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Antihypertensive Drugs
Dr Khaled M Hasan, MD,MSc, Mphil, PhD
Pharmacology and Clinical Pharmacology
University of London, UKDr Khaled M Hasan
-
Dr Khaled M Hasan
I. OVERVIEW
• Hypertension (HT) 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.
• Hypertension results from increased peripheral vascular
smooth muscle tone, which leads to increased arteriolar
resistance and reduced capacitance of the venous system.
• Hypertension is common disorder, affecting 15% of the
population of the USA (60 million). Although many of these
individuals have no symptoms, chronic HT- either systolic
or diastolic-can lead to congestive heart failure, myocardial
infarction, renal damage, and cerebrovascular accidents.
Dr Khaled M Hasan
• The incidence of morbidity and mortality significantly decreases
when hypertension is diagnosed early and is properly treated.
• Classification of hypertension
• Normal (SBP/DBP, <120/<80)
• Prehypertension (SBP/DBP, 120-139/80-89)
• Stage 1 hypertension (SBP/DBP, 140-159/90-99)
• Stage 2 hypertension (SBP/DBP ≥ 160/≥100)
Dr Khaled M Hasan
II. ETIOLOGY OF HYPERTENSION
• Although hypertension may occur secondary to other
disease processes, more than 90% 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.
• Essential hypertension is four-fold more frequent among
blacks than among whites, and it occurs more often among
middle-aged males than among middle-aged females.
• Environmental factors, such as a stressful lifestyle, high
dietary intake of sodium, obesity, and smoking, all further
predispose an individual to the occurrence of hypertension.
Dr Khaled M Hasan
Dr Khaled M Hasan
Fig. 13.116 Digital subtraction angiography, showing
typical unilateral atheromatous renal artery stenosis
with post-stenotic dilatation (Kumar).
Dr Khaled M Hasan
III. Mechanisms for Controlling Blood Pressure
• Arterial blood pressure is regulated within a narrow range to
provide adequate perfusion of the tissues without causing damage
to the vascular system, particularly the arterial intima.
• Arterial blood pressure is directly proportional to the product of
the cardiac output and the peripheral vascular resistance.
Dr Khaled M Hasan
III. Mechanisms for Controlling Blood Pressure
• In both normal and hypertensive individuals, cardiac output and
peripheral resistance are controlled mainly by two overlapping
control mechanisms:
• Baroreflexes, which are mediated by the sympathetic nervous
system
• Reninangiotensin-aldosterone system (RAAS)
• Most antihypertensive drugs lower blood pressure by reducing
cardiac output and/or decreasing peripheral resistance.
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
A. Baroreceptors and the sympathetic nervous system
• 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
(Fig).
Dr Khaled M Hasan
B. Renin-angiotensin-aldosterone system (RAAS)
• Kidney provides for long-term control of blood pressure
by altering blood volume.
• Baroreceptors in kidney respond to reduced arterial
pressure (and to sympathetic stimulation of
adrenoceptors) by releasing the enzyme renin (Fig).
• This peptidase converts angiotensinogen to angiotensin
I, which is converted in turn to angiotensin II in presence
of (ACE). Angiotensin II is the body's most potent
circulating vasoconstrictor, causing an increase in blood
pressure. 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.
Dr Khaled M Hasan
TREATMENT STRATEGIES
• The goal of antihypertensive therapy is to reduce cardiovascular
and renal morbidity and mortality.
• Pre hypertension emphasizes need for decreasing BP in the
general population by education and adoption of blood pressure-
lowering behaviors.
• Mild hypertension can often be controlled with a single drug.
Current treatment recommendations are to initiate therapy with
a thiazide diuretic unless there are compelling reasons to employ
other drug classes (Fig).
• If BP is inadequately controlled, a second drug is added, with the
selection based on minimizing the adverse effects of the
combined regimen. A beta-blocker is usually added if the initial
drug was a diuretic, or a diuretic is usually added if the first drug
was a β-blocker. A vasodilator can be added as a third step for
those patients who still fail to respond.
Dr Khaled M Hasan
• A. Individualized care
• Black patients respond well to diuretics and
calcium channel blockers, but therapy with β-
blockers or ACE inhibitors is often less effective.
• Elderly respond well to calcium channel blockers,
ACE inhibitors, and diuretics, whereas β-blockers
and αantagonists are less well tolerated.
• Furthermore, hypertension may coexist with
other diseases that can be aggravated by some
of the antihypertensive drugs.
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
Compelling indications
for individual drug classes.
Dr Khaled M Hasan
The main drugs for treating hypertension can
usefully be grouped as:
A: angiotensin-converting enzyme inhibitors
(ACEI) and angiotensin AT1 receptor antagonists
(sartans);
B: beta-adrenoceptor antagonists;
C: calcium channel antagonists;
D: diuretics.
Dr Khaled M Hasan
Dr Khaled M Hasan
Initiating and titrating
antihypertensive drug
treatment, 2011
Dr Khaled M Hasan
Dr Khaled M Hasan
Algorithm for treatment of hypertension
Dr Khaled M Hasan
•Diuretics may aggravate diabetes
•Beta-blockers worsen glucose
intolerance and mask symptoms of
hypoglycaemia
•Both diuretics and beta-blockers
disturb the lipid profile
•Verapamil and diltiazem may
exacerbate heart failure, although
amlodipine appears to be safe
•Patients with peripheral vascular
disease may also have renal artery
stenosis; therefore ACE inhibitors
should be used cautiously
Dr Khaled M Hasan
• B. Patient compliance in antihypertensive therapy
• Lack of patient compliance is the most common reason for
failure of antihypertensive therapy. The hypertensive patient is
usually asymptomatic and is diagnosed by routine screening
before the occurrence of overt end-organ damage.
