Antihypertensives

Treatment

Also known as: Blood pressure medicines

Anatomy or system affected: Cardiovascular system

Definition: Medications that lower blood pressure (BP), used to treat hypertension and related complications.

Key terms:

diastole: period of time during which the heart relaxes and fills with blood

hyperkalemia: excessively high blood levels of potassium

hypokalemia: abnormally low blood levels of potassium

orthostatic hypotension: a sudden fall in blood pressure when a person stands up

systole: the contraction of the heart and the forcible expulsion of blood into large blood vessels

vasoconstriction: narrowing of blood vessels as a result of the contraction of the smooth muscles that surround the walls of blood vessels

vasodilation: expansion of blood vessels as a consequence of the relaxation of the smooth muscles that surround the walls of blood vessels

Indications and Procedures

Blood pressure (BP) refers to the force exerted by the circulating blood against the walls of blood vessels. BP is the product of two physiological parameters: the pumping of the heart that propels blood through blood vessels and the resistance provided by those vessels against which the heart must work. These two parameters are referred to as cardiac output (CO) and peripheral vascular resistance (PVR). Mathematically, BP = CO x PVR. Consequently, if either CO or PVR increases, BP increases, and, conversely, if either of these decreases, BP decreases.

The heart undergoes a cycle of contracting and relaxing. When the heart contracts and ejects blood from its chambers, it undergoes systole. After systole, the heart relaxes and allows its chambers to fill, a period known as diastole. At systole, the BP has its highest reading, and at diastole, its lowest reading. BP is measured in units called millimeters of mercury (mm Hg). Blood pressure is recorded as two numbers: the higher number (systolic pressure), representing pressure during heart contraction, and the lower number (diastolic pressure), representing pressure during relaxation. Normal BP is defined as a systolic pressure of around 120 mm Hg and a diastolic pressure of around 80 mm Hg, which is reported as 120/80 or “120 over 80.”

Although the BP rises and falls during the day, if someone's BP remains consistently above normal, that person has high BP or hypertension. A systolic BP between 120 and 129 mm Hg with a diastolic BP less than 80 mm Hg is classified as elevated blood pressure. Stage 1 hypertension is defined as a systolic BP between 130 and 139 mm Hg or a diastolic BP between 80 and 89 mm Hg. Stage 2 hypertension is defined as a systolic BP of 140 mm Hg or higher or a diastolic BP of 90 mm Hg or higher. Hypertension increases the risk of heart disease, congestive heart failure (CHF), kidney disease, blindness, and stroke. Also, hypertension tends to have no symptoms until the patient suffers a cardiovascular event. For this reason, hypertension has been called “the silent killer.” Controlling hypertension remains one of the most important goals of preventive medicine.

In most people, hypertension arises without a clear, direct cause and is classified as essential (or primary) hypertension. However, secondary hypertension—caused by identifiable conditions such as chronic kidney disease, adrenal tumors, coarctation of the aorta, or certain medications—requires targeted treatment of the underlying issue.

Nonpharmacologic strategies are the foundation of hypertension management and often the first line of intervention, particularly for individuals with elevated blood pressure or Stage 1 hypertension without additional cardiovascular risk factors. Lifestyle changes target modifiable risk factors, such as obesity, smoking, inactivity, high sodium intake, and excessive alcohol use. Research indicates that even minimal weight loss can significantly improve blood pressure. Regular physical activity is also critical. Adults should engage in about two hours of moderate-intensity aerobic exercise (brisk walking or cycling) and two or three resistance training sessions each week. Managing stress using cognitive behavioral therapy, meditation, yoga, and breathing techniques, and getting adequate sleep are also essential components of blood pressure control.

A dietary approach called the DASH (Dietary Approaches to Stop Hypertension) diet remains a cornerstone for addressing blood pressure. The DASH diet emphasizes fruits, vegetables, whole grains, low-fat dairy products, fish, and poultry while limiting red meats, sweets, sugar-sweetened beverages, and foods high in saturated fat and cholesterol. Sodium intake should also be less than 2,300 milligrams per day, with an ideal target of less than 1,500 milligrams, especially in salt-sensitive individuals, those with chronic kidney disease, and older adults.

