Hypertension Drugs

Hypertension, or high blood pressure, is a common medical condition manifesting as

elevated systemic arterial pressure. Hypertension is most often asymptomatic and
discovered as part of a routine physical examination, or during triage for an unrelated
medical encounter. Age, gender, smoking, obesity, and diet are all contributing
factors to hypertension and can lead to heart attack, stroke, heart failure, and CKD if
not managed properly. If blood pressure cannot be controlled with lifestyle
modifications, medications are employed for the management of hypertension. The
1st-line medication classes include thiazide-like diuretics, angiotensin-converting
enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), and calcium
channel blockers (CCBs). Contraindications, adverse effects, and drug-to-drug
interactions are agent specific.

Last updated: January 17, 2024

CONTENTS

Overview
Thiazide and Thiazide-like Diuretics
ACEis and ARBs
Calcium Channel Blockers
Comparison of Antihypertensive Medications
References
Overview
Etiology
Primary hypertension (also known as idiopathic or essential hypertension):
90% or more of all hypertensive individuals
Risk factors:
Usually 30+ years of age
Nutritional factors: ↑ weight, alcohol consumption, ↑ sodium in diet
Stress
Smoking
↑ Age
Secondary hypertension (a manifestation of another disease process):
Sleep apnea
Vascular:
Aortic isthmus stenosis
Atherosclerosis
Coarctation of the aorta
Certain toxins and drugs:
Oral contraceptives
Steroids
Stimulants
Illicit drugs (e.g., cocaine, methamphetamine)
Renal:
Renal artery stenosis
Renal parenchyma diseases
Endocrine:
Primary and secondary hyperaldosteronism
Pheochromocytoma
Cushing syndrome
Thyrotoxicosis
Neurogenic, psychogenic, and iatrogenic forms are also present.
Pregnancy

Pathophysiology
 Hypertension develops due to a disturbance of the regulatory mechanism, which
maintains constant blood pressure:
↑ Peripheral resistance
↑ Cardiac output
Combination of both
Several compensatory mechanisms occur and maintain ↑ blood pressure:
Cardiac hypertrophy
Blood vessel hypertrophy
Baroreceptor reflex is shifted.
↑ Sodium excretion (pressure natriuresis)

Classes of antihypertensive medications

1st line:
Thiazide-like diuretics
Angiotensin-converting enzyme inhibitors (ACEis)
Angiotensin II receptor blockers (ARBs)
Calcium channel blockers (CCBs)
Miscellaneous:
Beta blockers
Loop diuretics
Aldosterone antagonist
Alpha-1 blockers
Nonselective alpha blockers
Alpha-2 agonist
Vasodilators
Nitrates

Current guidelines
American Heart Association and American College of Cardiology guidelines
(2017, 2021):
 Blood pressure < 120/< 80 mm Hg (normal):
No indication to treat
Health lifestyle education and promotion
BP measurement annually
Blood pressure 120–129/< 80 mm Hg (elevated):
No indication for pharmacologic intervention
Initiate nonpharmacologic intervention (i.e., healthy diet, exercise,
weight loss, smoking cessation)
BP assessment every 3–6 months
Blood pressure 130–139/80–89 mm Hg (stage 1 hypertension) in individuals with
a 10-year risk of cardiovascular death of < 10% (per risk calculator) and no known
atherosclerotic cardiovascular disease (ASCVD):
Initiate nonpharmacologic intervention (i.e., healthy diet, exercise,
weight loss, smoking cessation) to achieve a goal BP of < 120/< 80 mm Hg
BP assessment every month until at goal; intensify treatment as needed
BP assessment every 3–6 months after goal achieved and maintained
Blood pressure 130–139/80–89 mm Hg (stage 1 hypertension) in individuals with
a 10-year risk of cardiovascular death of > 10% (per risk calculator) or known
ASCVD:
Initiate nonpharmacologic intervention (i.e., healthy diet, exercise,
weight loss, smoking cessation) AND
Initiate pharmacologic treatment to achieve a goal BP of < 120/< 80 mm Hg
BP assessment every month until at goal; intensify treatment as needed
BP assessment every 3–6 months after goal achieved and maintained
Blood pressure ≥ 140/≥ 90 mm Hg (stage 2 hypertension):
Initiate nonpharmacologic intervention (i.e., healthy diet, exercise,
weight loss, smoking cessation) AND
Initiate pharmacologic treatment to achieve goal BP of < 120/< 80 mm Hg
BP assessment every month until at goal; intensify treatment as needed
BP assessment every 3–6 months after goal achieved and maintained
Eighth Joint National Committee (JNC 8, 2014) guidelines:
Blood pressure ≥ 150/90 mm Hg, age > 60, no diabetes mellitus (DM) or CKD:
Initiate pharmacologic treatment to achieve a goal BP of < 150/< 90 mm Hg
BP assessment every month until at goal; intensify treatment as needed
Blood pressure ≥ 140/90 mm Hg, age < 60, no DM or CKD:
Initiate pharmacologic treatment to achieve a goal BP of < 140/< 90 mm Hg
BP assessment every month until at goal; intensify treatment as needed
Blood pressure ≥ 140/90 mm Hg (regardless of age), with DM and/or CKD:
Initiate pharmacologic treatment to achieve a goal BP of < 140/< 90 mm Hg
BP assessment every month until at goal; intensify treatment as needed
Selection of antihypertensive agent should be based on:
 Medical comorbidities (particularly DM and CKD):
ACEis
ARBs
African American and older individuals:
CCBs
Thiazide diuretics
Younger individuals:
ACEis
ARBs
Combination therapy of 1st-line agents often includes:
ACEis/ARBs
Addition of either thiazide diuretics or CCBs

