PHA 824

THE THERAPY OF HYPERTENSION

MICHAEL T. PIASCIK

 

OBJECTIVES

  1. Identify the classes of pharmacologic agents used to treat hypertension as well as which of these agents are first and second line agents.
  2. Discuss the mechanisms of action by which antihypertensive drugs reduce blood pressure.
  3. Know the prominent side effects of clinically useful antihypertensives.
  4. Describe the pharmacologic and nonpharmacologic approaches to the therapy of hypertension.

 

Perspective

There are over 100 drug products (individual agents and fixed dose combinations) that are available for the treatment of hypertension. Of the top 200 drugs by prescription sales (see http://www.rxlist.com) nearly 10 percent are used to treat hypertension. Despite this, hypertension provides a unique therapeutic challenge. The goal of therapy is not the reduction in blood pressure per se. Rather, it is to decrease the end organ damage and subsequent pathophysiology that occurs with sustained, untreated elevated blood pressure. Another goal of therapy is minimize the number of drugs prescribed as well as the times that drugs have to be taken. Hypertension is a unique clinical problem because it is an asymptomatic disease. Therefore, therapy with antihypertensive drugs can cause a variety of unpleasant side effects which can reduce patient compliance.

Key drugs not mentioned in other lectures

Minoxidil
Fenoldopam

DEFINITION AND PREVALENCE OF THE CLINICAL PROBLEM

 

In preparing this, handout material was taken from The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7). This report can be found at:

http://www.nhlbi.nih.gov/guidelines/hypertension/

 

Elevated blood pressure is the most common chronic illness in the United States, affecting more than 50 million people. There are differences in the prevalence of this disease which are based on age, race, sex and socioeconomic status. Guidelines for the classification of hypertension are as follows:

 

 

THE MANAGEMENT OF HIGH BLOOD PRESSURE

Untreated hypertension leads to end-organ damage and death. Reduction of blood pressure is associated with a decrease in the morbidity and mortality of other cardiovascular diseases such as stroke, congestive heart failure, left ventricular hypertrophy and renal failure, as well as an increase in the quality of life. In addition to pharmacologic means to lower blood pressure, life-style modifications can also decrease blood pressure. These would include weight reduction, smoking cessation, decreases in alcohol consumption and an increase in regular exercise.

Potential Sites of Action for Antihypertensive Drugs

 Recall B.P. = (Stroke Volume x Heart Rate) x Peripheral Vascular Resistance

Classes of Antihypertensive Drugs

Special Considerations

Elderly: Drug metabolism and distribution are altered. Therefore, begin treatment with smaller doses. While beta blockers and diuretics has been proposed as being are particularly effective in the elderly, any of the recommended drugs in the treatment algorithm can be used in the elderly.

African Americans: Hypertension is more prevalent and severe. There is also an increase in the incidence ofdiabetes, stroke and renal failure. Diuretics are particularly effective in African Americans. ACE inhibitors are less effective.

NSAID and COX2 inhibitors: These agents blunt the hypotensive response to a variety of antihypertensives.

Orthostatic hypotension

Volume expansion

 

These tables are not intended to be all inclusive but rather to give you an idea of number of drug classes and combination products available to treat hypertension.

 

SELECTED COMMENTS ON INDIVIDUAL DRUG CLASSES

The points listed below have been previously discussed. Key features are reiterated for emphasis.

Diuretics
The major diuretic class used in the long term treatment of hypertension are the thiazides. K+ sparing and loop diuretics can also be used. Thiazides are one of the cornerstones of hypertensive therapy. Numerous clinical studies have shown these agents to decrease the risks of other cardiovascular diseases. Diuretics can be used as monotherapy for mild hypertension as well as in combination with other antihypertensives. Many, but not all, antihypertensive agents induce water and salt retention. Diuretics counter this increase in fluid retention. This allows for lower concentrations of both drugs to be used. Thiazide diuretics are particularly effective in African Americans and the elderly. These agents are available as generics, thus are not very expensive. Potential side effects include hyponatremia, hypokalemia and the potential for rhythm disturbance, glucose intolerance and a reduction in the efficacy of oral hypoglycemic agents, impotence and increases in lipid and cholesterol levels. Despite these potential deleterious effects on glucose and lipids, diuretics can still decrease the risks associated with diabetes or elevated lipids and cholesterol. These agents increase uric acid levels and should be used carefully in individuals with gout. K+ sparing diuretics can be given with thiazides or loop diuretics to counter the hypokalemia.

