1. Antihypertensive Drugs26
Antihypertensive Drugs

2. Blood Pressure Blood pressure is determined by two factors:
Cardiac output (CO)
Peripheral resistance (PR)
Other factors can influence BP.
When renal blood flow is decreased, the RAA mechanism is activated:
Vasoconstriction and sodium and water retention
Learning Outcomes
26.1 Describe the major physiological factors that regulate blood pressure.
26.2 Understand the role of the kidneys and renin angiotensin- aldosterone system in blood pressure regulation.
Blood pressure is mainly determined by two factors: cardiac output (CO) and peripheral resistance (PR). Cardiac output (CO) is the amount of blood that is pumped out of the heart per minute. Two factors determine cardiac output: the heart rate (HR) in beats per minute and the stroke volume (SV), the amount of blood pumped per beat. The peripheral resistance (PR) is the resistance or friction that the arterioles have against the flow of blood. The main factor that increases the peripheral resistance is vasoconstriction.
A number of factors have been shown to affect BP. While these factors are not believed to be the cause of hypertension, controlling these factors can produce modest decreases in BP. These factors include sodium restriction, weight loss, elimination of smoking, regular physical exercise, and various relaxation techniques aimed at reducing stress. If renal blood flow is reduced, the enzyme renin is released by the kidneys into the bloodstream. Release of renin activates the renin-angiotensin-aldosterone (RAA) mechanism. Activation of the RAA mechanism causes vasoconstriction, and sodium and water retention, which increases blood pressure.

3. Diuretics Increased sodium excretion: Used in mild hypertension alone
Lowers blood pressure
Used in mild hypertension alone
Usually takes several weeks to produce vasodilating effects
In moderate to severe hypotension the diuretics are combined with other antihypertensive drugs.
Learning Outcomes
26.3 Explain the antihypertensive actions of thiazide and loop diuretics.
The diuretics, which increase the excretion of sodium from the kidneys, have been shown to lower blood pressure. Both salt restriction and diuretic therapy are effective measures to reduce BP.
The hypotensive effect of these drugs is initially caused by increased excretion of sodium and water, which reduces blood volume and cardiac output.
The antihypertensive effect of thiazide and thiazide-like diuretics occurs at low dosages. Higher diuretic dosages do increase urine output but do not result in greater decreases in peripheral resistance.
Diuretics are used alone in mild hypertension. Usually several weeks of treatment are required for the vasodilating effect to fully develop. In moderate or severe hypertension, the diuretics are combined with other antihypertensive drugs.

4. Sympathetic Activity
In hypertension there is often increased sympathetic activation.
NE and EPI stimulate alpha-1 and beta-1 receptors, causing vasoconstriction and increased cardiac output.
Learning Outcomes
26.4 Compare the pharmacologic actions of the different classes of drugs that reduce sympathetic nervous system activity.
The sympathetic division of the autonomic nervous system has a vital function in the control of blood pressure. In hypertension there is often increased sympathetic activation.
The adrenergic neurotransmitters norepinephrine and epinephrine stimulate alpha-1 and beta-1 receptors to cause vasoconstriction and increased cardiac output. Alpha-blockers, beta-blockers, adrenergic neuronal blockers, and drugs that act on the vasomotor center in the brain reduce sympathetic activity and lower BP.

