Pharmacology: Anticoagulants

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Hemostatsis

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Cessation of blood loss from a damaged vessel

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Thrombosis

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Pathological formation of a "hemostaic plug"

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Thrombus

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A blood clot that forms in a vessel and stays there.
Arterial thrombus - consists mainly of platelets and leukocytes in a fibrin mesh
Venous thrombus - similar in composition to a blood clot, with a jelly-like red tail

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Embolism

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all or part of a thrombus that had become dislodged and moves to a distant site

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Fibrinolysis

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A normal body process that prevents blood coagulation from growing and causing problems.

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Coagulation: Platelet Reactions

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Platelet reactions
Generally lead to platelet aggregation and
Stimulate blood coagulation
Release: ADP*, thromboxane A2*, Ca2+, platelet factors

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Coagulation: Blood coagulation

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Blood coagulation
Extrinsic pathway
Begins with release of tissue factor and activation of factor VIIa and Ca2+
Intrinsic pathway
Begins with activation of pro-enzymes (XII or XI) through contact with thrombin (or with glass in a laboratory)

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Coagulation: Cascade

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Coagulation cascade (beginning with Extrinsic (faster) or Intrinsic (slower) pathway) leads to the proteolytic conversion of prothrombin to thrombin
Soluble fibrinogen is converted by thrombin to insoluble fibrin forming mesh network that along with the aggregated platelets forms a thrombus

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Coagulation Flow chart:

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Pic

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Coagulation: Regulation

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The process of thrombus formation is highly regulated

Antithrombin is a serine protease inhibitor that inactivates thrombin (factor IIa), IXa, and Xa

Aided by Protein C (another anticoagulant)

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Vitamin K

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Vitamin K must be converted from the epoxide form back to a reactive hydroquinone
Required for the γ-carboxylation and activation of coagulation factor molecules in the liver

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Three ways drugs affect hemostasis and thrombosis:

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- Blood coagulation (fibrin formation)
-- Drug therapy is rarely used to promote hemostasis (unless there is a defect). Therapy to prevent coagulation is used extensively.
- Platelet function
- Fibrin removal (fibrinolysis)

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Indirect thrombin Inhibitors: Heparin

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Low-molecular-weight heparin (Enoxaparin (Lovenox®) - others)
Unfractionated Heparin (Heparin sodium - generic)
Fondaparinux® (synthetic pentasaccharide)
Danaparoid (Orgaran) – FYI

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Heparin: Structure

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- Heterogenous mixture of sulfated mucopolysaccharides found in the granules of basophils and mast cells
- Unfractionated heparin has a MW range of 5,000-30,000
- Low-molecular weight heparin are enzymatically produced fragments of UFH, and have an average MW of 6,000

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Heparin: MOA

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Mechanism of Action
- Anti-thrombin is a suicide inhibitor, forming a 1:1 comblex with thrombin. Heparin enhances (by 1000 fold) the activity of anti-thrombin to form inactive complexes with thrombin(IIa), IXa, and Xa

- Binding of active heparin (UF) to anti-thrombin exposes a motif that rapidly inactivates its target

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Heparin: MOA Low MW

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Mechanism of Action
- Low-molecular weight heparin is shorter and lacks a binding motif required for the inhibition of thrombin (IIa), but rapidly inactivates factor Xa (left side of figure)

- All preparations (Unfractionated, LMW, fondaparinux) have similar efficacy
- UF and LMW heparin is extracted from beef lung, or hog intestine

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Heparin: Therapeutic uses

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Therapeutic Uses
Initiate treatment of venous thrombosis and pulmonary embolism
Oral anticoagulant is initiated concurrently
Thrombosis on prosthetic heart valves
Thrombosis and embolization in patients with atrial fibrillation
Myocardial infarction in patients with unstable angina

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Heparin: Pharmacokinetics

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Pharmacokinetics
Administration
UFH
- IV-most rapid and predictable, maintenance doses may be given subcutaneously-absorption variable
- Intramuscular injections should be avoided
- Dosing based on weight is most effective
LMWH
- SC absorption more predictable than for UFH

Metabolism
- Cleared by reticuloendothelial system, some active heparin is excreted in the urine

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Heparin: Toxicity

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Toxicity
- Bleeding
- The major adverse effect
-- Minimized with tight control of dosage, patient selection (recent surgery, peptic ulcer, etc.), monitoring
-- Elderly and those with renal failure are more prone to hemorrhage
-- Allergy due to animal origin of heparin preparations
-- Osteoporosis

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Heparin: Induced Thrombocytopenia

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Heparin-induced thrombocytopenia (HIT)
- Rare but serious increased risk for thrombosis due to the formation of antibodies to heparin and platelet factor 4
- Generally occurs 2-14 days after beginning therapy – usually with UF Heparin
- Observed as decreased platelet counts, may lead to thrombosis

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Heparin: Treating Overdose

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Treating heparin overdose
- Intravenous injection of protamine which forms a stable, inert complex
- Should calculate amount of protamine based on the dose of heparin

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Heparin: Contraindications

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Contraindications
- Hypersensitivity to UFH
- LMWH-hypersensitivity to UFH, LMWH, pork products, methylparaben
- History of HIT

