HYPERTENSION

Hypertension is defined as:

“A condition in which there is persistently increased in Systolic BP ≥140mm Hg or Diastolic BP
≥90mm Hg. It is also known as High or Raised BP.”
Hypertension , or high blood pressure, is a very common and serious condition that can lead to or
complicate many health problems. The risk of cardiovascular morbidity and mortality is directly
correlated with blood pressure. Risks of stroke, MI, angina, heart failure, kidney failure or early
death from a cardiovascular cause are directly correlated with BP. Hypertension is often called
"the silent killer" because it generally has no symptoms until serious complications develop.
When symptoms do occur, they can differ between individuals depending on such factors as the
level of blood pressure, age, underlying cause, medical history, the presence of complications and
general health.
Hypertension is largely a condition of older individuals. While diastolic pressure peaks at age 50,
systolic pressure continues to increase with advancing age, making isolated systolic hypertension
a common feature of old age. Generally, the risk of cardiovascular disease doubles for every
20/10mmHg rise in blood pressure. An increase of 5mmHg in usual Diastolic blood pressure is
associated with 35-40% increased risk of stroke. The risk of Heart failure is increased six folds in
hypertensive subjects.

Stages of Hypertension
The Joint National Committee (JNC-8) classification of BP in adults (age ≥ 18 years) is based on
the average of two or more properly measured BP readings from two or more clinical encounters.
If the systolic blood pressure and diastolic blood pressure values fall into different categories, the
overall classification is determined based on the higher of two blood pressures.It includes four
categories:
Normal values considered to be an SBP of less than 120mmHg and a DBP of less than 80mmHg.
Pre hypertension is not considered a disease category but identifies patients whose BP is likely to
increase into the classification of hypertension in the future.
There are two stages of hypertension, and all patients in these categories warrant drug therapy.
TYPES OF HYPERTENSION
It is divided into two types
1) Primary hypertension (Essential hypertension)
2) Secondary hypertension (Non-essential hypertension)

1. PRIMARY HYPERTENSION
It results when arterial blood pressure is increased due to increased peripheral resistance. It is
further divided in to two types namely: benign and malignant hypertension
1.1. Benign hypertension
Here, there is a moderate increase in blood pressure with systolic pressure of 200 mm Hg and the
diastolic pressure of above 100 mm Hg. However, in resting condition and sleep, the blood
pressure returns to normal level. Later, if there is increase in blood pressure it will not come back
to normal level in resting conditions.
1.2. Malignant hypertension
Here, the blood pressure elevated to a great extends of about 250 mm Hg of systolic pressure and
150 mm Hg of diastolic pressure. It produces severe symptoms like renal disease, retinal disease,
and being a fatal disease, it causes death within few years.
Some of the characteristics of primary or essential hypertension are,
1) The mean arterial pressure is increased 40-60 %.
2) The renal blood flow in the later stages is decreased about one half of normal.
3) The resistance to blood flow through the kidney is increased 2-4 fold.
4) The kidneys will not excrete adequate amounts of salt and water unless the arterial pressure is
high.

2 SECONDARY HYPERTENSION
 2.1 Hypertension induced by genetic mutation

Genetic factors play an important role for this type. Genetic mutations affecting Na+ balance, NO
release or aldosterone secretion and angiotensinogen play an important role in developing this
type of hypertension.

2.2 Hypertension associated with pregnancy

Hypertension in pregnant woman is known as pre-eclampsia. Pre eclampsia can progress to a

life threatening condition called eclampsia which is the development of protein in urine,
generalized swelling and severe seizures. Other symptoms include nausea, headache, vision loss
and vomiting. Pre-eclampsia and eclampsia, is one of the common cause of maternal and fetal
mortality.

2.3 Cardiovascular hypertension

It is produced due to
a) Atherosclerosis- hardening and narrowing of blood vessels
b) Coarctation of aorta- narrowing of aorta.

2.4 Renal Hypertension

It is produced due to
a) Stenosis renal arteries- narrowing of one or both renal arteries, so that the renal function is
impaired.
b) Glomerulonephritis- nephritis with inflammation of the capillary loops in the renal glomeruli.

2.5 Endocrine hypertension

It occurs due to
a) Pheochromocytoma- tumer in adrenal medulla
b) Hyperaldosteronism- excess secretion of aldosterone from adrenal cortex Conn’s syndrome.
c) Cushing’s syndrome- excess secretion of cortisone.
d) Gigantism or Acromegaly- excess secretion of growth hormone.

2.6 Neurogenic hypertension

Acute hypertension can be caused by strong stimulation of the sympathetic nervous system.
a) Section of the baroreceptors nerves.
b) Lesions in tractus solitarius.
c) Increased intracranial pressure.
3) OTHER TYPES:
However, there are several types of hypertension that are less common but are not less important.
This means it is important to know how to monitor your hypertension based on its type.

Pulmonary Hypertension
Pulmonary hypertension is high blood pressure in the arteries to your lungs.Some forms of
pulmonary hypertension are serious conditions that progressively become worse and are
sometimes fatal. Although some forms of pulmonary hypertension are not curable, treatment can
help lessen symptoms and improve the quality of life. There are several types of pulmonary
hypertension and the treatment plan depends on the type. Symptoms can include but are not
limited to:
Shortness of breath during routine activity, such as climbing two flights of stairs, Fatigue, Chest
pain, A racing heartbeat, Pain in the upper right quadrant of the abdomen near the liver,
Decreased appetite.

Pseudo-Hypertension
Pseudo hypertension is a falsely elevated blood pressure reading obtained by the blood pressure
machine due to calcification of the blood vessels which cannot be compressed. In pseudo
hypertension, blood vessels become stiff and thick because of calcification and resist compression
from the bladder of the inflatable BP cuff. Greater pressure is needed to occlude the artery, and
this can result in an overestimation of true SBP.

White coat hypertension

This is a fairly common phenomenon whereby blood pressure is only elevated when a patient is in
the doctor’s surgery. People with white coat hypertension have normal readings at home, and only
have high readings when their BP is taken by a doctor.

