Hypertension lecture3

Pharmacological Treatment
• Pharmacological treatment of hypertension reduces the incidence of
heart failure, stroke, and MI, and decreases the mortality rate due to
cardiovascular causes in middle-aged and older adults. Drug therapy
is indicated if lifestyle modifications do not bring BP into the desired
range within a reasonable period of time.
Guideline Indication for pharmacological therapy Treatment goal

AHA/ACC 2017 BP ≥ 140/90 mm Hg Age < 65: BP < 130/80 mm Hg

BP ≥ 130/80 mm Hg with a 10-year-risk of Age ≥ 65: systolic BP < 130 mm Hg
cardiovascular death ≥ 10% For patients with significant comorbidities or
(e.g., patients with age ≥ 65 years, diabetes limited life expectancy, the BP goal is
mellitus, chronic kidney disease, heart failure, determined based on clinical judgment and the
table ischemic sheart disease, peripheral patient's preference.
artery disease, and/or previous stroke)

JNC 8 Adults without diabetes mellitus or chronic BP less than threshold for initiating pharmacological
kidney disease therapy
Age ≥ 60 years: BP ≥ 150/90 mm HgAge < 60
years: BP ≥ 140/90 mm Hg
Adults with diabetes mellitus and/or chronic
kidney disease: ≥ 140/90 mm Hg
Initiation of treatment
• Number of antihypertensives
• Newly diagnosed hypertension with BP < 150/90 mm Hg: Begin therapy
with one primary antihypertensive.
• Newly diagnosed hypertension with BP > 150/90 mm Hg: Begin therapy
with two primary antihypertensives.
• Choice of antihypertensive drug
• Non-African American patients (including individuals with diabetes):
thiazide-type diuretic, calcium channel blocker (CCB),
angiotensin-converting enzyme inhibitor (ACE-I), or angiotensin receptor
blocker (ARB)
• African American patients (including individuals with diabetes):
thiazide-type diuretic or CCB
• In adults with chronic kidney disease: initial (or add-on) treatment should
include an ACE inhibitor or ARB to improve kidney outcome.
Follow-up

• Reassess within one month of initiating or changing pharmacological

therapy.
• If the treatment goal is not reached with one drug, increase the dose
of the initial drug or add a second drug.
• If the treatment goal cannot be reached with two drugs:
• Add a third drug.
• Evaluate for secondary causes of hypertension.
• If blood pressure is controlled: Reassess after 3–6 months and
annually thereafter.
Overview of antihypertensive drugs
First-line drugs

• ACE inhibitors (Angiotensin-converting enzyme inhibitors)

A group of antihypertensive drugs that inhibit the enzyme responsible
for the conversion of angiotensin I to angiotensin II. Other uses include
slowing the progress of chronic kidney disease, delaying the onset of
nephropathy in patients with diabetes mellitus, and treatment of left
ventricular systolic dysfunction.

Lisinopril, captopril, enalapril

Angiotensin-receptor blockers (ARB)

• A group of drugs that blocks AT1 receptors, which decreases the

binding of angiotensin II. This decreases vasoconstriction, which
lowers the blood pressure. Also leads to decreased secretion of
aldosterone, which causes decreased reabsorption of Na+ and water
and lowers blood pressure. Used if angiotensin-converting enzyme
(ACE) inhibitors are not tolerated.

• Losartan, valsartan, irbesartan, candesartan.

ACEi and ARBs
• Preferred as a first-line drug in patients with diabetes mellitus, renal
disease (nephroprotective), ischemic heart disease, and heart failure
• ACEi and ARBs should not be used in combination.

• Side effects
• Dry cough, angioedema
• ↑ K+
• Teratogenic
Thiazide diuretics
A group of diuretic agents that act as Na⁺-Cl⁻ cotransporter inhibitors in the
early distal renal tubule. Used mainly to treat hypertension..
Adverse effects include metabolic alkalosis, electrolyte abnormalities
(hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia), metabolic
effects (hyperglycemia, hyperuricemia), and sulfonamide hypersensitivity.

• Hydrochlorothiazide- inhibits Na+ and Cl- resorption in the distal

convoluted tubule
• Chlorthalidone -  inhibits Na+ and Cl- reabsorption in the loop of Henle.
Thiazide diuretics
• Preferred as a first-line drug in African Americans, salt-sensitive
patients, and patients with isolated systolic hypertension.

• Side effects
• ↓ K+, ↓ Na
• ↑ Glucose and cholesterol
Calcium channel blockers, CCB
• A group of drugs that inhibit L-type voltage-gated calcium channels
found in cardiomyocytes and arterial smooth muscle cells. In the
heart, CCBs cause negative inotropic, chronotropic, and dromotropic
effects. In arteries, they lead to muscle relaxation and vasodilation.
• Three main classes of CCBs are phenylalkylamines (e.g., verapamil),
benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g.,
nifedipine, amlodipine). Mainly used to treat hypertension, coronary
artery disease, and cardiac arrhythmias.
Dihydropyridine calcium channel blockers
• A class of calcium channel blockers that cause systemic vasodilation.
Commonly used in antihypertensive therapy. In contrast to
non-dihydropyridines, they have minimal myocardial depressant activity.
Adverse effects include peripheral edema, headaches, dizziness, facial
flushing, reflex tachycardia, and gingival hyperplasia.
• Agents include nifedipine, nicardipine, and amlodipine.
• Preferred as a first-line drug among African Americans and patients with
isolated systolic hypertension
• Side effects
• Headache
• Constipation
• Gastroesophageal reflux
• Pedal edema
Nondihydropyridine calcium channel blockers
Abbreviation: ndHP CCBs
• A class of calcium channel blockers that do not contain the dihydropyridine
molecule. They include phenylalkylamines (e.g., verapamil), which are
purely cardioselective, and benzothiazepines (e.g., diltiazem), which act on
both heart and vascular smooth muscle.
• Nondihydropyridines are contraindicated in patients with reduced ejection
fraction.
• Side effects
• Headache
• Constipation
• Gastroesophageal reflux
• Pedal edema
• Bradycardia
Second-line drugs
• Beta blockers (Beta antagonists)

