Pharmacology 1 Anticoagulants

Pharmacolog y
anticoagulants
Dr.Nasser A. H. Al-Harchan
Lec.6

Total Lectures No. 10

Dr.Nasser A. H. Al-Harchan

Lec.6

Pharmacology 2 Anticoagulants

ANTICOAGULANTS
Formation of thrombus: Prothrombin
xa

thrombin (II a) +

Fibrinogen (I) Plasminogen

+ +

Fibrin (Ia)
+

plasmin

--

Fibrionlysis

1. Heparin: (Direct anticoagulants)

y y y 1. Strong acid, -ve charged mucopolysaccharide. Various ++ release from liver and lung mast cell into circulation. Mechanism of Action: act in vitro and in vivo: Antithrombin III (heparin cofactor) + IX, X, XI, XII

Heparin

++

Complex (anticoagulant action) 2. Antithrombin III + thrombin

Heparin
Dr.Nasser A. H. Al-Harchan Lec.6

Pharmacology 3 Anticoagulants

30- time

complex (anticoagulant action)

(+ +) means stimulation while (- -) means inhibition.

Thrombin + + 3. Platelets _ _ Heparin Platelets aggregation

4. Heparin intake by endothelial cells

stimulate collateral circulation.

Pharmacological Actions:
1. Anticoagulant action. 2. Lipemia clearing factors production: Triglyceride cleaning factor "lipoprotein lipase free fatty acid

3. Suppresses aldosterone production. 4. Increase free plasma thyroxin. 5. Inhibits antifibrinolytic drugs and antifibrinolysis.

Kinetics:
- S.C, LV (not orally because it will be destroyed in the stomach). - I.M hematoma.

- Infusion with glucose or saline.

Dr.Nasser A. H. Al-Harchan

Lec.6

Pharmacology 4 Anticoagulants

- Low molecular wt. heparin (once daily), safe, not required daily control (Dalteparen, Enoxaparin, Tineaparin ).

Lab. control:
1. Activated Partial thromboplastin Time (APTT). 2. Kaolin Cephalin Clotting Time (KCCT).

Adverse effects:
1. 2. 3. 4. 5. 6. Bleeding (may be cerebral hemorrhage). Acute thrombocytopenia (reversible). Osteoporosis and spontaneous fractures. Hypersensitivity as severe asthma, urticaria, anaphylaxis. Diarrhea (rare). Alopecia = boldness (transient).

Heparin Antagonist: Protamine SO4 :

Basic drug from fish : - 1.sudden BP 2.Flushing 3.Dyspnea

Contraindication:
1. Active bleeding or bleeding tendency e.g. Pu, SBE, sever HPT 2. Heparin hypersensitivity. 3. Eye, Brain & spinal cord surgery (closed chamber surgery).

2. Warfarin: (Indirect oral anticoagulants)

Mechanism: It INHIBITS activation of factors:
Dr.Nasser A. H. Al-Harchan Lec.6

Pharmacology 5 Anticoagulants

1. II (prothrombin) 2. VII, IX,X (vit.K dependent factors)

Inactive II, VII, IX, X

Inactive II, VII, IX, X

carboxylase

Vit. K (active)

Vito K epoxide (inactive)

reductase onset of action: 72 hrs, this delayed time because the conc. of factor II must enough to show their effects, so we start with heparin (which acts immediately). Side effects 1. GIT upset. 2. Cutaneous lesion as purpura and other bleeding. 3. Teratogenic abnormality. Control: y Prothrombin time: y INR, PT control: Contraindication: 1. bleeding or bleeding tendency e.g. Pu. 2. Severe renal, liver diseases. 3. HPT and increase risk of cerebral hemorrhage.
Dr.Nasser A. H. Al-Harchan Lec.6

normal during therapy 2-3 times of normal

Pharmacology 6 Anticoagulants

Warfarin Antagonists 1. Whole blood transfusion. 2. K1 = Phytomenadione. Side effects: Anaphylaxix (I.V.) and Haemolysis (in G6PD deficiency)