Patients should limit their intake of alcohol, ultra-processed foods, and refined sugars, and smoking should be eliminated. The rise of digital health tools—smartphone-based coaching, wearable activity trackers, and artificial intelligence-assisted diet logging—allows patients to monitor their blood pressure management progress from home.

If nondrug strategies fail to lower BP, medications will be prescribed. First-line agents typically include thiazide-type diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs). The choice between medications depends on the patient's age, comorbidities, race/ethnicity, kidney function, and risk of cardiovascular events. Many patients require combination therapy using two or more medications for optimal BP control. Fixed-dose combinations, which simplify dosing and improve adherence, are increasingly preferred. Additional agents such as beta blockers, alpha blockers, centrally acting antiadrenergics, or peripheral vasodilators may be used in high-risk or resistant cases. Modern therapeutic options, including SGLT2 inhibitors and mineralocorticoid receptor antagonists, are being employed in patients with heart failure, chronic kidney disease, or diabetes, especially when blood pressure and organ protection are both clinical goals.

ACE inhibitors inactivate the enzyme angiotensin-converting enzyme (ACE). Present mainly in the capillary beds of the lungs, ACE converts the polypeptide angiotensin I to angiotensin II, a molecule that causes blood vessels to narrow (vasoconstriction), thus increasing PVR. The liver produces a blood protein called angiotensinogen, and an enzyme called renin converts angiotensinogen to angiotensin I. The kidney secretes renin in response to lower arterial BP, decreased salt in the urine, or sympathetic nerve activity. Angiotensin II also signals to the adrenal glands to release the hormone aldosterone, which directs the kidneys to retain more salt. This signaling pathway, the renin-angiotensin-aldosterone system, raises BP. By blocking the production or action of angiotensin II, ACE inhibitors and ARBs prevent vasoconstriction and sodium retention, which leads to wider blood vessels and reduced PVR and BP. ARBs prevent angiotensin II from binding to its receptor on the surfaces of smooth muscles that surround blood vessels and adrenal gland cells. Thus, even though ARBs do not prevent the synthesis of angiotensin II, they prevent angiotensin II from causing vasoconstriction and sodium retention, and consequently lower PVR and BP.

If, after adding these additional antihypertensive agents, the patient's BP still remains abnormally high, then the physician prescribes a combination of two or three antihypertensive agents and may consider other drugs such as alpha blockers, direct-acting blood vessel dilators, or centrally or peripherally acting antiadrenergics. Alpha blockers bind alpha-1 receptors on the surfaces of the smooth muscles that surround blood vessels and prevent them from receiving signals that tell them to contract. Thus, alpha blockers cause blood vessels to dilate, reducing PVR and BP. Direct-acting blood vessel dilators (or vasodilators) work through a variety of mechanisms to cause blood vessel dilation and reduce PVR and, therefore, BP. Antiadrenergics inhibit the sympathetic nervous system. Some work in the brain and spinal cord (central nervous system), and others work at the level of the peripheral nervous system. Typically, some combination of these drugs reduces the blood pressure to the normal range.

Uses and Complications

The first-line drugs for treating hypertension include thiazide-type diuretics, calcium channel blockers (CCBs), ACE inhibitors, and angiotensin II receptor blockers (ARBs). Beta blockers are no longer considered first-line for uncomplicated hypertension but remain important in specific clinical situations such as heart failure, post-myocardial infarction (MI), or arrhythmias. These drugs are generally well-tolerated and often relatively inexpensive.

Several types of diuretics exist: thiazide-type diuretics, loop diuretics, potassium-sparing diuretics, and mineralocorticoid receptor antagonists (MRAs). All diuretics reduce blood volume by promoting the excretion of salt and water through the kidneys, thereby decreasing peripheral vascular resistance and lowering BP. Diuretics are also used to treat edema caused by congestive heart failure, liver and kidney disease, and some are used in glaucoma and cerebral edema. Thiazide-type diuretics, particularly chlorthalidone and indapamide, are preferred over the older hydrochlorothiazide due to longer duration of action and improved cardiovascular outcomes.

