2014 Pleno Pakar Pc2 Blok EMD

8/12/2019 2014 Pleno Pakar Pc2 Blok EMD

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2014Pleno Pakar Pc2 Blok EMD

Dr.Datten Bangun MSc,SpFK

Dept.Farmakologi & Therapeutik

Fak.Kedokteran USUMEDAN


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Virchows Triad


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Thrombus

=Thrombus in the left heart chambers can leadto embolic stroke and other systemic embolicevents, while

= Pulmonary emboli and paradoxical embolioriginate from either deep venous thrombusor thrombus in the right heart chambers.

Low cardiac output, decreased physicalactivity, and peripheral edema all predisposeto venous thrombi.


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Thrombi

According to location & composition

Arterial Occur in areas of rapid

flow (arteries)

In response to aninjured or abnormal

vessel wall White

Composed:

primarily of platelets, alsofibrin & occasional

leukocytes

Associated with

MI

Strokeischemia

Venous

Occur primarily in the

venous circulation

In response to venous

stasis or vascular injuryRed

Composed

almost entirely of fibrin &

erythrocytes

Associated with

Congestive Heart Failure,

Cancer

Surgery.


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Antithrombotic Agents: Mechanism of

Action

Anticoagulants: prevent clot formation and

extension

Antiplatelet drugs: interfere with platelet

activity

Thrombolytic agents: dissolve existing

thrombi


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HFSA 2010 Practice GuidelineAcute HFVT Prophylaxis

Recommendation 12.16 (NEW in 2010) 1 of 2

Venous thromboembolism prophylaxis with lowdose unfractionated heparin, low molecular weight

heparin, or fondaparinux to prevent proximal deepvenous thrombosis and pulmonary embolism isrecommended for patients who are admitted to thehospital with ADHF and who are not alreadyanticoagulated and have no contraindication toanticoagulation.

Strength of Evidence = B

HFSA :Heart Failure Society of America


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HFSA 2010 Practice GuidelineAcute HFVT Prophylaxis

Recommendation 12.16 (NEW in 2010) 2of 2

Venous thromboembolism prophylaxis with amechanical device (intermittent pneumaticcompression devices or graded compressionstockings ) to prevent proximal deep venousthrombosis and pulmonary embolism shouldbe considered for patients who are admitted to thehospital with ADHF, who are not already

anticoagulated, and who have acontraindication toanticoagulation.

Strength of Evidence = C


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Risk FactorAtrial Fibrillation Class/Level of

Evidence

For patients with ischemic stroke or TIA with paroxysmal (intermittent) or permanent AF,

anticoagulation with a vitamin K antagonist (target INR 2.5; range, 2.0 to 3.0) is

recommended.

Class I; LOE A

For patients unable to take oral anticoagulants, aspirin alone is recommended.

The combination of clopidogrel plus aspirin carries a risk of bleeding similar to that of

warfarin and therefore is not recommended for patients with a hemorrhagic

contraindication to warfarin.

Class I; LOE A

Class III; LOE B

New

Recommendation

For patients with AF at high risk for stroke (stroke or TIA within 3 months, CHADS2score of

5 or 6, mechanical valve or rheumatic valve disease) who require temporary interruption

of oral anticoagulation, bridging therapy with an LMWH administered subcutaneously is

reasonable.

Class IIa; LOE C

New

Recommendation

Recommendations for Patients With Cardioembolic

Stroke Types

2010 American Heart Association, Inc. All rights reserved.


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ANTIPLATELET THERAPY

=Aspirin: Primary prevention of MI in high riskpersons

= inhibits cyclo-oxygenase

=thromboxane A2 synthesis= inhibits both COX 1 and COX 2irreversibly

Secondary prevention of MI,TIA & stroke Clopidogrel: for persons who cant take aspirin

Aspirin+clopidogrel: Acute coronary

syndromes


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The Most Plausible Mechanism Of Aspirin In

Reducing Risks Of Cardiovascular Disease

Aspirin irreversibly acetylates the active site ofcyclooxygenase, which is required for the

production of thromboxane A2, a powerful

promoter of platelet aggregation

Possible Additional Beneficial Mechanisms of

Action of Higher Doses of Aspirin on CVD

Enhance nitric oxide formation

Decrease inflammation

Stabilize endothelial function


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Effects On Platelets

S Irreversible inhibitionNS IDS Reversible inhibition

Possible but unproven small clinicalCVD benefits of naproxenPossible but unproven inhibition ofclinical CVD benefits of aspirin byibuprofen

COXIBS Prothrombotic effects andrisks of similar magnitudeto NS IDS on CVD

cetaminophen No effects on platelets butrisks on liver and kidneysHennekens CH, Borzak S: JCPT, 2008


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Double Cheeseburger,Large Fries, JumboCoffee.. Oh And An

Aspirin -Gotta TakeCare Of The TickerYKnow.

Aspirin May

Reduce Risk Of

Heart Attack

New Yorker Magazine. 1988.


