Cardiovascular and Diuretic Drugs

Cardiovascular and Diuretic Drugs

CARDIAC GLYCOSIDES AND POSITIVE INOTROPES

A. Chemistry

1. Almost all of the cardiac glycosides (also called cardiotonics) are naturally occurring steroidal glycosides obtained f rom plant sources. Digitoxin is obtained from Digital is purpurea, digoxin from Digital is lanata, and ouabain from Strophanthus gratus.

2. The cardiac glycosides are closely related structurally, consisting of one or more sugars (i.e., glycone portion) and a steroidal nucleus (i.e., aglycon or genin portion) bonded through an ether (glycosidic) linkage. These agents also have an unsaturated lactone subst i tuent (cycl ic ester) on the genin por tion. The prototypical agent is digitoxin.

a. Digoxin (Lanoxin) has an additional hydroxyl group at position 12.

b. Ouabain has a rhamnose glycone portion and additional hydroxyl groups at positions 1, 5, 11, and 19.

3. Removing the glycone portion causes decreased activity and increased toxicity from changes in polarity that cause erratic absorption from the gastrointestinal tract.

4. The duration of action of a cardiac glycoside is inversely proportional to the number of hydroxyl groups, which increase polarity. Increased polarity results in decreased protein binding, decreased liver biotransformation, and decreased renal tubular reabsorption.

a. Digitoxin has a long duration of action and may accumulate.

b. Ouabain, in contrast, has an extremely short duration of action and is effective only when given intravenously.

5. Amrinone, inamrinone, and milrinone are bipyridine derivatives with positive inotropic action.

B. Pharmacology. Cardiac glycosides increase myocardial contractility and efficiency, improve systemic circulation, improve renal perfusion, and reduce edema. Angiotensin-converting enzyme (ACE) inhibitors and perhaps AT1 angiotensin- receptor antagonists; vasodilators such as nitroprusside, nitroglycerin, and hydralazine; and diuretics may be important adjuncts to cardiac glycosides. ACE inhibitors may be considered as first -line treatment.

1. When given in therapeutic doses, cardiac glycosides produce positive inotropic effects by inhibiting membrane-bound Na+ /K+ -activated adenosine triphosphatase (ATPase). These effects of cardiac glycosides increase the rate of tension development, the contractility, and the rate of relaxation of cardiac muscle. The effects include

a. Increase in intracellular sodium concentration

b. Reduction in calcium transport from the cell by the sodium-calcium exchanger

c. Facilitation of calcium entry via voltage-gated membrane channels

d. Increased release of calcium from sarcoplasmic reticulum

2. Therapeutic doses of cardiac glycosides also cause

a. A negative chronotropic effect from increased vagal tone of the sinoatrial (SA) node

b. Diminished central nervous system (CNS) sympathetic out flow from increased carotidsinus baroreceptor sensitivity

c. Systemic arteriolar and venous constriction, which increases venous return and thus increases cardiac output

3. Amrinone and milrinone produce positive inotropic effects and vasodilation via selective inhibition of type-III phosphodiesterase (PDE) isozyme, leading to an increase in cyclic adenosine monophosphate (cAMP) in cardiac and smooth muscle. Inhibtion of type-III PDE produces

a. Vasodilation and fallin vascular resistance

b. Increased force of cardiac contraction

c. Increased velocity of cardiac relaxation

DRUGS FOR TREATMENT OF MYOCARDIAL ISCHEMIA

A. Chemistry

1. Antianginal agents include nitrites (i.e., organic esters of nitrous acid) such as amylnitrite, nitrates (i.e., organic esters of nitric acid) such as nitroglycer in and isosorbide, β-blockers such as propranolol, and calcium antagonists such as verapamil and nifedipine.

a. Amylnitrite is a volatile and flammable liquid administered by inhalation. It requires special precautions (especially restriction of smoking) during administration.

b. Nitroglycerin is also a volatile and flammable liquid and requires great care during storage. It must be dispensed from its original glass containers and protected from body heat.

