‫جمهورية العراق‬

‫وزارة التعليم العالي والبحث العلمي‬

‫جامعة بغداد ‪ /‬كلية الطب‬

‫‪Antihypertensive drugs‬‬

‫إعداد‪:‬‬
‫حذيفة هيثم سلمان‬
‫حسن اهليل اكليهم‬
‫حسن يونس عيسى‬
‫حسنين ماهر عبد الحسين‬

‫باشراف‪:‬‬
‫د‪ .‬باسل عويد‬
 LIST OF CONTENTS
Hypertension…………………….……………………………........….3
Introduction to Antihypertensive drugs………………...……......…....3
Classification of Antihypertensive drugs………………….….........…5
Vasodilators………………………………………………………..….6

 Dihydropyridine CCBs…………………….………….....…...…6
 Non-dihydropyridine CCBs……………………....……..…...….7
 Direct acting vasodilators………………………………..…..…..9
 Nitrovasodilators……………………………………..……..….11
Sympatholytics……………………………………………………….12

 Central sympatholytics…………………………………………12
 β-Adrenoceptor–blocking Agents………………………..…….16
 α-Adrenoceptor–blocking Agents………………………….…..21
 β-/α- Adrenoceptor–blocking Agents…………………………..22
Renin-Angiotensin-Aldosterone Inhibitors…………………………..22

 Direct renin inhibitors………………………………….……….24

 ACE inhibitors………………………………………….…...….24
 ARBs……………………………………………………...……27
Diuretics………………………………………………………….…...29

 Thiazide diuretics………...…………………………………….29
 Loop diuretics……….………………………………….………30
 Potassium-sparing diuretics…………………………….………30
Conclusion…………………………….……………………………...31
References............................................................................................32
1-1 Hypertension
Hypertension is usually defined by the presence of a chronic elevation of
systemic arterial pressure above a certain threshold value. However, increasing
evidence indicates that the cardiovascular (CV) risk associated with elevation of
blood pressure (BP) above approximately 115 ⁄75 mm.

Hypertension is a progressive CV syndrome arising from complex and interrelated

etiologies. Early markers of the syndrome are often present before BP elevation is
sustained; therefore, hypertension cannot be classified solely by discrete BP
thresholds. Progression is strongly associated with functional and structural cardiac
and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and
other organs and lead to premature morbidity and death. Reduction of BP when
target organ damage is demonstrable or the functional precursor of target organ
damage is present and still reversible generally reduces the risk for CV events.

2-1 Introduction to Antihypertensive drugs

For most patients with systemic hypertension, long-term drug treatment is
indicated and is beneficial. There is overwhelming evidence to suggest that
antihypertensive drugs offer protection against complications of hypertension.
Whereas nondrug therapeutic options should be implemented in all patients, a vast
majority will require pharmacological treatment to achieve goal blood pressure
levels. Fortunately, a number of drugs are available to accomplish successful
treatment of hypertensive disorders. While it is conventional to initiate treatment
with a single drug, a suitable combination of drugs is often required to control the
blood pressure effectively. Although diuretics and beta-blockers are effective and
well tolerated, other classes of drugs are being increasingly used as the initial
choice of therapy for hypertension. Every class of antihypertensive drugs offer

3
advantages and some disadvantage; the physician should weigh the benefits and
risks in selecting one drug over another. While the clinical parameters are
followed in the management of patients with hypertension, it is also necessary to
monitor the patients' biochemical profile periodically in order to modify and
adjust the therapy accordingly. A careful selection of drug therapy along with
close follow-up offers the best prospect to reduce the burden of morbidity and
mortality in hypertension.

