Overview

• Antihypertensives aim to reduce cardiac output and/or total peripheral resistance.
  – For a review of how cardiac output and total peripheral resistance, please see our tutorial on hypertension pathophysiology.
• Lowering blood pressure in hypertensive patients reduces their risk of cardiovascular disease and cerebrovascular events.
  – Recent guidelines recommend a target blood pressure of less than 130/80 mmHg.
• The following lifestyle modifications are typically suggested:
  – Changes in diet, increased physical activity, stress reduction, smoking and alcohol cessation or reduction, and weight loss.
  – DASH:
  Dietary changes to reduce hypertension are encapsulated by the Dietary Approaches to Stop Hypertension (DASH) plan, which recommends reductions in sodium and emphasizes whole grains, fruits, vegetables, low-fat dairy, fish, poultry, and legumes, nuts, and seeds.
• In many individuals, however, lifestyle modifications are inadequate or even inappropriate for reducing blood pressure; these patients will need antihypertensive medications.
• Initial treatment may rely on a single medication, depending on the stage of hypertension.
• However, many patients ultimately require two or more drugs with complementary actions to reach their target blood pressure.
• Individuals vary in their responses to antihypertensive medications, and that specific recommendations are made for some populations.
  – For example, African Americans, the elderly, and patients with certain medical conditions may respond differently to an antihypertensive drug than the rest of the populations.
• Resistant hypertension is when an individual’s blood pressure remains elevated above the target goal, despite concurrently using three or more antihypertensive medications, including a diuretic.

Thiazide and thiazide-like diuretics

• These drugs act on the distal convoluted tubule of the nephron to prohibit sodium and water reabsorption; sodium and water are excreted in the urine, so blood volume and blood pressure are reduced.
  – Often a first line choice, particularly in salt-sensitive individuals
  – They are associated with hypokalemia.
• Chronic use causes vasodilation, which also contributes to reduction in blood pressure; the exact mechanism by which these diuretics cause vasodilation is uncertain.

Renin-Angiotensin System

Two drugs that block the actions of angiotensin II, which is a powerful vasoconstrictor that also triggers the release of other blood pressure mediators, including aldosterone.

• Briefly illustrate the renin-angiotensin system:
  – The liver releases angiotensinogen.
  – The kidneys release renin, which transforms angiotensinogen to angiotensin I.
  – Then, as angiotensin I circulates in the blood, especially in the pulmonary blood, it encounters angiotensin-converting enzyme (ACE), which is released from vascular endothelial cells.
  – Angiotensin converting enzyme, as its name suggests, converts angiotensin I to angiotensin II.
  – Angiotensin II binds with arterial receptors and induces vasoconstriction.

Angiotensin-converting enzyme inhibitors

• ACE inhibitors prohibit the formation of angiotensin II by blocking the actions of angiotensin-converting enzyme.
• First-line drugs.
• Can cause hyperkalemia.
• Angiotensin II also breaks down bradykinin, which is an important vasodilator; thus, angiotensin-converting enzyme inhibitors effectively increase bradykinin levels, which ultimately enhances vasodilation.
  – Increased bradykinin is associated with cough and angioedema.

Angiotensin-receptor blockers

• Block the arterial receptors for angiotensin II.
• Like ACE inhibitors, they prevent angiotensin II from increasing blood pressure.
• Also like ACE inhibitors, they are associated with hyperkalemia.
• However, since they don’t prohibit the formation of angiotensin II, they don’t effect bradykinin, so patients don’t experience cough and angioedema.

Three “blockers” that act directly on the heart and/or vasculature.

Calcium channel blockers prevent calcium binding:

• In the heart, receptors are located at the sinoatrial and atrioventricular nodes, as well as in the cardiac tissue; thus, calcium channel blockers reduce conduction velocity, contractility, and heart rate.
• In the vasculature, prevention of calcium blocking reduces vasoconstriction.
• Calcium channels are considered a first line treatment, particularly for African Americans, in whom other antihypertensive drugs are often less effective.
• Calcium channel blockers are associated with swelling in the lower extremities, rash, flushing, and dizziness.

Beta blockers prevent norepinephrine and epinephrine binding

• In the heart, like calcium channel blockers
• Third generation beta blockers also produce vasodilation.
• Beta blockers block renin secretion from the kidney, which blocks the formation of angiotensin II and elevates bradykinin levels.
• Commonly reported side effects include fatigue, cold hands/feet, depression, sleep disturbances, and erectile dysfunction.
• Furthermore, some beta blockers can trigger bronchospasm in patients with asthma and chronic obstructive pulmonary disease.

Alpha blockers prevent norepinephrine from binding

• In the vasculature, this reduces vasoconstriction.
• Orthostatic hypotension is common, particularly in the elderly.