• Thus, therapy is generally directed at preventing disease
sequelae (that occur in the future), rather than in relieving the
patient's present discomfort.
• The adverse effects associated with the hypertensive therapy
may influence the patient more than the future benefits. For
example, β-blockers can decrease libido and induce impotence
in males, particularly middleaged and elderly men. This drug-
induced sexual dysfunction may prompt the patient to
discontinue therapy. Thus, it is important to enhance
compliance by carefully selecting a drug regimen that both
reduces adverse effects and minimizes the number of doses
required daily.
Dr Khaled M Hasan
V. DIURETICS
• Diuretics are currently recommended as the first-line drug therapy
for hypertension unless there are compelling reasons to chose
another agent. Low-dose diuretic therapy is safe and effective in
preventing stroke, myocardial infarction, and congestive heart
failure, all of which can cause mortality.
• Recent data suggest that diuretics are superior to β-blockers in
older adults.
• A. Thiazide diuretics
• B. Loop diuretics
Dr Khaled M Hasan
A. Thiazide diuretics
Thiazides have found the most widespread
use.
Spironolactone, a potassiumsparing
diuretic, is used with thiazides.
Spironolactone has the additional benefit
of diminishing the cardiac remodeling that
occurs in heart failure.
1. Actions: Thiazide diuretics lower BP
initially by increasing sodium and water
excretion. This causes a decrease in
extracellular volume, resulting in a
decrease in cardiac output .
With long-term treatment, plasma volume
approaches a normal value, but peripheral
resistance decreases.
Dr Khaled M Hasan
(b) Ventricular
remodelling in
diastolic and
systolic heart
failure
(a) Ventricular
remodelling
after acute
infarction
Dr Khaled M Hasan
• 2. Therapeutic uses: Thiazide diuretics decrease BP in
both supine and standing positions.
• These agents counteract the sodium and water retention
observed with other agents used in treatment of
hypertension (e.g, hydralazine).
• Thiazides are useful in combination therapy with β-
blockers and ACE inhibitors. Thiazide diuretics are useful
in the treatment of black or elderly patients.
• They are not effective in patients with inadequate
kidney function (creatinine clearance <50 mL/min). Loop
diuretics may be required in these patients.
Dr Khaled M Hasan
• B. Loop diuretics
• The loop diuretics act promptly, even in patients with
poor renal function or who have not responded to
thiazides or other diuretics.
• The loop diuretics cause decreased renal vascular
resistance and increased renal blood flow.
Dr Khaled M Hasan
Dr Khaled M Hasan
β-Adrenoceptor-blocking Agents
• β-Blockers are currently recommended as first-line drug therapy for
hypertension when indicated-for example, with heart failure.
• A. Actions
• The Beta-blockers reduce BP primarily by decreasing cardiac output (Fig).
They may also decrease sympathetic outflow from CNS and inhibit the
release of renin from the kidneys, thus decreasing the formation of
angiotensin II and secretion of aldosterone.
• Prototype β-blocker is propranolol, which acts at both β1 and β2
receptors.
• Selective blockers of β1 receptors, such as metoprolol and atenolol, are
among the most commonly prescribed β-blockers.
• The selective β-blockers may be administered cautiously to hypertensive
patients who also have asthma, for which propranolol is contraindicated
due to its blockade of β2-mediated bronchodilation.
Dr Khaled M Hasan
Dr Khaled M Hasan
• B. Therapeutic uses
• The β-blockers are more effective for treating
hypertension in white than in black patients, and in young
compared to elderly patients.
• Conditions that discourage the use of β-blockers (for
example, severe chronic obstructive lung disease, chronic
congestive heart failure, or severe symptomatic occlusive
peripheral vascular disease) are more commonly found in
the elderly and in diabetics.
• 2. Hypertensive patients with concomitant diseases: The
β-blockers are useful in treating conditions that may
coexist with hypertension, such as supraventricular
tachyarrhythmia, previous myocardial infarction, angina
pectoris, chronic heart failure, and migraine headache.
Dr Khaled M Hasan
• C. Pharmacokinetics
• The β-blockers are orally active. The β-blockers may take several
weeks to develop their full effects.
• D. Adverse effects
• Bradycardia, fatigue, lethargy, insomnia, and hallucinations,
hypotension, decrease libido, impotence. Drug-induced sexual
dysfunction can severely reduce patient compliance.
• Decrease HDL and increase plasma triacylglycerol.
• 3. Drug withdrawal: Abrupt withdrawal may cause rebound
hypertension, probably as a result of up-regulation of β-receptors.
Removal from β-blocker therapy should therefore be tapered to
avoid precipitation of arrhythmias.
• The β-blockers should be employed cautiously in the treatment of
patients with asthma, acute heart failure, or peripheral vascular
disease.
Dr Khaled M Hasan
VII. ACE Inhibitors
•The ACE inhibitors, such as
enalapril or lisinopril, are
recommended when the
preferred first-line agents
(diuretics or β-blockers) are
contraindicated or
ineffective.
Dr Khaled M Hasan
Alacepril,
Benazepril,
Captopril,
Cilazapril,
Delapril,
Enalapril,
Enalaprilat,
Fosinopril,
Imidapril,
Lisinopril,
Moexipril,
Perindopril,
Quinapril,
Ramipril,
Spirapril,
Temocapril,
Teprotide,
Trandolapril,
Zofenopril,
ACE Inhibitors
Dr Khaled M Hasan
• A. Actions
• The ACE inhibitors lower blood pressure by reducing peripheral
vascular resistance without reflexively increasing cardiac output,
rate, or contractility. These drugs block the ACE that cleaves AngI
to form the potent vasoconstrictor AngII (Fig).
