A Brief Look at the Cardiovascular System - Pharmacology

The cardiovascular system includes the heart, blood vessels (arteries and veins), and blood. Blood rich in oxygen, nutrients, and hormones moves through vessels called arteries that narrow to arterioles. Capillaries transport oxygenated blood to cells and absorb waste products such as CO2, urea, creatinine, and ammonia. The deoxygenated blood is returned to the circulation by the venulesand veins for elimination of waste products by the lungs and kidneys.The pumping action of the heart circulates blood through blood vessels.

The heart is divided into four chambers.

  1. Right atrium. The right atrium receives deoxygenated blood from the circulation.
  2. Right ventricle. The right ventricle pumps un oxygenated blood to the pulmonary artery to the lungs for gas exchange (CO2 for O2).
  3. Left atrium. The left atrium receives oxygenated blood via the pulmonary vein.
  4. Left ventricle. The left ventricle pumps the blood into the aorta for systemic circulation.

THE HEART

The heart muscle, called the myocardium, has a fibrous covering called the pericardium. The endocardium is a three-layered membrane that lines the interior of the heart chambers.

The heart has four valves two atrioventricular (tricuspid and mitral) and two semilunar (pulmonic and aortic). Atrioventricular valves control blood flow between the atria and ventricles. Semilunar valves control the blood flow between the ventricles and the pulmonary artery and the aorta.

There are three major coronary arteries: the right, left, and circumflex. Each provides nutrients to the myocardium. Blockage in one or more of these arteries can result in a myocardial infarction (“heart attack.”)

The myocardium is capable of generating and conducting its own electrical impulses. The impulse begins in the sinoatrial (SA) node and moves to the atrioventricular (AV) node. The heart beats about 60 to 80 beats a minute. The ventricle can beat independently at a rate of about 30 to 40 beats per minute.

Drugs can affect cardiac contraction by stimulating or inhibiting the heart. Contractions are also influenced by the autonomic nervous system (ANS). The sympathetic nervous system increases heart rate and the parasympathetic nervous system decreases heart rate. (Nervous System Drugs.)

BLOOD PRESSURE AND CARDIAC PERFORMANCE

Resistance develops as the blood travels through the circulatory system. This resistance is known as blood pressure. The average systemic arterial pressure (blood pressure) is 120/80 mmHg. The higher the resistance, the higher the blood pressure.

The total volume of blood expelled by the heart in a minute is referred to as cardiac output. The average cardiac output is 4 to 8 L/min. The amount of blood ejected from the left ventricle during each heartbeat is called the stroke volume. The average stroke volume is 70 mL/beat.

As blood flows into the ventricles the ventricles fill and stretch. The force in which blood flows into the ventricle is called preload. The force used to contract the ventricle is called the heart’s contractility. The resistance to blood ejected by the ventricle is called the after load. After load is the opposing pressure in the aorta and systemic circulation to the contraction of the ventricle.

Drugs can be used to ease the workload of the heart by increasing or decreasing the preload and after load resulting in adjusting the stroke volume and cardiac output. Vasodilators decrease the preload and after load decreasing arterial pressure and cardiac output. Vasopressors increase the preload and after load increasing the arterial pressure and cardiac output.

CIRCULATION

There are two types of circulation.

  1. Pulmonary circulation. The pulmonary circulation is when the heart pumps deoxygenated blood that contains CO2 from the right ventricle through the pulmonary artery to the lungs. Oxygenated blood returns to the left atrium by the pulmonary vein.
  2. Systemic (peripheral) circulation. In systemic circulation, the heart pumps blood from the left ventricle to the aorta into the general circulation. Blood is carried by the arteries to the arterioles down to the capillary beds where nutrients in the blood are exchanged with waste products at the cellular level. Blood then returns through the venules to the veins back to the heart.

BLOOD

Blood is composed of plasma, red blood cells (erythrocytes), white blood cells, (leukocytes) and platelets. Plasma is the fluid component of blood that is comprised of 90% water and 10% solutes, and constitutes 55% of the total blood volume.