Isolated systolic hypertension

It’s not uncommon for patients to have either a systolic number that’s elevated while the diastolic
number remains normal.
It’s less common to have an elevated diastolic number. This condition is known as isolated
systolic hypertension, usually affects older people and tends to result from a clear and defined
condition somewhere else in the body.
As a general rule of thumb, the systolic reading tends to be very high in these cases, often close to
200. If it isn’t then general high blood pressure is usually diagnosed. Where the systolic reading is
especially high treatment options are generally different to treating general high blood pressure.
This type of blood pressure needs urgent treatment too since recent research carried out at The
Heart Disease Prevention Program, University of California uncovered evidence to suggest that
the higher the systolic pressure the greater the risk of death from heart disease.
Hypertensive crisis
Hypertensive crisis are situations in which measured BP values are markedly elevated typically in
the upper range of stage 2 hypertension (≥180/110mm Hg). They are classified as either:
Hypertensive emergengy(with acute or progressive target organ damage)
Hypertensive urgency(without acute or progressive target organ damage)
Hypertensive emergencies require hospitalization for immediate BP lowering using intravenous
medication and intra-arterial BP monitoring.
Hypertensive urgencies do not require immediate BP lowering; instead BP should slowly reduced
within 24 hours.

ETIOLOGY OF HYPERTENSION
Although hypertension may occur secondary to other disease processes, more than 90% of
patients have essential hypertension, a disorder of unknown origin affecting blood pressure
regulating mechanism. A family history of hypertension is increases the likelihood that an
individual will develop hypertensive disease. Essential hypertension occurs four times more
frequently among blacks than among whites, and it occur more often among middle-aged males
than among middle-aged females. Environmental factors such as stressful lifestyle, high dietary
intake of sodium, obesity, and smoking all further predispose an individual to the occurrence of
hypertension.

EPIDEMIOLOGY OF HYPERTENSION
Overall approximately 20% of the world adults are estimated to have high BP the prevalance
dramatically elevates in patients older than 60 years. In many countries, 50% of individuals in this
age group have hypertension. Worldwide approximately one billion people have hypertension
contributing to more than 7.1 million deaths per day.
National health surveys in various countries have shown a high prevalence of poor control of
hypertension. These studies have reported that prevalence of hypertension is 22% in Canada of
which 16% is controlled; it is 26.3% in Egypt, of which 8% is controlled; and it is 13.6% in china,
of which 3% is controlled.

PATHOGENESIS OF HYPERTENSION
BP=CO×TPR
Blood pressure is normally regulated by some compensatory mechanisms that respond to change
in cardiac demand. An increase in cardiac output (CO) normally results in compensatory decrease
in total peripheral resistance (TPR) & vice versa. When these compensatory mechanisms are not
functioning properly then there is disturbance in normal body processes
The mechanism of hypertension constitutes aberrations of the normal physiologic regulation of
blood pressure. Regulation of normal blood pressure: The blood pressure level is a complex trait
that is determined by the interaction of multiple genetic, environmental, and demographic factors
that influence to hemodynamic variables: cardiac output and total peripheral resistance. Cardiac
output affected by the blood volume, itself greatly dependent on body sodium homeostasis. Total
peripheral resistance is predominantly determined at the level of the arterioles and depends on the
effect of neutral and hormonal influence. Normal vascular tone reflects the balance between
humoral vasoconstriction influences (including angiotensin II and catecholamine) and
vasodilators (including kinins, prostagladins, and nitric oxide). Resistance vessels also exhibit
autoregulation, whereby increased blood flow induced vasoconstriction to protect against tissue
hyper perfusion. Other local factors such as pH and hypoxia, as well as neural interactions (α- and
β- adrenergic systems), May important.

Patient compliance with a good treatment plan generally results in a normalization

of blood pressure and also minimizes complications.
REGULATION OF BLOOD PRESSURE
It means maintaining a constant blood pressure within a narrow variation. Both increase in blood
pressure (hypertension) and decrease in blood pressure (hypotension) are harmful in the body.
The mechanism of regulation of BP is divided in to two groups.
1) Rapidly acting mechanism
2) Slow acting mechanism

RAPID ACTING MECHANISM

Nervous Regulation of BP
The smooth muscles of blood vessels will always remain in a state of contraction. Because of this
the blood vessels remain in state of constriction-vasoconstriction. The degree of vasoconstriction
depends on the sympathetic tone . When sympathetic tone increase the degree of vasoconstriction
will also increase. When vasoconstriction increases total peripheral resistance increases which
will in turn increases BP. Suppose the BP increases that will be detected by baroreceptors situated
at the aortic arch and carotid sinus. These baroreceptors send impulses to medulla oblongata . In
the medulla oblongata there is a group of nervous concerned with control of BP. It is known as
vasomotor centre. There are two different area, pressor area and Depressor area. These impulses
coming from baroreceptors will inhibit the pressor area; this will decrease the sympathetic tone.
This will increase vasodilatation. TPR decreases so BP decreases to normal level. This
mechanism operated very fast. It corrects BP within few seconds.

Baroreceptors and the sympathetic nervous system

Baroreflexes involving the sympathetic nervous system are responsible for the rapid moment to
moment regulation of blood pressure. A fall in blood pressure causes pressure-sensitive neurons
(baro-receptors in the aortic arch and carotid sinuses) to send fewer impulses to cardiovascular
centers in the spinal cord.
This prompts a reflex response of increased sympathetic and decreased parasympathetic output to
the heart and vasculature, resulting in vasoconstriction and increased cardiac output. These
changes result in a compensatory rise in blood pressure.

LONG TERM REGULATION

Endocrine or Hormonal Regulation of BP
There are three important hormones taking part in regulation of BP.
1) Renin- Angiotensin- Aldosterone mechanism or system.
2) Regulation of BP by Vasopressin or ADH.
3) Adrenalin (Epinephrine) and noradrenalin (nor epinephrine).