• The converting enzyme is also responsible for the breakdown of
bradykinin. Vasodilation occurs as a result of the combined effects
of lower vasoconstriction caused by diminished levels of
angiotensin II and the potent vasodilating effect of increased
bradykinin.
• By reducing circulating angiotensin II levels, ACE inhibitors also
decrease the secretion of aldosterone, resulting in decreased
sodium and water retention.
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
• B. Therapeutic uses
• Like β-blockers, ACE inhibitors are most effective in hypertensive patients who are
white and young. However, when used in combination with a diuretic, the
effectiveness of ACE inhibitors is similar in white and black patients with
hypertension.
• Along with the angiotensin receptor blockers, ACE inhibitors slow the progression of
diabetic nephropathy and decrease albuminuria.
• ACE inhibitors are also effective in the management of patients with chronic heart
failure. ACE inhibitors are a standard in the care of a patient following a myocardial
infarction.
• C. Adverse effects
• Common side effects include dry cough, rash, fever, altered taste, hypotension (in
hypovolemic states), and hyperkalemia.
• The dry cough, which occurs in about 10% of patients, is thought to be due to
increased levels of bradykinin in the pulmonary tree.
• Potassium levels must be monitored, and potassium supplements or spironolactone
are contraindicated.
• Angioedema is a rare but potentially life-threatening reaction and may also be due to
increased levels of bradykinin. Because of the risk of angioedema and first-dose
syncope, ACE inhibitors are first administered in the physician's office with close
observation.
• Reversible renal failure can occur in patients with severe renal artery stenosis. ACE
inhibitors are feto-toxic and should not be used by women who are pregnant.
Dr Khaled M Hasan
Angiotensin-converting enzyme inhibitors
• CAPTOPRIL
• CILAZAPRIL
• ENALAPRIL MALEATE
• FOSINOPRIL SODIUM
• IMIDAPRIL HYDROCHLORIDE
• LISINOPRIL
• MOEXIPRIL HYDROCHLORIDE
• PERINDOPRIL ERBUMINE
• QUINAPRIL
• RAMIPRIL
• RAMIPRIL WITH FELODIPINE
• TRANDOLAPRIL
Dr Khaled M Hasan
VIII. Angiotensin II-receptor Antagonists
• The Ang- II-receptor blockers (ARBs) are alternatives to the ACE
inhibitors.
• Losartan, is the prototypic ARB; currently, there are six additional
ARBs. Their pharmacologic effects are similar to those of ACE
inhibitors in that they produce vasodilation and block aldosterone
secretion, thus lowering blood pressure and decreasing salt and
water retention.
• ARBs decrease the nephrotoxicity of diabetes, making them an
attractive therapy in hypertensive diabetics. Their adverse
effects are similar to those of ACE inhibitors, although the risks of
cough and angioedema are significantly decreased. They are
feto-toxic.
•
Dr Khaled M Hasan
Angiotensin-II receptor antagonists
• CANDESARTAN CILEXETIL
• EPROSARTAN
• IRBESARTAN
• LOSARTAN POTASSIUM
• OLMESARTAN MEDOXOMIL
• TELMISARTAN
• VALSARTAN
Dr Khaled M Hasan
IX. Calcium Channel Blockers (CCB)
• CCBs are recommended when the preferred firstline
agents are contraindicated or ineffective.
• They are effective in treating hypertension in patients
with angina or diabetes. High doses of short-acting
CCBs should be avoided because of increased risk of
myocardial infarction.
• Classes of calcium channel blockers
• Verapamil
• Diltiazem
• Dihydropyridines (nifedipine, amlodipine, felodipine,
isradipine, nicardipine, and nisoldipine)
Dr Khaled M Hasan
• Verapamil is the least selective of any calcium channel
blocker, and has significant effects on both cardiac and
vascular smoothmuscle cells. It is used to treat angina,
supraventricular tachyarrhythmias, and migraine
headache.
•
• Diltiazem, like verapamil, diltiazem affects both cardiac
and vascular smoothmuscle cells; however, it has a less
pronounced negative inotropic effect on heart compared
to that of verapamil. Diltiazem has a favorable side-effect
profile.
Dr Khaled M Hasan
• Dihydropyridines include nifedipine, amlodipine,
felodipine, isradipine, nicardipine, and nisoldipine.
• These new-generation calcium channel blockers differ in pharmacokinetics, approved uses, and drug
interactions.
• All dihydropyridines have a much greater affinity for
vascular calcium channels than for calcium channels in
the heart. They are therefore particularly attractive in
treating hypertension.
• Newer agents, such as amlodipine and nicardipine, have
the advantage that they show little interaction with
other cardiovascular drugs, such as digoxin or warfarin,
which are often used concomitantly with calcium
channel blockers.
Dr Khaled M Hasan
Dr Khaled M Hasan
Calcium-channel blockers
• AMLODIPINE
• DILTIAZEM HYDROCHLORIDE
• FELODIPINE
• ISRADIPINE
• LACIDIPINE
• LERCANIDIPINE HYDROCHLORIDE
• NICARDIPINE HYDROCHLORIDE
• NIFEDIPINE
• NIMODIPINE
• NISOLDIPINE
• VERAPAMIL HYDROCHLORIDE
Dr Khaled M Hasan
• B. Actions
• The intracellular concentration of calcium plays an important role in
maintaining the tone of smooth muscle and in the contraction of the
myocardium.
