Antithrombotic drugs

       

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Antithrombotics Classification:

1.       Anticoagulants; limit the ability of the blood to clot.

2.       Thrombolytic or Fibrinolytic Drugs; act to dissolve clots after they have formed.

3.       Antiplatelet Drugs; limit the migration or aggregation of platelets.

      Anticoagulants Classification (Mechanism):

      1) Indirect Thrombin Inhibitors (Heparins).

      2) Direct Thrombin Inhibitors (DTIs).

      3) Direct Factor Xa Inhibitors.

      4) Vitamin K Antagonist (Coumarin Anticoagulants).

 

 

 

 

 

·         Heparin (from Greek word 'hêpar "liver") was discovered in 1916 by McLean, a second-year medical student, was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue.

·         Heparin is an injectable rapidly acting anticoagulant that is often used acutely to interfere with the formation of thrombi. Heparins also called; indirect thrombin inhibitors because their anti-thrombotic effect is exerted by their interaction with a separate protein, antithrombin.

·         Source; Heparin occurs naturally as a macromolecule complexed with histamine in mast cells. It is extracted for commercial use from porcine or cattle intestinal mucosa.

 

 

 

Unfractionated Heparin (UFH)
Heparin (Calciparine®)
Unfractionated Heparin (UFH): is a mixture of varying chain size of sulfated glycosaminoglycans with a wide range of molecular weights.
Low Molecular Weight Heparins (LMWHS)
Enoxaparin (Clexane®)	Dalteparin (Fragmin®)	Tinzaparin (Innohep®)
Low Molecular Weight Heparins (LMWHS) such as; Enoxaparin, Tinzaparin  and Dalteparin are heterogeneous compounds about one- third the size of unfractionated heparin, produced by enzymatic depolymerization of UFH.

 

 

 

 

 

	Unfractionated Heparin (UFH)	Low Molecular Weight Heparins (LMWHS)
Routes	Must be SC or IV only - The LMWHS are administered SC. - UFH is often initiated as an IV bolus followed by    continuous infusion. - Avoid IM; cause, irritation, erythema, pain,   hematoma or ulceration.
Mwt.	> 30000 Dalton	< 8000 Dalton
Bioavailability	Low	High
Dose	Loading dose, followed by continuous infusion (Unfixed dose)	once or twice daily (Fixed dose)
Half-life	1.5 hours	3-12 hours
Price	Cheep	Expensive
Monitoring	activated partial thromboplastin time (aPTT)	None
Factors Effected	Thrombin, IXa and Xa (less effect on Xa)	Xa
-          Anticoagulant effect with unfractionated heparin occurs within minutes of IV administration or 1 to 2 hours after subcutaneous injection. -          Activated partial thromboplastin time (aPTT) is the standard test used to monitor the extent of anticoagulation with heparin. -          The maximum anti-factor Xa activity of the LMWHS occurs about 4 hours after subcutaneous injection. -          Not necessary to monitor coagulation values with LMWHS because the plasma levels and pharmacokinetics are more predictable, but in renally impaired, pregnant and obese patients monitoring of factor Xa levels is recommended with LMWHS. -          Dose of LMWHs should be reduced in patients with renal impairment
-          In the absence of heparin, antithrombin III interacts very slowly with thrombin and factor Xa. -          UFH; Heparin molecules bind to antithrombin III (AT-III) à conformational change occurs à activation of AT-III à inhibition of thrombin about 1000-fold and factor Xa. -          LMWHS; One molecules bind to with AT-III à inactivate factor Xa. -          A unique pentasaccharide sequence contained in Heparin and LMWHS permits their binding to antithrombin III.
-          heparin and the LMWHs limit the expansion of thrombi by preventing fibrin formation.   -          These agents are used for:   - Treatment of acute venous thromboembolism (DVT or PE).   - Prophylaxis of postoperative venous thrombosis in patients undergoing     surgery and those with acute MI.   - Drug of choice for using in pregnant women (do not cross the placenta).
-          Dose;        - UFH;     - Initial bolus injection; 80-100 units/kg, followed by;        Continuous infusion; 15-22 units/kg/h (monitoring is needed).     - Prophylaxis; 5000 units SC every 8-12 h (monitoring is needed). - Enoxaparin; SC 30 mg twice daily or 40 mg once daily,                   alternatively; 1 mg/kg SC every 12 hours or 1.5 mg/kg once a day. - Dalteparin; 200 units/kg once a day for venous disease or 120 units/kg every                          12 hours for acute coronary syndrome. - Tinzaparin; 175 units/kg SC once daily.          -       Monitoring of Heparin Effect;      -Activated Partial Thromboplastin Time (aPTT) is necessary in patients       receiving UFH; reference range = 30-50 seconds.                    - LMWHS levels are not generally measured except in renal insufficiency,       obesity (> 150 kg) and pregnancy.     - LMWHS levels can be determined by anti-Xa units; therapeutic levels        should be 0.5-1 unit/mL for twice-daily dosing, determined after 4 hours        administration and 1.5 units/mL for once-daily dosing.
1)      Bleeding; ·         Major adverse effect of heparin. ·         Monitoring is required to minimize bleeding. ·         Excessive bleeding may be managed by discontinuing the drug or treating with protamine sulfate. 2)      Hypersensitivity Reaction; ·         Such as; chills, fever, urticaria, and anaphylactic shock, due to; heparin is of animal origin. ·         Heparin and LMWHS are contraindicated in patients who have hypersensitivity to heparin. 3)      Thrombocytopenia; ·         Heparin-induced thrombocytopenia (HIT) is a serious condition that occurs in 1-4% of individuals treated with UFH for a minimum of 7 days. ·         The risk of HIT may be higher in individuals treated with UFH of bovine origin compared with porcine heparin and is lower in those treated exclusively with LMWH. ·         HIT is caused by the formation of abnormal antibodies (immune- mediated) that activate platelets. ·         Morbidity and mortality in HIT are related to thrombotic events (venous thrombosis occurs most commonly). ·         Heparin therapy should be discontinued when patients develop HIT. ·         In cases of HIT, heparin can be replaced by another anticoagulant, such as Argatroban. 4)      Other Side Effects; ·         Osteoporosis has been observed in patients on long-term therapy. ·         Hair loss and alopecia have been reported.