1) Renin- Angiotensin- Aldosterone mechanism or system

Suppose BP falls, it will stimulate the kidney. The juxta glomerular apparatus of the kidney will
secrete renin. Renin acts as an enzyme. It acts on a plasma protein, angiotensin substrate and
converts in to angiotensin I. The angiotensin I is converted in to angiotensin II by the action of
converting enzyme. Angiotensin II is a vasoconstrictor in action. It acts on the walls of blood
vessels and increases the degree of vasoconstriction. TPR will increase; this will in turn increase
the BP to normal. In addition to that angiotensin II stimulates adrenal cortex. This will increase
the secretion of the hormone aldosterone. Aldosterone acts on kidneys. It increases the
reabsorption of sodium and water. This will increase blood volume. When blood volume
increases that will in turn increase BP

2) Regulation of BP by Vasopressin or ADH

Suppose BP falls, that will stimuli hypothalamus. Hypothalamus in turn stimulate posterior
pituitary. Posterior pituitary secrete vasopressin. It acts on the wall of blood vessels. It increases
vasoconstriction. TPR increases and BP will increases to the normal level. In addition to this,
ADH acts at the kidneys. It increases the reabsorption of water. That will increase blood volume,
so BP increases to the normal level.

3) Adrenaline (Epinephrine) and noradrenaline (nor epinephrine)

Suppose BP falls that will stimulate hypothalamus. Hypothalamus in turn stimulates sympathetic
nervous system. This will in turn stimulate adrenal medulla. It secretes more adrenaline.
Adrenaline acts at the wall of the blood vessels. It increases vasoconstriction. This will increase
TPR, this will in turn increase BP

Sodium regulation
The contribution of sodium to the development of primary hypertension is related to
excess sodium intake &/or abnormal sodium excretion by the kidneys. It is generally
accepted that dietary salt is associated with increase in blood pressure that can be
lowered with reduction of sodium intake. The threshold level of sodium appears to be
1.2 to 2.4 grams per day (equivalent to 3 to 6 grams sodium chloride).
About 50% of the hypertensive patients are classified as sodium-sensitive. Proposed
mechanism behind salt sensitivity includes a defect in renal sodium excretion &
increased rate of sodium reabsorption.
In addition, abnormal sodium retention may be primary event in the development of
hypertension, & it includes congenital reduction in the number of nephrons or enhanced
renin secretion from the nephrons that are ischemic.
Other theories involve abnormalities in pressure-natriuresis mechanism. Atrial
natriuretic hormone is potentially increased to facilitate sodium & water excretion in
response to an increase in renal sodium retention & extracellular fluid volume.
Natriuretic hormone might also cause an increase in intracellular sodium & calcium,
resulting in increased vascular tone & hypertension.

Role of calcium
There is an inverse relationship between calcium & blood pressure. One proposed
mechanism for this relationship involves alteration in the balance between intracellular
& extracellular calcium. Increased intracellular calcium concentrations can increase
peripheral vascular resistance, resulting in increased blood pressure.

Role of Potassium
A decrease in potassium has been associated with an increase in peripheral vascular
resistance.
Diuretics-induced hypokalemia could counteract some of hypotensive effect of diuretic
therapy.

Role of Nitric Oxide

Nitric oxide (NO) is produced in the endothelium & is potent vasodilatory chemical that
relaxes vascular epithelium. Some patients with hypertension have an intrinsic
deficiency in NO release & inadequate vasodilation, which contributes to hypertension.

Causes:
1. Essential Hypertension

2. Renal
Acute nephritis, Interstitial nephritis and pyelonephritis, Polycystic kidneys Renal artery stenosis

2. Vascular:
Arteriosclerosis, coaractation of aorta.

3. Endocrine:
Pheochromocytoma, Cushing’s syndrome, thyrotoxicosis, myxedema.

4. Neurological:
Raised intracranial tension, lead encephalopathy, etc

5. Miscellaneous:
Polycythemia, aortic incompetence, toxemia of pregnancy, periarteris nodosa, gout, etc.

EFFECT OF HYPERTENSION
 The common organ damage by long standing hypertension are heart, blood vessels, retina and
central nervous system. The common organ damage by long standing hypertension are heart,
blood vessels, retina and central nervous system.
1. CVS: Increased myocardial work leads to concentric hypertrophy of left ventricle, angina
pectoris and accelerated coronary artery diseases. There is systolic as well as diastolic
dysfunction.
2. Kidneys: Progressive arteriosclerosis involves both the efferent and afferent renal arteriols and
capillaries of glomerular truft. This leads to compromise in renal function, shrinkage of kidneys,
proteinuria.
3. CNS: Hypertension may cause micro aneurysms, which may rupture and cause cerebral
hemorrhage. Accelerated atherosclerosis may cause cerebral thrombosis, embolism and infection.
Cerebral arteriolar spasm may cause hypertensive encephalopathy.
4. Fundus: The following changes may occur:
• Grade I: Arteriolar narrowing leading to copper wire and silver wire appearance.
• Grade II: Arteriovenous nipping where arteries cross the vein.
• Grade III: In addition to Grade II changes, superficial flame shaped and deep dot like
hemorrhages and cotton wool exudates.
• Grade IV: Grade III change with papilledema.

CLINICAL FINDINGS:
Symptoms:
The clinical features may be due to the elevated BP itself, target organ involvement or due to
underlying diseases, as in secondary hypertension. Symptoms due to hypertension:
1. Head ache: This occurs usually in morning hours. It is throbbing and usually frontal.
2. Dizziness: The patients feel unsteadly.
3. Epistaxis: This occurs due to increased pressure, causing repture of the capillaries of the nose.
The bleeding reduces circulating volume, and lowers the BP
Symptoms due to affection of organs:
1. CVS:
a) Dyspnea on exertion (insipient LVF)
b) Anginal chest pain (IHD)
c) Palpitation
2. Kidneys: Hematuria, nocturia, polyuria
3. CNS:
 a) Transient ischemic attacks (TIA or strocke) with focal neurological deficit.
b) Hypertensive encephalopathy (head ache, vomiting, convulsion, unconciousness, focal
neurological deficit).
c) Dizziness, tinnitus and syncope.
4. Retina: Blurred vision or sudden blindness.

