Unit-3

Drugs Affecting the

Cardiovascular System

1
 1. Congestive heart failure
 Definition: HF is a complex, progressive disorder in
which the heart is unable to pump sufficient blood
to meet the needs of the body.
 HF is due to an impaired ability of the heart to
adequately fill with and/or eject blood.
 Classification
Right ventricular Vs Left ventricular failure
Acute Vs Chronic Heart failure
Diastolic Vs Systolic heart failure

2
 Action potential
• Cardiac muscle cells are electrically excitable.
• However, unlike the cells of other muscles and nerves,
– the cells of cardiac muscle show a spontaneous, intrinsic
rhythm generated by specialized “pacemaker” cells
located in the sinoatrial (SA) and atrioventricular (AV)
nodes.
• The cardiac cells also have an unusually long action potential,
which can be divided into five phases (0–4).

3
Figure: Action potential of a Purkinje fiber.

4
 Cardiac contraction
• The force of contraction of the cardiac muscle is directly
related to the concentration of free (unbound) cytosolic
calcium.
– agents that increase these calcium levels increase the force
of contraction (inotropic effect).
Sources of free intracellular calcium:
• The first is from outside the cell,
– opening of voltage-sensitive calcium channels causes an
immediate rise in free cytosolic calcium.
– Calcium may also enter by exchange with sodium.
• Calcium is also released from the sarcoplasmic reticulum
and mitochondria.

5
 Cardiac contraction cont…
Mechanisms of removal of cytosolic calcium
• Sodium/calcium exchange:
– Sodium/calcium exchange reaction reversibly exchanges
calcium ions (out) for sodium ions (in) across the cell
membrane.
• Uptake of calcium by the sarcoplasmic reticulum and
mitochondria:
– Calcium is also recaptured by the sarcoplasmic reticulum and
the mitochondria.
– >99 % intracellular calcium is located in these organelles.

6
 Cardiac contraction cont…

Figure: Ion movements during the contraction of cardiac muscle.

• ATPase = adenosine triphosphatase. 7
 Compensatory physiological responses in HF

• The failing heart evokes three major compensatory

mechanisms to enhance cardiac output.
• Although initially beneficial, these alterations ultimately
result in further deterioration of cardiac function.
– 1. Increased sympathetic activity
– 2. Activation of the renin-angiotensin system and
– 3. Myocardial hypertrophy

8
 1. Increased sympathetic activity
• Baroreceptors sense a decrease in blood pressure and activate
the sympathetic nervous system.
• In an attempt to sustain tissue perfusion, this stimulation of
β-adrenergic receptors results in an increased HR and a
greater force of contraction of the heart muscle.
• In addition, vasoconstriction (α1 mediated) enhances
venous return and increases cardiac preload.
– increase the work of the heart,
– in the long term, contribute to further decline in
cardiac function.

9
 2. Activation of the renin-angiotensin system
• A fall in cardiac output decreases blood flow to the kidney,
– prompting the release of renin,
– resulting in increased formation of angiotensin II and
release of aldosterone.
– results in increased peripheral resistance and retention of
sodium and water.
• Blood volume increases, and more blood is returned to the
heart.
• If the heart is unable to pump this extra volume, venous
pressure increases, and peripheral edema and pulmonary
edema occur.
• increases the work of the heart
– can contribute to further decline in cardiac function.
10
Figure: Cardiovascular
consequences of heart failure.

11
 3. Myocardial hypertrophy
• The heart increases in size, and the chambers dilate and
become more globular.
• Initially, stretching of the heart muscle leads to a stronger
contraction of the heart.
• However, excessive elongation of the fibers results in weaker
contractions, and the geometry diminishes the ability to eject
blood.
– This type of failure is termed “systolic failure” and is the
result of a ventricle being unable to pump effectively.

12
 3. Myocardial hypertrophy cont…

• Less commonly, patients with HF may have “diastolic

dysfunction,”
– when the ability of the ventricles to relax and accept blood
is impaired by structural changes such as hypertrophy.
• The thickening of the ventricular wall and subsequent
decrease in ventricular volume decrease the ability of heart
muscle to relax.
– ventricle does not fill adequately → ↓CO
– a particularly common feature of HF in elderly women.
• However, both systolic and diastolic dysfunctions commonly
coexist in HF.

13
 Decompensated HF

• If the adaptive mechanisms adequately restore cardiac

output,
– the HF is said to be compensated.
• However, these compensations increase the work of the
heart and contribute to further decline in cardiac
performance.
• If the adaptive mechanisms fail to maintain cardiac output,
HF is decompensated.

14
 Therapeutic strategies in HF
• Chronic HF is typically managed by:
– a reduction in physical activity;
– low dietary intake of sodium (<1500 mg/day);
– treatment of comorbid conditions; and
– judicious use of drugs
• Drugs that may precipitate or exacerbate HF, such as
– Non steroidal anti-inflammatory drugs (NSAIDS),
alcohol, calcium-channel blockers, high dose β-blockers,
and some antiarrhythmic drugs, should be avoided if
possible.

15
 Pharmacologic intervention in HF
• Six classes of drugs have been shown to be effective:
– 1) inhibitors of the renin-angiotensin system,
– 2) β-adrenoceptor blockers,
– 3) diuretics,
– 4) direct vasodilators,
– 5) inotropic agents, and
– 6) aldosterone antagonists.
• Beneficial effects of pharmacologic intervention include;
– reduction of the load on the myocardium,
– decreased extracellular fluid volume,
– improved cardiac contractility, and
– slowing the rate of cardiac remodeling.
16
 1.Inhibitors of the Renin-angiotensin System
• The production of angiotensin II, a potent vasoconstrictor,
and the subsequent stimulation of aldosterone release that
causes salt and water retention lead to the increases in both
preload and afterload that are characteristic of the failing
heart.
• In addition, high levels of angiotensin II and of aldosterone
have direct detrimental effects on the cardiac muscle,
favoring remodeling, fibrosis, and inflammatory changes.

