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Various algorithms recommending nonpharmacologic and pharmacologic management
for typical and atypical patients are proposed,
with the underlying theme that achievement of
blood pressure targets mitigate end-organ
damage, leading to substantial reductions in
stroke, myocardial infarction, and heart failure.
 Although references to other algorithms will be
mentioned, we will focus primarily on the
Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure, more
commonly referred to as the JNC 7 report.
The JNC 7 report describes four stages of blood pressure
classification and provides guidance on non-pharmacologic and
pharmacologic approaches to managing patients with
The four stages of blood pressure classification include normal,
prehypertension, stage 1 hypertension, and stage 2 hypertension.
These stages are defined as such to connote a level of risk and
thus the need for varying intensities of intervention with drug
therapy. With the exception of individuals with “compelling
indications,” recommendations for drug therapy typically begin
with one or two (in the case of stage 2) antihypertensive drugs as
an initial step. Specific drug selection is guided by the presence of
compelling indications— specific comorbid conditions. These
compelling indications, such as heart failure, diabetes, and
chronic kidney disease (CKD).
Selection of drug therapy consequently involves an iterative
process of considering multiple antihypertensive drugs as needed
to achieve target blood pressures of less than 140/90 mm Hg for
all patients, with more aggressive targets of less than 130/80 mm
Hg for patients with diabetes or chronic kidney disease.
Treatment with drug therapy should be done in combination with
recommended lifestyle modifications to manage hypertension and
minimize risk.
Adult SBP (mm
Adult DBP (mm
centsSBP or
Less than 120
and less than 80
Less than 90th
Or 80–89
90–95th or 120/80
mm Hg
Stage 1
or 90–99
95–99th + 5 mm
Stage 2
Greater than or
equal to 160
Greater than or
equal to 100
Greater than 99th
+ 5 mm Hgc
Arterial blood pressure is determined by cardiac
output, peripheral vascular resistance and large artery
 Peripheral vascular resistance is determined by the
diameter of resistance vessels (small muscular arteries
and arterioles) in the various tissues.
 One or more of a ‘mosaic’ of interconnected
predisposing factors (including positive family history,
obesity and physical inactivity among others) are
commonly present in patients with essential
hypertension, some of which are amenable to changes
in diet and other habits.
Cardiac output may be increased in children or
young adults during the earliest stages of
essential hypertension, but by the time
hypertension is established in middle life the
predominant haemodynamic abnormality is an
elevated peripheral vascular resistance. With
ageing, elastic fibres in the aorta and conduit
arteries are replaced by less compliant collagen
causing arterial stiffening and systolic
hypertension, which is common in the elderly.
a. Essential hypertension: 90% (no identifiable cause)
i. Contributed to obesity
ii. Evaluate Na intake.
b. Secondary hypertension
i. Primary aldosteronism
ii. Renal parenchymal disease
iii. Thyroid or parathyroid disease
iv. Medications (e.g., cyclosporine, NSAIDs,
In addition to primary and secondary hypertension, the
clinician may encounter what is referred to as resistant
 Patients failing to achieve goal blood pressure despite
maximum doses of three antihypertensives including a
diuretic should be carefully screened for resistant
Benefits of lowering BP
a. 40 % decrease in stroke
b. 25 % decrease in MI
c. 50 % decrease in HF
2. Select treatment goal.
a. JNC 7 goals are less than 140/90 mm Hg for all
patients except for patients with diabetes and/or
significant chronic kidney disease (defined as
estimated glomerular filtration rate less than 60
mL/minute/1.73 m2 [about when SCr is greater than
1.5 mg/dL in men or greater than 1.3 mg/dL in
women]) OR albuminuria (greater than 300 mg/day or
greater than 200 mg alb/g creatinine)] in which the
goal is 130/80 mm Hg.
b. Other treatment goals exist; however, they are
controversial and not universally accepted.
American Heart Association 2007 recommendation
 Most Patients for General Prevention (Primary
Prevention Patients) < 140/90 mm Hg
 Patients with Diabetes mellitus; Significant chronic
kidney disease; Known CAD (MI, stable angina, unstable
angina)Non coronary atherosclerotic vascular disease
(ischemic stroke, TIA, PAD, abdominal aortic aneurism);
or Framingham risk score > 10% < 130/80 mm Hg
 Patients with left ventricular dysfunction (systolic heart
failure) < 120/80 mm Hg
Nonpharmacologic Treatment: Lifestyle Modifications
Therapeutic lifestyle modifications consisting of nonpharmacologic approaches to blood pressure reduction should
be an active part of all treatment plans for patients with
The most widely studied interventions demonstrating
effectiveness include:
• Weight reduction in overweight or obese individuals
• Adoption of a diet rich in potassium and calcium
• Dietary sodium restriction
• Physical activity
• Moderation of alcohol consumption
Implementation of these lifestyle modifications successfully lowers
blood pressure, often with results similar to those of therapy
with a single antihypertensive agent. Combinations of two or
more lifestyle modifications can have even greater effects with
blood pressure lowering.
In addition to their beneficial effects on lowering
blood pressure, lifestyle modifications also have a
favorable effect on other risk factors such as
dyslipidemia and insulin resistance, which are
commonly encountered in the hypertensive
population, and lifestyle modifications should be
encouraged for this reason as well.
JNC 7 provides a reasonable basis for guiding the selection
of drug classes for individuals based on their stage of
hypertension, comorbidities, and special circumstances.
 Many authorities recognize the value of diuretics as
first-line agents for the majority of patients with
hypertension (acquisition cost and availability as
combination agents).