Common side effects of diuretics include dehydration, electrolyte disturbances, and orthostatic hypotension. Thiazides may cause hypokalemia, elevated blood glucose, or gout. Potassium-sparing diuretics and MRAs (e.g., spironolactone) may cause hyperkalemia and, in some cases, gynecomastia. Osmotic diuretics and carbonic anhydrase inhibitors are used for specific conditions rather than routine hypertension management. Patients starting antihypertensives may experience lightheadedness, particularly when standing (orthostatic hypotension). These symptoms often resolve with time. Other potential complications include sexual dysfunction, fatigue, or photosensitivity, depending on the drug class. Medication selection is often guided by the patient's comorbidities, tolerability, and specific side effect profiles. Many patients benefit from fixed-dose combination therapies, which improve adherence and reduce pill burden.

Beta blockers can treat hypertension or the chest pain that results when the heart receives too little oxygen to perform its work (angina pectoris). Beta blockers may cause diarrhea, stomach pain, nausea, vomiting, rash, blurred vision, muscle cramps, fatigue, headache, depression, confusion, dizziness, nightmares, and hallucinations (Table 2). Beta blockers are essential for long-term management of certain types of heart failure, but must be used cautiously, especially in patients with decompensated heart failure, where they can temporarily worsen symptoms. They can also interfere with blood sugar regulation by slightly altering glucose metabolism and masking key symptoms of hypoglycemia, like rapid heartbeat, especially in people with diabetes; this effect is more pronounced with non-selective beta blockers than with cardioselective beta blockers. If withdrawn suddenly, they can cause heart attacks or sudden death. Beta blockers can also aggravate asthma attacks in asthmatics because of the presence of a different type of beta receptor in the lungs. This, however, can be alleviated by using cardioselective beta blockers that have a higher affinity for the heart-specific beta receptor (β1) than the lung-specific beta receptor (β2).

ACE inhibitors and ARBs can treat hypertension, congestive heart failure, or diabetics suffering from kidney problems. The side effects of ARBs and ACE inhibitors are a dry cough (ACE inhibitors usually), hyperkalemia, diarrhea (ARBs mainly), orthostatic hypotension, headache, drowsiness, weakness, a salty or metallic taste in one's mouth, and a rash (Table 3). Rarely, ARBs and ACE inhibitors cause a massive shift of fluid to areas under the skin (angioedema), allergies, a decrease in white blood cells, and kidney failure. Neither ARBs nor ACE inhibitors should be taken during pregnancy because they can cause congenital abnormalities.

CCBs are used to treat angina and hypertension. CCB side effects include dizziness, lightheadedness, nervousness, loss of muscle strength (asthenia), fatigue, nausea, constipation and upset stomach, edema, low blood pressure (hypotension), irregular heart rate, rash, flushing, nasal congestion, and cough. CCBs also interact with several other drugs (Table 4).

CCBs interact with St. John's Wort (herb, for depression, reduces blood concentrations of CCBs), digoxin (heart medicine, CCBs increase toxicity of digoxin), and rifampin (antituberculosis drug, decreases effects of CCBs).

Alpha blockers may be useful in older men with both hypertension and benign prostatic hyperplasia (BPH), as they improve urinary flow by relaxing prostate and bladder smooth muscle, although they are not first-line antihypertensives. Doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin) may cause dizziness, weakness, fatigue, upset stomach and loss of appetite, drowsiness, edema, and nasal congestion. However, these medications are not considered first-line antihypertensives due to their inferior cardiovascular outcomes compared to other drug classes and their tendency to cause orthostatic hypotension, especially after the first dose. Other side effects may include dizziness, fatigue, drowsiness, nasal congestion, peripheral edema, upset stomach, and loss of appetite. They may still have a role as adjunctive therapy in patients who benefit from both antihypertensive and urologic effects.

