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Vasodilators are multipurpose drugs in regimens of cardiovascular disease patients. Vasodilators are used in the treatment of angina pectoris as well as in the treatment for hypertension.67 Vasodilators are classified as direct or indirect. Direct implies that the drug acts directly to relax the smooth muscle in the walls of peripheral arterioles, the resistance vessels, more so than the capacitance vessels. Reduction of peripheral resistance reduces blood pressure.72
Effect. NTG is the first drug used to treat angina pectoris attacks; if typically brings rapid relief from the pain of angina.33, 36 The basic mechanism of action is relaxation of vascular smooth muscle. The cellular mechanism underlying this effect is not clear. It is theorized that NTG may retard the electromechanical coupling processes mediated by the calcium ion.
Administered intravenously, NTG has been shown to reduce left ventricular end systolic and end diastolic volumes, left ventricular filling pressure, and mean arterial pressure. The changes are the result of reduction of preload and afterload by the venous and arteriolar dilation. The effect on the venous circulation is greater than on the arterioles.
A heart rate increase usually occurs with administration of NTG. This is presumed to be a result of reflex sympathetic stimulation due to reduced arterial pressure. Reduction of arterial pressure has some notable side effects: first, a reflex tachycardia, which increases oxygen demand, and second, decreased diastolic coronary flow and a decrease in coronary perfusion pressure. Nitroglycerin delivers a beneficial effect on myocardial oxygen supply-demand ratio by decreasing cardiac workload, therefore decreasing myocardial oxygen demand (a pharmacologic revas-cularization). A decrease in left ventricular filling pressure due to the peripheral vasodilatation causes better perfusion of the subendocardial myocardium. Rapid infusion of a bolus may cause a transient arteriolar dilatation with sudden excessive drop in blood pressure. Hemodynamic changes can be recorded within 30 seconds of intravenous administration and 1-2 minutes after sublingual administration.
Although nitroglycerin increases regional myocardial blood supply, its duration of effect is extremely short. Intracoronary nitroglycerin dilates normal and stenotic coronary arteries. Intracoronary nitroglycerin does not produce most of the hemodynamic effects of sublingual or intravenous nitroglycerin. Left ventricular pressure and volumes are unchanged, and there is a very small, transient rise in heart rate.
Adverse reactions to this agent include headache in about 2% of those treated. A lesser number experience tachycardia, nausea, vomiting, apprehension, muscle twitching, retrosternal discomfort, palpitations, dizziness, and abdominal pain with short-term IV administration of rates up to 440 mcg/m. Extremely high doses are toxic and can produce convulsions, paralysis, respiratory distress, and cyanosis. Accidental overdose results in severe hypotension and tachycardia, which may be treated by stopping the infusion and elevating the patient's legs.
New types of administration are:
The mechanism of action of this drug is relaxation of vascular smooth muscle. It has a rapid onset and a short duration of action. It is a vasodilator affecting arterial and venous beds, thereby reducing both preload and afterload. Nitroprusside has been successful in treatment of congestive heart failure, low-output syndromes, and hypertensive emergencies. It is a uniquely selective relaxant of smooth muscle cells in vascular walls. The mechanism of this effect is not clearly understood. Nitroprusside, being a balanced vasodilator affecting the arterial and venous beds, produces decreased or unchanged CO and decreased left ventricular filling pressure. In the absence of heart failure, cardiac output (CO) either falls or stays the same. The most impressive hemodynamic effect of nitroprusside is the balanced vasodilatation.
In acute myocardial infarction patients, nitroprusside produces hemodynamic improvement by lowering myocardial oxygen demand. However, it is also suggested that sodium nitroprusside may increase ischemia in patients with ischemic myocardium because the dilatory effect of nitroprusside is greater on small coronary arteries than on large ones. This may produce impaired collateral flow to the ischemic areas. There is, however, dilatory effect in the larger coronary arteries. In acute hypertensive crisis, sodium nitroprusside is the drug of choice; it lowers blood pressure within minutes after intravenous administration. Nitroprusside is also very useful for rapid reduction of blood pressure in dissecting aneurysm of the aorta. The drug may also be used in combination with a beta adrenoreceptor antagonist.
The side effects encountered with this agent are similar to all rapid vasodilators:
The basic activity of this drug is relaxation of smooth muscle; it is considered a safe, useful, easily administered agent for the treatment of angina pectoris. It is more useful as a prophylactic treatment than for relief of an acute anginal attack. It is considered to be an effective long-acting coronary vasodilator.
