Transcript lec.8-426
Anticonvulsants • Anticonvulsants (antiepileptics) are drugs which selectively depress the central nervous system. • Epilepsy is characterized by abnormal and excessive electroencephalographic discharge and a disturbance or loss of consciousness. • Three principle types of epilepsy are found: 1. Grandmal 2. Petitmal 3. Psychomotor seizures • Grandmal – in which the seizures last from 2-5 min, being characterized by sudden loss of consciousness, tonic and clonic convulsions of all muscles, urinary incontinence. • Petitmal – the seizures last from 5 to 30 s, being characterized by brief attacks of unconsciousness; occurs often in children at the at the age of 4 to 8 years. • Psychomotor seizures – characterized by attacks without convulsions lasting from 2 to 3 min. • The primary use of anticonvulsants drugs is in the prevention and control of epileptic seizures. • The ideal antiepileptic drug should completely suppress seizures in doses that do not cause sedation or other undesired CNS toxicity. • It should be well tolerated and highly effective against various types of seizures, devoid of undesirable side effects on vital organs and functions. • The onset of action should be rapid after parental injection for control of status epilepticus, and it should have a long duration of effect after oral administration for prevention of recurrent seizures. Classification • The different chemical classes of anticonvulsants agents are: • (a) Barbiturates, (e) Sulfonamides, • (b) Hydantoins, (f) Benzodiazepines, • (c) Oxazolidinediones, (g) GABA analogs, • (d) Succinimides, (h) Miscellaneous – semicarbazones. Based on their mechanism of action they can be classified as follows: Enhancement of Na+ channel inactivation. Phenytoin, Carbamazepine and valproate. 2. Enhanced GABA synaptic transmission. a. Agents acting on the GABA/Cl- ionophore complex. Progabide. b. Agents that potentiate GABA: i. GABA transaminase inhibitors. Vigabatrin. ii. GABA reuptake inhibitors. c. Agents that bind to benzodiazepine receptors. Clobazam, flumazenil. d. Agents that laid to barbiturate receptors. Phenobarbital, mephobarbital 3. Reduction of current through T-type Ca+ channels. Ethosuximide, Dimethdione, Valproate. 1. • Most of the anticonvulsant drugs contain the ureide structure. An overall pattern is that R` and R`` should be hydrocarbon radicals. If both are lower alkyl groups, the tendency is to be active against petit mal. If one is an aryl group, activity tends to be directed to grand mal epilepsy. O R1 R2 O R1 R2 O NH N R O NH N R O R1 R2 O N R O R1 R2 O N R O O Barbiturates Barbiturates are 5,5 disubstituted barbituric acid Phenobarbital • It is the most widely used anticonvulsant. • It is the drug of choice for infants and young children. • It is clinically used in grandmal and partial (psychomotor) seizures. • Phenobarbital is metabolized by hydroxylation to………. Mephobarbital • It is used in the treatment of grandmal, petitmal and partial seizures. O NH • It is metabolized by demethylation 1 O 2 N O CH3 1-Methyl-5-ethyl-5-phenylbarbituric acid Methbarbital • It is used only for the grandmal seizures. • It is metabolized to barbital in the body. General Method of Synthesis Structure-Activity Relationship A. Factors that abolish activity: 1. Both hydrogen atoms at position 5 should be substituted (pka ≈ 7.6). The unsubstituted or monosubstituted are very acidic (pka ≈ 4) so the compounds are largely ionized at physiological pHs, with little lipid soluble compound available to cross the BBB. 2. Polar functions at C5. 3. Methylene and benzylidene moiety. 4. Substituents with total number of carbon atoms greater than 9 B. Factors that increase the activity: 1. Spiro compounds increase the activity safely. 2. C5-phenylsubstituent. C. Factors that shorten the duration of action 1. there is inverse correlation between the total number of carbon atoms on C5 and the duration. 2. Branching of the alkyl group.