(1) When given intravenously, nitroglycer in requires the use of special plastic administration sets to avoid absorption and loss of potency.

(2) Nitroglycer in is metabolically unstable and undergoes extensive first -pass metabolism.

2. Peripheral vasodi lators include the dipiperidino-dipyrimidine dipyridamole.

B. Pharmacology

1. Nitrites and nitrates are fast -acting antianginal agents that directly relax vascular smooth muscle by formation of the free radical nitric oxide (NO), which is identical to endothelium-derived relaxing factor (EDRF). NO activates guanylyl cyclase to increase synthesis of cyclic guanosine monophosphate (cGMP) within smooth muscle, resulting in dephosphorylation of light chain myosin and muscle relaxation. This causes peripheral pooling of the blood, diminished venous return (reduced preload), decreased systemic vascular resistance, and decreased arterial pressure (reduced af terload). These vascular effects:

a. Reduce myocardial oxygen demand

b. Cause redistribution of coronary blood flow along the collateral coronary arteries, improving perfusion of the ischemic myocardium

2. β-Adrenergic blockers decrease sympathetic-mediated myocardial stimulation. The resulting negative inotropic and negative chronotropic effects reduce myocardial oxygen requirements.

3. Calcium antagonists (also known as calcium channel blockers) block calcium entry through the membranous calciumion (Ca++) channels of coronary and peripheral vascular smooth muscle.

a. Peripheral arterioles dilate and total peripheral resistance decreases, reducing afterload and reducing myocardial oxygen requirements.

b. Calcium antagonists also increase oxygen delivery to the myocardium by dilating coronary arteries and arterioles.

4. Dipyridamole relaxes smooth muscles, decreasing coronary vascular resistance and increasing coronary blood flow.

ANTIARRHYTHMIC AGENTS

A. Chemistry. Antiarrhythmic agents have widely diverse chemical structures. They include representatives of the following groups:

1. Cinchona alkaloids—such as quinidine (an optical isomer of quinine)

2. Amides—such as procainamide (Pronestyl), flecainide (Tambocor), and disopyramide (Norpace)

3. Xylyl derivatives—such as lidocaine (Xylocaine) and mexiletine (Mexitil)

4. Quaternary ammonium salts—such as bretylium (Bretylol)

5. Diiodobenzyloxyethylamines—such as amiodarone (Cordarone)

6. β-Blockers—such as, nadolol (Corgard) , propranolol (Inderal), esmolol (Brevibloc), and acebutolol (Sectral )

7. Calcium antagonists—such as diltiazem (Cardizem) and verapamil (Calan)

8. Hydantoins—such as phenytoin (Dilantin)

B. Pharmacology. Antiarrhythmic agents are classified according to their ability to alter the action potential of cardiac cells.

1. Class IA drugs (e.g., quinidine, procainamide, disopyramide) produce statedependent sodium channel blockade to slow the rate of rise of phase 0 ( the phase of rapid depolarization and reversal of transmembrane voltage) and prolong repolarization and effective refractory period.

2. Class IB drugs (e.g., lidocaine, tocainide, mexiletine, phenytoin) have a minimal effect on the rate of rise of phase 0 and shorten repolarization.

3. Class IC drugs (e.g., flecainide, propafenone) have a marked effect in slowing the rate of rise of phase 0 and in slowing conduction. They have little effect on repolarization. Encainide was withdrawn from the market but is available on a limited basis.

4. Class II drugs (e.g., propranolol, nadolol, esmolol, acebutolol) are β-adrenergic antagonists that competitively block catecholamine- induced stimulation of cardiac β-receptors and depress depolarization of phase 4.

5. Class III drugs (e.g., bretylium, amiodarone, sotalol, ibutilide, dofetilide) increase action potential duration by prolonging repolarization via blockade of the delayed rectifier potassium current IKr.