This drug decreases both diastolic and systolic blood pressure, lowering total peripheral resistance by direct relaxation of smooth muscle in the walls of peripheral arterioles.48 The arterioles are affected to a greater degree than the veins. The drug produces a reflex stimulation of the sympathetic nervous system due to the reduction in total peripheral resistance. Stroke volume, heart rate, cardiac output, and myocardial oxygen demand rise.
Diazoxide (Hyperstat), related to the thiazide diuretics, dilates the resistance arteries but not the capacitance vessels (veins). Unlike nitroprusside, it increases cardiac output and rate, even when beta blockage is present. It is initially given as a 300 mg bolus within 10-30 seconds to create the antihyper-tensive effect. The response is usually an immediate, rather precipitous fall in blood pressure, which then rises slightly in the next few minutes. Problems with cerebral and myocardial ischemia have been reported. To prevent the precipitous fall in pressure, a slow infusion over 15-30 minutes is suggested or a smaller bolus injection of 75-100 mg every 5-15 minutes. The major advantage of this drug is the rapid and consistent lowering of pressure with no central nervous system depression. The effect lasts for several hours. This drug is used for hypertensive crisis.
A new drug, still under investigation, endrala-zine is a direct-acting vasodilator related to hydrala-zine. It is used alone or in combination with diuretics and beta blockers to reduce hypertension. It has a marked antihypertensive effect. It is a safer drug than hydralazine to use to improve the hemodynamic status of the hypertensive patient with congestive failure.75 Endralazine, as a direct-acting vasodilator, produces relaxation of vascular smooth muscle, particularly in the arterioles. On a milligram-to-milligram basis, this drug has five times the potency of hydralazine.
The most important hemodynamic effect for the hypertensive patient is the peripheral vasodilatation. This effect results in a lowered blood pressure and a compensatory rise in heart rate, plasma renin activity, adrenalin, and noradrenaline. The side effects of this drug are similar to other vasodilators, tachycardia, palpitations, headache, and flushing. Because of its potency, a reduced dose is effective. Lupus syndrome is not reported.
More potent and long lasting than hydralazine, minoxidil produces a direct vasodilatation. Its effects are almost solely limited to the arterial system.15'48 Because of its potency, the resultant reflex sympathetic discharge is very pronounced. This drug has become a primary therapy for severe hypertension associated with renal insufficiency. Because of side effects, its use is limited to patients with severe hypertension refractory to, or who do not tolerate, other drugs. Minoxidil has a long duration of action—8-24 hours. Minoxidil reduces peripheral resistance and creates a reflex increase in cardiac output, water and sodium retention, and a plasma renin activity elevation. Combined with other drugs such as beta blockers and diuretics, this drug was shown to control elevated blood pressure refractory to other therapies. The use of a beta blocker during initial treatment with minoxidil will overcome the patient's compensatory mechanisms. Long-term use of minoxidil reduces the need for the beta blockers. When the drug is abruptly discontinued, rebound elevated blood pressure may occur with hypertensive encephalopathy. Gradual withdrawal is suggested. Minoxidil is shown to improve congestive failure, although its use is associated with fluid retention.
Improvement is via afterload reduction by arteriolar vasodilatation, as shown by elevated cardiac output, decreased systemic resistance, and little or no effect on pulmonary pressure. The side effects, most commonly hirsutism, limit its use, particularly for women. Pericarditis and pericardial effusion, or both, have been reported. The reasons for this reaction and knowing which patients are at risk cannot be predicted. This reaction is not dose-related and is considered an idiosyncratic reaction. An additional side effect is that minoxidil may create ECG changes; specifically, about 60% of patients show T-wave changes in direction and magnitude. Changes usually disappear with continued treatment and revert to pretreatment state if the drug is discontinued. This may be the result of left ventricular volume changes.
Pinacidil is a new precapillary vasodilator still under investigation. The antihypertensive effect of pinacidil results from direct relaxation of vascular smooth muscle.17 The direct action on vascular smooth muscle reduces total peripheral resistance and blood pressure with few, mild side effects. It is used to treat mild to moderate hypertension. The drug has a duration of 6 hours of effectiveness; this may limit its use unless it is developed as a slow release tablet. Pinacidil reduces mean blood pressure an average of 30 mm/Hg. It also decreases pulmonary blood pressure. The side effects of vasodilatation are present when the drug is used: it increases heart rate, increases cardiac contractility, and increases CO. These effects occur as compensatory mechanisms for the lowering blood pressure. This hemodynamic counterregulation is probably due to a reflex increase in sympathetic tone mediated by baroreceptors activated by the fall of arterial pressure. The use of beta blockade concomitant with administration of pinacidil will modify these effects. Pinacidil is 300%-400% more effective than hydralazine for treatment of hypertension, with fewer side effects. The side effects are more readily mediated by adding beta blockers to the treatment regimen.