Symptoms due to underlying disease:

1. Edema and puffy face- Acute nephritis.
2. Weight gain, hirsutism and stira- Cushing’s syndrome.
3. Weight loss, tremors, palpitation and sweating.
4. Hyperthyroidism/ pheochromocytoma.
5. Weakness- hyperaldosteronism.
6. Joint pain, bronchospasm and peripheral vascular disease.
7. Symptoms- polyarteritis nodosa.

LABORATORY FINDINGS:
Blood Tests
Diagnosis of hypertension includes performing a complete evaluation that includes a medical
history and physical examination and a series of blood pressure readings. Blood tests may be
needed to determine if you have secondary hypertension due to a serious or treatable health
condition. Blood tests that may be ordered to assist in the diagnosis of hypertension include:

 Electrolyte levels
 Blood glucose
 Thyroid function tests
 Kidney function tests: blood urea nitrogen (BUN) and creatinine levels

Urine Tests
Urine tests can help determine if diabetes, kidney failure, or illegal drugs are causing or
contributing to high blood pressure.
Imaging and Other Tests
Blood pressure is very closely tied to heart and kidney function, and imaging tests can assist in
the diagnosis of hypertension and its associated causes and complications.

Electrocardiogram (EKG)
An EKG is a fairly simple and rapid test that assesses your heart rhythm. Heart rhythm
abnormalities can cause high blood pressure. Likewise, hypertension can produce long-term
changes that result in heart rhythm abnormalities.

Echocardiogram
Your heart function can be examined using an imaging test that visualizes your heart as it moves.
Excessively high blood pressure may produce changes that can be identified using
echocardiography, and some heart function abnormalities can produce high blood pressure.

Ultrasound
A test that is useful for evaluating the kidneys and the blood vessels, an ultrasound may be needed
if your doctor is concerned about certain aspects of your blood flow. For example, if your
doctor believes that you may have excessive narrowing in one or more of your blood vessels, this
can be evaluated using an ultrasound.

CAT Scan or MRI

If your doctor suspects a tumor as the cause of your high blood pressure, you may need to have an
imaging test, such as CAT scan or MRI, usually to evaluate the kidneys or adrenal glands.

Home Blood Pressure Monitoring (HBPM)

You can measure your own blood pressure at home, a process referred to as home blood pressure
monitoring (HBPM). HBPM has become much easier and more accurate in recent years, and it is
now a viable option for diagnosing hypertension and helping manage it once identified.This is
particularly help HBPM uses easy-to-use, electronic blood pressure devices and are readily
available.

Ambulatory Blood Pressure Monitoring (ABPM)

An ABPM device consists of a blood pressure cuff that is worn on the arm and attached to a
recording device, which can be worn on a belt.
Remember, hypertension is most accurately determined by average blood pressure during an
entire day. ABPM takes and logs blood pressure at 15-minute or 30-minute intervals over a 24-or
48-hour period. This means that the blood pressure fluctuations that normally occur in a day can
be accounted for as your doctor assesses your recorded average.At the same time, if you have
fluctuating hypertension, your doctor would be able to pick that up using ABPM because the
measures span a longer time period than measures in the office. The diagnosis of hypertension
with ABPM has been well-validated and is more accurate for diagnosing stage 1 hypertension
than a single visit to the doctor’s office.

HYPERTENSION MANAGEMENT
Treatment of hypertension includes two types of approaches that are
• Non-pharmacological approaches
• Pharmacological treatment
Non-pharmacological management of hypertension
 In the initial phase of hypertension (high, normal or mild hypertension), the non-
pharmacological measures can lower the BP in most of individuals. In some patients, who do not
show any reduction even after 04-06 months need drug therapy. It is harmless treatment and
helpful either to eliminate the requirement of drug or reduce the dose as well as dose regimen.
Non pharmacological approaches to the reduction of blood pressure generally are advisable as the
initial approach to treatment of patients with diastolic blood pressure in the range of 90 to 95
mmHg. Further, these approaches will augment the effectiveness of pharmacological therapy in
patients with higher level blood pressure. Non pharmacological methods to lower blood pressure
allow the patient to participate actively in the management of his or her disease. Reduction of
weight, restriction of salt, and moderation in the use of alcohol may be reduced blood pressure
and improve the effect of drug treatment. In addition, regular isotonic exercise also lowers blood
pressure in hypertensive patients.
Life style modifications include:

 Weight reduction
 Dietary sodium intake
 Intake of calories
 Alcohol intake
 Aerobic exercise
 Smoking
Weight reduction:
Weight loss as small as 5% to 10% in overweight individuals may significantly lower
CV risk. For most patients an average weight loss of 10kg can reduce SBP by 5-
20mmHG, a reduction which is comparable to that achieved from the addition of an
antihypertensive drug used as monotherapy.
DASH eating plan:
The DASH (Dietary Approaches to Stop Hypertension) diet is rich in fruits, vegetables
and low fat dairy foods, coupled with reduced saturated and total fat. The DASH diet
can substantially reduce BP 8-14mmHG in SBP for most patients.
Dietary sodium intake:
Subject should reduce their salt intake for example, by not adding salt to food on the
plate. A daily sodium intake of <100mmol (i.e. 6g sodium chloride or 2.4g elemental
sodium) should be the aim.
Intake of calories:
Most subjects will need to control their intake of calories and saturated fat.
Alcohol intake:
 Alcohol intake should be restricted to two (females) or three (males) units per day.
Excessive alcohol intake can elevate BP, decreases the effectiveness of
antihypertensive medication and increases the risk of stroke. Reduction in alcohol
intake can cause decrease in SBP approximately 2-4mmHG.
Aerobic Exercise:
Regular aerobic exercise, at a level appropriate to the individual subject, at least 3 times
a week for at least 30 min derives maximum benefit. This result in improved physical
fitness as well as reduction in blood pressure.
Smoking:
Although smoking does not affect blood pressure, it increases cardiovascular risk and patient
should quit or if not possible reduce their cigarette consumption

PHARMACOTHERAPY
Numerous clinical trials have demonstrated that antihypertensive pharmacotherapy reduces
the risk of hypertension associated complications e.g. CV (morbidity and mortality).

CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS

1. FIRST-LINE AGENTS

i. Angiotensin - Converting Enzyme Inhibitors

ii. Angiotensin Receptor Blockers
iii. Calcium Channel Blockers
iv. Thiazide Diuretics

2. SECOND-LINE AGENTS
i. Beta Blockers
ii. Aldosterone Antagonists
iii. Other Agents

FIRST-LINE AGENTS
i. Angiotensin-Converting Enzyme Inhibitors
The ACEIS directly inhibit ACE, blocking the conversion of angiotensin I to angiotensin II.
This action reduces angiotensin-II mediated vasoconstriction and aldosterone secretion, and
ultimately lowers BP. Inhibiting ACE also prevents breakdown and inactivation of
bradykinin, which may lead to additive vasodilation by enhancing NO. However, bradykinin
accumulation can also cause a non productive cough in some patients, which is the most
frequent, yet harmless, side effect of ACEI therapy.

ii. Angiotensin Receptor Blockers

The ARBs modulates the RAAS by directly blocking the angiotensin II type 1 receptor site,
preventing angiotensin II mediated vasoconstriction and aldosterone release. Overall ARBs
 are he well tolerated of the first line agents. They do not affect bradykinin and are therefore
associated with less incidence of cough.

iii. Calcium Channel Blockers

The CCBs are pharmacologically complex. They reduce calcium entry into smooth muscles,
which causes coronary and peripheral vasodilation and lowers BP. All decrease cardiac
contractility (except amlodipine and felodipine). Dihydropyridine CCBs are primarily
vasodilators that can cause a reflex tachycardia. This is in contrast to the nonhydropyridine
CCBs (verapamil and diltiazem) that directly block the atrioventricular (AV) node, decrease
heart rate, and decrease cardiac contraction, yet still have vasodilatory effects.

iv. Thiazide Diuretics

Diuretics, particularly thiazide and thiazidelike diuretics induce natriuresis. Thiazide
diuretics are generally well tolerated, and most can be given once daily. They are especially
effective in lowering BP in elderly and black patients. Dose related electrolyte and
metabolic alterations (e.g. hypokalemia, hyperuricemia, hyperglycemia, and
hypercholesterolemia) can occur with thiazide diuretics. These effects were particularly
problematic when high doses were used many years ago (e.g. hydrochlorothiazide [HCTZ]
100-200 mg /day), but are drastically minimized by using lower doses that care now
considered the standard of care (e.g. HCTZ 12.5-25 mg/day). Thiazide diuretics can be used
in combination with a potassium sparing diuretic (i.e. triamterene and amiloride) to
minimize potassium potential depletion. Other chemical changes in glucose and cholesterol
are minimal and mostly transient with low-dose therapy.

SECOND LINE AGENTS

i. Beta Blockers
Beta blockers have several direct effects in the CV system. They can decrease cardiac
contractility and CO, lower heart rate, blunt sympathetic reflex with exercise, reduce central
release of adrenergic substances, inhibit nor epinephrine release peripherally, and decrease
renin release from the kidney. All these contribute to their antihypertensive effects. These
agents are considered first line for the treatment if most patients with hypertension. In
primary prevention patients, beta blockers should be used as add-on-therapy in combination
with first line agents (ACEI, ARB, CCB or thiazide diuretics). However, in patients with the
compelling indications of CAD or left ventricular dysfunction, they should remain a first-line
therapy.

ii. Aldosterone Antagonists

Spironolactone and eplerenone are aldosterone antagonists. Potent blockade of aldosterone
receptor inhibits sodium and water retention and inhibits vasoconstriction. These agents are
also considered potassium sparing diuretics.

iii. Other Agents

Loop diuretics (e.g. furosemide, torsemide) can be used in some patients for hypertension.
When dosed appropriately, they can provide BP reductions similar to those seem with a
thiazide diuretic. Because they are short-acting and subject to significant post-dose
 antinatriureticeffect, they should generally be reserved for patients with heart failure or
severe CKKD in whom their diuretic action remains prolonged.

Aliskiren is the only direct renin inhibitor. Similar to an ACEI, ARB, this agent is a RAAS
blocker. It is approved for treatment of hypertension.

Alpha blockers (e.g. doxazosin, prazosin, terazosin) attach to peripheral α1-receptors,

inhibiting the uptake of catecholamines in smooth muscle, and cause vasodilation. It is
effective in lowering BP.

Direct vasodilators (e.g. hydralazine, minoxidil) work on the arterial vasculature. They
should be reserved for patients with specific conditions (e.g. severe CKD) or those with very
difficult to control BP. Concomitant drug therapy with both a diuretic and an agent that
lowers heart rate (a beta blocker, diltiazem, or verapamil) is usually needed to mitigate the
associated fluid retention and reflex tachycardia that frequently occur.

Central α2- agonists (e.g. clonidine, methyldopa) work in the vasomotor centers of the
brain where they stimulate inhibitory neurons and decrease sympathetic outflow from the
CNS. The resultant decrease in PVR and CO lowers BP.
Adrenergic antagonists (e.g. reserpine, guanadrel, and guanethidine) are not frequently
used to treat hypertension. Reserpine depletes catecholamines from storage granules to
decrease BP.

