PHARMACOLOGY

II
PHA 306
Antihypertensive Drugs
Hypertension:
Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or a
sustained diastolic blood pressure (DBP) of greater than 90 mm Hg.

Etiology:
◦ Although hypertension may occur secondary to other disease processes, more than 90 percent of patients have
essential hypertension, a disorder of unknown origin affecting the blood pressure regulating mechanism.
◦ A family history of hypertension increases the likelihood that an individual will develop hypertensive disease.
◦ Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking, further predispose
an individual to the occurrence of hypertension.
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Mechanisms of Blood Pressure Control
◦ Arterial blood pressure is directly proportional to the product of the cardiac output and the peripheral vascular
resistance.
◦ Cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms:
A. the baroreflexes, which are mediated by the sympathetic nervous system, and
B. the renin-angiotensin-aldosterone system.
Most antihypertensive drugs lower blood pressure by reducing cardiac output and/or decreasing peripheral
resistance.
A. Baroreflexes
◦ Baroreflexes involving the sympathetic nervous system are responsible for the rapid, moment-to-moment regulation of
blood pressure.
◦ A fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the aortic arch and carotid sinuses) to send
fewer impulses to cardiovascular centers in the spinal cord.
◦ This prompts a reflex response of increased sympathetic and decreased parasympathetic output to the heart and
vasculature, resulting in vasoconstriction and increased cardiac output.
◦ These changes result in a compensatory rise in blood pressure
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Mechanisms of Blood Pressure Control-
B. Renin-angiotensin-aldosterone system
◦ The kidney provides for the long-term control of blood pressure by altering the blood volume.
◦ Baroreceptors in the kidney respond to reduced arterial pressure (and to sympathetic stimulation of β-adrenoceptors) by
releasing the enzyme renin.
◦ Low sodium intake and greater sodium loss also increase renin release.
◦ This peptidase converts angiotensinogen to angiotensin I, which is converted in turn to angiotensin II in the presence of
angiotensin-converting enzyme (ACE).
◦ Angiotensin II is the body's most potent circulating vasoconstrictor, constricting both arterioles and veins, causing an
increase in blood pressure.
◦ Angiotensin II exerts a preferential vasoconstrictor action on the efferent arterioles of the renal glomerulus, increasing
glomerular filtration.
◦ Furthermore, angiotensin II stimulates aldosterone secretion, leading to increased renal sodium reabsorption and
increased blood volume, which contribute to a further increase in blood pressure.
◦ These effects of angiotensin II are mediated by stimulation of angiotensin II-AT1 receptors.
Antihypertensive Drugs
Diuretics:
◦ Diuretics increase the excretion of Na+ and water.
◦ They decrease the reabsorption of Na+ and (usually) Cl- from the filtrate, increased water loss being secondary to the increased excretion of
NaCl (natriuresis).
◦ This can be achieved by-
- a direct action on the cells of the nephron
- indirectly, by modifying the content of the filtrate.
◦ Because a very large proportion of salt (NaCl) and water that passes into the tubule via the glomerulus is reabsorbed, a small decrease in
reabsorption can cause a marked increase in Na+ excretion.
Types:
The main therapeutically useful diuretics act on the:
- thick ascending loop of Henle
- early distal tubule
- collecting tubules and ducts.
1. Loop diuretics
2. Thiazide diuretics
3. Potassium sparing diuretics
Diuretics
 Antihypertensive Drugs
1. Loop diuretics
Drug Examples- furosemide, bumetanide.
◦ Loop diuretics are the most powerful diuretics, capable of causing the
excretion of 15-25% of filtered Na+.
◦ Their action is often described in a phrase- causing 'torrential urine flow’.
Mechanism of Action:
◦ These drugs act on the thick ascending limb, inhibiting the Na+/K+/2Cl- carrier in
the luminal membrane by combining with its Cl- binding site.
◦ Loop diuretics increase the delivery of Na+ to the distal nephron, causing loss of
H+ and K+. Because Cl- but not HCO3- is lost in the urine, the plasma
concentration of HCO3- increases as plasma volume is reduced-a form of
metabolic alkalosis therefore referred to as 'contraction alkalosis’.
◦ Loop diuretics increase excretion of Ca2+ and Mg2+ and decrease excretion of
uric acid.
Na+ pump (P)
Na+, K+ and Cl- enter by a co-transport system (C1)
K+/Cl- co-transport system (C2)
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Loop diuretics-
Unwanted effects:
Unwanted effects directly related to the renal action of loop diuretics are common, which include-
◦ Excessive Na+ and water loss which can cause hypovolaemia and hypotension.
◦ Potassium loss, resulting in low plasma K+ (hypokalaemia)
◦ Hypokalaemia increases the effects and toxicity of several drugs (e.g. digoxin and type III antidysrhythmic drugs)à
hypokalaemia can be averted or treated by concomitant use of K+-sparing diuretics
◦ Metabolic alkalosis.
◦ Hypomagnesaemia (less often)