4
3-1 Classification of Antihypertensive drugs
The classes of antihypertensive medications used for the treatment of HTN are:

1- Vasodilators:
Arterial vasodilators: Venodilators:
– Dihydropyridine CCBs. – Nitrovasodilators.
– Non-dihydropyridine CCBs.
– Direct acting vasodilators.
– Nitrovasodilators.
2- Sympatholytics:
– Central sympatholytics.
– β- Adrenergic blockers.
– α- Adrenergic blockers.
– β+α Adrenergic blockers.
3- Renin-Angiotensin-Aldosterone inhibitors )RAAI):
– Direct renin inhibitors.
– Angiotensin converting enzyme inhibitors (ACE inhibitors).
– Angiotensin II receptor blockers (ARBs).
4- Diuretics:
– Thiazide diuretics.
– Loop diuretics.
– Potassium-sparing diuretics (Aldosterone antagonists).

The most recommended classes used as first-line for treatment of HTN are:

• Thiazide-type diuretics.

• Calcium channel blockers (CCBs).

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• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor
blockers (ARBs).

3-1-1 Vasodilators
 Arterial vasodilators:
1- Dihydropyridine calcium channel blockers: are drugs used to treat
high blood pressure and severe angina (chest pain caused by lack of oxygen to the
heart muscle). Dihydropyridines are one of the different types of calcium channel
blockers; they predominately act on blood vessels with less effect on the heart.

Dihydropyridine calcium channel blockers work by blocking the entry of calcium

into the cells through voltage-gated calcium channels present on the cells.
Calcium present in the cells is responsible for contractions of the cells and
muscles. Blocking the calcium channels located on the smooth muscle of blood
vessels decreases calcium levels in the cells and causes vasodilation (widening of
blood vessels), so the systemic pressure is decreased and the free flow of the
blood to the tissues is increased

Side effects

Common side effects of dihydropyridine calcium channel blockers may include:

 Headache
 Flushing (involuntary, temporary reddening of the skin, usually seen in the
face)
 Dizziness
 Lightheadedness
 Blood pressure fluctuation
 Swelling of foot, ankles, and hands
 Heart burn

6
  Constipation

Names of dihydropyridine CCBs

Generic and brand names of dihydropyridine calcium channel blockers drugs
include:

 amlodipine (is the most prescribe agent than other)

 Clevidipine
 Felodipine
 Isradipine
 Levamlodipine
 Nicardipine
 Nifedipine (Adalat)
 Nimodipine (Nimotop)
 Nisoldipine(Sular)
 Nilvadipine
 Barnidipine
 Benidipine
 Cilnidipine
 Lacidipine
 Levamlodipine

2-Non-dihydropyridine calcium channel blockers: are a class of

antiarrhythmic drugs used to treat tachydysrhythmias (abnormal cardiac rhythm
with a rate greater than 100 beats per minute) and hypertension (high blood
pressure). Nondihydropyridines are one of the different types of calcium channel

7
blockers; they act mainly on the heart with less effect on blood vessels. They have
a greater depressive effect on cardiac conduction and contractility but are less
potent vasodilators than other types of calcium channel blockers
(dihydropyridines).

Nondihydropyridines work by blocking the calcium channels present in the heart

muscle and reduce the influx of calcium into cardiac muscle cells (myocytes),
leading to a decrease in the heart rate and contractions of the heart muscle.

Normally, the influx of calcium into cardiac myocytes increases the automaticity
and conduction velocity of pacemaker cells, thereby increasing the heart rate.
Calcium also increases the force of contraction of nonpacemaker cardiac
myocytes, thereby increasing the stroke volume.

Side effects
Side effects of nondihydropyridine calcium channel blockers may include:

 Constipation
 Tiredness
 Reduced contractility of the heart
 Worsening of cardiac output
 Bradycardia (low heart rate)
 Gingival hyperplasia (overgrowth of gum tissue around the teeth)
 Hyperprolactinemia (increase in serum prolactin levels)
 Atrioventricular block (heart block caused by impairment of electrical
impulses traveling from atria to other chambers of the heart)
 Cardiotoxicity

8
Names of Non-dihydropyridine CCBs

Generic and brand names of nondihydropyridine calcium channel blockers

drugs include:

 Dilatrate
 Diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cartia XT, Dilacor,
Dilacor XR, Dilt-CD, Diltazem, Diltazem CD, Diltia XT, Diltiaz, Diltiaz
CD, Diltiaz SR, Diltiazem CD, Diltiazem SR, Taztia XT, Tiazac)
 Dilzem
 Verapamil (Calan, Calan SR, Covera HS, Isoptin, Isoptin IV, Isoptin SR,
Verap, Verapamil SR, Verelan, Verelan PM)

3- Direct acting vasodilators (Hydralazine):

Hydralazine is in a class of medications called vasodilators. It works by

relaxing the blood vessels so that blood can flow more easily through the body.

