1

HYPERTENSION
Mohammad Dweib
MSc, Clinical Pharmacy
PhD, Oncology
2024
 2

Overview
•Hypertension is defined as either a
sustained systolic BP of greater than 140
mm Hg or a sustained diastolic BP of
greater than 90 mm Hg.
•HTN results from ↑ peripheral vascular
arteriolar smooth muscle tone, which leads
to ↑ arteriolar resistance and reduced
capacitance of the venous system.
•In most cases, the cause of the ↑ vascular
tone is unknown.
 3

•Although many patients have no

symptoms, chronic HTN can lead to
heart disease and stroke, the top two
causes of death in the world.
•Also an important risk factor in the
development of chronic kidney
disease and heart failure.
•The incidence of morbidity and
mortality significantly ↓ when HTN is
diagnosed early and is properly
treated.
4
5
 6

•HTN is classified into four categories

for the purpose of treatment
management
 7

ETIOLOGY OF HTN
•>90% of patients: essential HTN (HTN
with no identifiable cause).
•A family history of HTN ↑ the likelihood
that an individual will develop HTN.
•The prevalence of HTN ↑ with age, but ↓
with education and income level.
 8

Predisposing factors
•Diabetes, obesity, or disability
status
•Environmental factors: stressful
lifestyle, high dietary intake of
sodium, and smoking,
 9

MECHANISMS FOR CONTROLLING

BP
•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 and peripheral vascular
resistance.
10
 11

•Cardiac output and peripheral

resistance, in turn, are controlled
mainly by 2 overlapping control
mechanisms: the baroreflexes and the
renin–angiotensin–aldosterone
system.

•Most antihypertensive drugs ↓ BP by ↓

cardiac output and/or decreasing
peripheral resistance.
12
 13

Renin–angiotensin–aldosterone
system
•The kidney provides long-term
control of BP by altering the blood
volume.
•Baroreceptors in the kidney
respond to ↓ arterial pressure (and
to sympathetic stimulation of
ß1-adrenoceptors) by releasing
the enzyme renin
 14

•Low sodium intake and greater sodium

loss also ↑ renin release.
Angiotensinogen

RENIN
Angiotensin I

ACE
Angiotensin II
AT I

AT I

AT I
 15

TREATMENT STRATEGIES
•Goal in most patients systolic <140
mm Hg and diastolic < 90 mm Hg.
•Current recommendations are to
initiate therapy with a thiazide diuretic,
ACE inhibitor, angiotensin receptor
blocker (ARB), or calcium channel
blocker.
 16

•If BP is inadequately controlled, a

second drug should be added, with the
selection based on minimizing the
adverse effects of the combined
regimen and achieving goal BP.
•If SBP >160 mm Hg or DBP >100 mm
Hg (or SBP >20 mm Hg above goal or
DBP >10 mm Hg above goal) should
be started on 2 antihypertensives
simultaneously.
 17

Individualized care
•HTN may coexist with other diseases that
can be aggravated by some of the
antihypertensive drugs or that may benefit
from the use of some antihypertensive
drugs independent of BP control.
•In such cases, it is important to match
antihypertensive drugs to the particular
patient.
 18

•In addition to the choice of therapy, BP

goals may also be individualized based
on concurrent disease states.
•Ex: in patients with diabetes, some
experts recommend a BP goal of less
than 140/80 mm Hg. Likewise, in patients
with CKD and proteinuria, lower goals of
less than 130/80 mm Hg may be
considered.
•Elderly patients may have less stringent
goals (for example, less than 150/90 mm
Hg).
 19

DIURETICS
• Thiazide diuretics can be used as initial drug
therapy for HTN unless there are compelling
reasons to choose another agent.
• Regardless of class, the initial mechanism of
action of diuretics is based upon decreasing
blood volume, which ultimately leads to ↓d BP.
• Low-dose diuretic therapy is safe, inexpensive,
and effective in preventing stroke, myocardial
infarction, and heart failure.
• Routine serum electrolyte monitoring should be
done for all patients receiving diuretics.
 20

Thiazide diuretics
•Thiazide diuretics, such as
hydrochlorothiazide and
chlorthalidone lower BP initially by
increasing sodium and water excretion.
•This causes a ↓ in extracellular volume,
resulting in a ↓ in cardiac output and
renal blood flow
 21

•With long-term treatment, plasma

volume approaches a normal value,
but a hypotensive effect persists that
is related to a ↓ in peripheral
resistance.
•Thiazides are useful in combination
therapy with a variety of other
antihypertensive agents, including
ß-blockers, ACE inhibitors, ARBs, and
potassium-sparing diuretics.
22
 23

