Color Atlas of Pharmacology (Part 13): Antianemics

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B12a; exchange of -CN for -OH group). Adverse effects, in the form of hypersensitivity reactions, are very rare. Folic Acid (B). Leafy vegetables and liver are rich in folic acid (FA). The minimal requirement is approx. 50 µg/d. Polyglutamine-FA in food is hydrolyzed to monoglutamine-FA prior to being absorbed. FA is heat labile. Causes of deficiency include: insufficient intake, malabsorption in gastrointestinal diseases, increased requirements during pregnancy. Antiepileptic drugs (phenytoin, primidone, phenobarbital) may decrease FA absorption, presumably by inhibiting the formation of monoglutamine-FA. Inhibition of dihydro-FA reductase (e.g., by methotrexate, p. 298) depresses the formation of the active...

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138 Antianemics Drugs for the Treatment of Anemias B12a; exchange of -CN for -OH group). Adverse effects, in the form of hyper- Anemia denotes a reduction in red sensitivity reactions, are very rare. blood cell count, hemoglobin content, Folic Acid (B). Leafy vegetables and or both. Oxygen (O2) transport capacity liver are rich in folic acid (FA). The min- is decreased. imal requirement is approx. 50 µg/d. Erythropoiesis (A). Blood corpus- Polyglutamine-FA in food is hydrolyzed cles develop from stem cells through to monoglutamine-FA prior to being ab- several cell divisions. Hemoglobin is sorbed. FA is heat labile. Causes of defi- then synthesized and the cell nucleus is ciency include: insufficient intake, mal- extruded. Erythropoiesis is stimulated absorption in gastrointestinal diseases, by the hormone erythropoietin (a gly- increased requirements during preg- coprotein), which is released from the nancy. Antiepileptic drugs (phenytoin, kidneys when renal O2 tension declines. primidone, phenobarbital) may de- Given an adequate production of crease FA absorption, presumably by in- erythropoietin, a disturbance of eryth- hibiting the formation of monogluta- ropoiesis is due to two principal causes: mine-FA. Inhibition of dihydro-FA re- 1. Cell multiplication is inhibited be- ductase (e.g., by methotrexate, p. 298) cause DNA synthesis is insufficient. This depresses the formation of the active occurs in deficiencies of vitamin B12 or species, tetrahydro-FA. Symptoms of de- folic acid (macrocytic hyperchromic ficiency are megaloblastic anemia and anemia). 2. Hemoglobin synthesis is mucosal damage. Therapy consists in impaired. This situation arises in iron oral administration of FA or in folinic deficiency, since Fe2+ is a constituent of acid (p. 298) when deficiency is caused hemoglobin (microcytic hypochromic by inhibitors of dihydro—FA—reductase. anemia). Administration of FA can mask a vitamin B12 deficiency. Vitamin B12 is re- Vitamin B12 (B) quired for the conversion of methyltet- Vitamin B12 (cyanocobalamin) is pro- rahydro-FA to tetrahydro-FA, which is duced by bacteria; B12 generated in the important for DNA synthesis (B). Inhibi- colon, however, is unavailable for ab- tion of this reaction due to B12 deficien- sorption (see below). Liver, meat, fish, cy can be compensated by increased FA and milk products are rich sources of intake. The anemia is readily corrected; the vitamin. The minimal requirement however, nerve degeneration progress- is about 1 µg/d. Enteral absorption of vi- es unchecked and its cause is made tamin B12 requires so-called “intrinsic more difficult to diagnose by the ab- factor” from parietal cells of the stom- sence of hematological changes. Indis- ach. The complex formed with this gly- criminate use of FA-containing multivi- coprotein undergoes endocytosis in the tamin preparations can, therefore, be ileum. Bound to its transport protein, harmful. transcobalamin, vitamin B12 is destined for storage in the liver or uptake into tis- sues. A frequent cause of vitamin B12 de- ficiency is atrophic gastritis leading to a lack of intrinsic factor. Besides megalo- blastic anemia, damage to mucosal lin- ings and degeneration of myelin sheaths with neurological sequelae will occur (pernicious anemia). Optimal therapy consists in paren- teral administration of cyanocobal- amin or hydroxycobalamin (Vitamin Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antianemics 139 Inhibition of DNA Inhibition of synthesis hemoglobin synthesis (cell multiplication) Vit. B12 deficiency Iron deficiency Folate deficiency A very few large A few small hemoglobin-rich hemoglobin-poor erythrocytes erythrocytes A. Erythropoiesis in bone marrow Folic acid H4 DNA synthesis Vit. B12 Folic acid H3C- Folic acid H4 H3C- Vit. B12 Vit. B12 H3C- HCl Trans- cobalamin II Storage supply for Intrinsic 3 years Vit. B12 factor Parietal cell i.m. Streptomyces griseus B. Vitamin B12 and folate metabolism Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
