PHM 1.02-Drugs-Used-in-Coagulation-Disorder.pdf

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 OVERVIEW Simultaneously, the coagulation system cascade is activated, resulting in thrombin generation and a fibrin clot, which stabilizes the platelet pl...

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 OVERVIEW Simultaneously, the coagulation system cascade is activated, resulting in thrombin generation and a fibrin clot, which stabilizes the platelet plug HEMOSTASIS BASIC PHARMACOLOGY OF ANTICOAGULANT DRUGS BASIC PHARMACOLOGY OF THE FIBRINOLYTIC DRUGS BASIC PHARMACOLOGY OF ANTIPLATELET AGENTS DRUGS USED IN BLEEDING DISORDERS HEMOSTASIS Finely regulated dynamic process of maintaining fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs Extreme—excessive bleeding or thrombosis— represents a breakdown of the hemostatic mechanism Common causes of dysregulated hemostasis include hereditary or acquired defects in the clotting mechanism and secondary effects of infection or cancer Atrial fibrillation is associated with stasis of blood in the atria, formation of blood clots, and increased risk of occlusive stroke Because of the high prevalence of chronic atrial fibrillation, especially in the older population, use of anticoagulants is common. Guidelines for the use of oral anticoagulants (CHA2DS2-VASC) score are based on various risk factors: congestive heart failure, hypertension, age diabetes, history of stroke, vascular disease and sex) Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand factor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI2) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin (5-HT). MECHANISM OF BLOOD COAGULATION The vascular endothelial cell layer lining blood vessels has an anticoagulant phenotype, and circulating blood platelets and clotting factors do not normally adhere to it to an appreciable extent. Injury exposes reactive subendothelial matrix proteins such as collagen and von Willebrand factor→ platelet adherence and activation Thromboxane A2(TXA2) is synthesized from arachidonic acid within platelets and is a platelet activator and potent vasoconstrictor Products secreted from platelet granules include Adenosine Diphosphate (ADP), a powerful inducer of platelet aggregation, and serotonin (5-HT), which stimulates a conformational change in the IIb/IIIa receptor, enabling it to bind fibrinogen, which cross-links adjacent platelets, resulting in aggregation and formation of a platelet plug 1 | Page Patients with defects in the formation of the primary platelet plug (defects in primary hemostasis, e.g., platelet function defects, von Willebrand disease) typically bleed from surface sites (gingiva, skin, heavy menses) with injury. In contrast, patients with defects in the clotting mechanism (secondary hemostasis, e.g., Hemophilia A) tend to bleed into deep tissues (joints, muscle, retroperitoneum), often with no apparent inciting event, and bleeding may recur unpredictably. The platelet is central to normal hemostasis and thromboembolic disease, and is the target of many therapies ○ Platelet-rich thrombi (white thrombi) form in the high flow rate and high shear force environment of arteries. Occlusive arterial thrombi cause serious disease by producing downstream ischemia of extremities or vital organs, and can result in limb amputation or organ failure. ○ Venous clots tend to be more fibrin-rich, contain large numbers of trapped red blood cells, and are recognized Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 pathologically as red thrombi. [Deep venous thrombi (DVT)/pulmonary embolism (PE)] BLOOD COAGULATION CASCADE Blood coagulates due to the transformation of soluble fibrinogen into insoluble fibrin by the enzyme thrombin. Several circulating proteins interact in a cascading series of limited proteolytic reactions. At each step, a clotting factor zymogen undergoes limited proteolysis and becomes an active protease (e.g., factor VII is converted to factor VIIa). Each protease factor activates the next clotting factor in the sequence, culminating in the formation of thrombin (factor IIa). Several of these factors are targets for drug therapy BLOOD CLOTTING FACTORS AND DRUGS THAT AFFECT THEM Initiation of Clotting: The Tissue A model of blood coagulation. With tissue factor (TF), factor VII forms an activated complex (VIIa-TF) that catalyzes the activation of factor IX to factor IXa. Activated factor XIa also catalyzes this reaction. Tissue factor pathway inhibitor inhibits the catalytic action of the VIIa-TF complex. The cascade proceeds as shown, resulting ultimately in the conversion of fibrinogen to fibrin, an essential component of a functional clot Xa is the common rate limiting factor/step ! 2 | Page Factor VIIa complex _________________________________________ The main initiator of blood coagulation in vivo is the tissue factor (TF)—Factor VIIa pathway Tissue factor is a transmembrane protein ubiquitously expressed outside the vasculature, but not normally expressed in an active form within vessels. The exposure of TF on damaged endothelium or to blood that has extravasated into tissue binds TF to factor VIIa. This complex, in turn, activates factors X and IX. Factor Xa along with factor Va forms the prothrombinase complex on activated cell surfaces, which catalyzes the conversion of prothrombin (factor II) to thrombin (factor IIa). Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 Thrombin, in turn, activates upstream clotting factors, primarily factors V, VIII, and XI, resulting in amplification of thrombin generation. The TF-factor VIIa-catalyzed activation of factor Xa is regulated by tissue factor pathway inhibitor (TFPI). Thus, after initial activation of factor X to Xa by TF-VIIa, further propagation of the clot is by feedback amplification of thrombin through the intrinsic pathway factors VIII and IX (this provides an explanation of why patients with deficiency of factor VIII or IX—hemophilia A and hemophilia B, respectively— have a severe bleeding disorder). Antithrombin (AT) is an endogenous anticoagulant and a member of the serine protease inhibitor (serpin) family; it inactivates the serine proteases IIa, IXa, Xa, XIa, and XIIa. The endogenous anticoagulants protein C and protein S attenuate the blood clotting cascade by proteolysis of the two cofactors Va and VIIIa. Defects in natural anticoagulants result in an increased risk of venous thrombosis. The most common defect in the natural anticoagulant system is a mutation in factor V (factor V Leiden), which results in resistance to inactivation by the protein C, protein S mechanism. Fibrinolysis _________________________________________ Process of fibrin digestion by the fibrin-specific protease, plasmin The fibrinolytic system is similar to the coagulation system in that the precursor form of the serine protease plasmin circulates in an inactive form as plasminogen. In response to injury, endothelial cells synthesize and release tissue plasminogen activator (t-PA), which converts plasminogen to plasmin 3 | Page Schematic representation of the fibrinolytic system. Plasmin is the active fibrinolytic enzyme. Several clinically useful activators are shown on the left in bold. Anistreplase is a combination of streptokinase and the proactivator plasminogen. Aminocaproic acid (right) inhibits the activation of plasminogen to plasmin and is useful in some bleeding disorders. t-PA, tissue plasminogen activator. Plasmin remodels the thrombus and limits its extension by proteolytic digestion of fibrin Both plasminogen and plasmin have specialized protein domains (kringles) that bind to exposed lysines on the fibrin clot and impart clot specificity to the fibrinolytic process. It should be noted that this clot specificity is only observed at physiologic levels of t-PA. At the pharmacologic levels of t-PA used in thrombolytic therapy, clot specificity is lost and a systemic lytic state is created, with attendant increase in bleeding risk. As in the coagulation cascade, there are negative regulators of fibrinolysis: endothelial cells synthesize and release plasminogen activator inhibitor (PAI), which inhibits t-PA; in addition, α2 antiplasmin circulates in the blood at high concentrations and under physiologic conditions will rapidly inactivate any plasmin that is not clot-bound. However, this regulatory system is overwhelmed by therapeutic doses of plasminogen activators. If the coagulation and fibrinolytic systems are pathologically activated, the hemostatic system may careen out of control, leading to generalized intravascular clotting and bleeding. This process is called disseminated intravascular Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 coagulation (DIC) and may follow massive tissue injury, advanced cancers, obstetric emergencies such as abruptio placentae or retained products of conception, or bacterial sepsis. The treatment of DIC is to control the underlying disease process; if this is not possible, DIC is often fatal. Regulation of the fibrinolytic system is useful in therapeutics. Increased fibrinolysis is effective therapy for thrombotic disease. Tissue plasminogen activator, urokinase, and streptokinase all activate the fibrinolytic system. Conversely, decreased fibrinolysis protects clots from lysis and reduces the bleeding of hemostatic failure. Aminocaproic acid is a clinically useful inhibitor of fibrinolysis. Heparin and the oral anticoagulant drugs do not affect the fibrinolytic mechanism BASIC PHARMACOLOGY OF THE ANTICOAGULANT DRUGS The ideal anticoagulant drug → Prevent pathologic thrombosis → limit reperfusion injury, yet allow a normal response to vascular injury → limit bleeding Theoretically this could be accomplished by preservation of the TF-VIIa initiation phase of the clotting mechanism with attenuation of the secondary intrinsic pathway propagation phase of clot development. At this time such a drug does not exist; ALL anticoagulants and fibrinolytic drugs have an increased bleeding risk as their principle toxicity. INDIRECT THROMBIN INHIBITORS Indirect thrombin inhibitors are so-named because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin. Unfractionated heparin (UFH), also known as high-molecular-weight (HMW) heparin, low-molecular-weight (LMW) heparin, and the synthetic pentasaccharide fondaparinux bind to antithrombin and enhance its inactivation of factor Xa Unfractionated heparin and to a lesser extent LMW heparin also enhance antithrombin’s inactivation of thrombin. HEPARIN _________________________________________ CHEMISTRY AND MECHANISM OF ACTION: —---------------------------------------------------------- Its biologic activity is dependent upon the endogenous anticoagulant antithrombin. 4 | Page Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), IXa, and Xa, by forming equimolar stable complexes with them. In the absence of heparin, these reactions are slow; in the presence of heparin, they are accelerated 1000-fold. Heparin functions as a cofactor for the antithrombin-protease reaction without being consumed. Once the antithrombin-protease complex is formed, heparin is released intact for renewed binding to more antithrombin. Unfractionated heparin (UFH) has a molecular weight range of 5000–30,000. In contrast, the shorter-chain, low-molecular- weight fractions of heparin inhibit activated factor X but have less effect on thrombin than the HMW species. Nevertheless, numerous studies have demonstrated that LMW heparins such as ENOXAPARIN, DALTEPARIN, and TINZAPARIN are effective in several thromboembolic conditions. In fact, these LMW heparins—in comparison with UFH—have equal efficacy, increased bioavailability from the subcutaneous site of injection, and less frequent dosing requirements (once or twice daily is sufficient). MONITORING OF HEPARIN EFFECT: —------------------------------------------------------------- close monitoring of the activated partial thromboplastin time (aPTT or PTT) is necessary in patients receiving UFH. Levels of UFH may also be determined by protamine titration (therapeutic levels 0.2–0.4 unit/mL) or anti-Xa units (therapeutic levels 0.3–0.7 unit/mL). Weight-based dosing of the LMW heparins results