e-content of Anticonvulsant and H1 and H2 receptor antagonist for M.pharm students.

1. ANTI-CONVULSANT AND
H1 & H2 RECEPTOR ANTAGONIST
Presenting by:
Mr. PURSHOTHAM K N
Asst. Professor,
Dept. of Pharmaceutical Chemistry
SAC College of Pharmacy.
2021-2022

2. DEFINATION:
• Epilepsy is a brain disorder in which clusters of nerve cells, or neurons,
in the brain sometimes signal abnormally.
• Neurons normally generate electrochemical impulses that act on other
neurons, glands, and muscles to produce human thoughts, feelings, and
actions.
• In epilepsy, the normal pattern of neuronal activity becomes disturbed,
causing strange sensations, emotions, and behavior, or sometimes
convulsions, ,and loss of consciousness.

3. TYPES OF SEIZURES:
1) Generalised seizures: affects both sides of the brain.
a. Absence seizures.
b. Tonic-clonic seizures.
a. Absence seizures,
sometimes called petit mal seizures, can cause rapid blinking
or a few seconds of staring into space.
b. Tonic-clonic seizures.
also called grand mal seizures, can make a person. Cry out,
Lose consciousness, Fall to the ground, Have muscle jerks or spasms.

4. 2) Focal seizures:
are located in just one area of the brain. These seizures are also called
partial seizures
a. Simple focal seizures affect a small part of the brain. These seizures
can cause twitching or a change in sensation, such as a strange taste or
smell.
b. Complex focal seizures can make a person with epilepsy confused or
dazed. The person will be unable to respond to questions or direction for
up to a few minutes.
c. Secondary generalized seizures begin in one part of the brain, but then
spread to both sides of the brain. In other words, the person first has a
focal seizure, followed by a generalized seizure.

5. ANTI-CONVULSANT DRUG
• These drugs that is used to prevent or treat seizures or convulsions by
controlling abnormal electrical activity in the brain.
• Are used to treat epilepsy and other seizure disorders.

6. CLASSIFICATION OF ANTIEPILEPTIC DRUGS
a. Hydantoins: phenytoin, phosphenytoin.
b. Barbiturates: phenobarbitone.
c. Iminostilbenes: carbamazepine, oxcarbazepine.
d. Succinimides: ethosuximide.
e. Aliphatic carboxylic acid: Valproic acid, divalproex
f. Benzodiazepines: clonazepam, diazepam, lorazepam.
g.Newer compounds: gabapentin, lamotrigine, tiagabine, topiramate,
vigabatrin, zonisamide, felbamate.

7. PHENYTOIN PHENOBARBITONE CARBAMAZEPINE
ETHOSUXIMIDE VALPROIC ACID

9. Mechanism Of Action Barbiturates
• Barbiturates are general depressants of all cell of the body, acting as a
cellular histotoxic agent. But the cell of the CNS are more sensitive to
barbiturate action.
1.Barbiturate induce sleep by selectively depressing RAS inthe brain stem.
2.Barbiturate selectively depress neuronal activity in posterior
hypothalamus, amygdaloid nucleus& limbic structure (CNS depression)
3.Barbiturates depress monosynptic pathway of spinalcord (anticanvulsion)
Barbiturates have also GABA like activity or enhance GABA activity.

10. MECHANISM OF ACTION BENZODIAZEPINES
• Benzodiazepines work by increasing the efficiency of a natural brain
chemical, GABA, to decrease the excitability of neurons. This reduces
the communication between neurons and, therefore, has a calming effect
on many of the functions of the brain.
• GABA controls the excitability of neurons by binding to the GABA
receptor. GABA receptors contain an ion channel that conducts chloride
ions across neuronal cell membranes, GABAa receptor complexes also
contain a single binding site for benzodiazepines.
• Binding of benzodiazepines to this receptor complex promotes binding
of GABA, which in turn increases the conduction of chloride ions across
the neuronal cell membrane. This increased conductance raises the
membrane potential of the neuron, resulting in inhibition of neuronal
firing.

11. Mechanism of action of Gabapentin:
• Enhances GABA activity.
• Binds to alpha-2-delta subunit of voltage gated calcium channels
• Inhibits high-voltage-activated calcium currents.
• Result is decreased synaptic transmission

12. STRUCTURE ACTIVITY RELATIONSHIP OF:
• Hydantoin.
• Barbiturates.
• Benzodiazepins.
• Valproic acid.
• Succinimides.

13. HYDANTOIN:
• A phenyl or other aromatic substituents at C5 is essential for the
activity.
• Alkyl substituents at position 5 may contribute to sedation, a property
absent in phenytoin.
• Among other hydantoins some exhibits activity against chemically
induced convulsions.
• While remaining are ineffective against electro shock induced
convulsions.