Alpha adrenoreceptor blocking agents block the stimulation of alpha adrenergic receptors. The drug effects occur more selectively in peripheral vascular beds with vasodilatation as vasoconstriction is inhibited. As with the direct vasodilators, alpha blockers can increase heart rate either by the reflex effect of peripheral vasodilatation or by the direct effect of alpha blockade in the heart, which produces increased norepinephrine release.
Prazosin acts on vascular smooth muscle, blocking alpha adrenergic activity, thus inhibiting the va-soconstrictive action of norepinephrine. This drug selectively blocks alphai adrenergic receptors to reduce peripheral vascular resistance. Hemodynamically, the drug vasodilates arterioles and venules equally. There is decreased systemic resistance, resulting in reduced blood pressure. The fall in blood pressure is not accompanied by any clinically significant change in CO, heart rate, renal blood flow, or glomerular filtration rate. This drug can be used to treat hypertension and congestive failure. Side effects are mild and uncommon. The first dose may produce syncope, believed to be due to excessive postural hypo-tensive effect. Incidence is more common with initial doses of 2-5 mg.
A balanced vasodilator drug resembling prazosin (Minipress), trimazosin is an alpha adrenoreceptor blocker.4, 20 It is shown to exert immediate and symptomatic improvement in patients with congestive heart failure71 or hypertension. Long-term treatment with trimazosin does not produce tolerance and is not associated with tachycardia or activation of compensatory mechanisms brought on by treatment with classic vasodilators. Studies show that this drug is a direct arteriolar dilator and a venodilator69, 76 with some preferential effect on the venous vascular bed. Additional recent studies recognize trimazosin's alpha adrenergic blocking properties, which probably are responsible for its vasodilator effects. This effect, although recognized, is still controversial.
The alpha blocking potency of trimazosin is much less than that of prazosin. Trimazosin was found to improve the patient's hemodynamic and clinical condition during short-term administration. The drug has a balanced vasodilator effect in congestive heart failure, reducing both preload and afterload. Trimazosin is also shown to decrease peripheral vascular resistance, increase CO, and decrease left ventricular filling pressure. In trials of various dosages (300-900 mg/d) (300-450 mg/d), the hemodynamic status and the clinical status of patients with congestive heart failure showed improvement for several months.
Fluid retention was one side effect. As an antihyper-tensive, trimazosin lowers both systolic and diastolic blood pressure in patients with essential hypertension in both supine and standing position. Action occurs within 30 minutes and persists for 4 hours.
An advantage of the use of trimazosin for long-term antihypertensive treatment is that compensatory mechanisms are either minimal or do not occur at all. Plasma volume, heart rate, and plasma renin activity are not increased. Systolic and diastolic blood pressure is significantly decreased, but complete normalization of blood pressure is not successful in all patients. Trimazosin, combined with a thiazide diuretic, reduced blood pressure in trials to near normal. Prolonged treatment with high doses of trimazosin in patients with essential hypertension showed a possible impairment of renal function.
This drug acts like a combination of prazosin and clonidine.81 Another alpha adrenoreceptor blocker, urapidil lowers blood pressure by (1) peripheral vasodilatation by alpha adrenoreceptor blockade (a prazosin-like effect); (2) inhibition of peripheral release of norepinephrine; and (3) stimulation of alpha; adrenoreceptor in the central nervous system (a cloni-dine-like effect). Under study at present, urapidil has been shown to reduce blood pressure by 35 mm/Hg systolic and 20 mm/Hg diastolic. Like other centrally acting antihypertensive agents, it has a sedative effect.
This is a potent alpha adrenoreceptor antagonist with high affinity for alphai receptors. It is a possible second-line antihypertensive after diuretics. Its antihypertensive effect probably results from the hemodynamic changes of peripheral vasodilatation with prevention of compensatory increase in cardiac output. Indoramin exerts a potent vasodilatory effect, the most important component of its therapeutic effect. The venodilatory effect appears to be more potent than the effect on resistance vessels. With this vasodilatory effect, there is no increase in heart rate. The lack of increase in the heart rate of patients treated with indoramin, 4n contrast to the increase produced by the other vasodilators, may be due to a direct effect on the sinus node, a result of the membrane-stabilizing effects of this drug, which resemble that of lidocaine. Indoramin has been shown to decrease both systolic and diastolic blood pressure at rest and during exercise. The antihypertensive effects were found both in supine and in standing positions. When indoramin was used alone for a three-year period, a significant weight gain occurred. Indoramin administered with a diuretic agent allowed lower doses of indoramin and control of the edema usually associated with long-term administration of alpha blockers. Weight gain did not occur with Indoramin and diuretic therapy given concomitantly. Indoramin also has been shown to have some antiarrhythmic effect, probably due to alpha adrenergic blockade. This drug is rapidly absorbed via the gastrointestinal tract with oral administration.