5. Centrally Acting Sympatholytic Drugs
Act directly on CNS to decrease BP
Clonidine:
Stimulates inhibitory alpha-2 receptors
Reduces activity of nerves to heart, kidneys, and blood vessels
Reduces BP
Adverse effects—dry mouth, constipation, and drowsiness
Withdrawal symptoms if discontinued without tapering
Learning Outcomes
26.4 Compare the pharmacologic actions of the different classes of drugs that reduce sympathetic nervous system activity.
There are several drugs that decrease sympathetic activity and BP by an action in the central nervous system. These drugs include clonidine (Catapres), guanabenz (Wytensin), guanfacine (Tenex), and methyldopa (Aldomet). Clonidine is the preferred drug of this group and will be used to describe the actions of this drug class.
Clonidine is a centrally acting drug used in the treatment of hypertension. The main action of clonidine is exerted on the vasomotor center located in the medulla oblongata. Clonidine and the other centrally acting drugs stimulate inhibitory alpha-2 receptors. This reduces the activity of the sympathetic nerves that travel from the vasomotor center to the heart (decrease heart rate and cardiac output), kidneys (decrease release of renin), and blood vessels (vasodilation), resulting in a reduction of blood pressure.
The adverse effects of clonidine include dry mouth, constipation, and drowsiness. If clonidine is abruptly discontinued, a withdrawal reaction may occur, with patients experiencing rebound sympathetic activity and hypertensive crisis. To avoid withdrawal symptoms of clonidine, the dose should be reduced gradually over a 2-week period.

6. Alpha, Beta, and Adrenergic Blockers
Alpha-1 blockers:
Block receptors on vascular smooth muscle
Vasodilation and decreased peripheral resistance
Beta-blockers:
Block receptors on heart, decreasing CO
Block release of renin in kidneys
Adrenergic neuronal blockers:
Prevent release of NE and deplete stored NE
Learning Outcomes
26.4 Compare the pharmacologic actions of the different classes of drugs that reduce sympathetic nervous system activity.
The alpha-blockers doxazosin, prazosin, and terazosin selectively block the alpha-1 receptors located on vascular smooth muscle. The main antihypertensive effects are vasodilation and decreased peripheral resistance.
The beta-blockers produce two actions that are of benefit in the treatment of hypertension. First, they block beta-1 receptors in the heart, lowering blood pressure by decreasing CO, especially when there is increased sympathetic activity. Second, they block the release of renin from the kidneys, which reduces activation of the renin-angiotensin-aldosterone (RAA) mechanism.
Guanethidine and guanadrel are adrenergic neuronal blockers that cause a significant inhibition of sympathetic activity. First, these drugs prevent the release of NE from adrenergic nerve endings. Second, they deplete the storage vesicles of NE. Adrenergic neuronal blockers are only indicated for the treatment of severe hypertension that is unresponsive to other preferred drugs.

7. Learning Outcomes
26.4 Compare the pharmacologic actions of the different classes of drugs that reduce sympathetic nervous system activity.
The alpha-blockers doxazosin, prazosin, and terazosin selectively block the alpha-1 receptors located on vascular smooth muscle. The main antihypertensive effects are vasodilation and decreased peripheral resistance.
The beta-blockers produce two actions that are of benefit in the treatment of hypertension. First, they block beta-1 receptors in the heart, lowering blood pressure by decreasing CO, especially when there is increased sympathetic activity. Second, they block the release of renin from the kidneys, which reduces activation of the renin-angiotensin-aldosterone (RAA) mechanism.
Guanethidine and guanadrel are adrenergic neuronal blockers that cause a significant inhibition of sympathetic activity. First, these drugs prevent the release of NE from adrenergic nerve endings. Second, they deplete the storage vesicles of NE. Adrenergic neuronal blockers are only indicated for the treatment of severe hypertension that is unresponsive to other preferred drugs.