6. Class IV drugs (e.g., verapamil, diltiazem, bepridil) are calcium antagonists that block the slow inward current carried by calcium during phase 2 (i.e., long-sustained depolarization or the plateau of the action potential), increase the effective refractory period, and depress phase 4 depolarization.

7. Digoxin and adenosine. Digitalis glycosides (digoxin) elicit a vagotonic response that increases AV nodal refractoriness. Adenosine acts at G-protein-coupled adenosine receptors to increase AV nodal refractor iness.

8. Moricizine is a type I antiarrhythmic but not A, B, or C. It exhibits potent local anesthetic activity and myocardial membrane stabilizing activity. Moricizine reduces fast inward sodium current, decreasing the action potential duration and effective refractory period, and increases the PR, QRS, and QT e interval.

ANTIHYPERTENSIVE AGENTS

A. Chemistry. Antihypertensive agents vary so widely in chemical structure that they are usually classified by mechanism of action rather than chemical class.

B. Pharmacology. Antihypertensive agents lower blood pressure by reducing total peripheral resistance or cardiac output through a variety of mechanisms.

1. Diuretics such as thiazides create a negative sodium balance, reduce blood volume, and decrease vascular smooth muscle responsiveness to vasoconstrictors.

2. Vasodilators such as diazoxide and minoxidil are potassium channel activators that produce membrane hyperpolarization, whereas hydralazine may stimulate formation of EDRF (NO) to decrease arterial resistance. Human brain natriuretic peptide (BNP) via receptor stimulation and sodium nitroprusside via release of NO activate guanylyl cyclase, forming cGMP to relax both arterioles and veins.

3. Peripheral sympatholytics interfere with adrenergic function by blocking postganglionic adrenergic receptors (e.g., propranolol, prazosin), limiting the release of neurotransmitters from adrenergic neurons (e.g., guanethidine), or depleting intraneuronal catecholamine storage sites (e.g., reserpine).

4. Central α₂ -sympathomimetics (e.g., clonidine, methyldopa) appear to mediate their effects by stimulating presynaptic α₂-inhibitory receptors, resulting in a negative sympathetic outflow and lowered peripheral resistance.

5. Calcium channel blockers (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, verapamil) lower vascular resistance and blood pressure via blockade of voltage-gated calcium channels. Arterioles are more sensitive than veins.

6. ACE inhibitors (e.g., captopril) block the conversion of inactive angiotensin I to the potent vasoconstrictor angiotensin II. The reduced angiotensin II concent ration also lowers aldosterone concentration, which limits sodium retention.

7. Angiotensin II receptor antagonists (e.g., losartan) are nonpeptide antagonists of the AT1 angiotensin II receptor subtype located in vasculature, myocardium, brain, kidney, and adrenal glomerulosa. They produce vasodi lation, cause loss of salt and water to decrease plasma volume, and decrease myogenic activity.

8. Endothel in receptor antagonists (e.g., bosentan) are potent orally active nonpeptide endothelin receptor antagonists.

DIURETICS

A. Osmotic diuretics

1. Chemistry. Osmotic diuretics (e.g., mannitol, urea, glycerin, isosorbide) are highly polar, water-soluble agents with a low renal threshold.

2. Pharmacology

a. Osmotic diuretics are relatively inert chemicals that are freely filtered at the glomerulus and poorly reabsorbed from the renal tubule. By increasing the osmolarity of the glomerular filtrate, they limit tubular reabsorption of water and thus promote diuresis.

b. Because these agents increase water, sodium, chloride, and bicarbonate excretion, they cause an increase in urinary pH.

B. Carbonic anhydrase inhibitors

1. Chemistry. Carbonic anhydrase inhibitors are aromatic or heterocyclic sulfonamides with a prominent thiadiazole nucleus. Acetazolamide is the prototypical agent.

