Antihypertensives
Dr. M. Ahsan, MBBS, MD

Learning Outcomes…
• What are antihypertensive agents
• Classify different types of antihypertensives
• Describe the utilization of antihypertensives
• Describe the mode of action and side effects of antihypertensives
• Discuss the rationale for combined antihypertensive therapy

Overview
• Elevated blood pressure is a common disorder, affecting approx. 30%
of adults
• Hypertension is an important risk factor for:
Heart disease
Stroke
Chronic kidney disease
• The risk of organ damage is directly related to the extent of elevation
of BP
BP of the patient should be measured in more than two occasions and he/she should have been
resting for at least 5 mins and should not have consumed coffee or smoked during the last 30 mins

Overview
• Hypertension is classified into four categories
Systolic
(mm Hg)
Diastolic
(mm Hg)
Normal < 120 And < 80
Elevated 120 – 129 Or < 80
Stage 1
hypertension
130 – 139 Or 80 – 89
Stage 2
hypertension
≥ 140 Or ≥ 90

Etiology of hypertension
• Essential hypertension (90% cases)
• Secondary hypertension (10 – 15%)
A healthy lifestyle decreases blood pressure, enhances
antihypertensive drug efficacy and decreases the overall
cardiovascular risk:
 Weight reduction
 Increase in physical activity
 Dietary sodium reduction
 Limited fat intake
 Increased fibre intake
 Restriction on alcohol consumption
 Stopping tobacco products

Mechanism for controlling blood pressure
• Arterial blood pressure is directly proportional to cardiac output and
peripheral vascular resistance
• Most antihypertensives lower BP by reducing cardiac output and/or
decreasing peripheral resistance

Cardiac output and peripheral resistance are controlled by:
Baroreflexes
Renin-angiotensin-aldosterone system

Classification of antihypertensives
Diuretics
• Thiazides: Hydrochlorothiazide, Chlorthalidone,
Indapamide
• High ceiling: Furosemide
• K+ Sparing: Spironolactone, Amiloride
ACE inhibitors
• Captopril, Enalapril, Lisinopril, Perindopril,
Ramipril, Fosinopril
Angiotensin (AT1 receptor) blockers
• Losartan, Candesartan, Irbesartan, Valsartan,
Telmisartan
Direct renin inhibitor
• Aliskiren
Calcium channel blockers
• Verapamil, Diltiazem, Nifedipine, Felodipine,
Amlodipine, Nitrendipine, Lacidipine
β Adrenergic blockers
• Propranolol, Metoprolol, Atenolol
β+ α Adrenergic blockers
• Labetalol, Carvedilol
α Adrenergic blockers
• Prazosin, Terazosin, Doxazosin Phentolamine,
Phenoxybenzamine
Central sympatholytics
• Clonidine, α-Methyldopa
Vasodilators
• Arteriolar: Hydralazine, Minoxidil, Diazoxide
• Arteriolar+venous: Sodium nitroprusside

Diuretics
• Diuretics can be used as first-line drug therapy.
• Diuretics decrease blood volume which ultimately leads to decrease
in blood pressure
• Routine serum electrolyte monitoring should be done in all patients
receiving diuretics

Diuretics
Thiazides are most commonly used as antihypertensives
Actions:
• Lower blood pressure by increasing Na and water excretion
• Decrease in extracellular volume, Decrease in cardiac
output and renal blood flow
• With long-term treatment, plasma volume approaches a
normal value, but peripheral resistance decreases.
• Potassium-sparing diuretics are often used combined with
thiazides.

Diuretics
Therapeutic uses:
• Thiazide diuretics are particularly useful in the treatment of black or
elderly patients.
• Counteract the sodium and water retention observed with other agents
(eg, hydralazine).
Thiazides are not effective in patients
with inadequate kidney function
(creatinine clearance, <50 mL/min)
……..Loop diuretics may be required in
these patients

Diuretics
Adverse effects: Thiazides induce:
• Hypokalemia and
• Hyperuricemia
• Hyperglycemia
• Hypomagnesemia
Serum potassium levels should be monitored closely in patients who are
predisposed to cardiac arrhythmias

Diuretics
Loop diuretics
• Loop diuretics act even in patients with poor renal function or who have
not responded to thiazides or other diuretics.
• Loop diuretics cause decreased renal vascular resistance and increased
renal blood flow.
Loop diuretics increase the
Ca2+ content of urine,
whereas thiazide diuretics
decrease it.

