Blood Drugs

• describes drugs that are useful in treating three important dysfunctions of blood: thrombosis, bleeding, and anemia.

Drugs used in treatment of thrombosis

Objectives

• To learn how Blood Clots are formed and broken down ?

• What drugs can be used to regulate clotting ?

THROMBOSIS

• Thrombosis is the formation of an unwanted clot within a blood vessel.

• it is the most common abnormality of hemostasis.

Consequences of thrombus

Thrombus versus embolus• A clot that adheres to a vessel wall is called

a thrombus

• whereas an intravascular clot that floats in the blood is termed an embolus.

• Thus, a detached thrombus becomes an embolus.

• Both thrombi and emboli are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients.

Blood Clotting

• Vascular Phase

• Platelet Phase

• Coagulation Phase

• Fibrinolytic Phase

Vascular Phase

Vasoconstriction Exposure of tissues activate Tissue

factor and initiate coagulation

Tissue Factor

Platelet activation

1- resting platelets:

•In the absence of injury, resting platelets circulate freely, because the balance of chemical signals indicates that the vascular system is not damaged.

A- Chemical mediators synthesized by endothelial cells: •Chemical mediators, such as prostacyclin and nitric oxide, are synthesized by intact endothelial cells and act as inhibitors of platelet aggregation.•Prostacyclin (prostaglandin I2) acts by binding to platelet membrane receptors that are coupled to the synthesis of cyclic adenosine monophosphate (cAMP).•Elevated levels of intracellular cAMP are associated with a decrease in intracellular Ca2+. This leads to inhibition of platelet activation and inhibit release of platelet aggregation agents.

• Damaged endothelial cells synthesize less prostacyclin, resulting in a localized reduction in prostacyclin levels.

• The binding of prostacyclin to platelet receptors is decreased, resulting in lower levels of intracellular cAMP, which leads to platelet aggregation.

B- Roles of thrombin, thromboxane, and collagen:

•The platelet membrane also contains receptors that can bind thrombin, thromboxane2, and exposed collagen, that when occupied triggers platelet aggregation.

• In the intact, normal vessel, circulating levels of thrombin and thromboxane are low

•the intact endothelium covers the collagen in the subendothelial layers.

•The corresponding platelet receptors are thus unoccupied and remain inactive; as a result, platelet activation and aggregation are not initiated.

2- Platelet adhesion

•When the endothelium is injured, platelets adhere to and virtually cover the exposed collagen of the subendothelium.

• This triggers a complex series of chemical reactions, resulting in platelet activation

• 3- platelet activation• Receptors on the surface of the adhering platelets are

activated by the collagen of the underlying connective tissue.

• This causes morphologic changes in the platelets and the release of platelet granules containing chemical mediators, such as:

• adenosine diphosphate (ADP)• thromboxane A2• Serotonin• platelet-activation factor• thrombin. • .

• These signaling molecules bind to receptors in the outer membrane of resting platelets circulating nearby.

• The previously dormant platelets become activated and start to aggregate

4- Platelet aggregation

Platelet activation leads to :

1)activation of the glycoprotein (GP) IIb/IIIa receptors that bind fibrinogen and, ultimately, regulate platelet-platelet interaction and thrombus formation.

Fibrinogen, simultaneously binds to GP IIb/IIIa receptors on two separate platelets, resulting in platelet cross-linking and platelet aggregation.

This leads to an avalanche of platelet aggregation, because each activated platelet can recruit other platelets

Bhatt D. N Engl J Med 2007;357:2078-2081

Role of Platelet Activation and Aggregation in Ischemic Syndromes

ANTIPLATELET THERAPY

Platelet aggregation inhibitors

• Platelet aggregation inhibitors decrease the formation or the action of chemical signals that promote platelet aggregation.

• The most important of these is the GP IIb/IIIa receptor that ultimately regulates platelet-platelet interaction and thrombus formation.

• The platelet aggregation inhibitors described below act by:

1.Inhibit cyclooxygenase-1 (COX-1) or

2.block GP IIb/IIIa or

3.block ADP receptors

Thereby interfering in the signals that promote platelet aggregation.