Centrally acting antiadrenergic drugs, such as clonidine (Catapres), guanfacine (Tenex), and methyldopa (Aldomet). Drugs that work within the central nervous system cause more severe side effects and are typically only used as a last resort or for emergencies. Heavy sedation, fainting, dry mouth, constipation, impotence, dizziness, and drowsiness are some of the most common side effects. Psychological side effects that range from depression, nightmares, mood changes, and psychosis also occur. Despite these side effects, methyldopa is the drug of choice to treat high blood pressure during pregnancy (gestational hypertension).

Centrally acting antiadrenergic drugs, such as clonidine (Catapres), guanfacine (Tenex), and methyldopa (Aldomet), reduce blood pressure by decreasing sympathetic nervous system outflow. While effective, they are associated with significant side effects—heavy sedation, dry mouth, dizziness, constipation, impotence, fatigue, and drowsiness. Psychological effects include depression, nightmares, mood changes, and even psychosis. Methyldopa remains the drug of choice for treating hypertension during pregnancy. Clonidine, once widely used, is mainly reserved for hypertensive urgencies or as a secondary agent in treatment-resistant cases. Patients with poor medication adherence may benefit from its transdermal patch formulation. Guanabenz is unavailable in most markets in the twenty-first century, and guanfacine has found utility in non-hypertensive indications, such as attention-deficit/hyperactivity disorder.

The peripheral vasodilators include hydralazine (Apresoline), minoxidil (Loniten), diazoxide (Hyperstat), and sodium nitroprusside (Nitropress). These drugs cause many serious side effects and are only used in emergencies.

Peripheral vasodilators, including hydralazine (Apresoline) and minoxidil (Loniten), directly relax vascular smooth muscle, significantly reducing peripheral resistance. These aid in severe or refractory hypertension—BP that remains out of control after trying five different classes of antihypertensive medications. Hydralazine is also used in pregnancy-related hypertension and combination therapy for heart failure (particularly in Black patients). Minoxidil, while effective, is associated with side effects such as fluid retention, reflex tachycardia, and hypertrichosis (excessive hair growth) and is rarely a first or second choice. More potent agents like sodium nitroprusside (Nitropress) and diazoxide (Hyperstat) are limited to emergency settings due to risks such as cyanide toxicity (nitroprusside) and hyperglycemia (diazoxide). These drugs require close monitoring; medical professionals usually administer them in controlled inpatient environments.

Perspective and Prospects

In 2600 BC, the ancient Chinese diagnosed hypertension by the quality of one's pulse and treated it with bleeding and leeches. Revolutionary work by the English reverend Stephen Hales in 1733, Italian physician Scipione Riva-Rocci in 1896, and Russian surgeon Nikolai Korotkoff in 1905 culminated in the invention of the blood pressure cuff, which gave clinicians a way to easily measure blood pressure.

Hypertension remained an untreated disease over the initial part of the twentieth century. Even President Franklin Delano Roosevelt's hypertension was treated with phenobarbital, a low-sodium diet, and rest. Then, in 1957–58, thiazide diuretics were shown by the US Veterans Administration (VA) to significantly reduce cardiovascular morbidity and mortality. These successes led to the establishment of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC) in 1978, which established national clinical guidelines for hypertension management and treatment.

For recalcitrant cases of hypertension, composite drugs that combine two or more antihypertensives in one dose have been developed, and these have revolutionized hypertension treatment. For example, Zestoretic combines hydrochlorothiazide and lisinopril. Hydrochlorothiazide may counteract hyperkalemia and enhance blood pressure reduction when used with ACE inhibitors, which is why they are commonly combined in fixed-dose regimens like Zestoretic. Since beta blockers sometimes can cause edema in some people, the thiazide diuretic gets rid of all that extra swelling and further reduces blood pressure. Such combinations have made treating the harder hypertension cases much easier and much more convenient for patients.

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