in predictable pharmacokinetics and plasma levels in patients with normal renal function. (Levels are not generally measured except in the setting of renal insufficiency, obesity, and pregnancy) LMW heparin levels can be determined by antiXa units. For enoxaparin, peak therapeutic levels should be 0.5–1 unit/mL for twice-daily dosing, determined 4 hours after administration, and approximately 1.5 units/mL for once-daily dosing. TOXICITY: —----------------------------------------------------------A. BLEEDING AND MISCELLANEOUS EFFECTS major adverse effect of heparin is bleeding risk can be decreased by scrupulous patient selection, careful control of dosage, and close monitoring. Increased loss of hair and reversible alopecia have been reported. Long-term heparin therapy is associated with osteoporosis and spontaneous fractures. Heparin accelerates the clearing of postprandial lipemia by causing the release of lipoprotein Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 lipase from tissues, and long-term use associated with mineralocorticoid deficiency is B. HEPARIN-INDUCED THROMBOCYTOPENIA Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable state that occurs in 1–4% of individuals treated with UFH Surgical patients are at greatest risk Morbidity and mortality in HIT are related to thrombotic events Venous thrombosis occurs most commonly, but occlusion of peripheral or central arteries is not infrequent Skin necrosis has been described, particularly in individuals treated with warfarin in the absence of a direct thrombin inhibitor, presumably due to acute depletion of the vitamin K-dependent anticoagulant protein C occurring in the presence of high levels of procoagulant proteins and an active hypercoagulable state points to be considered in all patients receiving heparin: a. Platelet counts should be performed frequently b. thrombocytopenia appearing in a time frame consistent with an immune response to heparin should be considered suspicious for HIT c. any new thrombus occurring in a patient receiving heparin therapy should raise suspicion of HIT. Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor ARGATROBAN. CONTRAINDICATIONS: —---------------------------------------------------------- contraindicated in patients with HIT, hypersensitivity to the drug, active bleeding, hemophilia, significant thrombocytopenia, purpura, severe hypertension, intracranial hemorrhage, infective endocarditis, active tuberculosis, ulcerative lesions of the gastrointestinal tract, threatened abortion, visceral carcinoma, or advanced hepatic or renal disease. should be avoided in patients who have recently had surgery of the brain, spinal cord, or eye; and in patients who are undergoing lumbar puncture or regional anesthetic block. ADMINISTRATION AND DOSAGE: —---------------------------------------------------------- A plasma concentration of heparin of 0.2–0.4 unit/mL (by protamine titration) or 0.3– 0.7 unit/mL (anti-Xa units) is considered to be the therapeutic range for treatment of venous thromboembolic disease. This concentration generally corresponds to a PTT of 1.5–2.5 times baseline. When intermittent heparin administration is used, the aPTT or anti-Xa activity should be measured 6 5 | Page hours after the administered dose to maintain prolongation of the aPTT to 2–2.5 times that of the control value. However, LMW heparin therapy is the preferred option in this case, as no monitoring is required in most patients. Continuous intravenous administration of heparin is accomplished via an infusion pump. After an initial bolus injection of 80–100 units/kg, a continuous infusion of about 15–22 units/kg/h is required to maintain the anti-Xa activity in the range of 0.3–0.7 units/Ml Low-dose prophylaxis is achieved with subcutaneous administration of heparin, 5000 units every 8–12 hours. Because of the danger of hematoma formation at the injection site, heparin must NEVER be administered intramuscularly. Prophylactic ENOXAPARIN is given subcutaneously in a dosage of 30 mg twice daily or 40 mg once daily. FONDAPARINUX _________________________________________ synthetic pentasaccharide molecule that avidly binds antithrombin with high specific activity, resulting in efficient inactivation of factor Xa has a long half-life of 15 hours, allowing for once-daily dosing by subcutaneous administration. effective in the prevention and treatment of venous thromboembolism, and does not appear to cross-react with pathologic HIT antibodies in most individuals. REVERSAL OF HEPARIN ACTION —---------------------------------------------------------- Excessive anticoagulant action of heparin is treated by discontinuance of the drug. If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. PROTAMINE _________________________________________ is a highly basic, positively charged peptide that combines with negatively charged heparin as an ion pair to form a stable complex devoid of anticoagulant activity. For every 100 units of heparin remaining in the patient, 1 mg of protamine sulfate is given intravenously; the rate of infusion should not exceed 50 mg in any 10-minute period. Excess protamine must be avoided; it also has an anticoagulant effect. Neutralization of LMW heparin by protamine is incomplete. Limited experience suggests that 1 mg of protamine sulfate may be used to partially neutralize 1 mg of enoxaparin. Protamine will not reverse the activity of fondaparinux. Antidote for excessive heparin / used to counteract Heparin Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 WARFARIN AND OTHER COUMARIN ANTICOAGULANTS CHEMISTRY & PHARMACOKINETICS: —---------------------------------------------------------- The clinical use of the coumarin anticoagulants began with the discovery of an anticoagulant substance formed in spoiled sweet clover silage which caused hemorrhagic disease in cattle. At the behest of local farmers, a chemist at the University of Wisconsin identified the toxic agent as BISHYDROXYCOUMARIN. DICUMAROL, a synthesized derivative, and its congeners, most notably warfarin (Wisconsin Alumni Research Foundation, with “-arin” from coumarin added; were initially used as rodenticides. In the 1950s, WARFARIN (under the brand name Coumadin) was introduced as an antithrombotic agent in humans. Warfarin is one of the most commonly prescribed drugs, used by approximately 1.5 million individuals, and several studies Warfarin is generally administered as the sodium salt and has 100% oral bioavailability. Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution (the albumin space), its long half-life in plasma (36 hours), and the lack of urinary excretion of unchanged drug. MECHANISM OF ACTION: —---------------------------------------------------------- Coumarin anticoagulants block the γcarboxylation of several glutamate residues in prothrombin and factors VII, IX, and X as well as the endogenous anticoagulant proteins C and S The blockade results in incomplete coagulation factor molecules that are biologically inactive. The protein carboxylation reaction is coupled to the oxidation of vitamin K. The vitamin must then be reduced to reactivate it. When patients are on warfarin, we tell them not consume green-leafy vegetable (good source of vit K- inactivate action of warfarin) Warfarin prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form TOXICITY —---------------------------------------------------------- Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus. fetal proteins with γ-carboxyglutamate residues found in bone and blood may be affected by warfarin; the drug can cause a serious birth defect characterized by abnormal bone formation. warfarin should never be administered during pregnancy 6 | Page ❖ Cutaneous necrosis with reduced activity of protein C sometimes occurs during the first weeks of therapy in patients who have inherited deficiency of protein C. Rarely, the same process causes frank infarction of the breast, fatty tissues, intestine, and extremities. The pathologic lesion associated with the hemorrhagic infarction is venous thrombosis, consistent with a hypercoagulable state due to warfarin induced depletion of protein C. ADMINISTRATION & DOSAGE —---------------------------------------------------------- initiated with standard doses of 5–10 mg. The initial adjustment of the prothrombin time takes about 1 week, which usually results in a maintenance dosage of 5–7 mg/d. The prothrombin time (PT) should be increased to a level representing a reduction of prothrombin activity to 25% of normal and maintained there for long-term therapy. When the activity is less than 20%, the warfarin dosage should be reduced or omitted until the activity rises above 20%. Therapeutic range for oral anticoagulant therapy is defined in terms of an international normalized ratio (INR). The recommended INR for prophylaxis and treatment of thrombotic disease is 2–3. Patients with some types of artificial heart valves (e.g., tilting disk) or other medical conditions increasing thrombotic risk have a recommended range of 2.5–3.5. DRUG INTERACTIONS —---------------------------------------------------------- Pharmacokinetic mechanisms for drug interaction with warfarin mainly involve cytochrome P450 CYP2C9 enzyme induction, enzyme inhibition, and reduced plasma protein binding Pharmacodynamic mechanisms for interactions with warfarin are: ○ synergism (impaired hemostasis, reduced clotting factor synthesis, as in hepatic disease), ○ competitive antagonism (vitamin K), and and ○ altered physiologic control loop for vitamin K (hereditary resistance to oral anticoagulants). most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. Pharmacodynamic reductions of anticoagulant effect occur with increased vitamin K intake (increased synthesis of clotting factors), the diuretics chlorthalidone and spironolactone (clotting factor concentration), hereditary resistance (mutation of vitamin K reactivation cycle molecules), and hypothyroidism (decreased turnover rate of clotting factors) Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 ❖ ❖ ❖ ❖ Metronidazole, fluconazole, and trimethoprim sulfamethoxazole also stereoselectively inhibit the metabolic transformation of S-warfarin, whereas amiodarone, disulfiram, and cimetidine inhibit metabolism of both enantiomorphs of warfarin. Aspirin, hepatic disease, and hyperthyroidism augment warfarin’s effects—aspirin by its effect on platelet function and the latter two by increasing the turnover rate of clotting factors. The third- generation cephalosporins eliminate the bacteria in the intestinal tract that produce vitamin K and, like warfarin, also directly inhibit vitamin K epoxide reductase. Barbiturates and rifampin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes that transform racemic warfarin. Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability. Drugs with no significant effect on anticoagulant therapy include ethanol, phenothiazines, benzodiazepines, acetaminophen, opioids, indomethacin, and most antibiotics. PHARMACOKINETIC AND PHARMACODYNAMIC DRUG AND BODY INTERACTIONS WITH ORAL ANTICOAGULANTS. REVERSAL OF WARFARIN ACTION —---------------------------------------------------------- Excessive anticoagulant effect and bleeding from warfarin can be reversed by stopping the drug and administering oral or parenteral vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa (rFVIIa). The disappearance of excessive effect is not correlated with plasma warfarin concentrations but rather with reestablishment of normal activity of the clotting factors. A modest excess of anticoagulant effect without bleeding may require no more than cessation of the drug. ORAL DIRECT FACTOR Xa INHIBITORS New class of direct oral anticoagulant (DOAC) drugs is having a major impact on antithrombotic pharmacotherapy. (rivaroxaban, apixaban, and edoxaban) PHARMACOLOGY —---------------------------------------------------------- Rivaroxaban, apixaban, and edoxaban inhibit factor Xa, in the final common pathway of clotting. These drugs are given as fixed doses and do not require monitoring. They have a rapid onset of action and shorter half-lives than warfarin. RIVAROXABAN _________________________________________ Has high oral bioavailability when taken with food. Peak plasma level is achieved within 2–4 hours; the drug is extensively protein-bound. It is a substrate for the cytochrome P450 system and the P-glycoprotein transporter. Drugs inhibiting both CYP3A4 and P- glycoprotein (e.g., ketoconazole) result in increased rivaroxaban effect. One third of the drug is excreted unchanged in the urine and the remainder is metabolized and excreted in the urine and feces. The drug half-life is 5–9 hours in patients age 20–45 years and is increased in the elderly and in those with impaired renal or hepatic function. Approved for prevention of embolic stroke in patients with atrial fibrillation without valvular heart disease, prevention of venous thromboembolism following hip or knee surgery, and treatment of venous thromboembolic disease (VTE). Prophylactic dosage is 10 mg orally per day for 35 days for hip replacement or 12 days for knee replacement. For treatment of DVT/PE the dosage 7 | Page Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 is 15 mg twice daily for 3 weeks followed by 20 mg/d. Depending on clinical presentation and risk factors, patients with VTE are treated for 3–6 months; rivaroxaban is also approved for prolonged therapy in selected patients to reduce recurrence risk at the treatment dose. APIXABAN _________________________________________ Has an oral bioavailability of 50% and prolonged absorption, resulting in a half-life of 12 hours with repeat dosing. The drug is a substrate of the cytochrome P450 system and P-glycoprotein and is excreted in the urine and feces. As with rivaroxaban, drugs inhibiting both CYP3A4 and P-glycoprotein, as well as impairment of renal or hepatic function, result in increased drug effect. approved for prevention of stroke in nonvalvular atrial fibrillation, for prevention of VTE following hip or knee surgery, and for treatment and long-term prevention of VTE. The dosage for atrial fibrillation is 5 mg twice daily; the dose for VTE is 10 mg twice a day for the first week, followed by 5 mg twice a day. The prophylactic dose for prevention of VTE following hip or knee surgery or long-term prevention of VTE following initial therapy is 2.5 mg twice a day. The recommended duration of therapy in hip and knee replacement is the same as for rivaroxaban. EDOXABAN _________________________________________ Is a once-daily Xa inhibitor with a 62% oral bioavailability. Peak drug concentrations occur 1–2 hours after dosage and are not affected by food. The drug half-life is 10–14 hours. Edoxaban does not induce CYP450 enzymes. No dose reduction is required with concurrent use of P-glycoprotein inhibitors. Edoxaban is primarily excreted unchanged in the urine. Approved for prevention of stroke in nonvalvular atrial fibrillation, and to treat VTE following treatment with heparin or LMWH for 5–10 days. The dose for atrial fibrillation and VTE treatment is 60 mg once daily. For patients with creatinine clearance of 15–50 mL/min or those taking concomitant Pglycoprotein inhibitors, the dose is 30 mg once daily. Edoxaban is contraindicated in patients with atrial fibrillation and creatinine clearance >95 mL/min, due to the increased rate of ischemic stroke in this group compared with patients taking warfarin. 8 | Page DIRECT THROMBIN INHIBITORS The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin’s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMW heparin (see above), which act through antithrombin. Hirudin and bivalirudin are large, bivalent DTIs that bind at the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site. PARENTERAL DIRECT THROMBIN INHIBITORS HIRUDIN _________________________________________ From medicinal leeches (Hirudo medicinalis),it is a specific, irreversible thrombin inhibitor from leech saliva that for a time was available in recombinant form as lepirudin. Its action is independent of antithrombin, which means it can reach and inactivate fibrin-bound thrombin in thrombi. Lepirudin has little effect on platelets or the bleeding time. Like heparin, it must be administered parenterally and is monitored by aPTT Lepirudin is excreted by the kidney and should be used with great caution in patients with renal insufficiency as no antidote exists. BIVALIRUDIN _________________________________________ bivalent inhibitor of thrombin, is administered intravenously, with a rapid onset and offset of action. short half-life with clearance that is 20% renal and the remainder metabolic. also inhibits platelet activation and has been FDA-approved for use in percutaneous coronary angioplasty. ARGATROBAN _________________________________________ is a small molecule thrombin inhibitor that is FDA-approved for use in patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT. short half-life, is given by continuous intravenous infusion, and is monitored by aPTT. clearance is not affected by renal disease but is dependent on liver function; dose reduction is required in patients with liver disease. Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 Patients on argatroban will demonstrate elevated INRs, rendering the transition to warfarin difficult (ie, the INR will reflect contributions from both warfarin and argatroban). ORAL DIRECT THROMBIN INHIBITOR Advantages of oral direct thrombin inhibition include predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable anticoagulant response and make routine coagulation monitoring unnecessary. Similar to the direct oral anti-Xa drugs described above, the rapid onset and offset of action of these agents allow for immediate anticoagulation. DABIGATRAN ETEXILATE MESYLATE _________________________________________ the only oral direct thrombin inhibitor approved by the FDA. Dabigatran is approved for reduction in risk of stroke and systemic embolism with nonvalvular atrial fibrillation, treatment of VTE following 5–7 days of initial heparin or LMWH therapy reduction of the risk of recurrent VTE, and VTE prophylaxis following hip or knee replacement surgery. PHARMACOLOGY —---------------------------------------------------------- Dabigatran