Angiotensin Converting Enzyme Inhibitors and AT1-Receptor Antagonists.
ACE inhibitors are effective regardless of the circulating renin levels. Side effects to be aware of include; persistent cough, angioedema and loss of taste (dysgusia). These side effects are less likely to occur with AT1-receptor antagonists.  There is no evidence that one class is superior to the other. ACE inhibitors and AT1- receptor antagonists are first line agents for the treatment of hypertension. These drugs might have particular benefit in patients who also have congestive heart failure or following myocardial infarction.

Beta Blockers
Beta blockers are first line agents in the treatment of hypertension. These drugs have diverse effects on cardiovascular function and have a variety of cardiovascular and noncardiovascular uses. They also block the release of renin (mediated by beta1-receptors). There are selective and nonselective beta blockers. Prominent side effects include sedation, fatigue, and an impairment of sexual function. In addition, all beta blockers mask the tachycardia associated with hypoglycemia. As a result, the diabetic patient is deprived of one of the earliest physiologic responses to hypoglycemia. Despite this action on glucose or potential effects on lipid levels, beta blockers have been shown to be effective in improving outcomes in diabetic patients (especially selective beta1-blockers) and patients with elevated lipids. Recall that a disadvantage of nonselective beta blockers is the fact that they will block beta2 receptors associated with airway or vascular smooth muscle. This unwanted action can exacerbate airways disease (asthma, emphysema, chronic bronchitis) or peripheral vascular disease (Raynaudís Disease).

Calcium Channel Blockers
Possible side effects for verapamil and diltiazem include bradycardia and atrio-ventricular node block. In general, patients tolerate diltiazem better than other calcium channel blockers. The most significant drug interactions are with other drugs that have inhibitory effects on cardiac output (beta-adrenergic blockers) or conduction across the AV node (beta-adrenergic blockers, digoxin). The dihydropyridines have a high incidence of side effects directly related to vasodilation, including edema and headache. Reflex tachycardia due to rapid lowering of blood pressure can be a serious problem with some dihydropyridines.

Prazosin and Analogs
Prazosin and its analogs are selective alpha1-receptor blockers. These drugs are of particular benefit in hypertensive males who have BPH. Treatment with these drugs can result in fluid retention as a response to the lowering of blood pressure. The hypotensive action of prazosin is decreased as a result of the expansion of plasma volume. Another side effect is first dose syncope and orthostatic hypotension. The effectiveness of this class of drugs for the treatment of hypertension in patients with evelated lipids was recently called into question by results from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The ALLHAT study showed that patients taking doxazosin were 25 % more like to have "cardiovascular events" and twice as likely to be hostipalized for heart failure than patients taking the thiazide diuretic, chlorthalidone.

Centrally Acting Alpha2 Agonists
These agents stimulate alpha2 receptors in the nucleus tractus solitarius (NTS) to decrease sympathetic outflow to the heart and blood vessels resulting in a decrease in peripheral vascular resistance. These drugs have side effects typical of agents that work in the CNS including sedation, fatigue, dry mouth and sexual dysfunction. Methyldopa cause hemolytic anemia.

 

Hydralazine and Minoxidil

Hydralazine

The predominate activity is to decease peripheral vascular resistance.
The use of hydralazine has decreased due to the introduction of safer, more effective agents. Hydralazine can induce a Lupus-like syndrome. Other side effects are typical arterial vasodilator side, effects including headache and tachycardia. Hydralazine is not effective alone in the treatment of hypertension. This is because of the reflex tachycardia and water and salt retention. Beta blockers and diuretics must be given to blunt these effects. Hence, hydralazine (and minoxidil) are reserved for the treatment of moderate to severe hypertension and only then in combination with these other drugs.

Minoxidil
This is an agent that has not been discussed. Minoxidil is also an arterial vasodilator. It stimulates an outward K+ channels which hyperpolarizes the vascular smooth muscle cell. Like hydralazine, minoxidil is reserved for the treatment of moderate to severe hypertension. It has typical arterial vasodilator side effects. In addition, minoxidil also causes hair growth. It is marketed as Rogaine for this use.

Adrenergic Neuron Blocking Agents-

 

TREATMENT OF HYPERTENSIVE CRISIS

Hypertensive crisis is an elevation in blood pressure in which diastolic pressure exceeds 120 mmHg. In the presence of ongoing end-organ damage this is referred to as a hypertensive emergency. Without such complications, it is referred to as a hypertensive urgency. Hypertensive emergencies require blood pressure to be reduced within a few hours. The blood pressure in hypertensive urgencies can be lowered over a period of 1-2 days. Intravenous medications are often used to treat these conditions. Some agents are used in the chronic treatment of hypertension while some are reserved for hypertensive crises.

Drugs Used to Treat Hypertensive Emergencies

 

 

 


Copyright © 2004, Michael T. Piascik, University of Kentucky. 
Comments to
Jenny Smith.
Last modified: December 12, 2005