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Bivalent Agents

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Lepirudin (Refludan®) (lepirudin is recombinant form of hirudin)
Bivalirudin (Angiomax®) (semisynthetic recombinant of hirudin)

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Monovalent Agents

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Argatroban

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Direct Thrombin Inhibitors: MOA

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Bivalent Agents
- Hirudin is isolated from leach saliva
- Binds both substrate recognition and catalytic site of thrombin (factor IIa) to inhibit the coagulation cascade

Monovalent Agents
- Binds to and blocks the catalytic site on thrombin

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Direct Thrombin Inhibitors: Adverse effects

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Hemorrhage – most serious/common
Lepirudin – contraindicated in renal insufficiency
Argatroban – contraindicated in hepatic insufficiency

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Direct thrombin Inhibitors: Therapeutic use

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Primary use is treatment of HIT
Drug selection often based on presence of renal/hepatic insufficiency

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Oral Agents: Warfarin

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Warfarin (Coumadin – generics)

(Wisconsin Alumni Research Foundation + “arin”) – bishydroxycoumarin

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Warfarin: Pharmacokinetics

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- Isolated from spoiled sweet clover silage
- 100% bioavailability, over 99% is bound to plasma albumin
- Effects delayed 12-16 hours no effect on circulating clotting factors
- Full clotting effect not seen for 8-16 days
- t½ is 36 hours

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Warfarin: MOA

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Mechanism of action
- Block the γ-carboxylation of glutamate residues in prothrombin, factors VII, IX, and X
- Without the carboxylation reaction the coagulation factors are biologically inactive
- The γ-carboxylation reaction requires hydroxylation of the cofactor, vitamin K, for the carboxylation to occur
- Warfarin inhibits the enzyme that reduces vitamin K and thereby prevents the activation of the coagulation factors

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Warfarin: Toxicity

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- Hemorrhage of the bowel or brain is the main adverse effect
- Significant interpatient variability in pharmacodynamic response and pharmacokinetic handling of warfarin
- Correct dosing requires continual monitoring
Pregnancy:
- Freely crosses the placenta to cause birth defects

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Warfarin: Drug Interactions

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Drug interactions
- Certain drugs decrease metabolism of warfarin and lead to increased risk of bleeding (pharmacokinetic interactions)

- Other factors such as asprin or hyperthyroidism may increase the risk of bleeding through altered pharmacodynamic effects

Altered vitamin K intake (diet or through antibiotics)
- Green tea, broccoli, liver are high in vitamin K

Reversal of warfarin actions may be accomplished by administering vitamin K (fresh frozen plasma, parenteral vitamin K

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Clinical Uses: Warfarin, Heparin

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Heparin is used acutely, warfarin is used for prolonged therapy
Anticoagulants are used to prevent:
- Deep vein thrombosis
- Pulmonary embolus
- Thrombosis and embolisation in patients with atrial fibrillation
- Thrombosis on prosthetic heart valves
- Clotting in extracorporeal circulations (e.g. during hemodialysis)
- Myocardial infarction in patients with unstable angina

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Contraindications to anticoagulation therapy

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General
- Active bleeding
- Hemophilia
- Severe liver disease
- Severe thrombocytopenia
- Inability to meticulously supervise and monitor treatment
Heparin
- History or suspected HIT
Warfarin
- Pregnancy

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Fibrinolysis (Thrombolysis)

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Fibrinolysis system
- Activated along with the coagulation cascade
- Plasminogen activators – convert plasminogen to plasmin
- Tissue plasminogen activator (tPA)
- Urokinase-type plasminogen activator
- Kallikrein, neutrophil elastase

Plasminogen is deposited along with fibrin in the thrombus, activities are localized to the clot

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Fibrinolytic Drugs: Streptokinase MOA

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- A protein originally isolated from streptococci
- Binds to and activates plasminogen to cause the conversion of plasminogen to plasmin
- Low fibrin specificity

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Fibrinolytic Drugs: MOA

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All are recombinant proteins
Reteplase and teneteplase have mutations that give them longer half-lives than alteplase

Enzymatically convert plasminogen to plasmin
Alteplase, and teneteplase, like endogenous t-PA, has specificity for fibrin-bound plasminogen over circulating plasminogen
Considered clot-specific drug
All have similar efficacy

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Contraindications to Thromblytic Therapy

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- Surgery within last 10 days
- Serious GI bleeding w/in 3 months
- History of hypertension
- Active bleeding or hemorrhagic disorder
- Previous cerebrovascular accident or active intracranial process
- Aortic dissection
- Acute pericarditis

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Fibrinolytic Drugs: Therapeutic Uses

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Therapeutic Uses – time is critical element
- Pulmonary embolism with hemodynamic instability
- Severe deep venous thrombosis
- Ischemic stroke – tPAs
-- AHA recommends fibrin-specific over nonspecific agents
- Acute myocardial infarction (20% reduction in mortality)
- The choice- the recombinant proteins are expensive (>12x the cost of streptokinase)

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Fibrinolytic Drugs: Side Effects