17
 Inhibitors of the Renin-angiotensin System cont…
Remodeling
• is the term applied to dilation and
other slow structural changes that
occur in the stressed myocardium.
• may include proliferation of
connective tissue cells as well as
abnormal myocardial cells.
• Ultimately, myocytes in the failing
heart die at an accelerated rate through
apoptosis, leaving the remaining
myocytes subject to even greater
stress.
18
 1. Angiotensin-converting enzyme (ACE) inhibitors
Include: Captopril, Enalapril, Fosinopril, Lisinopril, Quinapril,
Ramipril, Benazepril, Moexipril, Perindopril, Trandolapril.
• block the enzyme that cleaves angiotensin I to form the potent
vasoconstrictor angiotensin II.
• also diminish the rate of bradykinin inactivation.
• Vasodilation occurs as a result of
– lower vasoconstriction caused by diminished levels of
angiotensin II, and
– the potent vasodilating effect of increased bradykinin.
• By reducing circulating angiotensin II levels,
– also decrease the secretion of aldosterone,
– resulting in decreased sodium and water retention. 19
 ACE inhibitors

• Figure: Interrelationship between the renin–angiotensin system and

bradykinin.

20
 1. ACE inhibitors cont…
Actions on the heart:
• Decrease vascular resistance, venous tone, and BP.
• Reduce preload and afterload,
– resulting in an increased cardiac output.
• also blunt the usual angiotensin II–mediated increase in
epinephrine and aldosterone seen in HF.
• Significantly decreased both morbidity and mortality from
HF.
• Treatment with ACEIs
reduces arrhythmic death,
myocardial infarction, and strokes.

21
 1. ACE inhibitors cont…

Figure: Effects of angiotensin-converting enzyme (ACE) inhibitors.

• The reduced retention of sodium and water results from two

causes:
– decreased aldosterone production and release, and
– decreased angiotensin II, which acting on the kidney
increases sodium reabsorption. 22
 1. ACE inhibitors cont…
Indications:
• are the agents of choice in HF.
• may be considered for single-agent therapy in patients who
present with mild dyspnea on exertion and do not show
signs or symptoms of volume overload (edema).
• Are indicated in patients with all stages of left
ventricular failure.
• In HF, depending on the disease severity, ACE inhibitors
may be used in combination with diuretics, β-blockers,
digoxin, and aldosterone antagonists.
• It is recommended that ACE inhibitors be initiated
immediately after myocardial infarction.
• are also used in the treatment of hypertension.
23
 1. ACE inhibitors cont…
Pharmacokinetics:
• All ACE inhibitors are adequately but incompletely absorbed
following oral administration.
• they should be taken on an empty stomach,
– presence of food may decrease absorption.
• Except for captopril, ACE inhibitors are prodrugs that require
activation by hydrolysis via hepatic enzymes.
• Enalapril is an oral prodrug that is converted by hydrolysis to
a converting enzyme inhibitor, enalaprilat, with effects similar
to those of captopril.
• Enalaprilat itself is available only for intravenous use,
primarily for hypertensive emergencies.
24
 Adverse effects: ACE inhibitors
• Hypotension,
• Renal insufficiency,
– Serum creatinine levels should also be monitored,
particularly in patients with underlying renal disease.
• Hyperkalemia,
– Potassium levels must be monitored, and potassium
supplements, high-potassium diets, and use of potassium-
sparing diuretics are contraindicated.
• A persistent dry cough,
– Bradykinin and substance P seem to be responsible for the
cough and angioedema seen with ACE inhibition.
– resolves a few days after therapy discontinuation.
25
 Adverse effects: ACE inhibitors cont…
• Angioedema is a rare but potentially life-threatening reaction
– may also be due to increased levels of bradykinin.
• are contraindicated in pregnancy (esp. 2nd and 3rd )
– Because of the risk of fetal hypotension, renal failure,
sometimes associated with fetal malformations or death.
• Minor toxic effects include:
– altered sense of taste, allergic skin rashes, and drug fever.
• Interaction with potassium supplements or potassium-sparing
diuretics,
– can result in hyperkalemia.
• NSAIDs may impair the hypotensive effects of ACE inhibitors
by blocking bradykinin- mediated vasodilation, which is at least
in part, prostaglandin mediated. 26
 2. Angiotensin-receptor blockers (ARBs)
Include: Losartan, Valsartan, Candesartan, Eprosartan,
Irbesartan, Telmisartan, and Olmesartan
• are nonpeptide, orally active compounds
• are extremely potent competitive antagonists of the
angiotensin II type 1 (AT1) receptor.
• They have no effect on bradykinin metabolism.
• They also have the potential for more complete inhibition of
angiotensin action compared with ACE inhibitors because
– there are enzymes other than ACE that are capable of
generating angiotensin II.

27
 2. Angiotensin-receptor blockers (ARBs) cont…

Actions on the cardiovascular system:

• Although ARBs have actions similar to those of ACE
inhibitors,
– they are not therapeutically identical.
• All the ARBs are approved for treatment of hypertension
– based on their clinical efficacy in lowering BP and
reducing the morbidity and mortality associated with
hypertension.
• Their use in HF is as a substitute for ACE inhibitors in
those patients with severe cough or angioedema.

28
 Pharmacokinetics: ARBs
• All the drugs are orally active and require only once-a-day
dosing.
• Losartan,
– the first approved member of the class,
– differs from the others in that it undergoes extensive first-
pass hepatic metabolism, including conversion to its active
metabolite.
• The other drugs have inactive metabolites.
• Elimination of metabolites and parent compounds occurs in
urine and feces.
• All are highly plasma protein bound (> 90%) and, except for
candesartan, have large volumes of distribution. 29
 Adverse effects: ARBs
• ARBs have an adverse effect profile similar to that of ACE
inhibitors.
• As with ACE inhibitors, ARBs are contraindicated in
pregnancy.
• Cough and angioedema can occur but are less common with
ARBs than with ACE inhibitors.
– the ARBs do not affect bradykinin levels.

