This document provides information on various types of antihypertensive drugs (drugs used to treat high blood pressure) including their mechanisms of action and clinical uses. It discusses classes of antihypertensives such as ACE inhibitors (e.g. captopril), beta blockers (e.g. timolol, bisoprolol), calcium channel blockers, alpha blockers (e.g. clonidine, guanabenz), vasodilators (e.g. sodium nitroprusside, diazoxide, minoxidil), and others (e.g. reserpine). For each drug, the summary provides a brief overview of its mechanism for reducing blood pressure and

1. ANTI-HYPERTENSIVES
By
Dr. Kalam Sirisha,
Associate Professor & Head,
Department of Pharmaceutical Chemistry,
Vaagdevi College of Pharmacy, Ramnagar,
Warangal, Telangana
E-mail: ragisirisha@yahoo.com

2. •Blood pressure is the pressure of circulating blood on the walls
of blood vessels.
•Most of this pressure is due to work done by the heart by
pumping blood through the circulatory system.
•“Blood pressure" usually refers to the pressure in large arteries
of the systemic circulation.
•It is the pressure of the blood in the circulatory system, often
measured for diagnosis since it is closely related to the force and
rate of the heartbeat and the diameter and elasticity of the
arterial walls.
•“Heart failure is common in patients with high blood pressure"

4. Hypertension (HTN or HT), also known as high blood pressure
(HBP), is a long-term medical condition in which the blood
pressure in the arteries is persistently elevated. High blood
pressure typically does not cause symptoms.

8. Eating a healthier diet with less salt, exercising regularly, avoiding stress and taking
medication can help lower blood pressure.

9. ● Antihypertensives are a class of drugs that are used to treat
hypertension (high blood pressure). Antihypertensive therapy
seeks to prevent the complications of high blood pressure, such
as stroke and myocardial infarction.
● They are used in the treatment of acute or chronic vascular
HYPERTENSION regardless of pharmacological mechanism.

15. 3D structure of human ACE (PDB ID: 1o8A), visualized through CHIMERA.

16. Captopril at active site of ACE

31. β-blockers-Classified into three generations
first generation
(Propranolol, Sotalol, Timolol, Nadolol)
nonselective: block β1 and β2 receptors.
second-generation agents
(Atenolol, Bisoprolol, Celiprolol,
Metoprolol)
cardioselective agents
block β1-receptors in low doses, block
β2-receptors in higher doses.
more suitable in chronic lung disease or
insulin-requiring diabetes mellitus
Bisoprolol most selective
third generation agents
either selective (Nebivolol) or
nonselective (Carvidolol and Labetolol)
vasodilatory properties mediated either
by nitric oxide release (Nebivolol or
Carvedilol) or by alpha-adrenergic
blockade (Labetolol and Carvedilol)

33. Beta-2 adrenergic receptor
Norepinephrine

34. Interaction of agonists with helix VI of beta 2 receptor

35. Timolol
Timolol is a nonselective beta-adrenergic antagonist given in an eye drop solution to
reduce intraocular pressure, or pressure in the eyes. It is also used in tablet form as a
drug to treat hypertension. Timolol was first approved by the FDA in 1978. This drug
is marketed by several manufacturers and is an effective agent for the management
of conditions such as open-angle glaucoma and hypertension. In certain cases,
timolol is used in the prevention of migraine headaches.

36. Mechanism of action:
Timolol competes with adrenergic neurotransmitters for binding to beta(1)-
adrenergic receptors in the heart and the beta(2)-receptors in the vascular
and bronchial smooth muscle. This leads to diminished actions of
catecholamines. Beta(1)-receptor blockade by timolol leads to a decrease in
both heart rate and cardiac output during rest and exercise, and a decrease
in both systolic and diastolic blood pressure. The blockade of beta(2)
receptors by timolol in the blood vessels leads to a decrease in peripheral
vascular resistance, reducing blood pressure.
The exact mechanism by which timolol reduces ocular pressure is unknown
at this time, however, it likely decreases the secretion of aqueous humor in
the eye. According to one study, the reduction of aqueous humor secretion
may occur through the decreased blood supply to the ciliary body resulting
from interference with the active transport system or interference with
prostaglandin biosynthesis.