 The endorsement by JNC 7 as an initial drug therapy
selection for stage 1 and stage 2 hypertensive patients
without compelling indications is based on a litany of
placebo-controlled studies.
Who should be treated with pharmacotherapy?
 Recommendations
 JNC 8
 Patients <60 years of age: start pharmacotherapy at
140/90 mmHg.
 Patients with diabetes: start pharmacotherapy at 140/90
 Patients with CKD: start pharmacotherapy at 140/90
 Patients 60 years of age and older: start pharmacotherapy
at 150/90 mmHg.
What is the goal blood pressure?
 Recommendations
 JNC 8
 Patients <60 years of age: <140/90 mmHg
 Patients with diabetes: <140/90 mmHg
 Patients with CKD: <140/90 mmHg
 Patients 60 years of age and older: <150/90
What pharmacotherapy is recommended? Recommendation
Nonblack, including those with diabetes: thiazide, CCB, ACEI, or
African American, including those with diabetes: thiazide or CCB
CKD: regimen should include an ACEI or ARB (including African
Can initiate with two agents, especially if systolic >20 mmHg above
goal or diastolic >10 mmHg above goal.
If goal not reached:
Reinforce lifestyle and adherence Titrate medications to maximum
doses or consider adding another medication (ACEI, ARB, CCB,
If not reached Reinforce lifestyle and adherence Add a
medication class not already selected (i.e. beta blocker,
aldosterone antagonist, others) and titrate above medications
to max if not refer to a specialist.
Nonblack <60 years of age:
First-line: ACEI or ARB
Second-line (add-on): CCB or thiazide
Third-line: CCB plus ACEI or ARB plus thiazide
Nonblack 60 years of age and older:
First-line: CCB or thiazide preferred, ACEI, or ARB
Second-line (add-on): CCB, thiazide, ACEI, or ARB (don’t
use ACEI plus ARB)
Third-line: CCB plus ACEI or ARB plus thiazide
African American:
First-line: CCB or thiazide
Second-line (add-on): ACEI or ARB
Third-line: CCB plus ACEI or ARB plus thiazide
Initial Drugs of Choice for Hypertension
• ACE inhibitor (ACEI)
• Angiotensin receptor blocker (ARB)
• Thiazide diuretic
• Calcium channel blocker (CCB)
Strategy Description
 A
Start one drug, titrate to maximum dose, and then add a second drug.
 B
Start one drug, then add a second drug before achieving max dose of first
Begin 2 drugs at same time, as separate pills or combination pill.
Initial combination therapy is recommended if BP is greater than
20/10mm Hg above goal
Lifestyle changes:
• Smoking Cessation
• Control blood glucose and lipids
• Diet
Eat healthy
Moderate alcohol consumption
Reduce sodium intake to no more than 2,400 mg/day
•Physical activity
Moderate-to-vigorous activity 3-4 days a week averaging 40 min per session.
1- starting drug treatment
Start with low moderate recommended dose of a first-line drug. If
not well tolerated, change to a different drug class, again starting
with a low moderate dose.
2- if target not reached after 3 months
Add a second drug from a different pharmacological class at a low
moderate dose, rather than increasing the dose of the first drug
(max antihypertensive efficacy, min adverse effects).
3- if target not reached after 3 months
If both antihypertensive drugs have been well tolerated, increase
the dose of one drug (excluding thiazide duiretics)
incrementally to the max recommended dose before increasing the
dose of the other drug.
4- if target is not reached after 3 months
If, despite max doses of at least 2 drugs, a third drug class may be
started at a low-moderate dose. It is advisable for non-adherence
secondary hypertension and hypertensive effects of other drugs,
treatment resistant state due to sleep apnoea, undisclosed use of
alcohol or recreational drugs or high salt intake.
5- if Bp remains elevated, consider seeking specialist advice.
Classes of antihypertensive drugs
and their sites of action.
Vasomotor centre
 α2-Adrenoceptor agonists (e.g. clonidine)
 Imidazoline receptor agonists (e.g. moxonidine)
Vascular smooth muscle
 ACE inhibitors (‘A’ drugs)
 Angiotensin receptor blockers (‘A’ drugs)
 Calcium channel blockers (‘C’ drugs)
 Diuretics (‘D’ drugs)
 α1-Blockers (e.g. doxazosin)
 Mineralocorticoid antagonists
Juxtaglomerular cells
 β-blockers (‘B’ drugs)
 Renin inhibitors
Kidney tubules
 Diuretics (‘D’ drugs)
 ACE inhibitors
 Angiotensin receptor blockers
Consider blood pressure in the context of other risk factors: use
cardiovascular risk to make decisions about whether to start drug
treatment and what target to aim for. (Guidance, together with risk
tables, is available, for example, at the back of the British National
Formulary). Use non-drug measures (e.g. salt restriction) in addition
to drugs.
• Explain goals of treatment and agree a plan the patient is comfortable
to live with (concordance).
• Review the possibility of co-existing disease (e.g. gout, angina) that
would influence the choice of drug.
• The ‘ABCD’ rule provides a useful basis for starting drug treatment. A
(and B) drugs inhibit the renin–angiotensin–aldosterone axis and are
effective when this is active – as it usually is in young white or Asian
people. An A drug is preferred for these unless there is some reason to
avoid it (e.g. in a young woman contemplating pregnancy) or some
additional reason (e.g. co-existing angina) to choose a B drug. Older
people and people of Afro-Caribbean ethnicity often have a low plasma
renin and in these patients a class C or D drug is preferred.
