Lecture 22: Blood drugs

Question 1

DRUGS USED IN DISORDERS OF COAGULATION

Answer 1

1. DRUGSUSEDTOREDUCECLOTTING

• Platelet Aggregation Inhibitors
• Anticoagulants
• Thrombolytics

2. DRUGSUSEDINBLEEDINGDISORDERS

• Plasminogen Activation Inhibitors
• Protamine Sulfate
• Vitamin K

Plasma Fractions

Question 2

PLATELET AGGREGATION INHIBITORS

Answer 2

• CYCLOOXYGENASE INHIBITORS
• ADP RECEPTOR BLOCKERS
• PHOSPHODIESTERASE INHIBITORS
• BLOCKERS OF PLATELET GP IIb/IIIA RECEPTORS

Question 3

ADP RECEPTOR BLOCKERS

Answer 3

• CLOPIDOGREL & TICLOPIDINE
• Irreversible inhibitors of P2Y12, one of the two
• subtypes of ADP receptor on the platelet surface.
• Clopidogrel has fewer adverse effects than ticlopidine.
• Clopidogrel is preferred over ticlopidine.

Question 4

CLOPIDOGREL

Answer 4

• Clopidogrel is a prodrug converted to an active metabolite, mainly by CYP2C19.
• Patients who are CYP2C19 poor metabolizers have lower plasma levels of the active metabolite -> at risk of cardiovascular events.
• The concomitant use of clopidogrel and CYP2C19 inhibitors should be avoided.
• Omeprazole, a CYP2C19 inhibitor, reduces plasma levels of the active metabolite of clopidogrel.
• Concurrent use of clopidogrel and omeprazole should be avoided.

Uses: Indicated to reduce the rate of stroke, MI, and death in patients with recent MI or stroke or acute coronary syndrome.

Question 5

DIPYRIDAMOLE

Answer 5

• PHOSPHODIESTERASE INHIBITORS
• Coronary vasodilator.
• Used to prophylactically treat angina pectoris.

Uses

• Dipyridamole by itself has little beneficial effect.
• Used in combination with warfarin or aspirin.

Question 6

BLOCKERS OF PLATELET GP IIb/IIIA RECEPTORS

Answer 6

• Activation of this receptor is the final common pathway for platelet aggregation.
• ABCIXIMAB: Monoclonal antibody against the GPIIb/IIIareceptor.
• EPTIFIBATIDE: Cyclicpeptide reversible antagonist of the GPIIb/IIIa receptor.
• TIROFIBAN: Nonpeptide reversible antagonist oft he GPIIb/IIIa receptor.

Uses

• To reduce thrombotic cardiovascular events in patients with non-ST elevation acute coronary syndrome (NSTE-ACS)
• Adjuncts to PCI for the prevention of cardiac ischemic complications.

Question 7

ANTICOAGULANTS

Answer 7

• Indirect Thrombin and Factor Xa inhibitors
• Direct Thrombin Inhibitors
• Direct Factor Xa Inhibitors
• Coumarin Anticoagulants.

Question 8

Indirect Thrombin and Factor Xa inhibitors

Answer 8

• Unfractionated heparin (UFH)
• Low-molecular-weight heparins (LMWH)
• Fondaparinux

Question 9

UNFRACTIONATED & LOW-MOLECULAR-WEIGHT HEPARINS

Answer 9

• Mixture of straight-chain,sulfated mucopolysaccharides.
• Isolated from bovine lung or porcine intestinal mucosa.
• Unfractionated heparin (UFH) has a MW range of 5,000 - 30,000.
• Low-Molecular-Weight Heparins are produced by depolymerization of UFH; MW range from 1,000 – 5,000.
• 3 LMWH: enoxaparin, dalteparin, tinzaparin.

MOA

• Heparins of different molecular weights have different anticoagulant activities.
• UFH efficiently inactivates both thrombin and factor Xa due to ternary complex
• **LMWH efficently inhibit Xa but have less effect on thrombin. **

Question 10

MONITORING OF HEPARIN LEVELS

Answer 10

• aPTT assay (not accurate for small MW heparin)
• aPTT is a test of the integrity of the intrinsic and common pathways of coagulation.
• Dosing of LMWH results in predictable plasma levels.
• It is not usually necessary to monitor LMWH blood levels.
• The potency of LMWH can be assessed with anti-factor Xa assays.

Uses

• DVT
• Pulmonary embolism
• MI
• DOC during pregnancy

Adverse

• Bleeding
• Hypersensitivity reactions
• Heparin-induced Thrombocytopenia (HIT): Antibodies recognize complexes of heparin and a platelet protein, Platelet Factor 4.
  
  • Rx: ARgatroban

Question 11

HEPARIN-INDUCED THROMBOCYTOPENIA TYPE II

Answer 11

• This can result in thrombocytopenia and thrombosis that can be life-threatening.
• Therapy: Discontinuance of heparin and administration of a DTI or fondaparinux.

Question 12

REVERSAL OF HEPARIN ACTION

Answer 12

• Excessive anticoagulant action of heparin is treated by discontinuance of the drug.
• If bleeding occurs protamine sulfate is given.