When indoramin is given alone at high doses, there are relatively high incidences of side effects, mainly in the first few weeks. The most important of these are sedation and impotence, along with lethargy, drowsiness, syncope, blackouts, depression, and anxiety; occasionally described are edema, leg weakness, cramps, nervousness, dry mouth, and nasal congestion. With the addition of a diuretic and decreased dose, most adverse effects disappeared. Abrupt discontinuation did not produce rebound hypertension.
The renin-angiotensin-aldosterone system and its effect on blood pressure is discussed in Chapter 3. Agents are on the market and in various stages of development that either block angiotensin converting enzyme (ACE) activity, preventing the formation of angiotensin II, or block angiotensin II receptors. These agents are usually used sequentially with diuretics.
This is a synthetic, orally active angiotensin I converting enzyme (ACE) inhibitor. The action of captopril in hypertension is characterized by arteriolar and possibly venous dilatation. Heart rate and cardiac output are not altered significantly. Captopril was shown to produce hemodynamic and clinical improvement in patients with congestive heart failure as evidenced by:
An increase in cardiac output and cardiac stroke indices has been noted in patients at rest and during exercise.
Some of the side effects related to treatment with captopril are uncommon and usually are associated with the negative chronotropic effect. The side effects include hypotension and occasionally a decrease in white blood cells. Neutropenia or agranulocytosis is a rare side effect. Elevated serum creatinine is common in patients with renovascular hypertension. This effect is explained by the finding that an intact reninangiotensin system is essential for autoregulation of glomerular filtration rate at low renal perfusion pressure. Captopril should be used with caution in patients with bilateral renal artery stenosis or a non-functioning kidney. Severe hyperkalemia can be attributed to inhibition of aldosterone production. Impaired renal function—a side effect in the hyper-tensive patient—is found less in patients treated for congestive heart failure. This is possibly due to lower treatment doses and shorter periods of captopril therapy. Rash, associated with pruritis and fever, is dose-related and disappears when captopril is discontinued. Loss of taste—reversible and self-limiting—and tongue ulcers have also occurred. Other commonly reported adverse effects are gastric irritation, abdominal pain, constipation or diarrhea, nausea, anorexia, dizziness, dry mouth, dyspnea, and paresthesia.
Captopril potentiates the hypotensive effects of diuretics and beta blockers when used in combination. It also potentiates effects of K+ -sparing diuretics.
If other oral antihypertensive agents are gradually being discontinued, start concomitant therapy with oral doses of 6.25-12.5 mg three times daily (TID). For patients already receiving a diuretic, give 6.25 mg initially. For untreated patients, the initial dose is 25 mg TID; 200-400 mg is the daily average dose. In mild to moderate hypertension, doses of 150 mg/d are proving adequate. The drug should be given not less than 2 hours after a meal and not less than 1 hour before a meal. For treatment of congestive heart failure, 6.5-50 mg TID orally is the usual therapy dose.
Enalapril is indicated in the treatment for hypertension.28 This agent inhibits ACE, reducing pressor effects, and it has been shown to have some suppressor effect on plasma catecholamines. It was developed to attain the converting enzyme properties of captopril without serious adverse effects.38, 90
Recent studies show enalapril produces hemodynamic improvement in patients with congestive heart failure because of its peripheral vasodilatory effect. It is a unique and well-tolerated agent for long-term treatment of congestive heart failure. It is used in combination with a diuretic to alleviate the fluid retention associated with vasodilatation. In the treatment of hypertension, enalapril decreases blood pressure by decreasing peripheral vascular resistance. The drug's antihypertensive effect is enhanced by the addition of a diuretic. Inhibition of the converting enzyme is considered the predominant mechanism of action. Enalapril decreases the pressor response of norepinephrine in various tissues. The effect on renal vasculature is much higher with captopril, but enalapril has a much longer duration of action. The onset of effect to the initial dose is delayed several hours.
This agent is well tolerated; there are very few reported adverse effects. Treatment may produce headache, dizziness, and fatigue. Adverse effects are mild and transient.