Protamine Sulfate

·         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 IV infusion (rate should not exceed 50 mg in any 10-minute period). ·         Excess protamine must be avoided (it also has an anticoagulant effect). ·         Neutralization of LMWHs by protamine is incomplete, limited experience suggests that 1 mg of protamine sulfate may be used to partially        neutralize 1 mg of enoxaparin.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

-          There are two types of DTIS, dependent on their interaction with the thrombin molecule;

- Bivalent DTIs bind both to the active site and exosite 1.

           - Includes; Hirudin, Bivalirudin, Lepirudin and Desirudin.

- Univalent DTIS bind only to the active site.

           - Includes; Argatroban, Ximelagatran (withdrawn due to hepatotoxicity) and

                              Dabigatran.

Parenteral Direct Thrombin Inhibitors
Bivalirudin (Angiomax®)	Lepirudin (Refludan®)	Desirudin (Iprivask®)
-          In 1884 John Berry Haycraft described a substance found in the saliva of leeches "Hirudo medicinalis" that had anticoagulant effects. He named the substance 'Hirudin'. -          Hirudin is a specific, direct thrombin inhibitor. -          Leeches have been used in medicine for centuries and were first employed in Egypt about 2,500 years ago. -          Leech Therapy; -          Many people are now taking to leech therapy varicose arthritis and skin problems. -          Demi Moore (American actress) said she let leeches suck her blood treat hypertension, veins, hemorrhoids, as part of a therapy to look fresh and young it made headlines. -          Direct Thrombin Inhibitors (DTIS) have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant Hirudin was made possible which opened the door to this new group of drugs. -          Bivalirudin, Lepirudin and Desirudin are parenteral direct thrombin inhibitor that are analogs of Hirudin. -          Mechanism; Directly inhibits thrombin by binding both to catalytic site and anion-binding exosite. -          Pharmacokinetics;                - Like heparin, it must be administered parenterally and is monitored by the aPTT.                - Bivalirudin; elimination related to glomerular filtration rate.                - Lepirudin; about 48% of the administered dose is excreted by the kidney.                - Desirudin; metabolized and eliminated by the kidney.                - So; they are should be used with great caution in patients with renal insufficiency                         as no antidote exists. -          Uses; - Bivalirudin also inhibits platelet activation and has been FDA-approved for use                              in  percutaneous coronary intervention (PCI).                                 - Dose, initial: 0.75 mg/kg /V bolus, followed by continuous infusion: 1.75                                     mg/kg/hour over 4 hours, may be continued at 0.2 mg/kg/hour for up to                                        20 hours, patients should also receive aspirin 300-325 mg/day.       - Lepirudin is approved by the FDA for use in patients with thrombosis related to                              heparin-induced thrombocytopenia (HIT).              - Dose; Initial: 0.4 mg/kg /V slowly (over 15 to 20 seconds) followed by 0.15                      mg/kg/hr IV continuous infusion for 2 to 10 days or longer if clinically needed.       - Desirudin is approved by the FDA for use for prophylaxis of deep vein thrombosis,                            which may lead to pulmonary embolism, in patients undergoing elective hip                              replacement surgery.                - Dose, 15 mg SC every 12 hr. initiate 5-15 min before surgery (but after induction of                          regional block anesthesia) and continue for 9-12 days. -          Side effects; Like the others, bleeding is the major side effect of these agents.       - Up to 40% of patients who receive long-term infusions of Lepirudin develop an         antibody, which may develop life-threatening anaphylactic reactions.
Argatroban (Argatroban®)
- Argatroban is a synthetic parenteral direct thrombin inhibitor that is derived from L-arginine   amino acids. - Mechanism; It is a direct thrombin inhibitor that reversibly binds to the thrombin active site. It                          does not require the co-factor antithrombin III for antithrombotic activity. - Pharmacokinetics; It is metabolized in the liver and has a Half-life of about 39-51 minute. - Uses; -          Prophylaxis of thrombosis in patients with heparin-induced treatment thrombocytopenia (HIT). -          During percutaneous coronary interventions (PCI) in patients who have HIT or are at risk for developing it. - Dose: Before administering Argatroban; discontinue heparin therapy and obtain a baseline               aPTT. The recommended initial dose for adult patients without hepatic impairment is 2 mcg/kg/min as a continuous infusion, monitoring is needed (aPTT). - Side effects; As with other anticoagulants, the major side effect is bleeding. - Contraindication; Patients with hepatic impairment.
Oral Direct Thrombin Inhibitors
- Advantages of oral direct thrombin inhibitors: -          Predictable pharmacokinetics and bioavailability, which allow for fixed dosing. -          Predictable anticoagulant response. -          - Routine coagulation monitoring unnecessary.
Dabigatran Etexilate (Pradaxa®)
- Dabigatran Etexilate is the direct thrombin inhibitor approved by the FDA in 2010. - Mechanism; is a direct thrombin inhibitor bind only to the active site. - Pharmacokinetics; Dabigatran Etexilate is the prodrug of the active moiety Dabigatran. o   Oral bioavailability is 3-7%. * Oral bioavailability may increase by up to 75% when pellets are taken out of the hydroxypropylmethylcellulose (HPMC) capsule. Therefore, capsules should not be opened and pellets taken alone. o   The half-life of the drug is 12-17 hours. o   Renal impairment results in prolonged drug clearance and may require dose adjustment (should be avoided in patients with severe renal impairment). o   The drug is a substrate for the P-glycoprotein efflux pump: however, P- glycoprotein inhibitors or inducers do not have a significant effect on drug clearance. - Uses,        - Prevention of stroke in non-valvular atrial fibrillation.        - Prevention of venous thromboembolism (DVT and PE) in patients who have undergone hip          or knee replacement surgery. - Dose,        - For patients with creatinine clearance (CrCI) >30 mL/min), 150 mg taken orally, twice daily        - For patients with severe renal impairment (CrCl 15-30 mL/min), 75 mg twice daily        - No monitoring is required, - Side effects; The primary toxicity is bleeding, GI adverse effects are common with this drug and                          may include dyspepsia, abdominal pain, esophagitis, and GI bleeding - Drug interactions, Ketoconazole, Amiodarone, Quinidine, and Clopidogrel increases drug effect. - Dabigatran antidote; Idarucizumab (Praxbind®) is a monoclonal antibody and the first reversal                                  agent for the Dabigatran has been approved by the FDA in October 16, 2015.

