Drugs Affecting

the Cardiovascular
System
By Tauseef Ahmad
Hypertension
 Hypertension is defined as either a sustained
systolic blood pressure of greater than 140 mm
Hg or a sustained diastolic blood pressure of
greater than 90 mm Hg.
 Hypertension results from increased peripheral
 vascular arteriolar smooth muscle tone, which
leads to increased arteriolar resistance and
reduced capacitance of the venous system.
 many patients have no symptoms, chronic
hypertension can lead to heart disease and
stroke,
ETIOLOGY OF HYPERTENSION
 Although hypertension may occur secondary to other
disease processes,
 more than 90% of patients have essential hypertension
(hypertension with no identifiable cause).
 A family history of hypertension increases the likelihood
that an individual will develop hypertension.
 The prevalence of hypertension increases with age,
Persons with diabetes, obesity, or disability status are all
more likely to have hypertension than those without.
 In addition, environmental factors, such as a stressful
lifestyle, high dietary intake of sodium, and smoking,
may further predispose an individual to hypertension.
MECHANISMS FOR CONTROLLING BLOOD
PRESSURE
 Arterial blood pressure is directly proportional
to cardiac output and peripheral vascular
resistance.
 Cardiac output and peripheral resistance, in
turn, are controlled mainly by two overlapping
control mechanisms:
 the baroreflexes and the renin–angiotensin–
aldosterone system
Baroreceptors and the sympathetic
nervous system
 Baro reflexes act by changing the activity of the
sympathetic nervous system.
 Therefore, they 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
Renin–angiotensin–aldosterone system
 Baroreceptors in the kidney respond to reduced
arterial pressure (and to sympathetic stimulation of
β1-adrenoceptors) by releasing the enzyme renin.
 Low sodium intake and greater sodium loss also
increase renin release.
 Renin converts angiotensinogen to angiotensin I,
which is converted in turn to angiotensin II, in the
presence of angiotensin-converting enzyme (ACE).
 Angiotensin II is a potent circulating
vasoconstrictor, constricting both arterioles and
veins, resulting in an increase in blood pressure.
 Angiotensin II exerts a preferential
vasoconstrictor action on the 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 type 1 (AT1)
receptors
TREATMENT STRATEGIES
 The classification of “prehypertension” recognizes this
relationship and emphasizes the need for decreasing
blood pressure in the general population by education
and the adoption of blood pressure–lowering
behaviors.
 For most patients, the blood pressure goal when
treating hypertension is a systolic blood pressure of
less than 140 mm Hg and a diastolic blood pressure of
less than 90 mm Hg.
 Mild hypertension can sometimes be controlled with
monotherapy, but most patients require more than one
drug to achieve blood pressure control.
 Current recommendations are to initiate therapy with
a thiazide diuretic, ACE inhibitor, angiotensin receptor
blocker (ARB), or calcium channel blocker.
 If blood pressure is inadequately controlled, a
second drug should be added,
 Patients with systolic blood pressure greater
than 160 mm Hg or diastolic blood pressure
greater than 100 mm Hg (or systolic blood
 pressure greater than 20 mm Hg above goal or
diastolic blood pressure more than 10 mm Hg
above goal) should be started on two
antihypertensives simultaneously.
β-ADRENOCEPTOR–BLOCKING AGENTS
 β-Blockers are a treatment option for
hypertensive patients with concomitant heart
disease.
 Actions:
 The β-blockers reduce blood pressure primarily
by decreasing cardiac output.
 They may also decrease sympathetic outflow
from the central nervous system (CNS) and
inhibit the release of renin from the kidneys, thus
decreasing the formation of angiotensin II and the
secretion of aldosterone.
 The 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.
 Nebivolol is a selective blocker of β1 receptors,
which also increases the production of nitric
oxide, leading to vasodilation.
 The selective β-blockers may be administered
cautiously to hypertensive patients who also
have asthma.
 β-Blockers should be used cautiously in the
treatment of patients with acute heart failure or
peripheral vascular disease.
