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ANTIPLATELET AND FIBRINOLYTICS DRUGS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Antithrombotic drugs

The role of platelets

Overview of antiplatelet drugs

ADP receptor blockerCLOPIDOGRELTICLOPIDINE

COX inhibitor (Aspirin)

Phosphodiesterase inhibitor-

DIPYRIDAMOLE,CILOSTAZOLE

Gb IIb/IIIa receptor blockers

ABCIXIMABEPTIFIBATIDE

TIROFIBAN

TXA2 receptorTERUTROBAN

Mechanism of action of Aspirin

Aspirin

N.B. Aspirin inhibits Thromboxane A2 & prostacyclin too, but the former is more affected because platelets don’t have nuclei can’t synthesize

new enzymes for next 7 daysplatelets life span

ASPIRIN

Most authorities recommend initial therapy with a dose of 160 mg (one half-tablet) to 325 mg (one adult tablet)

Aspirin should be crushed/chewed (to facilitate faster absorption by breaking the enteric-coated delayed release tablet

Uses & adverse effect

Prophylaxis against unstable angina Post MI Post stroke

Adverse effects GI –ulcerationProlonged bleeding time ↑ risk of hemorrhage

II- Glycoprotein IIb/IIIa Receptor Antagonists

ABCIXIMAB is composed of 7E3 Fab fragments.derived from murine (mouse) Humanised monoclonal antibody. directed against glycoprotein receptor type GPIIb/IIIa. Mechanism: The m7E3 Fab binds selectively to the

glycoprotein GPIIb/IIIa receptors inhibiting platelet aggregation

Plasma T1/2- 30min Bolus –followed by slow IV infusion Major side effect- bleeding

II- Glycoprotein IIb/IIIa Receptor Antagonists

TIROFIBAN -non-peptic Synthetic arginine-glycine-aspartic acid (R-G-D)

sequence mimetics Hence, it blocks the binding of fibrinogen to

glycoprotein GPIIb/IIIa receptors They are given intravenously for the reduction of

thrombotic complications during coronary angioplasty (if they are given orally they are toxic)

Clinical trials showed reductions in the incidence of death and non-fatal MI in response to the use of tirofiban.

IV- Platelet ADP Receptor Antagonists Thienopyridines

TICLOPIDINE & CLOPIDOGRELThey inhibit irreversibly ADP binding to receptors

inhibit platelet aggregationNo effect on PG synthesisUsed in aspirin intolerant patients

Phoshodiesterase inhibitors Dipyridamole

Acts by in inhibiting phoshodiesterase enzyme Incompletely absorbed from the gastrointestinal

tract with peak plasma concentration occuring about 75 minutes after oral administration

More than 90% bound to plasma proteins A terminal half-life of 10 to 12 hours Metabolised in the liver Mainly excreted as glucuronides in the bile;

a small amount is excreted in the urine

Phoshodiesterase inhibitors Cilastazole

It is an inhibitor of phosphodiesterase III (PDE III) enzyme

Vasodilator and inhibitor of platelet aggregation Intermittent claudication Indicated for the reduction of events (myocardial

infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent MI or established peripheral arterial disease

C/I- CHF patients

New Oral Antiplatelet Drugs

PrasugrelThienopyridineMore rapid onset of action than clopidogrelIrreversible inhibitor of the P2Y12 receptorBeneficial in the treatment and prevention of ACS

and the prevention of thromboembolic events

Adenosine Diphosphate-Receptor Antagonists

New Oral Antiplatelet Drugs

Ticagrelor Cyclo-pentyl-triazo-pyrimidine (CPTP)More rapid onset of action than clopidogrelReversible inhibitor of the P2Y12 receptor

Therapeutic uses

Myocardial infarction Unstable angina Coronary bypass implants Prosthetic heart valves and arteriovenous shunts Venous thromboembolism and PVD Cerebrovascular transient ischemic attacks

FIBRINOLYTICS

StreptokinaseUrokinaseAnistreplaset-PAReteplasetenecteplase

Antithrombotic drugs

Thrombolytic drugs – mechanism of action

Thrombolytic drugs – mechanism of action

FIBRINOLYTICS

1ST GEN: STREPTOKINASE (SK)▪ Derived from ß-hemolytic streptococci▪ Binds & activates plasminogen plasmin “systemic”

fibrinolysis▪ 1-1.5 million U IV over 60min▪ Cheap

ANTISTREPLASE (plasminogen-SK)▪ 30mg IV over 5 min*Allergic reactions (6%)*Avoid re-treatment for 6 months (+Ab)

FIBRINOLYTICS

2ND GEN: ALTEPLASE (TPA) Cleaves plasminogen plasmin fibrinolysis Specific activity in thrombus, less systemic

fibrinolysis Weight-based IV infusion over 60-90min Half-life<5 min Heparin commonly administered shortly after

FIBRINOLYTICS

3RD GEN: modifications of TPA RETEPLASE▪ Half-life= 18 min▪ Double bolus regimen

TENECTEPLASE (TNK)▪ Half life= 20 min▪ Single-weight tiered bolus dosing over 5-10s

* No absolute mortality benefit in AMI

Thrombolytic drugs – pharmacokinetics

The plasma half-life of the third generation drugs is 14-45 minutes, allowing administration as a single or double intravenous bolus.

This is in contrast to second generation t-PA, which with a half-life of 3-4 minutes, must be administered an initial bolus followed by infusion

Uses of Thrombolytics:

Coronary Thrombolytics Pulmonary embolism DVT Arterial occlusion e.g. Popliteal artery Ischaemic stroke Occluded AV shunts Blocked central vacuum catheters

C/ I ABSOLUTE:

Intracranial hemorrhage or hemorrhagic stroke Ischemic Stroke within 3 month Known structural cerebrovascular lesion (AVMs,

aneurysms, tumor) Closed head injury with in 3 months. Aortic dissection Severe uncontrolled hypertension SBP > 180 DBP >

110 Active bleeding or bleeding diathesis Acute pericarditis

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