 

 

 

 

Parenteral Direct Factor Xa Inhibitors

Fondaparinux (Arixtra®)

-          Fondaparinux is a pentasaccharide anticoagulant that is synthetically derived, is a chemically related to low molecular weight heparins (LMWHS). -          Mechanism; Act by selective inhibition of factor Xa only, by selective binding to antithrombin III, it is potentiates (300- to 1000-fold) the innate neutralization of factor Xa by antithrombin III. -          Pharmacokinetics;  - SC administration.  - Long half-life; 15 hours (once-daily).  - Elimination; in the urine as unchanged drug elimination half-life 17-21 hours. -          Uses; Treatment or prophylaxis of venous thromboembolism (DVT and PE). -          Dose; A) Treatments,       - Under 50 kg: 5 mg subcutaneously once a day       - 50 to 100 kg: 7.5 mg subcutaneously once a day.       - Over 100 kg: 10 mg subcutaneously once a day.           B) Prophylaxis,       -2.5mg SC once a day for 5 to 9 days. -          Side effects; Major side effect is bleeding (no antidote). -          Contraindication; Patients with severe renal impairment (CrCl less than 30 mL/min). -          FDA warning; Fondaparinux should not be used in the setting of lumbar puncture or spinal cord surgery, Due to risk of epidural or spinal hematomas.

Oral Direct Factor Xa Inhibitors

Rivaroxaban (Xarelto®)

- Rivaroxaban is the first oral factor Xa inhibitor approved by the FDA in 2011. - Mechanism; Selectively blocks the active site of factor Xa. - Pharmacokinetics;         - Bioavailability;                - 10 mg dose; 80-100% and is not affected by food.                - 20 mg dose; 66% in the fasted state, with food increase the bioavailability.         - Metabolism; mainly by the CYP 3A4/5 and CYP 2J2 to inactive metabolites.         - Elimination; 51% of dose was recovered as metabolites in urine. - Uses;         - Prevention of stroke in non-valvular atrial fibrillation.                  Dose; 20 mg orally once a day.         - Prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE)           in patients undergoing knee or hip replacement surgery. - Dose;     - In DVT or PE, Initial 15 mg orally twice a day for first 21 days of therapy Maintenance:       20 mg orally once a day for the remaining duration of treatment.     - In DVT or PE recurrence, 20 mg orally once a day     - In DVT prophylaxis after hip or knee replacement surgery,                - Initial: 10 mg orally once a day starting 6 to 10 hours after surgery.                - Duration of therapy Hip: 35 days - Knee: 12 days. - Side effects; Major side effect is bleeding. - Contraindication; Patients with severe renal impairment (CrCl less than 30 mL/min in DVT                                   and CrCl less than 15 mL/min in non-valvular atrial fibrillation).

Apixaban (Eliquis®)

- Apixaban is an oral selective inhibitor of factor Xa. - Pharmacokinetics; Metabolism; Mainly by the CYP 3A4. Elimination; 27% is excreted renally. - Uses; - Prevention of stroke in non-valvular atrial fibrillation. - Dose; 5 mg taken orally twice daily.              - Prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in                patients undergoing knee or hip replacement surgery.                  Dose; - In DVT or PE; 10 mg orally twice daily for the first 7 days. After 7 days, the                                recommended dose is 5 mg taken orally twice daily.                              - In DVT or PE recurrence; 2.5 mg taken orally twice daily after at least 6 months of                                treatment for DVT or PE.                              - In DVT prophylaxis after hip or knee replacement surgery; 2.5 mg taken orally twice                                           daily, taken 12-24h after surgery                                            - Duration of therapy. Hip: 35 days - Knee: 12 days. - Side effects; Major side effect is bleeding . - FDA warning; Apixaban should not be used in the setting of lumbar puncture or spinal cord surgery,                            Due to risk of epidural or spinal hematomas.                           - Premature discontinuation of Apixaban, increases the risk of thrombotic events.

 

 

 

 

·         Vitamin K antagonists were the only class of oral anticoagulants available to clinicians for decades.

·         However, after FDA approval of new oral anticoagulants or novel oral anticoagulants (NOACS) including Dabigatran, Rivaroxaban, and Apixaban have been shown to be as better than the vitamin K antagonists with less serious side effects.