2. Pharmacology

a. Carbonic anhydrase inhibitors noncompetitively inhibit the enzyme carbonic anhydrase. This prevents the enzyme from providing the tubular hydrogenions needed for exchange with sodium in the proximal tubule, resulting in sodium bicarbonate diuresis.

b. Because these agents increase water, sodium, potassium, and bicarbonate excretion, they cause an alkaline urinary pH.

C. Benzothiadiazide diuretics

1. Chemistry

a. The commonly used thiazide diuretics are primarily closely related benzothiadiazides with variable substituents. The prototypical agent is chlorothiazide.

b. Optimal diuretic activity depends on certain structural features.

(1) The benzene ring must have a sulfonamide group (preferably unsubstituted) in position 7 and a halogen (usually a chloro group) or a trifluoromethyl group in position 6.

(2) Saturation of the 3,4-double bond increases potency, as with hydrochlorothiazide.

(3) Lipophilic substituents at position 3 or methyl groups at position 2 enhance potency and prolong activity, as with cyclothiazide and bendroflumethiazide.

(4) Replacement of the sulfonyl group in position 1 by a carbonyl group prolongs activity, as with quinethazone.

c. A few sulfamoylbenzamides (e.g., indapamide, chlorthalidone) have activity similar to that of the benzothiadiazides.

d. Benzothiadiazines without the sulfonamide group (e.g., diazoxide) exhibit antihypertensive activity but lack diuretic activity.

2. Pharmacology

a. Benzothiadiazides directly inhibit sodium and chloride reabsorption on the luminal membrane of the early segment of the distal convoluted tubule.

b. These agents increase water, sodium, chloride, potassium, and bicarbonate excretion and decrease calcium excretion and uric acid secretion. They may cause an alkaline urinary pH by inhibiting carbonic anhydrase.

D. Loop diuretics

1. Chemistry. Loop diuretics are anthranilic acid derivatives with a sulfonamide substituent (e.g., furosemide, bumetanide) or aryloxyacetic acids without a sulfonamide substituent (e.g., ethacrynic acid).

2. Pharmacology

a. These agents act principally at the thick ascending limb of the loop of Henle, where they inhibit the cotransport of sodium, potassium, and chloride from the luminal filt rate.

b. Loop diuretics increase excretion of water, sodium, potassium, calcium, and chloride; decrease uric acid secretion; and cause no change in urinary pH.

E. Potassium-sparing diuretics

1. Chemistry. The potassium-sparing diuretics are pteridine or pyrazine derivatives (e.g., triamterene, amiloride) or steroid analog antagonists of aldosterone (e.g., spironolactone).

2. Pharmacology

a. Spironolactone and eplerenone act as competitive inhibitors of aldosterone at mineralocorticoid receptors in the late distal tubule and collecting duct . They interfere with aldosterone-mediated sodium-potassium exchange, decreasing potassium secretion.

b. Triamterene and amiloride, which are not aldosterone antagonists, act directly on the late distal tubule and collecting duct. They disrupt sodium exchange with potassium and hydrogen by blocking sodium channels and decreasing the driving force for secretion of potassium and hydrogen.

c. The potassium-sparing diuretics increase bicarbonate excretion and cause an alkaline urinary pH.

ANTIHYPERLIPIDEMIC AGENTS

A. Chemistry. Antihyperlipidemic agents vary in chemical structure and are usually classified by their site of action—locally in the intestine (nonabsorbable agents) or systemically (absorbable agents) .

1. Nonabsorbable agents are bile acid sequestrants. These agents are hydrophilic, water- insoluble resins that bind to bile acids in the intestine. Examples include colesevelam hydrochloride; cholestyramine chloride, a basic anionexchange resin consisting of trimethylbenzylammonium groups in a large copolymer of styrene and divinylbenzene; colestipol hydrochloride, a copolymer of diethylpentamine and epichlorohydr in, and ezetimibe, a 2-azetidinone blocker of the gastrointestinal cholesterol transporter .