• Calcium enters muscle cells through special voltagesensitive calcium channels. This triggers release of
calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level
of calcium.
• Calcium channel antagonists block the inward movement of calcium by
binding to L-type calcium channels in the heart and in smooth muscle of
the coronary and peripheral vasculature. This causes vascular smooth
muscle to relax, dilating mainly arterioles.
•
• C. Therapeutic uses
• Calcium channel blockers have an intrinsic natriuretic effect and,
therefore, do not usually require the addition of a diuretic. These agents
are useful in the treatment of hypertensive patients who also have asthma,
diabetes, angina, and/or peripheral vascular disease (Fig). Black
hypertensives respond well to calcium channel blockers.
Dr Khaled M Hasan
• D. Pharmacokinetics
• Most of these agents have short half-lives (3-8 hours).
Treatment is required three times a day to maintain good
control of hypertension. Sustained-release preparations permit
less frequent dosing.
•
• E. Adverse effects
• Infrequent side effects: constipation 10%, as dizziness,
headache, and a feeling of fatigue caused by a decrease in
blood pressure, edema (Fig).
• Verapamil should be avoided in patients with congestive heart
failure due to its negative inotropic effects.
Dr Khaled M Hasan
Alpha(α )-Adrenoceptor-blocking Agents
• Prazosin, doxazosin, and terazosin produce a competitive block of α-
adrenoceptors.
• They decrease the peripheral vascular resistance and lower the
arterial blood pressure by causing relaxation of both arterial and
venous smooth muscle.
• These drugs cause only minimal changes in cardiac output, renal
blood flow, and glomerular filtration rate. Therefore, long-term
tachycardia does not occur, but salt and water retention does.
• Postural hypotension may occur in some individuals. Reflex
tachycardia and first-dose syncope are almost universal adverse
effects. Concomitant use of a beta-blocker may be necessary to
blunt the short-term effect of reflex tachycardia.
Dr Khaled M Hasan
• DOXAZOSIN
• INDORAMIN
• PRAZOSIN
• TERAZOSIN
• Prostatic hyperplasia
• Alfuzosin, doxazosin, indoramin, prazosin,
tamsulosin, and terazosin are indicated for benign
prostatic hyperplasia
Dr Khaled M Hasan
Centrally Acting Adrenergic Drugs
A. Clonidine
• This α2 agonist diminishes central adrenergic outflow. Clonidine
is used primarily for the treatment of mild to moderate
hypertension that has not responded adequately to treatment
with diuretics alone. Clonidine does not decrease renal blood
flow or glomerular filtration and, therefore, is useful in the
treatment of hypertension complicated by renal disease.
• Clonidine is absorbed well after oral administration and is
excreted by the kidney. Because it causes sodium and water
retention, clonidine is usually administered in combination with a
diuretic.
• Side effects: mild (sedation, drying nasal mucosa)
• Rebound HT occurs following abrupt withdrawal of clonidineDr Khaled M Hasan
B. α-Methyldopa
• This α2-agonist is converted to methylnorepinephrine
centrally to diminish the adrenergic outflow from the
CNS, leading to reduced total peripheral resistance
and a decreased blood pressure.
• Cardiac output is not decreased and blood flow to
vital organs is not diminished. Because blood flow to
the kidney is not diminished by its use, α-methyldopa
is especially valuable in treating HT patients with renal
insufficiency.
• Side effects : sedation and drowsiness.
Dr Khaled M Hasan
Dr Khaled M Hasan
Vasodilators
• Direct-acting smooth muscle relaxants: hydralazine ,minoxidil.
• Vasodilators produce relaxation of vascular smooth muscle, which
decreases resistance and therefore decreases blood pressure.
• These agents produce reflex stimulation of the heart, resulting in
the competing symptoms of increased myocardial contractility,
heart rate, and oxygen consumption. These actions may prompt
angina pectoris, myocardial infarction, or cardiac failure in
predisposed individuals.
• Vasodilators also increase plasma renin concentration, resulting in
sodium and water retention. These undesirable side effects can
be blocked by concomitant use of a diuretic and a beta-blocker.
Dr Khaled M Hasan
Dr Khaled M Hasan
A. Hydralazine
• Hydralazine is used to treat moderately severe HT. It is
almost always administered in combination with a beta-
blocker such as propranolol (to balance the reflex
tachycardia) and a diuretic (to decrease sodium
retention). Together, the three drugs decrease cardiac
output, plasma volume, and peripheral vascular
resistance.
• A lupus-like syndrome can occur with high dosage, but it
is reversible on discontinuation of the drug.
Dr Khaled M Hasan
B. Minoxidil
• This drug causes dilation of resistance vessels
(arterioles) but not of capacitance vessels (venules).
• Minoxidil is administered orally for treatment of severe
to malignant hypertension that is refractory to other
drugs.
• Minoxidil causes serious sodium and water retention,
leading to volume overload, edema, and congestive
heart failure.
• Minoxidil treatment also causes hypertrichosis (growth
of body hair). This drug is now used topically to treat
male pattern baldness.
Dr Khaled M Hasan
Hypertensive Emergency
• Hypertensive emergency is a rare but life-threatening
situation in which the DBP is either >150 mm Hg (with
SBP >210 mm Hg) in an otherwise healthy person, or a
DBP of 130 mm Hg in an individual with preexisting
complications, such as encephalopathy, cerebral
hemorrhage, left-ventricular failure, or aortic stenosis.