Nursing ManagementPriorities when administering vasodilators are:
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Improvement of a depressed contractile state and an overloaded hemodynamic status may not correct the basic defect in refractory congestive failure; however, it is possible to assist the process with judicious use of diuretic agents. Reduction of sodium and fluid accumulation is an effective treatment. The diuretics as a group are the most frequently prescribed drugs in the treatment of hypertension.48
There are three main classes of diuretics: (1) thiazides and their derivatives; (2) loop diuretics; and (3) potassium-sparing agents. The classes divide according to site and mode of activity.36
This group (chlorothiazide, cyclothiazide, hydro-clorothiazide, and others) acts by inhibiting sodium and chloride reabsorption. (Although not chemically the same, chlorthalidone, metolazone, and guinetha-zone have the same actions as the thiazide diuretics.) Volume is decreased, and cardiac output is reduced. Over time there is an accommodation, and plasma volume returns toward normal, but peripheral resistance remains decreased. This phenomenon may be the response to a decrease in vascular reactivity to vasoconstrictor stimuli. The thiazides depress the glomerular filtration rate and renal blood flow. The individual agents differ with respect to their duration of action and maximal dosage for optimal diuresis. The thiazides differ from loop diuretics in not promoting urinary calcium excretion. Hypercalcemia may occur in some patients. Adverse effects are similar for all of the thiazide diuretics. Most side effects are dose-related and include:
The loop diuretics (furosemide, ethacrynic acid, bumetanide) are used in treatment of congestive heart failure, edema, and hypertension. These agents block chloride reabsorption in the thick ascending limb of Henle's loop and interfere with sodium reabsorption. The loop diuretics are more potent than the thiazides, with a much more rapid onset of action. Ethacrynic acid and furosemide also increase potassium excretion in the distal tubule. The loop diuretics are indicated in the treatment of edema associated with congestive heart failure and acute pulmonary edema. These agents have rapid onsets of activity when administered intravenously—Bumetanide within minutes, ethacrynic acid and furosemide in 5 minutes. Given orally, ethacrynic acid will produce results in 30 minutes, furosemide and bumetanide in 30-60 minutes. The dosage is related to patient need and is evaluated by clinical response. The lowest dosage should be used initially to minimize the potential for fluid and electrolyte imbalance. When a loop diuretic is added to the medical regimen for hypertension control, the dose of other agents may need alteration to prevent hypotension.
Adverse effects reported are ototoxicity, gastrointestinal testinal bleeds, hematuria, and gastrointestinal distress. The adverse effect of furosemide (LASIX) is an increased sensitivity to sunlight.
The loop diuretics have many adverse effects in common, producing:
These agents are amiloride, spironolactone, and triamterene. Spironolactone is an aldosterone antagonist, and the other two, amiloride and triamterene, are direct inhibitors of potassium secretion, acting in the distal tubule to prevent potassium loss. The three agents are in use as diuretics or as antihypertensive medication. The effects of the three are due to action in the distal renal tubule to block sodium exchange for potassium, resulting in an increase in water and sodium secretion and retention of potassium.
Spironolactone (Aldactone) is a major drug in the treatment of hypertension. It is administered alone or in combination with hydrochlorothiazide (Aldacta-zide). It is also an agent for treatment of edema due to congestive heart failure.
Side effects reported for spironolactone include gynecomastia; amenorrhea; gastrointestinal distress; mental disturbances of confusion, lethargy, and impotence; and skin rash. The endocrine and antiandro-genic adverse effects are dose-related at higher doses (100 mg/d).
Triamterene (Dyrenium) has less intrinsic antihypertensive activity than spironolactone. Its acts to inhibit potassium-wasting with no hormonal side effects. When combined with a thiazide (Dyazide tablets with 25 mg hydrochlorothiazide and 50 mg triamterene), its antihypertensive activity is comparable to spironolactone. A new tablet formulation of 50 mg hydrochlorothiazide and 75 mg of triamterene (Maxzide) appears to be a more effective antihypertensive agent. In the Maxzide preparation, more of both drugs is available for use and is effective in daily dosing.
Triamterene is used to treat edema, congestive heart failure, and hypertension. When used in combination with the thiazide, the diuresis occurs, but hypokalemia is prevented.
Treatment with triamterene is associated with nephrolithiasis, megaloblastoc anemia, blood dyscrasias, and photosensitivity; occasionally, signs of hy-perkalemia such as irregular heartbeat occur.
Amiloride (Midamor) is indicated in the treatment of hypertension. It is usually used in combination with hydrochlorothiazide (Moduretic), containing 50 mg HCTZ and 5 mg of amiloride. Side effects are infrequent and include headache, diarrhea, vomiting, and nausea. Flatulence and skin rash are also reported. Hyperkalemia is also a possible problem with this agent, and elderly patients have reported hyponatremia.