Use a low dose and, except in emergency situations, titrate
this upward gradually.
• Addition of a second drug is often needed. A drug of the
other group is added, i.e. an A drug is added to patients
started on a C or D drug, a C or D drug is added to a
patient started on an A drug. A third or fourth drug may be
needed. It is better to use such combinations than to use
very high doses of single drugs: this seldom works and often
causes adverse effects.
• Loss of control – if blood pressure control, having been well
established, is lost, there are several possibilities to be
 non-adherence;
 drug interaction – e.g. with non-steroidal anti-inflammatory
drugs (NSAIDs)
 intercurrent disease – e.g. renal impairment, atheromatous
renal artery stenosis.
Several angiotensin-converting enzyme inhibitors (ACEI)
are in clinical use (e.g. ramipril, trandolapril,
enalapril, lisinopril, captopril). These differ in their
duration of action. Longer-acting drugs (e.g.
trandolapril, ramipril) are preferred.
 They are given once daily and produce good 24-hour
control. Their beneficial effect in patients with heart
failure or following myocardial infarction makes them
or a sartan particularly useful in hypertensive patients
with these complications. Similarly an ACEI or sartan is
preferred over other anti-hypertensives in diabetic
patients because they slow the progression of diabetic
Treatment is initiated using a small dose given
last thing at night, because of the possibility of
first-dose hypotension.
 If possible, diuretics should be withheld for one or
two days before the first dose for the same
 The dose is subsequently usually given in the
morning and increased gradually if necessary,
while monitoring the blood-pressure response
i. Contraindicated in pregnancy
ii. Contraindicated with bilateral renal artery stenosis
iii. Monitor K closely, especially if renal insufficiency
exists or another K-sparing drug is in use.
iv. The presence of diabetic nephropathy should
influence the choice of ACE inhibitor versus ARB.
ACE inhibitors are a key class of antihypertensive agents
used in a vast array of patients with or without
comorbidities and/or cardiovascular risk factors.
 This broad utility extends to the list of compelling
indications for patients as described in JNC 7.
 These compelling indications include their qualified role
in managing patients with hypertension who have type 1
diabetes, heart failure, post–myocardial infarction, type 2
diabetes, chronic kidney disease, or recurrent stroke
Adverse effects
ACE inhibitors are generally well tolerated. Adverse effects include:
• First-dose hypotension.
• Dry cough – this is the most frequent symptom during chronic dosing.
It is often mild, but can be troublesome. due to kinin accumulation
stimulating cough afferents. Sartans do not inhibit the metabolism of
bradykinin and do not cause cough.
• Functional renal failure – this occurs predictably in patients with
haemodynamically significant bilateral renal artery stenosis, and in
patients with renal artery stenosis in the vessel supplying a single
functional kidney. Plasma creatinine and potassium concentrations
should be monitored and the possibility of renal artery stenosis
considered in patients in whom there is a marked rise in creatinine.
Provided that the drug is stopped promptly, such renal impairment is
reversible. The explanation of acute reduction in renal function in this
setting is that glomerular filtration in these patients is critically
dependent on angiotensin-II-mediated efferent arteriolar
vasoconstriction, and when angiotensin II synthesis is
inhibited, glomerular capillary pressure falls and glomerular
filtration ceases. This should be borne in mind particularly in ageing
patients with atheromatous disease.
Hyperkalaemia is potentially hazardous in patients with
renal impairment and great caution must be exercised in
this setting. This is even more important when such
patients are also prescribed potassium supplements and/or
potassium-sparing diuretics.
Fetal injury – ACEI cause renal agenesis/failure in the
fetus, resulting in oligohydramnios. ACEI are therefore
contraindicated in pregnancy and other drugs are usually
preferred in women who may want to start a family.
Urticaria and angio-oedema – increased kinin concentration
may explain the urticarial reactions and angioneurotic
oedema sometimes caused by ACEI.
Sulphhydryl group-related effects – high-dose captopril
causes heavy proteinuria, neutropenia, rash and taste
disturbance, attributable to its sulphhydryl group.
Diuretic treatment increases plasma renin activity and
the consequent activation of angiotensin II and
aldosterone limits their efficacy. ACE inhibition
interrupts this loop and thus enhances the hypotensive
efficacy of diuretics, as well as reducing thiazide-induced
 Conversely, ACEI have a potentially adverse interaction
with potassium-sparing diuretics and potassium
supplements, leading to hyperkalaemia, especially in
patients with renal impairment
 As with other antihypertensive drugs, NSAIDs increase
blood pressure in patients treated with ACE inhibitors.
Several angiotensin receptor blockers (ARB or ‘sartans’) are in
clinical use (e.g. losartan, candesartan, irbesartan, valsartan).
Sartans are pharmacologically distinct from ACEI, but clinically
similar in hypotensive efficacy. However, they lack the common ACEI
adverse effect of dry cough. Long-acting drugs (e.g. candesartan,
which forms a stable complex with the AT1 receptor) produce
good 24-hour control. Their beneficial effect in patients with heart
failure or following myocardial infarction makes them or an ACEI
useful in hypertensive patients with these complications.
Similarly, an ACEI or a sartan is preferred over other antihypertensive drugs in diabetic patients where they slow the
progression of nephropathy. Head to head comparison of losartan
versus atenolol in hypertension (the LIFE study) favoured the
sartan. Their excellent tolerability makes them first choice ‘A’ drugs
for many physicians, but they are more expensive than ACEI.
