Continuing Education:  Cardiac Drugs – Lecture IV
Antihypertensive Agents
Larry Birnbaum, PhD, FASEP, EPC
Associate Professor
Department of Exercise Physiology
The College of St. Scholastica
Duluth, MN  55811

There are several groups of drugs that are used to treat hypertension.  Alpha₁ adrenergic antagonists (e.g., prazosin/Minipress) block alpha₁ adrenergic receptors resulting in vasodilation in both arteries and veins.  The vasodilation reduces systemic vascular resistance (SVR) leading to decreased blood pressure (BP).  It may also produce orthostatic hypotension, particularly in fasting, volume-depleted, salt-restricted, or elderly patients, or patients on other antihypertensives.  Other side effects include dizziness, palpitations, headache, and lethargy.

Calcium channel blockers and beta-blockers may be used to treat hypertension as well as combined alpha/beta-adrenergic antagonists (e.g., labetalol/Normodyne or Trandate).  These drugs were discussed in the October issue of JPEP. 

Adrenergic neuron blocking agents include guanethidine (Ismelin) and reserpine (Serpasil).  Guanethidine prevents the release of norepinephrine from nerve terminals.  In addition to negative inotropic and chronotropic effects, it produces vasodilation by reducing sympathetic activity to blood vessels thereby reducing total peripheral resistance.  Due to blockage of postganglionic sympathetic nerve terminals, guanethidine may cause sympathoplegia (paralysis of the sympathetic nervous system).  Other potential adverse effects include orthostatic hypotension, bradycardia, impotence, diarrhea, and increased airway resistance as guanethidine leaves the constricting effect of the parasympathetic system on the lungs unopposed.  Interestingly, guanethidine can produce hypertension in patients who are also taking sympathomimetic agents (e.g., phenylpropanolamine) or tricyclic antidepressants.  A rather unique feature of this drug is that it is too polar to enter the central nervous system, and hence has none of the central effects seen with many antihypertensive agents.

Reserpine also blocks postganglionic sympathetic nerve terminals, but does so by a different mechanism.  It impairs the storage of biogenic amines by interfering with an uptake mechanism resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons.  Reserpine produces the same therapeutic effects as guanethidine and similar adverse effects.  Additionally, since reserpine enters the brain and depletes cerebral amine stores, it can cause sedation, nightmares, mental depression, and Parkinsonism symptoms.  Both reserpine and guanethidine are contraindicated in patients with reduced ventricular function, peripheral vascular insufficiency, slow HR, and AV node conduction problems.

Antihypertensives that act on the central nervous system (CNS) include clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin).  These agents act on the alpha₂ adrenergic receptors in cardiovascular regulatory centers in the brain stem and spinal cord.  Methyldopa is an analog of levodopa, a precursor to the catecholamines.  They decrease sympathetic tone and increase parasympathetic tone, which decreases heart rate (HR) and cardiac output (Q).  They also produce vasodilation leading to a reduction in SVR.  Sedation is a common side effect.  Methyldopa may cause nightmares, depression, movement disorders, endocrine disturbances, hypersensitivity reactions, and lactation.  Contraindications are essentially the same as those for the adrenergic neuron blocking agents.  Withdrawal must be gradual to avoid a life-threatening hypertensive crisis.  

Anti-angiotensin II agents are also used to treat hypertension.  This group includes angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists.  The ACE inhibitors inhibit peptidyl dipeptidase which hydrolyzes angiotensin I to angiotensin II.  Peptidyl dipeptidase is also referred to as plasma kininase because it inactivates bradykinin, a potent vasodilator.  The therapeutic effects of ACE inhibitors are multiple.  They lower the levels of angiotensin II producing vasodilation and reduced sympathetic activity.  They also decrease the level of aldosterone, which reduces salt and water retention, and consequently, preload.  Bradykinin levels increase thereby augmenting vasodilation.  Vasodilation reduces afterload by decreasing SVR.  As vasodilators, ACE inhibitors are commonly prescribed for long term therapy of congestive heart failure (CHF) [1].  Undesirable effects produced by ACE inhibitors include severe hypotension particularly in patients who are hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid loss, acute renal failure, hyperkalemia, angioneurotic edema, and minor toxicities (e.g., skin rashes, cough).  Examples of ACE inhibitors include captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), ramipril (Altace), benazopril (Lotensin). 

Angiotensin II receptor antagonists block the angiotensin receptor found primarily in vascular smooth muscle.  As expected this produces vasodilation with a consequent reduction in BP.  Side effects reported included diarrhea, muscle cramps, dizziness, insomnia, and nasal congestion.  Losartan (Cozaar), valsartan (Diovan), candesartan (Actacan), eprosartan (Teveten), irbesartan (Avapro), olmesartan (Benicar) are angiotensin II receptor antagonists.