Plasma contains glucose, protein, lipids, amino acids, electrolytes, minerals, lactic and pyruvic acids, hormones, enzymes, oxygen, and carbon dioxide.

Blood provides nutrients including oxygen to body cells. Oxygen is carried in the hemoglobin of red blood cells (RBCs). The white blood cells are the major defense mechanism of the body and act by engulfing microorganisms. Platelets are present in the blood. They gather at the site of a wound and aggregate (stitch together) to form a clot to stop the bleeding.

Cardiac drugs

Cardiac drugs regulate heart contraction, heart rate, and heart rhythm. Cardiac drugs also regulate blood flow to the heart muscle. There are three groups of cardiac drugs: glycosides, antianginals, and antidysthythmics.

Glycosides, known as digitalis glycosides, inhibit the sodium-potassium pump and increase intracellular calcium. This causes the cardiac muscle fibers to contract better.

Glycosides have three effects on the heart:

  1. A positive in otropic action that increases cardiac muscle contraction.
  2. Negative chronotropic action that decrease the heart rate.
  3. A negative dromotropic action that decreases conduction of the electrical stimulus.

The effects of glycosides improve heart, peripheral, and kidney function because

  • Cardiac output is increased.
  • Preload is decreased, improving blood flow to the periphery and kidneys.
  • Edema decreases.
  • Fluid excretion increases.
  • Fluid retention in the lung and extremities is decreased.

Glycoside preparations are also used to correct atrial fibrillation and atrial flutter (cardiac dysrhythmia).

Glycosides include digoxin (Lanoxin), inamrinone lactate (Inocor) and milrinone lactate (Primacor), and positive inotropic bipyridines. The antidote for glycoside toxicity is digoxin immune Fab (Ovine, Digibind).

Heart Failure Medication

Heart failure is treated by using vasodilators to decrease venous blood return to the heart. This results in a decrease in cardiac filling, decreased ventricular stretching, and decreased oxygen demand on the heart. Vasodilators work in three ways. They

  • Reduce cardiac after load, which increases cardiac output.
  • Dilate the arterioles of the kidneys to improve renal perfusion and increase fluid loss.
  • Improve circulation to the skeletal muscles.

Examples of vasodilators include: hydralozine (apresoline), and Minoxidil (Lonitin).

Heart failure is also treated with angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme (ACE) inhibitors dilate venules and arterioles to improve renal blood flow and decreases blood fluid volume. Angiotensin-converting enzyme (ACE) inhibitors moderately decrease the release of aldosterone; sodium retention is reduced as is fluid retention.

Diuretics are also prescribed to treat heart failure. Diuretics, which will be discussed in detail later in this chapter, are the first line of treatment for reducing fluid volume and are frequently prescribed with digoxin.Spironalactone (Aldactone) is a potassium-sparing diuretic and is effective in treating moderate to severe heart failure. It is more effective than ACE inhibitors. Beta-blockers have been contraindicated for patients in heart failure.

Antianginal Drugs

Antianginal drugs (see Table (Effects of antianginal drugs on angina) ) are used to treat angina pectoris by increasing blood flow either by increasing oxygen supply or by decreasing oxygen demand of the heart. Angina pectoris is acute cardiac pain caused by inadequate blood flow as a result of plaque occlusion in the coronary arteries of the myocardium or spasms of the coronary arteries. The decreased blood flow causes a decrease in oxygen to the myocardium, which is the cause of the pain. Anginal attacks may last for a few minutes and can lead to myocaradial infarction (heart attack).

There are three types of angina.

  1. Classic (stable). Classic angina occurs with stress and exertion and is caused by the narrowing or partial occlusion of coronary arteries.
  2. Unstable (preinfarction). Unstable angina occurs over the course of a day with progressive severity and is caused by the narrowing or partial occlusion of coronary arteries. This often indicates an impending heart attack— a medical emergency.
  3. Variant (Prinzmetal, vasospastic). Variant angina occurs at rest and is due to a vessel spasm (vasospasm).