Diuretics
Potassium-sparing diuretics.
• Inhibitors of epithelial sodium transport at the late distal and collecting
ducts :
Amiloride and triamterene
• Aldosterone-receptor antagonists:
Spironolactone and eplerenone
• Spironolactone has the additional benefit of diminishing the cardiac
remodeling that occurs in heart failure.

ACE inhibitors
• These drugs block the ACE that cleaves angiotensin I to form the
potent vasoconstrictor angiotensin II
• ACE inhibitors lower blood pressure by reducing peripheral vascular
resistance without reflexively increasing cardiac output, rate, or
contractility.
• By reducing circulating angiotensin II levels, ACE inhibitors also
decrease the secretion of aldosterone, resulting in decreased sodium
and water retention

Physiological regulation of electrolytes, plasma volume
and blood pressure by the renin-angiotensin system

ACE inhibitors

ACE inhibitors: Therapeutic uses
Hypertension:
• The ACE inhibitors are first line drugs in all grades of hypertension
• ACE inhibitors are highly effective and first choice drugs in
renovascular and resistant hypertension
• Particularly suitable for diabetic hypertensives

ACE inhibitors: Therapeutic uses
They offer the following advantages:
No postural hypotension
Safe in asthmatics, diabetics and
peripheral vascular disease
patients
Secondary hyperaldosteronism and
K+ loss due to diuretics is
prevented
No rebound hypertension on
withdrawal
Left ventricular hypertrophy is
reversed
No hyperuricaemia, no deleterious
effect on plasma lipid profile
Minimum worsening of quality of
life parameters like general
wellbeing, work performance,
sleep, sexual performance, etc.

ACE inhibitors: Therapeutic uses
• CHF
• Myocardial infarction (MI)
• Diabetic nephropathy
• Scleroderma crisis

ACE inhibitors: Adverse effects
• Hypotension
• Hyperkalaemia
• Cough
• Rashes, urticaria
• Angioedema
• Dysgeusia
• Foetopathic
• Acute renal failure: in patients of
bilateral renal artery stenosis
Dry cough: It is not dose related and appears to be caused by inhibition of
bradykinin/substance P breakdown in the lungs of susceptible individuals

Angiotensin II receptor blockers
• These drugs block the AT1 receptors.
• Pharmacologic effects are similar to those of ACE inhibitors
• ARBs do not increase bradykinin levels.
Their adverse effects are similar to those of ACE inhibitors
Risks of cough and angioedema are significantly decreased.
ARBs are also fetotoxic.

Renin inhibitors
• Aliskiren is a selective renin inhibitor, used for the treatment of
hypertension
Aliskiren can cause diarrhea, especially at the higher doses.
Aliskiren can also cause cough and angioedema
Contraindicated during pregnancy.

Calcium channel blockers
• Calcium-channel antagonists block the inward movement of calcium by
binding to L-type calcium channels
(in the heart and in smooth muscle of the coronary and peripheral
vasculature.)
• Causes vascular smooth muscle to relax, dilating mainly arterioles.
• They are recommended first-line agents (especially in black patients)

Classes of calcium channel blockers
Diphenylalkylamines:
Verapamil
Benzothiazepines:
Diltiazem
Dihydropyridines:
• First-generation:
Nifedipine
• Second-generation:
Isradipine, Felodipine,
Amlodipine,
Nitrendipine,
Nimodipine, Lacidipine,
Lercanidipine

Calcium channel blockers: Therapeutic uses
Hypertension:
• Safe in cases of COPD and peripheral vascular disease (β blockers are
contraindicated)
• Black hypertensives respond well to calcium-channel blockers
• Intrinsic natriuretic effect and, therefore, do not require addition of a
diuretic.

Calcium channel blockers: Therapeutic uses
Angina pectoris
Cardiac arrhythmias
• Verapamil and diltiazem for PSVT and supraventricular arrhythmias
Hypertrophic cardiomyopathy
Other uses
• Premature labour (nifedipine)
• Nocturnal leg cramps (verapamil)
• Raynaud’s episodes (DHPs)

Calcium channel blockers
Adverse effects:
• Palpitation, flushing, ankle edema
• Hypotension, headache, drowsiness and nausea
• First-degree AV block
• Constipation
• Urine voiding difficulty in elderly males (nifedipine)
• Gastroesophageal reflux may be worsened (all DHPs)
• Gingival hyperplasia (nifedipine)
Verapamil and
diltiazem should be
avoided in heart
failure and AV block
due to negative
inotropic effect