2. Absorbable agents include nicotinic acid (but not the st ructurally similar nicotinamide), the aryloxyisobutyric acid derivatives fenofibrate (prodrug) and gemfibrozil, the 3-hydroxy-3-methylglutaryl -coenzyme A (HMG-CoA) reductase inhibitor lovastatin, and the fatty fish oils containing large amounts of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

B. Pharmacology. Antihyperlipidemic agents increase catabolism or reduce lipoprotein production (e.g., lovastatin, gemfibrozil) or increase the efficiency of lipoprotein removal (e.g., cholestyramine, colestipol) .

ANTICOAGULANT, ANTIPLATELET, AND THROMBOLYTIC AGENTS

A. Anticoagulants. The major anticoagulant agents are heparin, low molecular weight heparin (LMWH) and the oral anticoagulants.

1. Chemistrya. Heparin is a large, highly acidic mucopolysaccharide composed of sulfated D-glucosamine and D-glucuronic acid molecules extracted from bovine lung and porcine intestine.

b. LMWH fragments (1-10 kDa) enoxaparin, dalteparin, tinzaparin, and ardeparin are produced through controlled depolymerization of heparin, but they are not interchangeable with heparin in their actions and use.

(1) Because they are highly acidic, heparin and LMWH fragments exist as anions at physiologic pH and are poorly absorbed from the GI tract . Thus they are usually administered parenterally as the sodium salt.

(2) The action of heparin and LMWH fragments is quickly terminated by protamine sulfate, a highly basic protein that combines chemically with them in approximately equal amounts (mg:mg) .

c. Low molecular weight heparinoids (danaparoid) are glycosaminoglycans extracted from porcine mucosa.

d. Lepirudin is a recombinant -DNA-derived 65 amino acid polypeptide nearly identical to hirudin, which belongs to the group of isopolypeptides of the leech Hi rudo medicinal is.

e. Argatroban is an L-arginine-based structure.

f . Bivalirudin is a 20 amino acid peptide. Lepirudin, bivalirudin, and argatroban are synthetic thrombin inhibitors.

g. Drotrecogin α is a recombinant form of human-activated protein C that inactivates factors Va and VI IIa.

h. Fondaparinux is a pentasaccharide that resembles the antithrombin binding region of heparin.

i . Coumarin derivatives, which are highly effective, and the relatively unimportant indanedione derivatives are oral anticoagulants.

(1) The coumarin derivatives (e.g., warfarin, dicumarol ) are water insoluble, weakly acidic 4-hydroxycoumar in lactones.

(a) These agents are chemically related to vitamin K, and their mechanism of action is directly related to their antagonism of the reductase responsible for reducing vitamin K epoxide to the reduced hydroquinone.

(b) These agents are also highly protein bound and extensively metabolized in the liver. These characteristics, in addition to a relatively narrow therapeutic index, make the coumarin derivatives susceptible to significant drug interactions.

(2) Phenindione represents a typical indanedione derivative.

2. Pharmacology

a. Heparin catalyzes the inhibition of thrombin by antithrombin III (heparin cofactor), preventing the conversion of fibrinogen to fibrin.

b. LMWH fragments are unable to catalyze inhibition of thrombin, but they catalyze inhibition by antithrombin III of factor Xa, which is responsible for conversion of prothrombin to thrombin. Heparin prolongs blood clotting time both in vivo and in vitro, whereas LMWH fragments have minimal in vitro effect .

c. Glycosaminoglycans (Danaparoid) inhibit fibrin formation by inhibition of clotting factors Xa and IIa ( lesser effect) .

d. Lepirudin, desirudin, argatroban, and bivalirudin bind to and block the catalytic activity of thrombin.

e. Drotrecogin inhibits proteolytic inactivation of factors Va and VIIIa.

f . Fondapar inux facilitates inhibition of factor Xa by antithrombin by 300-fold but has no direct effect on thrombin.

g. Oral anticoagulants interfere with the vitamin K-dependent hepatic synthesis of the active clotting factors II (prothrombin), VII, IX, and X and the anticoagulant proteins C and S. These agents prolong blood clotting time in vivo only.