Warfarin (Coumadin® - Marevan®)
- Warfarin is a synthetic derivative of dicumarol (natural chemical substance of combined plant and   fungal origin). Dicumarol is derived from Coumarin, a sweet-smelling found naturally in Sweet clover   and Tonka beans (also known as "cumaru" from which coumarin's name derives). - In the early 1920s, Coumarin anticoagulants began with the discovery of an anticoagulant substance   formed in spoiled sweet clover silage which caused hemorrhagic disease in cattle. - The name Warfarin' stems from its discovery at the University of Wisconsin, incorporating the   acronym for for the Wisconsin Alumni Research Foundation and the organization that funded the   key research, "WARF" the ending "-arin", indicating its link with Coumarin. - Warfarin was first registered for use as a rodenticide in the US in 1948, and was immediately   popular. - After an incident in 1951, where a US Army inductee unsuccessfully attempted suicide with multiple   doses of warfarin in rodenticide and recovered fully after presenting to a hospital, and being treated   with vitamin K (specific antidote), studies began in the use of warfarin as a therapeutic   anticoagulant. - In 1954 Warfarin (under the brand name Coumadin) was approved for medical use in humans. - Now Warfarin is one of the most commonly prescribed drugs, used by approximately 1.5 million   individuals. - Phenindione (Dindevan®) is another synthetic derivative of dicumarol, has actions similar to   warfarin, but it is now rarely employed because of its higher incidence of severe adverse effects.
Pharmaco       Kinetics	Chemistry; Warfarin used clinically is a racemic mixture composed of equal                     amounts of two enantiomorphs. The levorotatory S- warfarin is 4                     times more potent than the dextrorotatory R-warfarin. - Absorption;                - Oral bioavailability = 100%.                - Rapidly absorbed after oral administration. - Distribution;                - Warfarin readily crosses the placental barrier.                - Over 99% of racemic warfarin is bound to plasma albumin. - Metabolism;                - Warfarin is metabolized by the CYP450 system. - Excretion;                - Half-life; Mean half-life is approximately 40 hours.                - The inactive metabolites are excreted in urine and feces. - Drugs that affect warfarin binding to plasma proteins or warfarin metabolism   can lead to numerous drug interactions that may potentiate or attenuate its   anticoagulant effect.
Mechanism OF Action	- Warfarin inhibits vitamin K epoxide reductase enzyme, resulting in depletion   of the reduced form of vitamin K. - Vitamin K is a cofactor for the carboxylation of glutamate residues on the   N-terminal regions of vitamin K-dependent proteins, this limits the gamma-  carboxylation and subsequent activation of the vitamin K-dependent coagulant  proteins. - The synthesis of vitamin K-dependent coagulation factors II. VII, IX. and X and    anticoagulant proteins C and S is inhibited. - Depression of vitamin K-dependent coagulation factors (factors II, VII, and X)   results in decreased prothrombin levels and a decrease in the amount of   thrombin generated and bound to fibrin.
Actions	- Production of clotting factors are diminished activity (10-40% of normal) by   warfarin treatment. Unlike heparin, the anticoagulant effects of warfarin are   not observed immediately after drug administration;            - Peak anticoagulant effect may be delayed 72-96 hours (the time              required to deplete the pool of circulating clotting factors).            - Treatment initiated with UFH or LMWH for the first 5-7 days, with an              overlap with Warfarin. Once therapeutic effects of warfarin have been              established, therapy with warfarin is continued for a minimum of 3-6              months. - The duration of action of a single dose of racemic warfarin is 2-5 days. - The anticoagulant effects of warfarin can be overcome by the administration   of vitamin K, takes approximately 24 hours (the time necessary for   degradation of already synthesized clotting factors).
Therapeutic uses	- Prophylaxis and treatment of deep vein thrombosis (DVT) and its extension,    pulmonary embolism (PE). - Prophylaxis and treatment of thromboembolic complications associated with   atrial fibrillation (AF) and/or cardiac valve replacement. - Reduction in the risk of death, recurrent myocardial infarction (MI) and    thromboembolic events such as stroke. - Protein C and S deficiency symptoms (is an inherited disorder causes abnormal   blood clotting). - Antiphospholipid syndrome (is an autoimmune, hypercoagulable state caused   by antiphospholipid antibodies).
Dose	- The dosage and administration of warfarin must be individualized for each   patient according to the patient's INR response to the drug. - International Normalized Ratio (INR); is the prothrombin time ratio (patient    prothrombin time/mean of normal prothrombin time for lab). - Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0- 3.0)   for all treatment durations. - Initial dose: 2-5 mg orally or IV once a day for 1-2 days, then adjust dose   according to results of the INR or prothrombin time (PT). - Maintenance dose: 2-10 mg orally or IV once a day.
Side effects	1) Hemorrhage; o   The major side effect is hemorrhage and the agent has a black box warning for bleeding risk. o   Therefore, it is important monitoring. o   Minor bleeding may be treated by withdrawal of the drug or administration of oral vitamin K (warfarin antidote), but severe bleeding may require high doses of vitamin K given IV.   2) Warfarin Necrosis; o   Rare complications of warfarin therapy, predominantly 4 times more common in obese women. o   Typically occurs within 10 days occurred after several mnonths or of the initiation of therapy, but has several years of therapy. o    80% occur in areas with abundant adipose such as the thighs, breasts, abdomen, buttocks, and the extremities. o   Usually painful, abrupt in onset, erythematous, purpuric and sharply demarcated. Mechanism of warfarin-induced skin necrosis involves an imbalance between proteins C or S and vitamin K-dependent clotting factors. 3) Osteoporosis; o   Due to reduced intake of vitamin K, which is necessary for bone. 4) Purple Toe Syndrome;       - Rare complication. This condition is result from small and causing         embolisms in blood deposits of cholesterol breaking loose vessels in feet,         causes a blueish purple color and may be painful.
pregnancy	- Warfarin is teratogenic and should never be used during pregnancy. - If anticoagulant therapy is needed during pregnancy, Heparin or LMWH may  be administered.   - Color-Coded for Safety; Generic warfarin tablets may come in different   shapes, but each strength comes in just one color. - Generic warfarin tablets may come in different shapes, but each strength comes in just one color. - For example, 5 mg tablet; peach/light orange color.
	Increased Prothrombin Time		Decreased Prothrombin Time
	Pharmacokinetic	Pharmacodynamic	Pharmacokinetic	Pharmacodynamic
	Amiodarone	Drugs	Barbiturates	Drugs
	Cimetidine	Aspirin	Cholestyramine	Diuretics
	Disulfiram	Cephalosporins(third-generation)	Rifampin	Vitamin K
	Metronidazole	Heparin
	Fluconazole	Body factors		Body factors
	Phenylbutazone	Hepatic disease		Hereditary resistance
	Sulfinpyrazone	Hyperthyroidism		Hypothyroidism
	Trimethoprim- Sulfamethoxazole
	-          Metronidazole, Fluconazole and Trimethoprim-Sulfamethoxazole also stereo selectively inhibit metabolism of S-warfarin. -          Amiodarone, Disulfiram and Cimetidine inhibit metabolism of both enantiomorphs of warfarin. -          Aspirin augment warfarin's effects by its effect on platelet function. -          Hepatic disease and hyperthyroidism augment warfarin's effects by increasing the turnover rate of clotting factors. -          Third-generation cephalosporins kill the bacteria in the intestinal tract that produce vitamin K. -          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. -          Diuretics; Chlorthalidone and Spironolactone (clotting factor concentration). -          Vitamin K; increased synthesis of clotting factors. -          Hereditary resistance; mutation of vitamin K reactivation cycle molecules. -          Hypothyroidism; decreased turnover rate of clotting factors.
Food interactions	- Food (or drink) and supplements that may interact with warfarin includes:            - Vitamin A or E and Glucosamine, Ginseng, Ginkgo biloba, Ginger,              Coenzyme Q10 and Bilberry.            - Alcohol, cranberries/cranberry juice and Green tea.            - Chickpeas and animal liver.