and its metabolites are direct thrombin inhibitors. Following oral administration, dabigatran etexilate mesylate is converted to dabigatran. oral bioavailability is 3–7% in normal volunteers. The half-life of the drug in normal volunteers is 12–17 hours. Renal impairment results in prolonged drug clearance. ADMINISTRATION & DOSAGE —---------------------------------------------------------- For prevention of stroke and systemic embolism in nonvalvular atrial fibrillation, the dosage is 150 mg twice daily for patients with creatinine clearance greater than 30 mL/min. For decreased creatinine clearance of 15–30 mL/min, the dosage is 75 mg twice daily. No monitoring is required. ASSESSMENT OF AND REVERSAL OF ANTITHROMBIN DRUG EFFECT —---------------------------------------------------------- the primary toxicity of dabigatran is bleeding. Dabigatran will prolong the PTT, thrombin time, and ecarin clotting time, which can be used to estimate drug effect if necessary Idarucizumab is a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect. The drug 9 | Page is approved for use in situations requiring emergent surgery or for life-threatening bleeding. SUMMARY OF THE DIRECT ORAL ANTICOAGULANT DRUGS —---------------------------------------------------------- direct oral anticoagulant drugs have consistently shown equivalent antithrombotic efficacy and lower bleeding rates when compared with traditional warfarin therapy. offer the advantages of rapid therapeutic effect, no monitoring requirement, and fewer drug interactions in comparison with warfarin, which has a narrow therapeutic window, is affected by diet and many drugs, and requires monitoring for dosage optimization. short half-life of the newer anticoagulants has the important consequence that patient noncompliance will quickly lead to loss of anticoagulant effect and risk of thromboembolism convenience of once- or twice-daily oral dosing, lack of a monitoring requirement, and fewer drug and dietary interactions documented thus far, the new direct oral anticoagulants represent a significant advance in the prevention and therapy of thrombotic disease. BASIC PHARMACOLOGY OF THE FIBRINOLYTIC DRUGS Fibrinolytic drugs ○ rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin from its precursor zymogen, plasminogen. ○ create a generalized lytic state when administered intravenously. ○ both protective hemostatic thrombi and target thromboemboli are broken down. PHARMACOLOGY —---------------------------------------------------------- STREPTOKINASE _________________________________________ is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen. enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. UROKINASE _________________________________________ human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors (antiplasmins) in plasma prevent its effects. However, the absence of inhibitors for urokinase and the streptokinase-proactivator complex permits their use clinically. Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins; this allows it to lyse the thrombus from within Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs). These activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Recombinant human t-PA is manufactured as alteplase. RETEPLASE _________________________________________ another recombinant human t-PA from which several amino acid sequences have been deleted. TENECTEPLASE _________________________________________ is a mutant form of t-PA that has a longer halflife, and it can be given as an intravenous bolus. ❖ Reteplase and tenecteplase are as effective as alteplase and have simpler dosing schemes because of their longer half-lives. INDICATIONS & DOSAGE —---------------------------------------------------------- Administration of fibrinolytic drugs by the intravenous route ○ pulmonary embolism with hemodynamic instability ○ severe deep venous thrombosis such as the superior vena caval syndrome, and ○ ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema. These drugs are also given intra-arterially, especially for peripheral vascular disease. Thrombolytic therapy in the management of acute myocardial infarction requires careful patient selection, the use of a specific thrombolytic agent, and the benefit of adjuvant therapy. STREPTOKINASE —----------------------------------is administered by intravenous infusion of a loading dose of 250,000 units, followed by 100,000 units/h for 24–72 hours. UROKINASE—-----------------------------------------requires a loading dose of 300,000 units given over 10 minutes and a maintenance dose of 300,000 units/h for 12 hours. Alteplase (t-PA) is given as a 15-mg bolus followed by 0.75 mg/kg (up to 50 mg) over 30 minutes and then 0.5 mg/kg (up to 35 mg) over 60 minutes. RETEPLASE—------------------------------------------is given as two 10-unit bolus injections, the second administered 30 minutes after the first injection. 10 | Page TENECTEPLASE—-------------------------------------is given as a single intravenous bolus ranging from 30 to 50 mg depending on body weight. RECOMBINANT T-PA _________________________________________ has also been approved for use in acute ischemic stroke within 3 hours of symptom onset. ○ In patients without hemorrhagic infarct or other contraindications, this therapy has been demonstrated to provide better outcomes in several randomized clinical trials. The recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1-hour infusion. Streptokinase has been associated with increased bleeding risk in acute ischemic stroke when given at a dose of 1.5 million units, and its use is not recommended in this setting BASIC PHARMACOLOGY OF ANTIPLATELET AGENTS Platelet function is regulated by three categories of substances. ○ The first group consists of agents generated outside the platelet that interact with platelet membrane receptors, eg, catecholamines, collagen, thrombin, and prostacyclin ○ The second category contains agents generated within the platelet that interact with membrane receptors, eg, ADP, prostaglandin D2, prostaglandin E2, and serotonin. ○ A third group comprises agents generated within the platelet that act within the platelet, eg, prostaglandin endoperoxides and thromboxane A2, the cyclic nucleotides cAMP and cGMP, and calcium ion. From this list of agents, several targets for platelet inhibitory drugs have been identified: inhibition of prostaglandin synthesis (aspirin), inhibition of ADP induced platelet aggregation (clopidogrel, prasugrel, ticlopidine), and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole and cilostazol are additional antiplatelet drugs. ASPIRIN _________________________________________ The prostaglandin thromboxane A2 is an arachidonate product that causes platelets to change shape, release their granules, and aggregate. Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 Drugs that antagonize this pathway interfere with platelet aggregation in vitro and prolong the bleeding time in vivo. Aspirin is the prototype of this class of drugs. inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. THIENOPYRIDINES: TICLOPIDINE,CLOPIDOGREL, & PRASUGREL _________________________________________ Ticlopidine, clopidogrel, and prasugrel reduce platelet aggregation by inhibiting the ADP pathway of platelets. These drugs irreversibly block the ADP P2Y12 receptor on platelets. Use of ticlopidine, clopidogrel, or prasugrel to prevent thrombosis is now considered standard practice in patients undergoing placement of a coronary stent. TICLOPIDINE _________________________________________ approved for prevention of stroke in patients with a history of a transient ischemic attack (TIA) or thrombotic stroke, and in combination with aspirin for prevention of coronary stent thrombosis. Adverse effects of ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients, hemorrhage in 5%, and, most seriously, leukopenia in 1%. The leukopenia is detected by regular monitoring of the white blood cell count during the first 3 months of treatment. Development of thrombotic thrombocytopenic purpura has also been associated with the ingestion of ticlopidine. Dosage of ticlopidine is 250 mg twice daily orally. The use of ticlopidine for stroke prevention should be restricted to those who are intolerant of or have failed aspirin therapy. CLOPIDOGREL _________________________________________ approved for patients with unstable angina or non-ST-elevation acute myocardial infarction (NSTEMI) in combination with aspirin; for patients with ST-elevation myocardial infarction (STEMI); or recent myocardial infarction, stroke, or established peripheral arterial disease. STEMI/ NSTEMI, the dosage is a 300-mg loading dose orally followed by 75 mg daily of clopidogrel, with a daily aspirin dosage of 75– 325 mg. for recent myocardial infarction, stroke, or peripheral vascular disease, the dosage is 75 mg/d. maintenance dosage of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. duration of the antiplatelet effect is 7–10 days. 11 | Page antithrombotic effects of clopidogrel are dose dependent; within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. fewer adverse effects than ticlopidine and is rarely associated with neutropenia, superior adverse effect profile and dosing requirements, clopidogrel is frequently preferred over ticlopidine prodrug that requires activation via the cytochrome P450 enzyme isoform CYP2C19. Depending on the single nucleotide polymorphism (SNP) inheritance pattern in CYP2C19, individuals may be poor metabolizers of clopidogrel, and these patients may be at increased risk of cardiovascular events due to inadequate drug effect. Drugs that impair CYP2C19 function, such as omeprazole, should be used with caution. PRASUGREL _________________________________________ approved for patients with acute coronary syndromes. given orally as a 60-mg loading dose and then 10 mg/d in combination with aspirin as outlined for clopidogrel. The Trial to assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI38) compared prasugrel with clopidogrel in a randomized, double-blind trial with aspirin and other standard therapies managed with percutaneous coronary interventions. ○ This trial showed a reduction in the primary composite cardiovascular endpoint (cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) for prasugrel in comparison with clopidogrel. ○ However, the major and minor bleeding risk was increased with prasugrel. Prasugrel is contraindicated in patients with history of TIA or stroke because of increased bleeding risk. In contrast to clopidogrel, cytochrome P450 genotype status is not an important factor in prasugrel pharmacology. TICAGRELOR _________________________________________ newer type of ADP inhibitor (cyclopentyl triazolopyrimidine) and is also approved for oral use in combination with aspirin in patients with acute coronary syndromes. Now one of the newest drugs which is included in the treatment of STEMI/NSTEMI. Found to be superior to clopidogrel and Prasugrel. Cangrelor is a parenteral P2Y12 inhibitor approved for IV use in coronary interventions in Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 patients without previous ADP P2Y12 inhibitor therapy. ASPIRIN & CLOPIDOGREL RESISTANCE —---------------------------------------------------------- The reported incidence of resistance to these drugs varies greatly, from less than 5% to 75%. This is the condition where aspirin or clopidogrel becomes ineffective. Specially for Clopidogrel since it passes through CYP450 pathway. Accounts for the variability of the effect of the clopidogrel on different population. BLOCKADE OF PLATELET GLYCOPROTEIN IIb/IIIa RECEPTORS The platelet GP IIb/IIIa (integrin αIIbβ3) receptor functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the final common pathway for platelet aggregation. The GP IIb/IIIa antagonists are used in patients with acute coronary syndromes. These drugs target the platelet GP IIb/IIIa receptor complex ○ Abciximab ➔ chimeric monoclonal antibody directed against the IIb/IIIa complex including the vitronectin receptor, was the first agent approved in this class of drugs. ➔ approved for use in percutaneous coronary intervention