5 anticoagulants 408

8/3/2019 5 Anticoagulants 408

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Dr Manal Alem of 7

Systemic Pharmacology MDPM 408

Renal and Cardiovascular Pharmacology

Anticoagulant, thrombolytic and antiplatelet drugs

Haemostasis is a finely regulated dynamic process of maintaining the fluidity of the blood,

repairing vascular injury and limiting blood loss while avoiding vessel occlusion

(thrombosis); the consequences of which will be inadequate tissue perfusion of vital organs

such as the heart and the brain. To salvage, restore and to maintain adequate perfusion to vital

organs we need anticoagulant, thrombolytic and antiplatelet agents.

Anticoagulant drugs; the drugs that prevent coagulation, by stopping the drug from clotting.

Thrombolytic drugs; the drugs that cause lysis of blood clots ˝clot bursting˝.

Antiplatelet drugs; drugs that decrease platelet aggregation and inhibit thrombus formation.

FibrinolysisIt is the process of fibrin digestion by the fibrin-specific protease, plasmin. The precursor

form of plasmin circulates in an inactive form as "plasminogen". In response to injury,

endothelial cells synthesize and release tissue plasminogen activator (t-PA), which converts

plasminogen to plasmin. Plasmin accordingly remodels the thrombus and limits its extension

by proteolytic digestion of fibrin.

Figure (1) Fibrinolysis Pathway

Increased fibrinolysis is effective therapy for thrombotic diseases. Tissue plasminogen

activator, urokinase and streptokinase all activate the fibrinolytic system. Conversely,

decreased fibrinolysis protects clots from lysis and reduces bleeding of hemostatic failure.

Aminocaproic acid is a clinically useful inhibitor of fibrinolysis. Heparin/ oral anticoagulant

drugs do not affect fibrinolytic mechanism.



Dr Manal Alem of 7

1. Anticoagulant drugs

1.1 indirect thrombin inhibitors

1.2 direct thrombin inhibitors

1.3 warfarin & the coumarin anticoagulants

2. Fibrinolytic drugs

3. Antiplatelet agents

1. Anticoagulant drugs

1.1 Indirect thrombin inhibitors

This group includes Unfractionated heparin (UFH), low-molecular-weight heparin

(LMWH), and the synthetic pentasaccharide fondaparinux. Heparin is a

glycosaminoglycan found in the secretory granules of mast cells. It is commonly extracted

from porcine intestinal mucosa or bovine lung.

Mechanism of action

The biologic activity of heparin is dependant upon the endogenous anticoagulant

antithrombin. Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), IXa,

and Xa by forming stable complexes with them. These reactions are slow; in the presence of

heparin, they are accelerated 1000-fold, and thus heparin functions as a cofactor for the

antithrombin-protease reaction.

Low-molecular weight heparin (LMWH) such as enoxaparin, dalteparin and tinzaparin

have equal efficacy, increased bioavailability from S.C injections and need less frequent

dosing requirements (once or twice daily).

It is essential to monitor activated partial thromboplastin time (aPTT) in patients receivingUFH, because there is poor correlation between the heparin concentration given and the

effect on coagulation. In patients receiving LMWH, the dose is usually calculated based on

body weight, which results in predictable pharmacokinetics in patients with normal renal

function. LMWH levels can be determined by anti-Xa units (or factor Xa inhibition assay),

in the setting of renal insufficiency, obesity and pregnancy.

Molecular weight of UFH=5000-30,000 Dalton

LMWH <8000 Dalton

ADME

It is not absorbed through GI mucosa, therefore, administered by continuous I.V infusion

(with immediate onset of action) or S.C injections (variable bioavailability). LMWH is given

S.C (absorbed more uniformly). The half life of heparin depends on the dose (for example:

100 unit/kg has a half life of 1 hr). LMWH has longer half-life than UFH. Heparin is cleared

and degraded by reticuloendothelial system; a small amount of undegraded heparin appears in

the urine. Therefore, half life is prolonged in patients with liver cirrhosis or renal

insufficiency.

In contrast to warfarin, heparin does not cross the placenta and has not been associated with

fetal malformation; therefore it is the drug of choice for anticoagulation during pregnancy.



Dr Manal Alem of 7

Uses

Treatment of venous thrombosis and pulmonary embolism.

Unstable angina, acute myocardial infarction, coronary angioplasty or stent

placement, and during surgery requiring cardiopulmonary bypass.

Prophylactic low-dose to prevent venous thromboembolism in high-risk patients

Treatment starts with a bolus dose of 5000 units, followed by 1200-1600 unit/hr. Therapy is

monitored by aPTT (a clotting time 2-2.5 times the normal aPTT is therapeutic).

LMWH was first approved for prevention of venous thromboembolism. They are also

effective in treatment of venous thromboembolism, pulmonary embolism and unstable

angina.