First-dose hypotension can occur and it is sensible to apply similar
precautions as when starting an ACEI (first dose at night, avoid
starting if volume contracted).
AT1 receptor stimulation evokes a pressor response
via a host of accompanying effects on catecholamines,
aldosterone, and thirst. Consequently, inhibition of
AT1 receptors directly prevents this pressor response
and results in up-regulation of the RAAS. Upregulation of the RAAS results in elevated levels of
angiotensin II, which have the added effect of
stimulating the AT2 receptors. AT2-receptor
stimulation is generally associated with
antihypertensive activity; however, long-term effects of
AT2-receptor stimulation that involve cellular growth
and repair are relatively unknown.
 What is clear is that ARBs differ from ACE inhibitors
in that the former cause up-regulation of the RAAS
while the latter blocks the breakdown of bradykinin.
Like ACE inhibitors, the antihypertensive
effectiveness of ARBs is greatly enhanced by combining
them with diuretics.
 Furthermore, they have proven their value as welltolerated alternatives to ACE inhibitors for patients
with chronic kidney disease, diabetes mellitus, and
post–acute myocardial infarction (AMI)
 Beta-blockers lower blood pressure and reduce the risk of
stroke in patients with mild essential hypertension, but in
several randomized controlled trials (particularly of
atenolol) have performed less well than comparator
drugs. The explanation is uncertain, but one possibility is
that they have less effect on central (i.e. aortic) blood
pressure than on brachial artery pressure. ‘B’ drugs are no
longer preferred over ‘A’ drugs as first line in situations
where an A or B would previously have been selected.
 They are, however, useful in hypertensive patients with an
additional complication such as ischaemic heart disease or
heart failure. The negative inotropic effect of beta-blocking
drugs is particularly useful for stabilizing patients with
dissecting aneurysms of the thoracic aorta, in whom it is
desirable not only to lower the mean pressure, but also to
reduce the rate of rise of the arterial pressure wave.
β-Adrenoceptor antagonists reduce cardiac
output (via negative chronotropic and negative
inotropic effects on the heart), inhibit renin
secretion and some have additional central
actions reducing sympathetic outflow from the
central nervous system (CNS).
The JNC 7 identifies β-blockers as agents appropriate
for first-line therapy for many individuals with
hypertension. Based on JNC 7, the role of β-blockers in
patients with select comorbidities is extensive.
Patients with comorbidities such as heart failure,
recent myocardial infarction, and diabetes represent
opportunities for β-blocker use on the basis of proven
outcome based studies.
 The role of β-blockers for patients with ischemic
conditions including acute myocardial infarction is
based on their hemodynamic effects on heart rate,
blood pressure, and cardiac output, as well as their
possibly anti-arrhythmic properties.
Nonetheless, in the long run β-blockers, when
judiciously used in patients with heart failure,
have consistently been shown to reduce morbidity
and mortality relative to standard heart failure
therapies. Similarly, given their effects on
pancreatic β-cell release of insulin and metabolic
effects, such as reducing gluconeogenesis and
glycogenolysis, their role in managing diabetic
patients would also seem illogical.
One of these properties is cardioselectivity—the
property of some β-blockers that preferentially block
β1- versus β2-receptors.
 Another property exhibited by some β-blockers is
membrane stabilization activity, which relates to the
propensity of the β-blocker to possess some capacity for
antiarrhythmic properties, in addition to β-receptor
blocking properties.
 Some β-blockers possess properties referred to as
intrinsic sympathomimetic activity (ISA). β-Blockers
possessing this property effectively block the βreceptor at higher circulating catecholamine levels,
such as during exercise, while having modest βstimulating activity at times of lower catecholamine
levels, such as at rest.
Cardioselective drugs (e.g. atenolol, metoprolol,
bisoprolol, nebivolol) inhibit β1-receptors with less effect on
bronchial and vascular β2-receptors. However, even
cardioselective drugs are hazardous for patients with asthma.
Some beta-blockers (e.g. oxprenolol) are partial agonists
and possess intrinsic sympathomimetic activity. There is little
hard evidence supporting their superiority to antagonists for
most indications although individual patients may find such a
drug acceptable when they have failed to tolerate a pure
antagonist (e.g. patients with angina and claudication).
Beta-blockers with additional vasodilating properties are
available. This is theoretically an advantage in treating
patients with hypertension. Their mechanisms vary. Some
(e.g. labetolol, carvedilol) have additional α-blocking
activity. Nebivolol releases endothelium-derived nitric
Intolerance – fatigue, cold extremities, erectile dysfunction; less
commonly vivid dreams.
Airways obstruction – asthmatics sometimes tolerate a small dose
of a selective drug when first prescribed, only to suffer an
exceptionally severe attack subsequently, and β-adrenoceptor
antagonists should ideally be avoided altogether in asthmatics
and used only with caution in COPD patients, many of whom
have a reversible component.
Decompensated heart failure – β-adrenoceptor antagonists are
contraindicated (in contrast to stable heart failure)
Peripheral vascular disease and vasospasm – β-adrenoceptor
antagonists worsen claudication and Raynaud’s phenomenon.
Hypoglycaemia – β-adrenoceptor antagonists can mask symptoms
of hypoglycaemia and the rate of recovery is slowed, because
adrenaline stimulates gluconeogenesis.
Heart block – β-adrenoceptor antagonists can precipitate or
worsen heart block.
Metabolic disturbance – β-adrenoreceptor antagonists worsen
glycaemic control in type 2 diabetes mellitus.
