Color Atlas of Pharmacology (Part 14): Drugs used in Hyperlipoproteinemias

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Color Atlas of Pharmacology (Part 14): Drugs used in Hyperlipoproteinemias

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Drugs li KT used in Hyperlipoproteinemias port vehicles in the aqueous media of lymph and blood. To this end, small amounts of lipid are coated with a layer of phospholipids, embedded in which are additional proteins—the apolipoproteins (A). According to the amount and the composition of stored lipids, as well as the type of apolipoprotein, one distinguishes 4 transport forms: Lipid-Lowering Agents Triglycerides and cholesterol are essential constituents of the organism. Among other things, triglycerides represent a form of energy store and cholesterol is a basic building block of biological membranes. ...

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  1. 154 Drugs li KT used in Hyperlipoproteinemias Lipid-Lowering Agents port vehicles in the aqueous media of lymph and blood. To this end, small Triglycerides and cholesterol are essen- amounts of lipid are coated with a layer tial constituents of the organism. of phospholipids, embedded in which Among other things, triglycerides repre- are additional proteins—the apolipopro- sent a form of energy store and choles- teins (A). According to the amount and terol is a basic building block of biologi- the composition of stored lipids, as well cal membranes. Both lipids are water as the type of apolipoprotein, one dis- insoluble and require appropriate trans- tinguishes 4 transport forms: Origin Density Mean sojourn Diameter in blood (nm) plasma (h) Chylomicron Gut epithelium
  2. Drugs used in Hyperlipoproteinemias 155 Dietary fats Cell metabolism Cholesterol LDL Chylomicron Fat tissue HDL Heart Skeletal muscle VLDL HDL LDL Chylomicron Lipoprotein Cholesterol remnant synthesis Triglycerides Cholesterol- ester Triglycerides Liver cell Cholesterol Cholesterol Fatty acids Apolipo- Lipoprotein protein OH OH Lipase OH A. Lipoprotein metabolism Colestyramine Gut:: Bile acids Lipoproteins binding and excretion of Liver cell bile acids (BA) Liver: BA synthesis Cholesterol Cholesterol consumption store !-Sitosterol LDL Gut: Cholesterol absorption Synthesis HMG-CoA-Reductase inhibitors B. Cholesterol metabolism in liver cell and cholesterol-lowering drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. 156 Drugs used in Hyperlipoproteinemias liver meets its increased cholesterol de- rare, but dangerous, side effect of the mand by enhancing the expression of statins is damage to skeletal muscula- HMG CoA reductase and LDL receptors ture. This risk is increased by combined (negative feedback). use of fibric acid agents (see below). At the required dosage, the resins Nicotinic acid and its derivatives cause diverse gastrointestinal distur- (pyridylcarbinol, xanthinol nicotinate, bances. In addition, they interfere with acipimox) activate endothelial lipopro- the absorption of fats and fat-soluble vi- tein lipase and thereby lower triglyce- tamins (A, D, E, K). They also adsorb and ride levels. At the start of therapy, a decrease the absorption of such drugs as prostaglandin-mediated vasodilation digitoxin, vitamin K antagonists, and occurs (flushing and hypotension) that diuretics. Their gritty texture and bulk can be prevented by low doses of acetyl- make ingestion an unpleasant experi- salicylic acid. ence. Clofibrate and derivatives (bezafi- The statins, lovastatin (L), simvasta- brate, etofibrate, gemfibrozil) lower plas- tin (S), pravastatin (P), fluvastatin (F), ma lipids by an unknown mechanism. cerivastatin, and atorvastatin, inhibit They may damage the liver and skeletal HMG CoA reductase. The active group of muscle (myalgia, myopathy, rhabdo- L, S, P, and F (or their metabolites) re- myolysis). sembles that of the physiological sub- Probucol lowers HDL more than strate of the enzyme (A). L and S are lac- LDL; nonetheless, it appears effective in tones that are rapidly absorbed by the reducing atherogenesis, possibly by re- enteral route, subjected to extensive ducing LDL oxidation. first-pass extraction in the liver, and 3-Polyunsaturated fatty acids (ei- there hydrolyzed into active metab- cosapentaenoate, docosahexaenoate) olites. P and F represent the active form are abundant in fish oils. Dietary sup- and, as acids, are actively transported by plementation results in lowered levels a specific anion carrier that moves bile of triglycerides, decreased synthesis of acids from blood into liver and also me- VLDL and apolipoprotein B, and im- diates the selective hepatic uptake of proved clearance of remnant particles, the