Hypertension Medication

Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, or high blood pressure, is a common disease manifesting as elevated systemic arterial pressure. Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, and diet are all contributing factors to hypertension and can lead to heart attack, stroke, congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure, and CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease 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 Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) (CCBs). Contraindications, adverse effects, and drug-to-drug interactions are agent specific.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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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 Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep apnea
    • Vascular:
      • Aortic isthmus stenosis
      • Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis
      • Coarctation of the aorta Coarctation of the aorta Coarctation of the aorta is a narrowing of the aorta between the aortic arch and the iliac bifurcation commonly around the point of insertion of the ductus arteriosus. Coarctation of the aorta is typically congenital and the clinical presentation depends on the age of the patient. Coarctation of the Aorta 
    • Certain toxins and drugs:
      • Oral contraceptives
      • Steroids
      • Stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants
      • Illicit drugs (e.g., cocaine, methamphetamine)
    • Renal:
      • Renal artery stenosis Renal artery stenosis Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis
      • Renal parenchyma diseases
    • Endocrine:
      • Primary and secondary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism
      • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
      • Cushing syndrome
      • Thyrotoxicosis Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
    • Neurogenic, psychogenic, and iatrogenic forms are also present.
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

Pathophysiology

  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics
    • Aldosterone antagonist
    • Alpha-1 blockers
    • Nonselective alpha blockers
    • Alpha-2 agonist
    • Vasodilators
    • Nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. 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 Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus ( DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus) or CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
      • Age > 60 and blood pressure ≥ 150/90 mm Hg
      • Age < 60 and blood pressure ≥ 140/90 mm Hg
    • Adults with DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus and/or CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease: blood pressure ≥ 140/90 mm Hg (regardless of age)
  • Antihypertensive agent selections should be based upon:
    • Medical comorbidities (particularly DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus and CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease):
      • ACEis
      • ARBs
    • African American and older individuals:
      • CCBs
      • Thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. 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 category Systolic BP (mm Hg) Diastolic BP (mm Hg)
Normal BP < 120 mm Hg AND < 80 mm Hg
Elevated BP 120–129 mm Hg OR < 80 mm Hg
Stage 1 hypertension 130–139 mm Hg OR 80–89 mm Hg
Stage 2 hypertension ≥ 140 mm Hg OR ≥ 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 Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. 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 Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia).
    • Diuresis → lower plasma volume → lower blood pressure
  • Thiazide use results in:
    • ↑ Excretion of Na+, Cl, K+, and water 
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia: ↑ reabsorption of Ca2+
  • Development of hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia and metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. 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 Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
      • Stimulates the K+-H+ exchanger → reabsorbs the extra K+ in the tubule in exchange for H+ (excreted) → metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis via H+ loss

Pharmacokinetics

Table: Pharmacokinetics of thiazide diuretics
Drug Absorption Metabolism Excretion
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
Chlorthalidone Peak effect 2–6 hours Hepatic
  • Urine
  • Half-life: 40 hours
Indapamide
  • Rapid and complete absorption
  • Peak effect: 2 hours
Extensive hepatic metabolism
  • Urine: 75%
  • Feces: 25%
Metolazone Onset of action: 1 hour Not metabolized Urine
HCTZ: hydrochlorothiazide

Contraindications

  • Hypersensitivity reactions
  • Anuria and/or renal failure
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Hypokalemia
  • Allergy to sulfa drugs
  • Gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. 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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension (1st-line agent), especially in individuals who have:
    • Type 2 DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
    • 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 Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
    • ↓ Efferent arteriole resistance in the kidney → diminishes proteinuria and stabilizes renal function in CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
  • 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.