Beta blockers
• First-line drug therapy for hypertension when concomitant disease is present,
eg. with heart failure
Actions:
• Decrease cardiac output
• Decrease sympathetic outflow from the central nervous system (CNS)
• Inhibit the release of renin from the kidneys
• Propranolol……acts at both β-1 and β-2 receptors.
• Metoprolol and atenolol…..…Selective blockers of β-1 receptors
• More effective in white than in black patients
Selective β-blockers are preferred in asthmatics

Beta blockers
• Conditions that discourage the
use of β-blockers:
severe COPD
1st and 2nd degree heart block
Severe peripheral vascular
disease
• β-blockers are useful in treating
conditions that may coexist with
hypertension, such as:
supraventricular tachyarrhythmia
previous MI
angina pectoris
migraine headache
Chronic heart failure

Beta blockers
Adverse effects:
• Bradycardia
• Hypotension
• Fatigue, lethargy, insomnia, and hallucinations
• Decrease libido and cause impotence
• Alterations in serum lipid patterns: decrease in HDL and increase in TGs
Drug withdrawal: Abrupt withdrawal may induce angina, myocardial infarction, or
even sudden death in patients with ischemic heart disease

Alpha blocking agents
• Competitive blockers of α1-adrenoceptors
• Dilatation of both arteries and veins  tpr  BP
• Reflex tachycardia and Postural hypotension often occur at the onset
of treatment and with increase in dose….slow titration of dose is
required
Prazosin
Doxazosin
Terazosin

Alpha + beta blocking agents
• Labetalol and carvedilol block both α1- and β1- and β2- receptors.
•
Carvedilol: Nonselective β + weak selective α1 blocker
Additional antioxidant/free radical scavenging properties.
Used for long-term treatment of CHF, and is approved as an antihypertensive as well.
Labetalol: Used for rapid BP reduction in hyperadrenergic states, cheese reaction,
clonidine withdrawal, eclampsia, etc.

Centrally acting adrenergic drugs
• Two important antihypertensive agents act primarily in the brain:
Clonidine and methyldopa
• Both drugs are α2-adrenergic receptor agonists
• Decrease sympathetic outflow from the brain to the cardiovascular
system
• Both drugs are well absorbed orally
[clonidine is also available as a transdermal patch]
Clonidine
Methyldopa

Alpha methyldopa
• α-methyldopa is converted to α-methylnorepinephrine in the brain
• α-methylnorepinephrine activates CNS α2-receptors  decrease
sympathetic outflow  reduced total peripheral resistance 
decreased BP
• Used in hypertensive pregnant patients
Adverse effects:
• Sedation and drowsiness.

Clonidine
• Clonidine decreases central sympathetic outflow
• The only difference is that clonidine acts directly on α2-receptors,
whereas methyldopa must first be converted to α-methylnorepinephrine

Clonidine
• Used for hypertension that has not responded adequately to treatment
with two or more drugs.
• Does not decrease renal blood flow  useful in the treatment of
hypertension complicated by renal disease
• Can cause sodium and water retention (add diuretic)
Adverse effects:
Sedation and drying of the nasal mucosa.
Rebound hypertension on abrupt withdrawal
Rebound hypertension
is due to
supersensitivity of
adrenergic receptors
caused by chronic
clonidine-induced
reduction in
sympathetic outflow

Vasodilators
• Vasodilators decreases tpr  decreases blood pressure
• Produce reflex stimulation of the heart
……..This can cause angina pectoris, myocardial infarction, or cardiac
failure in predisposed individuals.
• Vasodilators also increase plasma renin concentration, resulting in
sodium and water retention.
• Undesirable side effects can be blocked by concomitant use of a
diuretic and a β-blocker
Hydralazine
Minoxidil
Diazoxide
Sodium nitroprusside
The three drugs together decrease cardiac output, plasma volume
and peripheral vascular resistance

Vasodilators
Hydralazine:
• Acts primarily on arteries and arterioles
• Used in pregnancy-induced hypertension.
Adverse effects:
• Headache, tachycardia, nausea, sweating, arrhythmia, and precipitation
of angina.
• A lupus-like syndrome can occur with high dosage, but it is reversible on
discontinuation of the drug

Vasodilators
Minoxidil:
• Causes dilation of resistance vessels (arterioles) but not of
capacitance vessels (venules).
• Used for severe to malignant hypertension that is refractory to other
drugs.
Adverse effects:
• Sodium and water retention, leading to volume overload, edema, and
congestive heart failure.
• Hypertrichosis (the growth of body hair)….used for treating male
pattern baldness