B. Antiplatelet agents

1. Chemistry. Antiplatelet drugs include aspirin, a salicylate; ticlopidine, a thienopyridine; dipyridamole, a dipiperidino-dinitro pyrimidine; prostacyclin analogs, and the Fab fragments of human monoclonal antibody to the glycoprotein IIb/ IIIa (GPIIb/ IIIa) receptor .

2. Pharmacology

a. Aspirin in low doses inhibits platelet cyclooxygenase production of thromboxane A2, preventing platelet aggregation. Cyclooxygenase is permanently inhibited for the life of the platelet (7-10 days) .

b. Ticlopidine and clopidogrel interfere with adenosine diphosphate- (ADP) induced membrane-mediated platelet -fibrinogen binding, leading to inhibition of platelet -platelet aggregation.

c. Fab fragments (e.g., abciximab) are monoclonal antibodies against the GPIIb/ IIIa receptor that permanently inhibit platelet-platelet interaction.

d. GPIIb/ IIIa- receptor antagonists (e.g. , tirofiban, eptifibatide) are reversible antagonists of fibrinogen, von Willebrand factor , and other adhesion ligands at the GPIIb/ IIIa receptor, leading to inhibition of platelet aggregation.

e. Anagrelide decreases platelet production.

f . Cilostazol and its metabolites are type III PDE inhibitors that increase cAMP, leading to vasodilation and decreased platelet aggregation.

g. Treprostinil is a prostacycl in analog of prostaglandin-I₂ (PGI₂), which is a direct vasodilator and inhibitor of platelet aggregation.

h. Dipyridamole may inhibit platelet aggregation via inhibition of:

(1) Red blood cell adenosine, which acts on thromboxane A2 receptors of platelets

(2) Phosphodiesterase to increase intracellular concentrations of cAMP

(3) Thromboxane A2 formation

C. Thrombolytic agents

1. Chemistry

a. Alteplase, reteplase, and tenecteplase are recombinant DNA-derived tissue plasminogen activators (t-PAs) consisting of 527, 355, and 527 amino acids, respectively, of the natural t-PA, which catalyzes conversion of plasminogen to plasmin.

b. Streptokinase is a nonenzymatic 47-kDa protein der ived f rom cul tures of Group

C β-hemolytic st reptococci .

c. Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC) is a complex of humanlys-plasminogen and streptokinase with an anisoyl group blocking the catalytic site.

d. Urokinase is a two-chain serine protease obtained from cultured human kidney cells.

2. Pharmacology. Thrombolytic agents facilitate the conversion of plasminogen to plasmin, which subsequently hydrolyzes fibrin to dissolve clots.

a. Alteplase and reteplase are referred to as clot selective because conversion of plasminogen to plasmin by t -PA is enhanced several hundred- fold in the presence of fibrin.

b. Streptokinase, which has no enzymatic activity, forms a one- to-one complex with plasminogen, resulting in a conformational change that exposes the catalytic site of plasminogen. The stable activated complex subsequently cleaves free plasminogen to form plasmin.

c. Anistreplase is a prodrug activated in vivo by deacylation of the anisole moiety from the active site of the plasminogen-st reptokinase complex. The activated complex conver ts plasminogen to plasmin in the bloodstream or thrombus.

d. Urokinase, in contrast to streptokinase, is enzymat ic and directly converts plasminogen to plasmin.

ANTIANEMIC AGENTS

A. Chemistry. The major antianemic agents are iron preparations, cyanocobalamin (vitamin B-12 ) , folic acid, and hematopoietic growth factors (erythropoietin, colonystimulating factors, and interleukin 11).

