This document provides a detailed overview of various antihypertensive agents, their classifications, mechanisms of action, and specific examples, such as alpha blockers, beta blockers, ACE inhibitors, and angiotensin II receptor antagonists. It includes descriptions of drugs like prazosin, propranolol, losartan, and hydralazine, highlighting their effects on blood pressure and cardiovascular health. The text emphasizes the pharmacological significance of these agents in managing hypertension through their unique actions on the vascular system and adrenergic receptors.

1. By-
Dr. Prerana B. Jadhav
M. Pharm, Ph.D.
Pharmaceutical Chemistry
Assistant Professor,
Sanjivani College of Pharmaceutical Education and
Research, Kopargaon.
ANTIHYPERTENSIVE
AGENTS

2. Classification of Antihypertensive
Agents
• Alpha Blocker: Prazosin, Terazosin
• Beta Blocker: Propranolol, Timolol, Atenolol
• ACE Inhibitors: Captopril, Lisinopril, Enalapril, Quinapril
hydrochloride
• Angiotensin II receptor antagonist: Losartan, Telmisartan,
Valsartan
• Misc. Class: Methyldopate hydrochloride, clonidine
hydrochloride, guanethidine monosulphate, Reserpine,
Hydralazine HCl.

3. Alpha Blocker
• Prazosin Hydrochloride
Prazosin inhibits the postsynaptic alpha-1 adrenoceptors. This
inhibition blocks the vasoconstricting (narrowing) effect of
catecholamines (epinephrine and norepinephrine) on the
vessels, leading to peripheral blood vessel dilation.

4. • Terazosin Hydrochloride
• Structural similarity with Prazosin
• Terazosin blocks adrenaline's action on alpha-1
adrenergic receptors, causing relaxation of smooth
muscle in blood vessels. Less potent than Prazosin
• Half life is approx. 12 hr.

5. Beta Blocker
• Reversible binding with Beta adrenergic
receptors and competitively antagonises the
action of catecholamines in heart and blood
vessels.
• They reduce heart rate, force of contraction
and cardiac output.
• Also inhibit renin release.

6. Timolol
Non slective Beta adrenoceptor blocker
Binds with beta 1 adrenoreceptor in heart and vascular smooth
muscle and beta 2 adreno receptor in bronchi and reduce
cardiac output and blood pressure.
Uses:
To treat hypertension,
Glaucoma

7. • Propranolol
• Structure Activity Relationship
• Increasing the chain length of the side chain prevents
appropriate binding of the required functional groups to the
same receptors side.
• Side chain of aryloxypropanolamines can adopt a
conformation that places the hydroxyl and amine groups into
approximately the same position in space.
• Aryloxypropanolamines are more potent than
aryloxyethanolamines.

8. ACE Inhibitors
Renin Angiotensin Pathway

11. • All ACE inhibitors have 4 distinct binding sites to it’s
target
• Contains anionic site as COO-
• Contains Hydrogen forming group as C=O
• Contain –SH, - COO- or phosphinate group to react
with Zn++
• Contains hydrophobic moiety

12. SAR of ACE Inhibitors

15. Enalapril
Quinapril

19. Angiotensin II receptor antagonist
• AT1 receptor responsible for managing specific
cardiovascular diseases.
• Stimulation of AT1 receptors by Angiotensin II results in
vasoconstriction, aldosterone synthesis and secretion and
several other physiological events.
• Administration of competitive antagonist that inhibits
angiotensin II at AT1 receptor will produce vasodilatory
effect.

20. Losartan
• First successful agent.
• Biphenylmethyl derivatives possessing certain acidic moieties
which can interact with various positions on the receptor
angiotensin II.
• First non peptide imidazole, orally active Angiotensin II
receptor antagonist.
• Undergoes first pass metabolism with 5 methanol oxidised to
carboxylic acid.

21. Telmisartan
• Replacement of acidic tetrazole system with simple
carboxylic acid.
• This acid like tetrazole plays important role in
receptor binding.
• The second imidazole ring can hydrogen bond with
the angiotensin II receptor.

22. Valsartan
• Possess acidic tetrazole system
• Biphenyl system serves to separate the tetrazole
from aliphatic nitrogen.
• Carboxylic acid side chain in the valine moiety serves
to bind to the angiotensin II receptor.

23. Methyldopa
• Alpha methyldopa lowers blood pressure by inhibiting the outflow of
sympathetic vasoconstrictor impulses from the brain.
• Methyldopa on conversion to alpha methyl norepinephrine acts on alpha 2
adrenergic receptors to inhibit the release of norepinephrine resulting in
decreased outflow from the CNS and activation of parasympathetic
outflow.
• Step 2 agent in the treatment of hypertension, who are not responsive to
diuretic therapy alone.
OH
OH
HOOC
N
H2
CH3

24. Clonidine HCl
• First antihypertensive agent known to act on the CNS.
• Derivative of alpha sympathomimetic drugs nephazoline and tolazoline,
potential vasoconstrictor, but proved effective in the treatment of
hypertension.
• Stimulate peripheral alpha adrenergic receptors to produce
vasoconstriction. It also acts centrally to inhibit to inhibit sympathetic tone
and cause hypotension that is of much longer duration than the initial
hypertensive effect.

25. Guanethidine monosulphate
• Guanethidine monosulfate produces a gradual, prolonged fall in blood
pressure. Usually, 2 to 7 days of therapy are required before the peak
effect is reached, and usually, this peak effect is maintained for 3 or 4
days.
• Guanethidine monosulfate is metabolized by microsomal enzymes 2-(6-
carboxyhexylamino)ethylguanidine and guanethidine N-oxide. Both
metabolites have very weak antihypertensive properties.

26. Guanethidine monosulphate
• Guanethidine mons. sulfate is taken up by the amine pump located on the
neuronal membrane and retained in the nerve, displacing norepinephrine
from its storage sites in the neuronal granules. The displaced
norepinephrine is metabolized by mitochondrial MAO, depleting the nerve
ending of the neurotransmitter.
• The usefulness of guanethidine monosulfate also resides in the fact that
once it is taken up by the nerve, it produces a sympathetic blockade by
inhibiting release of norepinephrine.

27. Metabolism of Guanethidine

30. Reserpine

31. Hydralazine hydrochloride
• Hydralazine hydrochloride is useful in the treatment of
moderate-to-severe hypertension.
• It is often used in conjunction with less potent
antihypertensive agents, because side effects occur frequently
when it is used alone in adequate doses. In combinations, it
can be used in lower and safer doses.
• Hydralazine hydrochloride acts on vascular smooth muscle to
cause relaxation.

32. • Absorption of hydralazine hydrochloride taken orally is rapid
and nearly complete. The maximal hypotensive effect is
demonstrable within 1 hour.
• The drug is excreted rapidly by the kidneys, and within 24
hours
• Hydralazine hydrochloride undergoes benzylic oxidation,
glucuronide formation, and N-acetylation by the microsomal
enzymes in the tissues.
• When given with diuretics, it is useful in the treatment of CHF.

33. Metabolism of Hydralazine