30
 3.β-Blockers
• Although it may seem counterintuitive to administer drugs with
negative inotropic activity to a patient with HF,
– Studies clearly demonstrated improved systolic functioning
and reverse cardiac remodeling in patients receiving β-
blockers.
• These benefits arise in spite of occasional initial exacerbation of
symptoms.
– initiated cautiously at low doses (gradually titrated to
effective doses based on patient tolerance).
• The benefit of β-blockers is attributed, in part, to
– blockade of chronic activation of heart by sympathetic
nervous system
• decreasing the heart rate
– Inhibition of the release of renin.
31
 β-Blockers cont…
• β-blockers also prevent the direct deleterious effects of
norepinephrine on the cardiac muscle fibers,
– decreasing remodeling, hypertrophy, and cell death.
• Two β-blockers approved for use in HF,
– carvedilol and long-acting metoprolol.
• Carvedilol
– a nonselective β-adrenoceptor antagonist
– also blocks α-adrenoreceptors,
• Metoprolol
– a β1-selective antagonist.
• not recommended for patients who are in acute HF.
• Several months of therapy may be required before
improvement is noted. 32
 Diuretics
• Diuretics relieve pulmonary congestion and peripheral
edema.
• are also useful in reducing the symptoms of volume
overload, including orthopnea and paroxysmal nocturnal
dyspnea.
• Diuretics decrease plasma volume
– decrease venous return to the heart (↓preload).
• This decreases the cardiac workload and the oxygen demand.
• Diuretics may also decrease afterload by reducing plasma
volume,
– decrease blood pressure.
33
 Diuretics cont…
• Thiazide diuretics
– relatively mild diuretics and lose efficacy if patient
creatinine clearance is less than 50 mL/min.
• Loop diuretics are used for patients who require extensive
diuresis and those with renal insufficiency.
• Loop diuretics are the most commonly used diuretics in HF.
• Overdoses of loop diuretics can lead to profound
hypovolemia.

34
 Direct Vasodilators
• Dilation of veins leads to a decrease in cardiac preload by
increasing the venous capacitance.
• Arterial dilators reduce systemic arteriolar resistance and
decrease afterload.
• Nitrates are commonly used venous dilators for patients with
congestive HF.
• If the patient is intolerant of ACE inhibitors or β-blockers, or
if additional vasodilator response is required, a combination of
hydralazine and isosorbide dinitrate may be used.
• Such a combination is quite effective in black patients with HF.
• Hydralazine decreases afterload, and the organic nitrate reduces
preload.
• Calcium-channel blockers should be avoided in patients with
HF. 35
 Inotropic Drugs

• Positive inotropic agents

– enhance cardiac muscle contractility and, thus, increase
cardiac output.
• Although these drugs act by different mechanisms, in each
case the inotropic action is the result of an increased
cytoplasmic calcium concentration that enhances the
contractility of cardiac muscle.

36
 A. Digitalis
• Digitalis is the genus name for the family of plants that provide
most of the medically useful cardiac glycosides, eg, digoxin.
• Digoxin is obtained from Digitalis lanata, the white foxglove.
– the drugs have a low therapeutic index.
• The most widely used agent is digoxin.

• Mechanism of action: Digitalis

• Cardiac glycosides inhibit Na+/K+-ATPase, the membrane-
bound transporter often called the sodium pump,
– decrease the Na+ concentration gradient and,
consequently, the ability of the Na+/Ca2+-exchanger to
move calcium out of the cell.
37
 Mechanism of action cont…
• Further, the higher cellular Na+ is exchanged for extracellular
Ca2+ by the Na+/Ca2+-exchanger increasing intracellular Ca2+.
• Because more Ca2+ is retained intracellularly, a small but
physiologically important increase occurs in the free Ca2+ that is
available at the next contraction cycle of the cardiac muscle,
– increasing cardiac contractility.
• When the Na+/K+–ATPase is markedly inhibited by digoxin
(and for long term),
– the resting membrane potential may increase (–70 mV
instead of –90 mV),
• makes the membrane more excitable,
– increasing the risk of arrhythmias (toxicity).
38
 Mechanism of action cont…

Figure: Mechanism of action of digoxin. ATPase = adenosine triphosphatase. 39

 Mechanism of action cont…
Increased contractility of the cardiac muscle:
• Administration of digitalis glycosides increases the force of
cardiac contraction,
– causing the cardiac output to more closely resemble that of the
normal heart.
• Increased myocardial contraction leads to a decrease in end-
diastolic volume,
– Increase the efficiency of contraction (increased ejection
fraction).
• Improved circulation
– reduces sympathetic activity, which then reduces peripheral
resistance.
• Together, these effects cause a reduction in heart rate.
• Digoxin slows down conduction velocity through the AV node,
which accounts for its use in atrial fibrillation. 40
 Therapeutic uses
• Digoxin is indicated in patients with heart failure (left
ventricular systolic dysfunction) and atrial fibrillation.
• It is usually given only when diuretics and ACE inhibitors have
failed to control symptoms.
• Not indicated in patients with diastolic or right-sided HF.
• Only about 50% of patients with systolic dysfunction will have
relief of heart failure from digitalis.
• Better results are obtained in patients with atrial fibrillation.
• Digitalis remains notorious today for its very narrow therapeutic
window.
• Digitalis reduces hospitalization and deaths from progressive
heart failure at the expense of an increase in sudden death.
• Digitalis is useful in the management of atrial arrhythmias
because of its cardioselective parasympathomimetic effects.
41
 Pharmacokinetics
Digoxin
• the only digitalis glycoside available in the United States.
• is very potent, with a narrow margin of safety and long half-
life of around 36 hours.
• is mainly eliminated intact by the kidney,
– requiring dose adjustment based on creatinine clearance.
• has a large volume of distribution, because it accumulates in
muscle.
• dosage is based on lean body weight.
• A loading dose regimen is used when acute digitalization is
needed.
42
 Pharmacokinetics cont…
Digitoxin
• has a much longer half-life and is extensively metabolized by
the liver before excretion in feces,
• Patients with hepatic disease may require decreased doses.
– This creates difficulty in managing the drug, resulting in
its replacement with digoxin.

