Medical Pharmacology Topics
Cardiac failure is the inhability of the heart to deliver enough blood to peripheral tissues to meet metabolic demands. Cardiac performance is determined by four parameters of the cardiovascular system: preload, afterload, contractility and heart rate.
Preload is the tension placed on the ventricle at the end of diastole, when it is ready to contract and expel blood into the systemic circulation. Preload is a reflection of venous return to the heart.
Afterload is the pressure that has to be overcome by the contraction of the ventricle before the valve opens to expel the blood into the systemic circulation. The higher the afterload pressure, the harder the heart has to work in order to expel the blood.
Contractility is the ability of the myocardium to produce a contraction. With depolarization of the sarcolema and T-tubules, Ca channels open and allow inflow. The initial transarcolemal influx of Ca trigges the release of Ca stored in the sarcoplasmic reticulum. The higher Ca concentration in the cytoplasm allows binding to troponin, releaving the interacion with actin and thus allowing actin to interact wit myosin and produce a contraction. After contraction, an unknown stimulu starts the active uptake of Ca by the sarcoplasmic reticulum.
Cardiac failure arise from an initial injury, usually due to coronary artery disease or chronic hypertension, that weakens the heart (how? by damaging the fibers thus decreasing normal contractility?). This will be sensed by the body and reflex changes will take place to compensate for poor heart function. Overall, heart rate and blood preasure increase, and eventually the heart structure remodels (hypertrophy). In the long term, these changes promote circulatory congestion and strain on the heart.
Some of the major compensatory mechanisms in heart failure involve the autonomiuc nervous system and the renin-angiotensin-aldosterone axis. In other words, increased sympathetc activity and salt/water retention. Sympathetic stimulation includes cardiac stimulation (increased herat rate and contractility) and increased total peripheral resistance (increased afterload by arterial vasoconstriction and preload by venous vasoconstriction). Changes in the kidney vasculature, i.e arterial and venous vasoconstriction, and increased sodium/water retention will increase blood volume, leading to increased blood pressure but also preload, afterload and edema.
Drug treatment of chronic heart failure aims to either increase contractility, decrease preload or decrease afterload. Digitalis glycosides, sympathomimetic amines and hosphodiester inhibitors alter myocardial contractility. Arterial vasodilators reduce afterload. Venodilators and diuretics (like furosemide and the thiazides, to be discused in the "Renal Pharmacology" section) reduce afterload. Drugs that reduce both preload and afterload include nitroprusside, prazosin, ACE inhibitors and angiotensin II receptor blockers (the later two discused in the "Antihypertensives" section).
The digitalis glycosides inhibit te Na/K ATPase, thus increasing the concentration of intracellular Na. An increase intracellular [Na] attenuates te exchange of extracellular Na for intracellular Ca via the Na/Ca exchanger, and may even facilitate the exchange of intracellular Na for extracellular Ca. This process leads to an increased intracellular [Ca], therefore the net effect of Na/K ATPse inhibition is to increase intracellular Ca and thus contractility. The increase in cardiac contractility is thought to be responsible for the following effects of digitalis:
Digoxin is used most often that digitoxin because of its shorter half time (1-6 days vs. 7 days), which minimizes the occurrence of side effects. The digitalis glycosides have a very narrow therapeutic index, therefore serum levels should be monitored to account for interpatient variability. Digoxin is excreted in urin and does notdistribute to fat.
Digoxin is used in the treatment of congestive heart failure and supravenricular arrhythmias. Adverse effects include cardiac arrythmias, anorexia, vomiting, diarrhea, headache, fatigue, drowsiness, disorientation, delirium and blurred vision. To treat digitalis toxicity:
Other Drugs That Increase Contractility
Sympathomimetic amines like norepinephrine, isoproterenol, epinephrine, dopamine and dobutamine, estimulate b-adrenergic receptors, causing an increase in cAMP which in turn increases Ca influx, presumably by signaling the phosphorylation of Ca channels. Isoproterenol, epinephrine, dopamine and dobutamine must be given intravenously, thus are only used for short term management of severe heart failure.
Dobutamine is the most widely use, a synthetic analog of dopamine that has no effect on renal dopamine receptors, thus increases myocardial contractility with no substantial alteration of total peripheral resistance. Dopamine increases contractility and peripheral resistance by constricting renal blood vessels.
Phosphodiestersae inhibitors like amninone and milrinone increase cAMP levels, increasing contractility and vasodilation. They increase heartrate and may cause arrhythmias. Amninone and milrinone are used for short term management of severe heart failure. Side effects include vomiting, diarrhea, thrombocytopenia and hepatic toxicity.
Drugs that Reduce Afterload or Preload
Hydralazine and minoxidil reduce afterload by relaxing arteriolar smooth muscle. Either drug results in increased cardiac output. Minoxidil may relax arterial smooth muscle by increasing K permeability, and is used as an antihypertensive or most commonly as topical solution to promote hair growth. The mechanism by which hydralazine relaxes arterial smooth muscle is unclear. Hydralazine is used to reduce afterload in patients with congestive heart failure and as an antihypertensive.
The venodilators and diuretics are used to decrease preload. The venodilators include nitroglycerine and isosorbide dinitrite. They are used as antianginals and antihypertensives but may cause hypotension and tolerance.
Nitroglycerine relaxes venous smooth muscle with little effect on arteries, probably due to the formation of nitric oxide which increases the activity of soluble guanylyl cyclase and thus cGMP levels. This results in decreased preload due to peripheral pooling of blood and decreased venous return. Decreased preload can reduce myocardial dilation and oxygen demand.
Diuretics like furosemide, bumetanide and hydrochlorothiazide are used to reduce blood volume, thus reducing preload. Excessive diuresis can lead to volume depletion and a fall in cardic output. Hypokalemia may be proplematic, especially in patients taking digitalis.
Drugs that Decrease both Afterload and Preload
Drugs that reduce both prelod and afterload include nitroprusside, prazosin, ACE inhibitors and angiotensin II receptor blockers. These agents reduce ventricular filling pressures by facilitating venous pooling and improve cardiac output by reducing total peripheral resistance.
Prazosin is a selective a1-adrenergic receptor blocker, thus relaxes arteries and veins. It is administered oraly and excreted hepatically. It is used to treat systemic or pulmonary hypertension and congestive heart failure. Tolerance may develop.
Angiotensin converting enzyme (ACE) inhibitors like captopril and enalprilat, prevent the conversion of angiotensin I to angiotensin II (a vasoconstrictor, also increased aldosterone activity and sympathetic activity). These agents relax arterioles and veins and decrease the degradation of brdikinin (a vasodilator) by inhibiting kinninase II. ACE inhibitors seem to slow the progression of disease and increase life expectancy. They are administered orally for chronic threatment of heart failure.
Angiotensin II receptor blockers like losartan and valsartan act by displacing angiotensin II from its type I receptor subtipe AT1. They do not inhibit the breakdown of bradykinin. Side effects include angioedema, dizziness and induction of liver enzymes.
Studies suggest that long-term use of b-blockers can improve left ventricular function and reduce the symptoms of congestive heart failure. The compensatory increase in sympathetic tone during heart failure may, in the long term, be toxic to the myocardium and contribute to the progression of the disease. Beta blockers may protect the heart from such increase in sympathetic tone. Carvediol is a non-selective b-blocker and a-blocker used to treat mild to moderate heart failure. Side effects of b-blockers include bradycardia, hypotension and decreased contractility.
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