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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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