HIGH-BLOOD PRESSURE

Hypertension is diagnosed when the blood pressure exceeds 140/90mm Hg (Hg-

mercury) in young and middle-age adults irrespective of sex. Blood pressure is a
product of cardiac output and total peripheral resistance.

Blood Pressure (BP) = CO x TRP

CO = Cardiac Output.

TPR = Total Peripheral Resistance

Drugs used in the treatment of hypertension are called anti-hypertensives. Anti-

hypertensives are classified by their site or mechanism of action viz.

DIURETICS

1. Diuretics
a. Thiazide like diuretics –eg. Indapamide, Chlorthalidone, etc
b. Loop diuretics – eg Bumetanide, Ethacrynic acid, Furosemide, Torsemide.
c. Potassium - sparing diuretic eg. Amiloride, Triamterene, Spironolactone.
2. Sympatholytic Drugs
a. Centrally acting – Methyldopa, Clonidine, Guanabenz, Guanfacine.
b. Adrenergic neuron blocking drugs – Reserpine, Bretylium, Guanadrel,
Guanethidine, Debrisoquin, Bethanidine.
c. Beta-Adrenergic antagonist – Propranolol, Metoprolol etc
d. Alpha-Adrenergic angatonist – Prazosin, Tetrazosin, Doxazosin,
Phenoxybenzamine, Phentolamine.
3. Vasodilators
a. Aterial – Hydralazine, Minoxidil, Diaoxide, Fenoldopam.
b. Aterial and Venous – Nitroprusside
c. Calcium-channel blockers – Verapamil, Felodipine, Diltiazem, Nifedipine,
Amlodipine, Nicardipine etc.
d. Angiotensin Converting Enzyme Inhibitor – (ACE inhibitors), Captopril, Enalapril,
Lisinopril, Ramipril, Quinopril.
e. Angiotensin Receptor Blocker (ARB) – Losartan, Valsartan, Cavidesartan,
Irbesartan, Eprosartan.
4. Non-pharmacological therapy of hypertension

1
 Stop – smoking
 Body weight reduction
 Sodium restriction – table –salt
 Alcohol restriction
 Physical exercise
 Relaxation – rest

Note: Propranonol, Carvedilol, Medroxalol and Bucindolol are non-selective β-

blocker.

 DIURETIC

Diuretics help the kidneys eliminate salt and water from the body’s tissue and
blood.

Loop Diuretics

 Bumethanide
 Ethacrynic acid
 Furosemide
 Torsemide

Thiazides diuretics

 Epitizide
 Hydrochlorothiazide
 Chlorthalidone
 Bendroflumethiazide
 Methylclothiazide
 Polythiazide

Thiazide like Diuretic

 Indapamide
 Chlorthalidone
 Metolazone

Potassium-sparing diuretics

 Amiloride
2
 Triamterene
 Spironolactone

Diuretics – Lower blood pressure by depleting body sodium stores, reduce volume
and cardiac out. However, some diuretics e.g. indapamide has vasodilating effect
as well as diuretic properties. Amiloride inhibit smooth muscle response to
contractile stimuli of volume reduction. Diuretics are effective in the treatment of
mild to moderate essential hypertension. In severe hypertension, diuretics are
needed in combination with sympatholytics and vasodilators.

SYMPATHOLYTICS OR SYMPATHOPELGIC AGENTS: This lower blood

pressure by reducing peripheral vascular resistance, inhibiting cardiac activities
and increasing pooling in capacitance vessels leading to a reduction in cardiac out.
Their adverse effects are orthostatic hypotension, sexual dysfunction, diarrhea and
fluid retention. A combination of the diuretics and vasodilators can overcome these
adverse effects.

2. Alpha-2 adrenergic receptor agonists

Central alpha agonist lowers blood pressure by stimulating alpha-receptors in the

brain which open peripheral arteries easing blood flow. These alpha 2 receptors are
known as autoreceptors which provide a negative feedback in neurotransmission
(in this case, the vasoconstriction effects of adrenaline). For treating hypertension,
these drugs are usually administered in combination with diuretics.