37. Co-crystal structures of timolol (left) and carazolol (right) in the β -adrenergic receptor

40. Clonidine
Clonidine is an imidazole derivate that acts as an
agonist of alpha-2 adrenoceptors. This activity is
useful for the treatment of hypertension, severe pain,
and ADHD.
Clonidine was granted FDA approval on 3 September
1974
Mechanism of action:
Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive
and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins
Go and Gi. Gi inhibits adenylyl cyclase and activates opening of a potassium channel that
causes hyperpolarization.
The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the
hypnotic effects of clonidine as this region of the brain helps regulate
wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally
clonidine can affect regulators of blood pressure in the ventromedial and rostral-
ventrolateral areas of the medulla.

43. Methyldopa
An alpha-2 adrenergic agonist that has both central and peripheral nervous system
effects. Its primary clinical use is as an antihypertensive agent.
Mechanism of action:
Although the mechanism of action has yet to be conclusively demonstrated, the
resultant hypotensive effect is most likely due to the drug's action on the CNS.
Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS,
where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a
reduction in sympathetic tone, total peripheral resistance, and blood pressure.

45. Synthesis of Methyldopa hydrochloride
HCl

48. Guanethidine monosulphate
An antihypertensive agent that acts by
inhibiting selectively transmission in post-
ganglionic adrenergic nerves.
It is believed to act mainly by preventing the
release of norepinephrine at nerve endings
and causes depletion of norepinephrine in
peripheral sympathetic nerve terminals as well
as in tissues.
 Indication: For the treatment of moderate
and severe hypertension, either alone or as an
adjunct, and for the treatment of renal
hypertension.

49. Guanabenz acetate
An alpha-2 selective adrenergic
agonist used as an antihypertensive
agent.

50. Guanabenz's antihypertensive effect is thought to be due to central alpha-
adrenergic stimulation, which results in a decreased sympathetic outflow to the heart,
kidneys, and peripheral vasculature in addition to a decreased systolic and diastolic
blood pressure and a slight slowing of pulse rate.
Chronic administration of guanabenz also causes a decrease in peripheral vascular
resistance.

51. Sodium Nitroprusside
Nitroprusside serves as a source of nitric oxide, a potent peripheral vasodilator that
affects both arterioles and venules (venules more than arterioles). Nitroprusside is often
administered intravenously to patients who are experiencing a hypertensive emergency.
For immediate reduction of blood pressure of patients in hypertensive crises, reduce
bleeding during surgery, and for the treatment of acute congestive heart failure
Sodium nitroprusside is more active on veins than on arteries.

53. Diazoxide
A benzothiadiazine derivative that is a peripheral vasodilator used for hypertensive
emergencies. It lacks diuretic effect, apparently because it lacks a sulfonamide group.
Used parentally to treat hypertensive emergencies. Also used to treat hypoglycemia
secondary to insulinoma.
Diazoxide is a potassium channel activator. Its mechanism of action revolves around
enhancing cell membrane permeability to potassium ions. This action consequently elicits
the relaxation of local smooth muscles. This switches off voltage-gated calcium ion
channels which inhibits the generation of an action potential.

54. Diazoxide inhibits insulin release from the pancreas, by opening potassium channels in
the beta cell membrane. Diazoxide is chemically related to thiazide diuretics but does not
inhibit carbonic anhydrase and does not have chloriuretic or natriuretic activity. It also
exhibits hypotensive activity by reducing arteriolar smooth muscle and vascular resistance.