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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 polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affected

By Heparin

Vit. K dependent Factors

Affected by Oral

Anticoagulants


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5/98 MedSlides.com 15

Coagulation Cascade

XIIa

XIa

IXa

Intrinsic Pathway

(surface contact)

Xa

Extrinsic Pathway

(tissue factor)

VIIa

Thrombin (IIa)

Thrombin-Fibrin

Clot

aPTT

PT

Heparin / LMWH(AT-III dependent)

Hirudin/Hirulog

(direct antithrombin)

Courtesy of VTI


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CoumarinsWarfarin, Dicumarol

Mechanism of action:

Block the Vitamin K-dependent

glutamate carboxylation of

precursor clotting factors II, VII, IX

and X

8-12 hour delay in action because of T1/2 of

clotting factors in plasma

recovery needs synthesis of new clotting factors

action is reversed with vitamin K


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Warfarin: Indications

Prophylaxis and/or treatment of:

Venous thrombosis and its extension

Pulmonary embolism

Thromboembolic complications associated with

AF and cardiac valve replacement

Post MI, to reduce the risk of death,

recurrent MI, and thromboembolic eventssuch as stroke or systemic embolization

Prevention and treatment of cardiac

embolism


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Prothrombin Time (PT)

Historically, a most reliable and relied uponclinical test

However:

Proliferation of thromboplastin reagents withwidely varying sensitivities to reduced levels of

vitamin K-dependent clotting factors has occurred

Concept of correct intensity of anticoagulant

therapy has changed significantly (low intensity)

Problem addressed by use of INR (International

Normalized Ratio)


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J Clin Path 1985; 38:133-134; WHO Tech RepSer. #687 983.

INR: International Normalized Ratio

A mathematical correction (of the PT ratio) for

differences in the sensitivity of thromboplastin

reagents

Relies upon reference thromboplastins with known

sensitivity to antithrombotic effects of oralanticoagulants

INR is the PT ratio one would have obtained if the

reference thromboplastin had been used

Allows for comparison of results between labs and

standardizes reporting of the prothrombin time


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( )Patients PT in Seconds

Mean Normal PT in SecondsINR =

ISI

INR = International Normalized Ratio

ISI = International Sensitivity Index

INR Equation


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MeanNormal(Seconds)

PTR ISI INR

12

12

13

11

14.5

1.3

1.5

1.6

2.2

2.6

A

B

C

D

E

Blood from asingle patient

PatientsPT(Seconds)

16

18

21

24

38

ThromboplastinReagent

How Different Thromboplastins

Influence the PT Ratio and INR


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MeanNormal(Seconds)

PTR ISI INR

12

12

13

11

14.5

1.3

1.5

1.6

2.2

2.6

3.2

2.4

2.0

1.2

1.0

2.6

2.6

2.6

2.6

2.6

A

B

C

D

E

Blood from asingle patient

PatientsPT(Seconds)

16

18

21

24

38

Thromboplastinreagent

How Different Thromboplastins

Influence the PT Ratio and INR


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Conversion from Heparin to Warfarin

May begin concomitantly with heparin

therapy

Heparin should be continued for a minimum

of four days

Time to peak antithrombotic effect of warfarin is

delayed 96 hours (despite INR)

When INR reaches desired therapeutic range,discontinue heparin (after a minimum of four

days)


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* Elderly, frail, liver disease, malnourished: 2 mg/day

Warfarin: Dosing & Monitoring

Start low

Initiate 5 mg daily*

Educate patient

Stabilize

Titrate to appropriate INR

Monitor INR frequently (daily then weekly)

Adjust as necessary

Monitor INR regularly (every 14 weeks) and adjust


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Indication INRRange Target

Prophylaxis of venous thrombosis (high-risk surgery) 2.03.0 2.5

Treatment of venous thrombosis

Treatment of PE

Prevention of systemic embolism

Tissue heart valves

AMI (to prevent systemic embolism)

Valvular heart disease

Atrial fibrillation

Mechanical prosthetic valves (high risk) 2.53.5 3.0

Certain patients with thrombosis and the antiphospholipid syndrome

AMI (to prevent recurrent AMI)

Bileaflet mechanical valve in aortic position, NSR 2.03.0 2.5

Warfarin: Current Indications/Intensity


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Warfarin


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Fibrinolytics

Streptokinase, Urokinase, Alteplase (rt-PA),Reteplase, Tenecteplase

MOA: Plasminogen activators

Plasmin degrades fibrin and breaks up thrombi


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Streptokinase

Derived from bacterial protein

Antigenic (abys after 4 days)

Cleaves Plasminogen

Low fibrin specificity

Cheap

Urokinase Intrinsic compound

Isolated from urine or renal cell cultures

Non-antigenic

Cleaves plasminogen

Not licensed for MI


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Tissue plasminogen activator

Intrinsic compound

Recombinant DNA manufacture

Non-antigenic

Short half-lifegive heparin afterwards

Higher fibrin specificity

Expensive

? More effective

2014 Pleno Pakar Pc2 Blok EMD

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