Anticonvulsants

1
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

2

• 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.

3

• 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.

4
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.

5

• Based on their mechanism of action they
  can be classified as follows
• Enhancement of Na channel inactivation.
  Phenytoin, Carbamazepine and valproate.
• 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
• Reduction of current through T-type Ca
  channels. Ethosuximide,
• Dimethdione, Valproate.

6

• 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.

7
(No Transcript)
8
Barbiturates

• Barbiturates are 5,5 disubstituted barbituric acid

9
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.

10
Mephobarbital

• It is used in the treatment of grandmal, petitmal
  and partial seizures.
• It is metabolized by demethylation

11
Methbarbital

• It is used only for the grandmal seizures.
• It is metabolized to barbital in the body.

12
General Method of Synthesis
13
Structure-Activity Relationship

• 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

14

• Factors that increase the activity
• 1. Spiro compounds increase the activity
  safely.
• 2. C5-phenylsubstituent.
• 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.