14. BARBITURATES:
• Optimum activity is observed when one of the substituents at C5 is
phenyl.
• The 5, 5-diphenyl derivatives have less activity than phenobarbitone.
• N2 and N3 substituents, in some cases also results in an increased
activity.
• 5,5-dibenzyl barbituric acid causes convulsions.

15. BENZODIAZEPINES:
• The electron withdrawing atom or group at position 7 increases the anti-
epileptic activity while electron donating substituents at 7, 8 or 9
positions decrease it.
• A phenyl group at position 5 is necessary for activity. But only halogen
substituents are allowed in the ortho position.
• The electron withdrawing groups at ortho or di-ortho positions at 5-
phenyl increase the activity while any substituents on meta or para
position at 5-phenyl decreases the activity.
• Methyl substitution at position 1 confirms high activity.

16. VALPROIC ACID:
• Among other relatives of valproic acid, 3, 3, 4-trimethylpentanoic acid
is also as active as valproic acid.
• The anticonvulsant activity increases with increased chain length.
• Introduction of a double bond decreases the activity.

17. SUCCINIMIDES:
• Methsuximide and phensuximide have phenyl substituents which makes
them active against electrically induced convulsion.
• N-Methylation decreases activity against electroshock seizures and
impart more activity against chemically induced convulsion.

18. Synthesis of phenytoin:

19. H1 AND H2 RECEPTORS ANTAGONIST:
• Histamine is a chemical messenger which are synthesized in the mast cells.
• Structurally histamines is 4-(2-amino ethyl)- imidazole.
• The histamines are available in two tautomeric forms.

20. • Generally histamines are found in the animal tissue, venoms of insect,
bacteria and plant.
• Pharmacologically histamine causes the vasodilatation of capillaries
and which increase the rate of flow and this cause edema, increase heart
rate, stimulate gastric fluids and which lead to the formation of ulcers.
• The human body contains histaminic receptor and are divided into three
different types upon their action.
1. H1-receptors.
2. H2-receptors.
3. H3-receptors

23. CLASSIFICATION OF H1 RECEPTOR ANTAGONIST:
• Ethylene diamine derivative:
ex: 1.Meperamine(Pyrilamine)
Uses:
a. Antihistaminic.
b. Antitussive
c. Less sedative.

24. • Aminoalkyl ethers:
ex: Diphenhydramine.
Uses:
Anticholinergic.
Sedative
Treat motion sickness

25. • Aminopropyl compound:
ex: Pheneramine.
• Tricyclic ring system:
ex: Promethazine.

26. CLASSIFICATION OF H2 RECEPTOR ANTAGONIST:
• Cimetidine:
Uses:
To treat ulcer.
Used to treat GERD.

27. • Ranitidine:
Uses
To treat ulcer.
To treat GERD.
Zollengers-Ellison syndrome.

28. Mechanism of action of Ranitidine:
Ranitidine
competitively block H2 receptor
Histamine cannot act
Decreases cAMP formation
Reduce acid secretion Healing of ulcer.

29. SAR OF H1 RECEPTOR ANTAGONIST:
• In the above general structure, Ar is aryl group and Ar' is aryl or aryl
methyl group.
• In the general structure the X part determines the class of drug to which
that belongs I.e. if X=O (amino alkyl analogue), X-N (Ethylene diamine
derivative).
• Some times two aromatic rings are bridges that constitutes the tricycle
ring derivative.

30. • Most of the H1 antagonist have ethylene chain, extension of this chain
or branching of this chain lead to reduce the activity of the compound.
• Homologation played to improve the drug like tricyclic anti-
depressents, neruroleptics.
• Due to the close resemblance of antihistamine structure to the
cholinergic blocking agent, most of the antihistamines show the activity
of anti- cholinergic activity.

31. SAR OF H2 RECEPTOR ANTAGONIST:
• In the H2 receptor, imidazole structure believed tobe important for
receptor action.
• The imidazole structure exist in two forms.

32. • The form (1) seems to be necessary for maximal H2-antagonist activity.
Where the R is substituted with CH3 the activity becomes potent.
• Chain of four carbon atom is optional for the activity, shorter chain
drastically lowers the activity. The presence of thioether (-S-) in the
methylene place (-CH3-) lead to more activity.
• The presence of terminal N group increase the activity.