Transcript Chapter 48 Antidysrhythmic Drugs

BLOOD COAGULATION,
ANTICOAGULANT,
THROMBOLYTICS &
ANTIPLATELET DRUGS.
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Physiology and Pathophysiology
of Coagulation
• Hemostasis
– Stage 1—formation of platelet
plug
• Platelet aggregation
– Stage 2—coagulation
• Intrinsic coagulation pathway
• Extrinsic coagulation pathway
– Keeping hemostasis under control
– Physiologic removal of clots
• Thrombosis
– Arterial thrombosis
.
– Venous thrombosis
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A Blood Clot
• Consists of platelets
meshed into fibrin
• A web-like
accumulation of
strands with RBCs
• There are two major
facets of the clotting
mechanism – the
platelets, and the
thrombin system
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Anticoagulants – General
Overview
• Drugs that help prevent the clotting
(coagulation) of blood
• Coagulation will occur instantaneously
once a blood vessel has been hurt.
• Blood begins to solidify to prevent
excessive blood loss and to prevent
invasive substances from entering
the bloodstream
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MECHANISM OF PLATELET
AGGREGPATION
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Mechanism of platelet aggregation and actions of antiplatelet drugs.
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Anticoagulant Use
• Anticoagulant drugs help prevent the development of
harmful clots in the blood vessels by lessening the
blood's ability to cluster together
• The function of these drugs is often misunderstood
because they are sometimes referred to as blood
thinners; they do not in fact thin the blood
• These drugs will not dissolve clots that already have
formed, but it will stop an existing clot from becoming
worse and prevent future clots
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1-Anticoagulant Drugs
• Heparin and warfarin are the two traditional
anticoagulants
• Anticoagulants are used for acute coronary syndromes,
deep-vein thrombosis (DVT), pulmonary embolism
(PE), and heart surgery
• Thrombus - A blood clot that forms abnormally within
the blood vessels
• Embolus - When a blood clot becomes dislodged from
the vessel wall and travels through the bloodstream
• It is also given to certain people at risk for forming
blood clots, such as those with artificial heart valves or
who have atrial fibrillation (AF)
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A-Parenteral Anticoagulants
1-Heparin and Related Drugs
1-Heparin (unfractionated)
• Sources
– Lungs of cattle
– Intestines of pigs
• Rapid-acting anticoagulant
• Uses
– Pulmonary embolism (PE)
– Stroke evolving
– Massive deep venous thrombosis (DVT)
.
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A-Parenteral Anticoagulants I:
1-Heparin and Related Drugs
(cont’d)
• Adverse effects
– Hemorrhage
– Heparin-induced thrombocytopenia
– Hypersensitivity reactions
• Protamine Sulfate[ antidote]
• Activated partial thromboplastin time
(APTT) for monitoring.
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2-Low-Molecular-Weight
Heparins
• Heparin preparations composed of molecules that
are shorter than those found in unfractionated
heparin as ENOXAPARIN.
• Therapeutic use
– Prevention of DVT following surgery
– Treatment of established DVT
– Prevention of ischemic complications
• Adverse effects and interactions
– Bleeding
– Immune-mediated thrombocytopenia
– Cost
.
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3-Fondaparinux
[Arixtra]
• Synthetic anticoagulant
• Selective inhibition
• Therapeutic use
– Prevention of DVT following surgery
– Treatment of acute PE (in conjunction with
warfarin)
– Treatment of acute DVT (in conjunction with
warfarin)
• Adverse effects
– Bleeding
– Patients weighting less than 50 kg
– Thrombocytopenia
– Spinal or epidural hematoma
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4-Direct Thrombin Inhibitors
• Bivalirudin [Angiomax], Lepirudin
• Argatroban
• Desirudin
• Therapeutic use
– Prevent clot formation (combined with aspirin)
• Mechanism of action
– Facilitates the actions of antithrombin
– Prevents the conversion of fibrinogen into fibrin
– Prevents the activation of factor XIIIa
• Adverse effects
– Back pain
– Nausea
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B-Oral Anticoagulant
1-WARFARIN
Oral anticoagulant
•
• Antagonist to vitamin K
• Blocks the biosynthesis of factors VII, IX, X, and
prothrombin
• Therapeutic uses
– Long-term prophylaxis of thrombosis
• Prevention of venous thrombosis and
associated pulmonary embolism
• Prevention of thromboembolism (in patients
with prosthetic heart valves)
• Prevention of thrombosis during atrial
fibrillation
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Warfarin, an Oral Anticoagulant
(cont’d)
• Adverse effects
– Hemorrhage
– Fetal hemorrhage and teratogenesis from
use during pregnancy
– Not to be Used during lactation
WARNING?
.
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Warfarin, an Oral Anticoagulant
(cont’d)
• Drug interactions
– Drugs that increase anticoagulant effects[
CYT P450 inhibitors as cimetidine]
– Drugs that promote bleeding
– Drugs that decrease anticoagulant
effects[CYT P 450 INDUCERS AS
PHENYTOIN]
– Heparin
– Aspirin
– Acetaminophen
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2-Dabigatran etexilate
• Dabigatran etexilate is a new oral direct
thrombin inhibitor and the prodrug of
dabigatran
• Dabigatran is a small molecule that
reversibly inhibits both free and clotbound thrombin by binding to exosite
1 and/or the active site of thrombin
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The future for anticoagulants
• Molecular targets are factor IIa (thrombin)
and factor Xa
• The two candidate compounds, one direct
thrombin inhibitor (dabigatran etexilate)
and one direct factor Xa inhibitor
(rivaroxaban) are hoping to be approved
as new oral anticoagulants in the near
future
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2-Antiplatelet Drugs
• Aspirin (ASA)
– Inhibition of cyclooxygenase
– Adverse effect
• Increase risk of GI bleeding
• Ticlopidine [Ticlid]
– Inhibits ADP-mediated aggregation
– Adverse effects
• Hematologic effects
• Clopidogrel [Plavix]
– ADP receptor antagonist
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Antiplatelet Drugs (cont’d)
• Glycoprotein (GP) IIb/IIIa receptor
antagonists
– Most effective antiplatelet drugs esp.
in acute coronary syndromes.
– Reversible blockade of platelet GP
IIb/IIIa receptors
– EXAMPLE: ABCIXIMAB
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3-Thrombolytic Drugs
• Drugs that break down, or lyse, preformed
clots
• Older drugs
– streptokinase and urokinase
• Newer drugs
– Tissue plasminogen activator (t-PA)
– Anisoylated plasminogen-streptokinase
activator complex (APSAC)
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Thrombolytic Drugs (cont’d)
• Streptokinase
– Binds plasminogen
• Uses
– Myocardial infarction
– Deep vein thrombosis
– Massive pulmonary emboli
• Adverse effects
– Bleeding
– Antibody production
– Hypotension
– Fever
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Thrombolytic Drugs (cont’d)
NEW COMPOUNDS
•
•
•
•
anistreplase (Eminase)
alteplase (t-PA, Activase)
reteplase (Retavase)
tenecteplase (TNKase)
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Thrombolytic Drugs
Indications
•
•
•
•
•
•
Acute MI
Arterial thrombolysis
DVT
Occlusion of shunts or catheters
Pulmonary embolus
Acute ischemic stroke
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Thrombolytic Drugs:
Adverse Effects
• Bleeding
Internal
Intracranial
Superficial
• Other effects
Nausea, vomiting, hypotension, anaphylactic
reactions
Cardiac dysrrhythmias; can be dangerous
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Thank
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you !
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