140 Antianemics Iron Compounds tageous in that it is impossible to over- load the body with iron through an in- Not all iron ingested in food is equally tact mucosa because of its demand-reg- absorbable. Trivalent Fe3+ is virtually ulated absorption (mucosal block). not taken up from the neutral milieu of Adverse effects. The frequent gas- the small bowel, where the divalent Fe2+ trointestinal complaints (epigastric is markedly better absorbed. Uptake is pain, diarrhea, constipation) necessitate particularly efficient in the form of intake of iron preparations with or after heme (present in hemo- and myoglo- meals, although absorption is higher bin). Within the mucosal cells of the gut, from the empty stomach. iron is oxidized and either deposited as Interactions. Antacids inhibit iron ferritin (see below) or passed on to the absorption. Combination with ascorbic transport protein, transferrin, a !1-gly- acid (Vitamin C), for protecting Fe2+ coprotein. The amount absorbed does from oxidation to Fe3+, is theoretically not exceed that needed to balance loss- sound, but practically is not needed. es due to epithelial shedding from skin Parenteral administration of Fe3+ and mucosae or hemorrhage (so-called salts is indicated only when adequate “mucosal block”). In men, this amount oral replacement is not possible. There is approx. 1 mg/d; in women, it is ap- is a risk of overdosage with iron deposi- prox. 2 mg/d (menstrual blood loss), tion in tissues (hemosiderosis). The corresponding to about 10% of the die- binding capacity of transferrin is limited tary intake. The transferrin-iron com- and free Fe3+ is toxic. Therefore, Fe3+ plex undergoes endocytotic uptake complexes are employed that can do- mainly into erythroblasts to be utilized nate Fe3+ directly to transferrin or can for hemoglobin synthesis. be phagocytosed by macrophages, ena- About 70% of the total body store of bling iron to be incorporated into ferri- iron (~5 g) is contained within erythro- tin stores. Possible adverse effects are, cytes. When these are degraded by mac- with i.m. injection: persistent pain at rophages of the reticuloendothelial the injection site and skin discoloration; (mononuclear phagocyte) system, iron with i.v. injection: flushing, hypoten- is liberated from hemoglobin. Fe3+ can sion, anaphylactic shock. be stored as ferritin (= protein apoferri- tin + Fe3+) or returned to erythropoiesis sites via transferrin. A frequent cause of iron deficiency is chronic blood loss due to gastric/in- testinal ulcers or tumors. One liter of blood contains 500 mg of iron. Despite a significant increase in absorption rate (up to 50%), absorption is unable to keep up with losses and the body store of iron falls. Iron deficiency results in impaired synthesis of hemoglobin and anemia (p. 138). The treatment of choice (after the cause of bleeding has been found and eliminated) consists of the oral admin- istration of Fe2+ compounds, e.g., fer- rous sulfate (daily dose 100 mg of iron equivalent to 300 mg of FeSO4, divided into multiple doses). Replenishing of iron stores may take several months. Oral administration, however, is advan- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antianemics 141 Fe III-Salts Oral intake Fe II-Salts Heme-Fe Fe III III Fe Absorption Fe III Duodenum upper jejunum Ferritin Parenteral administration Transport Fe III Fe III plasma Transferrin i.v. i.m. Uptake into Hemoglobin Fe III-complexes erythroblast bone marrow Fe III Erythrocyte Ferritin blood Hemosiderin = aggregated ferritin Loss through Uptake into macrophages bleeding spleen, liver, bone marrow A. Iron: possible routes of administration and fate in the organism Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
