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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.