. – Alkyl substituent at position 5 may contribute to sedation, a property absent in phenytoin. – Among other hypnotics 1,3- disubstituted hydantoins, exhibit activity against chemically induced convulsion, while it remains ineffective against electric shock induced convulsion phenytoin, mephenytoin, ethotoin.
- 9. • Phenytoin – White crystalline powder – Slightly hygroscopic – Insoluble in methylene chloride, soluble alcohol. – It is also used in the treatment of cardiac arrhythrmias. • Mephenytoin – It is one of the first hydantoin introduced into therapy. – It is converted into N-demethyl metabolite 5- phenyl-5-ethyl hydantoin. – It was introduced as a sedative- hypnotic and anticonvulsant under the name Nirvanol, but it was withdrawn because of toxicity.
- 10. OXAZOLIDINEDIONES • Oxazolidine-2, 4-dione is analogous to hydantoin differs in having of oxygen atom at position 1 instead of NH. • SAR: – Replacement of the -NH group at position 1 of the hydantoin system with an oxygen atom yields the OXAZOLIDINE-2,4-dione system. – 3,5,5-Trimethadione (tridione) was the fi rst drug introduced specifi cally for treating absence seizures. It is also important as a prototype structure. – The nature of the substituent on C--5 is important, example, lower alkyl substituents towards antipetitmal activity while acyl substituents towards antigrandmal activity. – The N-alkyl substituent does not alter or afford the activity since all the clinically used agents from this class undergo N-dealkylation in metabolism.
- 11. • Trimethadione – Colourless crystals – soluble in water and alcohol – It is first drug introduced specifically for treating absence seizures. – It is important as a prototype structure for antiabsence seizure compounds. – It is metabolized by N-demethylation to putative active metabolite dimethadone and it is further excreted unchanged. – It is used as an antipetitmal agent. It causes nephrosis, aplastic anaemia and bone marrow depression. • Paramethadione – It is an oily liquid – slightly soluble in water and freely soluble in ethanol.
- 12. SUCCINIMIDES • SAR: – The activity of antiepileptic agents, such as the oxazolidine 2,4-dione with substituted succinamides (CH2 replace O) was logical choice for synthesis and evaluation. – N-demethylation occurs to yield the putative active metabolite. – Both phensuximide and the N-demethyl metabolite are inactivated by p-hydroxylation and conjugation. • Phensuximide – It is a crystalline solid – soluble in water and freely soluble in ethanol. – N-demethylation occurs to yield active metabolite, both phensuximide and N-demethyl metabolites are inactived by para hydroxylation and conjugation. – The phenyl substituent confers some activity against generalized tonic clonic and partial seizures. It is used in the treatment of petitmal epilepsy.
- 13. • Methusuximide – It is more active than phensuximide, and used in the treatment of petitmal epilepsy. – It is metabolized into N-demethylsuximide and the metabolite is also an active compound. • Ethosuximide – White powder or waxy solid – Freely soluble in water, ethanol, and methylene chloride. – It is metabolized into 3-(1-hydroxyethyl) compound. – It is a calcium-T channel blocking drug, effective in the cure of petitmal epilepsy.
- 14. UREA AND MONOACYLUREAS • Phenacimide – Used mainly in psychomotor epilepsy. • Carbamazepine – White or almost white crystalline powder – shows polymorphism – slightly soluble in water, freely soluble in methylene chloride – It inhibits voltage-dependent sodium channels. – It is urea derivative (broad spectrum anti-seizure agent), but is toxic, used to treat partial seizures and grandmal seizures. – It is also useful in the treatment of pain associated with trigeminal neuralgia.
- 15. BENZODIAZEPINES • Benzodiazepines are the most commonly used anxiolytics and hypnotics. They act at benzodiazepine receptors, which are associated with gamma- aminobutyric acid (GABA) receptors. • SAR: – Almost all active benzodiazepines, except those possessing a fused heterocyclic ring or a thionyl group, have a carbonyl group at position 2. – The presence of electron attracting substituents (Cl, F, Br, NO2) at position C-7 is required for the activity, and the more electron attracting substituents leads to potent activity. – Position 6, 8, and 9 should be unsubstituted for the activity. – Phenyl (or) pyridyl at the C-5 position promotes activity. If the phenyl ring substituted with electron attracting groups at 2’ or 2’, 6’ position, then the activity is increased. – On the other hand, substituents at 3’, 4’, and 5’ positions decreases activity greatly.
- 16. – Saturation of 4, 5 double bond or shift of it to the 3, 4 position decreases the activity. – Alkyl substitution at position 3 decreases the activity, but the presence or absence of hydroxyl group is essential. Compounds without 3-hydroxyl group are nonpolar and usually have long half-life. Compounds with the 3-hydroxyl group have short half-life because of rapid conjugation with glucuronic acid. – Substitution at N1 by alkyl, halo alkyl, and amino alkyl group increases the activity. – Reduction of carbonyl function at C-2 position to CH2 yields less potent compound. • Clonazepam – A triazolobenzodiazepine derivative that structurally resembles alprazolam and triazolam. – It is useful in the management of insomnia. – It causes more serious toxicity and withdrawal reactions than other benzodiazepines.
- 17. MISCELLANEOUS • Primidone • Valproic acid • Gabapentin • Felbamate
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