Therapeutic uses
 The primary therapeutic benefits of β-blockers
are seen in hypertensive patients with
concomitant heart disease, such as
supraventricular
 tachyarrhythmia (for example, atrial
fibrillation), previous myocardial
 infarction, angina pectoris, and chronic heart
failure.
Pharmacokinetics
 The β-blockers are orally active for the
treatment of hypertension.
 Propranolol undergoes extensive and highly
variable first-pass metabolism.
 Oral β-blockers may take several weeks to
develop their full effects.
 Esmolol, metoprolol, and propranolol are
available in intravenous formulations.
Adverse effects
 Common effects: The β-blockers may cause
bradycardia, hypotension, and CNS side effects
such as fatigue, lethargy, and insomnia.
 The β-blockers may decrease libido and cause
erectile dysfunction, which can severely reduce
patient compliance
 Alterations in serum lipid patterns:
 Non cardioselective β-blockers may disturb
lipid metabolism, decreasing high-density
lipoprotein cholesterol and increasing
triglycerides.
 Drug withdrawal:
 Abrupt withdrawal may induce angina,
myocardial infarction, and even sudden death in
patients with ischemic heart disease.
 Therefore, these drugs must be tapered over a
few weeks in patients with hypertension and
ischemic heart disease.
ACE INHIBITORS
 The ACE inhibitors, such as enalapril and
lisinopril are recommended as first-line
treatment of hypertension in patients with a
variety of compelling indications, including
 high coronary disease risk or history of
diabetes,
 stroke,
 heart failure,
 myocardial infarction,
 or chronic kidney disease
Actions
 The ACE inhibitors lower blood pressure by reducing
peripheral vascular resistance .
 These drugs block the enzyme ACE which cleaves
angiotensin I to form the angiotensin II .
 ACE is also responsible for the breakdown of bradykinin,
a peptide that increases the production of nitric oxide
and prostacyclin by the blood vessels.
 Both are potent vasodilators. ACE inhibitors decrease
angiotensin II and increase bradykinin levels.
 Vasodilation of both arterioles and veins occurs as a
result.
 ACE inhibitors also decrease the secretion of aldosterone,
resulting in decreased sodium and water retention.
 ACE inhibitors reduce both cardiac preload and afterload,
thereby decreasing cardiac work.
Therapeutic uses
 Like the ARBs, ACE inhibitors slow the progression of diabetic
nephropathy.
 Beneficial effects on renal function may result from decreasing
intraglomerular pressures, due to efferent arteriolar
vasodilation.
 ACE inhibitors are a standard in the case of a patient following
a myocardial infarction and first-line agents in the treatment of
patients with systolic dysfunction.
 Chronic treatment with ACE inhibitors achieves sustained
blood pressure reduction, regression of left ventricular
hypertrophy, and prevention of ventricular remodeling after a
myocardial infarction.
 ACE inhibitors are first-line drugs for treating heart failure,
hypertensive patients with chronic kidney disease, and
patients at increased risk of coronary artery disease.
 All of the ACE inhibitors are equally effective in the treatment
of hypertension at equivalent doses.
Pharmacokinetics
 All of the ACE inhibitors are orally bioavailable as a
drug or prodrug.
 All but captopril and lisinopril undergo hepatic
conversion to active metabolites, so these agents may
be preferred in patients with severe hepatic
impairment.
 Fosinopril is the only ACE inhibitor that is not
eliminated primarily by the kidneys and does not
require dose adjustment in patients with renal
impairment.
 Enalaprilat is the only drug in this class available
intravenously.
Adverse effects
 Common side effects include dry cough, rash, fever, altered
taste, hypotension (in hypovolemic states), and hyperkalemia
 The dry cough, due to increased levels of bradykinin and
substance P in the pulmonary tree and resolves within a few
days of discontinuation.
 The cough occurs more frequently in women.
 Angioedema is a rare but potentially life-threatening reaction
that may also be due to increased levels of bradykinin.
 Potassium levels must be monitored while on
 ACE inhibitors, and potassium supplements and potassium-
sparing diuretics should be used with caution due to the risk of
hyperkalemia.