142 Antithrombotics Prophylaxis and Therapy of Thromboses gregated platelets, and in tissue throm- boplastin (B). The sequential activation Upon vascular injury, the coagulation of several enzymes allows the afore- system is activated: thrombocytes and mentioned reactions to “snowball”, cul- fibrin molecules coalesce into a “plug” minating in massive production of fibrin (p. 148) that seals the defect and halts (p. 148). bleeding (hemostasis). Unnecessary Progression of the coagulation cas- formation of an intravascular clot – a cade can be inhibited as follows: thrombosis – can be life-threatening. If 1) coumarin derivatives decrease the clot forms on an atheromatous the blood concentrations of inactive fac- plaque in a coronary artery, myocardial tors II, VII, IX, and X, by inhibiting their infarction is imminent; a thrombus in a synthesis; 2) the complex consisting of deep leg vein can be dislodged, carried heparin and antithrombin III neutraliz- into a lung artery, and cause complete es the protease activity of activated fac- or partial interruption of pulmonary tors; 3) Ca2+ chelators prevent the en- blood flow (pulmonary embolism). zymatic activity of Ca2+-dependent fac- Drugs that decrease the coagulabil- tors; they contain COO-groups that bind ity of blood, such as coumarins and hep- Ca2+ ions (C): citrate and EDTA (ethy- arin (A), are employed for the prophy- lenediaminetetraacetic acid) form solu- laxis of thromboses. In addition, at- ble complexes with Ca2+; oxalate pre- tempts are directed at inhibiting the ag- cipitates Ca2+ as insoluble calcium oxa- gregation of blood platelets, which are late. Chelation of Ca2+ cannot be used prominently involved in intra-arterial for therapeutic purposes because Ca2+ thrombogenesis (p. 148). For the thera- concentrations would have to be low- py of thrombosis, drugs are used that ered to a level incompatible with life dissolve the fibrin meshwork!fibrino- (hypocalcemic tetany). These com- lytics (p. 146). pounds (sodium salts) are, therefore, An overview of the coagulation used only for rendering blood incoagu- cascade and sites of action for coumar- lable outside the body. ins and heparin is shown in A. There are two ways to initiate the cascade (B): 1) conversion of factor XII into its active form (XIIa, intrinsic system) at intravas- cular sites denuded of endothelium; 2) conversion of factor VII into VIIa (extrin- sic system) under the influence of a tis- sue-derived lipoprotein (tissue throm- boplastin). Both mechanisms converge via factor X into a common final path- way. The clotting factors are protein molecules. “Activation” mostly means proteolysis (cleavage of protein frag- ments) and, with the exception of fibrin, conversion into protein-hydrolyzing enzymes (proteases). Some activated factors require the presence of phos- pholipids (PL) and Ca2+ for their proteo- lytic activity. Conceivably, Ca2+ ions cause the adhesion of factor to a phos- pholipid surface, as depicted in C. Phos- pholipids are contained in platelet fac- tor 3 (PF3), which is released from ag- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 143 XII XIIa Synthesis susceptible to inhibition by coumarins XI XIa Reaction susceptible to inhibition by heparin- antithrombin complex IX IXa VIIa VII VIII + Ca2+ + Pl Ca2+ + Pl (Phospholipids) X Xa V + Ca2+ + Pl Prothrombin II IIa Thrombin Fibrinogen I Ia Fibrin A. Inhibition of clotting cascade in vivo Platelets Endothelial Clotting factor defect COO– COO- XII COO– Tissue + thrombo- + C C kinase – – aa XIIa – – – PF3 VIIa VII – Phospholipids e.g., PF3 Vessel rupture Ca2+-chelation Citrate Fibrin EDTA Oxalate B. Activation of clotting C. Inhibition of clotting by removal of Ca2+ Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
144 Antithrombotics Coumarin Derivatives (A) Heparin (B) A clotting factor is activated when the Vitamin K promotes the hepatic !-car- factor that precedes it in the clotting boxylation of glutamate residues on the cascade splits off a protein fragment and precursors of factors II, VII, IX, and X, as thereby exposes an enzymatic center. well as that of other proteins, e.g., pro- The latter can again be inactivated phys- tein C, protein S, or osteocalcin. Carbox- iologically by complexing with anti- yl groups are required for Ca2+-mediat- thrombin III (AT III), a circulating gly- ed binding to phospholipid surfaces (p. coprotein. Heparin acts to inhibit clot- 142). There are several vitamin K de- ting by accelerating formation of this rivatives of different origins: K1 (phy- complex more than 1000-fold. Heparin tomenadione) from chlorophyllous is present (together with histamine) in plants; K2 from gut bacteria; and K3 the vesicles of mast cells; its physiologi- (menadione) synthesized chemically. cal role is unclear. Therapeutically used All are hydrophobic and require bile ac- heparin is obtained from porcine gut or ids for absorption. bovine lung. Heparin molecules are Oral anticoagulants. Structurally chains of amino sugars bearing -COO– related to vitamin K, 4-hydroxycouma- and -SO4 groups; they contain approx. rins act as “false” vitamin K and prevent 10 to 20 