Antihypertensive Drugs

PHRM 306: Drugs affecting CVS

Overview
Blood pressure (BP) is the pressure exerted by circulating blood upon the walls of blood vessels. Category Systolic, mmHg Diastolic, mmHg Normal 90 - 119 60 - 79

Overview
Blood Pressure = Cardiac Output x Peripheral Vascular Resistance (PVR) Cardiac Output = Stroke Volume Heart rate

Overview
Hypertension is defined as either A sustained systolic blood pressure (SBP) of greater than 140 mm Hg or A sustained diastolic blood pressure (DBP) of greater than 90 mm Hg

Overview
Hypertension results from increased peripheral vascular smooth muscle tone, which leads to: Increased arteriolar resistance and Reduced capacitance of the venous system.

In most cases, the cause of the increased vascular tone is unknown.

Overview
Although many of these individuals have no symptoms, chronic hypertension-either systolic or diastolic can lead to Cerebrovascular accidents (strokes) Congestive heart failure Myocardial infarction Renal damage Other end-organ Retinopathy damage

Overview
The categories are (on the basis of the progressive nature of hypertension) Normal (SBP/DBP, <120/<80) Prehypertension (SBP/DBP, 120-139/80-89), Stage 1 hypertension (SBP/DBP, 140-159/9099), and Stage 2 hypertension (SBP/DBP, 160/100).

Etiology of Hypertension
Hypertension may occur secondary to other disease processes: Secondary hypertension Essential hypertension (90%), a disorder of unknown origin affecting the blood pressure regulating mechanism: Primary hypertension.

Etiology of Hypertension
A family history of hypertension increases the likelihood that an individual will develop hypertensive disease. The incidence of essential hypertension is four-fold more frequent among blacks than among whites. It occurs more often among middle-aged males than among middle-aged females, and its prevalence increases with age and obesity.

Etiology of Hypertension
Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking, further predispose an individual to the occurrence of hypertension.

Mechanisms for Controlling Blood Pressure

Most antihypertensive drugs lower blood pressure by reducing cardiac output and/or decreasing peripheral resistance.

Blood Pressure = Cardiac Output x Peripheral Vascular Resistance (PVR) Cardiac Output = Stroke Volume Heart rate

Mechanisms for Controlling Blood Pressure

Cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: The baroreflexes, which are mediated by the sympathetic nervous system, and The renin-angiotensin-aldosterone system.

A. Baroreceptors and the sympathetic nervous system

A fall in blood pressure causes pressuresensitive neurons (baroreceptors in heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers in the brain.

Fig: A simple Reflex Arc

Baroreceptors and the sympathetic nervous system

This prompts a reflex response of increased sympathetic and decreased parasympathetic output to the heart and vasculature, resulting in vasoconstriction (1) and increased cardiac output (1) . These changes result in a compensatory rise in blood pressure.

Baroreceptors and the sympathetic nervous system

Baroreflexes involving the sympathetic nervous system are responsible for the rapid, moment-to-moment regulation of blood pressure.

B. Renin-angiotensin-aldosterone system
Baroreceptors in the kidney respond to reduced arterial pressure (and to sympathetic stimulation of - adrenoceptors) by releasing the enzyme renin. Low sodium intake and greater sodium loss also increase renin release.

Renin-angiotensin-aldosterone system
This peptidase converts angiotensinogen (from liver) to angiotensin I, which is in turn converted to angiotensin II in the presence of angiotensin converting enzyme (ACE).

Renin-angiotensin-aldosterone system
Angiotensin II is the body's most potent circulating vasoconstrictor, constricting both arterioles and veins, causing an increase in blood pressure. Angiotensin II exerts a preferential vasoconstrictor action on the efferent arterioles of the renal glomerulus, increasing glomerular filtration.

Fig: Nephron

Renin-angiotensin-aldosterone system
Furthermore, angiotensin II stimulates aldosterone secretion, leading to increased renal sodium reabsorption and an increase in blood volume, which contribute to a further increase in blood pressure. These effects of angiotensin II are mediated by stimulation of angiotensin II-AT1 receptors.

Figure: Response of the autonomic nervous system and the reninangiotensin-aldosterone system to a decrease in blood pressure.

Treatment Strategies
The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. Lowering of moderately elevated blood pressure significantly reduces cardiovascular disease.

Treatment Strategies
Prehypertension (SBP/DBP, 120-139/80-89) stage is ideal for regulation of hypertension and associated risk by education and adoption of blood pressure lowering behaviors.

Treatment Strategies
Mild hypertension can often be controlled with a single drug; however, most patients require more than one drug to achieve blood pressure control. Current recommendations are to initiate therapy with a thiazide diuretic unless there are compelling reasons to employ other drug classes.

Figure: Treatment of hypertension in patients with concomitant diseases. Drug classes shown in blue boxes provide improvement in outcome (for example diabetes or renal disease) independent of blood pressure. [Note: ARBs are an alternative to ACE inhibitors.] ACE = angiotensinconverting enzyme; ARB = angiotensin receptor blocker.

Treatment Strategies
If blood pressure is inadequately controlled, a second drug is added, with the selection based on minimizing the adverse effects of the combined regimen. A -blocker is usually added if the initial drug was a diuretic, or a diuretic is usually added if the first drug was a -blocker.

Treatment Strategies
A vasodilator can be added as a third step for those patients who still fail to respond. However, angiotensin II-converting enzyme inhibitors, angiotensin II-AT1 receptor blockers, and calcium-channel blockers can also be used to initiate therapy.

A. Individualized care
Certain subsets of the hypertensive population respond better to one class of drug than they do to another. For example, black patients respond well to diuretics and calcium-channel blockers, but therapy with -blockers or ACE inhibitors is often less effective.

A. Individualized care
Furthermore, hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs. In such cases, it is important to match antihypertensive drugs to the particular patient.

B. Patient compliance in antihypertensive therapy

Lack of patient compliance is the most common reason for failure of antihypertensive therapy. The hypertensive patient is usually asymptomatic and is diagnosed by routine screening before the occurrence of overt endorgan damage.

B. Patient compliance in antihypertensive therapy

Thus, therapy is generally directed at preventing future disease sequence, rather than relieving the patients present discomfort. The adverse effects associated with the hypertensive therapy may influence the patient more than the future benefits.

B. Patient compliance in antihypertensive therapy

For example, -blockers can decrease libido and induce impotence in males, particularly middle-aged and elderly men. This drug-induced sexual dysfunction may prompt the patient to discontinue therapy. ACE inhibitors: Produce dry cough in elderly women (10-15% patient)

B. Patient compliance in antihypertensive therapy

Thus, it is important to enhance compliance by carefully selecting a drug regimen that both reduces adverse effects and minimizes the number of doses required daily.