• The therapeutic goal is to rapidly reduce blood pressure.
• A. Sodium nitroprusside
• B. Labetalol
• C. Fenoldopam
• D. Nicardipine
Dr Khaled M Hasan
A. Sodium nitroprusside
• Nitroprusside is administered intravenously, and causes prompt
vasodilation with reflex tachycardia. It is capable of reducing
blood pressure in all patients regardless of the cause of
hypertension (Fig).
• The drug has little effect outside the vascular system, acting
equally on arterial and venous smooth muscle.
• Because nitroprusside also acts on the veins, it can reduce cardiac preload.
Nitroprusside is metabolized rapidly (halflife of minutes) and requires continuous
infusion to maintain its hypotensive action.
• Adverse effects: hypotension caused by overdose. Nitroprusside
metabolism results in cyanide ion production.
• Although cyanide toxicity is rare, it can be effectively treated with an infusion of
sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the
kidneys. [Note: Nitroprusside is poisonous if given orally because of its hydrolysis to
cyanide.]
Dr Khaled M Hasan
• B. Labetalol
• Labetalol is both an (alpha- and a beta-blocker and is given as an intravenous
bolus or infusion in hypertensive emergencies. Labetalol does not cause reflex
tachycardia. Labetalol carries the contraindications of a nonselective beta-
blocker. The major limitation is a longer half-life, which precludes rapid titration.
• C. Fenoldopam
• Fenoldopam is a peripheral dopamine-1 receptor agonist that is given as an
intravenous infusion. Unlike other parenteral antihypertensive agents,
fenoldopam maintains or increases renal perfusion while it lowers blood
pressure. Fenoldopam can be safely used in all hypertensive emergencies and
may be particularly beneficial in patients with renal insufficiency.
• D. Nicardipine
• Nicardipine, a calcium channel blocker, can be given as an intravenous infusion.
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan
Dr Khaled M Hasan

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Antihypertensive drugs

  • 1. Antihypertensive Drugs Dr Khaled M Hasan, MD,MSc, Mphil, PhD Pharmacology and Clinical Pharmacology University of London, UKDr Khaled M Hasan
  • 3. I. OVERVIEW • Hypertension (HT) 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. • Hypertension results from increased peripheral vascular smooth muscle tone, which leads to increased arteriolar resistance and reduced capacitance of the venous system. • Hypertension is common disorder, affecting 15% of the population of the USA (60 million). Although many of these individuals have no symptoms, chronic HT- either systolic or diastolic-can lead to congestive heart failure, myocardial infarction, renal damage, and cerebrovascular accidents. Dr Khaled M Hasan
  • 4. • The incidence of morbidity and mortality significantly decreases when hypertension is diagnosed early and is properly treated. • Classification of hypertension • Normal (SBP/DBP, <120/<80) • Prehypertension (SBP/DBP, 120-139/80-89) • Stage 1 hypertension (SBP/DBP, 140-159/90-99) • Stage 2 hypertension (SBP/DBP ≥ 160/≥100) Dr Khaled M Hasan
  • 5. II. ETIOLOGY OF HYPERTENSION • Although hypertension may occur secondary to other disease processes, more than 90% 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. • Essential hypertension is four-fold more frequent among blacks than among whites, and it occurs more often among middle-aged males than among middle-aged females. • Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, obesity, and smoking, all further predispose an individual to the occurrence of hypertension. Dr Khaled M Hasan
  • 6. Dr Khaled M Hasan
  • 7. Fig. 13.116 Digital subtraction angiography, showing typical unilateral atheromatous renal artery stenosis with post-stenotic dilatation (Kumar). Dr Khaled M Hasan
  • 8. III. Mechanisms for Controlling Blood Pressure • Arterial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without causing damage to the vascular system, particularly the arterial intima. • Arterial blood pressure is directly proportional to the product of the cardiac output and the peripheral vascular resistance. Dr Khaled M Hasan
  • 9. III. Mechanisms for Controlling Blood Pressure • In both normal and hypertensive individuals, cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: • Baroreflexes, which are mediated by the sympathetic nervous system • Reninangiotensin-aldosterone system (RAAS) • Most antihypertensive drugs lower blood pressure by reducing cardiac output and/or decreasing peripheral resistance. Dr Khaled M Hasan
  • 10. Dr Khaled M Hasan
  • 11. Dr Khaled M Hasan
  • 12. A. Baroreceptors and the sympathetic nervous system • 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 (Fig). Dr Khaled M Hasan
  • 13. B. Renin-angiotensin-aldosterone system (RAAS) • Kidney provides for long-term control of blood pressure by altering blood volume. • Baroreceptors in kidney respond to reduced arterial pressure (and to sympathetic stimulation of adrenoceptors) by releasing the enzyme renin (Fig). • This peptidase converts angiotensinogen to angiotensin I, which is converted in turn to angiotensin II in presence of (ACE). Angiotensin II is the body's most potent circulating vasoconstrictor, causing an increase in blood pressure. 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. Dr Khaled M Hasan
  • 14. TREATMENT STRATEGIES • The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. • Pre hypertension emphasizes need for decreasing BP in the general population by education and adoption of blood pressure- lowering behaviors. • Mild hypertension can often be controlled with a single drug. Current treatment recommendations are to initiate therapy with a thiazide diuretic unless there are compelling reasons to employ other drug classes (Fig). • If BP is inadequately controlled, a second drug is added, with the selection based on minimizing the adverse effects of the combined regimen. A beta-blocker is usually added if the initial drug was a diuretic, or a diuretic is usually added if the first drug was a β-blocker. A vasodilator can be added as a third step for those patients who still fail to respond. Dr Khaled M Hasan