 Clonidine
 Guanbenz
 Guanfacine
 Methyldopa
 Moxonidine

Methyldopa – is a centrally acting antihypertensive. It is a product that exerts its

anti-hypertensive action via an active metabolite. Methyldopa (-methly-3,
4dihyroxyl – 1 – phenylalanine is an analog 3, 4 – dihyroxy phenylalanine
(DOPA), it undergoes decarboxylation in adrenergic neurons to α-methyldopamine
and then to α methyl norepinephrine. α-norepinephrine is stored in the vesicles of
the adrenergic neurons replacing norepinephine. Then on stimulation, the
adrenergic neurons releases α-methyl norepinephrine instead of norepinephrine. α-
3
 methyl norepinephrine is as potent as norepinephrine as a vasoconstrictor vesicles
does not alter vasoconstrictor response to peripheral adrenergic neurotransmission.
Rather, α-methyl norepinephrine acts in the brain to inhibit adrenergic neuronal
outflow from the brain stem, this central effect is responsible for its anti-
hypertensive action. α-methyl norepinephrine acts as an α 2– adrenergic agonist in
the brain stem to reduce or inhibit the output of vasoconstrictor adrenergic signals
to the peripheral sympathetic nervous system.

Adverse Effect – Sedation, impaired mental concentration or depression, vertigo

and in some cases extra-pyramidal signs occur. Also is increased prolactin
secretion resulting in lactation in both males and females on α-methyldopa
(Aldoment). In long term use, patients develops positive coomb’s test. Drying of
the nasal mucosa and rebound hypertension.

3. Calcium Channel blockers or antagonist

Calcium channel blockers block the entry of calcium into muscle cells in artery
walls.

Dihydropyridines:

 Amlodipine
 Cilnidipine
 Clevidipine
 Felodipine
 Isradipine
 Lercadnipine
 Levamlodipine
 Nicardipine
 Nifedipine
 Nimodipine
 Nisoldipine
 Nitrendipine

Non-Dihydropridines:

 Dilitiazem
 Verapamil

4
These are group of drugs used in the treatment of hypertension, heart failure and
cardiac arrhythmia. Their use as anti-hypertensive agent come from the logic that
fixed hypertension is the result of increase peripheral vascular resistance since
contraction of vascular smooth muscle is dependent on intracellular concentration
of calcium ion (Ca2+), inhibition of trans membrane movement of Ca 2+ decreases
the total amount of Ca2+ that reaches intracellular sites. All Ca 2+channel blockers
lower blood pressure by relaxing arteriolar smooth muscle and decreasing
peripheral vascular resistance. As a result of decrease in peripheral vascular
resistance, the Ca2+ channel blockers evoked a baro-receptor mediated sympathetic
discharge. In the case of the dihydropyridines, mild to moderate tachycardia ensues
from the adrenergic stimulation of the sinoatrial node, whereas tachycardia is
minimal with Verapamil and Diltiazem because of their direct negative
chronotropic effect. The increase adrenergic stimulation of the heart counters the
negative inotropic effect of Ca2+ channel blocker such as in Verapamil, Dilatiazem
and Nifedipine, this compensatory support of myocardial contractility is important
regarding the concurrent use of β-adrenergic receptor blocker.

Ca2+ channel blockers should not be used in patient with SA or AV nodal

abnormalities or with congestive heart failure.

Clonidine, Guanabenz, Guanfacine: These drugs stimulate α2-adrenergic

receptors in the brainstem, resulting in reduction in sympathetic outflow from the
CNS. The decrease in plasma concentration of Nor-epinephrine is directly
proportional with the hypotensive effect. The α-adrenergic agonist lowers arterial
pressure by an effect on both cardiac output and peripheral resistance. In the supine
position, when the sympathetic vasculature is low, it reduces both the heart rate
and stroke volume, in the upright position, sympathetic outflow to the vasculature
is increased, these drugs reduces vascular resistance. α-adrenergic agonist are
better used with diuretics for the treatment of hypertension. Clonidine can also be
used in the diagnosis of pheochromocytoma. The lack of suppression of plasma
concentration of nor-epinephrine to less than 500pg/ml 3hours after an oral dose of
0.3mg of clonidine suggest the pressure of pheochromocytoma. Adrenergic
neurone blocking agents lowers BP by preventing release of norepinephrine from
post ganglionic sympathetic neurons.