43
 Adverse effects
• Digoxin toxicity is one of the most commonly encountered
adverse drug reactions.
• Side effects often can be managed by
– discontinuing cardiac glycoside therapy,
– determining serum potassium levels (decreased K+ increases
the potential for cardiotoxicity), and,
– if indicated, giving potassium supplements.
• Digoxin levels
– must be closely monitored in renally insufficient patients,
and dosage adjustment may be necessary.
• Severe toxicity resulting in ventricular tachycardia may require
– administration of antiarrhythmic drugs and
– the use of antibodies to digoxin (digoxin immune Fab),
which bind and inactivate the drug. 44
 Types of adverse effects include
• Cardiac effects:
– Arrhythmia, characterized by slowing of AV conduction
• Gastrointestinal effects:
– Anorexia, nausea, and vomiting.
• CNS effects:
– headache, fatigue, confusion, blurred vision, alteration of
color perception, and halos on dark objects.
• Gynecomastia is a rare effect reported in men.

45
 B. β-Adrenergic agonists
• β-Adrenergic stimulation improves cardiac performance by
causing positive inotropic effects and vasodilation.
Dobutamine
• selective β1 agonist, most widely used inotropic agent other
than digoxin in patients with heart failure.
• Produces an increase in cardiac output together with a
decrease in ventricular filling pressure.
• leads to an increase in intracellular cAMP, which results in
the activation of protein kinase.
• Slow calcium channels are one kind of important site of
phosphorylation by protein kinase.
• When phosphorylated, the entry of calcium ion into the
myocardial cells increases, thereby enhancing contraction. 46
 B. β-Adrenergic agonists cont…
• Some tachycardia and an increase in myocardial oxygen
consumption have been reported.
– the potential for producing angina or arrhythmias in
patients with coronary artery disease is significant.
• Dobutamine (t1/2 = 2 min) must be given by intravenous
infusion and is primarily used in the treatment of acute HF in
a hospital setting.
• Intermittent dobutamine infusion may benefit some patients
with chronic heart failure.

47
Figure: Sites of action by β-adrenergic agonists on heart muscle.
48
 C. Phosphodiesterase Inhibitors
• Inamrinone (formerly amrinone) and Milrinone are
bipyridine compounds that inhibit phosphodiesterase
isozyme 3 (PDE-3) that increase the intracellular
concentration of cAMP.
• This results in an increase of intracellular calcium and,
therefore, cardiac contractility.
• an increase in cAMP also causes vasodilation.
• are active orally as well as parenterally but are available only
in parenteral forms.
• They have elimination half-lives of 3–6 hours, with 10–40%
being excreted in the urine.
• Both long-term inamrinone and milrinone therapy may be
associated with a substantial increase in the risk of mortality.
49
 C. Phosphodiesterase Inhibitors cont…
• The toxicity of inamrinone includes
– Nausea, vomiting, arrhythmias, thrombocytopenia, and
liver enzyme changes.
• Inamrinone has been withdrawn in some countries.
• Milrinone
– appears less likely to cause bone marrow and liver toxicity
than inamrinone, but it does cause arrhythmias.
• Inamrinone and milrinone:
– are now used only intravenously and only for acute
heart failure or severe exacerbation of chronic heart
failure.
50
 Aldosterone Antagonists
• Patients with advanced heart disease have elevated levels of
aldosterone due to:
– angiotensin II stimulation and
– reduced hepatic clearance of the hormone.
Spironolactone
• is a direct antagonist of aldosterone, thereby preventing salt
retention, myocardial hypertrophy, and hypokalemia.
• reserved for the most advanced cases of HF.
• It promotes potassium retention,
– no potassium supplements.

51
• Adverse effects:
– gastric disturbances, such as gastritis and peptic ulcer;
– CNS effects, such as lethargy and confusion; and
– endocrine abnormalities, such as gynecomastia,
decreased libido, and menstrual irregularities.

52
 Aldosterone Antagonists cont…

• Eplerenone
– is a competitive antagonist of aldosterone at
mineralocorticoid receptors.
• similar in action to spironolactone at the aldosterone receptor,
• has a lower incidence of endocrine related side effects due to
its reduced affinity for glucocorticoid, androgen, and
progesterone receptors.

53
 Management of Chronic Heart Failure cont…
Table: Classification and treatment of chronic heart failure.

54
Dopamine or dobutamine-for acute
failing heart
positive inotropic drugs with prompt
onset and short durations of action;

55
2. Antihypertensives

56
 Hypertension
• Hypertension
– is the most common cardiovascular disease.
– is defined as either a sustained systolic BP >140 mm Hg
or a sustained diastolic BP > 90 mm Hg.
• Hypertension results from
– increased peripheral vascular smooth muscle tone which
leads to increase arteriolar resistance and decrease venous
capacitance.
• In most cases, the cause of the increased vascular tone is
unknown.
• Elevated BP is an extremely common disorder, affecting
approximately 15 % of the population of the US (60 million
people).
57
 Hypertension cont….
• The incidence of morbidity and mortality significantly
decreases when hypertension is diagnosed early and is
properly treated.
• In recognition of the progressive nature of hypertension,
hypertension is classified into four categories for the
purpose of treatment management.
• The diagnosis of hypertension is based on repeated,
reproducible measurements of elevated BP.

Table: Classification of
hypertension on the
basis of BP.