 Serum creatinine levels should also be monitored, particularly
in patients with underlying renal disease.
 However, an increase in serum creatinine of up to 30% above
baseline is acceptable and by itself does not warrant
discontinuation of treatment.
 ACE inhibitors can induce fetal malformations and should not
be used by pregnant women.
ANGIOTENSIN II RECEPTOR
BLOCKERS
 The ARBs, such as losartan and irbesartan are
alternatives to the ACE inhibitors.
 These drugs block the AT1 receptors,
decreasing the activation of AT1 receptors by
angiotensin II.
 Their pharmacologic effects are similar to those
of ACE inhibitors in that they produce arteriolar
and venous dilation and block aldosterone
secretion,
 thus lowering blood pressure and decreasing
salt and water retention
 ARBs do not increase bradykinin levels.
 They may be used as first-line agents for the
treatment of hypertension, especially in
 patients with a compelling indication of
diabetes, heart failure, or chronic kidney disease.
 Adverse effects are similar to those of ACE
 inhibitors, although the risks of cough and
angioedema are significantly decreased.
 ARBs should not be combined with an ACE
inhibitor for the treatment of hypertension due
to similar mechanisms and adverse effects.
 These agents are also teratogenic and should not
be used by pregnant women
RENIN INHIBITOR
 A selective renin inhibitor, aliskiren, is available for the
treatment of hypertension.
 Aliskiren 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.
 Aliskiren should not be routinely combined with an ACE
inhibitor or ARB.
 Aliskiren can cause diarrhea, especially at higher doses, and
can also cause cough and angioedema, but probably less
often than ACE inhibitors.
 As with ACE inhibitors and ARBs, aliskiren is contraindicated
during pregnancy.
 Aliskiren is metabolized by CYP 3A4 and is subject to many
drug interactions.
CALCIUM CHANNEL BLOCKERS
 Calcium channel blockers are a recommended
treatment option in hypertensive patients with
diabetes or angina.
 High doses of short-acting calcium channel
blockers should be avoided because of
increased risk of myocardial infarction due to
excessive vasodilation and marked reflex
cardiac stimulation.
Classes of calcium channel
blockers
 The calcium channel blockers are divided into
three chemical classes,
 each with different pharmacokinetic properties
and clinical indications.
 1. Diphenylalkylamines:
 2. Benzothiazepines:
 3. Dihydropyridines:
1. Diphenylalkylamines:
 Verapamil is the only member of this class that
is available.
 Verapamil is the least selective of any calcium
channel blocker and has significant effects on
both cardiac and vascular smooth muscle cells.
 It is also used to treat angina and
supraventricular tachyarrhythmias and to
prevent migraine and cluster headaches.
2. Benzothiazepines:
 Diltiazem is the only member of this class that
is currently approved in the United States.
 Like verapamil, diltiazem affects both cardiac
and vascular smooth muscle cells, but it has a
less pronounced negative inotropic effect
 on the heart compared to that of verapamil.
 Diltiazem has a favorable side effect profile.
3. Dihydropyridines:
 This class of calcium channel blockers includes
nifedipine (the prototype), amlodipine, felodipine ,
isradipine, nicardipine and nisoldipine.
 These agents 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 beneficial in treating
hypertension.
 The dihydropyridines have the advantage in that
they show little interaction with other cardiovascular
drugs, such as digoxin or warfarin, which are often
used concomitantly with calcium channel blockers.
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 arteriolar vasculature.
 This causes vascular smooth muscle to relax, dilating
mainly arterioles.
 Calcium channel blockers do not dilate veins.
Therapeutic uses
 In the management of hypertension, CCBs may be
used as an initial therapy or as add-on therapy.
 They are useful in the treatment of hypertensive
patients who also have asthma, diabetes, and/or
peripheral vascular disease, because unlike β-
blockers, they do not have
 the potential to adversely affect these conditions.
 All CCBs are useful in the treatment of angina.
 In addition, diltiazem and verapamil are used in
the treatment of atrial fibrillation.
Pharmacokinetics
 Most of these agents have short half-lives (3 to
8 hours) following an oral dose.