CNS side effects (e.g. nightmares) occur more
commonly. Polar (water-soluble) beta-blockers (e.g.
atenolol) are excreted by the kidneys and accumulate
in patients with renal impairment/failure.
Drug interactions
• Pharmacokinetic interactions: β-adrenoceptor
antagonists inhibit drug metabolism indirectly by
decreasing hepatic blood flow secondary to decreased
cardiac output. This causes accumulation of drugs
such as lidocaine that have such a high hepatic
extraction ratio that their clearance reflects hepatic
blood flow.
• Pharmacodynamic interactions: Increased negative
inotropic and atrioventricular (AV) nodal effects occur
with verapamil (giving both intravenously can be
fatal), lidocaine and other negative inotropes.
 Dihydropyridine calcium-channel blockers. It is a good
choice, especially in older patients and Afro-Caribbeans.
Amlodipine is taken once daily. The daily dose can be
increased if needed, usually after a month or more. Slowrelease preparations of nifedipine provide an
alternative to amlodipine.
 Exhibiting considerable interclass diversity, CCBAs have
been recognized as effective anti-hypertensives, for the
elderly in particular. Earlier trials demonstrated effective
event reduction for patients with isolated systolic
Often used to augment blood pressure lowering, CCBAs are
most commonly used as add-on therapy for patients who are
in need of further blood pressure lowering above and beyond
that afforded by diuretics or other antihypertensives.
Nonetheless, they have demonstrated their efficacy in select
patient populations as very effective blood pressure lowering
 The diversity of pharmacologic properties within the CCBA
class is significant. Knowledge of their subclass helps the
clinician to recognize their predominant effects on the
cardiovascular system and probable side-effect profile.
 Dihydropyridine CCBAs such as amlodipine are commonly
associated with edema, especially when used at higher
doses. Phenylalkylamine-verapamil and benzothiazepinediltiazem are more commonly recognized for their effects on
the cardiac conduction system and their propensity to be
negative inotropes and negative chronotropes.
Adverse effects
 Calcium-channel blocking drugs are usually well tolerated.
 Short-acting preparations (e.g. nifedipine capsules)
cause flushing and headache. Baroreflex activation causes
tachycardia, which can worsen angina. These formulations
of nifedipine should be avoided in the treatment of
hypertension and never used sublingually.
 Ankle swelling (oedema) is common, often troublesome, but
not sinister.
 The negative inotropic effect of verapamil exacerbates
cardiac failure.
 Constipation is common with verapamil.
 Intravenous verapamil can cause circulatory collapse
in patients treated concomitantly with β-adrenoceptor
 A low dose of a thiazide, or related diuretic, e.g.
chlortalidone, remains the best first choice for
treating older patients and Afro- Caribbeans with
uncomplicated mild essential hypertension, unless
contraindicated by some co-existent disease (e.g. gout).
They are also essential in more severe cases, combined
with other drugs. Diuretics reduced the risk of stroke
in several large clinical trials and in the Medical
Research Council (MRC) trial they did so significantly
more effectively than did beta blockade
Thiazides (e.g. bendroflumethiazide) are
preferred to loop diuretics for uncomplicated
essential hypertension. They are given by mouth as a
single morning dose. They begin to act within one to
two hours and work for 12–24 hours. Loop diuretics
are useful in hypertensive patients with moderate or
severe renal impairment, and in patients with
hypertensive heart failure.
Thiazide diuretics inhibit reabsorption of sodium and
chloride ions in the proximal part of the distal convoluted
 Excessive salt intake or a low glomerular filtration rate
interferes with their antihypertensive effect. Natriuresis
is therefore probably important in determining their
hypotensive action.
 However, it is not the whole story since although plasma
volume falls when treatment is started, it returns to
normal with continued treatment, despite a persistent
effect on blood pressure. During chronic treatment, total
peripheral vascular resistance falls slowly, suggesting an
action on resistance vessels. Responsiveness to pressors
(including angiotensin II and noradrenaline) is
reduced during chronic treatment with thiazides.
hypokalaemia – kaliuretis is a consequence of increased
sodium ion delivery to the distal nephron where sodium and
potassium ions are exchanged. Mild hypokalaemia is common
but seldom clinically important in uncomplicated
hypertension; hypomagnesaemia;
hyperuricaemia – most diuretics reduce urate clearance,
increase plasma urate and can precipitate gout;
hyperglycaemia – thiazides reduce glucose tolerance: high
doses cause hyperglycaemia in type 2 diabetes;
hypercalcaemia – thiazides reduce urinary calcium ion
clearance (unlike loop diuretics, which increase it) and can
aggravate hypercalcaemia in hypertensive patients with
hypercholesterolaemia – high-dose thiazides cause a small
increase in plasma LDL cholesterol concentration.
Erectile dysfunction which is reversible on stopping the drug.
Increased plasma renin, limiting the antihypertensive effect.
Idiosyncratic reactions, including rashes (which may be
photosensitive) and purpura, which may be thrombocytopenic
or non-thrombocytopenic.
Diuretics indirectly increase Li reabsorption in the
proximal tubule, by causing volume contraction. This
results in an increased plasma concentration of Li and
increased toxicity.
 Diuretic-induced hypokalaemia and hypomagnesaemia
increase the toxicity of digoxin. Combinations of a thiazide
with a potassium-sparing diuretic, such as amiloride (coamilozide), triamterene or spironolactone can
prevent undue hypokalaemia, and are especially useful in
patients who require simultaneous treatment with
digoxin, sotalol or other drugs that prolong the
electrocardiographic QT-interval.
