Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.

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Antihypertensive drugs
Hypertension affects about 20 % of total population of the USA. In more than
95% of cases, a specific underlying cause of hypertension cannot be found, such
patients are said to have “essential hypertension”
The pathogenesis of essential hypertension is not clearly understood.
Risk factors include:
 high salt intake,
 heavy alcohol consumption,
 obesity,
 lack of exercise, and
 impaired intrauterine growth.
NB: There is very little evidence that “stress” cause hypertension.
Threshold for intervention:
Hypertension requires treatment when there is sustained elevation in blood
pressure (systolic > 140 mm Hg) or (diastolic > 90 mm Hg) or both.

Non-drug therapy includes:

 Correcting obesity
 Reduce alcohol intake
 Restriction of salt intake
 Regular physical exercises
 Increasing consumption of fruits and vegetables
 Stop smoking
 Low intake of saturated fat
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Figurer -1- Major factors influencing blood pressure

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 Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

See also Figure 19.3 in text book (Response of the autonomic nervous system and the
renin-angiotensin-aldosterone system to a decrease in blood pressure).

Drug therapy of hypertension:

A- Diuretics: drugs that increase urine and solute excretion.
Classification of diuretics:
1. High efficacy (loop ) diuretics: e.g., frusemide, bumetanide, …etc
Site of action: loop of Henle
2. Moderate efficacy (thiazide) diuretics: e.g., hydrochlorothiazide, bendrofluazide,
Site of action: Ascending loop of Henle (diluting segment)
3. Low efficacy (potassium sparing) diuretics: e.g., Amiloride, spironolactone, …..
Site of action: they antagonize aldosterone action at the distal tubules
Mechanism of action of diuretics:
 (in general) They inhibit Na+ reabsorption in the renal tubules thus reducing
extracellular volume
 Thiazides : in addition to the above,
 Initially: they reduce blood pressure by reducing blood volume and cardiac output
 After 6-8 weeks: cardiac output returns to normal , and peripheral vascular
resistance declines (reduced responsiveness of resistance vessels to
vasoconstrictors, principally noradrenaline.
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All diuretics are effective in treatment of hypertension but thiazides have found the
most widespread use. Loop diuretics are more useful in renal impairment, heart failure,
and when used with ACE inhibitors. Amiloride “a K+ spairing diuretic” is useful when
combined with a thiazide as it augments sodium loss but limits potassium loss.
Indications of diuretics:
1. Hypertension .
2. Oedema associated with sodium retension e.g., in cardiac, renal, or hepatic
disease.
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 Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

Side effects of diuretics:

 Hypotension
 Hyponatremia (decrease Na+ in blood)
 Hypokalemia (decreased K+ in blood) (Except for K+-sparing diuretics)
 Hyperglycemia
 Hyperuricemia (increased uric acid in blood)

B- Calcium channel blockers (CCB)

Activation of Ca++ channels by an action potential allows Ca++ to enter cells
leading eventually to muscle contraction.
Mechanism of action of CCB:
They inhibit the passage of calcium through the voltage-dependent Ca++ channel
in cardiac muscle and conducting tissue, and vascular smooth muscle, reduce available
intracellular Ca++ and cause the muscle to relax.
Classification of CCB:
1. Dihydropyridines: e.g., nifedipine, amlodipine, …..
2. Phenylalkylamine : e.g., verapamil.
3. Benzothiazepines :e.g., diltiazem.
Pharmacological actions of CCBs:
All CCBs are vasodilators, and some have negative cardiac inotropic and
negative chronotropic effects. Verapamil and diltiazem affect both cardiac and
vascular smooth muscles. For that, they are used (in addition to hypertension) to treat
cardiac arrhythmia (antiarrhythmics). Dihydropyridines have a much greater affinity for
vascular Ca++ channels than for those in the heart. For that reason they are preferred for
treating hypertension.
Indications of CCBs:
1. Hypertension
2. Angina pectoris
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3. Cardiac arrhythmias (verapamil)

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4. Peripheral vascular disease.

 Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

Examples of CCBs:
Nifedipine: is the prototype dihydropyridine CCB
 Its negative myocardial inotropic and chronotropic effects are much less than
those of verapamil. T1/2=2 hours
 Sustained-release formulation permits once daily dosing with minimal peaks and
troughs in plasma concentration. So that adverse effects due to rapid fluctuation
of concentration are lessened.
 Severe hypotension may result with sublingual administration which may lead to
cerebral ischemia.
Amlodipine:
 t ½ = 40 hours
 can be used as a single daily dose.
 Safe in patients with cardiac failure.
Side effects of CCBs:
Flushing, hypotension, headache, palpitation, ankle oedema.
C. Angiotensin converting enzyme (ACE) inhibitors: e.g., captopril,
enalapril, lisinopril,….
Mechanism of action of ACE inhibitors: (see figure -1- below)
These drugs block the enzyme ACE which cleaves angiotensin I to form the
potent vasoconstrictor angiotensin II. ACE is also responsible for the breakdown of
bradykinin that increases the production of potent vasodilators (nitric oxide and
prostacyclin). ACE inhibitors decrease angiotensin II and increase bradykinin levels.
Vasodilation of both arterioles and veins occurs as a result of decreased
vasoconstriction (from diminished levels of angiotensin II) and enhanced vasodilation
(from increased bradykinin). By reducing circulating angiotensin II levels, ACE
inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and
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 Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

water retention. ACE inhibitors reduce both cardiac preload and afterload, thereby
decreasing cardiac work.
Indications of ACEIs;
1. Hypertension
2. Heart failure
3. Diabetic nephropathy: (by abolishing glomerular hyperfiltration caused by
angiotensin II in these patients)
4. After myocardial infarction (MI): angiotensin II stimulates cardiac cell growth
and plays a key role in “remodeling” of the heart after MI.
Side effects:
 Hypotension (start with small dose)
 Dry cough (due to increased bradykinin)
 Allergic reactions
 Impaired renal function: (check renal function before and 2 weeks after
treatment)
 hyperkalemia
Precautions and contraindication of ACE inhibitors
 pregnancy
 renal artery stenosis
 heart failure (start with small dose)

D. Angiotensin II receptor blockers (ARBs) (e.g., Losartan, valsartan,...)

 They are alternatives to ACEIs (see figure -1- below)
 Have similar pharmacological effects to those of ACEIs.
Indications of angiotensin II receptor blockers:
 Hypertension
 Diabetic nephropathy
Side effects: similar to ACEIs but they do not cause cough and allergic reactions and
they are used as alternatives to ACEIs in patients developing these side effects.
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 Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

E. Selective Renin inhibitor (aliskiren) (see figure -1- below)

It directly inhibits renin and, thus, acts earlier in the renin–angiotensin–aldosterone
system than ACE inhibitors or ARBs.
It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides.
Side effects:
 diarrhea, especially at higher doses
 cough and angioedema, (but probably less often than ACE inhibitors)
Aliskiren is contraindicated during pregnancy.

F. Adrenoceptor blocking drugs:

1. α – adrenoceptor blockers:
Phenoxybenzamine (α1, α2 blocker):
When patients taking such a drug rise from supine to erect posture or take
exercise, the sympathetic system is physiologically activated, and because the normal
vasoconstrictive (α1) effect (to maintain blood pressure) is blocked by the drug, this
leads to failure of maintaining blood pressure which result in more sympathetic
activation (normally reduced by α2 receptors) resulting in tachycardia (via β receptors
which are not blocked)
For that reason, non-selective α-blockers are not used alone in hypertension.
Selective α1-blockers (prazocin, terazocin, …) that spares the α2- receptors, so that
negative feedback inhibition of noradrenaline release is maintained, are more useful in
hypertension (less tachycardia and less postural and exercise hypotension)
2. β- blockers:
 they reduce blood pressure primarily by decreasing cardiac output.
 They may also inhibit the release of renin from kidney thus decreasing the
formation of angiotensin II and secretion of aldosterone.
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a. Non-selective β1, β2- blockers (e.g., propranolol…)