◦ Hyperuricaemia is common and can precipitate acute gout.
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2.Thiazide diuretics
Drug Example- Hydrochlorothiazide, bendroflumethiazide
◦ All oral diuretic drugs are effective in the treatment of hypertension, but the
thiazides are most widely used.
◦ Thiazides are less powerful than loop diuretics but are preferred in treating
uncomplicated hypertension.
◦ They are better tolerated than loop diuretics.
Mechanism of action:
◦ Lower blood pressure initially by increasing sodium and water excretion.
◦ They bind to the Cl- site of the distal tubular Na+/Cl- co-transport system,
inhibiting its action and causing natriuresis with loss of sodium and chloride ions in
the urine.
◦ This causes a decrease in extracellular volume, resulting in a decrease in
cardiac output and renal blood flow.
◦ With long-term treatment, plasma volume approaches a normal value, but Na+ pump (P)
peripheral resistance decreases. Na+/Cl- co-transport system (C1)
K+/Cl- co-transport system (C2)
*Potassium-sparing diuretics are often used combined with thiazides.
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Thiazide diuretics -
Therapeutic uses:
◦ Thiazide diuretics decrease blood pressure in both the supine and standing positions, and postural hypotension is rarely
observed.
◦ Although thiazides are milder than loop diuretics when used alone, co-administration with loop diuretics has a synergistic
effectàNa+ filtration load decreased.
◦ Thiazides are useful in combination therapy with a variety of other antihypertensive agents, including-
- β-blockers,
- ACE inhibitors,
- angiotensin-receptor blockers, and
- potassium-sparing diuretics.
◦ In contrast to loop diuretics, however, thiazides reduce Ca2+ excretion, which may be advantageous in older patients at risk of
osteoporosis.
◦ Thiazide diuretics also have a vasodilator action.
◦ They are not effective in patients with inadequate kidney function (creatinine clearance, <50 mL/min). Loop diuretics may be
required in these patients.
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Thiazide diuretics-
Adverse effects:
◦ Increase in urinary frequency.
◦ Erectile dysfunction (common but reversible).
◦ Hypomagnesemia.
◦ Impaired glucose tolerance due to inhibition of insulin secretion.
Thiazide diuretics induce hypokalemia and hyperuricemia in 70% of patients and hyperglycemia in 10% of
patients.
Precautions:
Serum potassium levels should be monitored closely in patients who are predisposed to cardiac
arrhythmias (particularly individuals with left ventricular hypertrophy, ischemic heart disease, or chronic heart
failure) and who are concurrently being treated with both thiazide diuretics and digoxin.
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3. Potassium-sparing diuretics:
Drug examples- spironolactone, triamterene, amiloride
Mechanism of Action:
◦ Act on Na+/K+ exchange-the site on the distal site (collecting tubule).
◦ Have very limited diuretic action when used singly, because the distal site (site
of action) accounts for reabsorption of only 2% of filtered Na+.
◦ They still have marked antihypertensive effects.
Clinical Use:
◦ With K+-losing (i.e. loop or thiazide) diuretics to prevent K+ loss, where
hypokalaemia is especially hazardous (e.g. patients
requiring digoxin or amiodarone).
◦ Spironolactone is used in:
Na+ pump (P)
- resistant essential hypertension (especially low-renin hypertension)
- heart failure, to improve survival
- primary hyperaldosteronism (Conn's syndrome)
- secondary hyperaldosteronism caused by hepatic cirrhosis.
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Potassium-sparing diuretics-
Adverse effects:
◦ Hyperkalaemia (can be dangerous, especially in patients with renal impairment or receiving other drugs that can
increase plasma K+).
◦ Gastrointestinal disturbances (uncommon)
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Diuretics that Act Indirectly by Modifying the Content of the Filtrate (Osmotic Diuretics)
Drug Example: mannitol
◦ Pharmacologically inert substances that are filtered in the glomerulus but not reabsorbed by the nephron.
◦ To cause a diuresis, they must constitute an appreciable fraction of the osmolarity of tubular fluid.
◦ Within the nephron, their main effect is exerted on those parts of the nephron that are freely permeable to water:
- the proximal tubule,
- descending limb of the loop and
- the collecting tubules.
Mechanism of Action:
◦ Reduce passive water reabsorption.
◦ Consequently a larger volume of fluid remains within the proximal tubuleà reducing Na+ reabsorption.
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Osmotic diuretics-
Clinical use:
◦ Main effect of osmotic diuretics is to increase the amount of water excreted, with a smaller increase in Na+ excretion.
◦ Acute renal failure, which can occur as a result of haemorrhage, injury or systemic infections.
◦ They are also used for the emergency treatment of acutely raised intracranial or intraocular pressure.

Unwanted effects :
◦ Transient expansion of the extracellular fluid volume (with a risk of causing left ventricular failure)
◦ Hyponatraemia.
◦ Headache, nausea and vomiting can occur.
Diuretics