Reserpine: Is an alkaloid extracted from the root of Rauwolfia serpentine, a

climbing shrub indigenous to India. Reserpine was introduced to western medicine
5
 in the 1950’s. It is the first drug found to interfere with functions of the
sympathetic nervous system in human beings. Reserpine binds tightly to storage
vesicles in central and peripheral adrenergic neurons and remains there for a
prolonged period of time. The storage vesicles are rendered dysfunctional due to
interaction with reserpine and nerve endings lose their ability to concentrate and
store nor-epinephrine and dopamine. Catecholamine leaks out of the vesicles into
the cytoplasm and are destroyed by monoamine oxidase. So no active
neurotransmitter is discharged. Reserpine induces depletion of biogenic amines
correlates with evidence of sympathetic dysfunction and anti-hypertensive effect.

Recover of sympathetic function requires synthesis of new norepinephrine storage

in vesicles, which takes several days after discontinuation of the drug. Since
reserpine depletes amines in the CNS as well as in the peripheral neurons, it is
probable that it anti-hypertensive effect are related to both a central and peripheral
action. Reserpine depletes biogenic amines. i.e. nor-epinephrine, dopamine and
serotonin.

4. ACE inhibits the activity of angiotensin-converting enzyme (ACE), an enzyme

responsible for the conversion of angiotensin I into angiotensin II, a potent
vasoconstrictor.
 Captopril
 Enalapril
 Fosinopril
 Lisinopril
 Moexipril
 Perindopril
 Quinapril
 Trandolapril

Angiotensin converting enzyme inhibitors (ACE inhibitors)

Angiotensin II is an important regulator or cardiovascular function, a reduction in

the level of angiotensin II with angiotensin converting enzyme inhibitor represent
advancement in the treatment of hypertension. Captopril was the first to be
developed, followed by enalapril, lisinopril, quinapril, ramipril, benazepril,
moexipril, fosinopril, trandolapril and preindopril, which are all available for the
treatment of hypertension.
6
 The angiotensin converting enzyme inhibitors slow the development of diabetic
glomerulopathy, glomerulosclerosis in hypertensive patients. Angiotensin
converting enzyme inhibitors are preferred agents in the initial treatment of
hypertensive patient with left ventricular hypertrophy, ischemic heart disease and
myocardial infarction. Angiotensin converting enzyme inhibitor blunt the normal
aldosterone response to Na+ loss, it opposes the role of aldosterone to diuretic
induce natriuresis. ACE inhibitors enhance the efficacy of diuretic drugs. Small
doses of diuretic markly improves the anti-hypertensive efficacy of ACE
inhibitors, so high doses of diuretic with ACE inhibitors together lead to excessive
reduction in blood pressure and Na+ loss.

The effect of ACE inhibitors on aldosterone influences K + homeostasis. In some

patient, it can lead to rise in serum K +. Hyperkalemia may arise when co-
administered with K-sparing diuretics (amiloride, triamterene, spironolactone),
non-steroidal anti-inflammatory drugs, K+supplement and β-blockers.

ACE inhibitors should not be used in pregnancy as it reduces glomerular filtration

rate.

5. Angiotensin II Receptor Antagonist or Blockers (ARB).

Antiogensin II receptor antagonists work by antagonizing the activation of

angiotensin receptors

 Azilsartan
 Candesartan
 Eprosartan
 Irbesartan
 Kosartan
 Olmesartan
 Telmisartan
 Valsartan
 Fimasartan

The importance of angiotensin II in regulating cardiovascular functions led to the

development of angiotensin II receptor antagonists. Losartan, Candesartan,
Irbesartan, Valsartan, Eprosartan and Telmisartan are all non-peptide used in the
treatment of hypertension. By preventing angiotensin II effects, they relax smooth
7
 muscles, promote vasodilatation, increase renal salts and water secretion, reduce
plasma volume and reduce blood pressure.

Angiotensin receptors blocker have an advantage over angiotensin II enzyme

inhibitor by preventing the degradation of bradykinin and substance P and is
devoid of intractable cough – associated with ACE – Inhibitor.

There are two-subtypes of angiotensin receptor blockers antagonist (ARB)

designed AT1 and AT2. AT1 are localized in the vascular bed myocardial tissue,
brain, kidney and adrenal glomerulosa cells which secretes aldosterone. AT 2 is
localized in the adrenal medulla and in the CNS. AT 1 mediates feedback inhibition
of rennin release, AT2 plays a role in vascular development. Some adverse effects
of ARB are hypotension and hyperkalemia especially when co-administered with
diuretics. ARB should not be given to pregnant women.