CONTRAINDICA-
CLASS EXAMPLES/ DOSE ADVERSE EFFECTS COMMENTS
TIONS
Bendroflumethiazide Hypokalaemia Potassium sparing Cheap, effective. Efficacy
Diuretics (1.25- 10 mg) Gout diuretics: proven in clinical trials
Furosemide Glucose intolerance Hyperkalaemia Concerns about long-term
(40 – 80 mg) Hyperlipidemia Metabolic acidosis metabolic effects
Spironolactone Impotence Gynaecomastia More appropriate in older
(50- 400 mg) Uraemia Patients
Dehydration Especially for patients with
Hyperkalaemia cardiac failure
Gynaecomastia Especially for resistant
hypertension
Atenolol Bradycardia Obstructive lung disease Cheap
β-Blockers (25 – 100 mg) Fatigue Peripheral vascular Adverse effects common
Propanolol Hypotension disease (PVD) Possibly less effective in
(40 – 640 mg) Decrease libido preventing cardiovascular
Metroprolol Impotence events
(50 – 400 mg) Bronchoconstriction Especially for patients with
Celiprolol ischaemic heart disease
(200- 400 mg)

Nifedipine Palpitations Congestive heart failure Not well tolerated

Calcium ( 10 – 90 mg) Swollen ankles (especially early in
antagonists: Amlodipine Constipation treatment).
Dihydropyridine (2.5- 10 mg) Headache Recent trials confirm
 Dizziness reductions in stroke and
myocardial infarction
Similar efficacy to
thiazides
Especially for elderly
patients and those with
ischaemic
heart disease or diabetes
Verapamil Swollen ankles Congestive heart failure Well tolerated. Suitable for
Calcium (120 – 480 mg) Constipation patients with ischaemic
antagonists: Diltiazem Headache heart disease who are
rate limiting (120 - 540 mg) Dizziness unable
to tolerate
β-blockers
Caution needed when used
in combination with
β-blockers
Captopril Dry cough Bad asthma More expensive. Cough
ACE Inhibitors (12.5 – 50 mg) Rash Pregnancy very
Enalapril Nausea Kidney disease (renal common
(5 – 40 mg) Vomiting’ stenosis) Appropriate for use in
Lisinopril Angioedema younger patients and those
(2.5 – 10 mg) with cardiac failure
Perindopril /diabetes
(4 – 8 mg)

Prazosin Edema Hypersensitivity More expensive. Adverse

α-Blockers ( 0.5 – 20 mg) Postural hypotension Heart failure effects common. No
Doxazosin Dizziness Angina evidence to date of long-
( 1 - 4 mg) Fast heart rate term efficacy. Less
effective than thiazides at
Terazosin preventing heart failure
(1 - 20 mg) and combined
cardiovascular outcomes
Second line
Losartan Headache Pregnancy More expensive
Angiotensin ( 25 – 100 mg) Nausea Renal stenosis Especially for patients in
receptor Valsartan Diarrhea Hypersensitivity whom ACE inhibitor
blockers (80 – 320 mg) Dizziness indicated but not tolerated
Irbesartan Back pain due to cough
(75 – 300 mg) More effective in
preventing
vascular events than
atenolol in patients with
LVH
Methyldopa Tiredness Renal dysfunction Poorly tolerated. Only used
Centrally acting (250 mg) Depression in severe hypertension
Vasodilators Moxonidine Impotence or hypertension of
(400 mg) pregnancy
Third line
 Diazoxide Edema Renal dysfunction Poorly tolerated. Only used
Direct-acting (10 – 25 mg) Postural hypotension in severe hypertension
Vasodilators Minoxidil Headache
(10 – 25 mg)
Nitroprusside
(50 mg)

PHARMACOTHERAPY FOR PATIENTS WITH COMPELLING

INDCATIONS
Compelling indications for specific therapy involves high – risk conditions that can be direct
sequelae of hypertension ( HF, IHD, Chronic kidney disease, Recurrent strokes).

Recommended Drugs
Compelling Beta – ACE Aldosterone
Diuretic ARB CCB
Indications Blockers Inhibitors Antagonist
Heart failure     
Postmyocardial
  
infarction
High coronary
  
disease risk
Diabetes
   
Chronic kidney
 
Disease
Recurrent stroke
 
Prevention

CASE STUDY
CASE I
Mr. A.R. is a 71-year-old man with a BP of 168/90mmHg (170/90mmHg when repeated) and
a heart rate of 88 beats per min. He has a history of chronic stable angina that is treated with
sublingual nitroglycerine as needed for ischemic symptoms. He also has severe chronic
obstructive pulmonary disease(COPD) that is worsened with beta-blocker therapy. He
currently have no ischemic symptoms. All laboratory results are normal, except his serum
creatinine is 1.3mg/dl. Which anti-hypertensive should be administered? Is a CCB
appropriate for A.R.? If yes, which type is preferred?
Chronic stable angina or chronic Coronary artery disease(CAD) is a compelling indication for use
of calcium channel blockers(CCB), but CCB are an alternative to beta-blocker, or sequential add-
on therapy to beta-blocker for patients who require additional anti-ischemic effects. Alternatives to
beta-blockers are needed when contraindications or intolerances to beta-blockers are present.
Sustained-released CCB formulations or long-acting products(i.e; amlodipine) are always
preferred when used as an alternative to beta-blockers, a non-dihydropyridine CCB is preferred
because they decrease myocardial oxygen demand, improve myocardial blood flow and have
negative ionotropic and chronotropic effects. All these may benefit patients with CAD.
Dihydropyridines CCB are similar but don’t lower heart rate and have less negative ionotropic
effects. They can be used in patients with chronic CAD and possibly acute CAD, but verapamil
and diltiazem are preferred when a CCB is used instead of beta-blockers.
Therapy with CCB is preffered in A.R. because beta-blockers worsened his severe COPD.
Verapamil will lower his elevated heart rate and BP as well as reduce episodes of ischemic
symptoms(i.e; chest pain). Constipation, which is more prevalent in elderly, is a common side
effect of verapamil. This can be mitigated with dietary changes, bulk forming laxatives or regular
use of stool softener.