Neuroendocrine pathways activated when
vasodilators are given
These pathways lead
ultimately to an
increase in blood
pressure and
compromise the
effectiveness of
vasodilators.
The effectiveness
can be preserved by
coadministration of
propranolol and
diuretics

Vasodilators: Sodium nitroprusside
• Acts rapidly (within seconds) and briefly (2 – 5 mins)….vascular tone
can be titrated with the rate of i.v. infusion.
• Relaxes both resistance and capacitance vessels
• Endothelial cells, RBCs (and may be other cells) split nitroprusside to
generate NO which relaxes vascular smooth muscle
• Side effects mainly due to vasodilatation are
— palpitation, nervousness, vomiting, perspiration, pain in abdomen,
weakness, disorientation, and lactic acidosis (caused by the released
cyanide).
Nitroprusside is light
sensitive, and when in
solution, it should be
protected from light.

Hypertensive emergencies
• Systolic BP > 180 or diastolic BP > 120 mm Hg with evidence of
impending or progressing end organ damage is labelled ‘hypertensive
emergency’,
• Controlled reduction of BP over minutes (in emergencies) or hours (in
urgencies) is required to counter threat to organ function
• Mean BP should be lowered by no more than 25% over a period of
minutes or a few hours and then gradually to not lower than 160/100
mm Hg.

Hypertensive emergencies
• Drugs employed are:
Sodium nitroprusside
Glyceryl trinitrate
Hydralazine
Esmolol
Phentolamine
Labetalol
Fenoldopam
Furosemide
Nicardipine

Individualized care
• Hypertension may coexist with other conditions…it is important to
match the antihypertensive to the patient
Concomitant disease Drug classes indicated in treating hypertension
Stable ischemic heart
disease
β-blocker ACE inhibitor ARBs CCBs
Diabetes Diuretics ACE inhibitor ARBs CCBs
Recurrent stroke Diuretics ACE inhibitor ARBs
Heart failure Diuretics β-blocker ACE inhibitor ARBs Aldosterone receptor antagonist
Previous myocardial
infarction
β-blocker ACE inhibitor Aldosterone receptor antagonist
Chronic kidney disease ACE inhibitor ARBs

Resistant hypertension
• Resistant hypertension is defined as blood pressure that remains elevated
despite administration of an optimal three-drug regimen that includes a
diuretic
Causes:
Poor compliance
Excess ethanol intake
Concomitant conditions (diabetes, obesity, sleep apnea, hyperalsosteronism,
high salt intake, metabolic syndrome)
Concomitant medications (sympathomimetics, NSAIDs, corticosteroids),
insufficient dose, use of drugs with similar mechanism of action

Hypertension in pregnancy
• α-methyldopa, β-blockers and vasodilators are preferred during
pregnancy
• ACE inhibitors and ARBs are contraindicated in pregnancy

Treatment strategies
• The goal of antihypertensive therapy is to reduce cardiovascular and
renal morbidity and mortality
• Antihypertensive therapy is indicated in case of :
• SBP ≥150 mm Hg or DBP ≥90 mm Hg [at age 60 years or more]
• SBP ≥140 mm Hg or DBP≥ 90 mm Hg [age < 60 years]
Current recommendation is to initiate therapy with a thiazide diuretic, ACE inhibitor,
ARB or CCB
 If BP is inadequately controlled after 1 month of therapy, either increase dose or add
another drug
 Add a third drug if two drugs don’t control the BP
 If SBP is greater than 20 mm Hg or DBP is 10 mm Hg above goal…..start with 2 drugs

Rational drug combinations
• The main objective of drug combinations is to achieve additional
blood pressure reduction by using drugs that act by different
mechanisms:
Minimization of adverse effects
Block opposing effects on the homeostatic mechanism
Permits the use of lower dose (less adverse effects)

Drug combinations in hypertension
Fully additive drug
combinations (Preferred
combination)
• Diuretics + β-blocker
• Diuretics + ACE inhibitors
• CCB +β-blocker
• CCB + ACE inhibitor
Questionable drug
combinations
• Nonadditive:
• β-blocker + ACE inhibitor
• ARB + ACE inhibitor
• Side effect additive
• β-blocker + Verapamil
• α blocker + CCB
Preferred combinations
with patients with
associated conditions
• Angina: β-blocker + CCB
• Heart failure: Diuretic + ACE
inhibitor
• Diabetes: ACE inhibitor + CCB
• COPD: Diuretic + CCB

Key points: Rational Drug combinations
• Drugs which increase plasma renin activity— diuretics, vasodilators, CCBs, ACE
inhibitors may be combined with drugs which lower plasma renin activity—β
blockers, clonidine, methyldopa.
• All sympathetic inhibitors (except β blockers) and vasodilators, except CCBs, cause
fluid retention leading to tolerance. Addition of a diuretic checks fluid retention
and development of tolerance.
• Use of combined formulation improves compliance and usually lowers cost.