Some older anti-hypertensives:

Guanethidine – replaces nor-epinephrine in vesicle

Mecamylamin – a ganglion blocker and anti-nicotinic
6. βeta –adrenergic receptor antagonist

Beta blockers

 Atenolol
 Bisoprolol
 Betaxolol
 Carteolol
 Carvedilol
 Labetalol
 Metoprolol
 Nadolol
 Nebivolol
 Oxyprenolol,
 Penbutolol
 Pindolol
 Propranolol
 Timolol

8
 Alpha blockers:

 Doxazosin
 Phentolamine
 Indoramin
 Phenyoxybenzamine
 Prozasin
 Terazosin
 tolazoline

Mixed Alpha + Beta Blockers:

 Bucindolol
 Carvedilol
 Labetalol

Antagonist of β-adrenergic receptors affects the regulation of blood pressure

through the following mechanism:

a. Reduction of myocardial contractility and cardiac out.

b. Reduction in the secretion of rennin with a resultant fall in angiotensin II levels.
c. Reduction in aldosterone levels

The β-adrenergic blockers vary in their lipid solubility, selectivity for the β-
adrenergic receptor subtype, presence of partial agonist or intrinsic
sympathomimetic activity and membrane stability properties. Regardless of these
differences, all β-adrenergic receptor antagonists are effective as anti-hypertensive
agents.

Sudden discontinuation of some β-adrenergic blockers produces withdrawal

syndrome similar to sympathetic hyperactivity, this can exacerbate symptoms of
coronary artery disease and rebound hypertension. Thus β-adrenergic blockers
should not be discontinued abruptly except under close observation.

Propranolol – Is a non-selective β-adrenergic blocker. It blocks B1 and B2 with

equal potency. Like carteolol, penbutolol, pindolol and timolol. Propranolol a
typical B-blocker is beneficial in lowering mild to moderate hypertension. In
severe hypertension, B-blockers are useful in preventing the reflex tachycardia that
results when vasodilators are used. Propranolol decreases blood pressure as a result
9
of decrease cardiac output and partial agonist activities. Propranolol inhibits the
stimulation of rennin production by catecholamines mediated by B 1 receptors. This
results in depression of rennin-angiotensin aldoesterone system. Beta receptors
also act on peripheral presynaptic B-adrenoceptors to reduce sympathetic
vasoconstrictor nerve activity. Propranolol should not be withdrawn abruptly
because it could lead to withdrawal syndrome; where the patient experience
nervousness, tachycardia, angina and rebound hypertension.

Metoprolol: Is equipotent to propranolol in inhibiting B 1-adrenoreceptors in the

heart but less potent in blocking B 2-adrenoreceptor. This confers it an advantage to
be used in hypertensive patient suffering asthmatic symptoms. Other Beta-
adrenergic blocking drugs are Nadolol, Carteolol, Atenolol, Betaxolol, Bisoprolol,
Pindolol, Acebutolol, Penbutolol, Esmolol etc.

Mixed adrenergic antagonist: Labetaolol, Carvedilol and Labetalol is a mixture

of four isomers. One isomer is α 1-adrenergic receptor antagonist like prazosin,
another is a non-selective β-adrenergic receptor antagonist with partial agonist
activity like Pindolol. The other two isomers are inactive. Labetalol lowers arterial
pressure by reducing vascular resistance as a result of blockade of α 1-adrenergic
receptors, it can be used intravenously in hypertensive emergencies and
pheochromocytoma.

Carvedilol – Is a β-adrenergic receptor antagonist, with ratio α 1 to β-adrenergic

receptor potency of 1:10. Carvedilol undergoes oxidative metabolism and
glucuronidation in the cytochrome of the liver. It is excreted via urine. The adverse
effect of Labetalol and Carvedilol is predictable based on their α 1 and B-adrenergic
properties.

Alpha-adrenergic Receptor antagonist.

Prazosin; tetrazosin and doxasin produce their anti-hypertensive effect by blocking

α1 receptors in the arterioles and venules. Selective α 1-receptor antagonist agent
used as anti-hypertensive produces reflex tachycardia than the non-selective α-
receptor antagonist i.e phentolamine. Phentolamine blocks both pre-synaptic and
post synaptic α-receptors. Alpha blockers reduce arterial pressure by dilating both
resistance and capacitance vessels.