of the units depicted in (B); regeneration of reduced (active) vita- mean molecular weight, 20,000. Antico- min K from vitamin K epoxide, hence agulant efficacy varies with chain the synthesis of vitamin K-dependent length. The potency of a preparation is clotting factors. standardized in international units of Coumarins are well absorbed after activity (IU) by bioassay and compari- oral administration. Their duration of son with a reference preparation. action varies considerably. Synthesis of The numerous negative charges are clotting factors depends on the intrahe- significant in several respects: (1) they patocytic concentration ratio of cou- contribute to the poor membrane pe- marins to vitamin K. The dose required netrability—heparin is ineffective when for an adequate anticoagulant effect applied by the oral route or topically on- must be determined individually for to the skin and must be injected; (2) at- each patient (one-stage prothrombin traction to positively charged lysine res- time). Subsequently, the patient must idues is involved in complex formation avoid changing dietary consumption of with ATIII; (3) they permit binding of green vegetables (alteration in vitamin heparin to its antidote, protamine K levels), refrain from taking additional (polycationic protein from salmon drugs likely to affect absorption or elim- sperm). ination of coumarins (alteration in cou- If protamine is given in heparin-in- marin levels), and not risk inhibiting duced bleeding, the effect of heparin is platelet function by ingesting acetylsali- immediately reversed. cylic acid. For effective thromboprophylaxis, a The most important adverse ef- low dose of 5000 IU is injected s.c. two fect is bleeding. With coumarins, this to three times daily. With low dosage of can be counteracted by giving vitamin heparin, the risk of bleeding is suffi- K1. Coagulability of blood returns to ciently small to allow the first injection normal only after hours or days, when to be given as early as 2 h prior to sur- the liver has resumed synthesis and re- gery. Higher daily i.v. doses are required stored sufficient blood levels of clotting to prevent growth of clots. Besides factors. In urgent cases, deficient factors bleeding, other potential adverse effects must be replenished directly (e.g., by are: allergic reactions (e.g., thrombocy- transfusion of whole blood or of pro- topenia) and with chronic administra- thrombin concentrate). tion, reversible hair loss and osteoporo- sis. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 145 Duration of action/days Vit. K1 Phytomenadione Phenprocoumon Vit. K2 Warfarin Vit. K3 Menadione Acenocoumarol Carboxylation of glutamine residues II, VII, IX, X 4-Hydroxy- Vit. K derivatives Coumarin derivatives A. Vitamin K-antagonists of the coumarin type and vitamin K Activated clotting factor IX a, Xa, XIa, XIIa , X a, III II a Inacti- Inacti- vation vation Mast cell AT III AT III + + + + + + + + - - - - Heparin 3 x 5000 IU s.c. + - 30 000 IU i.v. ++ - - - - - - + + + - + + + + Protamine + B. Heparin: origin, structure, and mechanism of action Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
146 Antithrombotics Low-molecular-weight heparin (av- lived (inactivation by complexing with erage MW ~5000) has a longer duration plasminogen activator inhibitor, PAI) of action and needs to be given only and has to be applied by infusion. Rete- once daily (e.g., certoparin, dalteparin, plase, however, containing only the enoxaparin, reviparin, tinzaparin). proteolytic active part of the alteplase Frequent control of coagulability is molecule, allows more stabile plasma not necessary with low molecular levels and can be applied in form of two weight heparin and incidence of side ef- injections at an interval of 30 min. fects (bleeding, heparin-induced throm- Inactivation of the fibrinolytic bocytopenia) is less frequent than with system can be achieved by “plasmin in- unfractionated heparin. hibitors,” such as !