CASE II
A 58-year-old male patient is noted to have high blood pressure by his primary care doctor.
There is no evidence of end-organ damage and he has no other cardiovascular risk factors.
The blood pressure remains greater than 160/100 mmHg each time it is checked in the
surgery over several weeks, in spite of salt and alcohol reduction. The patient buys a wrist
blood pressure monitor in a pharmacy and takes several readings at home. These are all
below 130/75mmHg. What advice should he be given about the need for drug treatment?
He may have ‘white coat’ hypertension. Since this is associated with lower risks than sustained
hypertension, he may not need drug treatment however, before making this judgment it is
important to check that his machine is accurate. This can be done by comparing readings with
validated machine.
CASE III
Mr PT, a 35-year-old man, is overweight and has a blood pressure of 178/114 mmHg. He
smokes 25 cigarettes daily and drinks 28 units of alcohol per week. He has a sedentary
occupation. He eats excessive quantities of saturated fat and salt. How should this patient be
managed? What pharmacological treatment for blood pressure would be appropriate if
non-pharmacological treatment was unsuccessful? Mr PT subsequently stopped smoking
and lost some weight but remained hypertensive. He was treated with atenolol 50mg daily.
His blood pressure fell to 136/84mmHg but he developed tiredness and bradycardia and
complained of erectile impotence. What are the treatment options for Mr PT?
Since he is a young man, his absolute risk of cardiovascular events is low, at least for the time
being. However, he has several additional risk factors that need to be addressed, including his
sedentary lifestyle and his smoking. Non-pharmacological methods have the potential of reducing
his blood pressure considerably, including reduction in weight and salt intake. Measurement of
plasma cholesterol may help him modify his diet, although he is unlikely to qualify for lipid-
lowering therapy in view of his young age.
If drug treatment was appropriate, initial treatment with an ACE inhibitor would be consistent
with current guidance, in view of his age. This is likely to be more effective for blood pressure
lowering than a calcium channel blocker or diuretic. β-Blockers have been recommended as an
option in younger patients but are now considered less suitable as initial therapy. Other drugs
could be added or substituted if he was intolerant to initial therapy or it did not reduce his blood
pressure to target levels.
It is possible that he would feel less tired using a β-blocker with intrinsic sympathomimetic
activity (e.g. pindolol) but this is by no means guaranteed. The effects on his sexual function are
unpredictable. It would probably be better to change him to a drug of a different class such as an
ACE inhibitor. A calcium channel blocker or thiazide diuretic (although these also commonly
cause impotence) may be added if necessary.

CASE IV
A 23-year-old woman has a normal blood pressure (118/82mmHg) when reviewed at 8
weeks of pregnancy. In the 24th week of pregnancy, she is reviewed by her midwife and
found to have a blood pressure of 148/96mmHg. Urinalysis is normal. What is the likely
diagnosis? What complications does the patient's high blood pressure place her at increased
risk of? Should she receive drug treatment? If so, with which drug? If not, how should she
be managed?
She may have gestation-induced hypertension or chronic hypertension that had previously been
masked by the fall in blood pressure that happens in early pregnancy.
She is at increased risk of pre-eclampsia.
There are differences of opinion between specialists as to whether blood pressure should be
treated at this level during pregnancy. In favour of treatment is the substantial rise over the earlier
blood pressure recording. Some specialists would not treat unless the blood pressure was >170/110
mmHg or other complications were present. If she were treated, methyldopa would be a suitable
choice. In any event, she needs close monitoring of her blood pressure, urinalysis and fetal growth.
CASE V
E.K. is a 78-year-old black man with a history of hypertension. He was hospitalized for an
acute MI 2 months ago and has been treated with metoprolol succinate 50 mg daily and
lisinopril 20 mg daily since then. Today his BP readings are 148/92 and 146/90 mm Hg, and
his heart rate is 80 beats/minute. He denies medication-related side effects. Because E.K. is
black and elderly, will β-blocker therapy be effective?

β-Blockers reduce morbidity and mortality in patients with certain compelling indications. These
include left ventricular dysfunction, CAD, and diabetes. β-Blocker therapy should not be the
primary antihypertensive agent for primary prevention patients, but is an effective alternative add-
on agent for primary prevention patients to lower BP. Elderly and black patients may have less BP
reduction than young or white patients. E.K. is elderly and might have more BP reduction with
another agent (i.e., thiazide diuretic or CCB), but these points are moot in E.K. Age and race
should also be considered while use of a β-blocker when a compelling indication is present.
Because of E.K.’s previous MI, a β-blocker as first-line is compellingly indicated.
β1-Adrenergic receptors are primarily located in the heart, and β2-adrenergic receptors are found
in the lungs, kidneys, and peripheral arteriolar endothelium. Low-affinity β1-receptors are also
present in the lung, and low-affinity β2-receptors are present in the heart. Someβ-blockers (e.g.,
atenolol, metoprolol) demonstrate relative cardioselectivity with greater antagonism of cardiac β1-
receptors and less activity on β2-receptors in the lung or bronchial tissue. Selectivity is not
absolute, however, because it is dose-dependent. For instance, asthma has been precipitated even
with cardioselective agents when they are used in higher doses, but not with low to moderate
doses. Nonselective β-blockers potentially have the disadvantage of blunting the symptoms of
hypoglycemia in patients with diabetes. β2-Blockade from nonselective β-blockers
(e.g.,propranolol) can lead to unopposed β1-induced peripheral
vasoconstriction(this may worsen hypertension). Despite these shortcomings, nonselective β-
blockers are preferred in patients with non-CV indications for β-blocker therapy (e.g.,migraine).
Absent these reasons, cardioselective β-blockers are preferred. E.K. is taking metoprolol, which is
a cardioselective agent and is appropriate therapy for E.K.

CASE VI

R.R. is a 52 year-old man with hypertension for 10 years. He has not yet experienced any
hypertension associated complications or target-organ damage. He does not have a history of
diabetes, and does not smoke. He has been treated with HCTZ 25 mg daily, amlodipine 10
mg daily, valsartan 320 mg daily, and carvedilol 12.5 mg twice daily for 1 year . He reports
rarely missing a dose of his medications, measures his BP at home everyday , and follows
recommended lifestyle modifications as diligently as possible. He has tried other medications
that resulted in intolerances (Ramipril , angioedema; doxazosin, dizziness; clonidine, dry
mouth). His BP has never been less than 140/90 mm Hg, which is his goal. All secondary
causes of hypertension have been ruled out. His BP today is 150/90 mm Hg (152/92 mm Hg
when repeated), his heart rate is 60beats/minute ,serum potassium is 4.2 mEq/L, and serum
creatinine is 1.0 mg/dL. Does R.R. have resistant hypertension? What are his treatment
options?