•With the exception of metolazone,

thiazide diuretics are not effective in
patients with inadequate kidney
function (estimated GFR < 30
mL/min/m).
•Loop diuretics may be required in
these patients.
•Thiazide diuretics can induce
hypokalemia, hyperuricemia and, to a
lesser extent, hyperglycemia in some
patients.
 24

Loop diuretics
•The loop diuretics (furosemide, torsemide,
bumetanide, and ethacrynic acid) act
promptly by blocking Na and Cl
reabsorption in the kidneys, even in
patients with poor renal function or those
who have not responded to thiazide
diuretics.
•Loop diuretics cause ↓ renal vascular
resistance and ↑ renal blood flow.
 25

•Like thiazides, they can cause

hypokalemia. However, unlike
thiazides, loop diuretics ↑ Ca
content of urine, whereas thiazide
diuretics ↓ it.
•These agents are rarely used alone
to treat HTN, but they are commonly
used to manage symptoms of heart
failure and edema.
 26

Potassium-sparing diuretics
• Amiloride and triamterene as well as
spironolactone and eplerenone (aldosterone
receptor antagonists) reduce K+ loss in the
urine.
• Aldosterone antagonists have the additional
benefit of diminishing the cardiac remodeling
that occurs in heart failure.
• Potassium-sparing diuretics are sometimes
used + loop diuretics and thiazides to reduce
the amount of K+ loss induced by these
diuretics.
 27

ß-ADRENOCEPTOR–BLOCKING
AGENTS
•ß-Blockers are a treatment option
for hypertensive patients with
concomitant heart disease or heart
failure
 28

Actions
•Reduce BP primarily by ↓ cardiac
output.
•They may also ↓ sympathetic
outflow from the CNS and ↓
release of renin from the kidneys,
thus ↓ the formation of angiotensin
II and the secretion of aldosterone.
29
 30

•Propranolol: nonselective.
•Metoprolol and atenolol:
selective.
•Nebivolol is a selective blocker
of ß receptors, which also ↑
the production of NO, leading
to vasodilation.
 31

•The selective ß-blockers may be

administered cautiously to HTN patients
who also have asthma.
•The nonselective ß-blockers, such as
propranolol and nadolol, are
contraindicated in patients with asthma
due to their blockade of ß2 -mediated
bronchodilation.
•ß-Blockers should be used cautiously in
the treatment of patients with acute heart
failure or peripheral vascular disease.
 32

Therapeutic uses
•Primary benefit: patients with concomitant
heart disease, such as supraventricular
tachyarrhythmia (for example, atrial
fibrillation), previous myocardial infarction,
angina pectoris, and chronic heart failure.
•Conditions that discourage the use of
ß-blockers include reversible
bronchospastic disease such as asthma,
second- and third-degree heart block, and
severe peripheral vascular disease.
 33

Pharmacokinetics
•The ß-blockers are orally active for the
treatment of HTN.
•Propranolol undergoes extensive and
highly variable first-pass metabolism.
•Oral ß-blockers may take several
weeks to develop their full effects.
Esmolol, metoprolol, and propranolol
are available in intravenous
formulations.
 34

Adverse effects
•1. Common effects: bradycardia,
hypotension, and CNS side effects such as
fatigue, lethargy, and insomnia, ↓ libido, and
erectile dysfunction.
•2. Alterations in serum lipid patterns:
may disturb lipid metabolism, ↓ high-density
lipoprotein cholesterol and ↑ triglycerides.
•3. Drug withdrawal: Abrupt withdrawal
may induce angina, MI, and even sudden
death in patients with ischemic heart
disease.
35
 36

ACE INHIBITORS
•Ex: enalapril and lisinopril
•Recommended as first-line
treatment of HTN in patients with a
variety of compelling indications,
including high CAD risk or history
of DM, stroke, HF, MI, or CKD
 37

Actions
•↓ BP by ↓ peripheral vascular
resistance without reflexively ↑
cardiac output, heart rate, or
contractility.
•These drugs block the enzyme
ACE which cleaves angiotensin I
to form the potent vasoconstrictor
angiotensin II
38
 39

•ACE is also responsible for the

breakdown of bradykinin, a peptide that ↑
the production of nitric oxide and
prostacyclin by the blood vessels.
•Both nitric oxide and prostacyclin are
potent vasodilators.
•ACE inhibitors ↓ angiotensin II and ↑
bradykinin levels.
•Vasodilation of both arterioles and veins
occurs as a result of ↓ vasoconstriction
and enhanced vasodilation (from ↑
bradykinin).
 40

•By ↓ circulating angiotensin II

levels, ACE inhibitors also ↓ the
secretion of aldosterone,
resulting in ↓ Na and water
retention.
•ACE inhibitors ↓ both cardiac
preload and afterload, thereby
↓ cardiac work.
 41