-aminocaproic acid, p-aminomethylbenzoic acid (PAMBA), Fibrinolytic Therapy (A) tranexamic acid, and aprotinin, which also inhibits other proteases. Fibrin is formed from fibrinogen Lowering of blood fibrinogen through thrombin (factor IIa)-catalyzed concentration. Ancrod is a constituent proteolytic removal of two oligopeptide of the venom from a Malaysian pit viper. fragments. Individual fibrin molecules It enzymatically cleaves a fragment polymerize into a fibrin mesh that can from fibrinogen, resulting in the forma- be split into fragments and dissolved by tion of a degradation product that can- plasmin. Plasmin derives by proteolysis not undergo polymerization. Reduction from an inactive precursor, plasmino- in blood fibrinogen level decreases the gen. Plasminogen activators can be infu- coagulability of the blood. Since fibrino- sed for the purpose of dissolving clots gen (MW ~340 000) contributes to the (e.g., in myocardial infarction). Throm- viscosity of blood, an improved “fluid- bolysis is not likely to be successful un- ity” of the blood would be expected. less the activators can be given very so- Both effects are felt to be of benefit in on after thrombus formation. Urokinase the treatment of certain disorders of is an endogenous plasminogen activator blood flow. obtained from cultured human kidney cells. Urokinase is better tolerated than is streptokinase. By itself, the latter is enzymatically inactive; only after bin- ding to a plasminogen molecule does the complex become effective in con- verting plasminogen to plasmin. Strep- tokinase is produced by streptococcal bacteria, which probably accounts for the frequent adverse reactions. Strepto- kinase antibodies may be present as a result of prior streptococcal infections. Binding to such antibodies would neu- tralize streptokinase molecules. With alteplase, another endoge- nous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasmin- ogen bound to fibrin. In concentrations needed for therapeutic fibrinolysis this preference is lost and the risk of bleed- ing does not differ with alteplase and streptokinase. Alteplase is rather short- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 147 Fibrinogen Thrombin Ancrod Fibrin Plasmin-inhibitors Plasmin Antibody from prior infection e.g., Tranexamic acid Fever, chills, and inacti- vation Urokinase Streptokinase Human kidney cell culture Plasminogen Streptococci A. Activators and inhibitors of fibrinolysis; ancrod Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
148 Antithrombotics Intra-arterial Thrombus Formation (A) brandt’s factor can be temporarily over- come by the vasopressin anlogue des- Activation of platelets, e.g., upon con- mopressin (p. 164), which increases the tact with collagen of the extracellular release of available factor from storage matrix after injury to the vascular wall, sites. constitutes the immediate and decisive step in initiating the process of primary Formation, Activation, and Aggregation hemostasis, i.e., cessation of bleeding. of Platelets (B) However, in the absence of vascular in- Platelets originate by budding off from jury, platelets can be activated as a re- multinucleate precursor cells, the me- sult of damage to the endothelial cell gakaryocytes. As the smallest formed lining of blood vessels. Among the mul- element of blood (dia. 1–4 µm), they can tiple functions of the endothelium, the be activated by various stimuli. Activa- production of NO˙ and prostacyclin plays tion entails an alteration in shape and an important role. Both substances in- secretion of a series of highly active sub- hibit the tendency of platelets to adhere stances, including serotonin, platelet ac- to the endothelial surface (platelet ad- tivating factor (PAF), ADP, and throm- hesiveness). Impairment of endothelial boxane A2. In turn, all of these can acti- function, e.g., due to chronic hyperten- vate other platelets, which explains the sion, cigarette smoking, chronic eleva- explosive nature of the process. tion of plasma LDL levels or of blood The primary consequence of activa- glucose, increases the probability of tion is a conformational change of an in- contact between platelets and endothe- tegrin present in the platelet mem- lium. The adhesion process involves brane, namely, GPIIB/IIIA. In its active GPIB/IX, a glycoprotein present in the conformation, GPIIB/IIIA shows high af- platelet cell membrane and von Wille- finity for fibrinogen; each platelet con- brandt’s factor, an endothelial mem- tains up to 50,000 copies. The high plas- brane protein. Upon endothelial con- ma concentration of fibrinogen and the tact, the platelet is activated with a re- high density of integrins in the platelet sultant change in shape and affinity to membrane permit rapid cross-linking of fibrinogen. Platelets are linked to each platelets and formation of a platelet other via fibrinogen bridges: they plug. undergo aggregation. Platelet aggregation increases like an avalanche because, once activated, platelets can activate other platelets. On the injured endothelial cell, a platelet thrombus is formed, which obstructs blood flow. Ultimately, the vascular lu- men is occluded by the thrombus as the