R.R. has resistant hypertension. Resistant hypertension is defined as a failure to attain BP goal
despite treatment with a three-drug regimen that uses full antihypertensive doses (one of
which is a diuretic), or any patient requiring four or more antihypertensive agents regardless of
BP goal attainment. R.R.’s treatment options are limited. Amlodipine and valsartan are both
at the maximal doses. Carvedilol could be increased to 25 mg twice daily, but this should not be
done because his heart rate is 60 beats/minute and increasing this dose would place him at
risk for bradycardia. It is possible to increase HCTZ to 50 mg daily because this higher dose
provides larger BP reductions than 12.5 or 25 mg daily based on 24-hour ABPM(ambulatory
blood pressure measurement). The limitation of this approach is an increased risk of electrolyte
abnormalities and metabolic side effects. For resistant hypertension, three global treatment
philosophies should be considered: (a) assuring appropriate diuretic therapy, (b) appropriate use
of effective drug combination, and (c) use of alternative antihypertensive agents
as appropriate. Options to assure appropriate diuretic therapy include switching diuretic agents,
switching diuretic classes, increasing the dose, or adding a different class of diuretic. Instead of
increasing HCTZ to 50 mg daily, switching HCTZ to the more long-acting chlorthalidone is
another possible option to enhance BP lowering. This is an option in R.R. Another option is
switching HCTZ to a loop diuretic (e.g., furosemide or torsemide).This should be considered for
patients with stage 4 or 5 CKD(chronic kidney disease) or for those who need diuresis because of
edema. This is not a reasonable treatment option for R.R. because he does not have CKD.
Another option is to add an aldosterone antagonist, which is considered an alternative anti
hypertensive agent.

Spironolactone and eplerenone are aldosterone antagonists that are especially useful as an add-on
therapy in patients with resistant hypertension and would be a reasonable addition to R.R.’s
regimen. Many patients with resistant hypertension have increased activation of the RAAS (Renin
angiotensin aldosterone system), which can result in increased aldosterone. Moreover, up to 20%
of patients with resistant hypertension have primary aldosteronism. These characteristics of
patients with resistant hypertension make the addition of an aldosterone antagonist very effective
in lowering BP in resistant hypertension. R.R.’s potassium is in the normal range, but could
increase after adding spironolactone. Therefore, it should be monitored 2 to 4 weeks after therapy
is started to assure R.R.
does not experience hyperkalemia. Eplerenone is more specific than spironolactone in aldosterone
blockade, although some data suggest that spironolactone is more effective in primary
aldosteronism. Compared with spironolactone, gynecomastia is less frequent with eplerenone. The
incidence of hyperkalemia may be greater with eplerenone, however. When used for hypertension
eplerenone is contraindicated in populations at higher risk for hyperkalemia.

In addition to nonadherence with drug therapy, lifestyle factors (obesity, sodium ingestion, heavy
alcohol intake) are a significant contributor to resistant hypertension. Lifestyle modifications
should continually be reinforced in patients, especially those with resistant hypertension. These
modifications should include dietary changes and physical activity. R.R should be instructed to
restrict his daily sodium to less than 1.5 g because this has been shown to decrease SBP (systolic
blood pressure) by more than 20 mm Hg in resistant hypertension.

CASE VII

A 24 years old women with a family history of hypertension is prescribed an oral contra
ceptive, six month after taking this, she is noted to have a blood pressure of 148/96
mmHg.How should this patient be managed?
Oral contraceptives produce change in renin angiotensin aldosterone system. Particularly increase
in plasma renin substrate concentration which may associated with increase in plasma renin
activity and aldosterone excretion.so combination of contra captive that is estrogen and
progesterone should be avoided. Only progesterone should be taken. Women should adopt
another methods for birth control. IUD, the birth control injection, the implant.
 If her blood pressure remain elevated after discontinue her oral contraception, she is likely to
have under line hypertension. This may be essential in nature in view of family history. She is at
low risk of complication and there is no urgency to consider drug treatment.
If there is strong wish to use combined oral contraception, it would be important to control risk
factor as far as possible and to use drug treatment for her hypertension that is the use of ACE
inhibitors(angiotensin converting enzyme) e.g. benazepril,captopril,enalapril.

CASE VIII
A 73-year-old lady has a long-standing history of hypertension and intolerance to
antihypertensive drugs. Bendroflumethiazide was associated with acute attacks of gout, she
developed breathlessness and wheezing while taking atenolol, nifedipine caused flushing and
headache, and doxazosin was associated with intolerable postural hypertension. Four weeks
earlier she had been started on enalapril but was now complaining of a day persistent
cough. Her blood chemistry has remained normal.Is the patient’s cough likely to be an
adverse effect of enalapril?What other options are available for controlling her blood
pressure
Yes it is. A dry cough is common adverse effect of ACE inhibitors. It affects approximately 10-
20% of recipients and is more common in women. Some patients are able to tolerate the
symptoms but in many the drug has to be discontinued.
Angiotensin receptor blockers can be used in patients intolerant of ACE inhibitors due to cough.
They are unlikely to produce this symptom since they do not inhibit the metabolism of pulmonary
bradykinin. Centrally acting agents such as methyldopa or moxonidine could also be considered.
However, these are not well tolerated and side effects are quite likely in this patient. A non-
dihydropyridine calcium channel blocker such as verapamil is another alternative. Measurement
of plasma uric acid could also be considered followed by prophylactic treatment with allopurinol
before introducing a diuretic. Alternatively, a trial of spironolactone or the renin antagonist
aliskiren could be considered.