Stress tests, cardiac profile laboratory tests, and cardiac catherization may be needed to determine the degree or blockage in the coronary arteries. A combination of pharmacologic and non pharmacologic measures (avoiding heavy meals, smoking, extremes in weather changes, strenuous exercise, and emotional stress) is necessary to control and prevent anginal attacks. Proper nutrition, moderate exercise, adequate rest, and relaxation techniques may be used to prevent attacks.

Antianginals

Nitrates

Nitrates reduce venous tone resulting in decreased workload of the heart and increased vasodilation. These are used to treat variant angina pectoris. The most commonly prescribed nitrate is nitroglycerin. There are various types of organic nitrates. Isosorbidedinitrate (Isordil, Sorbitrate) can be administered sublin-gually (SL) by tablets and orally by chewable tablets, immediate release tablets, sustained-release tablets, and capsules. Isosorbidemononitrate (Monoket, Imdur) can be given orally by immediate-release or sustained-release tablets.

Beta-Blockers

Beta-blockers (see Chapter (Nervous System Drugs) ) decrease the workload of the heart and decrease the heart’s oxygen demands. Beta-blockers include atenolol (Tenormin), meto-prolol tartrate (Lopressor), nadolol (Corgard), and propranolol HCl (Inderal)

Calcium Channel Blockers

Calcium channel blockers decrease the workload of the heart and decrease the heart’s oxygen demands and are used to treat variant angina pectoris. Calcium channel blockers include amlodipine (Norvasc), bepridilHCl (Vascor), and diltiazemHCl (Cardizem), Felodipine (Plendil), and verapamil HCl (Calan, Isoptin).

Effects of antianginal drugs on angina

TABLE (Effects of antianginal drugs on angina.) Effects of antianginal drugs on angina.

Antidysrhythmics

Antidysrhythmics are drugs that restore normal cardiac rhythm and are used to treat cardiac dysrhythmias. A cardiac dysrhythmia is a disturbed heart rhythm. It is also known as arrhythmia absence of heart rhythm. A disturbed heart rhythm is any deviation from the normal heart rate or heart pattern including slow rates (bradycardia) and fast rates (tachycardia). The electrocardiogram (ECG) is used to identify the type of dysrhythmia.

Table lists the actions of antidysrhythmics and Table 19-3 describes classes of antidysrhythmic drugs.

Antidysrhythmic actions.

Table : Antidysrhythmic actions.

Classes-and-actions-of-antidysthythmic-drugs

Mechanisms of Action

Block adrenergic stimulation of the heart

Depress myocardial excitability and contractility

Decrease conduction velocity in cardiac tissue

Increase recovery time (repolarization) of the myocardium

Suppress automaticity (spontaneous depolarization to initiate beats)

TABLE (describes classes of antidysrhythmic drugs) .Classes and actions of antidysthythmic drugs.

Cardiac dysrhythmias frequently follow a myocardial infarction (heart attack) or result from hypoxia (lack of oxygen to body tissues), hypercapnia (increased carbon dioxide in the blood), excess catecholamines, or electrolyte imbalance.

Antidysrhythmics are grouped into four classes.

  1. Fast (sodium) channel blockers. Fast (sodium) channel blockers are 1A (I) (quinidine and procainamide), 1B (II) (lidocaine), and IC (III) (encainide, flecainide).
  2. Beta blockers. Beta blockers were discussed previously in this chapter and discussed in Chapter (Nervous System Drugs) . This includes propanolol (Inderal).
  3. Prolong repolarization. Prolonged repolarization is the time when the electrical impulse returns to normal and is ready to fire again. These include bretylium (Bretylol) and amiodarone (Cordarone).
  4. Slow (calcium) channel blockers. Slow (calcium) channel blockers were discussed previously in this chapter and include verapamil (Calan, Isoptin) and diltiazem (Cardizem).

Antihypertensive drugs

Antihypertensive drugs are used to treat hypertension. Hypertension is classified as follows.

There are two types of hypertension.

