Hypertension Medication

Hypertension, or high blood pressure, is a common disease 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, congestive 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.

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Overview

Etiology

  • Primary hypertension: idiopathic:
    • 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 symptom from a 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

Indications for medical therapy

  • American Heart Association and American College of Cardiology guidelines: 
    • Blood pressure ≥ 140/90 mm Hg, OR
    • Blood pressure ≥ 130/80 mm Hg in individuals with a 10-year risk of cardiovascular death > 10% (per risk calculator)
  • Eighth Joint National Committee (JNC 8) guidelines:
    • Adults without diabetes mellitus (DM) or CKD: 
      • Age > 60 and blood pressure ≥ 150/90 mm Hg
      • Age < 60 and blood pressure ≥ 140/90 mm Hg
    • Adults with DM and/or CKD: blood pressure ≥ 140/90 mm Hg (regardless of age)
  • Antihypertensive agent selections should be based upon:
    • 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: 2017 JNC 8 guidelines

Table: Classification of hypertension (2017 JNC 8 guidelines)
BP categorySystolic BP (mm Hg)Diastolic BP (mm Hg)
Normal BP< 120 mm HgAND< 80 mm Hg
Elevated BP120–129 mm HgOR< 80 mm Hg
Stage 1 hypertension130–139 mm HgOR80–89 mm Hg
Stage 2 hypertension≥ 140 mm HgOR≥ 90 mm Hg
JNC 8: Eighth Joint National Committee

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
DrugAbsorptionMetabolismExcretion
HCTZ
  • Well absorbed
  • Peak effect in 4 hours
  • Bioavailability 65%–75%
Not metabolized
  • Urine
  • Half-life: 6–15 hours
Chlorothiazide
  • Poor oral absorption
  • Peak effect: 30 minutes IV
Not metabolized
  • Urine
  • Half-life: 45–120 minutes
ChlorthalidonePeak effect 2–6 hoursHepatic
  • Urine
  • Half-life: 40 hours
Indapamide
  • Rapid and complete absorption
  • Peak effect: 2 hours
Extensive hepatic metabolism
  • Urine: 75%
  • Feces: 25%
MetolazoneOnset of action: 1 hourNot metabolizedUrine
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
RAAS inhibitors and their location of action overview

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.

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Pharmacokinetics

Table: Pharmacokinetics of the renin–angiotensin–aldosterone system drugs angiotensin converting enzyme inhibitors and angiotensin II receptor blockers
DrugAbsorptionMetabolismExcretion
ACEis
  • Prodrugs have ↑ bioavailability compared with active drugs
  • Relatively quick onset of action: 15‒60 min
Prodrugs are activated via hydrolysis in the liver; active drugs are unchanged.
  • Primarily in the urine
  • Half-life: varies from 2‒24 hours depending on the drug
ARBs
  • Bioavailability: varies
  • Rapidly absorbed orally
Hepatic metabolism
  • Feces (60%)
  • Urine (35%, approximately 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 actionClassSubclass
Renal drugsDiuretics
  • Loop diuretics
  • Thiazide diuretics
  • Potassium-sparing diuretics
  • Carbonic anhydrase inhibitors
  • Osmotic diuretics
Drugs affecting RAAS
  • ACEis
  • ARBs
  • Direct renin inhibitors
Extrarenal drugsDirect vasodilators
  • CCBs
  • Potassium channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system
  • Drugs affecting CNS sympathetic outflow
  • 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 classMechanism of actionExamples of drugs in the classAdverse effectsOther
Thiazide-like diuretic
  • Inhibits the Na+-Cl transporter in the DCT
  • ↓ Cardiovascular events in hypertension
  • Chlorthalidone
  • HCTZ
  • Metolazone
  • ↓ K+
  • Gout
  • ↑ BG
  • Metabolic alkalosis
Excellent as 1st-line monotherapy or in combination
ACEiPrevents conversion of angiotensin I to angiotensin II
  • Captopril
  • Enalapril
  • Lisinopril
  • ↓ BP
  • ↑ K+
  • Angioedema
  • Cough
  • Best 1st-line therapy for DM (slows progression of renal disease)
  • ACEi preferred over ARB
ARBBlocks binding of angiotensin II to the receptor
  • Losartan
  • Valsartan
  • Candesartan
  • ↓ BP
  • Renal failure
CCBInhibits the voltage-gated Ca++ channel → smooth muscle relaxation
  • Amlodipine
  • Clevidipine
  • Nifedipine
  • Nicardipine
  • Diltiazem
  • Headache
  • Dizziness
  • Constipation
  • Peripheral edema
  • Gingival hyperplasia
1st-line therapy in individuals with abnormal renal function
DCT: distal convoluted tubule
HCTZ: hydrochlorothiazide
BG: blood glucose
ACEi: angiotensin-converting enzyme inhibitor
ARB: angiotensin II receptor blocker
CCB: calcium channel blocker
Ca++: calcium

