Drugs used in Thromboembolic Disorders - DSA Flashcards
Parenteral anticoagulants - indirect thrombin and factor Xa (FXa) inhibitors
• Unfractionated heparin
– Heparin sodium
• Low molecular weight heparins
– Enoxaparin
– Tinzaparin
– Dalteparin
• Synthetic pentasaccharide
– Fondaparinux
Parenteral anticoagulants - direct thrombin inhibitors
Lepirudin
Bivalirudin
Argatroban
Oral anticoagulants
Coumarin anticoagulatns - warfarin
Novel oral anticoagulants (NOAC): • Factor Xa inhibitors – Rivaroxaban – Apixaban – Edoxaban
• Direct thrombin inhibitor
– Dabigatran
Inhibitors of thromboxane A2 synthesis
Aspirin (acetylsalicylic acid)
ADP receptor blockers
Clopidogrel
Prasugrel
Ticlopidine
Ticagrelor
Platelet glycoprotein receptor blockers
Abciximab
Eptifibatide
Tirofiban
Inhibitors of phosphodiesterases
Dipyridamole
Cilostazol
Tissue-type plasminogen activator drugs (fibrinolytic)
Alteplase
Reteplase
Tenecteplase
Urokinase-type plasminogen activator (fibrinolytic)
Urokinase
Streptokinase preparations (fibrinolytic)
streptokinase
HMW vs LMW heparin
– Have practically equal efficiency in several thromboembolic conditions
– LMWs have increased bioavailability from the SC injection site and allow
for less frequent injections and more predictable dosing
Clinical use of heparins
• Very hydrophilic; must be given IV or SC
• Used to treat disorders secondary to red (fibrin-rich) thrombi and reduce the risk
of emboli
– Protects against embolic stroke, pulmonary emboli
– Administer to patients with deep vein thrombosis, atrial arrhythmias and
other conditions that predispose towards red thrombi
– Prevention of emboli during surgery or in hospitalized patients (reduces
risk of emboli)
– Heparin locks: prevents clots from forming in catheters
Activated Partial Thromboplastin Time (aPTT)
used primarily for HMV heparin
– Measures the efficacy of an intrinsic (contact activation) pathway and a common pathway
– In order to activate the intrinsic pathway, phospholipids, activator (kaolin or silica), and Ca2+ are mixed with patient’s plasma
– Evaluates serine protease factors (II, IX, X, XI,XII) affected by heparin
Anti-Xa assay
Designed to examine proteolytic activity of factor Xa
Adverse effects of heparin
– Bleeding
– Heparin-induced thrombocytopenia (HIT)
Heparin-induced thrombocytopenia (HIT)
• Mechanism: immunogenicity of the complex of heparin with platelet
factor 4 (PF4)
• A systemic hypercoagulable state
• Characterized by venous and arterial thrombosis
• Related to the immune response to heparin
• Treatment: to discontinue heparin and administer DTI
Contraindications to the use of heparin
– Severe hypertension
– Active tuberculosis
– Ulcers of GI tract
– Patients with recent surgeries
Reversal of heparin action
protamine sulfate
Fondaparinux
• Synthetic pentasaccharide (administered s.c.)
• Binds to antithrombin to indirectly inhibit Factor Xa
– High-affinity reversible binding to antithrombin III
– Conformational change in the reactive loop greatly enhances antithrombin
basal rate of factor Xa inactivation
– Fondaparinux acts as an antithrombin III catalyst
Difference of fondaparinux from heparins
– Does not inhibit thrombin activity
– Rarely induces HIT
– Its action is not reversed by Protamine sulfate
Clinical indications of fondaparinux
– Prevention of deep vein thrombosis
– Treatment of acute deep vein thrombosis (in conjunction with Warfarin)
– Treatment of pulmonary embolism
Lepirudin
– Recombinant form of hirudin (which was originally purified from medicinal
leeches)
– Lepirudin is identical to natural hirudin except for substitution of leucine for
isoleucine at the N-terminal end of the molecule and the absence of a
sulfate group on the tyrosine at position 63
– Irreversible inhibitor of thrombin
Bivalirudin
– A synthetic, 20 amino acid peptide
– Reversible inhibitor of thrombin
– Also inhibits platelet aggregation
Argatroban
– A small molecular weight inhibitor
– Short-acting drug – used intravenously
Clinical indications for parenteral direct thrombin inhibitors (DTIs)
HIT Coronary angioplasty (bivalirudin and argatroban)
Adverse effects of parental DTIs
– Bleeding (should be used with caution as no antidote exists)
– Repeated lepirudin use may cause anaphylactic reaction
MOA of warfarin
– Inhibits reactivation of vitamin K, by inhibiting enzyme vit K epoxide
reductase
– Inhibits carboxylation of glutamate residues by GGCX (-glutamyl carboxylase) in prothrombin and factors VII, IX, and X, making them inactive
Proteins affected by carboxylation
– Factor II (protrombin)
– Hemostatic Factors VII, IX, and X
– Other proteins that function in apoptosis, bone ossification, extracellular
matrix formation, etc.