These metabolic effects may clearly complicate the
management of higher-risk patients with common
comorbidities such as dyslipidemia or diabetes, or even
those likely to be sensitive to the potassium- or
magnesium- wasting effects of diuretics (patients with
dysrhythmias or those taking digoxin).
 While rates of diabetes are higher following
administration of thiazides, there is plenty of evidence
that this can be greatly minimized by keeping potassium
in the high normal range (i.e., above 4.0 mEq/L [4
 Another key feature of the thiazide-type diuretics is their
limited efficacy in patients whose estimated renal function
is reduced, such as the elderly. For example, patients with
estimates of reduced renal function, such as those with a
glomerular filtration rate (GFR) below 30 mL/minute,
should be considered for more potent loop type diuretics
such as furosemide.
In situations in which a patient has poor renal function, a loop
diuretic should be given at least twice a day, with the
exception of furosemide to augment blood pressure control with
combination antihypertensive therapy.
Diuretic resistance may result from extended use of loop
diuretics. In these circumstances, the addition of a thiazide to
a loop diuretic may dramatically enhance overall diuresis.
The most significant adverse effects related to loop diuretic use
concern their potential for excessive diuresis leading to
hyponatremia or hypotension. Additionally, hypokalemia,
hypomagnesemia, and hypocalcemia may develop over time
and contribute to the potential for cardiac arrhythmias.
Overall relevance of drug-drug interactions and potential for
aggravating select conditions (hyperglycemia, dyslipidemias,
and hyperuricemia) should be routinely considered in the
monitoring plan for those taking loop diuretics for extended
periods of time.
Potassium-sparing diuretics that do not act through
mineralocorticoid receptors include triamterene and
amiloride. These agents are often prescribed with
potassium-wasting diuretics in an attempt to mitigate the
loss of potassium. When administered as a single entity or
as one component of a combination product, these agents
result in moderate diuresis.
Potassium-sparing diuretics act on the late distal tubule
and collecting duct and thereby have limited ability to
affect sodium reabsorption, which translates into modest
The most important adverse effects associated with these
agents are their potential to contribute to hyperkalemia.
This is especially relevant in the context of those patients
receiving other agents with potassium-sparing properties,
such as ACE inhibitors, ARBs, and potassium supplements,
as well NSAIDs, in those with mild to moderate renal
These inhibitors of aldosterone are commonly used in
patients as components of select combination drug therapies to
balance the potassium wasting effects of more potent diuretics,
such as thiazide or loop diuretics, as well as for their direct
antihypertensive effects through aldosterone modulation.
Patients with resistant hypertension with and without primary
aldosteronism had significant additive blood pressure
reductions when adding low-dose spironolactone (12.5 to 50
mg/day) to diuretics, ACE inhibitors, and ARBs. Although
functional for these purposes, it is important to recognize their
potential to cause hyperkalemia when used in conjunction with
other select agents or in patients with comorbidities resulting
in reduced renal function. Classic examples include coadministration with ACE inhibitors and ARBs, known for their
potassium-sparing effects, as well as agents that may directly
or indirectly alter renal potassium load (e.g., potassium
supplements) or potassium excretory function (e.g., NSAIDs).
The most commonly used potassium-sparing
diuretic is spironolactone; however, eplerenone
has been increasingly used in patients with heart
failure following acute myocardial infarction.
 Although spironolactone is commonly associated
with gynecomastia, eplerenone rarely causes this
 The risk of hyperkalemia is also more commonly
reported with patients on spironolactone.
 Generally, α1-blockers are considered as second-line
agents to be added on to most other agents when
hypertension is not adequately controlled. They may have
a specific role in the antihypertensive regimen for elderly
males with prostatism;
 however, their use is often curtailed by complaints of
syncope, dizziness, or palpitations following the first dose
and orthostatic hypotension with chronic use.
Central Alpha2-Agonists
 Also limited by their tendency to cause orthostasis,
sedation, dry mouth, and vision disturbances,
clonidine, methyldopa and guanathedine represent
rare choices in contemporary treatment of patients
with hypertension
Their central α2-adrenergic stimulation is thought to
reduce sympathetic outflow and enhance
parasympathetic activity thereby reducing heart rate,
cardiac output, and total peripheral resistance.
Occasionally used for cases of resistant hypertension,
these agents may have a role when other more
conventional therapies appear ineffective.
 The availability of a transdermal clonidine patch that
is applied once weekly may offer an alternative to
hypertensive patients with adherence problems.
Key points
Drugs used in essential hypertension
 Diuretics: thiazides (in low dose) are preferred to loop
diuretics unless there is renal impairment. They may
precipitate gout and worsen glucose tolerance or
dyslipidaemia, but they reduce the risk of stroke and other
vascular events. Adverse effects include hypokalaemia, which
is seldom problematic, and impotence. They are suitable firstline drugs, especially in black patients, who often have low
circulating renin levels and respond well to salt restriction
and diuretics.
 Beta-blockers reduce the risk of vascular events, but are
contraindicated in patients with obstructive pulmonary
disease. Adverse events (dose-related) include fatigue and cold
extremities. Heart failure, heart block or claudication can be
exacerbated in predisposed patients. They are particularly
useful in patients with another indication for them (e.g.
angina, postmyocardial infarction). Patients of African descent
tend to respond poorly to them as single agents.