Classification of hypertension
Table: Classification of hypertension (2017 JNC 8 guidelines)

BP category Systolic BP (mm Diastolic BP (mm

Hg) Hg)

Normal BP < 120 mm Hg AND < 80 mm Hg

Elevated BP 120–129 mm Hg AND < 80 mm Hg

Stage 1 130–139 mm Hg OR 80–89 mm Hg

hypertension

Stage 2 ≥ 140 mm Hg OR ≥ 90 mm Hg
hypertension

Reference: American College of Cardiology/American Heart Association

(ACC/AHA)

Thiazide and Thiazide-like Diuretics

Drugs in the thiazide and thiazide-like class
 Hydrochlorothiazide (HCTZ) (the prototypical drug in the class)
Chlorothiazide
Chlorthalidone (1st-line agent in the treatment of hypertension)
Indapamide
Metolazone

Principles of therapy
Monitor:
Blood pressure
Creatinine clearance (CrCl)
Na+
K+
Chlorthalidone and Indapamide:
1st-line agent for monotherapy when treating hypertension
Compared to HCTZ: 1.5–2x as potent, longer half-life
Trials have shown ↓ in cardiovascular events.
May have ↑ side effects and risk of hypokalemia
HCTZ:
Commonly used as a 1st-line agent for hypertension (though less effective
than chlorthalidone or indapamide)
Available in combination pills with ACEis, ARBs, and/or CCBs
Not as effective when CrCl is < 30 ml/min.
Metolazone:
May be more effective than other thiazides when CrCl is < 30 ml/min.
Often combined with other diuretics

Mechanism of action
 ↓ Reabsorption of NaCl through inhibition of the Na+-Cl- cotransporter in the
distal convoluted tubule (DCT):
With the channel blocked → Na+ reabsorption ↓
Water stays with Na+ in the tubules (not reabsorbed).
Diuresis results from the osmotic effect of Na+ (hyponatremia).
Diuresis → lower plasma volume → lower blood pressure
Thiazide use results in:
↑ Excretion of Na+, Cl-, K+, and water
Hypercalcemia: ↑ reabsorption of Ca2+
Development of hypokalemia and metabolic acidosis:
↓ Na+ reabsorption in the DCT
↑ Na+ delivered to the collecting ducts (CDs)
Stimulates ↑ aldosterone release:
Stimulates the Na+-K+ exchanger → increases Na+ reabsorption,
excretes K+ → hypokalemia
Stimulates the K+-H+ exchanger → reabsorbs the extra K+ in the
tubule in exchange for H+ (excreted) → metabolic alkalosis via H+
loss

Pharmacokinetics
 Table: Pharmacokinetics of thiazide diuretics

Drug Absorption Metabolism Excretion

HCTZ Well absorbed Not Urine

Peak effect in metabolized Half-life:
4 hours 6–15
Bioavailability hours
65%–75%

Chlorothiazide Poor oral Not Urine

absorption metabolized Half-life:
Peak effect: 30 45–120
minutes IV minutes

Chlorthalidone Peak effect 2–6 Hepatic Urine

hours Half-life:
40 hours

Indapamide Rapid and Extensive Urine:

complete hepatic 75%
absorption metabolism Feces:
Peak effect: 2 25%
hours

Metolazone Onset of action: 1 Not Urine

hour metabolized

HCTZ: hydrochlorothiazide

Contraindications
Hypersensitivity reactions
Anuria and/or renal failure
Hypotension
Hypokalemia
Allergy to sulfa drugs
Gout
ACEis and ARBs
Drugs in the ACEis class
Captopril
Enalapril
Ramipril
Benazepril
Multiple others ending in "-pril"