 

 

 

 

-          Fibrinolytic drugs (thrombolytic drug) rapidly lyse thrombi (dissolve blood clots) by catalyzing the formation of plasmin (serine protease) from its precursor plasminogen.

-          The major side effects of these drugs are bleeding.

-          These drugs are contraindicated in pregnancy and in patients with healing wounds, a history of cerebrovascular accident, brain tumor, head trauma, intracranial bleeding and metastatic cancer.

Streptokinase (SK) (Kabikinase®)
- Streptokinase is a protein synthesized by streptococci. - Mechanism; Streptokinase combines with the pro-activator plasminogen to form enzyme   complex. This enzymatic complex catalyzes the conversion of inactive plasminogen to active   plasmin. - Uses; acute MI, DVT and PE. - Dose; IV infusion of a loading dose of 250,000 units, followed by 100,000 units/h for 24-72               hours. - Streptokinase has high antigenicity, so patients with anti-streptococcal antibodies can develop   fever, allergic reactions and therapeutic resistance. - Streptokinase is rarely used and is no longer available in many markets.
Urokinase (Angikinase®)
-          Urokinase also called urokinase-type plasminogen activator (uPA), it is produced naturally in the body by the kidneys. -          Therapeutic urokinase is isolated from cultures of Haman kidney cells and has low antigenicity -          Mechanism; directly cleaves the arginine-valine bond of plasminogen to yield active plasmin. -          Uses; PE, DVT, acute MI, coronary artery thromnbosis and arterial thrombosis. -          Dose; loading; 300,000 units over 10 min. and a maintenance; 300,000 units/h for 12 hours.
Anistreplase (Eminase®)
-          Anistreplase is also known as anisoylated plasminogen streptokinase activator complex (APSAC). -          Mechanism; It is consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme's active site. When the drug is administered, the acyl group gets hydrolyzed, thereby freeing the activator complex. It converts plasminogen to plasmin. -          Uses; acute MI, now this drug is discontinued in the USA. -          Dose; Single IV injection of 30 units over 2 to 5 min.
Alteplase (Cathflo® Activase®)	Reteplase (Retavase®)	Tenecteplase (TNKase®)
-          Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs). -          Human t-PA is manufactured as Alteplase (by recombinant DNA technology), Reteplase (by recombinant DNA technology) and Tenecteplase is another recombinant tPA with a longer half-life and greater binding affinity for fibrin. -          Uses,          - Alteplase; Treatment of acute MI, massive PE and acute ischemic stroke.               - Dose; IV infusion (due to very short half-life; 5-30 minutes); 60 mg over the first hour                            and then 40 mg at a rate of 20 mg/h.          - Reteplase; Treatment of acute MI (off-label used in DVT and massive PE).               - Dose; Double IV bolus (moderate half-life) injections of 10 units (10+10) each,                             separated by 30 minutes.          - Tenecteplase; Treatment of acute MI.               - Dose; Single IV bolus (long half-life) of 0.5 mg/kg. - N.B; Alteplase may cause angioedema, and there may be an increased risk of this effect when            combined with angiotensin-converting enzyme (ACE) inhibitors.

 

 

 

 

 

Thromboxane A2 Inhibitor

Aspirin (Aspocid®)

Aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of cyclooxygenase (COX) enzyme. Other non-steroidal anti-inflammatory drugs also inhibit COX but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase; that is their action is reversible. Aspirin inhibit platelet function within 60 min. Aspirin is used in the prophylactic treatment of transient cerebral ischemia and thromboembolic stroke, and reduce the incidence of recurrent MI. The recommended dose; ranges from 75-325 mg/d. Side effects; GI disturbances, increase bleeding time and may cause bronchospasm in susceptible patients.