Uses of Anticoagulants:
y Prophylactic (stop formation of Fibrin) . y Treatment (prevent propagation of thrombus). 1. Deep venous thrombosis, DVT (treatment & prophylactic). 2. Arterial thrombosis (valuable in prophylactic). 3. Thromboembolic pulmonary HPT (lifesaving). 4. Acute myocardial infarction. 5. Unstable angina. 6. Rheumatic mitral valve disease. 7. Cerebro Vascular Accident (CVA) : thrombosis, infarction. 8. Transient ischemic attacks (TIA), aspirin usually used. 9. Disseminated intravascular coagulopathy (DIC). 10. Dialysis (heparin to maintain blood fluidity).

Fibrinolytics *and antifibrinolytics**:

Plasminogen Activation y y y y Fibrynolytics(thrombolytics): Streptokinase & Urokinase Antistreplase Alteplase (TPA = tissue Plasminogen activator) Plasmin
Dr.Nasser A. H. Al-Harchan Lec.6

Inhibition Antifibrynolytics Amino caproic acid Tranexamic acid

Pharmacology 7 Anticoagulants

Degradation products

++

Fibrinogen

thrombin ++

Fibrin

++

Fibrin salt products

* also called plasminogen activators or thrombolytics. ** also called plasminogen inhibitors.

Plasminogen activator Clinical Uses: 1.Coronary thrombosis (emergency) [major application] 1-3 hrs recanalization 2.Multiple pulmonary emboli 3.DVT. Side effects: 1. Bleeding as cerebral hemorrhage. 2. Allergic reaction (streptokinase) Intra-arterial or I.V. Property Structure Route of Admn. Site of action Onset of action Mechanism Antidote uses

Plasminogen inhibitor Clinical uses: 1. Acute episode in hemophilia. 2. Other bleeding disorders.

Orally active Heparin large polymer, acidic parenteral blood Rapid (seconds) activate Antithrombin III protamine acute, over days warfarin small, lipid soluble oral liver slow, depend on t 1/2 of factors being replaced impairs synthesis of II, VII, IX, X vit. K, plasma chronic, over weeks or months

Antiplatelet drugs:
y Aspirin:
Dr.Nasser A. H. Al-Harchan Lec.6

Pharmacology 8 Anticoagulants

Mechanism : Inhibits cyclooxgenase (irreversible) (TX) synthesis. Uses: 1. Myocardial infarction (MI).

inhibits thrombaxans

2. transient ischemic attacks (TIAs), other thrombotic events. y Dipyridamole: Mechanism: inhibits phosphodiesterase inhibits cAMP in platelets.

Uses: prevent thrombosis of artificial valve (limited uses). y Ticlopidine: Mechanism: inhibits ADP (powerful stimulator of platelets aggregation). Uses: effective in preventing TIAs (particularly valuable for patient who can't tolerate aspirin). Side effects: 1. 2. 3. GIT upset. Bleeding in 5 %. Leucopenia in 1 %. y Clopidogril: Less side effects and the leucopenia is negligible.

Drugs used in clotting Disorders

A. 1) To reduce clotting: Anticoagulants: Heparin, Enoxaparin (LMW), Lepirudin, Danaparoid

Dr.Nasser A. H. Al-Harchan

Lec.6

Pharmacology 9 Anticoagulants

2) B. 1) 2) 3) 3)

Warfarin (oral) Antiplatelet drugs: Aspirin, Dipyridamole, Eptifibatide, Tirofiban Ticlopidine, clopidogril To facilitate clotting: Plaminogen inhibitors: Amino caproic acid Tranexamic acid Replacement factors: Factor VIII Factor IX thrombolytics or Fibrinolytics or Plasmingen activators Streptokinase, Urokinase Antistreplase Alteplase Vit. K: Kl = phytonadione K2= menadione

CHW Ali Mazin IBO Ibrahim Ghazi

Dr.Nasser A. H. Al-Harchan Lec.6

Pharmacology 10 Anticoagulants

Dr.Nasser A. H. Al-Harchan

Lec.6