Nursing ManagementPriorities when administering a diuretic agent are:
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Positive inotropic agents act directly on myocar-dial cells to increase contractility—the rate and extent of shortening of myocardial muscle fibers. Cardiac function is thus enhanced, particularly in the patient with congestive heart failure. Many positive inotropic agents act by increasing the amount of intracellular calcium ion available to augment contraction. Agents differ in structure, mechanism of action, hemody-namic effects, and adverse side effects. The group includes (1) digitalis glycosides; (2) beta-adrenorecep-tor stimulants (dopamine, dobutamine, isopro-terenol, prenalterol, and others); and (3) derivatives of bipyridine (amrimone, milrinone).
The positive inotropic agents also have peripheral vascular effects. Some are vasoconstrictors; others are dilators; some are both in differing degrees. Most of the agents also affect heart rate, slowing or accelerating. Evaluation of the agents' effectiveness is sometimes difficult. For example, a positive inotropic agent with vasodilatory effect causes an increase in cardiac contractility when administered. It is not proven whether this increase is secondary to the positive inotropic effect or the cardiac stimulation resulting from increased sympathetic activity from the vasodilatation. Problems are associated with the use of these agents. To be effective, the presence of some normal or only partially damaged myocardium is required in order to be stimulated. Additionally, in congestive heart failure due to myocardial damage, the remaining normal myocardium is already stimulated by various compensatory systems. Additional stimulation can cause additional damage. A further problem resulting from the use of positive inotropic agents is the possibility of development of arrhythmias.
Dopamine is a cardiac stimulant and vasopressor used successfully for cardiocirculatory support. In shock syndrome following a myocardial infarction (MI), dopamine is indicated for treatment of hypotension that does not respond to fluid volume replacement. It is also used to treat hypotension following heart surgery.83 Dopamine is a powerful vasopressin of arteries and veins. Additionally, this agent increases myocardial contraction and cardiac output. Dopamine is used primarily in the treatment of acute heart failure or acute situations of low cardiac output; it is useful for short-term management of severe congestive failure refractory to digitalis and diuretics. Dopamine used in conjunction with sodium nitro-prusside may produce a greater increase in cardiac output. The activity of dopamine results from stimulation of adrenergic receptors of the sympathetic nervous system. Dopamine also acts on dopaminergic receptors in the renal, mesenteric, and coronary vascular beds to induce vasodilatation. In low doses (0.5-2 mcg/kg/min), dopamine will cause renal and mesenteric vasodilatation, producing increased renal blood flow, glomerular filtration rate, and urine flow. In low to moderate doses of 2-10 mcg/kg/min, it exerts a positive inotropic effect on the myocardium, resulting in increased myocardial contractility, stroke volume, and increased cardiac output. Coronary blood flow and myocardial oxygen consumption are increased. In higher doses of 10 mcg/kg/min or above, the alpha adrenergic receptors are stimulated, resulting in increased peripheral resistance, renal vasocon-striction, and an increase in blood pressure. The onset of action occurs within 5 minutes of intravenous administration. Adverse reactions reported include chest pain, dyspnea, nausea, vomiting, hypotension, tachycardia or bradycardia, hypertension, palpitations, and if there is extravasation, necrosis and sloughing of tissue at the site of injection. Extravasation side effects may be treated with an injection of phentolamin at the site to limit ischemic injury. The most adverse effects are related to the cardiovascular system. Aggravation of myocardial ischemia and arrhythmias are primarily mentioned. Titration of the drug with care can minimize these effects.
Dobutamine has comparable positive inotropic effects to dopamine; it plays an important role in the treatment of criticially ill patients with congestive heart failure, hypotension, or cardiogenic shock. This drug has little or no vasoconstrictor activity, induces a less prominent effect on heart rate, and does not directly affect renal blood flow. Its main effect is augmentation of myocardial contractility. Dobutamine stimulates the beta1 receptors of the heart to increase myocardial contractility and stroke volume, resulting in an increased cardiac output. Coronary blood flow and myocardial oxygen consumption are increased with the increase in contractility. Systemic vascular resistance is decreased (afterload). Preload is also reduced. At therapeutic doses, heart rate is not increased. Onset of action is rapid—within 1-2 minutes. The intravenous infusion is usually 2.5-15 mcg/kg/min, titrated on response.
Adverse effects reported include chest pain, palpitations, dyspnea, headache, and nausea. The particular cardiovascular adverse effect is an excessive increase in blood pressure and heart rate and provocation of ventricular ectopic activity.