 

P2Y12 Receptor Inhibitors
Clopidogrel (Plavix®)		Ticlopidine(Brilinta®)	Prasugrel (Effient®)	Ticagrelor (Brilinta®)
- Clopidogrel , Ticlopidine, Prasugrel and Ticagrelor are P2Y12 receptor inhibitors that reduce   platelet aggregation by inhibiting the ADP pathway. - Clopidogrel (Plavix) was the second best-selling drug in the world. In 2010, it grossed over US$9   billion in global sales. - Acts by inhibit the binding of ADP to its receptors (P2Y12 receptor) on platelets inhibit the   activation of GP IIb/IIIA receptors required for platelets to bind to fibrinogen and to each other. - Ticagrelor binds to the P2Y12 receptor reversible. - The other agents bind irreversibly. - Max. inhibition of platelet aggregation; - Clopidogrel; 3-5 d. - Ticlopidine; 3-4 d. - Prasugrel; 2-4 h. - Ticagrelor; 1-3 h.
Pharmaco-      Kinetics	These agents require loading doses for quicker antiplatelet effect. - Absorption of Ticlopidine decrease with food but not with the other agents. - Plasma protein binding; extensively bound to plasma proteins. - Metabolism; by the cytochrome P450 (CYP) system.         - Clopidogrel is a prodrug that requires activation via the cytochrome P450            enzyme isoform CYP2C19. -          Genetic polymorphism of CYP 2C19 leads to a reduced clinical response in patients who are "poor metabolizers" of clopidogrel. Tests are currently available to identify poor metabolizers (In 2010, the FDA put a black box warning on Plavix to make patients and healthcare providers aware that CYP2C19-poor metabolizers). -          Drugs that impair CYP2C19 function, such as Omeprazole, should be used with caution pending clarification of the importance of CYP2C19 status (In 2009, the FDA issued a public-health warning about the -          Recent meta-analysis study (2015); In summary, suggest that the highly controversial interaction between PPIS (Omeprazole) and Clopidogrel observed in platelet aggregation studies has no clinical significance. possible interaction between clopidogrel and omeprazole). - Elimination; Renal and fecal routes.
Therapeutic Uses	-          Clopidogrel and Prasugrel are approved for; - Non ST-elevation acute myocardial infarction; NSTEMI (Unstable angina)    & ST-elevation myocardial infarction (STEMI) including those undergoing    PCI. - Stroke and peripheral arterial disease. -          Ticlopidine is approved for; - Stroke in patients with transient ischemic attack (TIA). - Thrombotic stroke and coronary stent thrombosis. -          Ticagrelor is approved for; Prevention of arterial thromboembolism in patients with unstable angina & acute MI including those undergoing PCI.
Dose	Clopidogrel loading dose; 300-600 mg once, followed by of 75 mg daily. Prasugrel; loading dose 60 mg followed by 10 mg daily. Ticlopidine; loading dose 500 mg followed by 250 mg twice daily, for Ticagrelor; loading dose 180 mg followed by 90 mg twice daily.
- Dual Antiplatelet Therapy (DAPT);    - Therapy with two antiplatelet agents; Thienopyridine agent (e.g. clopidogrel) & aspirin to       reduce the risk of blood clots following coronary stent implantation.    - Longer-term dual antiplatelet therapy expectedly increased bleeding    - Severe and/or fatal bleeding was uncommon.    - DAPT dosing strategies in acute coronary syndrome (ACS).
- These agents can cause prolonged bleeding (no antidote). - Ticlopidine:              - Nausea, dyspepsia, and diarrhea in up to 20% of patients.              - Hemorrhage in 5%.              - Leukopenia in 1% (most seriously):                     - The leukopenia is detected by regular monitoring of the white blood cell count                       during the first 3 months of treatment.              - Thrombotic Thrombocytopenic Purpurea (TTP):                - Is a rare blood disorder characterized by clotting in small blood vessels of the body. - Clopidogrel; has fewer adverse effects than Ticlopidine.                - Neutropenia and TTP (very rare). - N.B; due to life-threatening hematologic adverse reactions, Ticlopidine is generally reserved for patients who are intolerant to other therapies.
-          Prasugrel; is contraindicated in patients with history of transient ischemic attack (TIA) or stroke because of increased bleeding risk. -          Ticagrelor and Prasugrel can cause serious and sometimes fatal bleeding problems. -          Ticagrelor diminished effectiveness with concomitant use of aspirin doses above 100 mg.

 

 

 

Glycoprotein IIb/IIIa Inhibitors
Abciximab (ReoPro®)	Eptifibatide (Integrilin®)	Tirofiban (Aggrastat®)
- Glycoprotein IIb/IIIa receptors on platelets bind to fibrinogen in the final common pathway of   platelet aggregation. - Abciximab is a chimeric monoclonal antibody, inhibits the GP IIb/IIIA receptor and von   Willebrand factor, it was the first agent approved in this class of drugs. - Eptifibatide is a cyclic heptapeptide, inhibits the GP IIb/III receptor. - Tirofiban is a smaller molecule, inhibits the GP IIb/IIIA receptor. - All GP IIb/IIla inhibitor agents should be used in combination with anticoagulant therapy and   aspirin. - Uses; These agents are given IV, along with heparin and aspirin, as an adjunct to PCI for the              prevention of cardiac ischemic complications. - Dose;          - Abciximab: 0.25-mg/kg IV bolus, then 0.125 mcg/kg/min. (max 10 mcg/kg) for 12 hours.          - Eptifibatide; 180-mcg/kg IV bolus x 2 (10 minutes apart), 2 mcg/kg/min. initiated after first             bolus for 18-24 h.{maintenance dose in creatinine clearance < 50 ml/min. 1 mcg/kg/min.}          - Tirofiban; 25-mcg/kg IV bolus over 3 minutes, then 0.15 mcg/kg/minute for 18-24 hours. - Side effects; The major side effects of these agents is bleeding, especially if used with                          anticoagulants. - N.B: Oral formulations of IIb/IIIA antagonists are in various stages of development.

 

Protease-Activated Receptor-1 (PAR-1) Antagonists
Vorapaxar (Zontivity®)	Atopaxar
- Vorapaxar is the first drug inhibit the protease-activated receptor-1 (PAR-1), the   primary receptor for thrombin. - It is an antiplatelet agent, designed to decrease the tendency of platelets aggregation. - Vorapaxar approved by the FDA in 2014. - Uses; reduce thrombotic cardiovascular events in patients with a history of MI or with peripheral   arterial disease. - Dose; 2.08 mg orally once-daily, should be used with daily aspirin and/or clopidogrel according   to their indications or standard of care. - Side effects; increases the risk of bleeding. including life-threatening and fatal bleeding. -Atopaxar; is the second PAR-1 antagonist, tended cardiovascular adverse events in acute towards  reducing coronary syndrome patients in a phase II trial.