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 Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

b. Selective β1- blockers (e.g., atenolol, metoprolol,…) are among the

most commonly used β- blockers.
Notes:
 Propranolol is contraindicated in asthma (β2).
 Selective β1- blockers may be used cautiously in asthma (may precipitate asthma).
 Withdrawal of β- blockers should be gradual; if sudden it can be dangerous in
angina and hypertension ( due to up-regulation of receptors)

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Antianginal drugs
Angina pectoris is a clinical syndrome (caused by transient myocardial ischemia)
characterized by sudden, severe, pressing chest pain radiating to the neck, jaw, back and
arms. It may occur when there is an imbalance between myocardial oxygen supply (
coronary blood flow) and demand (cardiac work which is affected by heart rate, blood
pressure, contractility and ventricular volume). The most common cause of angina is
coronary atheroma.
Management of angina pectoris
1. Assessment of the extent and severity of arterial disease (e.g., exercise stress
testing, coronary angiography, ….)
2. Control of risk factors (e.g., smoking, hypertension, hyperlipidemia, ..)
3. Drug therapy to control symptoms and
4. Measures to improve life expectancy.
Antianginal drug therapy:
Four groups; used alone or in combination.
A. Nitrates: they are simple nitric or nitrous acid esters of polyalcohols.
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Mechanism of action of nitrates:

They relax vascular smooth muscle by their intracellular conversion to nitrite
ions, and then to nitric oxide, which in turn activates guanylate cyclase and increase
the cells’ cyclic GMP. Elevated cGMP leads to dephosphorylation of the myosin
light chain, resulting in vascular smooth muscle relaxation.
Nitrates cause generalized dilation of venules (capacitance vessels) and to a
lesser extent of arterioles (resistance vessels)
Although they are potent coronary vasodilators (improve coronary blood flow),
their principal benefit follows from a reduction in venous return which reduce the
left ventricular work.
Indications of nitrates:
1. Angina pectoris. 2. Left ventricular failure.
Side effects: Headache, facial flushing, tachycardia, postural hypotension.
Tolerance develops rapidly (the blood vessel become desensitized to the
vasodilation). To overcome tolerance: “nitrate-free interval” of about 10-12 hours to
restore sensitivity to the drug.
Important drug interaction:
Sildenafil “a phosphodiesterase inhibitor” potentiates the action of nitrates, and may
result in severe hypotension.
Drugs:
1. Glyceryl trinitrate (nitroglycerin): rapid action, can be given sublingually or
transdermal patch or gel.
2. Isosorbide mononitrate: orally
3. Isosorbide dinitrate: denitrated to 2 mononitrates, given orally or I.V. in
emergency conditions.
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B. β- blockers: (atenolol, metoprolol, propranolol,….)

Although they are not vasodilators, β- blockers are extremely useful in the
management of angina associated with effort.
The antianginal action of β- blockers is related primarily to their hemodynamic
effects (decreased heart rate, blood pressure and contractility) which decrease
myocardial oxygen requirements at rest and during exercise. Lower heart rate is also
associated with an increase in diastolic perfusion time that may increase myocardial
perfusion.
C. Calcium channel blockers:
They act as antianginal drugs by the following mechanisms:
1. They decrease oxygen demand by decreasing myocardial contractility, decreasing
blood pressure, and decreasing heart rate (e.g., verapamil, diltiazem)
2. Coronary vasodilation: this improves oxygen supply.
NB: heart failure may be precipitated when verapamil is combined with β- blockers.
D. Potassium-channel openers (Nicorandil):
It acts as a vasodilator through two mechanisms: First; it increases cGMP as nitrates.
Second; it opens ATP-dependent potassium channel to allow potassium efflux and
hyperpolarization of the membrane which reduces calcium ion entry and cause
muscular relaxation.
Antiplatelet therapy in angina:
Low dose aspirin reduce the risk of myocardial infarction and should be
prescribed for all patients with coronary artery disease indefinitely. Clopidogrel is an
equally effective to aspirin and can be used if aspirin causes side effects
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Lecture – 10 and 11 - Pharmacology (2019-2020 ) ‫أزهرعبد الحافظ جابر‬.‫د‬ h

Figure -1-

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