9
Hydralazine interferes with calcium transport to relax arteriolar smooth muscle
and lower blood pressure. Hydralazine has a short duration of action of 2-6h. This
drug has a wide therapeutic window, as patients can tolerate doses of up to
300mg. Patients should be cautioned regarding the risk of developing systemic
lupus erythematosus syndrome.

Hydralazine also competes with protocollagen prolyl hydroxylase (CPH) for free
iron. This competition inhibits CPH mediated hydroxylation of HIF-1α,
preventing the degradation of HIF-1α. Induction of HIF-1α and VEGF promote
proliferation of endothelial cells and angiogenesis.

Side effects
Headache, pounding/fast heartbeat, loss of appetite, nausea, vomiting, diarrhea,
or dizziness may occur as your body adjusts to the medication. If any of these
effects last or get worse, tell your doctor or pharmacist promptly.

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  Arterial + Venous Vasodilators
4- Nitrovasodilators: they relax vascular smooth muscle (especially venous)
via generation of nitric oxide (NO). The nitrate vasodilators are esters of nitrous
acid. They are metabolized to inorganic nitrite and denitrated metabolites.
Nitrites, organic nitrates, and nitroso compounds all act to activate the enzyme
guanylate cyclase, which in turn produces cyclic guanosine monophosphate
(GMP) in vascular smooth muscle and relax smooth muscle. Nitric oxide is also
known as the endothelium-derived relaxing factor (EDRF).

There are two basic types of nitrodilators: those that release NO spontaneously
(e.g., sodium nitroprusside) and organic nitrates that require an enzymatic
process to form NO. Organic nitrates do not directly release NO, however, their
nitrate groups interact with enzymes and intracellular sulfhydryl groups that
reduce the nitrate groups to NO or to S-nitrosothiol, which then is reduced to NO.
Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form
cGMP. Increased intracellular cGMP inhibits calcium entry into the cell,
decreasing intracellular calcium concentrations and causing smooth muscle
relaxation.

Owing to its capacity to rapidly release NO, sodium nitroprusside produces

potent systemic vasodilation and is effective as an antihypertensive.

Side effects and Contraindications

The most common side effects of nitrodilators are headache (caused by

cerebral vasodilation) and cutaneous flushing. Other side effects include postural
hypotension and reflex tachycardia. Excessive hypotension and tachycardia can
worsen the angina by increasing oxygen demand. Prolonged use of sodium
nitroprusside carries the risk of thiocyanate toxicity because nitroprusside
releases cyanide along with NO

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3-1-2 Sympatholytics
1- Central sympatholytics: Central sympatholytic agents were first
introduced into clinical use in the 1960s. α‐Methyldopa, the first drug to be
widely used, is the only prodrug in this class. It is converted to α‐
methylnorepinephrine, which was at first thought to act peripherally as a false
neurotransmitter. Clonidine, the prototype of the second‐generation drugs in this
class, all of which are imidazoline derivatives, was initially developed as a nasal
decongestant because of its potential vasoconstrictor effect via postsynaptic α2‐
adrenergic receptor (AR) stimulation but was surprisingly found to have
antihypertensive effects via activation of presynaptic α2‐AR in the brainstem. A
similar effect of centrally formed α‐methylnorepinephrine is now understood to
account for the blood pressure (BP)–lowering effect of methyldopa.
Subsequently, other direct‐acting central sympatholytic drugs such as guanfacine

