Positive Inotropic Agents

Agents that successfully increase the force of contraction of the heart may be particularly useful in the treatment of CHF. In CHF, the heart cannot maintain sufficient blood flow to various organs to provide oxygen-rich blood. Agents that increase the force of contraction allow greater amounts of blood to be distributed throughout the body and, in turn, reduce the symptoms associated with CHF. Most of the positive ino-tropic agents exhibit their effects on the force of contraction by modifying the coupling mechanism involved in the myocardial contractile process.

Digitalis glycosides, a mixture of products isolated from foxglove, Digitalis spp., were first used as a heart medication as early as 1500 bc when in the Ebers Papyrus, the ancient Egyptians reported their success in using these products. Throughout history, these plant extracts have also been used as arrow poisons, emetics, and diuretics. The dichotomy of the poisonous effects and the beneficial heart properties is still evident today. Cardiac glycosides are still used today in the treatment of CHF and atrial fibrillation, with careful attention paid in monitoring the toxicity that these agents possess.

The cardiac glycosides include two distinct classes of compounds—the cardenolides and the bufadienolides. These differ in the substitutions at the C-17 position, where the cardenolides possess an unsaturated butyrolactone ring, whereas the bufadienolides have an a-pyrone ring. Pharmacologically, both have similar properties and are found in many of the same natural sources, including plant and toad species. By far, the most important sources include Digitalis purpurea and Digitalis lanata. In 1785, William Withering published An Account of the Foxglove and Its Medical Uses: With Practical Remarks on Dropsy and Other Diseases, in which he describes the beneficial use of foxglove in dropsy (edema), which often exists in CHF.

Even with recent advances in synthetic organic chemistry coupled with the use of combinatorial chemistry, no new therapeutics have displaced the cardiac glycosides. Furthermore, the perennial use of these agents over many centuries is even more remarkable when one considers the useful life of a "blockbuster" drug in today's marketplace. This remarkable fact is based, quite simply, on the unique ability of nature to produce extraordinarily bioactive substances, which characteristically possess both a lipophilic portion in the steroidal ring and a hydrophilic moiety in the glycosidic rings. The therapeutic use of these agents depends largely on a balance between the different solubility characteristics of the steroid structure, and the type and number of sugar units attached to it. Although the fundamental pharmacological properties reside with the steroidal nucleus, the sugars play a critical role in the biological effects elicited, because they increase the water solubility of the lipid system, making them more available for translocation in an aqueous environment and, at the same time, allowing transportation across fatty sites. These properties uniquely balance each other and allow successful translocation to the receptive sites in the body. Ultimately, the lipophilic steroid also plays a specific role in the agent's onset and duration of action. As the steroidal rings are modified with polar groups (e.g., hydroxyls), the onset increases, and the duration of action decreases. The sugar residues are substituted on C-3 of the steroid and generally are digitoxose, glucose, rhamnose, or cymarose.

The cardiac glycosides elicit their effects through inhibition of the Na+/K+-ATPase pump. Inhibition of this pump increases the intracellular Na+ concentration, which affects Na+/Ca2+ exchange. This increases intracellular concentrations of Ca2+, which is available to activate the contractile proteins actin and myosin, thereby enhancing the force of contraction. Also, it is suggested that these agents have other compensatory mechanisms including baroreceptor sensitivity, which result in improved conditions for patients suffering from CHF.

Digoxin. Digoxin (Lanoxin) is a purified digitalis preparation from D. lanata and represents the most widely used digitalis glycoside. This wide use is primarily a result of its fast onset and short half-life. Position 3 of the steroid is substituted with three digitoxose residues that, when removed, provide a genin or aglycone steroid that is still capable of receptor binding but with altered pharmacokinetics.

Digitalis. Digitalis (Crystodigin) is isolated from d. lanata and d. purpurea among other Digitalis spp., and is the chief active glycoside in digitalis leaf, with 1 mg digitoxin equal to 1 g of digitalis leaf therapy. In patients who miss doses, digitalis is very useful for maintenance therapy because of the longer half-life it provides. The longer duration and increased half-life are a result of the lack of the C-12 hydroxy that is present in digoxin. In digoxin, this hydroxy plays two roles: (a) it serves as a site for metabolism, which reduces the compound's half-life; and (b) it gives more hy-drophilic character, which results in greater water solubility and ease in renal elimination.