Key points: Rational Drug combinations
• Hydralazine and DHPs cause tachycardia which is counteracted by β
blockers, while the initial increase in t.p.r. caused by nonselective β
blockers is counteracted by the vasodilator.
• ACE inhibitors/ARBs are particularly synergistic with diuretics; this
combination is very good for patients with associated CHF or left
ventricular hypertrophy.

Key points: Drug combinations
Combinations to be avoided:
• An α or β adrenergic blocker with clonidine: apparent antagonism of
clonidine action has been observed
• Hydralazine with a DHP or prazosin; because of similar pattern of
haemodynamic action
• Verapamil or diltiazem with β blocker, because marked bradycardia,
A-V block can occur
• Methyldopa with clonidine or any two drugs of the same class

Lifestyle modifications as per JNC 7 and
AHSA-ASA
Greater results are achieved when 2 or more lifestyle modifications are combined:
• Weight loss helps to prevent hypertension (range of approximate systolic BP reduction
[SBP], 5-20 mm Hg per 10 kg); recommendations include the DASH (Dietary
Approaches to Stop Hypertension) diet (range of approximate SBP reduction, 8-14
mm Hg), which is rich in fruits and vegetables and encourages the use of fat-free or
low-fat milk and milk products
• Limit alcohol intake to no more than 1 oz (30 mL) of ethanol per day for men (ie, 24 oz
[720 mL] of beer, 10 oz [300 mL] of wine, 2 oz [60 mL] of 100-proof whiskey) or 0.5 oz
(15 mL) of ethanol per day for women and people of lighter weight (range of
approximate SBP reduction, 2-4 mm Hg)

Lifestyle modifications as per JNC 7 and
AHSA-ASA
• Reduce sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g
sodium chloride; range of approximate SBP reduction, 2-8 mm Hg)
• Maintain adequate intake of dietary potassium (approximately 90 mmol/d)
• Maintain adequate intake of dietary calcium and magnesium for general health
• Stop smoking and reduce intake of dietary saturated fat and cholesterol for
overall cardiovascular health
• Engage in aerobic exercise at least 30 minutes daily for most days (range of
approximate SBP reduction, 4-9 mm Hg)

Key messages of JNC 8
• In the general population, pharmacologic treatment should be initiated
when blood pressure is 150/90 mm Hg or higher in adults 60 years and
older, or 140/90 mm Hg or higher in adults younger than 60 years
• In patients with hypertension and diabetes, pharmacologic treatment
should be initiated when blood pressure is 140/90 mm Hg or higher,
regardless of age
• Initial antihypertensive treatment should include a thiazide diuretic,
calcium channel blocker, ACE inhibitor, or ARB in the general nonblack
population or a thiazide diuretic or calcium channel blocker in the general
black population.
• If the target blood pressure is not reached within one month after initiating
therapy, the dosage of the initial medication should be increased, or a
second medication should be added.

Case 1
• A 19 year old male comes to your clinic to get a physical examination
for college sports. He has no h/o illnesses and is on no medication.
During clinic you notice a BP of 150/96 mm Hg.
• How would you manage this patients high BP?

Case 2
• A 42 year old male comes for follow up of his DM. His BP has been a
little high for the last two clinic visits (144/90 mm Hg, 142/96 mm
Hg). He is currently on glipizide and metformin. He has no history of
allergies.
• What is his BP goal?
• What medication do you want to start him on?
• What do you want to monitor

Case 3
• A 56 year old male with h/o HTN, CHF and fibromyalgias. Today his BP
is 152/102 mm Hg and HR is 84/ min. He is currently on
hydrochlorthiazide 25 mg po qd. All his lab reports are normal and
patient reports compliance with medication.
• What drug can you add for better control of his BP?
What things do you want to monitor?

References
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.
• Clinical Medicine: A Textbook for Medical Students &amp; Kumar PJ
and Clark ML (8th ed.); Elsevier Saunders
• Eighth Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8)
• Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)