Carboxylation of glutamate residues
common mechanisms of post translational modification of proteins
converts hypo functional hemostatic factors into functional ones
Pharmacokinetics of warfarin
– Two stereoisomers: R and S
• S-isomer is 3 to 5-fold more potent
– R-warfarin is metabolized by CYP3A4, and some other CYP isoforms
– S-warfarin is metabolized primarily by CYP2C9
– OH-derivatives are pumped out of hepatocytes by ABCB1 transporter into
bile, excreted with bile
– Administered orally
– Has 100% bioavailability
– Delayed onset of action (12 h)
– Long half-life (36 hr)
– 99% of it is bound to plasma albumin (responsible for its small volume of
distribution and a long half-life)
– Correct warfarin dose varies widely from patient to patient
• Significant individual variability based on disease states and genetic make-up
• Multiple drug interactions
Clinical use of warfarin
– Used to prevent thrombosis or prevent/treat thromboembolism
– Atrial fibrillation
– Prosthetic heart valves
Adverse effects of warfarin
– Teratogenic effect (bleeding disorder in fetus, abnormal bone formation)
– Skin necrosis, infarction of breasts, intestines, extremities
– Osteoporosis
– Bleeding
PT/INR
– Prothrombin time (PT) – time to coagulation of plasma after the addition of
a Tissue Factor (TF or factor III) – used for the evaluation of the extrinsic
pathway
– International normalized ratio (INR) • 0.9-1.3 – normal • 0.5 – high chance of thrombosis • 4.0-5.0 – high chance of bleeding • 2.0-3.0 – range for patients on warfarin
Pharmacokinetic drug interactions with warfarin increasing PT
Amiodarone Cimetidine Disulfiram Fluconazole Metronidazole Phenylbutazone Sulfinpyrazone Trimethoprim-sulfamethoxazole
Pharmacokinetic drug interactions with warfarin decreasing PT
Barbiturates
Cholestyramine
Rifampin
Pharmacodynamic drug interactions with warfarin increasing PT
Aspirin (high doses)
Cephalosporins, third-generation
Heparin, argatroban, dabigatran, rivaroxaban, apixaban
Pharmacodynamic drug interactions with warfarin decreasing PT
diuretics
Vit K
Body factors increasing PT with warfarin
hepatic disease (reduced clotting factor synthesis) hyperthyroidism
Body factors decreasing PT with warfarin
hereditary resistance
hypothyroidism
Pharmacogenomics of warfarin
– VKORC1 (vit K epoxide reductase complex subunit 1) – responsible for 30% variation in dose (low and high dose haplotypes)
• High dose haplotype is more common in African Americans, they are more resistant to warfarin
• Low dose haplotype is more common in Asian American patients, they are less resistant to warfarin
– CYP2C9 – responsible for 10% variation in dose, mainly among Caucasian patients
Warfarin drug interactions - pharmacokinetic interactions
– CYP enzyme induction
– CYP enzyme inhibition
– Reduced plasma protein binding
Warfarin drug interactions - pharmacodynamic interactions
Synergism with other antithrombotic drugs
Competitive antagonism (vit K)
Clotting factor concentration (diuretics)
Advantages of warfarin
– Oral administration
– Long duration of action
– Drug clearance is independent of renal function
– Reversal of action strategy has been developed
• Vit K administration usually reverses Warfarin action in 12-24 hours
• If more rapid reversal is needed fresh frozen plasma or prothrombin
complex concentrate are given
Drawbacks of warfarin
– Very high dosing variability, maintaining optimal drug concentration is difficult
– This may lead to bleeding complications, such as intracranial
hemorrhages
– Require INR monitoring
Clinical use of NOAC - Factor Xa inhibitors
– Prevention of thromboembolism (Rivaroxaban and Apixaban)
– Treatment of thromboembolism
– Prevention of stroke in patients with atrial fibrillation
Advantages of NOAC - Factor Xa inhibitors
– Given orally
– Administered at fixed doses and do not require monitoring
– Shown non-inferiority compared with Warfarin (efficacy and bleeding
complications)
– Rapid onset of action as compared to warfarin
Drawbacks to NOAC - Factor Xa inhibitors
– No antidotes currently exist for direct Xa inhibitors
• In the Pipeline – Andexanet alfa (modified recombinant FXa with a higher affinity for FXa inhibitors as compared to natural FXa
– Excreted by kidneys; dose adjustment is needed in renal patients