latter is solidified by a vasoconstriction produced by the release of serotonin and thromboxane A2 from the aggregat- ed platelets. When these events occur in a larger coronary artery, the conse- quence is a myocardial infarction; in- volvement of a cerebral artery leads to stroke. The von Willebrandt’s factor plays a key role in thrombogenesis. Lack of this factor causes thrombasthenia, a patho- logically decreased platelet aggregation. Relative deficiency of the von Wille- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 149 Aggregation Adhesion dysfunctional endothelial cell Platelet Activated von Willebrandt’s Fibrinogen platelet factor A. Thrombogenesis Megakaryocyte Contact with collagen Activation ADP Thrombin Thromboxane A2 Serotonin Platelet Activated platelet Glycoprotein Fibrinogen IIB/IIIA Fibrinogen binding: impossible possible B. Aggregation of platelets by the integrin GPIIB/IIIA Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
150 Antithrombotics Inhibitors of Platelet Aggregation (A) gregation-inducing stimulus. Abciximab is a chimeric human-murine monoclo- Platelets can be activated by mechanical nal antibody directed against GPIIb/IIIa and diverse chemical stimuli, some of that blocks the fibrinogen-binding site which, e.g., thromboxane A2, thrombin, and thus prevents attachment of fi- serotonin, and PAF, act via receptors on brinogen. The peptide derivatives, epti- the platelet membrane. These receptors fibatide and tirofiban block GPIIB/IIIA are coupled to Gq proteins that mediate competitively, more selectively and ha- activation of phospholipase C and hence ve a shorter effect than does abciximab. a rise in cytosolic Ca2+ concentration. Among other responses, this rise in Ca2+ Presystemic Effect of Acetylsalicylic Acid triggers a conformational change in (B) GPIIB/IIIA, which is thereby converted to its fbrinogen-binding form. In con- Inhibition of platelet aggregation by trast, ADP activates platelets by inhibit- ASA is due to a selective blockade of ing adenylyl cyclase, thus causing inter- platelet cyclooxygenase (B). Selectivity nal cAMP levels to decrease. High cAMP of this action results from acetylation of levels would stabilize the platelet in its this enzyme during the initial passage of inactive state. Formally, the two mes- the platelets through splanchnic blood senger substances, Ca2+ and cAMP, can vessels. Acetylation of the enzyme is ir- be considered functional antagonists. reversible. ASA present in the systemic Platelet aggregation can be inhibit- circulation does not play a role in plate- ed by acetylsalicylic acid (ASA), which let inhibition. Since ASA undergoes ex- blocks thromboxane synthase, or by re- tensive presystemic elimination, cyclo- combinant hirudin (originally harvest- oxygenases outside platelets, e.g., in en- ed from leech salivary gland), which dothelial cells, remain largely unaffect- binds and inactivates thrombin. As yet, ed. With regular intake, selectivity is en- no drugs are available for blocking ag- hanced further because the anuclear gregation induced by serotonin or PAF. platelets are unable to resynthesize new ADP-induced aggregation can be pre- enzyme and the inhibitory effects of vented by ticlopidine and clopidogrel; consecutive doses are added to each these agents are not classic receptor an- other. However, in the endothelial cells, tagonists. ADP-induced aggregation is de novo synthesis of the enzyme per- inhibited only in vivo but not in vitro in mits restoration of prostacyclin produc- stored blood; moreover, once induced, tion. inhibition is irreversible. A possible ex- planation is that both agents already Adverse Effects of Antiplatelet Drugs interfere with elements of ADP receptor signal transduction at the megakaryo- All antiplatelet drugs increase the risk of cytic stage. The ensuing functional de- bleeding. Even at the low ASA doses fect would then be transmitted to newly used to inhibit platelet function (100 formed platelets, which would be inca- mg/d), ulcerogenic and bronchocon- pable of reversing it. strictor (aspirin asthma) effects may oc- The intra-platelet levels of cAMP cur. Ticlopidine frequently causes diar- can be stabilized by prostacyclin or its rhea and, more rarely, leukopenia, ne- analogues (e.g., iloprost) or by dipyrida- cessitating cessation of treatment. Clo- mole. The former activates adenyl cy- pidogrel reportedly does not cause he- clase via a G-protein-coupled receptor; matological problems. the latter inhibits a phosphodiesterase As peptides, hirudin and abciximab that breaks down cAMP. need to