Since these agents have different mechanisms of actions, synergistic or additive effects may be achieved when agents from different classes are combined.

These agents are beneficial in

1. the prevention and treatment of occlusive cardiovascular diseases

2. in the maintenance of vascular grafts and arterial patency

3.As adjuncts to thrombin inhibitors or thrombolytic therapy in myocardial infarction.

A- aspirin• Activation of platelets results in stimulation of platelet

membrane phospholipases that liberate arachidonic acid from membrane phospholipids.

• Arachidonic acid is converted into thromboxane A2 by COX enzyme

• Activated platelets releases thromboxane which activates further platelets.

• Aspirin inhibits thromboxane A2 synthesis by irreversible inhibition of platelet COX enzyme.

• This shifts the balance of chemical mediators to favor the antiaggregatory effects of prostacyclin, thus impeding platelet aggregation.

• \

• The aspirin-induced suppression of thromboxane last for the life of the anucleated platelet; approximately 7 to 10 days.

• Aspirin is currently employed in the prophylactic treatment of :

1. transient cerebral ischemia

2. to reduce the incidence of recurrent myocardial infarction

3. and to decrease mortality in pre and post myocardial infarct patients.

• The recommended dose of aspirin ranges from 81 to 325 mg, with side effects determining the dose chosen.

• Side effects:

• Bleeding time is prolonged by aspirin treatment, causing complications that include increased incidence of hemorrhagic stroke as well as gastrointestinal bleeding, especially at higher doses of the drug.

•

• NSAID, such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic site. Ibuprofen, if taken concomitantly with, or 2 hours prior to aspirin, can obstruct the access of aspirin to the catalytic site and, thereby, antagonize the platelet inhibition by aspirin.

• Therefore, aspirin should be taken at least 30 minutes before ibuprofen or at least 8 hours after ibuprofen.

• Although celecoxib (a selective COX-2 inhibitor) does not interfere in the antiaggregation activity of aspirin there is some evidence that it may contribute to cardiovascular events by shifting the balance of chemical mediators in favor of thromboxane A2.

• Aspirin: Primary prevention of MI in high risk persons

Secondary prevention of MI, & stroke

• Clopidogrel: for persons who can’t take aspirin

• Aspirin+clopidogrel: Acute coronary syndromes

• Treatment failures occur with aspirin therapy; approximatly 40% of human patients on aspirin therapy develop an ischemic event.

• There are many possible causes for this. Aspirin is a relatively weak inhibitor of platelet function. It inhibits only one pathway of platelet activation and aggregation.

• Moreover, platelet aggregation is only one pathway of thrombus formation.

• True „aspirin resistance‟ refers to failure of aspirin to inhibit TXA2 production.

Potential mechanisms include:

(1) decreased bioavailability

(2) competition with other NSAIDs

(3) accelerated platelet turnover, introducing newly-formed, non aspirinated platelets into the circulation

(4) TXA2 production by the aspirin-insensitive COX-2 in newly-formed platelets.

Ticlopidine and clopidogrel Mechanism of action:• These drugs irreversibly inhibit the binding of ADP to its receptors on platelets

Therapeutic use: •Ticlopidine is approved for the prevention of transient ischemic attacks and strokes for patients with prior cerebral thrombotic event. It is also used as adjunct therapy with aspirin following coronary stent implantation to decrease the incidence of stent thrombosis.

• However, due to its life-threatening hematologic adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia, it is generally reserved for patients who are intolerant to other therapies

• Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial infarction, stroke, or established peripheral arterial disease. It is also approved for prophylaxis of thrombotic events in acute coronary syndrome (unstable angina).

• Additionally, clopidogrel is used to prevent thrombotic events associated with percutaneous coronary intervention with or without coronary stent.

• Compared to ticlopidine, clopidogrel is the preferred agent in ischemic heart disease events, because there is more data to support use of clopidogrel in these cardiac patients.

• Furthermore, clopidogrel has a better overall side-effect profile although TTP may also occur with this agent.

Pharmacokinetics:

•Food interferes with the absorption of ticlopidine but not with clopidogrel.

•After oral ingestion, both drugs are extensively bound to plasma proteins.