12
and guanabenz were approved for treatment of hypertension in the United States.
Moxonidine and rilmenidine are also centrally acting drugs used in England and
other European countries but are not available in the United States. In contrast to
clonidine and other α2 agonists, moxonidine and rilmenidine predominantly
reduce sympathetic nerve activity (SNA) and BP by stimulating imidazoline‐1
(I1) receptor, rather than α2‐AR in the brainstem. Central sympatholytic drugs
reduce BP mainly by activation of α2‐AR in the rostral ventrolateral medulla
resulting in decreased SNA and, to a lesser extent, by inhibition of presynaptic
release of norepinephrine from peripheral sympathetic nerve terminals.
Activation of I1 receptors in the brainstem centers also contributes to
sympatholytic action and BP‐lowering effects of all the second‐generation drugs
(ie, except for methyldopa), independent of central α2‐ARs. Clonidine activates
both I1 receptors and α2‐ARs. Guanfacine and guanabenz are more selective for
α2‐AR than clonidine.

13
A. 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 well absorbed after oral
administration and is excreted by the kidney. It is
also available in a transdermal patch. Adverse
effects include sedation, dry mouth, and

14
constipation. Rebound hypertension occurs following abrupt withdrawal of
clonidine.The drug should, therefore, be withdrawn slowly if discontinuation is
required. Treatment with oral clonidine has been shown to decrease resting
cardiac output by 15% to 20% without affecting total peripheral resistance (TPR)
in hypertensive patients. Reduction in heart rate, rather than stroke volume, is
mainly responsible for decreased resting cardiac output. Reduction in plasma
renin activity and urinary aldosterone excretion is also observed after clonidine,
likely related to reduction in renal SNA.

B- Guanfacin:
Is an α2 agonist with 12 to 25 times higher selectivity than clonidine for the α2‐
AR vs the α1‐AR. In individuals with normal renal function, the average
elimination half‐life is approximately 17 hours. Peak plasma concentrations occur
from 1 to 4 hours after single oral doses. Steady‐state blood levels are achieved
within 4 days in most patients. In contrast to clonidine, studies in hypertensive
patients have suggested that guanfacine reduces BP mainly by reducing total
vascular resistance rather than cardiac output. Guanfacine reduces resting heart rate
with minimal effect on heart rate during exercise. In contrast, guanfacine reduces
TPR similarly both at rest and during exercise with minimal effects on cardiac
output. Guanfacine is typically administered once daily at bedtime. Most of the
side effects of guanfacine, such as dry mouth, sedation, and fatigue, are similar to
those seen with clonidine. Rebound hypertension, however, occurs less frequently
than clonidine because of its longer half‐life.

C. 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

15
and the need for multiple daily doses. It is mainly used for management of
hypertension in pregnancy, where it has a record of safety.

D- Guanabenz:

Is another direct central α2‐agonist, which is predominantly eliminated via

hepatic biotransformation. Thus, unlike clonidine, dose adjustment is not required
in patients with renal failure but required in those with chronic liver diseases.
Guanabenz has been shown to be effective in reducing left ventricular hypertrophy
in hypertensive patients and in attenuating morning hypertension when
administered at nighttime. The half‐life of guanabenz is between 12 and 14 hours
and the drug is typically given twice daily at a dosage between 8 mg/d and 32
mg/d.

2- β-Adrenoceptor–blocking Agents: are a treatment option for

hypertensive patients with concomitant heart disease or heart failure.

A. Actions;

The β-blockers reduce blood pressure primarily by decreasing cardiac output

(Figure below). 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 [proe-PRAN-oh-lol], which acts at both β1 and
β2 receptors. Selective blockers of β1 receptors, such as metoprolol [met-OH-pro-
lol] and atenolol [ah-TEN-oh-lol], are among the most commonly prescribed β-
blockers. Nebivolol [ne-BIV-oh-lole] is a selective blocker of β1 receptors, which
also increases the production of nitric oxide, leading to vasodilation.