be injected; therefore their use The integrin (GPIIB/IIIA)-antago- is restricted to intensive-care settings. nists prevent cross-linking of platelets. Their action is independent of the ag- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 151 Arachidonic Thrombin acid Hirudin Serotonin PAF Argatroban Thromb- Abciximab oxane A2 Tirofiban ASA Eptifibatide GPIIB/IIIA GPIIB/IIIA [without ATP [Affinity for affinity for fibrinogen fibrinogen] high] Phospho- diesterase Adenylate- cyclase Dipyridamole ADP Ticlopidine, Clopidogrel Inactive Active A. Inhibitors of platelet aggregation Platelet with Platelet acetylated and blocked cyclooxygenase Low dose of acetyl- salicylic acid COOH O CCH3 O B. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acid Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
152 Plasma Volume Expanders Plasma Volume Expanders graded by cells of the reticuloendothe- lial system. Apart from restoring blood Major blood loss entails the danger of volume, dextran solutions are used for life-threatening circulatory failure, i.e., hemodilution in the management of hypovolemic shock. The immediate blood flow disorders. threat results not so much from the loss As for microcirculatory improve- of erythrocytes, i.e., oxygen carriers, as ment, it is occasionally emphasized that from the reduction in volume of circu- low-molecular-weight dextran, unlike lating blood. dextran 70, may directly reduce the ag- To eliminate the threat of shock, re- gregability of erythrocytes by altering plenishment of the circulation is essen- their surface properties. With pro- tial. With moderate loss of blood, ad- longed use, larger molecules will accu- ministration of a plasma volume ex- mulate due to the more rapid renal ex- pander may be sufficient. Blood plasma cretion of the smaller ones. Consequent- consists basically of water, electrolytes, ly, the molecular weight of dextran cir- and plasma proteins. However, a plasma culating in blood will tend towards a substitute need not contain plasma higher mean molecular weight with the proteins. These can be suitably re- passage of time. placed with macromolecules (“col- The most important adverse effect loids”) that, like plasma proteins, (1) do results from the antigenicity of dex- not readily leave the circulation and are trans, which may lead to an anaphylac- poorly filtrable in the renal glomerulus; tic reaction. and (2) bind water along with its solutes Hydroxyethyl starch (hetastarch) is due to their colloid osmotic properties. In produced from starch. By virtue of its this manner, they will maintain circula- hydroxyethyl groups, it is metabolized tory filling pressure for many hours. On more slowly and retained significantly the other hand, volume substitution is longer in blood than would be the case only transiently needed and therefore with infused starch. Hydroxyethyl complete elimination of these colloids starch resembles dextrans in terms of from the body is clearly desirable. its pharmacological properties and Compared with whole blood or therapeutic applications. plasma, plasma substitutes offer several Gelatin colloids consist of cross- advantages: they can be produced more linked peptide chains obtained from easily and at lower cost, have a longer collagen. They are employed for blood shelf life, and are free of pathogens such replacement, but not for hemodilution, as hepatitis B or C or AIDS viruses. in circulatory disturbances. Three colloids are currently em- ployed as plasma volume expanders— the two polysaccharides, dextran and hydroxyethyl starch, as well as the poly- peptide, gelatin. Dextran is a glucose polymer formed by bacteria and linked by a 1!6 instead of the typical 1!4 bond. Com- mercial solutions contain dextran of a mean molecular weight of 70 kDa (dex- tran 70) or 40 kDa (lower-molecular- weight dextran, dextran 40). The chain length of single molecules, however, varies widely. Smaller dextran mole- cules can be filtered at the glomerulus and slowly excreted in urine; the larger ones are eventually taken up and de- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Plasma Volume Expanders 153 Circulation Blood loss danger of shock Gelatin colloids = cross-linked peptide chains MW 35, 000 Plasma Plasma- proteins Peptides MW ~ 15, 000 Gelatin MW ~ 100, 000 Collagen MW ~ 300, 000 Dextran MW 70, 000 Plasma- MW 40, 000 substitute Erythrocytes with colloids Hydroxyethyl starch MW 450, 000 Sucrose Fructose Bacterium Leuconostoc Hydroxy- mesenteroides ethylation Starch A. Plasma substitutes Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.