•They undergo hepatic metabolism by the cytochrome P450 system to active metabolites that are yet to be identified.

•The maximum effect is achieved in 3 to 5 days

• when treatment is suspended, the platelet system requires time to recover.

Side effects

•Ticlopidine has a black box warning due to the severe hematologic adverse reactions associated with its use.

•Both drugs can cause prolonged bleeding for which there is no antidote.

•Serious adverse effects of ticlopidine include neutropenia, TTP, and aplastic anemia requiring frequent blood monitoring, especially during the first 3 months of treatment.

Drug interaction:

•Because these drugs can inhibit cytochrome P450, they may interfere with the metabolism of drugs such as phenytoin, tolbutamide, warfarin, fluvastatin, and tamoxifen if taken concomitantly.

•Indeed, phenytoin toxicity has been reported when taken with ticlopidine.

Abciximab

• chimeric monoclonal antibody

• composed of the constant regions of human immunoglobulin joined to the Fab fragments of a murine monoclonal antibody directed against the GP IIb/IIIa complex.

• By binding to GP IIb/IIIa, the antibody blocks the binding of fibrinogen; consequently, aggregation does not occur

• Abciximab is given intravenously along with heparin or aspirin as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications.

• After cessation of infusion, platelet function gradually returns to normal, with the antiplatelet effect persisting for 24 to 48 hours.

• The major adverse effect of abciximab therapy is the potential for bleeding, especially if the drug is used with anticoagulants or if the patient has a clinical hemorrhagic condition.

• Abciximab is expensive, limiting its use in some settings.

Eptifibatide and tirofiban• These two antiplatelet drugs act similarly to

abciximab, blocking the GP IIb/IIIa receptor.

• These compounds, like abciximab, can decrease the incidence of thrombotic complications associated with acute coronary syndromes.

• When intravenous infusion is stopped, these agents are rapidly cleared from the plasma, but their effect can persist for as long as 4 hours.

• Only intravenous formulations are available, because oral preparations of GP IIb/IIIa blockers are too toxic.

• Eptifibatide and its metabolites are excreted by the kidney.

• Tirofiban is excreted unchanged by the kidney.

• The major adverse effect of both drugs is bleeding.

Dipyridamole

• Dipyridamole [dye-peer-ID-a-mole], a coronary vasodilator, is employed prophylactically to treat angina pectoris.

• It is usually given in combination with aspirin or warfarin

• it is ineffective when used alone.• Dipyridamole increases intracellular levels

of cAMP by inhibiting cyclic nucleotide phosphodiesterase.

Copyright restrictions may apply.

Schulman, S. P. JAMA 2004;292:1875-1882.

Sites of Action of Antiplatelet Therapy on Mechanisms of Platelet Activation and Aggregation

Thrombosis - Pathogenesis• 3 primary influences

predispose to thrombus formation

Virchow’s Triad (1856):1.Endothelial Injury2.Stasis3.Hypercoagulability

Venous Thrombi• Most occur in the superficial

or deep veins of the leg (DVT)

• Superficial thrombi– Swelling and pain– Rarely embolize

• DVT– Pain, redness and swelling– Asymptomatic in 50%– Risk of emboli

Tapson V. N Engl J Med 2008;358:1037-1052

Pathophysiology of Pulmonary Embolism

anticoagulants

Coagulation Phase

Two major pathways

Intrinsic pathway

Extrinsic pathway

Both converge at a common point

• Biosynthesis of these factors are dependent on Vitamin K1 and K2

Normally inactive and sequentially activated

Intrinsic Pathway

All clotting factors

are within the blood

vessels

Clotting slower

Activated partial

thromboplastin test

(aPTT)

Extrinsic Pathway

Initiating factor is

outside the blood

vessels - tissue

factor

Clotting - faster - in

Seconds

Prothrombin test (PT)

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Fibrin polymer

Intrinsic Pathway Extrinsic Pathway

Factors affectedBy Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

The Coagulation and Fibrinolytic Pathways

Activated factor X (FXa) + FVa + Ca++ + phospholipids

Prothrombin thrombin

Fibrinogen fibrin blood clot

Present on platelets’ surfaces. Act by

accelerating thrombus formation.