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 ↑ bioavailability compared with active drugs
  • Relatively quick onset of action: 15‒60 min
Prodrugs are activated via hydrolysis in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • Cough
  • Pancreatitis
  • Angioedema

Contraindications

  • History of angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema 
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

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 Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Flushing
    • Peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (dose-dependent; usually with amlodipine)
    • Gingival hyperplasia
  • Nondihydropyridines:
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation (dose-dependent)
    • Fatigue
    • Bradycardia
    • Atrioventricular nodal block
    • Worsening of cardiac output
    • Gingival hyperplasia

Contraindications

  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. 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 action Class Subclass
Renal drugs Diuretics
  • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics
  • Thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics
  • Potassium-sparing diuretics Potassium-sparing diuretics Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts to induce diuresis that does not result in excretion of potassium. These diuretics include 2 subclasses: sodium channel blockers and aldosterone antagonists. Potassium-sparing Diuretics
  • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors
  • Osmotic diuretics Osmotic diuretics Osmotic diuretics increase tubular fluid osmolarity, pulling water into the collecting tubules and preventing water reabsorption, which results in osmotic diuresis. The primary osmotic diuretic used clinically is mannitol. The primary indication for mannitol is to treat cases of increased intracranial or intraocular pressure. Osmotic Diuretics
Drugs affecting RAAS
  • ACEis
  • ARBs
  • Direct renin inhibitors
Extrarenal drugs Direct vasodilators
  • CCBs
  • Potassium channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the 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 class Mechanism of action Examples of drugs in the class Adverse effects Other
Thiazide-like diuretic
  • Inhibits the Na+-Cl transporter in the DCT
  • ↓ Cardiovascular events in hypertension
  • Chlorthalidone
  • HCTZ
  • Metolazone
  • ↓ K+
  • Gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout
  • ↑ BG
  • Metabolic alkalosis
Excellent as 1st-line monotherapy or in combination
ACEi Prevents conversion of angiotensin I to angiotensin II
  • Captopril
  • Enalapril
  • Lisinopril
  • ↓ BP
  • ↑ K+
  • Angioedema
  • Cough
  • Best 1st-line therapy for DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (slows progression of renal disease)
  • ACEi preferred over ARB
ARB Blocks binding of angiotensin II to the receptor
  • Losartan
  • Valsartan
  • Candesartan
  • ↓ BP
  • Renal failure
CCB Inhibits the voltage-gated Ca++ channel → smooth muscle relaxation
  • Amlodipine
  • Clevidipine
  • Nifedipine
  • Nicardipine
  • Diltiazem
  • Headache
  • Dizziness
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). 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 class Mechanism of action Examples of drugs in the class Adverse effects Other
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 diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics Blockade of the Na+/K+-2Cl cotransporter in the loop of Henle
  • Furosemide
  • Torsemide
  • ↓ K+
  • ↓ Mg
  • ↑ Uric acid
Used in CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure-related hypertension
Aldosterone antagonists
  • Blocks aldosterone receptors in the RCT
  • ↑ NaCl + water excretion + K+ retention
  • Spironolactone
  • Eplerenone
  • ↑ K+
  • Gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia
May have superior benefit in refractory hypertension
Alpha-1 blockers Selective blockade of the alpha-1 adrenergic receptor
  • Prazosin
  • Terazosin
Orthostatic hypotension Used in benign prostatic hypertrophy and hypertension
Nonselective alpha blockers Blockade of alpha-1 and alpha-2 receptors
  • Phenoxybenzamine
  • Phentolamine
Orthostatic hypotension
  • Useful in cocaine-induced hypertension
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
Alpha-2 agonists ↓ Overall sympathetic activity Clonidine
  • Bradycardia
  • Rebound hypertension
Useful in opioid-withdrawal hypertension
Vasodilators Direct arteriolar vasodilation Hydralazine
  • Reflex tachycardia
  • Lupus
  • Headache
Treats hypertension in pregnancy
Nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates ↑ cGMP + vasodilation of veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins > arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries
  • Nitroglycerine
  • Isosorbide dinitrate
  • Headache
  • Reflex tachycardia
Na+ nitroprusside for hypertensive emergency
CO: cardiac output
RCT: renal collecting duct
cGMP: cyclic GMP
CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure: congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. 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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