  • 15. • A. Individualized care • Black patients respond well to diuretics and calcium channel blockers, but therapy with β- blockers or ACE inhibitors is often less effective. • Elderly respond well to calcium channel blockers, ACE inhibitors, and diuretics, whereas β-blockers and αantagonists are less well tolerated. • Furthermore, hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs. Dr Khaled M Hasan
  • 16. Dr Khaled M Hasan
  • 17. Dr Khaled M Hasan
  • 18. Compelling indications for individual drug classes. Dr Khaled M Hasan
  • 19. The main drugs for treating hypertension can usefully be grouped as: A: angiotensin-converting enzyme inhibitors (ACEI) and angiotensin AT1 receptor antagonists (sartans); B: beta-adrenoceptor antagonists; C: calcium channel antagonists; D: diuretics. Dr Khaled M Hasan
  • 20. Dr Khaled M Hasan
  • 21. Initiating and titrating antihypertensive drug treatment, 2011 Dr Khaled M Hasan
  • 22. Dr Khaled M Hasan
  • 23. Algorithm for treatment of hypertension Dr Khaled M Hasan
  • 24. •Diuretics may aggravate diabetes •Beta-blockers worsen glucose intolerance and mask symptoms of hypoglycaemia •Both diuretics and beta-blockers disturb the lipid profile •Verapamil and diltiazem may exacerbate heart failure, although amlodipine appears to be safe •Patients with peripheral vascular disease may also have renal artery stenosis; therefore ACE inhibitors should be used cautiously Dr Khaled M Hasan
  • 25. • B. Patient compliance in antihypertensive therapy • Lack of patient compliance is the most common reason for failure of antihypertensive therapy. The hypertensive patient is usually asymptomatic and is diagnosed by routine screening before the occurrence of overt end-organ damage. • Thus, therapy is generally directed at preventing disease sequelae (that occur in the future), rather than in relieving the patient's present discomfort. • The adverse effects associated with the hypertensive therapy may influence the patient more than the future benefits. For example, β-blockers can decrease libido and induce impotence in males, particularly middleaged and elderly men. This drug- induced sexual dysfunction may prompt the patient to discontinue therapy. Thus, it is important to enhance compliance by carefully selecting a drug regimen that both reduces adverse effects and minimizes the number of doses required daily. Dr Khaled M Hasan
  • 26. V. DIURETICS • Diuretics are currently recommended as the first-line drug therapy for hypertension unless there are compelling reasons to chose another agent. Low-dose diuretic therapy is safe and effective in preventing stroke, myocardial infarction, and congestive heart failure, all of which can cause mortality. • Recent data suggest that diuretics are superior to β-blockers in older adults. • A. Thiazide diuretics • B. Loop diuretics Dr Khaled M Hasan
  • 27. A. Thiazide diuretics Thiazides have found the most widespread use. Spironolactone, a potassiumsparing diuretic, is used with thiazides. Spironolactone has the additional benefit of diminishing the cardiac remodeling that occurs in heart failure. 1. Actions: Thiazide diuretics lower BP initially by increasing sodium and water excretion. This causes a decrease in extracellular volume, resulting in a decrease in cardiac output . With long-term treatment, plasma volume approaches a normal value, but peripheral resistance decreases. Dr Khaled M Hasan
  • 28. (b) Ventricular remodelling in diastolic and systolic heart failure (a) Ventricular remodelling after acute infarction Dr Khaled M Hasan
  • 29. • 2. Therapeutic uses: Thiazide diuretics decrease BP in both supine and standing positions. • These agents counteract the sodium and water retention observed with other agents used in treatment of hypertension (e.g, hydralazine). • Thiazides are useful in combination therapy with β- blockers and ACE inhibitors. Thiazide diuretics are useful in the treatment of black or elderly patients. • They are not effective in patients with inadequate kidney function (creatinine clearance <50 mL/min). Loop diuretics may be required in these patients. Dr Khaled M Hasan
  • 30. • B. Loop diuretics • The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics. • The loop diuretics cause decreased renal vascular resistance and increased renal blood flow. Dr Khaled M Hasan
  • 31. Dr Khaled M Hasan
  • 32. β-Adrenoceptor-blocking Agents • β-Blockers are currently recommended as first-line drug therapy for hypertension when indicated-for example, with heart failure. • A. Actions • The Beta-blockers reduce BP primarily by decreasing cardiac output (Fig). They may also decrease sympathetic outflow from CNS and inhibit the release of renin from the kidneys, thus decreasing the formation of angiotensin II and secretion of aldosterone. • Prototype β-blocker is propranolol, which acts at both β1 and β2 receptors. • Selective blockers of β1 receptors, such as metoprolol and atenolol, are among the most commonly prescribed β-blockers. • The selective β-blockers may be administered cautiously to hypertensive patients who also have asthma, for which propranolol is contraindicated due to its blockade of β2-mediated bronchodilation. Dr Khaled M Hasan
  • 33. Dr Khaled M Hasan
  • 34. • B. Therapeutic uses • The β-blockers are more effective for treating hypertension in white than in black patients, and in young compared to elderly patients. • Conditions that discourage the use of β-blockers (for example, severe chronic obstructive lung disease, chronic congestive heart failure, or severe symptomatic occlusive peripheral vascular disease) are more commonly found in the elderly and in diabetics. • 2. Hypertensive patients with concomitant diseases: The β-blockers are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, chronic heart failure, and migraine headache. Dr Khaled M Hasan