  1. Essential hypertension. Essential hypertension affects 90% of patients who are hypertensive and is caused by conditions other than those related to renal and endocrine disorders.
  2. Secondary hypertension. Secondary hypertension affects 10% of patients who are hypertensive and is caused by secondary disorders of the renal and endocrine systems.

The exact cause of essential hypertension is unknown. However, there are nine factors that contribute to hypertension. These are:

  • Family history of hypertension.
  • Hyperlipidemia.
  • African-American descent.
  • Diabetes.
  • Obesity.
  • Aging.
  • Stress.
  • Diet.
  • Excessive smoking and alcohol ingestion.

There are three stages of hypertension. Along with normal blood pressure (systalic and distalic) these are

  1. Normal <120> and <80>
  2. Pre-hypertension: 120-129/80-89 mm Hg.
  3. Stage 1 hypertension: 140-159/90-99 mm Hg.
  4. Stage 2 hypertension: at or greater than 160-179/100-109 mm Hg.

KIDNEYS AND BLOOD PRESSURE

The kidneys use the renin-angiotensin system to maintain blood pressure. The renin-angiotensin system increases blood pressure by retaining sodium and water. Once baroreceptors in the aorta and carotid sinus detect adequate blood pressure, the baroreceptors signal the vasomotor center in the medulla to signal the renin-angiotensin system to excrete sodium and water, thereby lowering the blood pressure.

Hypertension is treated using a stepped-care approach. Each step uses a different group of antihypertensive drugs to control hypertension. There are four steps.

Step 1: Diuretic, beta blocker, calcium blocker, angiotensin-convertingenzyme (ACE)
Step 2: Diuretic with beta blocker, sympatholytics
Step 3: Direct-acting vasodilator; sympatholytic with diuretic
Step 4: Adrenergic neuron blocker; combinations from Steps 1, 2, and 3.

COMBINING ANTIHYPERTENSIVE DRUGS

An antihypertensive drug can be used alone or in combination with one or more drugs that fall into one of five categories.

Diuretics

Diuretics promote sodium depletion, which decreases extracellular fluid volume. It is the first-line drug for treating mild hypertension. Hydrochlorothiazide (HydroDIURIL), a thiazide, is the most frequently prescribed diuretic to control mild hypertension.

Thiazides are not used in patients who have renal insufficiency. Loop diuretics, such as furosemide (Lasix), are usually recommended for these patients because they do not depress renal flow.

Diuretics are not used if hypertension is the result of renal-angiotensin-aldosterone involvement because these drugs tend to elevate the serum renin level. Hydrochlorothiazides are combined with beta blockers, and angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors tend to increase serum potassium (K) levels. When they are combined with the thiazide diuretic, serum potassium loss is minimized.

Sympathetic depressants (sympatholytics)

Sympatholytics (see Chapter (Nervous System Drugs) ) are divided into five groups. These are

  • Beta-adrenergic blockers: (acebutolol HCL (Sectral), atenolol (Tenormin), metoprolol (Lopressor), Nadolol (Corgard), propranolol (Inderal).
  • Centrally acting sympatholytics (adrenergic blockers): clonidine HCl (Catapres) methyldopa (Aldomet).
  • Alpha-adrenergic blockers: phentolamine (Regitine); doxazosinmesylate (Cardura), terazosin HCl (Hytrin).
  • Adrenergic neuron blockers (peripherally acting sympatholytics): guanethi-dine monosulfate (Ismelin), resperine (Serpasil).
  • Alpha- and beta-adrenergic blockers: carteololHCl (Cartrol, Ocupress).
  • Direct-acting arteriolar vasodilators

    Direct-acting arteriolar vasodilators are Step 3 drugs that act by relaxing the smooth muscles of the blood vessels mainly the arteries causing vasodilation. Direct-acting arteriolar vasodilators promote an increase in blood flow to the brain and kidneys. Diuretics can be given with direct-acting vasodilators to decrease edema. Reflex tachycardia is caused by vasodilation and the decrease in blood pressure. Beta blockers are frequently prescribed with arteriolar vasodilators to decrease the heart rate, counteracting the effect of reflex tachycardia. Nitroprusside and diazoxide are prescribed for acute hypertensive emergencies.