16
The selective β-blockers may be administered cautiously to hypertensive patients
who also have asthma.

The nonselective β-blockers are contraindicated in patients with asthma due to

their blockade of β2-mediated bronchodilation. β-Blockers should be used
cautiously in the treatment of patients with acute heart failure or peripheral
vascular disease.

β-Blockers antagonize catecholamines at β-adrenoceptors. These Gs type G-

protein-coupled receptors are classified as β1, present mainly within the heart and
kidneys; and β2, present throughout the body in lungs, blood vessels, and muscle.
The reduction in arterial pressure achieved by β-blockers is attributable to their
effects upon multiple pathways. Block of β1 receptors in the sinoatrial node
reduces heart rate and block of myocardial receptors reduces contractility (reduced
chronotropy and inotropy, respectively). They also reduce sympathetic nervous
system activity, while block of receptors in the juxtaglomerular apparatus reduces
renin secretion.

Actions of beta adrenergic blockers

17
B. 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, stable ischemic heart
disease, and chronic heart failure. Conditions that discourage the use of β-blockers
include reversible bronchospastic disease such as asthma, second- and third-
degree heart block, and severe peripheral vascular disease.

Beta blockers aren't recommended as a first treatment in people who have only
high blood pressure. Beta blockers aren't usually prescribed for high blood
pressure unless other medications, such as diuretics, haven't worked well. Also, a
doctor may prescribe a beta blocker as one of several medications to lower blood
pressure.

Beta blockers may not work as effectively for black people and older people,
especially when taken without other blood pressure medications.

Beta blockers are used to prevent, treat or improve symptoms in people who have:

• Irregular heart rhythm (arrhythmia)

• Heart failure

• Chest pain (angina)

• Heart attacks

• Migraine

• Certain types of tremors.

18
C. 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.

β-Blockers are categorized according to cardioselectivity. Metoprolol, esmolol,

and atenolol have greater affinity for β1 receptors than β2 at therapeutic doses
(selectivity is reduced at higher doses). This contrasts with non-cardioselective
drugs such as propranolol and sotalol. Most β-blockers are pure antagonists;
however, some drugs are partial antagonists at β receptors and exhibit some
agonist/sympathetomimetic activity (pindolol, timolol). The clinical relevance of
this is uncertain. Some β-blockers (propranolol, metoprolol) block sodium
channels and have membrane stabilizing activity, that is, may be classed as
Vaughan-Williams class 1 antiarrhythmics. Labetalol is a β-blocker which also
has α-blocking activity. In addition to their antihypertensive effects, β-blockers
improve the myocardial oxygen supply:demand ratio and help reduce myocardial
ischaemia by prolonging the period of diastole. While β-blockers are used in
stable heart failure, they have the potential to worsen symptoms in some patients
by reducing cardiac output. Poor peripheral circulation and Raynaud's
phenomenon may be precipitated both by reduced cardiac output and block of
peripheral β2 receptors. Bronchospasm caused by β2 block may be a significant
respiratory side-effect in susceptible individuals, for example, asthmatics. Central
nervous system effects include malaise, tiredness, and vivid dreams, particularly
with lipid-soluble drugs. In insulin-dependent diabetic patients, the symptoms of
hypoglycaemia may be suppressed by sympathetic block.

19
More than 30 β-blockers are currently available. Oral administration is common
as most have good absorption and bioavailability. I.V. preparations are available
for some, including atenolol, metoprolol, and esmolol. Lipid-soluble drugs, for
example, metoprolol and propranolol, are generally metabolized by the liver and
have shorter half-lives than water-soluble drugs, for example, atenolol, which are
excreted largely unchanged in the urine. An exception is esmolol, which is
metabolized by ester hydrolysis accounting for its rapid offset of action

D. Adverse effects

1. The β-blockers may decrease libido and cause

erectile dysfunction, which can severely reduce
patient compliance.

2. Alterations in serum lipid patterns

Noncardioselective β-blockers may disturb lipid
metabolism, decreasing high-density lipoprotein
cholesterol and increasing triglycerides.