Amrinone. During normal heart function, cAMP performs important roles in regulating intracellular calcium levels. That is, certain calcium channels and storage sites for calcium must be activated by cAMP-dependant protein kinases. Because cAMP plays an indirect role in the contractility process, agents that inhibit its degradation will provide more calcium for cardiac contraction. One phosphodiesterase enzyme that is involved in the hydrolysis of myocardium cAMP is F-III. Amrinone, 5-amino (3,4'-dipyridin)-6 1

(H)-one (Inocor), possesses positive isotropic effects as a result of its ability to inhibit this phosphodiesterase. In 1999, the USP Nomenclature Committee and the United States Adopted Names (USAN) Council approved changing the nonproprietary name and the current official monograph title of amrinone to inamrinone. This change in nomenclature was a result of amrinone being confused with amiodarone because of the similarity of the names. This was reported to cause confusion between the products that led to medication errors, some of which resulted in serious injury or death.

Amrinone (Inocor)

atherosclerotic disease can be treated through medication or surgery.

Hyperlipidemia is the most prevalent indicator for susceptibility to atherosclerotic heart disease; it is a term used to describe elevated plasma levels of lipids that are usually in the form of lipoproteins. Hyperlipidemia may be caused by an underlying disease involving the liver, kidney, pancreas, or thyroid, or it may not be attributed to any recognizable disease. In recent years, lipids have been implicated in the development of atherosclerosis in humans. Atherosclerosis may be defined as degenerative changes in the intima of medium and large arteries. This degeneration includes the accumulation of lipids, complex carbohydrates, blood, and blood products and is accompanied by the formation of fibrous tissue and calcium deposition on the intima of the blood vessels. These deposits or plaques decrease the lumen of the artery, reduce its elasticity, and may create foci for thrombi and subsequent occlusion of the blood vessel.

Amrinone (Inocor)

Milrinone. Milrinone, 1,6-dihydro-2-methyl-6-oxo-3,4'-bipyridine-5-carbonitrile (Primacor), is another dipyridine phosphodiesterase F-III inhibitor that possesses pharmacological properties similar to those of amrinone. The inhibition of the degradation of cAMP results in an increase in the cardiac muscle's force of contraction.

Milrinone (Primacor)

Dopamine. Dopamine (Intropin) acts primarily on a1-and ^-adrenergic receptors, increasing systemic vascular resistance and exerting a positive inotropic effect on the heart. It must be administered by an intravenous route, because oral administration results in rapid metabolism by MAO and/or catechol-O-methyltransferase (COMT).

Dobutamine. Dobutamine (Dobutex) is a sympathomimetic drug that is a ^-adrenergic agonist with ^-activity. It is primarily used in cases of cardiogenic shock, which result from its jS rinotropic effects, which increase heart contractility and cardiac output. The drug is dispensed and administered as a racemic mixture consisting of both (+) and (—) isomers. The (+) isomer is a potent j1-agonist, whereas the (—) isomer is an a1-agonist.

o ANTIHYPERLIPIDEMIC AGENTS

The major cause of death in the Western world today is vascular disease, of which the most prevalent form is atherosclerotic heart disease. Although many causative factors of this disease are recognized (e.g., smoking, stress, diet),

Lipoprotein Classes

Lipoproteins are macromolecules consisting of lipid substances (cholesterol, triglycerides) noncovalently bound with protein and carbohydrate. These combinations solubi-lize the lipids and prevent them from forming insoluble aggregates in the plasma. They have a spherical shape and consist of a nonpolar core surrounded by a monolayer of phospholipids whose polar groups are oriented toward the lipid phase of the plasma. Included in the phospholipid monolayer are a small number of cholesterol molecules and proteins termed apolipoproteins. The apolipoproteins appear to be able to solubilize lipids for transport in an aqueous surrounding such as plasma (Fig. 19.17).

The various lipoproteins found in plasma can be separated by ultracentrifugal techniques into chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). These correlate with the electrophoretic separations of the lipoproteins as follows: chylomicrons, pre-jS-lipoprotein (VLDL), broad

Figure 19.17 • Hypothetical model of lipoprotein particle.

S-lipoprotein (IDL), jS-lipoprotein (LDL), and a--lipoprotein (HDL).

Chylomicrons contain 90% triglycerides by weight and originate from exogenous fat from the diet. They are the least dense of the lipoproteins and migrate the least under the influence of an electric current. Chylomicrons are normally absent in plasma after 12 to 24 hours of fasting. The VLDL is composed of about 60% triglycerides, 12% cholesterol, and 18% phospholipids. It originates in the liver from FFAs. Although VLDL can be isolated from plasma, it is catabo-lized rapidly into IDL, which is degraded further into LDL. Normally, IDL also is catabolized rapidly to LDL, but it is usually not isolated from plasma. The LDL consists of 50% cholesterol and 10% triglycerides. This is the major cholesterol-carrying protein. In normal persons, this lipoprotein accounts for about 65% of the plasma cholesterol and is of major concern in hyperlipidemic disease states. The LDL is formed from the intravascular catabolism of VLDL. The HDL is composed of 25% cholesterol and 50% protein and accounts for about 17% of the total cholesterol in plasma.