mycotoxin, amanitin (A). Atorvasta- although total and LDL cholesterol are tin has the longest duration of action. not decreased or are even increased. Normally viewed as presystemic elimi- High dietary intake may correlate with a nation, efficient hepatic extraction reduced incidence of coronary heart serves to confine the action of the sta- disease. tins to the liver. Despite the inhibition of HMG CoA reductase, hepatic cholesterol content does not fall, because hepato- cytes compensate any drop in choleste- rol levels by increasing the synthesis of LDL receptor protein (along with the re- ductase). Because the newly formed re- ductase is inhibited, too, the hepatocyte must meet its cholesterol demand by uptake of LDL from the blood (B). Ac- cordingly, the concentration of circulat- ing LDL decreases, while its hepatic clearance from plasma increases. There is also a decreased likelihood of LDL be- ing oxidized into its proatheroslerotic degradation product. The combination of a statin with an ion-exchange resin intensifies the decrease in LDL levels. A Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. Drugs used in Hyperlipoproteinemias 157 Low systemic availability 3-Hydroxy-3-methyl- Mevalonate glutaryl-CoA HMG-CoA Reductase Cholesterol Bio- activation Active form Extraction Active of lipophilic uptake of lactone anion HO HO O COOH OH O O F CH3 H3C O Oral H3C CH3 administration N CH3 H3C Lovastatin Fluvastatin A. Accumulation and effect of HMG-CoA reductase inhibitors in liver Inhibition of HMG-CoA reductase LDL- Receptor HMG-CoA Expression Expression reductase Cholesterol Increased receptor- LDL mediated uptake of LDL in blood B. Regulation by cellular cholesterol concentration of HMG-CoA reductase and LDL-receptors Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. 158 Diuretics Diuretics – An Overview Prophylaxis of renal failure. In circu- latory failure (shock), e.g., secondary to Diuretics (saluretics) elicit increased massive hemorrhage, renal production production of urine (diuresis). In the of urine may cease (anuria). By means of strict sense, the term is applied to drugs diuretics an attempt is made to main- with a direct renal action. The predomi- tain urinary flow. Use of either osmotic nant action of such agents is to augment or loop diuretics is indicated. urine excretion by inhibiting the reab- Massive use of diuretics entails a sorption of NaCl and water. hazard of adverse effects (A): (1) the The most important indications for decrease in blood volume can lead to diuretics are: hypotension and collapse; (2) blood vis- Mobilization of edemas (A): In ede- cosity rises due to the increase in eryth- ma there is swelling of tissues due to ac- ro- and thrombocyte concentration, cumulation of fluid, chiefly in the extra- bringing an increased risk of intravascu- cellular (interstitial) space. When a diu- lar coagulation or thrombosis. retic is given, increased renal excretion When depletion of NaCl and water of Na+ and H2O causes a reduction in (EFV reduction) occurs as a result of diu- plasma volume with hemoconcentra- retic therapy, the body can initiate tion. As a result, plasma protein concen- counter-regulatory responses (B), tration rises along with oncotic pres- namely, activation of the renin-angio- sure. As the latter operates to attract tensin-aldosterone system (p. 124). Be- water, fluid will shift from interstitium cause of the diminished blood volume, into the capillary bed. The fluid content renal blood flow is jeopardized. This of tissues thus falls and the edemas re- leads to release from the kidneys of the cede. The decrease in plasma volume hormone, renin, which enzymatically and interstitial volume means a dimi- catalyzes the formation of angiotensin I. nution of the extracellular fluid volume Angiotensin I is converted to angioten- (EFV). Depending on the condition, use sin II by the action of angiotensin-con- is made of: thiazides, loop diuretics, al- verting enzyme (ACE). Angiotensin II dosterone antagonists, and osmotic diu- stimulates release of aldosterone. The retics. mineralocorticoid promotes renal reab- Antihypertensive therapy. Diuretics sorption of NaCl and water and thus have long been used as drugs of first counteracts the effect of diuretics. ACE choice for lowering elevated blood pres- inhibitors (p. 124) augment the effec- sure (p. 312). Even at low dosage, they tiveness of diuretics by preventing this decrease peripheral resistance (without counter-regulatory response. significantly reducing EFV) and thereby normalize blood pressure. Therapy of congestive heart failure. By lowering peripheral resistance, diu- retics aid the heart in ejecting blood (re- duction in afterload, pp. 132, 306); car- diac output and exercise tolerance are increased. Due to the increased excre- tion of fluid, EFV and venous return de- crease (reduction in preload, p. 306). Symptoms of venous congestion, such as ankle edema and hepatic enlarge- ment, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diu- retics. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. Diuretics 159 Protein molecules Edema Hemoconcentration Colloid osmotic pressure Collapse, Mobilization of danger of edema fluid thrombosis Diuretic A. Mechanism of edema fluid mobilization by diuretics Salt and Diuretic Diuretic fluid retention EFV: Na+, Cl-, H2O Angiotensinogen Renin Angiotensin I ACE Angiotensin II Aldosterone B. Possible counter-regulatory responses during long-term diuretic therapy Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  7. 160 Diuretics NaCl Reabsorption in the Kidney (A) Osmotic Diuretics (B) The smallest functional unit of the kid- Agents: mannitol, sorbitol. Site of action: ney is the nephron. In the glomerular mainly the proximal tubules. Mode of capillary loops, ultrafiltration of plasma action: Since NaCl and H2O are reab- fluid into Bowman’s capsule (BC) yields sorbed together in the proximal tubules, primary urine. In the proximal tubules Na+ concentration in the tubular fluid (pT), approx. 70% of the ultrafiltrate is does not change despite the extensive retrieved by isoosmotic reabsorption of reabsorption of Na+ and H2O. Body cells NaCl and water. In the thick portion of lack transport mechanisms for polyhy- the ascending limb of Henle’s loop (HL), dric alcohols such as mannitol (struc- NaCl is absorbed unaccompanied by ture on p. 171) and sorbitol, which are water. This is the prerequisite for the thus prevented from penetrating cell hairpin countercurrent mechanism that membranes. Therefore, they need to be allows build-up of a very high NaCl con- given by intravenous infusion. They also centration in the renal medulla. In the cannot be reabsorbed from the tubular distal tubules (dT), NaCl and water are fluid after glomerular filtration. These again jointly reabsorbed. At the end of agents bind water osmotically and re- the nephron, this process involves an al- tain it in the tubular lumen. When Na dosterone-controlled exchange of Na+ ions are taken up into the tubule cell, against K+ or H+. In the collecting tubule water cannot follow in the usual (C), vasopressin (antidiuretic hormone, amount. The fall in urine Na+ concentra- ADH) increases the epithelial perme- tion reduces Na+ reabsorption, in part ability for water, which is drawn into because the reduced concentration gra- the hyperosmolar milieu of the renal dient towards the interior of tubule cells medulla and thus retained in the body. means a reduced driving force for Na+ As a result, a concentrated urine enters influx. The result of osmotic diuresis is a the renal pelvis. large volume of dilute urine. Na+ transport through the tubular Indications: prophylaxis of renal cells basically occurs in similar fashion hypovolemic failure, mobilization of in all segments of the nephron. The brain edema, and acute glaucoma. intracellular concentration of Na+ is sig- nificantly below that in primary urine. This concentration gradient is the driv- ing force for entry of Na+ into the cytosol of tubular cells. A carrier mechanism moves Na+ across the membrane. Ener- gy liberated during this influx can be utilized for the coupled outward trans- port of another particle against a gradi- ent. From the cell interior, Na+ is moved with expenditure of energy (ATP hy- drolysis) by Na+/K+-ATPase into the ex- tracellular space. The enzyme molecules are confined to the basolateral parts of the cell membrane, facing the interstiti- um; Na+ can, therefore, not escape back into tubular fluid. All diuretics inhibit Na+ reabsorp- tion. Basically, either the inward or the outward transport of Na+ can be affect- ed. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  8. Diuretics 161 Aldosterone Na+, Cl- Na+, Cl- + H2O dT H2 O K+ C Lumen Inter- stitium BC pT Na+ "carrier" Na+ Cortex Na/K- Na+ ATPase Thick Medulla portion of HL Diuretics ADH HL A. Kidney: NaCl reabsorption in nephron and tubular cell Mannitol [Na+]inside = [Na+]outside [Na+]inside < [Na+]outside B. NaCl reabsorption in proximal tubule and effect of mannitol Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  9. 162 Diuretics Diuretics of the Sulfonamide Type tion of Ca2+ and Mg2+ also increases. Special toxic effects include: (reversible) These drugs contain the sulfonamide hearing loss, enhanced sensitivity to group -SO2NH2. They are suitable for renotoxic agents. Indications: pulmo- oral administration. In addition to being nary edema (added advantage of i.v. in- filtered at the glomerulus, they are sub- jection in left ventricular failure: imme- ject to tubular secretion. Their concen- diate dilation of venous capacitance tration in urine is higher than in blood. vessels preload reduction); refrac- They act on the luminal membrane of toriness to thiazide diuretics, e.g., in re- the tubule cells. Loop diuretics have the nal hypovolemic failure with creatinine highest efficacy. Thiazides are most fre- clearance reduction (
