~Hypertension, Part 4 - Pharmacology and Toxicology

~Hypertension, Part 4 - Pharmacology and Toxicology
Pharmacology and Toxicology
  • Mechanisms of Antihypertensives
  • Diuretics
  • Sympatholytics
  • Vasodilators
  • Calcium-Channel Blockers
  • ACE Inhibitors
  • Angiotensin II Receptor Antagonists
Mechanisms of Antihypertensives

There are six basic classes of drugs that are effective in controlling hypertension to varying degrees. Each of these drug classes acts through mechanisms that target a particular aspect of the cardiovascular system, the renin-angiotensin-aldosterone-axis, or the sympathetic nervous system. Collectively, they prevent sodium retention and fluid retention, modulate vascular tone, block common elements involved in the contractive process, or interfere with endocrine and other regulatory feedback loops designed to maintain blood pressure and plasma osmolarity.


Diuretics act by blocking sodium reuptake from plasma that has been filtered by the kidney. This results in both urinary excretion of salt (sodium chloride) and a considerable amount of water that is necessary to flush this salt from the kidney. The loss of salt and water from the blood stream directly lowers blood pressure by removing volume from the circulatory system. Compensatory physiological responses exist to replenish this volume. Some of these responses occur following prolonged hemorrhage. Others involve the migration of water from the intra- and intercellular compartments into the blood stream carrying a higher percentage of the intracellular cation, potassium. This leads to the side effects associated with potassium loss including hypokalemia and carbohydrate intolerance. Other side effects include hyperuricemia. High levels of uric acid in the blood have been associated with coronary heart disease. Some diuretics are available that spare potassium loss. Used alone, they can result in side effects due to hyperkalemia, such as arrhythmias (Oates and Brown and 2001).

Diuretics pose adverse metabolic effects, hypokalemia, hyperuricemia due to uric acid retention, carbohydrate intolerance, and hyperlipidemia that can, however, be minimized by using diuretic doses equivalent to hydrochlorothiazide below 25 mg. Clinical trials with the aldosterone antagonist spironolactone, which spares potassium loss, showed a 30% reduction in mortality, even when aldosterone levels were previously normal. However, these and other potassium-sparing drugs like triamterene and amiloride can cause hyperkalemia (Williams 2001).

These agents reduce stimulatory sympathetic mechanisms involved in increasing blood pressure through a variety of different mechanisms of action. Drugs that stimulate alpha-2 receptors in the vasomotor center of the brain reduce sympathetic outflow (Oates and Brown 2001).


Older Agents

Ganglionic blocking drugs block both sympathetic and parasympathetic receptors involved in reflex vasoconstriction. Unfortunately, there are too many serious side effects that the use of these drugs is very limited. Some drugs block the action of norepinephrine on postganglionic nerve terminals; others deplete norepinephrine from storage vesicles. Again their use is limited by side effects and these are older drugs (Oates and Brown 2001).


Older drugs that are still frequently used include drugs that block the vasoconstricting effects of norepinephrine at peripheral alpha-adrenergic receptors. Alpha-receptors reside on the peripheral vasculature and, when stimulated, cause vasoconstriction and an elevated blood pressure. During the course of the ALLHAT study, it was found that subjects taking the alpha-blocker doxazosin (Cardura®) had a 25% higher risk of death from coronary heart disease, nonfatal myocardial infarction, peripheral artery disease, stroke, angina, and congestive heart failure.

The high numbers of cardiovascular events reflected a doubling of risk for congestive heart failure. The other significant finding was that doxazosin was less effective (by an average of 3 mmHg) in controlling systolic blood pressure compared to other drugs evaluated. The researchers surmised that while this discovery may explain the higher risk for angina (16%) and stroke (19%), it could not fully account for the doubling of congestive heart failure (IHP Information for Health Professionals, 2000).


Other drugs block the beta-receptors in the heart responsible for increased cardiac output. Beta-adrenergic blockers are commonly used (i.e., atenolol) because they not only block the action of adrenaline on the heart, but also prevent reflex sympathetic stimulation secondary to the use of diuretic drugs or alpha-blockers. Cardio-selective beta-blockers block beta-1 receptors. This selective blockade has advantages because blockade of peripheral vascular beta-2 receptors is usually undesirable because it leads to passive vasoconstriction (Oates and Brown 2001). Beta-2 receptor stimulation opens airways in the lung for asthmatics.