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- Hemorrhage due to the lysis of fibrin in “physiological thrombi”
- Streptokinase is most likely to cause antibody production – limits long-term (short-term?) usage

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Antiplatelet Agents

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Resting platelets
- Intact endothelial cells release substances that inhibit platelet activation (NO, prostaglandin I2)
- Activation of the prostacyclin receptor by PGI2, a Gs-coupled receptor --> ↑ cAMP and decreased release of Ca2+ from the ER
- The GP IIb and IIIa receptors on the cell surface are in an inactive state, unable to bind fibrinogen

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Antiplatelet Agents: Regulation

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Regulation of platelet function leading to the formation of a thrombus
- Injury to the endothelium the underlying basal lamina is exposed to the blood stream, and decreased PGI2 release  ↓ cAMP and release of Ca2+ from the ER
- Activation of platelets begins with platets adhering tightly via von Willebrand factor, subsequent interaction of GPIa/IIa receptors with collagen initiate intracellular activity.
- Activation of COX-1 leading to production and release of TxA2, ADP, Ca2+, and other molecules involved in coagulation.

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Antiplatelet Agents: Autocrine and paracine MOA

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Autocrine and paracrine actions of ADP stimulate the activation of GPIIb/IIIa by inducing a conformational change. ADP is one of the most important signaling molecules leading to platelet aggregation.
- Stimulates the P2Y12 receptor-Gi-coupled -->↓ cAMP
- mainly found on platelets

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Antiplatelet Agents: Aspirin MOA

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Mechanism of action
- Thromboxane A2 is a platelet product that causes platelets to change shape, release granules and aggregate
- Aspirin irreversibly acetylates the active site of COX1, preventing the formation of a precursor of thromboxane A2 production
- The inhibition of COX1 is irreversible and results in permanent inhibition in each platelet because the COX1 enzyme cannot be regenerated

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Aspirin: Therapeutic Use

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Therapeutic Use
- Prevention of myocardial infarction Decreases “stickiness” of platelets
- Transient cerebral ischemia
- May be combined with other anticlotting drugs to increase benefits different MOA

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Aspirin: Adverse Effects

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Bleeding, salicylism – generally with larger doses than used for this indication

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Antiplatelet Agents – 
ADP antagonists

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Clopidogrel (Plavix®)
Prasugrel (Effient®) – New in July 2009
Ticlopidine (Ticlid®)

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Antiplatelet Agents – 
ADP antagonists: MOA

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Mechanism of Action
- Irreversibly bind to and inhibit (non-competitive antagonists) the P2Y12 receptor (Gi-coupled), the receptor for ADP release from the platelet
- Receptor blockade prevents platelet aggregation

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Antiplatelet Agents – 
ADP antagonists: Therapeutic Use

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- Used alone or in combination with aspirin (synergistic effect)
- Clopidogrel
-- Reduce the rate of stroke and MI in individuals with recent MI, peripheral artery disease or acute coronary syndrome
- Prasugrel approved to reduce risk of heart attack following angioplasty
-- Higher incidence of stroke in those that have had a stroke previously

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Antiplatelet Agents – 
ADP antagonists: Adverse Effects

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- Clopidogrel has fewer SEs than ticlopidine
- Both drugs: N/D in 20%
- Thrombotic thrombocytopenic purpura – more often with ticlopidine

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Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade

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Abciximab (ReoPro®) – Humanized monoclonal antibody that binds glycoprotein IIb/IIIa
Eptifibadine (Integrilin®) – Antagonist of glycoprotein IIb/IIIa
Tirofiban (Aggrastat®) – Antagonist of glycoprotein IIb/IIIa

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Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade: MOA

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Mechanism of Action
These agents prevent interaction of the glycoprotein IIB/IIIA to fibrinogen or von Willebrand factor
This prevents interaction with foreign surfaces (endothelium) and other platelets
Prevents platelet aggregation due to any agonist

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Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade: Therapeutic Uses

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Acute coronary syndromes

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Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade: Adverse Effects

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Bleeding

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Antiplatelet Agents – 
Dipyridamole: MOA

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Mechanism of action
- Phosphodiesterase, which prevents the degradation of cAMP, decreasing the activation and aggregation of the platelet

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Antiplatelet Agents – 
Dipyridamole: Therapeutic uses

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Therapeutic uses
- Most effective when used with warfarin to prevent the formation of emboli originating from prosthetic heart valves.

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Treatment of Bleeding Disorders: Hereditary

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Hereditary clotting defects
- Lack of factor VIII, IX, others.
- Missing factors can be supplied by fresh or concentrated plasma preparations
-- Potential for transmission of disease
-- Recombinant factors are now available, but expensive

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Treatment of Bleeding Disorders: Aquried

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Acquired bleeding disorders are much more common
- Liver disease, vitamin K deficiency, excessive oral anticoagulant therapy
-- May require vitamin K replacement
-- Replacement may be administered orally or parenterally
-- Frequently observed in hospitals
-- Commonly administered to newborns and especially premature infants to prevent the hemorrhagic disease of vitamin K deficiency
Digestive disorders
- Sprue, celiac disease, steatorrhea
- Lack of bile