3. Drug withdrawal Abrupt withdrawal may

induce severe hypertension, 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.

20
Examples of beta blockers taken orally include:

• Acebutolol

• Atenolol (Tenormin)

• Bisoprolol (Zebeta)

• Metoprolol (Lopressor, Toprol XL)

• Nadolol (Corgard)

• Nebivolol (Bystolic)

• Propranolol (Inderal, InnoPran XL)

3- α-Adrenoceptor–blocking Agents: used in the treatment of hypertension

include prazosin , doxazosin , and terazosin . These agents 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 the prostate are used in the treatment of
benign prostatic hyperplasia.

21
4- β-/α- Adrenoceptor–blocking Agents:
Labetalol and carvedilol block α1, β1, and β2 receptors. Carvedilol is indicated
in the treatment of heart failure and hypertension. It has been shown to reduce
morbidity and mortality associated with heart failure. Labetalol is used in the
management of gestational hypertension and hypertensive emergencies.

3-1-3 Renin-Angiotensin-Aldosterone Inhibitors (RAAI)

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the
pathogenesis of hypertension (HTN). It is a crucial mediator of cardiac, vascular,
and renal physiology through the regulation of vascular tone and salt and water
homeostasis.

In addition to the main physiological functions, the RAAS has a significant role in
the pathophysiological conditions of hypertension, heart failure, other
cardiovascular diseases, and renal diseases.

Mechanism of RAAS:

 When blood pressure falls (for systolic, to 100 mm Hg or lower), the

kidneys release the enzyme renin into the bloodstream (by sympathetic
stimulation and/or decreased renal perfusion).
 Renin splits angiotensinogen, a large protein that is made by the liver and
circulates in the bloodstream, into pieces. One piece is angiotensin I.

22
 Angiotensin I, which is relatively inactive, is split into pieces by
angiotensin-converting enzyme (ACE) in the capillary endothelium of the
lungs. One piece is angiotensin II, a hormone, which is very active.
 Angiotensin II causes the muscular walls of small arteries (arterioles) to
constrict, increasing blood pressure. Angiotensin II also triggers the release
of the hormone aldosterone from the adrenal glands and vasopressin
(antidiuretic hormone) from the pituitary gland.
 Aldosterone and vasopressin cause the kidneys to retain sodium (salt).
Aldosterone also causes the kidneys to excrete potassium. The increased
sodium causes water to be retained, thus increasing blood volume and blood
pressure.

23
There are three main classes of medicines that work on this system and inhibit it
(called RAS-acting agents):

1- direct renin inhibitors (aliskiren)

2- angiotensin-converting enzyme inhibitors (ACE-inhibitors)

3- angiotensin II receptor blockers (ARBs)

1- direct renin inhibitors: such as aliskiren, which are relatively new

compared to other antihypertensives. Aliskiren binds really tightly to the active
site of renin enzymes. This blocks angiotensinogen from binding, so angiotensin I
levels fall.

Aliskiren has a long half life, so one tablet taken peroral daily is enough. But,
since it’s “younger” in the medical field, it hasn’t been as extensively tested. So
it’s commonly used for patients who don’t respond to other antihypertensives, or
it can be given in combination with other antihypertensives. In addition, aliskiren
can cause GI side effects like diarrhea and abdominal pain. Other side effects
include headache, dizziness, and fatigue.

2- ACE inhibitors: are commonly used drugs to treat heart failure and high
blood pressure and are often prescribed to people following a heart attack.

ACE inhibitors stimulate the dilation of blood vessels by inhibiting the production
of angiotensin II. The major organs that ACE inhibitors affect are the kidney,
blood vessels, heart, brain, and adrenal glands. The inhibitory effects lead to
increased sodium and urine excreted, reduced resistance in kidney blood vessels,
increased venous capacity, and decreased cardiac output, stroke work, and
volume.