  • 35. • C. Pharmacokinetics • The β-blockers are orally active. The β-blockers may take several weeks to develop their full effects. • D. Adverse effects • Bradycardia, fatigue, lethargy, insomnia, and hallucinations, hypotension, decrease libido, impotence. Drug-induced sexual dysfunction can severely reduce patient compliance. • Decrease HDL and increase plasma triacylglycerol. • 3. Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of β-receptors. Removal from β-blocker therapy should therefore be tapered to avoid precipitation of arrhythmias. • The β-blockers should be employed cautiously in the treatment of patients with asthma, acute heart failure, or peripheral vascular disease. Dr Khaled M Hasan
  • 36. VII. ACE Inhibitors •The ACE inhibitors, such as enalapril or lisinopril, are recommended when the preferred first-line agents (diuretics or β-blockers) are contraindicated or ineffective. Dr Khaled M Hasan
  • 38. • A. Actions • The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexively increasing cardiac output, rate, or contractility. These drugs block the ACE that cleaves AngI to form the potent vasoconstrictor AngII (Fig). • The converting enzyme is also responsible for the breakdown of bradykinin. Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin. • By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention. Dr Khaled M Hasan
  • 39. Dr Khaled M Hasan
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  • 43. • B. Therapeutic uses • Like β-blockers, ACE inhibitors are most effective in hypertensive patients who are white and young. However, when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black patients with hypertension. • Along with the angiotensin receptor blockers, ACE inhibitors slow the progression of diabetic nephropathy and decrease albuminuria. • ACE inhibitors are also effective in the management of patients with chronic heart failure. ACE inhibitors are a standard in the care of a patient following a myocardial infarction. • C. Adverse effects • Common side effects include dry cough, rash, fever, altered taste, hypotension (in hypovolemic states), and hyperkalemia. • The dry cough, which occurs in about 10% of patients, is thought to be due to increased levels of bradykinin in the pulmonary tree. • Potassium levels must be monitored, and potassium supplements or spironolactone are contraindicated. • Angioedema is a rare but potentially life-threatening reaction and may also be due to increased levels of bradykinin. Because of the risk of angioedema and first-dose syncope, ACE inhibitors are first administered in the physician's office with close observation. • Reversible renal failure can occur in patients with severe renal artery stenosis. ACE inhibitors are feto-toxic and should not be used by women who are pregnant. Dr Khaled M Hasan
  • 44. Angiotensin-converting enzyme inhibitors • CAPTOPRIL • CILAZAPRIL • ENALAPRIL MALEATE • FOSINOPRIL SODIUM • IMIDAPRIL HYDROCHLORIDE • LISINOPRIL • MOEXIPRIL HYDROCHLORIDE • PERINDOPRIL ERBUMINE • QUINAPRIL • RAMIPRIL • RAMIPRIL WITH FELODIPINE • TRANDOLAPRIL Dr Khaled M Hasan
  • 45. VIII. Angiotensin II-receptor Antagonists • The Ang- II-receptor blockers (ARBs) are alternatives to the ACE inhibitors. • Losartan, is the prototypic ARB; currently, there are six additional ARBs. Their pharmacologic effects are similar to those of ACE inhibitors in that they produce vasodilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. • ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of ACE inhibitors, although the risks of cough and angioedema are significantly decreased. They are feto-toxic. • Dr Khaled M Hasan
  • 46. Angiotensin-II receptor antagonists • CANDESARTAN CILEXETIL • EPROSARTAN • IRBESARTAN • LOSARTAN POTASSIUM • OLMESARTAN MEDOXOMIL • TELMISARTAN • VALSARTAN Dr Khaled M Hasan
  • 47. IX. Calcium Channel Blockers (CCB) • CCBs are recommended when the preferred firstline agents are contraindicated or ineffective. • They are effective in treating hypertension in patients with angina or diabetes. High doses of short-acting CCBs should be avoided because of increased risk of myocardial infarction. • Classes of calcium channel blockers • Verapamil • Diltiazem • Dihydropyridines (nifedipine, amlodipine, felodipine, isradipine, nicardipine, and nisoldipine) Dr Khaled M Hasan
  • 48. • Verapamil is the least selective of any calcium channel blocker, and has significant effects on both cardiac and vascular smoothmuscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migraine headache. • • Diltiazem, like verapamil, diltiazem affects both cardiac and vascular smoothmuscle cells; however, it has a less pronounced negative inotropic effect on heart compared to that of verapamil. Diltiazem has a favorable side-effect profile. Dr Khaled M Hasan
  • 49. • Dihydropyridines include nifedipine, amlodipine, felodipine, isradipine, nicardipine, and nisoldipine. • These new-generation calcium channel blockers differ in pharmacokinetics, approved uses, and drug interactions. • All dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are therefore particularly attractive in treating hypertension. • Newer agents, such as amlodipine and nicardipine, have the advantage that they show little interaction with other cardiovascular drugs, such as digoxin or warfarin, which are often used concomitantly with calcium channel blockers. Dr Khaled M Hasan
  • 50. Dr Khaled M Hasan
  • 51. Calcium-channel blockers • AMLODIPINE • DILTIAZEM HYDROCHLORIDE • FELODIPINE • ISRADIPINE • LACIDIPINE • LERCANIDIPINE HYDROCHLORIDE • NICARDIPINE HYDROCHLORIDE • NIFEDIPINE • NIMODIPINE • NISOLDIPINE • VERAPAMIL HYDROCHLORIDE Dr Khaled M Hasan
  • 52. • B. Actions • The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscle and in the contraction of the myocardium. • Calcium enters muscle cells through special voltagesensitive calcium channels. This triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level of calcium. • Calcium channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles. • • C. Therapeutic uses • Calcium channel blockers have an intrinsic natriuretic effect and, therefore, do not usually require the addition of a diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease (Fig). Black hypertensives respond well to calcium channel blockers. Dr Khaled M Hasan