 

 

 

Other Antiplatelet Drugs

Dipyridamole (Persantin®)

- Dipyridamole is a vasodilator that also inhibits platelet function by inhibiting adenosine uptake   and cGMP phosphodiesterase activity. - Uses; Dipyridamole by itself  has little or no beneficial effect. Therefore;              - Used in combination primarily with aspirin to prevent cerebrovascular ischemia à                 Aggrenox® (aspirin/extended-release Dipyridamole capsules)              - Used in combination with warfarin for primary prophylaxis of thromboemboli in patients                 with prosthetic heart valves. - Side effects; Headache and can lead to orthostatic hypotension (especially if administered IV).

Cilostazol (Pletal®)

- Cilostazol is a newer phosphodiesterase type III inhibitor that promotes vasodilation (↑ CAMP)    and inhibition of platelet aggregation. - Cilostazol is extensively metabolized in the liver by the CYP 3A4, 2C19, and 1A2 isoenzymes. - Uses; It is approved to reduce the symptoms of intermittent claudication.           - Intermittent Claudication; is a symptom that describes muscle pain (ache, cramp,                                                              numbness or sense of fatigue), classically in the calf muscle,                                                              which occurs during exercise, such as walking, and is relieved by                                                              a short period of rest. It is classically associated with early-stage                                                              peripheral artery disease, and can progress to critical limb                                                              ischemia unless treated or risk factors are modified. - Side effects; Headache, GI side effects (diarrhea, abnormal stools, dyspepsia, and abdominal                          pain) and palpitation. -FDA warning; Cilostazol is contraindicated in patients with congestive heart failure. - Drug interactions; Itraconazole, Erythromycin, Ketoconazole, Diltiazem, Omeprazole and                                     Grapefruit juice.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Vitamin K (konakion®)
- Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl   group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and    Protein Z. - Two natural forms exist: vitamins K1 and K2;  - Vitamin K1 (Phytonadione) is synthesized by plants and is found in highest amounts                                                     in green leafy vegetables.         - Vitamin K2: (Menaquinone) is found in human tissues and is synthesized by intestinal bacteria. - Vitamins K1 and K2: is a fat-soluble require bile salts for absorption from the intestinal tract. - Vitamin K1 is available clinically in oral and parenteral forms.   - Onset of effect is delayed for 6 hours but the effect is complete by 24 hours. - Administration; orally, SC, IM and IV. - FDA warning; IV administration of vitamin K1 should be very slowly, not exceeding 1 mg/minute,                            Severe hypersensitivity reactions, including anaphylactic reactions and deaths have                            been reported following parenteral administration. The majority of these reported                            events occurred following IV administration, IV route should be restricted to those                            situations where another route is not feasible. - Uses; Treating bleeding problems caused by low vitamin K blood levels or decreased vitamin K                activity, It may also be used to treat or prevent certain bleeding problems in newborns. Dosage Guidelines; Newborns prophylaxis 0.5 1 mg IM within 1 hour of birth Newborns treatment 1 mg SC or IM Usually adult dose 2.5 mg - 10 mg Prothrombin deficiency due to warfarin up to 25 mg Prothrombin deficiency due to other causes 2.5 mg - 25 mg
Aminocaproic Acid (Amicar®)	Tranexamic Acid (Cyklokapron®)
- Aminocaproic acid or Tranexamic acid are antifibrinolytic drugs. - Aminocaproic acid (EACA) were first described in 1957 which, it is chemically similar to the   amino acid lysine. Tranexamic acid is an analogue of Aminocaproic acid and has the same   properties and 10 times more potent than Aminocaproic acid. - Mechanism; Competitively inhibits plasminogen activation. - Both agents are synthetic, orally active and excreted in the urine. - Uses;          - Adjunctive therapy in haemophilia (is a group of hereditary genetic disorders that impair                                                                             body's ability to control blood clotting).          - Bleeding from fibrinolytic therapy.          - Prophylaxis for re-bleeding from intracranial aneurysms.          - Postsurgical GI bleeding, post-prostatectomy bleeding and bladder hemorrhage.          - Tranexamic acid; used as first-line nonhormonal treatment of dysfunctional uterine                                    bleeding (heavy menstrual bleeding or menorrhagia), dose; 650 mg three                                    times daily for five days during menses. - Dose;         - EACA; For acute bleeding syndromes; 5 g during the first hour of treatment, followed by a            continuing rate 1 g per hour. This method of treatment would ordinarily be continued for               about 8 hours or until the bleeding situation has been controlled.         - Tranexamic acid; short-term use (2-8 days) in patients with haemophilia to reduce/prevent               hemorrhage and reduce the need for replacement therapy during and following tooth               extraction; 10 mg/kg IV 3 to 4 times daily. - Side effects; Risk of intravascular thrombosis, hypotension, myopathy, abdominal discomfort,                         diarrhea, and nasal stuffiness.
Ethamsylate or Etamsylate (Dicynone®)
- Ethamsylate is a synthetic antihaemorrhagic and angioprotective drug acting on the first step of   haemostasis (endothelium-platelet interaction). - Mechanism; by improving platelet adhesiveness and restoring capillary resistance, it is able to    reduce bleeding time and blood losses (no vasoconstrictor action). - Pharmacokinetics; -          Absorption; is slowly absorbed from the GIT. After oral administration ethamsylate maximum plasma level is reached after 4 hours. -          Plasma half-life; about 3-7 h. -          Excretion; excreted unchanged in urine. -          Etamsylate crosses the placental barrier (pregnancy category C). - Uses;              - Prevention and treatment of pre- or postsurgical capillary haemorrhages.              - Prophylaxis and control of blood loss from small blood vessels.              - Control heavy menstrual periods or those who suffer from excessive bleeding due to an                intrauterine contraceptive device. - Dose;              - Before surgery; 500-1000 mg, followed by 500 mg every 4-6 hours.              - Usual adult dose; 500 mg 3-4 times daily.              - Usual children dose; 250 mg 3-4 times daily. - Side effects; GIT disturbance, nausea, headache, skin rash.