58
 Etiology of Hypertension
• A specific cause of hypertension can be established in only 10–
15% of patients.
• Patients in whom no specific cause of hypertension can be
found
– are said to have essential or primary hypertension.
• Patients with a specific etiology
– are said to have secondary hypertension.
• Essential hypertension
– Heritability is estimated to be about 30%.
– its incidence is four-fold more frequent among blacks than
among whites (USA).
– it occurs more often among middle-aged males than among
middle-aged females, and
– its prevalence increases with age and obesity. 59
 Etiology of Hypertension cont…
• Environmental factors, such as
– a stressful lifestyle, high dietary intake of sodium,
ethanol dose and smoking,
– further predispose an individual to the occurrence of
hypertension.
• In most cases, elevated BP is associated with an overall
increase in PVR, whereas CO is usually normal.
• Investigation of ANS function, baroreceptor reflexes, RAAS,
and the kidney has failed to identify a single abnormality as
the cause of increased PVR in essential hypertension.
• It appears, therefore, that elevated BP is usually caused by a
combination of several (multifactorial) abnormalities.
60
 Hypertension

Secondary
Essential (primary) - is secondary to some distinct disease:
• Most patients with • Renal + renovascular desease
persistent arterial (artery stenosis)
hypertension • Hormonal defects (e.g., Cushing´s
• genesis of hypertension syndrome, phaeochromocytoma)
unknown. • Mechanical defect (coarctation of aorta)
• Hypertension in pregnancy
• Drug-induced hypertension (e.g.,
sympathomimetics, glucocorticoids)
 Mechanisms for Controlling Blood Pressure
• Arterial BP is regulated within a narrow range to provide
adequate perfusion of the tissues without causing damage to the
vascular system, particularly the arterial intima (endothelium).
• Arterial BP is directly proportional to cardiac output (CO) and
peripheral vascular resistance (PVR).
BP = CO x PVR
• Cardiac output and peripheral resistance, in turn, are controlled
mainly by two overlapping control mechanisms:
– the baroreflexes and the renin-angiotensin-aldosterone
system.
• Most antihypertensive drugs lower BP by reducing CO and/or
decreasing PVR.
62
 Baroreceptors and the sympathetic nervous system
• Baroreflexes act by changing the activity of the sympathetic
nervous system.
– they are responsible for the rapid, moment-to-moment
regulation of BP.
• A fall in BP causes pressure-sensitive neurons (baroreceptors
in the aortic arch) to send fewer impulses to cardiovascular
centers in the spinal cord.
• This prompts a reflex response of ↑ed sympathetic and ↓ed
parasympathetic output to the heart and vasculature,
– resulting in vasoconstriction and increased CO.
• These changes result in a compensatory rise in BP.
63
 Baroreceptors and the sympathetic cont…

Figure: Major factors influencing blood pressure.

64
• Figure: Response of the autonomic nervous system and the renin-angiotensin-
aldosterone system to a decrease in blood pressure. 65
 Renin-angiotensin-aldosterone system (RAAS)
• The kidney provides for the long-term control of BP by
altering the blood volume.
• 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.
• This peptidase (renin) converts angiotensinogen to
angiotensin I, which is converted, in turn to angiotensin II, in
the presence of angiotensin-converting enzyme (ACE).
• Angiotensin II
– a potent circulating vasoconstrictor,
– constricting both arterioles and veins, causing an increase
in BP. 66
 Renin-angiotensin-aldosterone system cont…

• Angiotensin II also stimulates aldosterone secretion,

– leading to increased renal sodium reabsorption and
increased blood volume,
– which contribute to a further increase in BP.
• These effects of angiotensin II are mediated by stimulation of
angiotensin II–AT1 receptors.

67
 Treatment Strategies
• The initial step in treating hypertension may be
nonpharmacologic.
– Weight reduction, Exercise
– Salt restriction in diet, Moderation in alcohol intake
– Stress reduction
– DASH eating plan
• DASH = Dietary Approaches to Stop Hypertension
• Diets rich in fruits, vegetables, grains, low-fat dairy
products, and low in fat, cholesterol, and sodium
• The relationship between BP and the risk of a cardiovascular
event is continuous, and, thus, lowering of even moderately
elevated BP significantly reduces cardiovascular disease.
68
 Specific Antihypertensive Drugs: Include

• Diuretics
• β- Adrenoceptor–Blocking Agents
• ACE Inhibitors
• Angiotensin II–Receptor Blockers (ARBs)
• Calcium-Channel Blockers (CCBs)
• α-Adrenoceptor–Blocking Agents
• Centrally Acting Adrenergic Drugs
• Vasodilators

69
 1.Diuretics
• Diuretics can be used as a first-line drug therapy for
hypertension
• Low-dose diuretic therapy is safe, inexpensive, 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
for treating hypertension in older adults.

70
 Thiazide diuretics
• most commonly used diuretics type.
• Thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone)
– lower BP initially by increasing sodium and water
excretion.
– This causes a decrease in extracellular volume, resulting
in a decrease in CO and renal blood flow.
• With long-term treatment, plasma volume approaches a
normal value, but peripheral resistance decreases.
• Potassium-sparing diuretics are often used in combination
with thiazides
– to reduce the amount of potassium loss induced by the
thiazide diuretics.
71
 Thiazide diuretics cont…
Therapeutic uses:
• Thiazides counteract the sodium and water retention observed
with other agents used in the treatment of hypertension (E.g.,
hydralazine).
– useful in combination therapy with a variety of other
antihypertensive agents, including β-blockers, ACE
inhibitors, ARBs,
• are particularly useful in the treatment of black and elderly
patients.
• are not effective in patients with inadequate kidney function
(creatinine clearance < 50 mL/min).
– Loop diuretics may be required in these patients. 72
 Thiazide diuretics cont…
Pharmacokinetics:
Table: Thiazides and related diuretics.
• orally active.
• Absorption and elimination
rates vary considerably,
although no clear advantage
is present for one agent over
another.
• All thiazides are ligands for
the organic acid secretory
system of the nephron, and,
as such, they may compete
with uric acid for
elimination.
73
 Thiazide diuretics cont…
Adverse effects:
• induce hypokalemia and hyperuricemia in 70 % of patients
and hyperglycemia in 10 % of patients.
• Acute gout attacks may be triggered.
• Hypomagnesemia may also occur.
• Serum potassium levels should be monitored closely in
patients,
– who are predisposed to cardiac arrhythmias and
– those who are concurrently being treated with both
thiazide diuretics and digoxin.