55. Minoxidil
A potent direct-acting peripheral vasodilator
(vasodilator agents) that reduces peripheral
resistance and produces a fall in blood
pressure.
For the treatment of severe hypertension
and in the topical treatment (regrowth) of
androgenic alopecia in males and females and
stabilisation of hair loss in patients with
androgenic alopecia.
Minoxidil is an orally effective direct acting
peripheral vasodilator that reduces elevated
systolic and diastolic blood pressure by
decreasing peripheral vascular resistance.
Venodilation does not occur with minoxidil;
thus, postural hypotension is unusual with its
administration. The antihypertensive activity
of minoxidil is due to its sulphate metabolite,
minoxidil sulfate.

56. Minoxidil is thought to promote the survival of human dermal papillary cells (DPCs) or hair
cells by activating both extracellular signal-regulated kinase (ERK) and Akt and by preventing
cell death by increasing the ratio of BCl-2/Bax. Minoxidil may stimulate the growth of human
hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs.
Minoxidil, when used as a vasodilator, acts by opening adenosine triphosphate-sensitive
potassium channels in vascular smooth muscle cells. This vasodilation may also improve the
viability of hair cells or hair follicles.

57. Minoxidil-AR-
LBD complex
(Androgen
receptor-ligand
binding domain
(AR-LBD)

58. Reserpine
An alkaloid found in the roots of Rauwolfia serpentina and R. vomitoria.
Reserpine inhibits the uptake of norepinephrine into storage vesicles resulting in
depletion of catecholamines and serotonin from central and peripheral axon terminals.
It has been used as an antihypertensive and an antipsychotic as well as a research tool,
but its adverse effects limit its clinical use.

59. Reserpine is an adrenergic blocking agent used to treat mild to moderate hypertension
via the disruption of norepinephrine vesicular storage.
Reserpine's mechanism of action is through inhibition of the ATP/Mg2+ pump responsible
for the sequestering of neurotransmitters into storage vesicles located in the presynaptic
neuron. The neurotransmitters that are not sequestered in the storage vesicle are readily
metabolized by monoamine oxidase (MAO) causing a reduction in catecholamines.
•Common side effects
•Decreased Appetite.
•Diarrhea.
•Dry Mouth.
•Nausea.
•Stuffy Nose.
•Vomiting.

61. Hydralazine hydrochloride
Originally developed in the 1950s as a malaria treatment, hydralazine showed
antihypertensive ability and was soon repurposed.
 Hydralazine is a hydrazine derivative vasodilator used alone or as adjunct therapy in
the treatment of hypertension and only as adjunct therapy with isosorbide dinitrate in
the treatment of heart failure.
 Hydralazine is no longer a first line therapy for these indications since the
development of newer antihypertensive medications.
Hydralazine hydrochloride was FDA approved on 15 January 1953.

62. Hydralazine may interfere with calcium transport in vascular smooth muscle by an
unknown mechanism to relax arteriolar smooth muscle and lower blood pressure.
The interference with calcium transport may be by preventing influx of calcium into
cells, preventing calcium release from intracellular compartments, directly acting on
actin and myosin, or a combination of these actions.
Hydralazine has a short duration of action of 2-6h.

63. Amyl Nitrite
Amyl Nitrite is an antihypertensive medicine.
It is employed medically to treat heart diseases such as angina (rapid relief) and to treat
cyanide poisoning.
Its use as a prescription medicine comes from its ability to lower blood pressure. As an
inhalant, it also has psychoactive effect which has led to illegal drug use.
It is a potent vasodilator. It expands blood vessels, resulting in lowering of the blood
pressure. Alkyl nitrite functions as a source of nitric oxide, which signals for relaxation of
the involuntary muscles.
It's antianginal action is thought to be the result of a reduction in systemic and
pulmonary arterial pressure (afterload) and decreased cardiac output because of
peripheral vasodilation, rather than coronary artery dilation.

64.  As an antidote (to cyanide poisoning), amyl nitrite promotes formation of
methemoglobin, which combines with cyanide to form nontoxic cyanmethemoglobin.
Adverse effects include hypotension, headache, flushing of the face, tachycardia,
dizziness, and relaxation of involuntary muscles, especially the blood vessel walls and
the anal sphincter.