    Angiotensin antagonists

    Drugs in this group inhibit angiotensin-converting enzyme (ACE) which, in turn, inhibits the formation of angiotensin II (vasoconstrictor) and blocks the release of aldosterone. When aldosterone is blocked, peripheral resistance is lowered.

    Calcium channel blockers

    These drugs dilate coronary arteries and arterioles and decrease total peripheral vascular resistance by vasodilation.

    STEPPED-CARE TREATMENT

    The prescribed method of treating hypertension begins with a nonpharmacolog-ical approach such as lifestyle changes: losing weight, reducing sodium intake, limiting alcohol intake, smoking cessation, and increasing physical activity.

    If blood pressure remains elevated, then treatment moves to the next step. The patient is administered diuretics or beta-blockers.

    If blood pressure still remains high, then the dose of diuretics or beta-blockers is increased or a calcium channel blocker, ACE inhibitor, angrotension II blocker, or combination drug replaces or is added to the treatment plan.

    If blood pressure does not decrease, the patient is given a diuretic with a beta-blocker or a second drug is added such as a calcium channel blocker, ACE inhibitor, alpha blocker, or centrally acting sympatholytic.

    If blood pressure still does not decrease, two or three additional drugs are administered to the patient. These include alpha blockers, direct-acting vasodilators, or adrenergic neuron blockers.

    ANGIOTENSIN ANTAGONISTS, ACE INHIBITORS, ANGIOTENSIN II BLOCKERS

    Angiotensin antagonists (angiotensin-converting enzyme inhibitors) and ACE inhibitors inhibit the formation of angiotensin II (vasoconstrictor) and block the release of aldosterone. Aldosterone promotes sodium retention and potassium excretion. When aldosterone is blocked, sodium is excreted along with water and potassium is retained. These drugs cause little change in cardiac output or heart rate and lower peripheral resistance. They can be used in patients with elevated serum renin levels.

    They are used primarily to treat hypertension; some of the agents are also effective in treating heart failure. Examples of these drugs include benazepril (Lotensin), captopril (Capoten), enalapril maleate (Vasotec), enalaprilat (VasotecIV), lisinopril (Prinivil, Zestril), and ramipril (Altace).

    Losartan (Cozaar), valsartan (Diovan), and irbesartan (Avapro) are Angiotensin II blockers that block angiotension II at the receptor site. ACE inhibitors and angiotensin II receptor antagonists are less effective for treating hypertension in African-American persons. They both may cause angioedema. Angioedema is very similar to urticaria, with which it often coexists and overlaps. The swellings occurs especially in the lips and other parts of the mouth and throat, the eyelids, the genitals, and the hands and feet. Angioedema is life-threatening if swelling in the mouth or throat makes it difficult to breathe. Less often the sheer amount of swelling means that so much fluid has moved out of the blood circulation that blood pressure drops dangerously.

    CLALCIUM CHANNEL BLOCKERS

    As discussed previously in this chapter, calcium channel blockers decrease calcium levels and promote vasodilation. Calcium channel blockers include verapamil (Calan), diltiazem (Cardiazem), nifedipine (Procardia), amlodipine (Norvasc), felodipine (Plendil), nicardipineHCl (Cardene), and nisoldipine (Sular, Nisocor).

    Calcium channel blockers can be combined with ACE inhibitors. Such combinations include benazepril with amlodipine (Lotrel), enalapril with diltiazem (Teczem), enalapril with felodipine (Lexxel), and trandolapril with verapamil (Tarka).

    DIURETICS

    Diuretics lower blood pressure and decrease peripheral and pulmonary edema in congestive heart failure and renal or liver disorders by inhibiting sodium and water reabsorption from the kidney tubules resulting in increased urine flow (diuresis).

    Most sodium and water reabsorption occurs throughout the renal tubular segments. Diuretics affect one or more of these segments. Every one and one-half hours the kidneys (glomeruli) clean the body’s extracellular fluid (ECF).