Drugs in the ARBs class

Losartan
Telmisartan
Valsartan
Multiple others ending in "-tan"

Principles of therapy
Hypertension (1st-line agent), especially in individuals who have:
Type 2 DM
CKD
Coronary artery disease (CAD)
ACEis and ARBs are generally not used together (except in rare circumstances
and generally by nephrologists).
ACEis and ARBs are frequently combined with:
Diuretics (most commonly HCTZ)
CCBs
ARBs are better tolerated than ACEis.

Mechanism of action
Both ACEis and ARBs utilize RAAS.
ACEis:
Inhibits ACE, which prevents:
Conversion of angiotensin I to angiotensin II
Degradation of bradykinin (a potent vasodilator)
↓ Peripheral vascular resistance via ↓ angiotensin II levels:
↓ Vasoconstriction
↓ Sympathetic activity
↓ Na+ and water reabsorption in the kidney (direct effect)
↓ Aldosterone secretion
↑ Bradykinin:
Vasodilation
↑ Risk of cough and angioedema
↓ Efferent arteriole resistance in the kidney → diminishes proteinuria and
stabilizes renal function in CKD
ARBs:
Inhibits angiotensin type 1 (AT1) receptors
↓ Angiotensin II activity → ↓ aldosterone secretion:
↓ Vasoconstriction
↓ Sympathetic activity
↓ Na+ and water reabsorption in the kidney
No effect on bradykinin
Overview of RAAS inhibitors and their location of action:
ACE inhibitors block both the degradation of bradykinin and the generation of angiotensin II.
ARBs block the angiotensin II type 1 receptors. Direct renin inhibitors block the generation of
angiotensin I.
Spironolactone blocks mineralocorticoid receptors at the principal cells in the distal renal
tubules and cortical collecting duct.
Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics
 Table: Pharmacokinetics of the renin–angiotensin–aldosterone
system drugs angiotensin converting enzyme inhibitors and
angiotensin II receptor blockers

Drug Absorption Metabolism Excretion

ACEis Prodrugs have Prodrugs are Primarily in the

↑ bioavailability activated via urine
compared with hydrolysis in Half-life: varies
active drugs the liver; active from 2‒24 hours
Relatively quick drugs are depending on
onset of action: unchanged. the drug
15‒60 min

ARBs Bioavailability: Hepatic Feces (60%)

varies metabolism Urine (35%,
Rapidly approximately
absorbed orally 4% as
unchanged
drug)
Half-life: varies
from 2‒24 hours

Adverse effects
Hyperkalemia
Cough
Pancreatitis
Angioedema

Contraindications
History of angioedema
Pregnancy

Calcium Channel Blockers

Classes of CCBs
Dihydropyridines:
Binds more selectively to vascular smooth muscle calcium channels
(vasodilator)
Can lead to reflex tachycardia
Example: amlodipine
Nondihydropyridine:
Affects the heart contractility and conduction (less effective on
vasodilation)
Does not lead to reflex tachycardia
Benzothiazepine:
Mainly acts on the myocardium (myocardial depressant)
Acts as a cardiac depressant and a vasodilator
Example: diltiazem
Phenylalkylamine:
Acts on cardiac myocytes (strong myocardial depressant)
Example: verapamil

Mechanism of action
CCBs bind L-type calcium channels in cardiac myocytes, cardiac nodal tissues,
and vascular smooth muscle cells, which leads to:
The closure of L-type channels
↓ Calcium entry
Smooth muscle relaxation → systemic vasodilation
↓ Cardiac afterload leads to ↓ blood pressure (effective in hypertension).
↓ Myocardial contractility (negative inotropic effect)
↓ Atrioventricular node conduction velocity (negative dromotropic effect)
↓ Automaticity (negative chronotropic effect)

Absorption and excretion

Dosage forms: oral, IV
Metabolism: hepatic 1st-pass metabolism (primarily by CYP3A4)
Drug interactions:
Rifampicin accelerates CCB breakdown.
Protease inhibitors, macrolide antibiotics, fluconazole, and grapefruit juice
inhibit CCB breakdown.
Excretion: renal

Adverse effects
 Dihydropyridines:
Headache (cerebral vasodilation)
Reflex tachycardia (especially with short-acting nifedipine)
Hypotension
Flushing
Peripheral edema (dose-dependent; usually with amlodipine)
Gingival hyperplasia
Nondihydropyridines:
Constipation (dose-dependent)
Fatigue
Bradycardia
Atrioventricular nodal block
Worsening of cardiac output
Gingival hyperplasia

Contraindications
Hypotension
Hypersensitivity to CCBs
Acute coronary syndrome:
Avoid nifedipine or short-acting dihydropyridines.
Short-acting dihydropyridines cause reflex tachycardia and worsen
myocardial ischemia.