  10. Diuretics 163 Normal Sulfonamide state diuretics Anion secretory Hypokalemia system Loss of Uric acid Na+, K+ H 2O Thiazides Gout Na+ Cl- e.g., hydrochlorothiazide Carbonic anhydrase inhibitors Loop diuretics Na+ Na+ H+ H+ - HCO3 HCO3- Na+ HCO3- CAH K+ H2O 2 Cl- CO2 H2O CO2 e.g., acetazolamide e.g., furosemide A. Diuretics of the sulfonamide type Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  11. 164 Diuretics Potassium-Sparing Diuretics (A) Antidiuretic Hormone (ADH) and Derivatives (B) These agents act in the distal portion of the distal tubule and the proximal part ADH, a nonapeptide, released from the of the collecting ducts where Na+ is re- posterior pituitary gland promotes re- absorbed in exchange for K+ or H+. Their absorption of water in the kidney. This diuretic effectiveness is relatively mi- response is mediated by vasopressin re- nor. In contrast to sulfonamide diuretics ceptors of the V2 subtype. ADH enhanc- (p. 162), there is no increase in K+ secre- es the permeability of collecting duct tion; rather, there is a risk of hyperkale- epithelium for water (but not for elec- mia. These drugs are suitable for oral trolytes). As a result, water is drawn administration. from urine into the hyperosmolar inter- a) Triamterene and amiloride, in ad- stitium of the medulla. Nicotine aug- dition to glomerular filtration, undergo ments (p. 110) and ethanol decreases secretion in the proximal tubule. They ADH release. At concentrations above act on the luminal membrane of tubule those required for antidiuresis, ADH cells. Both inhibit the entry of Na+, stimulates smooth musculature, includ- hence its exchange for K+ and H+. They ing that of blood vessels (“vasopres- are mostly used in combination with sin”). The latter response is mediated by thiazide diuretics, e.g., hydrochlorothia- receptors of the V1 subtype. Blood pres- zide, because the opposing effects on K+ sure rises; coronary vasoconstriction excretion cancel each other, while the can precipitate angina pectoris. Lypres- effects on secretion of NaCl complement sin (8-L-lysine vasopressin) acts like each other. ADH. Other derivatives may display on- b) Aldosterone antagonists. The ly one of the two actions. mineralocorticoid aldosterone pro- Desmopressin is used for the thera- motes the reabsorption of Na+ (Cl– and py of diabetes insipidus (ADH deficien- H2O follow) in exchange for K+. Its hor- cy), nocturnal enuresis, thrombasthe- monal effect on protein synthesis leads mia (p. 148), and chronic hypotension to augmentation of the reabsorptive ca- (p. 314); it is given by injection or via pacity of tubule cells. Spironolactone, as the nasal mucosa (as “snuff”). well as its metabolite canrenone, are an- Felypressin and ornipressin serve as tagonists at the aldosterone receptor adjunctive vasoconstrictors in infiltra- and attenuate the effect of the hormone. tion local anesthesia (p. 206). The diuretic effect of spironolactone de- velops fully only with continuous ad- ministration for several days. Two pos- sible explanations are: (1) the conver- sion of spironolactone into and accumu- lation of the more slowly eliminated metabolite canrenone; (2) an inhibition of aldosterone-stimulated protein syn- thesis would become noticeable only if existing proteins had become nonfunc- tional and needed to be replaced by de novo synthesis. A particular adverse ef- fect results from interference with gon- adal hormones, as evidenced by the de- velopment of gynecomastia (enlarge- ment of male breast). Clinical uses in- clude conditions of increased aldoste- rone secretion, e.g., liver cirrhosis with ascites. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  12. Diuretics 165 Na+ K+ Triamterene Aldosterone Na+ Aldosterone antagonists K+ or H+ Canrenone Protein synthesis Transport capacity Amiloride Spironolactone A. Potassium-sparing diuretics Nicotine Neuro- hypophysis Ethanol Vasoconstriction V2 Adiuretin = Vasopressin V1 H2O permeability of collecting duct Desmopressin Ornipressin Felypressin B. Antidiuretic hormone (ADH) and derivatives Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.



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