  • 53. • D. Pharmacokinetics • Most of these agents have short half-lives (3-8 hours). Treatment is required three times a day to maintain good control of hypertension. Sustained-release preparations permit less frequent dosing. • • E. Adverse effects • Infrequent side effects: constipation 10%, as dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure, edema (Fig). • Verapamil should be avoided in patients with congestive heart failure due to its negative inotropic effects. Dr Khaled M Hasan
  • 54. Alpha(α )-Adrenoceptor-blocking Agents • Prazosin, doxazosin, and terazosin produce a competitive block of α- adrenoceptors. • They decrease the peripheral vascular resistance and lower the arterial blood pressure by causing relaxation of both arterial and venous smooth muscle. • These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therefore, long-term tachycardia does not occur, but salt and water retention does. • Postural hypotension may occur in some individuals. Reflex tachycardia and first-dose syncope are almost universal adverse effects. Concomitant use of a beta-blocker may be necessary to blunt the short-term effect of reflex tachycardia. Dr Khaled M Hasan
  • 55. • DOXAZOSIN • INDORAMIN • PRAZOSIN • TERAZOSIN • Prostatic hyperplasia • Alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, and terazosin are indicated for benign prostatic hyperplasia Dr Khaled M Hasan
  • 56. Centrally Acting Adrenergic Drugs A. Clonidine • This α2 agonist diminishes central adrenergic outflow. Clonidine is used primarily for the treatment of mild to moderate hypertension that has not responded adequately to treatment with diuretics alone. Clonidine does not decrease renal blood flow or glomerular filtration and, therefore, is useful in the treatment of hypertension complicated by renal disease. • Clonidine is absorbed well after oral administration and is excreted by the kidney. Because it causes sodium and water retention, clonidine is usually administered in combination with a diuretic. • Side effects: mild (sedation, drying nasal mucosa) • Rebound HT occurs following abrupt withdrawal of clonidineDr Khaled M Hasan
  • 57. B. α-Methyldopa • This α2-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure. • Cardiac output is not decreased and blood flow to vital organs is not diminished. Because blood flow to the kidney is not diminished by its use, α-methyldopa is especially valuable in treating HT patients with renal insufficiency. • Side effects : sedation and drowsiness. Dr Khaled M Hasan
  • 58. Dr Khaled M Hasan
  • 59. Vasodilators • Direct-acting smooth muscle relaxants: hydralazine ,minoxidil. • Vasodilators produce relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure. • These agents produce reflex stimulation of the heart, resulting in the competing symptoms of increased myocardial contractility, heart rate, and oxygen consumption. These actions may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals. • Vasodilators also increase plasma renin concentration, resulting in sodium and water retention. These undesirable side effects can be blocked by concomitant use of a diuretic and a beta-blocker. Dr Khaled M Hasan
  • 60. Dr Khaled M Hasan
  • 61. A. Hydralazine • Hydralazine is used to treat moderately severe HT. It is almost always administered in combination with a beta- blocker such as propranolol (to balance the reflex tachycardia) and a diuretic (to decrease sodium retention). Together, the three drugs decrease cardiac output, plasma volume, and peripheral vascular resistance. • A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug. Dr Khaled M Hasan
  • 62. B. Minoxidil • This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). • Minoxidil is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs. • Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure. • Minoxidil treatment also causes hypertrichosis (growth of body hair). This drug is now used topically to treat male pattern baldness. Dr Khaled M Hasan
  • 63. Hypertensive Emergency • Hypertensive emergency is a rare but life-threatening situation in which the DBP is either >150 mm Hg (with SBP >210 mm Hg) in an otherwise healthy person, or a DBP of 130 mm Hg in an individual with preexisting complications, such as encephalopathy, cerebral hemorrhage, left-ventricular failure, or aortic stenosis. • The therapeutic goal is to rapidly reduce blood pressure. • A. Sodium nitroprusside • B. Labetalol • C. Fenoldopam • D. Nicardipine Dr Khaled M Hasan
  • 64. A. Sodium nitroprusside • Nitroprusside is administered intravenously, and causes prompt vasodilation with reflex tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension (Fig). • The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. • Because nitroprusside also acts on the veins, it can reduce cardiac preload. Nitroprusside is metabolized rapidly (halflife of minutes) and requires continuous infusion to maintain its hypotensive action. • Adverse effects: hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production. • Although cyanide toxicity is rare, it can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. [Note: Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.] Dr Khaled M Hasan
  • 65. • B. Labetalol • Labetalol is both an (alpha- and a beta-blocker and is given as an intravenous bolus or infusion in hypertensive emergencies. Labetalol does not cause reflex tachycardia. Labetalol carries the contraindications of a nonselective beta- blocker. The major limitation is a longer half-life, which precludes rapid titration. • C. Fenoldopam • Fenoldopam is a peripheral dopamine-1 receptor agonist that is given as an intravenous infusion. Unlike other parenteral antihypertensive agents, fenoldopam maintains or increases renal perfusion while it lowers blood pressure. Fenoldopam can be safely used in all hypertensive emergencies and may be particularly beneficial in patients with renal insufficiency. • D. Nicardipine • Nicardipine, a calcium channel blocker, can be given as an intravenous infusion. Dr Khaled M Hasan
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