8. Vasodilators
They act directly on vascular smooth muscle to cause relaxation, resulting in vasodilation.
They are often used in combination with diuretics and beta-blockers.
Calcium channel blockers produce arteriolar vasodilation.
Adverse effects include nausea, headache, hypotension, and reflex tachycardia.
Learning Outcomes
26.5 Describe the mechanism of action of the vasodilator drugs.
The vasodilator drugs act directly on vascular smooth muscle to cause relaxation. This results in vasodilation and a reduction in BP. Vasodilators are often used in combination with diuretics and beta-blockers. This is necessary because vasodilators often cause fluid retention and reflex tachycardia.
Hydralazine is an arteriolar dilator used in moderate to severe hypertension in combination with both diuretics and beta-blockers (triple therapy). The main adverse effects are nausea, headache, hypotension, and reflex tachycardia. Long-term use may produce rheumatoid arthritis or a systemic lupus erythematosus–like syndrome.
Minoxidil is a more potent arteriolar dilator than hydralazine, and it is indicated for patients who do not respond to triple therapy with other drug combinations. Minoxidil has the potential to produce a number of serious adverse effects, including myocardial ischemia and pericardial effusion.
The primary action of calcium channel blockers in the treatment of hypertension is arteriolar vasodilation. This lowers peripheral resistance and blood pressure. These drugs are indicated for the treatment of hypertension and patients with CAD, particularly the variant or Prinzmetal form of angina pectoris.

9. Vasodilators Learning Outcomes
26.5 Describe the mechanism of action of the vasodilator drugs.
The vasodilator drugs act directly on vascular smooth muscle to cause relaxation. This results in vasodilation and a reduction in BP. Vasodilators are often used in combination with diuretics and beta-blockers. This is necessary because vasodilators often cause fluid retention and reflex tachycardia.
Hydralazine is an arteriolar dilator used in moderate to severe hypertension in combination with both diuretics and beta-blockers (triple therapy). The main adverse effects are nausea, headache, hypotension, and reflex tachycardia. Long-term use may produce rheumatoid arthritis or a systemic lupus erythematosus–like syndrome.
Minoxidil is a more potent arteriolar dilator than hydralazine, and it is indicated for patients who do not respond to triple therapy with other drug combinations. Minoxidil has the potential to produce a number of serious adverse effects, including myocardial ischemia and pericardial effusion.
The primary action of calcium channel blockers in the treatment of hypertension is arteriolar vasodilation. This lowers peripheral resistance and blood pressure. These drugs are indicated for the treatment of hypertension and patients with CAD, particularly the variant or Prinzmetal form of angina pectoris.

10. Drugs That Reduce Angiotensin Activity
Interfere with production of angiotensin II
Renin inhibitors:
Inhibit enzymatic activity of renin
ACE inhibitors:
Inhibit formation of angiotensin II
Decrease release of aldosterone and antidiuretic hormone
ARBs:
Block angiotensin II receptors
Learning Outcomes
26.6 Compare the pharmacologic actions of the ACE inhibitors and the angiotensin receptor blockers.
There are several drug classes that interfere with the activation of the renin-angiotensin-aldosterone (RAA) mechanism. A newer class of drugs that reduce the activity of angiotensin II and RAA activation is the renin inhibitors. The first approved drug of this class is aliskiren ( Tekturna ). Aliskiren inhibits the enzymatic activity of renin. This action decreases the conversion of angiotensinogen to angiotensin I and reduces the formation of angiotensin II.
The ACE inhibitors are an important class of drugs and are among the preferred therapies for treatment of hypertension. The ACEIs inhibit the formation of angiotensin II and decrease the release of aldosterone and antidiuretic hormone. These actions lower blood pressure by causing a balanced vasodilation of both arteries and veins. In addition, ACEIs also inhibit inactivation of bradykinin, which also produces vasodilation.
Angiotensin receptor blockers (ARBs) bind to the AT 1 receptor and competitively antagonize the actions of angiotensin II. This inhibits activation of the RAA mechanism to produce vasodilation and increased excretion of sodium and water, effects similar to those of the ACEIs.