ACE inhibitors are particularly useful as an addition to a
thiazide in moderately severe disease. The main adverse effect
on chronic use is cough; losartan, an angiotensin-II receptor
antagonist, lacks this effect but is otherwise similar to ACE
Calcium-channel antagonists are useful, especially in
moderately severe disease. Long-acting drugs/preparations are
preferred. The main adverse effect in chronic use is ankle
α1-Blockers are useful additional agents in patients who are
poorly controlled on one or two drugs. Long-acting drugs (e.g.
doxazosin) are preferred. Effects on vascular event rates are
unknown. Unlike other antihypertensives, they improve the
lipid profile.
α-Methyldopa is useful in patients with hypertension during
Other drugs that are useful in occasional patients with severe
disease include minoxidil, hydralazine and nitroprusside.
Minoxidil: Minoxidil sulphate (active metabolite) used in
Very severe hypertension that is resistant to other drugs is a Kchannel activator.
Nitroprusside Breaks down chemically to NO, which activates
guanylyl cyclase Given by intravenous infusion in intensive
care unit for control of malignant hypertension.
Hydralazine Direct action on vascular smooth muscle;
biochemical mechanism not understood. Previously used in
‘stepped-care’ approach to severe hypertension β-antagonist in
combination with diuretic. Retains a place in severe
hypertension during pregnancy
α-Methyldopa Taken up by noradrenergic nerve terminals
and converted to α-methylnoradrenaline which is released as a
false transmitter. This acts centrally as an α2-agonist and
reduces sympathetic outflow. Hypertension during pregnancy.
Occasionally useful in patients who cannot tolerate other
4. Considerations with specific antihypertensive agents
a. β-Blockers
i. Caution with asthma, severe chronic obstructive pulmonary disease
(especially higher doses) because of pulmonary β-receptor blockade
ii. Increased risk of developing diabetes compared with ACE inhibitor,
ARB, and calcium channel blocker; use caution in patients at high risk
of diabetes mellitus (e.g., family history, obese)
iii. May mask some signs of hypoglycemia in patients with diabetes
iv. May cause depression
b. Thiazides
i. May worsen gout by increasing serum uric acid
ii. Increased risk of developing diabetes compared with ACE inhibitor,
ARBs, and calcium channel blocker; use caution in patients at high
risk of diabetes mellitus (e.g., family history, obese)
iii. May assist in the management of osteoporosis by preventing urine
calcium loss
c. Angiotensin-converting enzyme inhibitors and ARBs
i. Contraindicated in pregnancy
ii. Contraindicated with bilateral renal artery stenosis
iii. Monitor K closely, especially if renal insufficiency exists or
another K-sparing drug is in use.
iv. The presence of diabetic nephropathy should influence the
choice of ACE inhibitor versus ARB.
d. Aliskiren
i. A direct rennin antagonist
ii. When combined with losartan (100 mg/day) in patients
with hypertension, type 2 diabetes mellitus, and
nephropathy (albumin-to-creatinine ratio greater than 300
mg/g or greater than 200 mg/g), aliskiren showed
renoprotective effects independent of its BP effects (N Engl
J Med 2008;358:2433–46).
iii. Whether this combination is superior to ACE
inhibitor/ARB combinations is questionable.
Considerations within specific patient populations
a. Patients with ischemic heart disease: Potent
vasodilators may cause reflex tachycardia, thereby
increasing myocardial oxygen demand (hydralazine,
minoxidil, and dihydropyridine calcium channel
blockers); can attenuate this by also using an
atrioventricular nodal depressant (non-dihydropyridine
calcium channel blocker or β-blocker).
b. Elderly patients:
i. Caution with antihypertensive agents and orthostatic
ii. Initiate with low dose and titrate slowly.
c. African American patients:
β-Blockers and ACE inhibitors are generally less effective as
monotherapy than in white patients; however, combination
therapy with thiazides improves effectiveness, and it should
still be used if comorbid conditions dictate.
d. Pregnant women
i. Methyldopa and hydralazine are recommended if a new
therapy is initiated.
ii. Most antihypertensives (except for ACE inhibitors and
ARBs) can be safely continued in pregnancy.
a. Have the patient return in 4 weeks to assess efficacy.
b. May have patient follow-up sooner if BP particularly
c. If there is an inadequate response from the first agent (and
adherence verified) and no compelling indication exists,
initiate therapy with a drug from a different class.
 Compelling Indications and Special Considerations
 While the main goal of antihypertensive therapy is to
achieve target blood pressures, the selection of agents for
an individual should also account for certain special
considerations and a patient’s comorbidities. Specific
antihypertensive therapy is warranted for certain patients
with comorbid conditions that may elevate their level of
risk for cardiovascular disease.
 Clinical conditions for which there is compelling evidence
supporting one or more classes of drug therapy include:
• Ischemic heart disease
• Heart failure
• Diabetes
• Chronic kidney disease
• Cerebrovascular disease
In patients with hypertension and chronic stable
angina, β-blockers and long-acting calcium channel
blockers are indicated due to their antihypertensive
and antianginal effects.
 In patients at high risk of ischemic heart disease, such
as diabetic patients with additional cardiovascular risk
factors or chronic coronary artery or vascular disease,
ACE inhibitors are particularly useful in reducing the
risk of cardiovascular events regardless of whether the
patient carries a concurrent diagnosis of hypertension.
 β-Blockers and ACE inhibitors are also indicated for
post–myocardial infarction for the reduction of
cardiovascular morbidity and mortality, as are
aldosterone antagonists, in post–myocardial infarction
patients with reduced left ventricular systolic function
and diabetes or signs and symptoms of heart failure.