    Small particles such as electrolytes, drugs, glucose, and waste products from protein metabolism are filtered in the glomeruli during this process. Sodium and water are the largest filtrate substances. Larger products such as protein and blood are not filtered with normal renal function. Instead, they remain in the circulation.

    Nearly all filtered sodium is reabsorbed. Half occurs in the proximal tubules, approximately 40% in the loop of Henle, about 7% in the distal tubules, and the remaining in the collecting tubules.

    Diuretics, such as Mannitol, that act on the tubules closest to the glomeruli have the greatest effect in causing sodium loss in the urine (natriuresis).

    Diuretics have an antihypertensive effect by promoting sodium and water loss. They block sodium and chloride reabsorption causing a decrease in fluid volume, a lowering of blood pressure, and a decrease of edema. If sodium is retained, water is also retained in the body and blood pressure increases.

    Many diuretics cause loss of other electrolytes, including potassium, magnesium, chloride, and bicarbonate. The diuretics that promote potassium excretion are classified as potassium-wasting diuretics. Potassium-sparing diuretics pro¬mote the reabsorption of potassium. Combination diuretics have been marketed that have both actions.

    There are five categories of duretics that remove water and sodium.

    Thiazide and thiazide-like diuretics

    Thiazide diuretics include: chlorothiazide (Diuril), hydrochlorothiazide (HydroDIURIL, HCTZ), bendroflumethiazide (Naturetin), benzthiazideAquatag, (Hydrex), hydroflumethiazide (Saluron, Diucardin); methychlothiazide(Aquatensen, Enduron), Polythiazide (Renese-R), trichlormethiazide (Metahydrin, Naqua); Thyzaide-like diuretics: chlorthalidone (Hygroton), indapamide (Lozol), metolazone (Zaroxolyn), and quinethazone (Hydromox).

    Loop or high-ceiling diuretics

    Loop or high-ceiling diuretics include bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), and toresemide (Demadox).

    Osmotic diuretics

    Osmotic diuretics include Mannitol and urea (Ureaphil).

    Carbonic anhydrase inhibitors

    Carbonic anhydrase inhibitors include acetazolamide (Diamox), dichlor-phenamide (Darnide, Oratrol), and methazolamide (Neptazane).

    Potassium-sparing diuretics

    Potassium-sparing diuretics include amilorideHCl (Midamor); spironolactone (Aldactone), and triamterene (Dyrenium). Combination diuretics include: amilorideHCl and hydrochlorothiazide (Moduretic); spironolactone and hydrochlorothiazide (Aldactazide), and triamterene and hydrochlorothiazide (Dyazide, Maxzide).

    THIAZIDE DIURETICS

    Thiazides influence the distal convoluted renal tubule beyond the loop of Henle to promote sodium, chloride, and water excretion. Thiazides are used in the treatment of hypertension and peripheral edema, but are not effective for immediate diuresis and should be used mainly with patients with normal kidney function.

    Thiazides cause a loss of sodium, potassium, and magnesium and promote calcium reabsorption. They affect glucose tolerance and should be used with caution in clients with diabetes mellitus. Monitor laboratory tests for electrolytes and glucose.

    Side effects and adverse reactions of thiazides are electrolyte imbalances, hyperglycemia, hyperuricemia (elevated serum uric acid level), and hyperlipi-demia (elevated blood lipid levels). They affect the metabolism of carbohydrates.

    Other side effects include dizziness, headaches, nausea, vomiting, constipation, and rarely urtacaria (hives) and blood dyscrasias.

    LOOP OR HIGH-CEILING DIURETICS

    Loop or high-ceiling diuretics act on the ascending loop of Henle by inhibiting chloride transport of sodium into the circulation. Sodium, potassium, calcium, and magnesium are lost. Loop or high-ceiling diuretics have little effect on blood sugar, but increase the uric acid level.

    Loop or high-ceiling diuretics are potent and cause marked depletion of water and electrolytes. They are more potent than thiazides and two to three times more effective when inhibiting reabsorption of sodium. However, loop or high-ceiling diuretics are less effective as antihypertensive agents.