11. Learning Outcomes
26.6 Compare the pharmacologic actions of the ACE inhibitors and the angiotensin receptor blockers.
There are several drug classes that interfere with the activation of the renin-angiotensin-aldosterone (RAA) mechanism. A newer class of drugs that reduce the activity of angiotensin II and RAA activation is the renin inhibitors. The first approved drug of this class is aliskiren ( Tekturna ). Aliskiren inhibits the enzymatic activity of renin. This action decreases the conversion of angiotensinogen to angiotensin I and reduces the formation of angiotensin II.
The ACE inhibitors are an important class of drugs and are among the preferred therapies for treatment of hypertension. The ACEIs inhibit the formation of angiotensin II and decrease the release of aldosterone and antidiuretic hormone. These actions lower blood pressure by causing a balanced vasodilation of both arteries and veins. In addition, ACEIs also inhibit inactivation of bradykinin, which also produces vasodilation.
Angiotensin receptor blockers (ARBs) bind to the AT 1 receptor and competitively antagonize the actions of angiotensin II. This inhibits activation of the RAA mechanism to produce vasodilation and increased excretion of sodium and water, effects similar to those of the ACEIs.

12. Hypertensive Crisis Treatment
Development of severe, sudden hypertension
Malignant hypertension:
Vascular inflammation
Necrosis of blood vessels
Diazoxide
Sodium nitroprusside
Learning Outcomes
26.7 Describe the treatment of hypertensive crisis.
Hypertensive crisis is a condition in which severe hypertension suddenly develops, usually in individuals who have untreated hypertension or in response to some acute disease state. When BP is extremely high and there is vascular inflammation and necrosis of blood vessels, the condition is referred to as malignant hypertension.
Structurally, diazoxide is similar to the thiazide diuretics. It is a very potent vasodilator, but it has no diuretic activity. It is used in hypertensive emergencies when a rapid reduction of BP is essential. The hypotensive effects usually last 6 to 12 hours. The main adverse effects of diazoxide involve fluid retention, tachycardia, and hyperglycemia.
Sodium nitroprusside is a potent vasodilating agent used in hypertensive emergencies. It is administered by slow IV infusion. Since the drug becomes chemically altered when exposed to light, precautions, such as wrapping the bottle with foil, are necessary. The duration of action is short, usually 1 to 5 minutes.

13. Patient Education and Monitoring
Hypertension is a chronic disease requiring lifelong treatment and medical supervision.
Patients must understand the importance of taking all their medications and having regular medical checkups.
Learning Outcomes
26.8 Explain some of the important factors involved in patient education concerning hypertension.
Essential hypertension is a chronic disease. It requires lifelong treatment and medical supervision. Often, people who are told they have high BP have experienced no symptoms. However, once drug therapy begins, they may experience some drug side effects and often claim they were better off before they began treatment.
Patients must understand the importance of taking all of their medications at the proper times. It is also important for hypertensive patients to have regular medical checkups to ensure that their BP is under control and that the medications are not producing any deleterious effects.

14. Preferred Therapy
Selection of therapy depends on other existing conditions:
Diuretics and beta-blockers have the longest record of proven effectiveness in treating hypertension.
ACE inhibitors and ARBs are the most frequently prescribed antihypertensive agents.
Adrenergic blocking drugs would be indicated for patients with excessive sympathetic activation.
Learning Outcomes
26.9 List the drug classes that are usually preferred for the treatment of hypertension.
As with most cardiovascular conditions, the selection of therapy often depends on other existing disease conditions that the patient may have. The drugs with the longest record of proven effectiveness to reduce high blood pressure and prevent mortality are the diuretics and beta-blockers. These drugs are often the preferred therapy of mild to moderate uncomplicated hypertension.
The ACEIs and ARBs have a proven record of effectiveness and along with diuretics and beta-blockers have become the most frequently prescribed antihypertensive drugs. The ability of ACEIs and ARBs to improve renal function makes them a preferred choice for most patients with renal disease.
Use of calcium channel blockers or beta-blockers in hypertensive patients who also have ischemic heart disease or cardiac arrhythmias can effectively treat both conditions. Adrenergic blocking drugs (alpha-blockers, beta-blockers, adrenergic neuronal blockers, and centrally acting drugs) would be indicated in patients where excessive sympathetic activation is present.