Adverse effects

Bleeding, especially in elderly, women and patients with renal failure.

Allergic reaction: due to its animal source Loss of hair and reversible alopecia

Long-term use is associated with osteoporosis and spontaneous fractures and

mineralocorticoid deficiency.

Heparin-induced thrombocytopenia (HIT)

Systemic hypercoagulable state that occurs in 1-4% of patients on UFH for a

minimum of 7 days. Morbidity and mortality in HIT are related to thrombotic events.

Venous thrombosis occurs most commonly, but occlusion of peripheral/central

arteries is not infrequent. The risk is higher with bovine-UFH than porcine heparin

and also lower with LMWH.

Platelet counts should be checked frequently; suspicious thrombocytopenia within

that time frame; and any new thrombus should raise the suspicion of HIT. Heparinshould be stopped and direct thrombin inhibitor or "fondaparinux" is used.

Contraindications

Patients with HIT, hypersensitivity to the drug, active bleeding, hemophilia,

thrombocytopenia, purpura, severe HPN, intracranial hemorrhage, threatened abortion, recent

surgery or advanced renal/hepatic disease.

Reversal of Heparin action

Discontinue heparin ± administer specific antagonist such as protamine sulfate, IV.

Neutralization of LMWH by protamine is incomplete.

The principal advantages of LMWH over UFH; more predictable pharmacokinetics,

longer half life, no lab monitoring, lower incidence of heparin-induced thrombocytopenia and

possible lower risks of bleeding and osteopenia.

Fondaparinux

Is a synthetic pentasaccharide that binds to antithrombin and enhance its inactivation of factor

Xa. It is licensed for prophylaxis of venous thromboembolism and also for treatment of deep

venous thrombosis and pulmonary embolism.



Dr Manal Alem of 7

1.2 direct thrombin inhibitors (DTIs)

DTIs exert their anticoagulant effect by directly binding to the active site of thrombin. In

contrast to heparin and LMWH, which act through antithrombin.

Hirudins

Hirudin is a specific, irreversible thrombin inhibitor from leech saliva. Lepirudin is a

recombinant form of hirudin that is administered parenterally and monitored by aPTT. It is

used in patients with HIT. It is excreted in the urine therefore not recommended for those

with renal insufficiency.

Argatroban

Can also be used in patients with HIT. It is given as I.V infusion and monitored by aPTT. Its

clearance is dependent on liver function.

It is not known whether lepirudin or argatroban is superior to the other in the treatment of

HIT. However, in practice the choice is usually dictated by the condition of the clearingorgan



Dr Manal Alem of 7

1.3 Warfarin & the coumarin anticoagulants (oral anticoagulants)

Warfarin (coumadin) is one of the most commonly prescribed drugs, yet, it is significantly

underused in clinical situations where it has proven benefit.

Mechanism of action

Oral anticoagulants are antagonists of vitamin K. Coagulation factors prothrombin (II) and

factors VII, IX and X along with the endogenous anticoagulant (protein C and S) are

synthesized mainly in the liver and are biologically inactive. Activation involves γ-

carboxylation of several glutamate residues in them. Such reaction requires reduced Vitamin

K. Oral anticoagulants inhibit the enzyme vitamin K epoxide reductase. Thus simply, they

inhibit the synthesis of Vit K dependent clotting factors.

The anticoagulant effect of warfarin results from a balance between partially inhibited

synthesis and unaltered degradation of the four clotting factors. Their half live are (II; 60hr,

VII; 6hr, IX; 24hr, X; 40hr). Therefore, the full antithrombotic effect of warfarin is not

achieved for several days.

Warfarin prolongs prothrombin time (PT). Therapeutic range for oral anticoagulant therapy is

defined by International normalized ratio (INR ): PT ratio (patient PT/ mean of normal PT

for lab). Recommended INR for prophylaxis and treatment of thrombotic disease is 2-3.

ADME

Orally administered, with 100% bioavailability. It is 99% bound to plasma proteins and its

half-life= 36 hr. It is metabolized in the liver and the inactive metabolites are excreted in the

urine and stool.

Important drug interactionsIncreased PT Decreased PT

Pharmacokinetic Pharmacodynamic Pharmacokinetic Pharmacodynamic

Amiodarone

Cimetidine

Disulfiram

Metronidazole

Fluconazole

Phenylbutazone

Sulfinpyrazone

Trimethoprim-

sulfamethoxazole

Drugs

Aspirin, 3rd

Cephalosporins,

heparin

Body factors

hepatic disease

hyperthyroidism

Barbiturates

Cholestyramine

rifampin

Drugs

Diuretics

Vit K

Body factors

Hereditary resistance

hypothyroidism

Clinical Uses are similar to heparin as a continuation of anticoagulant therapy.