Comparison of Antihypertensive
Medications
Drugs used to treat hypertension
Table: Class and subclass of drugs used to treat hypertension by
location of action

Location of Class Subclass

action

Renal drugs Diuretics Loop diuretics

Thiazide diuretics
Potassium-sparing
diuretics
Carbonic anhydrase
inhibitors
Osmotic diuretics

Drugs affecting RAAS ACEis

ARBs
Direct renin inhibitors

Extrarenal Direct vasodilators CCBs

drugs Potassium channel
openers
Nitrodilators
Endothelin
antagonists

Agents acting via the Drugs affecting CNS

sympathetic sympathetic outflow
nervous system Drugs affecting
ganglia
Drugs affecting nerve
terminals
Drugs affecting alpha
and beta receptors

RAAS: renin-angiotensin-aldosterone system

ACEi: angiotensin-converting enzyme inhibitor
ARB: angiotensin receptor block
CCB: calcium channel blocker
Comparison of potential 1st-line therapies for
hypertension
Table: Comparison of potential 1st-line therapies for hypertension

Drug Mechanism of Examples of Adverse

class action drugs in the effects
class

Thiazide- Inhibits the Chlorthalidone ↓ K+

like Na+-Cl- HCTZ Gout
diuretic transporter in Metolazone ↑ BG
the DCT Metabolic
↓ alkalosis
Cardiovascular
events in
hypertension

ACEi Prevents Captopril ↓ BP

conversion of Enalapril ↑ K+
angiotensin I to Lisinopril Angioedema
angiotensin II Cough

ARB Blocks binding Losartan ↓ BP

of angiotensin II Valsartan Renal failure
to the receptor Candesartan

CCB Inhibits the Amlodipine Headache

voltage-gated Clevidipine Dizziness
Ca2+ channel → Nifedipine Constipation
smooth muscle Nicardipine Peripheral
relaxation Diltiazem edema
Gingival
hyperplasia

DCT: distal convoluted tubule

HCTZ: hydrochlorothiazide
BG: blood glucose
ACEi: angiotensin-converting enzyme inhibitor
ARB: angiotensin II receptor blocker
CCB: calcium channel blocker
Ca2+: calcium
Additional medications
Table: Additional medications used in the management of arterial hyp

Drug class Mechanism of Examples of drugs in Adverse effe

action the class
Drug class Mechanism of Examples of drugs in Adverse effe
action the class

Beta- ↓ Sympathetic Propranolol Bronchosp

blockers output by Metoprolol ↓ HR
blockade of Atenolol Heart bloc
B-adrenergic Bisoprolol ↓ CO
receptors Labetalol Fatigue

Loop Blockade of Furosemide ↓ K+

diuretics the Torsemide ↓ Mg
Na+/K+-2Cl ↑ Uric acid
cotransporter
in the
loop of Henle

Aldosterone Blocks Spironolactone ↑ K+

antagonists aldosterone Eplerenone Gynecoma
receptors in
the RCT
↑ NaCl +
water
excretion +
K+ retention

Alpha-1 Selective Prazosin Orthostatic

blockers blockade of Terazosin hypotension
the alpha-1
adrenergic
receptor

Nonselective Blockade of Phenoxybenzamine Orthostatic

alpha alpha-1 and Phentolamine hypotension
blockers alpha-2
receptors
 Drug class Mechanism of Examples of drugs in Adverse effe
action the class

Alpha-2 ↓ Overall Clonidine Bradycard

agonists sympathetic Rebound
activity hypertens

Vasodilators Direct Hydralazine Reflex

arteriolar tachycardi
vasodilation Lupus
Headache

Nitrates ↑ cGMP + Nitroglycerine Headache

vasodilation Isosorbide dinitrate Reflex
of veins > tachycardi
arteries

CO: cardiac output

RCT: renal collecting duct
cGMP: cyclic GMP
HF: heart failure

References
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