Clinical use of NOAC- direct thrombin inhibitor
– To reduce the risk of stroke and systemic embolism in patients with non-
valvular atrial fibrillation
– Treatment of venous thromboembolism
Advantages of NOAC- direct thrombin inhibitor
– Predictable pharmacokinetics and bioavailability
– Fixed dosing and predictable anticoagulant action (no INR monitoring
required)
– Rapid onset and offset of action
– No interaction with P450-metabolized drugs
– Antidote approved by FDA in 2015
• Idarucizumab (Praxbind) – humanized antibody fragment that binds dabigatran with high affinity to prevent dabigatran inhibition of thrombin
Drawbacks of NOAC- direct thrombin inhibitor
– 80% renal excretion – may not be suitable in renal patients
MOA of aspirin
– Inhibition of cyclooxygenase
– Decreased TxA2 production
Clinical use of aspirin
Primary and secondary prevention of a heart attack and other vascular
events (ischemic stroke, arterial thrombosis of the limbs resulting in
intermittent claudication)
Adverse effects of aspirin
PUD
GI bleeding
MOA of blockers of ADP receptors
– Inhibition of AC by αi is relieved
– Increased production of cAMP
Pharmacogenomics of clopidogrel
– High variability of clopidogrel action
– Related primarily to metabolism by CYP2C19 isoenzyme
– Nonfunctional CYP2C19 allele is present in 50% Chinese, 34% African
Americans, 25% Caucasians, and 19% Mexican Americans
– Cytochrome P450 status does not affect the use of other ADP receptor antagonists
Clinical use of ADP receptor blockers
– Prevention of arterial thrombosis in stroke patients (Ticlopidine)
– Prevention of thrombosis in patients with ACS and recent AMI, stroke and
peripheral arterial disease (Clopidogrel, Prasugrel, Ticagrelor)
– Patients undergoing PCI and stenting (Prasugrel, Ticagrelor)
Adverse effects of Ticlopidine
- Thrombotic thombocytopenic purpura
- GI: nausea, dispepsia, diarrhea
- Bleeding
- Leukopenia
Adverse effects of Clopidogrel, prasugrel, ticagrelor
• Bleeding
• Dyspnea – Ticagrelor
• Less side effects that ticlopidine – they are preferred drugs over
ticlopidine
MOA of inhibitors of PDE
– Inhibition of cAMP degradation
– Levels of cAMP in platelets are increased
Clinical uses of inhibitors of PDE (adjunct anti platelet agents)
– Dipyridamole is used in combination with aspirin to prevent
cerebrovascular ischemia, and in combination with warfarin to prevent
thromboemboli in patients with prosthetic heart valves
– Cilostazol is primarily used to treat intermittent claudication
Clinical use of platelet glycoprotein (GP) receptor antagonists
– Prevention of thrombosis in unstable angina and other acute coronary
syndromes
– In patients undergoing percutaneous coronary angioplasty
– Often used in combination with other antiplatelet agents
– Administered by i.v. infusion because of short half-lives
Adverse effects of platelet glycoprotein (GP) receptor antagonists
– Hypotension
– Myalgia – Abciximab
– Thrombocytopenia (rare) – Abciximab and Tirofiban
Thrombolytic (fibrinolytic) drugs
Induce fibrinolysis (lyse fibrin in thrombi after they have formed)
General mechanism: activate endogenous fibrinolytic system by different mechanisms
Plasminogen – plasma zymogen that forms active enzyme upon cleavage of the peptide bond between Arg-560 and Val-561 by tPA or uPA
Plasmin – active serine protease that cleaves and degrades fibrin and other proteins (fibronectin, laminin, thrombospondin, vWf)
Types of fibrinolytic drugs
• Tissue-type plasminogen activator (tPA) – endogenous protein that cleaves
plasminogen, released by endothelium, needs fibrin as coactivator
• Urokinase-type plasminogen activator (urokinase, uPA) – endogenous protein,
produced in kidneys; a human enzyme directly converting plasminogen to
plasmin
• Streptokinase – protein released by -hemolytic Streptococci, forms the complex
with plasminogen, converts it into plasmin by a non-proteolytic mechanism
Clinical uses of thrombolytic drugs
- Acute embolic/thrombotic stroke (within 3 h)
- Acute myocardial infarction (within 3 to 6 h)
- Pulmonary embolism
- Deep venous thrombosis
- Ascending thrombophlebitis
Adverse effects of thrombolytic drugs
- Bleeding from systemic fibrinogenolysis (streptokinase, urokinase)
- Allergic reactions (streptokinase)