Beta-blockers are used as first line therapy because they block adrenergic-mediated release of renin. Beta-blockers are especially beneficial when combined with vasculature smooth muscle relaxants (vasodilators, including arginine) that otherwise cause reflex tachycardia. Use of diuretics usually elevates renin as a secondary response to lowered blood pressure in the renal vasculature. However, beta-blockers can aggravate congestive heart failure (by blocking the action of adrenaline on the heart), asthma, and block the presentation of symptoms used by the diabetic to monitor control of blood sugar (Williams 2001).

The administration of a beta-blocker and a diuretic is so common, some drug companies market combination drug products. The usefulness of beta-blockers in preventing adrenergic-mediated release of renin by the kidney, when the relevant renal cells sense the increased loss of sodium caused by diuretic drugs, cannot be overemphasized. Combinations with vasodilator drugs are also common. The side effects that result from the use of drug combinations can be more serious than just dizziness. Specifically, they can aggravate congestive heart failure (see Cardiovascular Disease: Comprehensive Analysis elsewhere in this volume) and asthma, and conceal warning signs in diabetic individuals (Oates and Brown 2001).

After all of these compensatory systems involving the cardiovascular system, adrenals, and renin-angiotensin-aldosterone-axis are blocked, quality of life is impaired. It remains uncertain which of the cardiovascular diseases are benefited, particularly in those with diabetes or lipid disorders predisposing to coronary heart disease, stroke, and arteriosclerosis.


In general, vasodilators (such as hydralazine, Apresoline R ) act by causing direct relaxation of vascular smooth muscle. Different drugs are available that act on arterial and/or venous smooth muscle. The problem inherent in their use derives from the fact that the circulatory system and blood pressure in particular, is highly regulated by several interlinked physiological mechanisms. Sensors exist in the carotid arteries, kidneys, and elsewhere that monitor blood pressure. When we stand up and gravity reduces blood pressure to the brain, these sensors detect this critical drop in pressure. This triggers a sympathetic outflow along the sympathetic autonomic nervous system that results in increased arterial vasoconstriction, heart rate, and cardiac output. If this reflex fails to operate (or is blocked by some combination of drugs), other mechanisms (including loss of consciousness) take over and cause us to faint. Blood pressure to the brain is easier to maintain when we are lying flat (Oates and Brown 2001).

Use of a vasodilator by itself is almost always counteracted in part by the reflex sympathetic output of the autonomic system. Accordingly, these drugs are often used with other drugs that block increases in heart rate (beta-blockers) or otherwise interfere with noradrenergic (sympathetic) function through a variety of different mechanisms. These drug combinations, though effective in reducing blood pressure, lead to obvious side effects of dizziness and faintness (Oates and Brown 2001).

Arginine is a borderline essential amino acid that produces nitric oxide (NO) that can cross the membranes of cells to regulate many cellular functions. In blood vessels, NO importantly regulates the tone of smooth muscle cells surrounding the endothelial cells lining the vasculature (Hambrecht et al. 2000). Dysfunctional endothelial cells produce biochemical intermediates that act upon smooth muscle cells to cause constriction of blood vessels leading to hypertension.

Dietary arginine enhances production of NO (Siani et al. 2000). Arginine-rich or arginine-supplementation diets (10 grams per day) decreased blood pressure (Siani et al. 2000). This indicates that over a two-fold increase in dietary arginine intake has significant hemodynamic and metabolic effects in healthy men. For greater discussion of arginine, see Nutritional Therapy, and also, the discussion of Vascular Endothelium.

Calcium-Channel Blockers

Calcium-channel blockers (CCBs) lower blood pressure through actions on arterial smooth muscle. All muscular contraction is predicated on the intracellular release of calcium. CCBs will block peripheral vasoconstriction because of the obligatory role played by calcium in smooth muscle contraction. CCBs also diminish the chronotopic effects (verapamil, diltiazem) and ionotropic effects of the adrenergic system (verapamil, diltiazem, nifedipine) on the heart because of the role played by calcium in nerve conduction and cardiac muscle depolarization (Oates and Brown 2001). It is important to note that CCBs are relatively nonselective for peripheral vasculature, exerting significant effects on the heart and nerve conduction in general. This is the basis of the limitations associated with CCB use and the observed side effects.

