Cardiovascular drugs

 Antihypertensive drugs
 Diuretics
 Antianginal
 Antihyperlipidimics
 Anticoagulant

Antihypertensive agents

Hypertension is the most common cardiovascular disease. Persistent rise of blood pressure
above normal upper level (120/80 mm Hg) according to age and sex is known as
hypertension.

A specific cause of hypertension can be established in only 10-15% patients. Patients in

whom specific cause of hypertension can be found are said to have secondary hypertension.
On the other hand 85 to 90% patients in whom no specific cause of hypertension can be
found are said to have essential or primary hypertension.

Drugs which lower the elevated blood pressure to normal level and which are used for
the treatment of hypertension are called antihypertensive drugs.

B.P = Cardiac output (CO) x Peripheral resistance

The drugs act by reducing cardiac output or reducing the total peripheral resistance without
correcting the cause of hypertension.

1) Sympatholytic agents
a) Centrally acting sympatholytic agents.
o Methyldopa,
o Clonidine
b) β – adrenergic receptor antagonists (β – blockers)
o Propranolol, labetalol (non selective β –blockers)
o Metoprolol, atenolol (β1 –selective)
c) α – adrenergic receptor antagonists
o Prazosin
o Terazosin

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2) Direct vasodilators
o Hydralazine,
o Sodium nitroprusside
++
3) Ca channel blockers
o Nifedipine,
o Verapamil,
o Diltiazem
4) Angiotensin converting enzyme inhibitors (ACE inhibitor)
o Captopril,
o Enalapril
5) Angiotensin II inhibitors
o Losartan
6) Diuretics

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 β –blockers
β–receptor blockers are the drugs that selectively and competitively block the actions of
catecholamines mediated through β – receptor stimulation.

Classification 0f β – adrenergic blocking agents:

1) Nonselective β–(β1 + β2) adrenergic antagonists:
o Propranolol
o Labetalol
o Nadolol
o Timolol
o Pindolol

2) Selective β1–adrenergic antagonists:

o Atenolol
o Metoprolol
o Esmolol
o Acebutolol

Vasodilators (Drugs Acting Directly on Smooth muscle)

Directly acting vasodilators have the ability to relax smooth muscles in blood vessels lead to
dilatation of vessels which results in reduction in systemic vascular resistance. Minoxidil
sulfate is a potassium channel opener. It has effect on androgenic alopecia.

1- Minoxidil

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Ca+2 channel blockers

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Mechanism of action:
• Contraction of the myocardial cells is mediated, in part, by calcium influx.
• The calcium channel blockers produce a negative inotropic effect by interrupting the
contractile response.
• The calcium channel blockers inhibit vascular smooth muscle contraction by
depriving the cell from the calcium ions.
• Verapamil and diltiazem are ionic at physiological pH so that they enter into the
binding site when channel is open.
• Nifedipine (Dihydropyridines) is neutral at physiological pH. It interacts with Ca
channel when it is open or closed due to its lipophillic nature.

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 ACE Inhibitors

Renin-Angiotensin system

Renin is a proteolytic enzyme that is secreted into the circulation by the cells of
juxtaglomerular apparatus. Renin acts on a plasma globulin, angiotensinogen, splitting off a
decapeptide, angiotensin I, from the N-terminal end of the protein. Angiotensin I has no
appreciable activity, but acted on by a second proteolytic enzyme, angiotensin converting
enzyme (ACE), that removes two more amino acids to form the highly active octapeptide,
angiotensin II.

ACE is a membrane bound enzyme on the surface of endothelial cells, and is particularly
abundant in the cells of lung. It is also present in the other vascular tissues including heart,
brain, striated muscle and kidney, and is not restricted to endothelial cells.

The main actions of angiotensin are-

 Vasoconstriction
 Secretion of aldosterone leading to sodium water retention

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Mechanism of action of ACE inhibitors:
The enzyme is a carboxy-peptidase which splits off pairs of basic amino acids. Its active site
contains a zinc atom. A variety of small peptides were found to be weak inhibitors of the
enzyme which were unsuitable because of their low patency and poor oral absorption. The
structure of captopril was designed to combine the steric properties of such peptide
antagonists in a non-peptide molecule which contains a sulphydryl group appropriately
placed to bind to the zinc atom, coupled to a proline residue which binds to the enzyme site
normally occupied by the terminal leucine of angiotensin I.

Examples of ACE inhibitors include:

Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril,
Ramipril, Trandolapril.

ACE inhibitors are classified into:

ACE is Zinc containing enzyme so according to the group that binds with Zn+2

ACE inhibitors are classified into

1. Sulhydryl containing inhibitors (e.g. Captopril)
2. Carboxylate containing inhibitors (e.g. Enalapril)
3. Phosphonate containing inhibitors (e.g.Fosinopril)

SAR of ACE inhibitors

 N-ring must contain COOH group to mimic C-terminal carboxylate in

ACE substrate.
 Compounds contain hydrophobic bicyclic rings are more lipid
soluble than than those which contain proline
 Groups A, B, or C can serve as zinc binding groups.
 -SH group show superior binding to zinc

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  X is usually methyl to mimic the side chain of alanine. Within
dicarboxylate series, when X equals n-butylamine (lysine side chain)
this produces a compound which is orally active without being a
prodrug

1) Sulfhydryl-Containing Inhibitors
Captopril

2) Dicarboxylate containing inhibitors

Enalapril Maleate

In comparing the activity of captopril and enalaprilat, it was found than enalaprilat is 10
fold more potent than captopril why?

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 3) Phosphonate containing inhibitors (fosinoprilat)

Angiotensin II Receptor Blocker/ Angiotensin II Inhibitor:

The angiotensin II receptor blockers (ARBs) represent a newer class of antihypertensive agents.
Their mechanism of action differs from that of the angiotensin-converting enzyme (ACE) inhibitors,
which also affect the renin-angiotensin system.
The ARBs were developed to overcome several of the deficiencies of ACE inhibitors: competitive
inhibition of ACE results in a reactive increase in renin and angiotensin I levels, which may
overcome the blockade effect; ACE is a relatively nonspecific enzyme that has substrates in addition
to angiotensin I, including bradykinin and other tachykinins, and thus, inhibition of ACE may result
in accumulation of these substrates; production of angiotensin II can occur through non-ACE
pathways as well as through the primary ACE pathway, and these alternative pathways are
unaffected by ACE inhibition.

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Mechanism of Action:
ARBs may offer more complete angiotensin II inhibition by interacting selectively with the receptor
site. Selective inhibition of angiotensin II by competitive antagonism of the angiotensin II receptors
has been speculated to reduce adverse effects and possibly improve clinical efficacy. ARBs displace
angiotensin II from the angiotensin II receptor and produce their blood pressure lowering effects by
antagonizing angiotensin II–induced vasoconstriction, aldosterone release and catecholamine
release. All 7 drugs in this class are approved by the Food and Drug Administration for the treatment
of hypertension, either alone or in combination with other drugs.

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