PHARMACOLOGY

II
PHA 306
 Antihypertensive Drugs
Renin-Angiotensin-Aldosterone System (RAAS)

Prorenin production in
Juxtaglomerular cell
Renin
In the kidneys, within the walls of afferent arterioles, there are
specialized cells producing prorenin called juxtaglomerular cells.
Upon activation by a drop in blood pressure, prorenin is cleaved to form
renin, which is released into the blood.

Renin converts a plasma protein called angiotensinogen,

Angiotensinogen Angiotensin I produced by the liver, into angiotensin I, a peptide of 10 amino
acids.

Angiotensin Converting
Enzyme (ACE)

Angiotensin I is further converted into angiotensin II, an 8-

Angiotensin II amino acid peptide, by the angiotensin-converting enzyme,
ACE, predominantly present in the lungs and kidneys.
Antihypertensive Drugs
Renin-Angiotensin-Aldosterone System (RAAS)
Antihypertensive Drugs

The renin-angiotensin-aldosterone system (RAAS) can be inhibited at several

points:
◦ Renin release: β-adrenoceptor antagonists inhibit renin release
◦ Renin activity: renin inhibitors
◦ ACE: ACE inhibitors (ACEIs)
◦ Angiotensin II receptors: AT1-receptor antagonists (ARBs)
◦ Aldosterone receptors: aldosterone-receptor antagonists.
Antihypertensive Drugs
Angiotensin II
◦ A hormone that binds to angiotensin II receptors in tissues to exert effects –
◦ Promotes sodium reabsorption in proximal convoluted tubules of the kidneys.
◦ Stimulates vasoconstriction in systemic arterioles.
◦ Induces the release of aldosterone from the adrenal cortex.
◦ Aldosterone promotes sodium and water retention in the kidneys.

◦ In the central nervous system, angiotensin II has several effects-

◦ It acts on the hypothalamus to stimulate thirst and encourage water intake.
◦ It induces the posterior pituitary to release antidiuretic hormone (ADH), which promotes water
retention by the kidneys.
◦ It reduces the sensitivity of the baroreceptor response to increased blood pressure.
Antihypertensive Drugs
Angiotensin-converting enzyme inhibitors (ACE Inhibitors)
◦ The first ACEI to be marketed was captopril.
◦ An early example of successful drug design based on a chemical knowledge of the target molecule.
◦ Various small peptides had been found to be weak inhibitors of the enzyme.
◦ Captopril was designed to combine the steric properties of such peptide antagonists in a non-peptide molecule that was
active when given by mouth.
 Antihypertensive Drugs
ACE Inhibitors-

benazepril
captopril
enalapril
fosinopril
lisinopril
moexipril
quinapril
ramipril
Antihypertensive Drugs
ACE Inhibitors-
Mechanism of Action:
◦ ACE inhibitors produce vasodilation by inhibiting the formation of angiotensin II.
◦ ACE also breaks down bradykinin (a vasodilator substance).
◦ They do not affect cardiac contractility.
◦ They act preferentially on angiotensin-sensitive vascular beds, which include those of the
kidney, heart and brain.
◦ This selectivity may be important in sustaining adequate perfusion of these vital organs in the face of
reduced perfusion pressure.
◦ Exception: Critical renal artery stenosis, where ACE inhibition results in a fall in glomerular filtration
rate
Antihypertensive Drugs
ACE Inhibitors-
Pharmacological effects:
◦ Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism.
This vasodilation reduces arterial pressure, preload and afterload on the heart.
◦ Downregulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on
sympathetic nerve release and reuptake of norepinephrine.
◦ Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the
effects of angiotensin II in the kidney and by blocking angiotensin II stimulation
of aldosterone secretion. This reduces blood volume, venous pressure and arterial pressure.
◦ Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure,
and myocardial infarction.
Antihypertensive Drugs
ACE Inhibitors-
Clinical uses:
◦ Hypertension
◦ ACE inhibitors are considered "first-line therapy" in the treatment of hypertension.
◦ Cardiac failure.
◦ Following myocardial infarction (especially when there is ventricular dysfunction).
◦ In people at high risk of ischaemic heart disease.
◦ Diabetic nephropathy.
◦ Progressive renal insufficiency.
 Antihypertensive Drugs
ACE Inhibitors-
Unwanted effects:
Directly related to ACE inhibition (common for all ACE inhibitors)-
◦ Hypotension-
◦ especially after the first dose and
◦ especially in patients with heart failure who have been treated with loop diuretics (renin-angiotensin
system is highly activated).
◦ Dry cough (as a result of accumulation of bradykinin)- the commonest persistent adverse effect.
◦ Kinin accumulation may also underly angioedema (painful swelling in tissues which can be life-threatening if
it involves the airway)
◦ Hyperkalemia (occurs because aldosterone formation is reduced).
Antihypertensive Drugs
Angiotensin Receptor Blockers (ARBs)
These drugs have very similar effects to angiotensin converting enzyme (ACE) inhibitors and are
used for the same indications (hypertension, heart failure, post- myocardial infarction).

Mechanism of Action:
Their mechanism of action is very different from ACE inhibitors.
◦ ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on-
◦ bloods vessels
◦ the heart.
◦ Unlike ACEIs, ARBs do not inhibit ACE, they do not cause an increase in bradykinin.
Antihypertensive Drugs
ARBs-
Suffix ‘sartan’
candesartan
eprosartan
irbesartan
losartan
olmesartan
telmisartan
azilsartan
valsartan
Antihypertensive Drugs

Angiotensin Receptor Blockers (ARBs)-

Pharmacological effects:
◦ Dilate arteries and veins and thereby reduce arterial pressure and preload and afterload on the heart.
◦ Down regulate sympathetic adrenergic activity by blocking the effects of angiotensin II on sympathetic
nerve release and reuptake of norepinephrine.
◦ Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of
angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion.
◦ Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial
infarction.
Antihypertensive Drugs
Angiotensin Receptor Blockers (ARBs)-
Clinical uses:
◦ ARBs are used in the treatment of hypertension and heart failure in a similar manner as ACE inhibitors.
◦ Valsartan is the only ARB approved for post-myocardial infarction.
As a drug class, ARBs have a relatively low incidence of side effects and are well-tolerated.
◦ Because they do not increase bradykinin levels like ACE inhibitors, the dry cough and angioedema that are
associated with ACE inhibitors are not a problem.

Unwanted effects:
◦ ARBs are contraindicated in pregnancy (fetotoxic).
◦ Patients with bilateral renal artery stenosis may experience renal failure if ARBs are administered.