This complex and Ca2+ comprise the prothrombinase complex

Thrombin stimulates platelet aggregation

Phospholipids on platelets stimulate clot formation

• The coagulation process that generates thrombin consists of two interrelated pathways the extrinsic and the intrinsic systems.

• The extrinsic system, which is probably the more important system in vivo, is initiated by the activation of clotting Factor VII by tissue factor, or thromboplastin.

• Tissue factor is a lipoprotein that is expressed by cells at the site of vascular injury.

• The intrinsic system is triggered by the activation of clotting Factors its contact in vitro with glass or highly charged surfaces.

• Intrinsic and extrinsic activation of the coagulation cascade leads to the generation of thrombin, the activation of fibrinogen, the release of fibrinopeptides, the formation of soluble fibrin, and finally, the formation of cross-linked, insoluble fibrin.

• (The activated form of the factor is indicated by "a.")

• It is important that coagulation is restricted to the local site of vascular injury.

• Endogenously, there are several inhibitors of coagulation factors, including protein C, protein S, antithrombin III, and tissue factor pathway inhibitor.

• The mechanism of action of several anticoagulant agents, including heparin and heparin-related products, involves activation of these endogenous inhibitors (primarily antithrombin III).

anticoagulants• The anticoagulant drugs either:

1. inhibit the action of the coagulation factors (the thrombin inhibitors, such as heparin and heparin-related agents)

2. interfere with the synthesis of the coagulation factors (the vitamin K antagonists, such as warfarin).

http://www.hopkinsmedicine.org/hematology/coagulation.swf

Hemostasis requires a fine balance between procoagulant and regulatory factors

Deficiency

Deficiency/Abnormality

Thrombosis

Bleeding

PC PS

ATIII…

CoagulationProteins/Platelets/

Vessel wall

Anticoagulants FACTORY

Scheme of anticoagulant drugs

Injected; THROMBIN INHIBITORS• Thrombin inhibitors can either inactivate thrombin

directly or block thrombin formation• Thrombin can be inhibited irreversibly by

glycosaminoglycans like heparin through an antithrombin III-dependent mechanism

• The enzyme can be inhibited reversibly by hirudin and hirudin derivatives in an antithrombin III-independent manner (direct acting)

• In addition to inhibiting thrombin, glycosaminoglycans also block thrombin generation

Antithrombin-III Dependent Antithrombin-III Dependent Thrombin InhibitorsThrombin Inhibitors

Standard Unfractionated Heparin (UFH) Heparin is a mixture of glycosaminoglycan molecules,

which are heterogenous in molecular size The mean molecular weight of heparin is 15,000 D Antithrombin III (ATIII) binding is necessary for its

anticoagulant activity Antithrombin III (ATIII) is a slow endogenous a slow endogenous

progressive inhibitorprogressive inhibitor of thrombin and other clotting enzymes (Xa)

Mode of Action of Heparin

It binds to ATIII through a unique pentasaccharide conformational change in ATIII ↑ activity of ATIII

It binds to ATIII through a unique pentasaccharide conformational change in ATIII ↑ activity of ATIII

N.B. ATIII alone can inhibit thrombin but in a very slow reaction

N.B. ATIII alone can inhibit thrombin but in a very slow reaction

Heparin acts as a template to create (thrombin-ATIII complex)

Heparin acts as a template to create (thrombin-ATIII complex)

N.B. only 1 ATIII bind to 1 thrombin (1:1)

N.B. only 1 ATIII bind to 1 thrombin (1:1)

Then heparin dissociates and is reused againThen heparin dissociates and is reused again

Heparin inactivates thrombin by binding both ATIII and thrombin

To inactivate thrombin

1. Heparin binds to ATIII by the unique penta-saccharidepenta-saccharide

2. Also binds to thrombin through the heparin-binding domainheparin-binding domain• heparn also inactivate factor Xa, but in such case it binds

only with ATIII through its pentasaccharide sequence

Anti-IIAnti-IIaa activity activity = Anti-X = Anti-Xaa activity activity

Every heparin molecule contains :

Pentasaccharide + heparin binding domain

Low molecular weight heparin have a mean molecular weight of 5000 D.