24
Examples of ACE inhibitors

ACE inhibitors are classified as either short-acting or long-acting, depending on

their duration of action. Both can be effective therapy options; however, long-
acting ACE inhibitors offer the advantage of less frequent dosing. For example,
Lisinopril is a long-acting ACE inhibitor that needs to be taken once a day,
whereas Captopril is a short-acting ACE inhibitor that has to be taken thrice daily.

Other examples of ACE inhibitors include:

 Benazepril,
 Fosinopril,
 Lisinopril,
 Captopril,
 Enalapril,
 Ramipril,
 Moexipril,
 Quinapril,
 Trandolapril.

An appropriate ACE inhibitor can be selected after considering the patient's health
and the condition to be treated.

Side effects
ACE inhibitors are a fairly well-tolerated class of drugs and produce only a few
side effects. Common side effects of this class of drugs include:

25
  A dry, irritating cough

This is one of the most common side effects reported in patients prescribed
ACE inhibitors. It is caused by the accumulation of inflammatory compounds
such as bradykinin and substance P, which are stimulated by ACE inhibitors.

 Light-headedness and dizziness

ACE inhibitors only offer modest improvements in blood pressure for most
patients; hence, light-headedness and dizziness are rarely reported. These effects
are more prominent in patients with hypotension (very low blood pressure).
Hypotension is frequently observed in patients with heart failure; thus, caution is
needed when beginning or changing ACE inhibitors in at-risk patients.

 Hyperkalemia (elevated potassium levels in the blood)

Aldosterone is a hormone that regulates the excretion of potassium in the

kidneys via urine. ACE inhibitors lower aldosterone levels, promoting potassium
retention in the kidneys and bloodstream.

People with diabetes and kidney disease are at increased risk of hyperkalemia, so
ACE inhibitors must be used with caution in these patients. Symptoms of
hyperkalemia include general weakness, confusion, and muscle cramps. In severe
cases, hyperkalemia can lead to dangerous cardiac arrhythmias (an abnormal
heartbeat).

 Angioedema (swelling under the skin)

Angioedema is the most severe symptom associated with ACE inhibitors and
occurs in 0.1-0.2% of patients. Airway swelling and obstruction due to the
accumulation of fluid (and bradykinin) are the main features of angioedema. The
severity of the condition depends on which area is affected.

26
Mild angioedema may appear as temporary swelling in the lips, tongue, or mouth.
In severe cases where the upper airway and larynx are affected, patients may have
difficulty breathing, and emergency care may be required. Patients experiencing
angioedema while using an ACE inhibitor must discontinue the medication and
avoid all ACE inhibitors in the future.

3- Angiotensin receptor blockers (ARBs), also known as angiotensin II receptor

antagonists, are used to treat high blood pressure and heart failure. They are also
used for chronic kidney disease and prescribed following a heart attack. They
include irbesartan, valsartan, losartan and candesartan. If the name of a medicine
ends in ‘sartan’, it is an ARB.

ARBs work by blocking receptors that the hormone angiotensis II acts on,
specifically AT receptors, which are found in the heart, blood vessels and kidneys.
Blocking the action of angiotensin II helps to lower blood pressure and prevent
damage to the heart and kidneys.

Examples of angiotensin II receptor blockers

Several angiotensin II receptor blockers are available. Which one is best for you
depends on your health and the condition being treated.

Examples of angiotensin II receptor blockers include:

 Azilsartan (Edarbi)
 Candesartan (Atacand)
 Eprosartan
 Irbesartan (Avapro)
 Losartan (Cozaar)

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  Olmesartan (Benicar)
 Telmisartan (Micardis)
 Valsartan (Diovan)

Side effects

Side effects may occur during the first few days of use. Some fade as your body
gets used to the medicine. If these side effects persist or worsen, call your
healthcare provider. Some side effects may require stopping the medicine right
away, as directed by your healthcare provider. Side effects can include:

 Cough
 Low blood pressure
 Dizziness
 Drowsiness
 Diarrhea
 Stuffy nose
 Raised potassium levels
 Swelling in the deep skin layers (angioedema)

Differences between ACE inhibitors and ARBs

ARBs and ACE inhibitors are similar in action and side effects. They differ in
how they are eliminated from the body and the extent to which they are distributed
throughout the body.