Therapeutic uses
• ACE inhibitors slow the progression of diabetic
nephropathy and ↓ albuminuria and, thus, have
a compelling indication for use in patients with
diabetic nephropathy.
• Beneficial effects on renal function may result
from ↓ intraglomerular pressures, due to
efferent arteriolar vasodilation.
• ACE inhibitors are a standard in the care of a
patient following an MI and first-line agents in
the treatment of patients with systolic
dysfunction.
 42

•Chronic treatment with ACE inhibitors

achieves sustained BP reduction,
regression of left ventricular hypertrophy,
and prevention of ventricular remodeling
after an MI.
•ACE inhibitors are first-line drugs for
treating HF, hypertensive patients with
CKD, and patients at ↑d risk of coronary
artery disease.
•All of the ACE inhibitors are equally
effective in the treatment of HTN at
equivalent doses.
 43

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.
 44

Adverse effects
•Common: dry cough, rash, fever, altered
taste, hypotension (in hypovolemic states),
and hyperkalemia.
•The dry cough, which occurs in up to 10%
of patients, is thought to be due to ↑d 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.
 45

• Angioedema: rare but potentially life-threatening

reaction that may also be due to ↑ 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 ↑ in serum creatinine of up to 30%
above baseline is acceptable and by itself does not
warrant discontinuation of treatment.
• Pregnancy category X.
 46

ANGIOTENSIN II RECEPTOR
BLOCKERS
•Losartan and irbesartan.
•Alternatives to the ACE inhibitors.
•Block the AT receptors, decreasing the
activation of AT receptors by angiotensin II.
•Pharmacologic effects are similar to ACE
inhibitors in that they produce arteriolar and
venous dilation and block aldosterone
secretion, thus ↓ BP and ↓ salt and water
retention
 47

•ARBs do not ↑ bradykinin levels. They may

be used as first-line agents for the
treatment of HTN, especially in patients
with a compelling indication of DM, HF, or
CKD.
•Adverse effects: similar to ACE inhibitors,
although the risks of cough and
angioedema are significantly ↓. ARBs
should not be combined with an ACE
inhibitor for the treatment of HTN due to
similar mechanisms and adverse effects.
•Pregnancy category X.
 48

RENIN INHIBITOR
•A selective renin inhibitor, aliskiren, is
available for the treatment of HTN.
•Aliskiren directly inhibits renin and, thus,
acts earlier in the RAAS than ACE
inhibitors or ARBs.
•It ↓ BP about as effectively as ARBs, ACE
inhibitors, and thiazides.
•Aliskiren should not be routinely combined
with an ACE inhibitor or ARB.
 49

•Can cause diarrhea, especially at

higher doses, and can also cause
cough and angioedema, but
probably less often than ACE
inhibitors.
•Contraindicated during pregnancy.
•Metabolized by CYP 3A4 and is
subject to many drug interactions.
 50

CALCIUM CHANNEL BLOCKERS

•CCBs are a recommended treatment
option in hypertensive patients with
diabetes or angina.
•High doses of short-acting CCBs
should be avoided because of ↑d risk
of myocardial infarction due to
excessive vasodilation and marked
reflex cardiac stimulation.
 51

Classes of calcium channel blockers

•The CCBsare divided into

three chemical classes, each
with different
pharmacokinetic properties
and clinical indications
 52

•1. Diphenylalkylamines: Verapamil

•Verapamil is the least selective of any
CCB 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.
 53

•2. Benzothiazepines: Diltiazem

•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.
 54

• 3. Dihydropyridines: nifedipine (the prototype),

amlodipine, felodipine, isradipine, nicardipine,
and nisoldipine.
• These agents differ in PK, approved uses, and
drug interactions.
• All dihydropyridines have a ↑ affinity for vascular
Ca channels than for Ca channels in the heart.
They are, therefore, particularly beneficial in
treating HTN.
• 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 CCBs.
55
 56

Actions
•The intracellular concentration of Ca plays
an important role in maintaining the tone of
smooth muscle and in the contraction of the
myocardium.
•Ca enters muscle cells through special
voltage sensitive Ca channels.
•This triggers release of Ca from the
sarcoplasmic reticulum and mitochondria,
which further ↑s the cytosolic level of Ca.
 57

•Ca channel antagonists block the

inward movement of Ca by binding to
L-type Ca 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.
 58

Therapeutic uses
• In the management of HTN, 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 ß-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.
 59

Pharmacokinetics
•Most of these agents have short (3 to
8 hours) following an oral dose.
•SR preparations are available and
permit once-daily dosing.
•Amlodipine has a very long t1/2 and
does not require a SR formulation.
 60