Question 13

FONDAPARINUX

Answer 13

• Synthetic pentasaccharide.
• Sequence of five carbohydrates that bind to antithrombin III.
• Specific inhibitor of Xa.
• Negligible antithrombin activity.
• Approved for prevention and treatment of DVT.

Question 14

DIRECT THROMBIN INHIBITORS (DTIs)

Answer 14

• exert their anticoagulant effect by directly binding to the active site of thrombin.
• PARENTERAL DTIs
  
  • LEPIRUDIN
  • BIVALIRUDIN
  • ARGATROBAN
• ORAL DTIs

Question 15

LEPIRUDIN

Answer 15

• PARENTERAL DTIs
• Its action is independent from antithrombin III, therefore lepirudin can inactivate fibrin-bound thrombin in thrombi.
• Given parenterally.
• Monitored by the aPTT.
• No antidote exists.

Question 16

BIVALIRUDIN

Answer 16

Synthetic derivative of hirudin.

Question 17

ARGATROBAN

Answer 17

Small molecule thrombin inhibitor.

Question 18

DABIGATRAN ETEXILATE

Answer 18

• ORAL DTIs
• Pro drug converted to dabigatran.
• Dabigatran reversibly blocks the active site of thrombin.
• Dabigatran produces a predictable anticoagulant response.
• Routine monitoring is unnecessary

Uses: Approved for prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation.

Question 19

APIXABAN & RIVAROXABAN

Answer 19

• DIRECT FACTOR Xa INHIBITORS
• Do not require monitoring.
• There is no antidote.

Question 20

COUMARIN ANTICOAGULANTS

Answer 20

WARFARIN

Called oral anticoagulants

MOA

• Warfarin inhibits vitamin K epoxide reductase.
• Treatment with warfarin results in the production of inactive clotting factors, because they lack the gamma-carboxyglutamyl side chains.
• Anticoagulant effect is apparent within 24h of warfarin administration, peak @ 72 to 96 h
• Duration of action: 2 to 5 days
• Monitored by PT & expressed by INR
• anticoagulant effects of warfarin can be overcome by the administration of vitamin K.

Adverse

• Warfarin has a narrow TI and participates in many drug–drug interactions.
• Monitoring is performed with the prothrombin time (PT).
• Test of extrinsic and common pathways of coagulation.
• The results are expressed as (International Ratio) INR
• Hemorrhage
• Cutaneous necrosis due to Protein C deficiency
• Teratogenic

Question 21

THROMBOLYTICS (fibrinolytics)

Answer 21

• Anticoagulants prevent formation of thrombi but are ineffective against pre-existing clots.
• Thrombolytic drugs lyse blood clots and restore the patency of obstructed vessels before distal tissue necrosis occurs.
• Thrombolytic agents act by converting plasminogen to plasmin.
• STREPTOKINASE
  
  • Protein produced by Beta-hemolytic streptococci.
  • Rarely used since the advent of newer agents.
• UROKINASE
• ALTEPLASE
• RETEPLASE
• TENECTEPLASE

Question 22

ALTEPLASE, RETEPLASE & TENECTEPLASE

Answer 22

• Tissue plasminogen activator (t-Pa) is a serine protease produced by human endothelial cells.
• t-Pa activates plasminogen bound to fibrin in a thrombus.
• t-Pa is “fibrin selective“, unlike streptokinase and urokinase, which are non-fibrin-selective

ALTEPLASE

Recombinant t-Pa.

Indicated for management of acute MI, and acute ischemic stroke.

RETEPLASE

• Modified recombinant human t-Pa.
• Indicated for management of acute MI.

TENECTEPLASE
• Mutantformoft-Pa.
• Indicated for management of acute MI.

Question 23

DRUGS USED TO TREAT BLEEDING

Answer 23

• PLASMINOGEN ACTIVATION INHIBITORS
• PROTAMINE SULFATE
• VITAMIN K
• PLASMA FRACTIONS

Question 24

AMINOCAPROIC ACID

Answer 24

• PLASMINOGEN ACTIVATION INHIBITORS
• Inhibits plasminogen activation.
• Uses: adjunctive therapy in hemophilia, and therapy for bleeding from fibrinolytic therapy.

Question 25

PROTAMINE SULFATE

Answer 25

• Chemical antagonist of heparin; If bleeding occurs protamine sulfate is given.
• High in arginine.
• The cationic protein interacts with anionic heparin to form complex with no anticoagulant activity.

Question 26

VITAMIN K

Answer 26

Used to correct the bleeding tendency or hemorrhage associated with its deficiency.

Uses

• PREVENTION OF VITAMIN K DEFICIENCY BLEEDING IN NEWBORNS
• All babies should receive vitamin K.
• Standard treatment is with vitamin K1 IM at birth.
• DRUG-INDUCED HYPOPROTHROMBINEMIA
• Vitamin K is available in oral and parenteral forms.
• Onset of effect: 6 hours.
• The effect is complete by 24 hours.
• If immediate hemostasis is required, fresh-frozen plasma should be infused.