10
 They reduce blood pressure more in the upright than in the supine posture. Salt and
water retention occur when the drug is not administered with a diuretic. They are
more effective when used in combination with a diuretic and a β-blocker. Long
term treatment with α-blocker may cause postural hypertension. This postural
hypertension has also been observed in some patient taking the drug for the first
dose (first dose phenomenon) is more common in patient who are Na + depleted and
also on diuretics.

Phentolamine and Phenoxybenzamine (Non-selective alpha blockers) are useful in

diagnosis and treatment of pheochromocytoma and other conditions in which
catecholamines are elevated or in the treatment of clonidine withdrawal syndrome.

7. Vasodilators – Arterial

Vasodilators act directly on the smooth muscle of arteries to relax their wall so
blood can move more easily through them; they are only used in hypertensive
emergencies or when other drugs have failed, and even so are rarely given along
time.

Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly

used for the quick, temporary reduction of blood pressure in emergencies (such and
malignant hypertension or aortic dissection). Hydralazine, though they should be
avoided in emergencies. They are no longer indicated as first-line therapy of high
blood pressure due to side effects and safety concerns, but hydralazine remains a
drug of choice is gestational hypertension.

Hydralazine- The use of arteriolar vasodilator resulted in compensatory

cardiovascular response leading to tachycardia and tachyphylaxis. This can be
resolved by a combination of a sympatholytic agent and a diuretic to achieve a
better outcome or beneficial fit. Hydralazine (I-hydralazinopthalzine) causes direct
relaxation of arteriolar smooth muscles and it is not dilator or the capacitance
vessels and cannot relax various smooth muscles. Hydralazine induces
vasodilation, stimulates sympathetic nervous system resulting in the following: (a)
increased heart rate and contractility (b) increased plasma rennin activity (c) fluid
retention. All these counteract the anti-hypertensive effect of hydralazine. The
decrease in blood pressure after hydralazine is administered is due to a decrease in
vascular resistance in the coronary, cerebral and renal circulations. Because of

11
hydralazine preferential dilation of arterior over veins, postural hypotension is not
a common problem. They hydralazine is more beneficial when combined with a
βeta-adrenergic blocker.

Hydralazine undergoes N-acetylation in the GIT and liver with peak plasma
concentration occurring 30minutes to 2 hours after administration.

Adverse effect: Headache, nausea, flushing, hypotension palpitation, tachycardia,

dizziness and angina pectoris.

Minoxidil: Is a metabolized by hepatic enzyme to the active molecule. It is the

active molecules that produces arteriolar vasodilation, without affecting the
capacitance vessels, resembling hydralazine and diazoxide in this regard.
Minoxidil increases blood flow to skin, skeletal muscle, GIT and more than the
CNS, this is due to reflex increase in myocardial contractility output. The effects of
minoxidil on the kidneys are complex. It is a renal vasodilator, a potent stimulator
of rennin secretion, an effect mediated by renal sympathetic stimulation and
activation of the intrinsic renal mechanism for the regulation of rennin release.

After oral administration, peak plasma concentration occurs 1 hour and maximal
hypotensive effect occurs later because of formation of active metabolite is
delayed. About 20% is excreted unchanged in urine and the majority undergoes
glucuronide conjugation in the liver. It has a half-life of 3-4horus but its duration
of action can last up to 24hours.

Adverse effects are salt and fluid retention, cardio-vascular effects and
hypertrichosis.

Minixodil: Is more beneficial when administered in combination with a diuretic

and B-adrenergic receptor blocker

Arterial and venous dilators: Sodium Nitroprusside is a nitro vasodilator. It is

metabolized by the blood vessels to nitric oxide, activates guanylyl cylase leading
to the formation of cyclic GMP and vasodilatation. The activation of nitroprusside
is catalyzed by a different nitric oxide generating system than that of nitroglycerin
accounting for a difference in potency of these drugs at the vascular sites.
Tolerance develops to nitroglycerin but not to nitroprusside. Nitroprusside dilates
both arterioles and venules resulting in venous pooling and arterial impedance. The

12
 hypotensive effect of nitroprusside maintains renal blood flow and glomerular
filtration but increases plasma rennin activity.