    Loop or high-ceiling diuretics can increase renal blood flow up to 40%. This drug is commonly the choice for patients who have decreased kidney function or end-stage renal disease.

    Loop or high-ceiling diuretics cause excretion of calcium and have a great saluretic (sodium-losing) affect that causes rapid diuresis, decreases vascular fluid volume, and decreased cardiac output and blood pressure.

    Loop or high-ceiling diuretics causes a vasodilatory effect and increase renal blood flow before diuresis. The most common side effects are fluid and electrolyte imbalances such as hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, and hypochloremia. Hypochloremic metabolic alkalosis may result. Orthostatic hypotension can also occur. Thrombocytopenia, skin disturbances, and transient deafness are seen rarely. Prolonged use can cause thiamine deficiency.

    OSMOTIC DIURETICS

    Osmotic diuretics increase the concentration (osmolality) of the plasma and fluid in the renal tubules. Sodium, chloride, potassium (to a lesser degree), and water are excreted. Osmotic diuretics are used to prevent kidney failure, decrease intra cranial pressure (ICP) (cerebral edema), and decrease intraocular pressure (IOP) as is the case with glaucoma. Mannitol is a potent potassium-wasting osmotic diuretic used in emergencies to treat intraocular pressure. Mannitol is also used with cisplatin and carboplatin in cancer chemotherapy to induce a frank diuresis for decreased side effects of treatment.

    Mannitol is the most frequently prescribed osmotic diuretic. The side effects and adverse reactions include fluid and electrolyte imbalance, pulmonary edema from rapid shift of fluids, nausea, vomiting, tachycardia from rapid fluid loss, and acidosis.

    CARBONIC ANHYDRASE INHIBITORS

    The carbonic anhydrase inhibitors block the action of the enzyme carbonic anhy-drase which is needed to maintain the acid-base balance (hydrogen and bicarbonate ion balance). Inhibition of this enzyme causes increased sodium, potassium, and bicarbonate excretion. Prolonged use can result in metabolic acidosis.

    Carbonic anhydrase inhibitors include acetazolamide dichlorphenamide (Diamox), and methazolamide (Daranide).

    Carbonic anhydrase inhibitors are used to decrease intraocular pressure in patients with open-angle (chronic) glaucoma and are not used in narrow-angle or acute glaucoma. Other uses include inducing diuresis, management of epilepsy, and treatment of high-altitude or acute mountain sickness.

    Carbonic anhydrase inhibitors can cause fluid and electrolyte imbalance, metabolic acidosis, nausea, vomiting, anorexia, confusion, orthostatic hypotension, and crystalluria. Hemolytic anemia and renal calculi can also occur. Carbonic anhydrase inhibitors are contraindicated in the first trimester of pregnancy.

    POTASSIUM-SPARING DIURETICS

    Potassium-sparing diuretics act primarily in the collecting distal duct renal tubules to promote sodium and water excretion and potassium retention. The drugs interfere with the sodium-potassium pump that is controlled by mineralo-corticoid hormone aldosterone (sodium retained and potassium excreted). Potassium is reabsorbed and sodium is excreted.

    Potassium-sparing diuretics are weaker than thiazides and loops and are used as mild diuretics or in combination with antihypertensive drugs. Continuous use of potassium-wasting diuretics requires a daily oral potassium supplement because potassium, sodium, and body water are excreted through the kidneys. However, potassium supplements are not used when the patient takes potassium-sparing diuretics.

    When potassium-sparing diuretics are used alone they are less effective in reducing body fluid and sodium than when used in combination. They are usually combined with a potassium-wasting diuretic, such as a thiazide or loop. The combination intensifies the diuretic effect and prevents potassium loss. The main side effect of these drugs is hyperkalemia.

    Caution should be used with patients who have poor kidney function. Urine output should be at least 600 mL per day. Patients should not use potassium supplements while taking this group of diuretics. If given with an ACE inhibitor, hyperkalemia could become severe or life-threatening because both drugs retain potassium. Gastrointestinal disturbances (anorexia, nausea, vomiting, diarrhea) can occur.


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