Concomitant use with beta-blockers is common, but care must be exercised in which CCB is selected. Amlodipine (Norvasc ® ) is a popular choice in conjunction with atenolol (Tenormin ® ) because amlodipine possesses minimal negative chronotropic actions. Use of CCBs is not preferred over use of angiotensinogen-converting enzyme (ACE) inhibitors in cases where there is left ventricular hypertrophy (congestive heart failure) because of direct adverse effects on diastolic function (Williams 2001). This adverse feature of CCBs is not overcome by the ability of chronic use of CCBs to reduce left ventricular mass (an important factor in allowing congestive heart failure to regress).

Secondly, ACE inhibitors are more effective than CCBs in reducing left ventricular hypertrophy anyway, without these side effects. Due to the essential roles calcium plays in nerve and muscle function, there are more serious side effects to consider. When used with beta-blockers, some CCBs can lead to bradycardia (a slow heart rate) and even cardiac arrest (Oates and Brown 2001). An adverse side effect profile can be expected from any drug which interferes with the functions of any of the basic anions or cations (such as calcium, Ca +2 or sodium, Na + or autonomic nervous system neurotransmitters (such as norepinephrine, aka norepinephrine). In fact, most authorities agree that interference with normal sodium homeostasis is the most likely cause of hypertension). Clearly, these common ions and transmitters serve multiple functions in normal physiology. Although there are benefits to those suffering from hypertension, these drugs may not be very selective in specifically altering the pathophysiology of hypertension.

ACE Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors prevent this enzyme from converting angiotensin I into angiotensin II. The latter is a very powerful vasoconstricting agent that acts directly on the arterial vasculature. This newer class of drug offers considerable benefit to people with hypertension and includes such drugs as lisinopril, enalapril, benazepril and many others. The advantage of this drug class derives from the selectivity of angiotensin II for specific vasoconstricting receptors in the arterial vasculature.

ACE inhibitors show additional health benefits in that they slow the advancement of diseases such as diabetes, renal disease, and congestive heart failure. ACE inhibitors enhance the efficacy of diuretics by blocking some of the actions of aldosterone that is released when the kidney senses sodium loss through increased diuresis. Blunted responses to aldosterone save potassium, but can lead to hyperkalemic side effects when ACE inhibitors are used, particularly along with potassium-sparing diuretics, potassium supplements, beta-blockers, and some non-steroidal anti-inflammatory drugs.

Angioedema is an uncommon but particularly serious side effect of ACE inhibitor use, but fortunately, the signs of this condition are easily recognized. Increased coughing has also been identified as another characteristic side effect to ACE inhibition (Oates and Brown 2001). ACE inhibitors additionally block catabolism of bradykinin, a potent vasodilator, alter prostaglandin metabolism, and modify the adrenergic nervous system. Because ACE inhibition can cause profound hypotension, care must be exercised in giving an ACE inhibitor on top of a regimen already containing a diuretic (Williams 2001). Some of these effects of bradykinin probably contribute to angioedema.

Angiotensin II Receptor Antagonists

Because angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II and mediates the metabolism of bradykinin and substance P (a mediator of pain responses), there is some advantage to selectively blocking the action of angiotensin II without impairing these other enzymatic functions. Losartin was the first marketed angiotensin II receptor antagonist. There is no risk of angioedema or cough. There are two subtypes of angiotensin II receptors; the AT1 subtype, which losartan blocks, occurs in vascular and myocardial tissue more so than in brain, kidney and in the adrenal glomerulosa cells that secrete aldosterone. The AT2 subtype exists in adrenal medulla and brain. Losartan is available alone as Cozaar R, or in combination with a low dose (12.5 mg) of hydrochlorthiazide (a common diuretic) marketed as Hyzaar R. The latter product has been shown to promote significantly better reductions in blood pressure than losartan alone (Oates and Brown 2001).

The best selling or most popular antihypertensive drugs are not the most effective. Drug company advertising and physician prescribing habits delays optimal drug choices, but do not slow our ability to communicate this information, particularly in the age of the internet. Long ago the Life Extension Foundation recommended angiotensin II receptor blockers for first line therapy by naming the first approved in this class: Cozaar® and Hyzaar®. The only disadvantage to these drugs is that they do not afford once-daily dosing.

Now there is a new member to this class called Benicar® that shows once-daily dosing (Neutel et al. 2002). Benicar® is usually given at a dose of 20 mg with a possible dose increase to 40 mg after two weeks. Remember, optimal individual control of your hypertension should not be predicated on the basis of drug company claims about efficacy in selected populations, nor should it be followed by only routine measurements at your doctor's office at times that probably are not over 23 hours after your last dosage. It is still up to you to determine what works for you and how your genetic/environmental variability influences your reaction to the drug.

Continued . . .

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