Indications and Procedures

Blood pressure (BP) refers to the force exerted by the circulating blood against the walls of blood vessels. BP consists of 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 increase, 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 units called torr or 1/760 of standard atmospheric pressure. BP measurements always record a higher number (the systolic pressure) and a lower number (the diastolic pressure). Normal BP is defined as a systolic pressure of 120 torr and a diastolic pressure of 80, which is reported as 120 / 80 or “120 over 80.”

Even though the BP rises and falls during the day, if someone’s BP remains above normal over time that person has high BP or hypertension. A systolic BP between 120 and 139 torr or a diastolic BP between 80 and 90 torr constitutes a condition known as prehypertension. People with prehypertension have a greater risk of developing hypertension. If an individual has a systolic BP between 140 and 159 torr or a diastolic BP between 90 and 99 torr, they have stage 1 hypertension. If they have a systolic BP above 160 or greater or a diastolic BP above 100 torr or greater they have stage 2 hypertension. Hypertension increases the risk of heart disease, congestive heart failure, kidney disease, blindness, and stroke. Also, hypertension tends to have no symptoms until the patient suffers a cardiovascular catastrophe. For this reason, hypertension has been called “the silent killer.” Controlling hypertension remains one of the most important goals of preventative medicine.

In many cases, a patient’s hypertension does not have an obvious direct cause. In such cases the patient has essential or idiopathic hypertension. In other cases, the patient’s hypertension results from an underlying condition. In such cases the patient has secondary hypertension, and kidney disease, tumors, and adrenal gland abnormalities constitute some of the most common causes of secondary hypertension.

Not all strategies for controlling hypertension include medications. Particular lifestyle choices increase someone’s risk for hypertension: cigarette smoking, obesity, diabetes, physical inactivity, chronic alcohol consumption, a family history of hypertension or heart disease, excessive consumption of sodium, and age or sex (women older than 55 and men older than 45). Therefore, nondrug strategies to manage hypertension include weight loss, stress reduction, regular aerobic exercise, smoking cessation, moderation of alcohol consumption, and dietary changes. Some people have a physiological sensitivity to salt and must decrease their consumption of sodium in order to control their BP. These people can usually reduce their BP by adhering to the Dietary Approaches to Stop Hypertension or DASH diet. Those who use the DASH diet eat fruits, vegetables, lowfat dairy foods, poultry, nuts, and fish that are low in sodium, saturated fat, and cholesterol, and avoid sweets, sugared drinks, red meats, and fats.

If nondrug strategies fail to properly low the BP to normal levels, then the next step requires the administration of an antihypertensive agent. One of the first agents used to lower BP are diuretics. Diuretics drugs work in the kidney to increase the amount of water filtered from the blood by the kidney and increase urine output. Because PVR depends on blood volume, the reduction of blood volume lowers BP. A second class of antihypertensive agents is the beta blockers. Beta blockers bind to receptors on the surfaces of heart muscle cells called beta receptors and prevent them from receiving signals from sympathetic nerves. The sympathetic nervous system mediates the “fight or flight” response, and sympathetic nerve inputs increase the heart rate. An increase in heart rate increases CO and therefore increases BP. By blocking sympathetic nerve inputs to the heart, beta blockers decrease CO and BP.

If BP remains high after administration of a diuretic or a beta blocker, then the physician either increases the dosages of these drugs or prescribes an additional antihypertensive agent. Such drugs include calcium channel blockers, angiotensin-Converting Enzyme (ACE) inhibitors, or angiotensin II Receptor Blockers (ARBs). Calcium channel blockers (CCBs) inhibit L-type calcium channels that reside in the membranes of the smooth muscles that surround blood vessels and heart cells. Since they prevent the entry of calcium ions into these cells, CCBs dilate blood vessels, reduce the force of contraction of heart muscles, and slow the conduction of electrical activity within the heart. In doing so, CCBs decrease PVR and CO and lower BP.

ACE inhibitors irreversibly 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 kidney to retain more salt. This signaling pathway, the renin-angiotensin-aldosterone system, raises BP. By blocking the production of angiotensin II, ACE inhibitors prevent vasoconstriction and sodium retention, which leads to wider blood vessels, reduced PVR and BP. ARBs prevent angiotensin II from binding to its receptor on the surfaces of the 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 the centrally or peripherally acting antiadrenergics. Alpha blockers bind alpha1 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 vessels dilators (or vasodilators) work through a variety of different mechanisms to cause blood vessel dilation or vasodilation 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 into the normal range.

Uses and Complications

The first-line drugs for treating hypertension tend to be diuretics and beta blockers. These drugs tend to work quite well, are usually rather inexpensive and, for the most part, well tolerated.

Several different types of diuretics exist: thiazides, loop diuretics, potassium-sparing diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. All diuretics prevent the reabsorption of salts and water by the kidney, increase water loss and urine output, and, consequently, reduce PVR and BP. Diuretics are used to reduce BP, but also to treat the swelling (edema) that results from congestive heart failure, liver and kidney disease, glaucoma, and swelling in the brain (cerebral edema). After beginning any antihypertensive agent, many patients feel lightheaded when they change from a sitting to a standing position (orthostatic hypotension). These symptoms typically fade after taking the drug for some time. Most antihypertensives also cause sexual dysfunction. The most common side effects of diuretics are dehydration and low potassium levels (hypokalemia), but other rarer side effects occur as well (Table 1). These represent the side effects patients have experienced while taking these drugs; no one has experienced all these side effects. Potassium-sparing diuretics can cause excessively high blood potassium levels (hyperkalemia).

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). They may cause heart failure in heart patients and interfere with blood sugar readings in diabetics. 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 (ß1) than the lung-specific beta receptor (ß2).

ACE inhibitors and ARBs can treat hypertension, congestive heart failure, or diabetics suffering 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 birth defects.

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 cimetidine (for ulcers, increases effects of CCBs), theophylline (for asthma, CCBs increase toxic effects of theophylline), 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 might be useful for treating hypertension in older men because these drugs have a tendency to shrink the prostate. Doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin) may cause these side effects: dizziness, weakness, fatigue, upset stomach and loss of appetite, drowsiness, edema, and nasal congestion.

The antiadrenergic drugs include peripherally acting drugs, such as guanadrel (Hylorel) and guanethidine (Ismelin), and the centrally acting drugs, such as clonidine (Catapres), guanabenz (Wytensin), guanfacine (Tenex), and methydopa (Aldomet). The side effects of guanadrel and guanethidine include blurred vision, orthostatic hypotension, sexual dysfunction, diarrhea, and swelling of feet or lower legs. Drugs that work within the central nervous system cause more severe side effects and typically are 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, methydopa is the drug of choice to treat high blood pressure during pregnancy (gestational hypertension).

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

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 in 1733 by the English Reverend Stephen Hales, Riva-Rocci in 1896, and 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), 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. Because ACE inhibitors can cause hyperkalemia and decrease urine output, hydro-chlorothiazide nullifies those side effects by increasing potassium and water loss and increasing the reduction in BP. Timolide combines hydrochlorothiazide with the beta blocker timolol. 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 to treat and much more convenient for patients.

See also

Cardiology; Hypertension; Hypotension; Kidneys; Pharmacology; Vascular medicine

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