 Sustained-release preparations are available
and permit once-daily dosing.
 Amlodipine has a very long half-life and does
not require a sustained-release formulation.
Adverse effects
 First-degree atrioventricular block and constipation
are common dose dependent side effects of verapamil.
 Verapamil and diltiazem should be avoided in patients
with heart failure or with atrioventricular block due to
their negative inotropic (force of cardiac muscle
contraction) and dromotropic (velocity of conduction)
effects.
 Dizziness, headache, and a feeling of fatigue caused by
a decrease in blood pressure are more frequent with
dihydropyridines.
 Peripheral edema is another commonly reported side
effect of this class.
 Nifedipine and other dihydropyridines may cause
gingival hyperplasia.
α-ADRENOCEPTOR–BLOCKING
AGENTS
 Prazosin, doxazosin, and terazosin produce a
competitive block of α1-adrenoceptors.
 They decrease peripheral vascular resistance
and lower 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.
 Reflex tachycardia and postural hypotension often
occur at the onset of treatment and with dose
increases, requiring slow titration of the drug in
divided doses.
 Due to weaker outcome data and their side effect
profile, α-blockers are no longer recommended as
initial treatment for hypertension, but may be used for
refractory cases.
 Other α1-blockers with greater selectivity for prostate
muscle are used in the treatment of benign prostatic
hyperplasia.
 Tamsolusin = α1A and α1D
α-/β-ADRENOCEPTOR–BLOCKING
AGENTS
 Labetalol and carvedilol block α1, β1, and β2
receptors.
 Carvedilol, although an effective antihypertensive,
is mainly used in the treatment of heart failure.
 Carvedilol, as well as metoprolol succinate, and
bisoprolol have been shown to reduce morbidity
and mortality associated with heart failure.
 Labetalol is used in the management of gestational
hypertension and hypertensive emergencies.
CENTRALLY ACTING ADRENERGIC DRUGS
 Clonidine
 Clonidine acts centrally as an α2 agonist to
produce inhibition of sympathetic vasomotor
centers, decreasing sympathetic outflow to the
periphery.
 This leads to reduced total peripheral resistance
and decreased blood pressure.
 Clonidine is used primarily for the treatment of
hypertension that has not responded adequately
to treatment with two or more drugs.
 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.
 It is also available in a transdermal patch.
 Adverse effects include sedation, dry mouth,
and constipation.
 Rebound hypertension occurs following abrupt
withdrawal of clonidine.
 The drug should, therefore, be withdrawn
slowly if discontinuation is required.
Methyldopa
 Methyldopa is an α2 agonist that is converted
to methylnorepinephrine centrally to diminish
adrenergic outflow from the CNS.
 The most common side effects of methyldopa
are sedation and drowsiness.
 Its use is limited due to adverse effects and the
need for multiple daily doses.
 It is mainly used for management of
hypertension in pregnancy, where it has a
record of safety.
VASODILATORS
 The direct-acting smooth muscle relaxants, such as
hydralazine and minoxidil are not used as primary
drugs to treat hypertension.
 These vasodilators act by producing relaxation of
vascular smooth muscle, primarily in arteries and
arterioles.
 This results in decreased peripheral resistance and,
therefore, blood pressure.
 Both agents produce reflex stimulation of the heart,
resulting in the competing reflexes of increased
myocardial contractility, heart rate, and oxygen
consumption.
 These actions may prompt angina pectoris,
myocardial infarction, or cardiac failure in
predisposed individuals
 Also increased renin concentration which in turn
increased Na/H2O retention.
 These undesirable side effects can be blocked by
concomitant use of a diuretic and a β-blocker.
 Together, the three drugs decrease cardiac output,
plasma volume, and peripheral vascular resistance.
 Hydralazine is an accepted medication for controlling
blood pressure in pregnancy induced hypertension.
 Adverse effects of hydralazine include headache,
tachycardia, nausea, sweating, arrhythmia, and
precipitation of angina.
 Minoxidil treatment causes hypertrichosis (the
growth of body hair).
 This drug is used topically to treat male pattern
baldness.