Sodium-nitroprusside decomposes under strong alkaline conditions and when

exposed to light. To be effective, it is given by continuous infusion. It’s onset of
action is within 2minutes. The metabolism of nitroprusside by smooth muscles is it
reduction to cyanide and the release of nitric oxide. Cyanide is further metabolized
in the liver rhodanse to thiocynate which is eliminated in the urine. In patients with
good renal function challenge, thiocynates is eliminated in 3 days.

Toxicity is due to accumulation of thiocynate, resulting in lactic acidosis.

Concomitant administration of sodium thiosulfate can prevent accumulation of
thiocynate especially in patient receiving high doses.

8. BENZODIAZEPINES:

Although controversial over this-off label purpose, benzodiazepine may play a role
in lowering blood pressure. They work as an agonist of the GABA – a receptors in
the brain, thus slowing down neurotransmission and dilating blood vessels. GABA
is an abbreviation for gamma-aminobutyric acid. It is an inhibitory
neurotransmitter among others (glycine, adenosine, etc) GABA – a receptor are ion
channels that are the primary target for the benzodiazepines. When an agonist
binds to this receptor site, the protein channel opens, allowing negative chloride
ions entering the channel and penetrating the voltage-gated ion site. Thus, giving
negative feedback in neurotransmission and easing stress, anxiety and tension in
patient that can be associated with elevated blood pressure. In addition to GABA,
benzodiazepines inhibit the re-uptake of a nucleoside chemical called Adenosine,
which serves as an inhibitory chemical. It also serves as a coronary vasodilator,
allowing the cardiac muscle to relax and dilating cardiac arteries. However, long-
term use of benzodiazepins is associated with dependence and tolerance, which is
likely the result of GABA- a receptor down regulation. Therefore, withdrawal
symptoms include hypertension, even in healthy individuals.

9. RENIN INHIBITORS

Rennin comes one level higher than angiotensin converting enzymes (ACE) in the
rennin-angiotensin system. Inhibitors of rennin can therefore effectively reduce

13
 hypertension. Aliskiren is a rennin inhibitor which has been approved by the U.S
FDA for the treatment of hypertension.

10.ALDOSTERONE RECEPTOR ANTAGONIST

Aldosterone receptor angatonist:

 Eplerenone
 Spironolactone

Aldosterone receptor antagonist are not recommended as first line agent for blood
pressure, but spironolactone and eplerenone are both used in the treatment of heart
failure and resistant hypertension.

11.ENDOTHELIN RECEPTOR BLOCKERS

Bosentan belongs to a new class of drug and works by blocking the receptors of the
hormone endothelin. It is specifically indicated only for the treatment of
pulmonary artery hypertension in patients with moderate to severe heart failure.

FUTURE TREATMENT OPTIONS

Blood pressure vaccines

Blood pressure vaccination is being tried and may become a treatment option for
high blood pressure in the future.

CHOICE OF INITIAL MEDICATION

For mild blood pressure elevation, consensus guidelines call for medically
supervised lifestyle changes and observation before recommending initiation of
drug therapy. However, according to the American Hypertension Association,
evidence of sustained damage to the body may be present even prior to observed
elevation of blood pressure. Therefore, the use of hypertensive medications may be
started in individuals with apparent normal blood pressures but who show evidence
of hypertension-related nephropathy, proteinuria, atherosclerotic vascular diseases,
as well as other evidence of hypertension-related organ damage.

If lifestyle changes are ineffective, then drug therapy is initiated, often requiring
more than one agent to effectively lower hypertension. Which type of many
medications should be used initially for hypertension has been the subject of
14
several large studies and various national guidelines. Consideration includes
factors such as age, race and other medical conditions. In the United States, JNC8
(2014) recommends any drug from one of the four classes to be a good choice as
either initial therapy or as add-on treatment: thiazide-type diuretics, calcium
channel blockers, ACE inhibitors, or angiotensin II receptor antagonist.