Prepared by controlled chemical or enzymatic depolymerization of standard unfractioned heparin are about ⅓ the size of starting material

Enoxaparin is the most used LMWHEnoxaparin is the most used LMWH

Low Molecular Weight Heparins (LMWHs)

They contain pentasaccharide inactivation of Factor Xa In contrast, only 25% to 50% of LMWH molecules that have

the pentasaccharide sequence are long enough to interact with both ATIII & thrombin

Mechanism of Action of Low Molecular Weight Heparin (LMWH)

Anti-IIAnti-IIa a < < Anti-XAnti-Xaa activity activity

25% of LMWH can interact with both ATIII and thrombin

The rest only inactivate factor X

Pharmacokinetic Profile of LMWHPharmacokinetic Profile of LMWH Bioavilability Bbioavailability (90% vs. 20% of

heparin) LMWH exhibit less binding to plasma proteins &

cell surfaces (better than heparin)more predictable anticoagulant response Laboratory monitoring of LMWH activity is not

required LMWH has low resistance in comparison to

heparin T1/2 = 4 hours (more than heparin) Given at fixed doses once to twice daily by S.C.

route, and is given for both inpatients as well as for outpatients.

Comparison of UFH & LMWH

CharacterCharacter UFHUFH LMWHLMWH

Average Mol wtAverage Mol wt 15,000 5,000

Anti-XAnti-Xaa/anti-II/anti-IIaa activity activity 1/1 2-4/1

aPTT monitoring requiredaPTT monitoring required Yes No

Inactivation of platelet-bound XInactivation of platelet-bound Xaa No Yes

Protein bindingProtein binding Powerful) 4+) Weak (+)

Endothelial cell bindingEndothelial cell binding Powerful) 4+) No

Dose-dependent clearanceDose-dependent clearance Yes No

Elimination half-lifeElimination half-life 30-150 min 2-5 times longer

Biophysical Limitations of Heparin and LMWH

Both heparin and LMWH can’t degrade fibrin-bound thrombin (only free thrombin is degraded)

nor Factor Xa within the prothrombinase complex.

Therapeutic Useso Heparin should be given either IV or S.C. injection.o onset of action: few minutes (IV) 1-2 hours (S.C.)o LMWHs are given by S.C. routeo I.M. injection hematoma formation (thus is avoided)

Treatment of deep vein thrombosis Treatment of pulmonary embolism Prevention of postoperative venous thrombosis in

patients with acute MI phase or one undergoing elective surgery (not emergency surgery)

Reduction of coronary artery thrombosis after thrombolytic treatment

Heparin is the anticoagulant of choice in pregnant women

• Heparin and LMWHs are the anticoagulants of choice for treating pregnant women with prosthetic heart valves or venous thromboembolism, because these agents do not cross the placenta (due to their large size and negative charge).

• Heparin has the advantage of speedy onset of action, which is rapidly terminated on suspension of therapy.

• However, it is being supplanted by the LMWHs, such as enoxaparin and dalteparin, because they can be conveniently injected subcutaneously on a patient weight basis, have predictable therapeutic effects, and have a more predictable pharmacokinetic profile

Adverse Effects• Bleeding: they both lead to bleeding but the bleeding is less in

LMWH To treat bleeding: inject antidote protamine sulphateprotamine sulphate (1mg IV for

each 100 units of UFH) (reversal effect)• Thrombosis and heparin induced Thrombocytopenia (HI)T: :

HIT is caused by the formation of abnormal antibodies that activate platelets. so someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls. 

HIT is a life threatening immune reactionOccurs in 3% of patientsUsually occurs a week from starting heparin therapy LMWHs, though of lower risk, are contraindicated with HIT.

How does HIT occur?