Adverse effects

1- Warfarin crosses placenta and causes hemorrhagic disorder in the fetus. It could also

cause serious birth defects characterized by abnormal bone formation.

2- Cutaneous necrosis, rarely; frank infarction

3- Bleeding due to excessive anticoagulant effect: discontinue the drug; administer

oral/parenteral Vit K, fresh frozen plasma, prothrombin complex concentrates, and

recombinant factor VIIa.



Dr Manal Alem of 7

2. Fibrinolytic drugs

Definition

Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of plasmin from its precursor, plasminogen. They are not specific for target thrombi; they create a generalized

lytic state.

Streptokinase

A protein synthesized by strepotococci that combines with plasminogen and catalyzes its

conversion to plasmin.

Urokinase

A human enzyme synthesized by the kidney with similar mechanism.

Tissue plasminogen activators (t-PAs); alteplase

These activators preferentially activate plasminogen that is bound to fibrin, which (in theory)

confines fibrinolysis to the formed thrombus and avoids systemic activation. Reteplase is

less expensive and less fibrin specific, given as two I.V bolus injections. Tenecteplase has

longer half life, more fibrin specific than t-PA and given by single I.V bolus.

Anistreplase (anisoylated plasminogen streptokinase activator complex) is another

thrombolytic agent that works through the same mechanism.

Indications

1- Acute myocardial infarction; beneficial if given early within 6 hrs after symptomaticonset of acute MI.

2- Thromboembolic stroke (not hemorrhagic); t-PA is the agent given if patient

presented within 3 hr. Streptokinase was associated with increased bleeding risk in

this condition.

3- Pulmonary embolism with hemodynamic instability

4- Severe DVT such as SVC syndrome and ascending thrombophlebitis of the

iliofemoral vein with severe lower limb edema.

The major toxicity of all fibrinolytic drugs is bleeding and in case of streptokinase;

patients with anti-streptococcal antibodies can develop fever, allergic reactions andtherapeutic resistance.

Contraindications to thrombolytic therapy

1. surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious

trauma and cardiopulmonary resuscitation

2. serious GI bleeding within 3 months

3. HPN (diastolic BP> 110mmHg)

4. active bleeding or hemorrhagic disorder

5. previous cerebrovascular accident (CVA) or active intracranial process

6. aortic dissection

7. acute pericarditis



Dr Manal Alem of 7

3. Antiplatelet agents

PathophysiologyPlatelet function is regulated by three categories of substances (read only):

1) Agents generated outside the platelets that interact with platelet membrane receptors

eg, catecholamines, collagen, thrombin and prostacyclin.

2) Agents generated within the platelets that interact with membrane receptors eg, ADP,

prostaglandin D2, prostaglandin E2 and serotonin.

3) Agents generated within the platelets that act within the platelet eg, prostacyclin

endoperoxides and thromboxane A2, cAMP and cGMP and Ca++.

Several targets for platelet inhibitory drugs have been identified

Aspirin

Thromboxane A2 causes platelets to change shape, release their granules and aggregate.

Aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme

cyclooxgenase.

Its use decreases the incidence of transient ischemic attacks (TIA), unstable angina,

myocardial infarction and thrombosis after coronary bypass grafting.

Its main adverse effects are gastric upset and GI ulcers, hepatotoxicity, asthma, rashes and

renal toxicity occurs less frequently.

Clopidogrel & Ticlopidine

They inhibit ADP-induced platelet aggregation by irreversibly blocking ADP receptor on platelets with no effect on prostaglandin metabolism. They are both effective in prevention of

vascular events (TIAs, stroke and unstable angina).

Adverse effects of ticlopidine; nausea, dyspepsia and diarrhea. Hemorrhage in 5% and most

seriously leukopenia in 1%. Clopidogrel has fewer side effects and is rarely associated with

neutropenia. Thus, it is preferred over ticlopidine. There are reports of thrombotic

thrombocytopenic purpura with both medicines.

They are useful in patients who cannot tolerate aspirin.

Blockers of platelet glycoprotein IIb/IIIa receptors

These are used in patients with acute coronary syndrome and during percutaneous coronary

intervention. They target platelet IIb/IIIa receptor complex, the activation of which constitutethe final common pathway for platelet aggregation. Examples; Abciximab (monoclonal

antibody directed against the ® complex). Another example; Tirofiban. They are all

administered parenterally.

Dipyridamole

It is a vasodilator that also inhibits platelet function by inhibiting adenosine uptake and

cGMP phosphodiesterase activity. It is used in combination with aspirin to prevent

cerebrovascular ischemia (secondary prevention) and in combination with warfarin for

primary prophylaxis of thromboemboli in patients with prosthetic heart valves.

5 anticoagulants 408

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