74
 Loop diuretics
Loop diuretics
• E.g., furosemide, bumetanide, and torsemide
– act promptly, even in patients with poor renal function or
who have not responded to thiazides or other diuretics.
• cause decreased renal vascular resistance and increased
renal blood flow.
• Loop diuretics increase the Ca2+ content of urine, whereas
thiazide diuretics decrease it.

75
 Potassium-sparing diuretics
• Amiloride and triamterene
– inhibitors of epithelial sodium transport at the late distal
and collecting ducts and
• Spironolactone and eplerenone
– aldosterone-receptor antagonists
• reduce potassium loss in the urine.
• Spironolactone has the additional benefit of diminishing the
cardiac remodeling that occurs in heart failure.

76
 β- Adrenoceptor–Blocking Agents
• are currently recommended as first-line drug therapy for
hypertension when concomitant disease is present, for
example, in post MI patients or in patients with a previous
MI.
• reduce BP primarily by decreasing CO.
• may also decrease sympathetic outflow from the CNS and
inhibit the release of renin from the kidneys,
– thus decreasing the formation of angiotensin II and the
secretion of aldosterone.
• Propranolol
– The prototype β-blocker,
– blocks both β1 and β2 receptors.
77
 β- Adrenoceptor–Blocking Agents cont…

• β1 selective blockers (e.g., metoprolol, atenolol)

– are among the most commonly prescribed β-blockers.
• Nebivolol is a selective blocker of β1 receptors,
– also increases the production of nitric oxide leading to
vasodilation.
• Selective β1 blockers
– may be administered cautiously to hypertensive patients
who also have asthma.
• The nonselective β-blockers (e.g., propranolol and nadolol)
– contraindicated in asthmatics.
78
 β- Adrenoceptor–Blocking Agents cont…

Figure: Actions of β–adrenoceptor blocking agents

79
 Therapeutic uses: β-blockers
Subsets of the hypertensive population:
• The β-blockers are more effective for treating hypertension
in white than in black patients and in young compared to
elderly patients.
Hypertensive patients with concomitant diseases:
• β-blockers are useful in treating conditions that may coexist
with hypertension, such as
– supraventricular tachyarrhythmia, previous myocardial
infarction, angina pectoris, and chronic heart failure.
• are also used to prevent migraine and cluster headaches.

80
 β- Adrenoceptor–Blocking Agents cont…
Pharmacokinetics
• are orally active.
• Propranolol undergoes extensive and highly variable first-
pass metabolism.
• β-blockers may take several weeks to develop their full
effects.
Adverse effects
• Common effects:
– bradycardia and CNS side effects such as fatigue, lethargy,
insomnia, and hallucinations,
– can also cause hypotension.
• libido and impotence.
– can severely reduce patient compliance.
81
 β- Adrenoceptor–Blocking Agents cont…

Adverse effects cont…

Alterations in serum lipid patterns:
• β-blockers may disturb lipid metabolism, decreasing HDL-
cholesterol and increasing plasma triglycerides.
Drug withdrawal:
• Abrupt withdrawal may induce angina, myocardial
infarction, and even sudden death in patients with ischemic
heart disease.
– Therefore, the dose must be tapered over 2 to 3 weeks in
patients with hypertension and ischemic heart disease.

82
 ACE Inhibitors
• Include: Benazepril, Captopril, Enalapril, Fosinopril,
Lisinopril, Moexipril, Quinapril,
Ramipril ,trandolapril,perindopril
• are recommended when the preferred first-line agents
(diuretics or β-blockers) are contraindicated or ineffective,
or if there are compelling reasons to use them such as in
diabetes mellitus.
Actions:
• ACE inhibitors lower BP by reducing PVR without
reflexively increasing cardiac output, rate, or
contractility.
• block the ACE that cleaves angiotensin I to form the potent
vasoconstrictor angiotensin II.
83
 Actions: ACE Inhibitors cont…
• The converting enzyme
– also responsible for the breakdown of bradykinin,
• Bradykinin
– increases the production of nitric oxide and of
prostacyclin by the blood vessels.
– Both nitric oxide and prostacyclin are potent vasodilators.
• decrease angiotensin II and increase bradykinin levels.
• Vasodilation of both arterioles and veins 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.
84
 Actions: ACE Inhibitors cont…
• By reducing circulating angiotensin II levels, 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.

Figure: Effects of angiotensin-converting enzyme (ACE) inhibitors.

85
 Therapeutic uses: ACE Inhibitors
• 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 ARBs, ACE inhibitors slow the progression of
diabetic nephropathy and decrease albuminuria,
– may result from decreasing intraglomerular pressures, due
to efferent arteriolar vasodilation.
– indicated for patients with diabetic nephropathy.
• Systolic dysfunction
– first-line agents in the treatment of patients with
systolic dysfunction. 86
 Therapeutic uses: ACE Inhibitors cont…
• Myocardial infarction (MI)
– ACE inhibitors are a standard in the care of a patient
following a MI
– Therapy is started 24 hours after the end of the infarction.
• ACE inhibitors are first-line drugs for treating heart failure,
to treat hypertensive patients with chronic renal disease, and
for patients with increased risk for coronary artery disease.

87
 Angiotensin II–Receptor Blockers (ARBs)
• The ARBs are alternatives to the ACE inhibitors.
• These drugs block the AT1 receptors, decreasing the
activation of AT1 receptors by angiotensin II.
• Losartan is the prototypic ARB, others,
– Azilsartan medoxomil, Candesartan, Eprosartan,
Irbesartan, Olmesartan , Telmisartan, Valsartan
• Their pharmacologic effects are similar to those of ACE
inhibitors,
– they produce arteriolar and venous dilation and block
aldosterone secretion, thus lowering BP and decreasing
salt and water retention.

88
 Angiotensin II–Receptor Blockers (ARBs) cont…
• ARBs do not increase bradykinin levels.
• 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.
• ARBs are also fetotoxic and should not be used by women
who are pregnant.