• Heparin injection immune reaction with body produce antibody against heparin & also bind to platelet receptor activation of platelet thrombosis

OsteoporosisOsteoporosis occurs with large doses of UFH >20,000 U/day for 6 months or longer (chronic use)

HyperkalemiaHyperkalemia rarely occurs with UFH It is attributed to inhibition of aldosterone

secretion It is reversible by therapy discontinuation Diabetic & renal failure patients are at higher riskHypersensitivity: (Antigenicity due to animal

source) rarely occurring reactions include urticaria, rash,

rhinitis, angioedema & reversible alopecia(hair loss)

HEPARIN TEST of CONTROL

ACTIVATED PARTIALTHROMBOPLASTIN TIME OR aPTT or PTTA THERAPEUTIC VALUE, ~ 0.3 u/ml

REVERSALUFH – ProtamineLMWH – Protamine not fully effective

Stead L and Judson K. N Engl J Med 2006;355:e7

Other Injectable Antithrombotic AgentsOther Injectable Antithrombotic Agents

• FondaparinuxFondaparinux, a pentasaccharide, is an AT-III-dependent selective for factor Xselective for factor Xaa

Prevents venous thrombosis associated with orthopedic surgery

Administered > 6 hours postoperatively and the dose is adjusted for patients with renal impairment.

FONDAPARINUX

• It is well absorbed from the subcutaneous route with a predictable pharmacokinetic profile.

• Fondaparinux requires less monitoring than heparin.

• Fondaparinux is eliminated in urine mainly as unchanged drug with an elimination half-life of 17 to 21 hours.

• It is contraindicated in patients with severe renal impairment (<30 mL/min).

• Bleeding episodes are the major side effect of fondaparinux therapy.

• Thrombocytopenia, is not a problem, and this agent may be used in patients with HIT.

Clinically Approved Direct Thrombin Clinically Approved Direct Thrombin InhibitorsInhibitors

• Lepirudin, recombinant hirudin*-like peptide.• Direct acting thrombin inhibitor• Used in HIT patients (IV injection)• Has renal clearance• It acts on free thrombin and thrombin bound to fibrin It has potential use in unstable angina patients and after

thrombolysis

* hirudin: is a leech derived anticoagulant

It binds to active site and substrate site of thrombin

• Bleeding is the major adverse effect of treatment with lepirudin, and it can be exacerbated by concomitant thrombolytic therapy, such as treatment with streptokinase or alteplase.

• About half the patients receiving lepirudin develop antibodies. However, the drug-antibody complex retains anticoagulant activity.

• Because renal elimination of the complex is slower than that of the free drug, the anticoagulant effect may be increased. It is important to monitor the aPTT and renal function when a patient is receiving lepirudin.

Argatroban

•is metabolized in the liver and has a half life of about 50 minutes.

•It is monitored by aPTT. The patient's hemoglobin and hematocrit must also be monitored.

•Because argatroban is metabolized in the liver, it may be used in patients with renal dysfunction but it should be used cautiously in patients with hepatic impairment.

•As with other agents in this class, the major side effect is bleeding.

Di Nisio, M. et al. N Engl J Med 2005;353:1028-1040

Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin

Synthesis of clotting factors

Oral Anticoagulants Vitamin K Antagonists (The Coumarins)Vitamin K Antagonists (The Coumarins)

• Vitamin K is co-factor for the hepatic synthesis of clotting factors II, VII, IX & X

Vit. K Vit. K epoxide (active form)By Vit.k reductase

warfarin

Warfarin inhibits Vit. K reductase no active form of

Vit. K no synthesis of clotting factors

Warfarin inhibits Vit. K reductase no active form of

Vit. K no synthesis of clotting factors

ROLE of VITAMIN K

Vitamin K Antagonists (Warfarin)

Onset:Onset: • Clinical anticoagulant activity needs several days to

develop (due to the already circulating clotting factors)

• So the action of warfarin will appear after the elimination of prior clotting factors.

• Elimination time (factor II needs: 60 hours, factor X: 40 hours)

• lasts for 4-5 days• Overlap heparin & warfarin therapyOverlap heparin & warfarin therapy taken together

until the effect of warfarin appears (after 5 days) then stop taking heparin.

