1. Dr. Laila M. Matalqah Ph.D. Pharmacology
Antiplatelet, Anticoagulant, & Thrombolytic Agents General Pharmacology M212
Dr. Laila M. Matalqah
Ph.D. Pharmacology

2. Coagulation Thrombus: A clot that adheres to a vessel wall
Embolus: is an intravascular clot that floats in the blood
Blood Coagulation: generates thrombin , consists of two pathways: the extrinsic and the intrinsic systems.
Thrombotic & thromboembolic disease is common. It has severe & serious consequences
Myocardial infarction
Stroke
Deep vein thrombosis
Pulmonary embolism

3. Coagulation process Clotting factors: II, VII, IX, X, XI, XII
inhibitors of coagulation factors: protein C, protein S, antithrombin III, and tissue factor pathway inhibitor.

4. Anticoagulants
Vitamin K antagonists: coumarin anticoagulants e.g., warfarin
Thrombin inhibitors:
heparin
low-molecular-weight heparins (LMWH) e.g., Dalteparin and Enoxaparin
Direct Thrombin inhibitor: dabigatran etexilate

5. Vitamin K antagonists: Warfarin
Inhibit synthesis of vitamin k dependent clotting factors: II, VII, IX, and X
Antidote of warfarin is vitamin K or fresh frozen plasma .
Narrow therapeutic index
Therapeutic uses: Prophylactically,
Deep Vein Thrombosis (DVT)
Pulmonary Embolism (PE)
Acute Myocardial Infarction (AMI)
Prosthetic Heart Valves (INR: )
Atrial Fibrillation (AF)

6. Warfarin: PK Oral administration Bioavailability almost 100%
Plasma protein binding: 99%
Monitored by INR: 2-3
sulfonamides, can displace Warfarin and lead to increase its activity
Warfarin C/I: pregnancy , crosses the placental barrier (teratogenic)
Metabolized by CYP450 (inhibitor and inducer interaction)
T1/2: 40 hrs

7. Warfarin Monitoring 1) The Prothrombin Time (PT) test
The normal prothrombin time is seconds
2) The International normalized ratio (INR)
Where ISI: the international sensitivity index which relates the sensitivity of a given thromboplastin to the WHO reference

8. Warfarin Drug interaction:
Inhibitors of warfarin metabolism: increase activity
Cimetidine, Chloramphenicol, Cotrimoxazole, Metronidazole
Inducer of warfarin metabolism: decrease activity
Barbiturates, Rifampin
Inhibition of platelet aggregation (Aspirin): increase activity
ADR:
Bleeding: treated by withdrawal of the drug and administration of oral vitamin K1
Skin lesions and necrosis
Purple toe syndrome

9. Thrombin inhibitors MOA: Heparin and LMWH binding to antithrombin
– Heparin inactivation of : Thrombin (IIa) and factor Xa, while LMWHs inactivate factor Xa only.
Heparin given I.V or S.C , LMWH (enoxaparin and dalteparin): S.C
Heparin and LMWHs are the anticoagulants of choice for treating pregnant women , with prosthetic heart valves or venous thromboembolism.
Heparin (Not LMWH) need monitoring by activated partial thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control (30 sec)

10. Thrombin inhibitors Uses: TT of Acute PE, Acute DVT ADR of heparin
Bleeding complication : antidote protamine sulfate
Hypersensitivity reactions
Thrombocytopenia (heparin- induced thrombocytopenia)

11. Direct Thrombin inhibitor: dabigatran etexilate
prodrug of the active moiety: dabigatran
Orally
does not require routine monitoring (INR)
Alternative to warfarin: for prevention of stroke in patients with atrial fibrillation.

12. THROMBOLYTIC DRUGS
Alteplase (tPA), Reteplase, Streptokinase, Urokinase
MOA: convert plasminogen to plasmin, which, in turn, cleaves fibrin, thus lysing thrombi
Administered intravenously (I.V)
Uses: Acute myocardial infarction (AMI), Acute PE, Acute DVT
ADR: hemorrhage (GIT and brain bleeding)
C/I: pregnancy, brain tumor, head trauma, intracranial bleeding, and metastatic cancer.

14. Aminocaproic acid and tranexamic acid
Fibrinolytic states can be controlled by the administration of aminocaproic acid or tranexamic acid.
Both agents are synthetic, orally active, and excreted in the urine, and they inhibit plasminogen activation.
Tranexamic acid is 10 times more potent than aminocaproic acid.
A potential side effect is intravascular thrombosis.

15. Platelet Aggregation Inhibitors
Aspirin : inhibits thromboxane A2 synthesis- preventing platelet aggregation.
2. Ticlopidine & clopidogrel: inhibit activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen
3. Dipyridamole: a coronary vasodilator, is used prophylactically to treat angina pectoris.
Uses: prevention of stroke

16. Anti-hyperlipidemias

17. Hyperlipidemias Coronary heart disease (CHD) associated with:
Elevated Plasma lipoproteins: low-density lipoprotein (LDL) cholesterol and triacylglycerols (TG)
Low levels of high-density lipoprotein (HDL) cholesterol

18. Antihyperlipidemia Drugs
HMG CoA reductase inhibitors (Statins)
Lovastatin
simvastatin
pravastatin
atorvastatin
Niacin (nicotinic acid)
The fibrates
Fenofibrate
gemfibrozil
Bile acid–binding resins
Cholestyramine
Colestipol
colesevelam

19. HMG CoA reductase inhibitors (Statins)
MOA: inhibit de novo cholesterol synthesis by inhibiting 3-hydroxy-3- methylglutaryl coenzyme, the rate-limiting step in cholesterol synthesis.
Uses: Lower LDL, TG and Cholesterol
oral administration
ADR:
Liver: increase serum transaminase levels
Muscle: Myopathy and rhabdomyolysis
Drug interactions: increase warfarin levels. Thus, it is important to evaluate INR frequently.
Contraindications: pregnancy and in nursing mothers, children or teenagers.

20. Fibrates
MAO: increasing lipoprotein lipase – decrease TG, LDL, VLDL and increase HDL
USES: treatment of hypertriacylglycerolemias
Orally
ADR:
Lithiasis: increase biliary cholesterol excretion- formation of gallstones
Muscle: Myositis
Drug interaction: displace warfarin Plasma protein – increase warfarin activity

21. Bile acid–binding resins
MOA: bind to bile acids, resin/bile acid complex is excreted in feces--- lowering the bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids
Orally
ADR:
GI disturbances, such as constipation, nausea, and flatulence.
Impair the absorption of the fat- soluble vitamins (A, D, E, and K).

22. Bile acid–binding resins
Decrease absorption of tetracycline, digoxin, warfarin, pravastatin, aspirin, and thiazide diuretics,
Therefore, these drugs should be taken at least 1–2 hours before, or 4–6 hours after bile acid–binding resins.