Digitalis glycosides have two therapeutic activities. The first, a positive inotropic effect, increases the force and velocity of myocardial contractility. This effect is attributed to the enhancement of calcium influx and to augmented release of free calcium ions within the myocardial cells, which, in turn, potentates the activity of the contractile muscle fibers of the heart.
The second effect is to enhance the electrophysiology-logic properties of cardiac tissues by inhibiting movement of sodium and potassium ions across myocardial cell membranes. Sinoatrial (SA) and atrioventricular (AV) nodal conduction rates are decreased, and ventricular sensitivity is increased with the use of digitalis. Digitalis is indicated as an antiar-rhythmic for treatment of atrial fibrillation and flutter. In the treatment for low-output congestive heart failure (CHF) secondary to depressed left ventricular function, this drug is effective. The positive inotropic action of digitalis improves cardiac output, and with this improvement, symptoms of edema, dyspnea, and venous congestion are modified or greatly improved.
The adverse effects of digitalis preparations include nausea, vomiting, and arrhythmias. Those symptoms may indicate digitalis toxicity. The patient may experience gastrointestinal disorders as the first symptoms of toxicity. Bradycardia is also an early symptom, followed by PVCs, arrhythmias, heart block, and atrial tachycardia. Visual disturbances, described as yellow or green halos seen around objects, is a frequent early sign of digitalis toxicity.
A number of new sympathomimetics are being investigated for favorable hemodynamic properties in treatment of patients with chronic refractory congestive heart failure. The partial beta agonists, those that possess only part of the inotropic effect of full agonists, increase low cardiac output and lower excessive ventricular end diastolic pressure by their vasodilator and positive inotropic effects.
Amrinone is a new positive inotropic agent that provides combined cardiotonic and vasodilator properties. Its vasodilator properties differentiate this agent from the cardiac glycosides or catecholamines. Amrinone has the ability to increase the force and velocity of cardiac contraction. It is used in the treatment regimen for short-term management of congestive failure. Amrinone causes significant improvement in cardiac output because it enhances the contractile ability of the heart and afterload reduction rather than increases heart rate. There is no added myocardial oxygen demand. Cardiac preload is reduced also, as is pulmonary capillary wedge pressure. Amrinone reduces pulmonary and systemic arterial resistance.
The most common adverse effects associated with amrinone therapy are gastrointestinal effects. The symptoms include nausea, vomiting, abdominal cramping, diarrhea, and anorexia. Other reports are of a virus-like illness with fever, and several patients report a reduction in tear secretion.
Intravenous amrinone is diluted only in normal saline (NS) or one-half NS because with dextrose solutions, a chemical interaction results in a loss of activity of the drug. The rate of infusion is titrated to patient response. Because there is a dose-related thrombocytopenia with prolonged use of amrinone, the drug is not recommended for chronic treatment.
An analog of amrinone, milrinone, appears to be less toxic. It is being investigated in trials and may be suitable for long-term oral use. Milrinone has a potent positive inotropic effect and a vasodilatory effect. It has been found useful in patients with congestive heart failure. Its use is not associated with the adverse effects limiting the use of amrinone. It is a promising agent in the treatment of CHF. In trials, this agent produced improved hemodynamic status evidenced by improved cardiac output, decreased pulmonary capillary wedge pressure, and reduced systemic vascular resistance. Heart rate did not change. Milrinone is relatively free of adverse effects.
Sulmazol is another new glycoside, noncatecholamine cardiotonic agent. Its effect is similar to amrinone, but there is no similarity in the structure of the two. Sulmazole produces a positive inotropic effect and a reduction in preload and afterload. The enhanced myocardial performance is accompanied by an increase in myocardial oxygen consumption, but there is no aggravation of ischemia. This agent produces a significant improvement in patients with congestive heart failure due to coronary artery disease (CAD) or primary cardiomyopathy. It is relatively free of adverse side effects. It is looked on as a promising therapeutic agent in the treatment of CHF. It has been suggested that sulmazol's action on myocardial contractility may involve direct activation of the myofibrils, resulting in increased affinity of their filament receptors for the calcium ions.
Short-term intravenous administration of sulma-zol produced a transient visual disturbance with regard to light and darkness. No other adverse effects were reported. High doses produced transient color vision disturbances. Headache, nausea, and a warm facial sensation are also reported.
Nursing ManagementPriorities when administering a positive inotropic agent are:
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This group of antihypertensive agents acts mainly by central mechanisms in the central nervous system.48 Several of these agents act by stimulation of alpha adrenoreceptors in the central nervous system (clonidine, quanabenz). Another important centrally acting agent is methyldopa, whose mechanism of action is somewhat more complicated. The main effect of these agents is a decrease in central sympathetic discharge, thereby lowering blood pressure.9 Many of these drugs have the side effect of impotence, which may reduce compliance of male patients with the drug regimen.
