Drugs Used In Thromboembolic Disorders Flashcards
3 major drug types used in thromboembolic disorders include anticoagulants, antiplatelet drugs, and thrombolytic (fibinolytic) drugs. There are two types of anticoagulants, parenteral or oral. What are the parenteral anticoagulants?
Indirect thrombin and factor Xa (FXa) inhibitors: unfractionated heparin (heparin sodium), low molecular weight heparin (enoxaparin, tinzaparin, dalteparin), and synthetic pentasaccharide (fondaparinux)
Direct thrombin inhibitors: lepirudin, bivalirudin, argatroban
3 major drug types used in thromboembolic disorders include anticoagulants, antiplatelet drugs, and thrombolytic (fibinolytic) drugs. There are two types of anticoagulants, parenteral or oral. What are the oral anticoagulants?
Coumarin anticoagulants: warfarin
Direct oral anticoagulants (DOAC): factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), direct thrombin inhibitor (dabigatran)
3 major drug types used in thromboembolic disorders include anticoagulants, antiplatelet drugs, and thrombolytic (fibinolytic) drugs. There are two types of anticoagulants, parenteral or oral. What are the antiplatelet drug families?
Inhibitors of thromboxane A2 synthesis:
Aspirin
ADP receptor blockers: Clopidogrel Prasugrel Ticlopidine Ticagrelor
Platelet glycoprotein receptor blockers:
Abciximab
Eptifibatide
Tirofiban
Inhibitors of phosphodiesterases:
Dipyridamole
Cilostazol
3 major drug types used in thromboembolic disorders include anticoagulants, antiplatelet drugs, and thrombolytic (fibinolytic) drugs. There are two types of anticoagulants, parenteral or oral. What are the thrombolytic drug classes?
Tissue-type plasminogen activator drugs:
Alteplase
Reteplase
Tenecteplase
Urokinase-type plasminogen activator:
Urokinase
Streptokinase preparations:
Streptokinase
Which category of drugs is primarily used to prevent clots from forming in the arteries (aka white thrombi)?
Antiplatelet drugs
Which category of drugs is primarily used to prevent clots from forming in the venous system and heart (red thrombi)?
Anticoagulants
MOA of indirect thrombin and FXa inhibitors
Indirect thrombin and factor Xa (FXa) inhibitors: unfractionated heparin (heparin sodium), low molecular weight heparin (enoxaparin, tinzaparin, dalteparin), and synthetic pentasaccharide (fondaparinux)
Bind plasma serine protease inhibitor ANTITHROMBIN III
Antithrombin III inhibits several clotting factor proteases, especially thrombin IIa, IXa, and Xa
In the absence of _______, protease inhibition reactions are slow, when it is present it increases antithrombin III activity by 1000-fold
Heparin
MOA of high molecular weight heparin vs. low molecular weight heparin vs. fondaparinux
HMW heparin = inhibits the activity of both thrombin and factor Xa
LMW heparin inhibits factor Xa with little effect on thrombin
Fondaparinux inhibits factor Xa activity with no effect on thrombin
Clinical use of HMW vs. LMW heparin
They have practically equal efficiency in several thromboembolic conditions
LMW have increased bioavailability from the SC injection site and allow for less frequent injections and more predictable dosing
[note they are very hydrophilic and must be given IV or SC]
Used to tx disorders secondary to red (fibrin-rich) thrombi and reduce the risk of emboli — protects against embolic stroke and PE, given to pts with DVT and atrial arrhythmias, prevention of emboli during surgery, heparin locks prevent clots from forming in catheters
Describe monitoring of pts on heparin
Activated partial thromboplastin time (aPTT) — measures the efficacy of the intrinsic (contact activation) pathway and a common pathway. In order to activate the intrinsic pathway, phospholipids, activator, and Ca are mixed with pts 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) — systemic hypercoagulable state d/t immunogenicity of the complex of heparin with platelet factor 4 (PF4); characterized by venous and arterial thromboses
Contraindications and methods for reversal of heparin
Contraindications: severe HTN, active TB, ulcers of GI tract, pts with recent surgeries
Reversal of heparin: protamine sulfate
MOA of fondaparinux
Binds to antithrombin to indirectly inhibit factor Xa
[High affinity reversible finding to antithrombin III; conformational change in the reactive loop greatly enhances antithrombin basal rate of factor Xa inactivation; thus fondaparinux acts a an antithrombin III catalyst]
T/F: unlike heparins, fondaparinux does not inhibit thrombin activity, rarely induces HIT, and is not reversed by protamine sulfate
True
Clinical indications for fondaparinux use
Prevention of DVT
Tx of acute DVT (in conjunction with warfarin)
Tx of PE
MOA of parenteral direct thrombin inhibitors
[Direct thrombin inhibitors: lepirudin, bivalirudin, argatroban]
Direct inhibition of the protease activity of thrombin
Lepirudin and bivalirudin are bivalent direct thrombin inhibitors (bind at both active site and substrate recognition site)
Argatroban binds only at the thrombin active site (small molecular weight inhibitor; short-acting drug — used IV)
Classify lepirudin and bivalirudin in terms of reversible vs. irreversible inhibition of thrombin
Lepirudin = irreversible inhibitor of thrombin
Bivalirudin = reversible inhibitor of thrombin; also inhibits platelet aggregation
Clinical indications and AEs for the direct thrombin inhibitors
[Direct thrombin inhibitors: lepirudin, bivalirudin, argatroban]
Indications: HIT, coronary angioplasty (bivalirudin and argatroban)
AEs: bleeding (no antidote exists!), repeated lepirudin use may cause anaphylactic reaction
Warfarin is the most commonly prescribed AC in the US. What is its MOA?