 

Plasma Fractions

- 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 haemophilia or haemophilia A) and factor IX deficiency   (Christmas disease or haemophilia B) account for most of the heritable coagulation defects. - Concentrated plasma fractions are available for the treatment of these deficiencies. - Administration of plasma-derived, heat- or detergent-treated factor concentrates and   recombinant factor concentrates are the standard treatments for bleeding associated with   haemophilia.

Dried Factor VIII Fraction (8Y®)

- It is a concentrate of Factor VIII and von Willebrand Factor (VWF) prepared from blood plasma   from screened donors and then heat-treated. - Uses; IV injection, to prevent & treat bleeding in patients with haemophilia A (an inherited   shortage of Factor VIII in the blood) or von Willebrand disease (VWD). - Dose, 10-50 IU/kg body weight, doses may be repeated at intervals of 8, 12 or 24 hours, as   required. - Warning; Because this product is made from human blood, it may carry a risk of transmitting      infectious agents and may cause hypersensitivity or allergic reactions.

Factor IX Complex (BEBULIN®)

- BEBULIN® is a nano-filtered and vapour heated is a purified, sterile, freeze-dried concentrate of    the coagulation factor IX (Christmas factor) as well as Factor II and Factor X and low amounts of      Factor VII. In addition, the product contains small amounts of heparin. - Uses; prevention and control of bleeding episodes in adult patients with haemophilia B   (congenital Factor IX deficiency or Christmas disease). - Dose; (IV only) Minor bleeding, 25-35 IU/kg once. Moderate, 50-65 IU/kg every 24 hours twice   or until adequate wound healing. Major, 75-90 IU/kg every 24 hours 3-4 times or until adequate   wound healing. - Warning; Hypersensitivity or allergic reactions may occurs.

Anti-Inhibitor Coagulant Complex Heat Treated (Autoplex®)

- Autoplex is a sterile product prepared from pooled human plasma. - The product is standardized by its ability to correct the clotting time of Factor VIII deficient    plasma or Factor VIII deficient plasma which contains inhibitors to Factor VIII. - Uses; This product is to be used only in patients with inhibitors to Factor VIII who are bleeding or                Are to undergo surgery. - Dose; (IV only) 25-100 Hyland Factor VIII Correctional Units/kg of body weight, depending upon      the severity of hemorrhage. If no hemostatic improvement is observed approximately 6 hours   following the initial administration, the dosage should be repeated. - Warning; Because this product is made from human blood, it may carry a risk of transmitting infectious agents and may cause hypersensitivity or allergic reactions.

Anti-Inhibitor Coagulant Complex (FEIBA-NF®)

- FEIBA (Factor Eight Inhibitor Bypass Activity); is a nano-filtered and vapour heated, is a freeze-   dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity. - It contains Factors II, IX, and X, mainly non-activated and Factor VII mainly in the activated form.   The product contains Factor VIII inhibitor bypassing activity and Prothrombin Complex Factors.  - Uses; Control of spontaneous bleeding episodes or to cover surgical interventions in    haemophilia A and haemophilia B patients with inhibitors. - Dose; (IV infusion) 50-100 Units of FEIBANF/kg/day is recommended.  - Warning; Hypersensitivity or allergic reactions or thromboembolic event or risk of transmitting infectious   agents.

Recombinant Human Coagulation Factor VIIA (rFVIIa) (NovoSeven®)

- NovoSeven is structurally similar to human plasma-derived Factor VIIA. - Uses; Control bleeding episodes and to prevent excessive bleeding during surgery in people who    have;           - Inhibitors to clotting factors VIII or IX.           - Congenital FVII deficiency.           - Glanzmann's Thrombasthenia (is an abnormality of the platelets, in which the platelets             contain defective or low levels of glycoprotein Ilb/lla) which cannot be treated effectively             with platelet transfusions. - Dose; 35-120 micrograms/kg (usually 90 micrograms/kg) given every two hours by bolus infusion              until hemostasis is achieved, or until the treatment has been judged to be inadequate. - Warning; thromboembolic event may occurs.

Cryoprecipitate (CRYO®)

- The main constituents of Cryoprecipitate are Factors VIII and XIII, von Willebrand Factor and   Fibrinogen. - Uses; Haemophilia, von Willebrand disease and hypofibrinogenaemia (low fibrinogen levels). - Dose; 1 U/5kg patient weight repeat if needed. - Warning; Hypersensitivity or allergic reactions or risk of transmitting infectious agents.

 

 

Other Agents
Aprotinin (Trasylol®)
- Aprotinin also known as bovine pancreatic trypsin inhibitor (BPTI) or serine protease inhibitor   (serpin). - Act by inhibits several serine proteases, specifically trypsin, chymotrypsin, plasmin and kallikrein;   leads to inhibition of fibrinolysis. - Used to reduce bleeding during complex surgery (e.g. cardiopulmonary bypass). - Warning; Aprotinin may cause severe and sometimes fatal allergic reactions (anaphylaxis).
Octreotide (Sandostatin®)
- Octreotide] is Somatostatin (growth hormone-inhibiting hormone) analogue. - Octreotide is often given as an infusion for management of acute haemorrhage from esophageal   varices in liver cirrhosis.
Desmopressin (Minirin®)	Terlipressin (Teripress®)
- They are a synthetic replacement for vasopressin, - Desmopressin increases the factor VIII activity of patients with mild haemophilia A or von   Willebrand disease in preparation for minor surgery such as tooth extraction. - Terlipressin; used in acute haemorrhage from esophageal varices in liver cirrhosis.