Clonidine (Catapres, Dixarit) lowers blood pressure by stimulating alpha adrenoreceptors in the central nervous system, resulting in a decrease in sympathetic discharge.11 This in turn results in slowing of the heart rate and a decrease in peripheral vascular resistance. These changes lead to a decrease in blood pressure. This drug is used independently or in combination with other antihypertensive agents. Cardiac output is not affected by clonidine, nor is renal blood flow. Abrupt withdrawal of clonidine is not recommended because a withdrawal syndrome has been reported. The syndrome occurs because of a sudden increase in plasma catecholamines and is evidenced by tachycardia, palpitations, arrhythmias, rebound hypertension, nausea, vomiting, and flushing.
The incidence of side effects of clonidine is relatively high. The most common side effects are drows-iness and dry mouth. Dividing the dosage may reduce the incidence of side effects. High doses of the drug may produce bradycardia. Other reported adverse effects include constipation, dizziness, headache, and fatigue. These effects tend to diminish as therapy continues.
Guanethidine is not considered a primary agent in the treatment of hypertension. It is frequently used in combination with diuretics and other first-line agents.36 Guanethidine is a postganglionic adrenergic blocking agent. It acts on peripheral circulation, inhibiting the release and depleting the presynaptic storage of norepinephrine, producing a fall in blood pressure and decreased pulse pressure. Side effects of this drug, such as edema of lower extremities, may result from fluid retention. Diarrhea, impotence, dizziness, lightheadedness, fatigue, symptoms of postural hypotension, and bradycardia are frequently reported. Less frequent occurrences of skin rash, blurred vision, loss of hair, dry scalp, and dry mouth are also reported.
Guanabenz is used in the treatment of hypertension. It may be useful because it does not cause postural hypotension as do the other central adrenergic blockers. It is frequently used in combination with a diuretic in antihypertensive therapy. The predominant effect of guanabenz is peripheral systemic vaso-dilatation. Many of the side effects of other guanidine derivatives (guanethidine) are not found in guanabenz. The most common adverse effect is drowsi-ness, followed by dry mouth. Less common side effects include dizziness, headache, nausea, and impaired micturition. Guanabenz, like clonidine, has been shown to produce withdrawal syndrome with palpitations, anxiety, diaphoresis, insomnia, and abdominal pain. Patients should be cautioned not to abruptly discontinue the drug.
Guanfacine is a central-acting antihypertensive agent with a mechanism of action similar to clonidine. Its activity is produced by stimulation of alpha adrenoreceptors in the brain, resulting in inhibition of sympathetic tone. This central effect is the predominant mechanism of the drug's action, followed by peripheral presynaptic alpha adrenoreceptor, a stimulating effect inhibiting the release of norepinephrine.42 This agent has been shown to control elevated systemic arterial systolic and diastolic blood pressure during acute and long-term administration. Withdrawal syndrome does not occur when guanfa-cine is discontinued. The side effects of this agent are orthostatic hypotension, sedation, mouth dryness, and constipation.
Methyldopa is an antihypertensive agent in use for a quarter-century.36 It is one of the most widely used drugs for blood pressure control. Methyldopa reduces the pressor response to adrenergic stimuli by suppressing central nervous system (CNS) sympathetic outflow through central alpha adrenergic stimulation. It is effective alone or in combination drug regimens. The effect is gained by reduction of peripheral vascular resistance. An advantage of this agent is that it may not reduce cardiac output. If cardiac output is reduced at all, it is secondary to vasodilatation rather than to an effect on contractility. Treatment with methyldopa is associated with several adverse effects. Fatigue, drowsiness, dry mouth, and depression are among those reported. A positive direct Coombs' test may occur in about 20% of patients treated with methyldopa.
Reserpine depletes stores of catecholamines by interference with storage and blockade of the uptake of norepinephrine. Its hypertensive effect is linked to reduced cardiac output and some decrease in peripheral resistance. This drug is used infrequently and should never be given to a patient with a history of depression because it can deepen depression. There is some suggestion that large doses of this drug over the long term may increase the risk of breast cancer in postmenopausal women. Side effects are numerous and include dizziness, diarrhea, dry mouth, anorexia black tarry stool, and bloody vomitus related to activation of peptic ulcer disease. Fluid retention may lead to edema in lower extremities. Nasal congestion is a frequent complaint.
Nursing ManagementPriorities with administering a central-acting anti-hypertensive agent are:
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