Additional medications

Table: Additional medications used in the management of arterial hypertension
Drug classMechanism of actionExamples of drugs in the classAdverse effectsOther
Beta-blockers↓ Sympathetic output by blockade of B-adrenergic receptors
  • Propranolol
  • Metoprolol
  • Atenolol
  • Bisoprolol
  • Labetalol
  • Bronchospasm
  • ↓ HR
  • Heart block
  • ↓ CO
  • Fatigue
2nd-line therapy for chronic hypertension (unless another indication for beta-blocker therapy is present)
Loop diureticsBlockade of the Na+/K+-2Cl cotransporter in the loop of Henle
  • Furosemide
  • Torsemide
  • ↓ K+
  • ↓ Mg
  • ↑ Uric acid
Used in CHF-related hypertension
Aldosterone antagonists
  • Blocks aldosterone receptors in the RCT
  • ↑ NaCl + water excretion + K+ retention
  • Spironolactone
  • Eplerenone
  • ↑ K+
  • Gynecomastia
May have superior benefit in refractory hypertension
Alpha-1 blockersSelective blockade of the alpha-1 adrenergic receptor
  • Prazosin
  • Terazosin
Orthostatic hypotensionUsed in benign prostatic hypertrophy and hypertension
Nonselective alpha blockersBlockade of alpha-1 and alpha-2 receptors
  • Phenoxybenzamine
  • Phentolamine
Orthostatic hypotension
  • Useful in cocaine-induced hypertension
  • Pheochromocytoma
Alpha-2 agonists↓ Overall sympathetic activityClonidine
  • Bradycardia
  • Rebound hypertension
Useful in opioid-withdrawal hypertension
VasodilatorsDirect arteriolar vasodilationHydralazine
  • Reflex tachycardia
  • Lupus
  • Headache
Treats hypertension in pregnancy
Nitrates↑ cGMP + vasodilation of veins > arteries
  • Nitroglycerine
  • Isosorbide dinitrate
  • Headache
  • Reflex tachycardia
Na+ nitroprusside for hypertensive emergency
CO: cardiac output
RCT: renal collecting duct
cGMP: cyclic GMP
CHF: congestive heart failure

References

  1. Whelton, P.K., Carey, R.M., et al. (2017). ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension. 71(6), p.e13–e115. https://www.ahajournals.org/doi/10.1161/HYP.0000000000000065
  2. Mann, J. (2021). Choice of drug therapy in primary (essential) hypertension. In Bakris, G. (Ed.), UpToDate. Retrieved June 6, 2021, from https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension
  3. Bloch, M., and Basile, J. (2021). Antihypertensive drugs and lipids. In Bakris, G. (Ed.), UpToDate. Retrieved June 6, 2021, from https://www.uptodate.com/contents/antihypertensive-drugs-and-lipids
  4. Basile, J., and Bloch, M. (2021). Overview of hypertension in adults. In Bakris, G., and White, W. (Ed.), UpToDate. Retrieved June 6, 2021, from https://www.uptodate.com/contents/overview-of-hypertension-in-adults
  5. Bloch, M., Basile, J., Bakris, G., Elliott, W., Forman, J. (2020). Major side effects and safety of calcium channel blockers. UpToDate. Retrieved November 6, 2020, from https://www.uptodate.com/contents/major-side-effects-and-safety-of-calcium-channel-blockers
  6. Blood Pressure Lowering Treatment Trialists’ Collaboration, Turnbull, F., et al. (2008). Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 336(7653), 1121–1123. https://pubmed.ncbi.nlm.nih.gov/18480116/
  7. Law, M.R., et al. (2009). Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 338, b1665. https://pubmed.ncbi.nlm.nih.gov/19454737/

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