• A group of drugs that inhibit sympathetic activation of β adrenergic

receptors. Cardioselective blockers (e.g., bisoprolol) primarily block
β1 receptors (the main β receptor of the heart), which causes
decreased heart rate and cardiac contractility, slower AVN
conduction, and decreased cardiac workload. Nonselective β blockers
(e.g., propranolol) inhibit all β receptors and thus are associated with
more adverse effects.
• Propranolol, metoprolol, labetalol
Beta blockers (Beta antagonists)
• Should be avoided in hypertension due
to aortic regurgitation • Side effects
• Often used as a primary drug in
patients with any of the following
comorbidities: • Bronchoconstriction with
noncardioselective beta blockers
• Ischemic heart disease
• Increased triglycerides
• Heart failure
• Atrial fibrillation
• Thoracic aortic disease (e.g.,
dissection, aneurysm)
• Thyrotoxicosis
• Migraine
• Essential tremor
Loop diuretics

• A group of drugs that block the Na+/K+/2Cl- cotransporters in the

thick ascending loop of Henle. This causes the gradient between the
renal medulla and cortex to diminish over time and reduces the
nephron's capacity to concentrate the urine, which leads to diuresis.
• Associated with the following metabolic imbalances: hypokalemia,
hypomagnesemia, hypocalcemia, hypochloremia, hyponatremia, and
metabolic alkalosis.
• Furosemide, torsemide
Loop diuretics
• Used in symptomatic heart failure and CKD (if GFR < 30 mL/min)

• Side effects
• ↓ K+, ↓ Na
• ↑ Glucose
• ↑ Cholesterol
Aldosterone receptor antagonists
( or Mineralocorticoid receptor antagonists)
• A group of drugs that act on the distal convoluted tubules and inhibit
the effects of aldosterone. Results in decreased Na⁺ reabsorption
(and thus decreased H₂O retention) and inhibited H⁺ and K⁺ excretion.

• Eplerenone, spironolactone
• Used in hypertension due to primary aldosteronism
• Can be used as add-on therapy in resistant hypertension
• Side effects:
• ↑ K+
• Gynecomastia (spironolactone)
• Direct renin inhibitors (e.g., aliskiren)

• Should not be used in combination with ACEi or ARBs

• ↑ K+
• Alpha-1 blocker (or Alpha-1 receptor antagonist)

• Drugs that act as antagonists on α-1 adrenoreceptors and induce relaxation of

blood vessels as well as the smooth muscle cells of the bladder, neck and the
urethra. Used to treat hypertension (e.g., doxazosin) or benign prostatic
hyperplasia (e.g., tamsulosin, alfuzosin).
• Used in hypertension due to pheochromocytoma
• May be used as an adjunct in patients with benign prostatic hypertrophy

• Side effects
• Postural hypotension
• Headache
• Alpha-2 adrenergic agonists
• A group of drugs that activate α2 receptors in presynaptic
sympathetic neurons of the central nervous system, which leads to a
decrease in sympathetic tone that causes vasodilation and lowers
blood pressure. Adverse effects include orthostatic hypotension,
sedation, and bradycardia.
• Rarely used, usually for resistant hypertension
• Direct arteriolar vasodilators (e.g., hydralazine)

• Hydralazine is a first-line treatment in pregnancy.

• Sodium nitroprusside is used only in hypertensive emergencies.

• Side effects
• Reflex tachycardia
• Sodium and water retention
• Cyanide toxicity with long-term use of sodium nitroprusside
• therapy with antihypertensive drugs should be initiated at low doses to minimize
side effects. Long-acting formulations with 24-hour efficacy are preferred over
shorter acting agents because of greater patient adherence to once-daily dosing
regimens and more consistent BP control throughout the day.
• Based on patient response, the dose of the initial agent can be slowly titrated
upward, or a small dose of a second agent can be added.
• Most patients with hypertension require multiple drugs for optimal BP control.
Effective drug combinations use medications from different classes and result in
additive BP lowering effects, while minimizing dose-dependent adverse effects.
• Thiazide diuretics potentiate the effect of ACE inhibitors, ARBs, and calcium
antagonists;
• Calcium antagonists (CCB) + ACE inhibitors or ARBs.
• A combination of an ACE inhibitor or ARB plus a thiazide diuretic and calcium
antagonist is often effective in patients who require three drugs.
• Lowering BP is but one mechanism by which cardiovascular risk can
be reduced in hypertensive patients.
• Irrespective of baseline cholesterol levels, statin therapy is
recommended to reduce the incidence of MI and stroke in patients at
intermediate or high risk of cardiovascular events. Low-dose aspirin
also reduces cardiovascular event rates in selected patients.