65. Nitroglycerin (Glyceryl trinitrate)
Nitroglycerin is a nitro-vasodilator drug used for the treatment of chest pain and high
blood pressure.
Nitroglycerin is available in various forms, including a spray form, sublingual tablet form,
intravenous form, extended-release tablet form, and transdermal form.
In addition to treating angina, nitroglycerin is also used in an ointment to treat the pain
that accompanies anal fissures.
Nitroglycerin causes the relaxation of vascular smooth muscles, causing arteriolar and
venous dilatation. It reduces cardiac preload and afterload and reduces coronary artery
spasm, decreasing systemic vascular resistance as well as systolic and diastolic blood
pressure. The reduction of cardiac work by nitroglycerin is thought to cause the most relief
of anginal symptoms, with some contributions from arteriolar dilatation effects.

66. Mechanism of action: Nitroglycerin is converted by mitochondrial aldehyde
dehydrogenase (mtALDH) to nitric oxide (NO), an active substance which then activates
the enzyme guanylate cyclase. The activation of this enzyme is followed by the synthesis
of cyclic guanosine 3',5'-monophosphate (cGMP), activating a cascade of protein kinase-
dependent phosphorylation events in smooth muscles. This process eventually leads to
the dephosphorylation of the myosin light chain of smooth muscles, causing relaxation
and increased blood flow in veins, arteries and cardiac tissue. The above processes lead
to decreased work of the heart decreased blood pressure, relief of anginal symptoms,
and increased blood flow to the myocardium.
Synthesis:

68. PENTAERYTHRITOL TETRANITRATE
Pentaerythritol tetranitrate is the lipid soluble polyol ester of nitric acid belonging to the
family of nitro-vasodilators.
Pentaerythritol tetranitrate is a coronary vasodilator used in the treatment of heart
conditions such as angina.
It is a vasodilator with properties that are quite similar to those of glyceryl trinitrate,
however, with a more prolonged duration of action.
It is also one of the most powerful high explosives known and is a component of the
plastic explosive known as Semtex.
Its mechanism of action is similar to nitroglycerin.

69. ISOSORBIDE DINITRATE
A nitro-vasodilator used in the treatment of angina pectoris due to coronary artery
disease.
Its actions are similar to nitroglycerin but with a slower onset of action.
Isosorbide dinitrate is a moderate to long acting oral organic nitrate used for the relief
and prophylactic management of angina pectoris.
It relaxes the vascular smooth muscle and consequent dilatation of peripheral arteries and
veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and
decreases venous return to the heart, thereby reducing left ventricular end- diastolic
pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces
systemic vascular resistance, systolic arterial pressure, and mean arterial pressure.
Mechanism of action is similar to nitroglycerin.

70. Synthesis:

71. DIPYRIDAMOLE
Dipyridamole, a non-nitrate coronary vasodilator that also inhibits platelet aggregation,
is combined with other anticoagulant drugs, such as warfarin, to prevent thrombosis in
patients with valvular or vascular disorders.
Dipyridamole is also used in myocardial perfusion imaging, as an antiplatelet agent, and
in combination with aspirin for stroke prophylaxis.
It is a phosphodiesterase inhibitor that blocks uptake and metabolism of adenosine by
erythrocytes and vascular endothelial cells.
Dipyridamole also potentiates the antiaggregating action of prostacyclin.

72. Mechanism of action: Dipyridamole likely inhibits both adenosine deaminase and
phosphodiesterase, preventing the degradation of cAMP, an inhibitor of platelet
function. This elevation in cAMP blocks the release of arachidonic acid from membrane
phospholipids and reduces thromboxane A2 activity. Dipyridamole also directly
stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby
raising the intraplatelet concentration of cAMP and further inhibiting platelet
aggregation.