and in acute coronary syndromes. ○ Eptifibatide ➔ cyclic peptide derived from rattlesnake venom that contains a variation of the RGD motif (KGD). ○ Tirofiban ➔ peptidomimetic inhibitor with the RGD sequence motif. ○ IIb/IIIa antagonists are in various stages of development. ADDITIONAL ANTIPLATELET-DIRECTED DRUGS DIPYRIDAMOLE _________________________________________ is a vasodilator that also inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A 12 | Page combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. CILOSTAZOL _________________________________________ is a phosphodiesterase inhibitor that promotes vasodilation and inhibition of platelet aggregation. used primarily to treat intermittent claudication DRUGS USED IN BLEEDING DISORDERS VITAMIN K _________________________________________ Vitamin K confers biologic activity upon prothrombin and factors VII, IX, and X by participating in their post ribosomal modification. Vitamin K is a fat-soluble substance found primarily in leafy green vegetables. The dietary requirement is low because the vitamin is additionally synthesized by bacteria that colonize the human intestine. Two natural forms exist: vitamins K1 and K2. Vitamin K1 (phytonadione) is found in food. Vitamin K2 (menaquinone) is found in human tissues and is synthesized by intestinal bacteria. Vitamins K1 and K2 require bile salts for absorption from the intestinal tract. Vitamin K1 is available clinically in oral and parenteral forms. Intravenous administration of vitamin K1 should be slow, as rapid infusion can produce dyspnea, chest and back pain, and even death. Vitamin K repletion is best achieved with intravenous or oral administration because its bioavailability after subcutaneous administration is erratic. Vitamin K1 is currently administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency, which is especially common in premature infants. PLASMA FRACTIONS SOURCES & PREPARATIONS —---------------------------------------------------------- Deficiencies in plasma coagulation factors can cause bleeding. Spontaneous bleeding occurs when factor activity is less than 5–10% of normal. Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease, or hemophilia B) account for most of the heritable coagulation defects. Concentrated plasma fractions and recombinant protein preparations are available for the treatment of these deficiencies. Eloctate is a factor VIII-Fc domain conjugate that prolongs the factor VIII half-life and allows twice-weekly dosing in many cases. Apple | Camille | Charitie | Klemson | Jennah PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.02 DRUGS USED IN DISORDERS OF COAGULATION Lecturer:DR. Desi James Ojascastro Date: January 16, 2023 Idelvion is a factor IX-albumin conjugate with a half-life of 100 hours (native factor IX has a half-life of 16 hours) and is FDA-approved for prophylaxis or treatment of bleeding in hemophilia B patients, offering the possibility of once-weekly dosing in the case of Idelvion. Vonicog alfa is a recombinant von Willebrand factor product approved for treatment and control of bleeding in adults with von Willebrand disease. Fresh frozen plasma is used for factor deficiencies for which no recombinant form of the protein is available. A four-factor plasma replacement preparation containing vitamin K– dependent factors II VII, IX, and X (4F PCC, Kcentra) is available for rapid reversal of warfarin in bleeding patients. RECOMBINANT FACTOR VIIa Recombinant factor VIIa is approved for treatment of: ○ inherited or acquired hemophilia A or B with inhibitors, ○ treatment of bleeding associated with invasive procedures in congenital or acquired hemophilia, or ○ factor VII deficiency. initiates activation of the clotting pathway by activating factor IX and factor X in association with tissue factor given by bolus injection For hemophilia A or B with inhibitors and bleeding, the dosage is 90 mg/kg every 2 hours until hemostasis is achieved, and then continued at 3- to 6-hour intervals until stable. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID AMINOCAPROIC ACID (EACA) _________________________________________ chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis. It competitively inhibits plasminogen activation It is rapidly absorbed orally and is cleared from the body by the kidney. usual oral dosage of EACA is 6 g four times a day. Clinical uses of EACA are as adjunctive therapy in hemophilia, as therapy for bleeding from fibrinolytic therapy, and as prophylaxis for rebleeding from intracranial aneurysms. TRANEXAMIC ACID _________________________________________ analog of aminocaproic acid and has the same properties. administered orally with a 15-mg/kg loading dose followed by 30 mg/kg every 6 hours. 13 | Page For congenital factor VII deficiency, the recommended dosage is 15–30 mg/kg every 4–6 hours. —----------------CHECKPOINT!!----------------------1. What is the the therapeutic range for treatment of venous thromboembolic disease. a. 0.2–0.4 unit/mL (by protamine titration) b. 0.3–0.7 unit/mL (anti-Xa units) c. 0.5–0.7 units/mL (anti-Xa units) d. a & b e. a & c 2. a synthetic pentasaccharide molecule that avidly binds antithrombin with high specific activity, resulting in efficient inactivation of factor Xa. a. Protamine b. Enoxaparin c. Fondaparinux d. Bishydroxycoumarin e. Dicumarol 3. It binds to antithrombin and enhance its inactivation of factor Xa a. Unfractionated heparin (UFH) b. high-molecular-weight (HMW) heparin c. low-molecular-weight (LMW) heparin d. fondaparinux e. all of the above 4. it is associated with stasis of blood in the atria, formation of blood clots, and increased risk of occlusive stroke a. atrial fibrillation b. platelet function defects c. von Willebrand disease d. heparin-induced thrombocytopenia e. none of the choices 5. it activates upstream clotting factors, primarily factors V, VIII, and XI, resulting in amplification of thrombin generation. a. Thrombin b. Antithrombin c. Aminocaproic acid d. Plasminogen e. Heparin Answers: 1. e 2. c 3. e 4. a 5. a Apple | Camille | Charitie | Klemson | Jennah