The largest study, Anthihypertenstive and Lipid-lowering Treatment to Prevent

Heart Attack Trial (ALLHAT) in 2002, concluded that thiazide-type diuretics are
better and cheaper than other major classes of drugs at preventing cardiovascular
disease, and should be preferred as the starting drug. ALLHAT used the thiazide
diuretic chlorthalidone. (ALLHAT showed that doxazosin, an alpha-adrenegic
receptor blocker, had a high incidence of heart failure event, and the doxazosin arm
of the study was stopped)

A subsequent smaller study (ANBP2) did not show the slight advantages in
thiazide diuretic outcomes observed in the ALLHAT study, and actually showed
slightly better outcomes for ACE-inhibitors in older white male patients.

Thiazide diuretics are effective, recommended as the best first-line drug for
hypertension by many experts, and are much more affordable than other therapies,
yet they are not prescribed as often as some newer drugs. Hydrochlorothiazide is
perhaps the safest and most inexpensive agent commonly used in this class and is
very frequently combined with other agents in a single pill. Doses in excess of
25milligram per day of this agent incur an unacceptable risk of low potassium of
Hypokalemia. Patients with an exaggerated hypokalemia response to a low dose of
thiazide diuretic should be suspected to have Hyperaldosteronism, a common cause
of secondary hypertension.

Other drugs have a role in treating hypertension. Adverse effects of thiazide

diuretic include hypercholesterolemia, and impaired glucose tolerance with
increased risk of developing diabetes mellitus type 2. The thiazide diuretics also
deplete circulating potassium unless combined with potassium-sparing diuretic or
supplemental potassium. Some authors have challenges thiazides as first line
treatment. However, as the Merck Manual of Geriatrics notes, “thiazide-type
diuretics are especially safe and effective in the elderly.

15
 Current UK guidelines suggest starting patient over the age of 55years and all
those of African/Afrocaribbean ethnicity firstly on calcium channel blockers or
thiazide diuretics, whilst younger patients of other ethnic group should be started
on ACE-inhibitors. Subsequently, if dual therapy is required to use ACE-inhibitor
in combination with either calcium channel blocker or a (thiazide) diuretic. Triple
therapy is then of all three groups and should the need arise then to add in a fourth
agent, to consider either further diuretic (e.g) spironolactone or furosemide, an
alpha-blocker or a beta-blocker. Prior to the demotion of beta-blockers as first line
agents, the UK sequence of combination therapy used the first letter of the drug
classes and was known as the “ABCD rule”

PATIENT FACTOR

The choice between the drugs is to a large degree determined by the characteristics
of the patient being prescribe for, the drugs’ side effects, and cost. Most drugs have
other uses; sometimes the presence of other symptoms can warrant the use of one
particular antihypertensive. Examples include:

 Age can affect the choice of medications. Current UK guidelines suggest starting
patients over the age of 55years first on calcium channel blockers or thiazide
diuretic.
 Anxiety may be improved with the use of beta-blockers.
 Asthmatics have been reported to have worsening symptoms when using beta
blockers.
 Benign prostatic hyperplasia may be improved with the use of alpha blocker.
 Chronic kidney disease. ACE inhibitors or ARBs should be included in treatment
plan to improve kidney outcomes regardless of race or diabetes mellitus.
 Gout may be worsened by thiazide diuretics, while losartan reduces serum urate
 Kidney stones may be improved with the use of thiazide-type diuretics
 Heart block. B-blocker and nondihydropyridine calcium channel blockers should
not be used in patient with heart block greater than first degree. JNC8 does not
recommend B-blockers as initial therapy for hypertension.
 Heart failure may be worsened with nondihydropyridine calcium channel blockers,
the alpha blocker doxazosin, and the alpha-2 agonists moxonidine and clonidine.
Whereas B-blockers, diuretics, ACE-inhibitors, angiotensin receptor blockers, and
aldosterone receptor antagonist have been shown to improve outcome.

16
 Pregnancy. Although α-methyldopa is generally regarded as a first line agent,
labetalol are also acceptable. Atenolol has been associated with intrauterine
growth retardation, as well as decreased placental growth and weight when
prescribed during pregnancy. ACE inhibitors and angiotensin II receptor blockers
(ARBs) are contraindicated in women who are or who intend to become pregnant.
 Race. Some guidelines particularly points out that when used as monotherapy,
thiazide diuretics, and calcium channel blockers have been found to be more
effective in reducing blood pressure in black hypertensive than B-blockers, ACE
inhibitors, or ARBs.
 Tremor may warrant the use of beta blockers.

17