Some ARBs are converted to an active form in the body before they can exert
their effects.

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Some ARBs are slightly better at reducing blood pressure than others; in some
studies, irbesartan (Avapro) and candesartan (Atacand) were slightly more
effective in reducing blood pressure than losartan (Cozaar).

All ARBs usually are administered once daily for treatment of hypertension. Some
patients may benefit from twice daily dosing of losartan (Cozaar) if blood pressure
is not controlled with once daily dosing.

3-1-4 Diuretics

For all classes of diuretics, the initial mechanism of action is based upon
decreasing blood volume, which ultimately leads to decreased blood pressure.
Routine serum electrolyte monitoring should be done for all patients receiving
diuretics.

1- Thiazide diuretics:

Thiazide diuretics, such as hydrochlorothiazide [hye-droe-klor-oh-THYE-a-

zide] and chlorthalidone [klor-THAL- ih-done], lower blood pressure initially by
increasing sodium and water excretion. This causes a decrease in extracellular
volume, resulting in a decrease in cardiac output and renal blood flow. With long-
term treatment, plasma volume approaches a normal value, but a hypotensive
effect persists that is related to a decrease in peripheral resistance. Thiazide
diuretics can be used as initial drug therapy for hypertension unless there are
compelling reasons to choose another agent. Thiazides are useful in combination
therapy with a variety of other antihypertensive agents, including β-blockers, ACE
inhibitors, ARBs, and potassium-sparing diuretics. With the exception of
metolazone [me-TOL-ah-zone], thiazide diuretics are not effective in patients with
inadequate kidney function (estimated glomerular filtration rate less

29
than 30 mL/min/m2). Loop diuretics may be required in these patients. Thiazide
diuretics can induce hypokalemia, hyperuricemia, and, to a lesser extent,
hyperglycemia in some patients.

B. Loop diuretics:

The loop diuretics (furosemide, torsemide, bumetanide, and ethacrynic acid) act
promptly by blocking sodium and chloride reabsorption in the kidneys, even in
patients with poor renal function or those who have not responded to thiazide
diuretics. Loop diuretics cause decreased renal vascular resistance and increased
renal blood flow. Like thiazides, they can cause hypokalemia. However, unlike
thiazides, loop diuretics increase the calcium content of urine, whereas thiazide
diuretics decrease it. These agents are rarely used alone to treat hypertension, but
they are commonly used to manage symptoms of heart failure and edema.

C. Potassium-sparing diuretics (Aldosterone antagonists)P:

Amiloride [a-MIL-oh-ride] and triamterene [tri-AM-ter-een] are inhibitors of

epithelial sodium transport at the late distal and collecting ducts, and
spironolactone [speer-on-oh-LAK-tone] and eplerenone [eh-PLEH-reh-none] are
aldosterone receptor antagonists. All of these agents reduce potassium 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 in combination with loop diuretics and thiazides to reduce the
amount of potassium loss induced by these diuretics.

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4-1 Conclusion

Choice of antihypertensive agent(s) is a clinical decision based on many factors,

including an individual patient's BP, BP goal, and risk conditions such as HF,
prior MI, classic angina, and edema. Consideration should be given not only to the
benefits of BP lowering which are well established and not in dispute, but also to
the metabolic risks of some BP lowering drugs. There are clear cardiovascular
outcome benefits as a result of BP lowering. It is less clear what the impact of new
onset diabetes is with regard to long term macrovascular complications. However,
as the prevalence of hypertension in those at risk for diabetes increases, it is
important to bear in mind the metabolic consequences of antihypertensive
medications. If thiazide diuretics and/or β blockers are agents of choice based on
an individual patient’s clinical characteristics, then the lowest possible dose and
close monitoring should be employed in order to recognize and manage metabolic
adverse outcomes early on, while still maintaining adequate BP control.

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