Diuretics are still another group of drugs included in the arsenal of antihypertensives.  Thiazides, high ceiling (loop), and potassium-sparing drugs belong to this group of drugs.  Thiazides block salt and fluid reabsorption in the kidneys, thereby increasing urine output (diuresis).  Adverse effects include weakness, low blood pressure, rash, light sensitivity, impotence, nausea, abdominal pain, electrolyte disturbances, pancreatitis, jaundice, anaphylaxis, and severe rashes.  In addition to hypertension, thiazides may also be used to reduce fluid retention (edema) in people with congestive heart failure, cirrhosis of the liver, or kidney disorders, or edema caused by taking steroids or estrogen.  Hydrochlorothiazide (Esidrix, Hydrodiuril), chlorthalidone (Hygroton), and metolazone (Zaroxolyn) are thiazides.

Furosemide is referred to as a high-ceiling or loop diuretic because it inhibits the coupled Na⁺/K⁺/2Cl^- transport system in the ascending limb of the loop of Henle.  By doing so, it reduces the reabsorption of NaCl and diminishes the normal lumen-positive potential that derives from K⁺ recycling [2].  Thus, furosemide lowers BP by depleting body sodium stores.  Initially, blood volume and Q decline; after 6-8 weeks, Q approaches normal while SVR declines.  Furosemide also decreases calcium and potassium reabsorption.  Several undesirable effects are usually reversible (e.g., hypokalemia, hypomagnesemia, hypovolemia, hyponatremia, ototoxicity).  Anorexia, nausea, vomiting, diarrhea, and decreased libido may also occur with furosemide treatment.  Like thiazides, furosemide may also be used to treat edema.  A couple of potential drug interactions are noteworthy.  NSAIDs decrease diuretic, natriuretic and antihypertensive response to furosemide due to prostaglandin inhibition.  Additionally, furosemide causes decreased metabolism of propranolol.

Potassium-sparing diuretics inhibit Na⁺ transport through ion channels in the luminal membrane of the cortical collecting tubule.  They inhibit K⁺ secretion which is coupled to Na⁺ reabsorption in the collecting tubule.  Inadvertently, they may cause hyperkalemia, acute renal failure (combination of triamterene with indomethacin has been reported to cause acute renal failure) [2], and kidney stones (triamterene is poorly soluble and may precipitate in the urine, causing kidney stones).  Triamterene has minimal if any antihypertensive effects on its own.  Its sole clinical use in this context is to reduce the potential for hypokalemia in adjunctive treatment with thiazides and loop diuretics.  Oral K⁺ administration should be discontinued if triamterene is administered, to prevent hyperkalemia.  Two potassium-sparing diuretics are triamterene (Dyrenium) and spironolactone (Aldactone).

The last group of antihypertensives is direct vasodilators.  These drugs may be used for chronic therapy (hydralazine/Apresoline, minoxidil/Loniten) or for hypertensive emergencies (nitroprusside/Nipride, diazoxide/Hyperstat IV).  Hydralazine dilates arterioles by relaxing arteriolar smooth muscle.  Minoxidil and diazoxide open potassium channels in smooth muscle membranes, which stabilizes the membrane at its resting potential and makes contraction less likely.  Nitroprusside activates guanylyl cyclase either via release of nitric oxide or by direct stimulation of the enzyme.  The result is increased intracellular cGMP, which relaxes vascular smooth muscle by decreasing calcium ion levels in the cell.  Marked arteriolar dilation occurs leading to decreased SVR and afterload and increased Q.  Unfortunately, hydralazine and minoxidil may also produce headache, palpitations, sweating, and/or flushing.  An additional potential side effect of hydralazine is lupus erythematosis, which is reversible and not associated with any renal damage.  Minoxidil may cause hypertrichosis (excessive hair growth) in both sexes.  Methemoglobinemia and thiocyanate toxicity may occur with nitroprusside.  Tachycardia may occur with nitroprusside or diazoxide.  Vasodilator drugs are usually reserved for combination therapy with a diuretic and a beta-blocker in resistant or advanced hypertension.  As indicated above, nitroprusside or diazoxide are used in hypertensive emergencies.  Vasodilators may also be used to treat CHF.

References

1.  Lehne, R. A. (1998). Pharmacology for Nursing Care, 3rd Ed. Philadephia: W. B. Saunders Co.

2.  http://heartdisease.about.com/cs/cardiacdrugs/index.htm