Lipoprotein Metabolism

The rate at which cholesterol and triglycerides enter the circulation from the liver and small intestine depends on the supply of the lipid and proteins necessary to form the lipoprotein complexes. Although the protein component must be synthesized, the lipids can be obtained either from de novo biosynthesis in the tissues or from the diet. Reduction of plasma lipids by diet can delay the development of atherosclerosis. Furthermore, the use of drugs that decrease assimilation of lipids into the body plus diet decreases mortality from cardiovascular disease.67

The lipid transport mechanisms that exists shuttle cholesterol and triglycerides among the liver, intestine, and other tissues. Normally, plasma lipids, including lipoprotein cholesterol, are cycled in and out of plasma and do not cause extensive accumulation of deposits in the walls of arteries. Genetic factors and changes in hormone levels affect lipid transport by altering enzyme concentrations and apoprotein content, as well as the number and activity of lipoprotein receptors. This complex relationship makes the treatment of all hyperlipoproteinemias by a singular approach difficult, if not impractical.

Lipids are transported by both exogenous and endogenous pathways. In the exogenous pathway, dietary fat (triglycerides and cholesterol) is incorporated into large lipoprotein particles (chylomicrons), which enter the lymphatic system and are then passed into the plasma. The chylomicrons are acted on by lipoprotein lipase in the adipose tissue capillaries, forming triglycerides and monoglycerides. The FFAs cross the endothelial membrane of the capillary and are incorporated into triglycerides in the tissue for storage as fat or are used for energy by oxidative metabolism. The chylomi-cron remnant in the capillary reaches the liver and is cleared from the circulation by binding to a receptor that recognizes the apoprotein E and B-48 protein components of the chylomicron remnant.

In the endogenous pathway of lipid transport, lipids are secreted from the liver. These are triglycerides and cholesterol combined with apoprotein B-100 and apoprotein E to form VLDL. The VLDL is acted on by lipoprotein lipase in the capillaries of adipose tissue to generate FFAs and an IDL.

Figure 19.18 • Exogenous and endogenous pathways of lipoprotein metabolism.

Some IDL binds to LDL receptors in the liver and is cleared from plasma by endocytosis. Approximately half of the circulating IDL is converted to LDL in the plasma by additional loss of triglycerides. This LDL has a half-life in plasma of about 1.5 days and represents 60% to 70% of the cholesterol in plasma. These LDL particles bind to LDL receptors in ex-trahepatic tissues and are removed from the plasma. Levels of LDL receptors vary depending on the need of extrahepatic tissues to bind LDL to use cholesterol. The extrahepatic tissue subsequently releases HDL. Free plasma cholesterol can be adsorbed onto HDL and the cholesterol esters formed by the enzyme lecithin-cholesterol acyltransferase (LCAT). These esters are transferred from HDL to VLDL or LDL in plasma to complete the cycle. The pathways for plasma lipoprotein metabolism by the exogenous and endogenous routes are shown in Figure 19.18.

Hyperlipoproteinemias

Lipid disorders are related to problems of lipoprotein metabolism68 that create conditions of hyperlipoproteinemia. The hyperlipoproteinemias have been classified into six types, each of which is treated differently (Table 19.5).

The abnormal lipoprotein pattern characteristic of type I is caused by a decrease in the activity of lipoprotein lipase, an enzyme that normally hydrolyzes the triglycerides present in chylomicrons and clears the plasma of this lipoprotein fraction. Because the triglycerides found in chylomicrons come primarily from exogenous sources, this type of hyper-lipoproteinemia may be treated by decreasing the intake of dietary fat. There are no drugs at present that can be used to counteract type I hyperlipidemia effectively.

Type II hyperlipoproteinemia has been divided into types IIa and IIb. Type IIa is characterized by elevated levels of LDL (S-lipoproteins) and normal levels of triglycerides. This subtype disorder is very common and may be caused by disturbed catabolism of LDL. Type IIb differs from type IIa, in that this hyperlipidemia has elevated VLDL levels in addition to LDL levels. Type II hyperlipoproteinemia is often clearly familial and frequently inherited as an autosomal dominant abnormality with complete penetrance and expression in infancy. Patients have been treated by use of dietary restrictions on cholesterol and saturated fats. This

TABLE 19.5 Characterization of Hyperlipoproteinemia Types

Abnormality

Hyperlipo- - Appearance Total proteinemia Electrophoresis Ultracentrifuge of Plasma3 Triglycerides Cholesterol

TABLE 19.5 Characterization of Hyperlipoproteinemia Types

Abnormality

Hyperlipo- - Appearance Total proteinemia Electrophoresis Ultracentrifuge of Plasma3 Triglycerides Cholesterol

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