Vitamin K AntagonistsWarfarin

• Warfarin has 100% oral bioavailability• high plasma protein binding • Warfarin is metabolized by hepatic Cytochrome

P450 enzymes • long plasma t1/2 of 36 hours• A high loading dose followed by an adjusted

maintenance dose • Warfarin is contraindicated with pregnancy as it

crosses the placental barrier and is teratogenic in the first trimester & and induce intracranial hemorrhage in the baby during delivery

• Prothrombin time, a measure of the extrinsic pathway, may be used to monitor warfarin therapy.

• In the 1990s, the international normalized ratio (INR) was adopted to monitor warfarin concentration.

• The INR corrects for variations that would occur with different thromboplastin reagents, between different hospitals, or when a single hospital gets a new lot of reagent.

• The goal of warfarin therapy is an INR of 2 to 3 for most indications and 2.5 to 3.5 in patients with mechanical heart valves.

• Warfarin is used to prevent the progression or recurrence of acute deep-vein thrombosis or pulmonary embolism after initial heparin treatment.

• It is also used for the prevention of venous thromboembolism during orthopaedic or gynecologic surgery.

• Prophylactically, it is used in patients with acute myocardial infarction, prosthetic heart valves, or chronic atrial fibrillation.

Warfarin Drug Pharmacokinetic & Pharmacodynamic Interactions

Potentiating warfarin Inhibitors of hepatic P450

enzymes (cimetidine, cotrimoxazole, imipramine, amiodarone)

Platelet aggregation inhibitors (NSAIDs e.g. aspirin)

3rd generation cephalosporins* Drugs displacing warfarin from

binding sites (NSAIDs) Drugs reducing the availability of

vitamin K Hepatic disease(↓ clotting factors) &

hyperthyroidism

Inhibiting Warfarin Vitamin K Inducers of hepatic P450

enzymes (rifampicin, barbiturates, … etc)

Reduction of GIT absorption (cholestyramine)

Diuretics Hypothyroidism

*Cephalosporins potentiate warfarin’s effect by killing vit.k producing normal flora

Warfarin Side-EffectsWarfarin Side-Effects

• Drug-drug interactions• Bleeding disorder (thus should be monitored)

Treatment for bleeding• Minor bleeding: stop therapy + oral Vitamin K• Severe Bleeding: stop therapy + I.V. Vitamin

K fresh frozen plasma, recombinant factor VIIa or prothrombin complex may be used

WARFARIN – DRUG INTERACTIONS

Diminished warfarin actions

Ethanol

Enhanced warfarin actions

Ethanol Aspirin

Cimetidine

Thrombolytics

• Fibrinolysis is initiated by tissue plasminogen activator (t-PA), urinary-type plasminogen activator (u-PA), and plasmin.

• Plasmin bound to the surface of fibrin initiates the lysis of insoluble, cross-linked fibrin, with the subsequent generation of fibrin-degradation products.

• The main fibrinolytic reactions involve the inhibition of fibrinolysis by plasminogen-activator inhibitor type 1 (PAI-1) and {α}2-antiplasmin.

•

Nesheim, M. Chest 2003;124:33S-39S

The balance between the formation and degradation of FN

Thrmobolytics

• Acute thromboembolic disease in selected patients may be treated by the administration of agents that activate the conversion of plasminogen to plasmin that hydrolyzes fibrin and, thus, dissolves clots.

• Streptokinase, one of the first such agents to be approved, causes a systemic fibrinolytic state that can lead to bleeding problems.

• Alteplase acts more locally on the thrombotic fibrin to produce fibrinolysis..

• Clinical experience has shown nearly equal efficacy betweenn streptokinase and alteplase..

• Plasmin bound to the surface of fibrin is better protected from inhibition by {α}2-antiplasmin than is plasmin generated in the fluid phase.

• thrombolytic therapy is unsuccessful in about 20 % of infarcted arteries, and about 15 % of the arteries that are opened will later close again.

• In the case of acute myocardial infarction, the thrombolytic drugs are reserved for those instances when angioplasty is not an option or until the patient can be taken to a facility that performs percutaneous coronary interventions.

• Clot dissolution and reperfusion occur with a higher frequency when therapy is initiated early after clot formation, because clots become more resistant to lysis as they age.

• Fibrinolytic drugs may lyse both normal and pathologic thrombi.