Adverse effects
• First-degree AV block and constipation are
common dose-dependent side effects of verapamil.
• Verapamil and diltiazem should be avoided in
patients with heart failure or with AV block due to
their negative inotropic and dromotropic effects.
• Dizziness, headache, and a feeling of fatigue
caused by a ↓ in BP are more frequent with
dihydropyridines.
• Peripheral edema is another commonly reported
side effect of this class.
• Nifedipine and other dihydropyridines may cause
gingival hyperplasia.
 61

a-ADRENOCEPTOR–BLOCKING
AGENTS
•Prazosin , doxazosin, and terazosin
produce a competitive block of
a-adrenoceptors.
•They ↓ peripheral vascular resistance and ↓
arterial BP 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.
 62

• 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 ↑s, requiring slow titration of the drug in
divided doses.
• Due to weaker outcome data and their side
effect profile, a-blockers are no longer
recommended as initial treatment for HTN,
but may be used for refractory cases.

• Other a1-blockers with greater selectivity for

prostate muscle are used in the treatment of
benign prostatic hyperplasia
 63

a-/ß-ADRENOCEPTOR–BLOCKING
AGENTS
• Labetalol and carvedilol block a1, ß1, and ß2
receptors.
• Carvedilol, although an effective
antihypertensive, is mainly used in the
treatment of HF.
• Carvedilol, as well as metoprolol succinate,
and bisoprolol have been shown to reduce
morbidity and mortality associated with HF.
• Labetalol is used in the management of
gestational HTN and hypertensive
emergencies.
 64

CENTRALLY ACTING
ADRENERGIC DRUGS
 65

A. Clonidine
•Clonidine acts centrally as an a agonist to
produce inhibition of sympathetic
vasomotor centers, ↓ sympathetic outflow
to the periphery.
•This leads to ↓ total peripheral resistance
and ↓ BP.
•Clonidine is used primarily for the treatment
of HTN that has not responded adequately
to treatment with two or more drugs.
 66

• Clonidine does not ↓ renal blood flow or

glomerular filtration and, therefore, is useful
in the treatment of HTN 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 HTN occurs following abrupt
withdrawal of clonidine.
• The drug should, therefore, be withdrawn
slowly if discontinuation is required.
 67

Methyldopa
•Methyldopa is an a2 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 HTN in
pregnancy, where it has a record of safety.
 68

VASODILATORS
•The direct-acting smooth muscle relaxants,
such as hydralazine and minoxidil, are not
used as primary drugs to treat HTN.
•These vasodilators act by producing
relaxation of vascular smooth muscle,
primarily in arteries and arterioles.
•This results in ↓ peripheral resistance and,
therefore, BP.
 69

• Both agents produce reflex stimulation of the heart,

resulting in the competing reflexes of ↑d myocardial
contractility, heart rate, and oxygen consumption.
• These actions may prompt angina, MI, or HF in
predisposed individuals.
• Vasodilators also ↑ plasma renin concentration, resulting
in sodium and water retention.
• These undesirable side effects can be blocked by
concomitant use of a diuretic and a ß-blocker.
• For example, hydralazine is almost always administered
in combination with a ß-blocker, such as propranolol,
metoprolol, or atenolol (to balance the reflex tachycardia)
and a diuretic (to ↓ sodium retention).
 70

• Together, the three drugs ↓ cardiac output, plasma

volume, and peripheral vascular resistance.
• Hydralazine is an accepted medication for controlling BP
in pregnancy induced HTN.
• Adverse effects of hydralazine include headache,
tachycardia, nausea, sweating, arrhythmia, and
precipitation of angina.

• A lupus-like syndrome can occur with high dosages, but it

is reversible upon discontinuation of the drug.
• Minoxidil treatment causes hypertrichosis (the growth of
body hair).
• This drug is used topically to treat male pattern baldness.
 71

HYPERTENSIVE EMERGENCY
•Hypertensive emergency is a rare but
life-threatening situation characterized by
severe elevations in BP (systolic >180 mm
Hg or diastolic >120 mm Hg) with evidence
of impending or progressive target organ
damage (for example, stroke, myocardial
infarction).
•[Note: A severe elevation in BP without
evidence of target organ damage is
considered a hypertensive urgency.]
 72

• Hypertensive emergencies require timely BP

reduction with treatment administered
intravenously to prevent or limit target organ
damage.
• A variety of medications are used, including
calcium channel blockers (nicardipine and
clevidipine), nitric oxide vasodilators
(nitroprusside and nitroglycerin), adrenergic
receptor antagonists (phentolamine, esmolol, and
labetalol), the vasodilator hydralazine, and the
dopamine agonist fenoldopam.
• Treatment is directed by the type of target organ
damage present and/or comorbidities present.