Patients with asymptomatic left ventricular systolic
dysfunction and hypertension should be treated with βblockers and ACE inhibitors. Those with heart failure
secondary to left ventricular dysfunction and hypertension
should be treated with drugs proven to also reduce the
morbidity and mortality of heart failure, including βblockers, ACE inhibitors, ARBs, aldosterone antagonists,
and diuretics for symptom control as well as
antihypertensive effect.
 In African-Americans with heart failure and left
ventricular systolic dysfunction, combination therapy with
nitrates and hydralazine not only affords a morbidity and
mortality benefit, but may also be useful as
antihypertensive therapy if needed.
The dihydropyridine calcium channel blockers
amlodipine or felodipine may also be used in patients
with heart failure and left ventricular systolic
dysfunction for uncontrolled blood pressure, although
they have no effect on heart failure morbidity and
mortality in these patients.
 For patients with heart failure and preserved ejection
fraction, antihypertensive therapies that should be
considered include β-blockers, ACE inhibitors, ARBs,
calcium channel blockers (including
nondihydropyridine agents), diuretics, and others as
needed to control blood pressure.
Patients with diabetes and hypertension should initially
be treated with either β-blockers, ACE inhibitors, ARBs,
diuretics, or calcium channel blockers. There is a general
consensus that therapy focused on RAAS inhibition by
ACE inhibitors or ARBs may be optimal if the patient has
additional cardiovascular risk factors such as left
ventricular hypertrophy or chronic kidney disease.
 In patients with chronic kidney disease and hypertension,
ACE inhibitors and ARBs are preferred, usually in
combination with a diuretic. ACE inhibitors in
combination with a thiazide diuretic are also preferred in
patients with a history of prior stroke or transient
ischemic attack. This therapy reduces the risk of
recurrent stroke, making it particularly attractive in these
patients for blood pressure control.
A hypertensive emergency occurs when severe elevations in blood
pressure are accompanied by acute or life-threatening target organ
damage such as acute myocardial infarction, unstable angina,
encephalopathy, intracerebral hemorrhage, acute left ventricular
failure with pulmonary edema, dissecting aortic aneurysm, rapidly
progressive renal failure, accelerated malignant hypertension with
papilledema, and eclampsia among others. Blood pressure is
generally greater than 220/140 mm Hg, although a hypertensive
emergency can occur at lower levels, particularly in individuals
without previous hypertension. The goal in a hypertensive emergency
is to reduce mean arterial pressure by up to 25% to the range of
160/100 to 110 mm Hg in minutes to hours. Intravenous therapy
Vasodilators: Sodium nitroprusside as IV infusion 0.25–10
mcg/kg/minute, Nicardipine hydrochloride 5–15 mg/hour IV,
Fenoldopam mesylate 0.1–0.3 mcg/kg/minute as IV infusion,
Nitroglycerin 5–100 mcg/kg/minute as IV infusion, Enalaprilat 1.25–
5 mg every 6 hours, Hydralazine hydrochloride10–20 mg IV 10–40
mg IM.
Adrenergic Inhibitors Labetalol hydrochloride 20–80 mg IV bolus
every 10 min, Esmolol hydrochloride 250–500 mcg/kg/minute IV
bolus, then 50–100 mcg/kg/minute by infusion; may repeat bolus
after 5 minutes or increase infusion to 300 mcg/minute,
Phentolamine 5–15 mg IV bolus.
A hypertensive urgency is manifested as a severe
elevation in blood pressure without evidence of acute or lifethreatening target organ damage. In these individuals,
blood pressure can usually be managed with orally
administered short-acting medications (i.e., captopril,
clonidine, or labetalol) and observation in the emergency
department over several hours, with subsequent discharge
on oral medications and follow-up in the outpatient setting
within 24 hours.
The treatment of elderly patients with hypertension, as
well as those with isolated systolic hypertension, should
follow the same approach as with other populations with
the exception that lower starting doses may be warranted
to avoid symptoms and with special attention paid to
postural hypotension. This should include a careful
assessment of orthostatic symptoms, measurement of blood
pressure in the upright position, and caution to avoid
volume depletion and rapid titration of antihypertensive
In patients of African origin, diminished blood
pressure responses have been seen with ACE
inhibitors and ARBs compared to diuretics or
calcium channel blockers.
 Hypertension in pregnancy is a major cause of
maternal, fetal, and neonatal morbidity and
mortality. There are many categories of
hypertension in pregnancy
Methyldopa Preferred first-line therapy on the basis of long-term
follow-up studies supporting safety after exposure in utero.
Surveillance data do not support an association between drug and
congenital defects when the mother took the drug early in the first
Labetalol Increasingly preferred to methyldopa because of reduced
side effects. The agent does not seem to pose a risk to the fetus, except
possibly in the first trimester.
β-Blockers Generally acceptable on the basis of limited data. Reports
of intrauterine growth restriction with atenolol in the first and second
Clonidine Limited data; no association between drug and congenital
defects when the mother took the drug early in the first trimester, but
number of exposures is small.
Calcium antagonists Limited data; nifedipine in the first was not
associated with increased rates of major birth defects, but animal data
were associated with fetal hypoxemia and acidosis. This agent should
probably be limited to mothers with severe hypertension.
Diuretics Not first-line agents; probably safe; available data suggest
that throughout gestation a diuretic is not associated with an
increased risk of major fetal anomalies or adverse fetal-neonatal
ACEIs and ARBs Contraindicated; reported fetal toxicity and death.