• thrombolytic agents are helpful in restoring catheter and shunt function, by lysing clots causing occlusions.

• Thrombolytic agents are also used to dissolve clots that result in strokes.

• thrombolytic agents are usually administered intravenously.

• These drugs are contraindicated in patients with healing wounds, pregnancy, history of cerebrovascular accident, or metastatic cancer.

streptokinase• Mechanism of action: • Streptokinase has no enzymic activity. Instead,

it forms an active one-to-one complex with plasminogen.

• This enzymatically active complex converts uncomplexed plasminogen to the active enzyme plasmin.

• In addition to the hydrolysis of fibrin plugs, the complex also catalyzes the degradation of fibrinogen as well as clotting Factors V and VII.

Therapeutic uses:

• Streptokinase is approved for use in acute pulmonary embolism, deep-vein thrombosis, acute myocardial infarction, arterial thrombosis, and occluded access shunts.

Pharmacokinetics:

•Streptokinase therapy is instituted within 4 hours of a myocardial infarction and is infused for 1 hour.

•Its half-life is less than half an hour.

• Thromboplastin time is monitored and maintained at two- to five-fold the control value.

• On discontinuation of treatment, either heparin or oral anticoagulants may be administered.

• Hypersensitivity: • Streptokinase is a foreign protein and is antigenic. • Rashes, fever, and rarely, anaphylaxis occur. • Because most individuals have had a streptococcal

infection sometime in their lives, circulating antibodies against streptokinase are likely to be present in most patients.

• These antibodies can combine with streptokinase and neutralize its fibrinolytic properties. Therefore, sufficient quantities of streptokinase must be administered to overwhelm the antibodies and provide a therapeutic concentration of plasmin.

• The incidence of allergic reactions is approximately 3 percent.

alteplase

• Alteplase [AL-te-place] (formerly known as tissue plasminogen activator, or tPA) is a serine protease originally derived from cultured human melanoma cells.

Mechanism of action:

•Alteplase has a low affinity for free plasminogen in the plasma, but it rapidly activates plasminogen that is bound to fibrin in a thrombus or a hemostatic plug.

•Thus, alteplase is said to be fibrin selective, and at low doses, it has the advantage of lysing only fibrin, without unwanted degradation of other proteins notably fibrinogen.

•This contrasts with streptokinase, which acts on free plasminogen and induces a general fibrinolytic state.

• Alteplase seems to be superior to streptokinase in dissolving older clots.

• Alteplase, administered within 3 hours of the onset of ischemic stroke, significantly improves clinical outcome that is, the patient's ability to perform activities of daily living.

• Reteplase (Retavase) is similar to alteplase and can be used as an alternative.

Anistreplase (plasminogen streptokinase activator complex)

• Anistreplase is a preformed complex of streptokinase and plasminogen and it is considered to be a prodrug.

Agents that control bleeding

Drugs Used to Treat Bleeding• A. Aminocaproic acid and tranexamic

acid

• Both agents are synthetic, inhibit plasminogen activation, are orally active, and are excreted in the urine.

• A potential side effect of treatment is intravascular thrombosis.

• Protamine sulfate

• antagonizes the anticoagulant effects of heparin.

• Adverse effects of drug administration include hypersensitivity as well as dyspnea, flushing, bradycardia, and hypotension when rapidly injected.

• Vitamin K

• That vitamin K1 (phytonadione) administration can stop bleeding problems due to the oral anticoagulants is not surprising, because those substances act by interfering with the action of the vitamin.

• The response to vitamin K is slow, requiring about 24 hours (time to synthesize new coagulation factors).

• Thus, if immediate hemostasis is required, fresh-frozen plasma should be infused.

• Aprotinin• stops bleeding by blocking plasmin. • It can inhibit streptokinase. • It is approved for prophylactic use to reduce

perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass surgery.

• Aprotinin may cause renal dysfunction and hypersensitivity (anaphylactic) reactions.

• In addition, aprotinin should not be administered to patients who have already been exposed to the drug within the previous 1 year due to the possibility of anaphylactic reactions.

Anti anaemic Drugs (1).ppt