1. Mostiron preparations consist of ferrous salts, which are better absorbed from the GI tract than ferric salts or elemental iron. Parenteral iron preparations— including sodium ferric gluconate complex in sucrose (Ferrlecit), iron sucrose (Saccharate), and iron dextran ( INFeD, Dexferrum)—should be employed only when clearly indicated.

a. Typical oral preparations include ferrous sulfate (Feosol), ferrous gluconate (Fergon), and ferrous fumarate (Feostat).

b. When parenteral administration is indicated, sodium ferric gluconate is preferred over iron dextran because it is associated with a lower risk of anaphylactic reaction. Iron sucrose may also have a better safety and adverse effect profile than iron dextran.

2. Cyanocobalamin (vitamin B-12 ) is a nucleotide- like macromolecule with a modified porphyrin unit (a corrin ring) containing a trivalent cobalt atom. A cyanide ion is also coordinated to the cobalt atom, as is a benzimidazole group. The benzimidazole group is bonded to an α-ribosyl phosphate.

3. Folic acid consists of three major components: a pteridine nucleus bonded to the nitrogen of p-aminobenzoic acid, which is bonded through an amide linkage to glutamic acid.

4. Epoetin α and darbepoetin α are glycoproteins produced via recombinant DNA technology. Epoet in α (165 amino acids; 30.4 kDa) is identical to natural erythropoietin.

5. Colony-stimulating factors filgrastim and pegfilgrastim (granulocyte colonystimulating factor; G-CSF) and sargramostim (granulocyte-macrophage colonystimulating factor; GM-CSF) are glycoproteins produced via recombinant DNA technology.

6. Oprelvekin (interleukin 11) is a recombinant DNA-produced nonglycosylated polypeptide growth factor that differs from the natural cytokine by one amino acid.

B. Pharmacology

1. Iron preparations ( ferrous sal ts) are readily absorbed from the GI tract and stored in the bone marrow, liver , and spleen as ferritin and hemosiderin. They are subsequently incorporated as needed into hemoglobin, where the iron reversibly binds molecular oxygen. A lack of body iron causes iron-deficiency anemia with hypochromic, microcytic red blood cells, which transport oxygen poorly.

2. Cyanocobalamin is readily absorbed from the GI tract in the presence of intrinsic factor (Castle factor), a glycoprotein produced by gastric parietal cells that is necessary for GI absorption of cyanocobalamin.

a. Cyanocobalamin is transported to tissue by transcobalamin II . It is essential for cell growth, for maintaining normal nerve cell myelin, and for the metabolic functions of folate.

b. Lack of dietary cyanocobalamin (or lack of intrinsic factor ) causes a vitamin B-12 deficiency and megaloblastic anemia with hyperchromic, macrocytic, immaturered blood cells. Demyelination of nerve cells also occurs, causing irreversible CNS damage.

3. Folic acid is readily absorbed from the GI tract , transported to tissue, and stored intracellularly. It is a precursor of several coenzymes (derivatives of tetrahydrofolic acid) that are involved in single carbon atom transfers. A lack of dietary folic acid causes folic acid deficiency and megaloblastic anemia with hyperchromic, macrocytic, immature red blood cells. Folic acid deficiency causes no neurologic impairment , but folic acid deficiency is associated with birth defects (e.g., spina bifida).

4. Endogenous erythropoietin, whose product ion in the kidneys is stimulated by blood loss, anemia, and hypoxia, is mimicked by epoetin α and darbepoet in α to increase proliferation and differentiation of erythroid progenitor cells.

5. Filgrastim and pegfilgrastim increase proliferation, differentiation, and activation of neutrophils in patients exhibiting neutropenia after undergoing myelosuppressive chemotherapy. Sargramostim stimulates maturation of granulocytes and macrophages and activation of mature cells via cell surface

receptors.

6. Oprelvekin increases platelet production via stimulation of hematopoietic stem cells, megakaryocytes progenitor cells, and maturation of megakaryocytes.