89
 Aliskiren
• A selective renin inhibitor, available for the treatment of
hypertension.
• directly inhibits renin and, thus, acts earlier in the RAAS than do
ACE inhibitors or ARBs.
• lowers BP about as effectively as ARBs, ACE inhibitors, and
thiazides.
• can also be combined other antihypertensives, such as diuretics,
ACE inhibitors, ARBs, and calcium-channel blockers.
• can cause diarrhea, especially at higher doses.
• can also cause cough and angioedema but probably less often than
ACE inhibitors.
• contraindicated during pregnancy.
• Hyperkalemia is significantly more common in patients who
received both valsartan and aliskiren.
• is metabolized by CYP 3A4. 90
 Calcium-Channel Blockers (CCBs)
Include: Amlodipine, Diltiazem, Felodipine, Isradipine,
Nicardipine, Nifedipine, Nisoldipine, Verapamil
• are recommended when the preferred first-line agents are
contraindicated or ineffective.
• are effective in treating hypertension in patients with
angina or diabetes.
Classes of calcium-channel blockers
• CCBs are divided into three chemical classes, each with
different pharmacokinetic properties and clinical indications.
– Diphenylalkylamines,
– Benzothiazepines,
– Dihydropyridines
91
 Diphenylalkylamines
• Verapamil
– the only member of this class that is currently approved in
the USA.
• 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, supraventricular
tachyarrhythmias, and to prevent migraine and cluster
headaches.
• Atrioventricular block and constipation are dose-
dependent common side effects of verapamil.
92
 Benzothiazepines
• Diltiazem
– the only member of this class that is currently approved
in the USA.
• 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.

93
 Dihydropyridines
• First-generation
– Nifedipine
• Five second-generation agents
– amlodipine, felodipine, isradipine, nicardipine, and
nisoldipine.
– 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.
– particularly attractive in treating hypertension.
• They have the advantage in that they show little interaction
with other cardiovascular drugs, such as digoxin or
warfarin, which are often used concomitantly with CCBs. 94
 Calcium-Channel Blockers (CCBs) cont…

Figure: Some therapeutic applications of calcium-channel blockers.

95
 CCBs Actions
• The intracellular concentration of calcium
– plays an important role in maintaining the tone of smooth
muscle and in the contraction of the myocardium.
• CCBs 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.
• CCBs do not dilate veins.

96
 CCBs Actions cont…
Therapeutic uses
• CCBs have an intrinsic natriuretic effect and, therefore, do not
usually require the addition of a diuretic.
• are useful in the treatment of hypertensive patients who also
have asthma, diabetes, angina, and/or peripheral vascular
disease.
• Black hypertensive patients respond well to CCBs.
Pharmacokinetics
• Most of these agents have short half-lives (3–8 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
97
sustained-release formulation.
Table: Clinical pharmacology of some calcium channel-blocking drugs.

Table: Adverse Effects of Calcium Channel Blockers

98
 Adverse effects
• Verapamil
– causes constipation in approximately 10% of patients.
– should be avoided in patients with CHF or with
atrioventricular block due to its negative inotropic and
dromotropic (velocity of conduction) effects.
• Dizziness, headache, and a feeling of fatigue caused by a
decrease in BP
– more frequent with dihydropyridines.
• Nifedipine has caused gingival enlargement.

99
 α1-Adrenoceptor–Blocking Agents
• Prazosin, doxazosin, and terazosin
– produce a competitive block of α1 adrenoceptors.
• They decrease PVR and lower arterial BP
– by causing relaxation of both arterial and venous smooth
muscle.
• Postural hypotension may occur in some individuals.
• may be used to treat mild to moderate hypertension
• And are prescribed in combination with propranolol and/or a
diuretic for additive effects.

100
 α1-Adrenoceptor–Blocking Agents cont…
• Reflex tachycardia and first-dose syncope
– are almost universal adverse effects.
• Concomitant use of a β-blocker may be necessary to blunt
the short-term effect of reflex tachycardia.
• Because of the side-effect profile, development of tolerance,
and the advent of safer antihypertensives,
– α-blockers are seldom used as monotherapy in the
treatment of hypertension.
• Tamsulosin,
– an α1-blocker with greater selectivity for prostate muscle,
– has been used in the treatment of BPH. 101
 α-/β-Adrenoceptor–Blocking Agents
• Labetalol and carvedilol block α1, β1, and β2 receptors.
Labetalol
• Because of its combined α- and β-blocking activity,
– is useful in treating the hypertension of
pheochromocytoma and hypertensive emergencies.
• is given as repeated IV bolus injections of 20–80 mg to treat
hypertensive emergencies.
• Oral daily doses of labetalol range from 200 to 2400 mg/d.
Carvedilol
• although an effective antihypertensive, is mainly used in the
treatment of heart failure.
• Carvedilol, as well as metoprolol, a selective β1 antagonist,
have been shown to reduce morbidity and mortality associated
with heart failure. 102
 Centrally Acting Adrenergic Drugs
Clonidine
• α2-receptor agonist that diminishes the central adrenergic
outflow,
– decreasing the firing rate of the sympathetic nerves and the
amount of norepinephrine release.
• is used primarily for the treatment of hypertension that has
not responded adequately to treatment with two or more
drugs.
• does not decrease renal blood flow or glomerular filtration,
– useful in the treatment of hypertension complicated by
renal disease.
• is absorbed well after oral administration and is excreted by
the kidney. 103
 Clonidine cont…

• it may cause sodium and water retention,

– may be administered in combination with a diuretic.
• Adverse effects are generally mild,
– but the drug can produce sedation, dry mouth, and
constipation.
• Rebound hypertension occurs following abrupt withdrawal
of clonidine.
– should, therefore, be withdrawn slowly if the clinician
wishes to change agents.

104
 α-Methyldopa

• is an analog of L-dopa and is converted to α-methyldopamine

and α-methylnorepinephrine;
– this pathway directly parallels the synthesis of
norepinephrine from dopa.
• Released α-methylnorepinephrine or α-methyldopamine
activates CNS α2 adrenoceptors whose function is to decrease
sympathetic outflow.
• This leads to reduced total peripheral resistance and decreased
blood pressure.
• Oral bioavailability ~ 50%.

105
 α-Methyldopa cont…
• A considerable amount of unchanged methyldopa and several
conjugated and decarboxylated metabolites can be found in
the urine.
• CO 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
hypertensive patients with renal insufficiency.
• The most common side effects of α-methyldopa are sedation
and drowsiness.
• It has been used in hypertensive pregnant patients. 106
 Vasodilators
• The direct-acting smooth muscle relaxants, such as
hydralazine and minoxidil, have traditionally not been used as
primary drugs to treat hypertension.
• These vasodilators act by producing relaxation of vascular
smooth muscle, which decreases resistance and, therefore,
blood pressure.
• A significant part of the blood pressure–lowering action of
these drugs is due to activation of the potassium channels,
increasing potassium efflux and inducing
hyperpolarization of the smooth muscle membrane.
• When the membrane is hyperpolarized, calcium influx is
inhibited and the arteriolar smooth muscle relaxes.

107
 Vasodilators cont…
• These 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.
• 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 β-blocker.

108
 Hydralazine

• This drug causes direct vasodilation, acting primarily on

arteries and arterioles.
• This results in decreased peripheral resistance, which, in turn,
prompts a reflex elevation in heart rate and cardiac output.
• is used to treat moderately severe hypertension.
• It is almost always administered in combination with a β-
blocker, such as propranolol, metoprolol, or atenolol (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.

109
 Hydralazine cont…
• Hydralazine monotherapy is an accepted method of
controlling blood pressure in pregnancy-induced
hypertension.
• Adverse effects of hydralazine therapy include headache,
tachycardia, nausea, sweating, arrhythmia, and precipitation
of angina.
• A lupus-like syndrome can occur with high dosage, but it is
reversible on discontinuation of the drug.

110
 Minoxidil
• This drug causes dilation of resistance vessels (arterioles) but
not of capacitance vessels (venules).
• is administered orally for treatment of severe to malignant
hypertension that is refractory to other drugs.
• Reflex tachycardia and fluid retention may be severe and
require the concomitant use of a loop diuretic and a β-
blocker.
• causes serious sodium and water retention, leading to volume
overload, edema, and congestive heart failure.
• Minoxidil treatment also causes hypertrichosis (the growth of
body hair).
– used topically to treat male pattern baldness.

111
 Hypertensive Emergency
• Hypertensive emergency is a rare but life-threatening situation
in which the diastolic blood pressure is either greater than 150
mm Hg (with systolic blood pressure greater than 210 mm Hg)
in an otherwise healthy person or greater than 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.
Sodium nitroprusside
• is administered IV and causes prompt vasodilation with reflex
tachycardia.
• It is capable of reducing BP in all patients regardless of the
cause of hypertension.
• The drug has little effect outside the vascular system.
112
 Sodium nitroprusside cont…
• act equally on arterial and venous smooth muscle .
• Because nitroprusside also acts on the veins, it can
reduce cardiac preload.
• The action occurs as a result of activation of guanylyl
cyclase, either via release of nitric oxide or by direct
stimulation of the enzyme.
• The result is increased intracellular cGMP, which relaxes
vascular smooth muscle.

113
 Sodium nitroprusside cont…
• is metabolized rapidly (half-life of minutes) and requires
continuous infusion to maintain its hypotensive action.
• exerts few adverse effects except for those of 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.
• Nitroprusside is poisonous if given orally because of its
hydrolysis to cyanide.
• Nitroprusside is light sensitive, and, when in solution, it
should be protected from light.
114
 Hypertensive Emergency cont…
Labetalol
• is both an α- and a β-blocker and is given as an intravenous
bolus or infusion in hypertensive emergencies.
• does not cause reflex tachycardia.
• The major limitation is a longer half-life, which precludes rapid
titration.
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 lowering blood
pressure.

115
 Hypertensive Emergency cont…
Fenoldopam cont…
• relaxes mainly the renal (renal artery, afferent and efferent
arterioles) and mesenteric arterial vessels, with a smaller
vasodilating action on coronary and cerebral arteries and on
veins (capacitance vessels).
• The diuretic action of fenoldopam is mainly caused by the
increase in renal blood flow.
• rapidly metabolized, primarily by conjugation.
• Its half-life is 10 minutes.
• Fenoldopam can be safely used in all hypertensive emergencies
and may be particularly beneficial in patients with renal
insufficiency.
• The drug is contraindicated in patients with glaucoma.
– b/c it increases intraocular pressure.
116
 Hypertensive Emergency cont…
Nicardipine
• a calcium-channel blocker, can be given as an intravenous
infusion.
• The initial dose is 5 mg/h and can be increased to a
maximum of 15 mg/h.
• The major limitation of nicardipine in treating hypertensive
emergency is its long half-life (approximately 8 hours), which
precludes rapid titration.

117
 Hypertensive Emergency cont…

• Figure: Time to peak effect and duration of action for some drugs used IV in
hypertensive emergency.
118
 Special Populations cont…
A. Pregnancy
• Mild hypertension associated with preeclampsia typically
does not warrant treatment.
• Severe hypertension (systolic pressures ≥150 mm Hg and
diastolic blood pressures ≥100 mm Hg) is treated acutely
with labetalol to prevent maternal cerebrovascular
complications.
• Avoid ACE inhibitors, ARBs, and aliskiren because these
drugs may cause fetal injury or death.
• Nitroprusside is contraindicated in the later stages of
pregnancy due to possible fetal cyanide poisoning if used
for more than 4 hours.

119
 Treatment Strategies cont…

Figure : Treatment of hypertension in patients with concomitant diseases.

• Drug classes shown in blue boxes provide improvement in outcome (e.g.,
diabetes or renal disease) independent of BP.
• ARBs are an alternative to ACE inhibitors. 120