Inhibits reactivation of vitamin K, by inhibiting enzyme vitamin K epoxide reductase
Inhibits carboxylation of glutamate residues by gamma-glutamyl carboxylase (GGCX) in prothrombin and factors VII, IX, and X, making them inactive
List proteins affected by warfarin
Factor II (prothrombin)
Hemostatic factors VII, IX, and X
Other proteins that affect function in apoptosis, bone ossification, ECM formation, etc.
Note: carboxylation fo glutamate residues is one of the common mechanisms of posttranslational modification of proteins — converts hypofunctional hemostatic factors into functional ones
Describe potency and metabolism of the warfarin isomers
2 stereoisomers: R and S
S-isomer is 3-5x 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 and excreted with the bile]
T/F: warfarin has low bioavailability, short half life, and dosage is relatively consistent among pts
False!
Warfarin has 100% bioavailability, delayed onset of action, long half life (36h), and the correct dose varies widely from pt to pt based on disease state, genetic makeup, and drug interactions
Clinical use and AEs of Warfarin
Clinical use: prevent thrombosis or prevent/tx thromboembolism, atrial fibrillation, prosthetic heart valves
AEs: teratogenic effect (bleeding d/o in fetus, abnormal bone formation), skin necrosis, infarction of breasts, intestines, extremities; osteoporosis, bleeding
Warfarin dose is titrated based on what lab tests?
Prothrombin time (PT) — time to coagulation of plasma after addition of tissue factor (factor III); used for evaluation of extrinsic path
INR = international normalized ratio; 0.9 to 1.3 is normal, 0.5 has high chance of thrombosis, 4-5 has high chance of bleeding, 2-3 is the range for pts on warfarin
Pharmacogenomics affecting variability in warfarin action
VKORC1 — responsible for 30% variation in dose. High dose haplotype more common in african americans (more resistant to warfarin); Low dose haplotype more common in asian americans (less resistant to warfarin)
CYP2C9 — responsible for 10% variation in dose, mainly among caucasian pts
Pharmacokinetic factors that increase prothrombin time d/t interactions with warfarin
Amiodarone Cimetidine Disulfuram Metronidazole* Fluconazole* Phenylbutazone* Sulfinpyrazone* TMP-SMX
[* = specific to S-warfarin]
Pharmacodynamic factors that increase prothrombin time d/t interactions with warfarin
Drugs:
High dose ASA
3rd gen. Cephalosporins
Heparin
Other factors:
Hepatic dz (red.clotting factor synth)
Hyperthryoidism
Pharmacokinetic factors that decrease prothrombin time d/t interactions with warfarin
Barbiturates
Cholestyramine
Rifampin
Pharmacodynamic factors that decrease prothrombin time d/t interactions with warfarin
Drugs:
Diuretics
Vitamin K
Other factors:
Hypothyroidism
Advantages to warfarin use
Oral admin, long duration, drug clearance independent of renal function
Reversal strategy = Vitamin K admin. usually reverses w/i 12-24 hrs; if more rapid reversal is needed: FFP or prothrombin complex concentrate are given
Disadvantages to warfarin use
Very high dosing variability, maintaining optimal drug concentration is difficult
This may lead to bleeding complications, such as intracranial hemorrhage
Requires INR monitoring
MOA of DOACs (rivaroxaban, apixaban, edoxaban)
Oral factor Xa inhibitors
Clinical use of DOACs (rivaroxaban, apixaban, edoxaban)
Prevention or tx of thromboembolism
Prevention of stroke in pts with afib
Advantages vs. disadvantages of DOACs (rivaroxaban, apixaban, edoxaban)
Advantages: given orally, administered at fixed doses and do not require monitoring. Shown non-inferiority to Warfarin in terms of efficacy and bleeding complications. Rapid onset of action compared to warfarin.
Disadvantages: excreted by kidneys; dose adjustment is needed in renal pts
Dabigatran is a direct thrombin inhibitor; it was the first oral DOAC approved by the FDA. What is its clinical use?
To reduce the risk of stroke and systemic embolism in pts with non-valvular atrial fibrillation
Tx of venous thromboembolism
Advantages and disadvantages to dabigatran
Advantages (compared w/ other coumarin derivatives) — 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 (idarucizumab)
Disadvantage — 80% renal excretion, may not be suitable for renal pts
In terms of parenteral anticoagulant drugs, Fondaparinux and DTI do not have antidotes. What is the antidote for HMW and LMW heparins?
Protamine sulfate
Antidotes to oral anticoagulants: warfarin, DOAC FXa inhibitors, and DOAC DTI
Warfarin = vitamin K, prothrombin complex concentrate
DOAC FXa inhibitors = andexanet alfa
DOAC DTI = idarucizumab
Blood coagulation tests used for pts taken heparin, warfarin, DOAC FXa inhibitors, or DOAC-DTI
Heparins = aPTT, anti-Xa
Warfarin = PT-based (INR)
DOAC FXa inhibitors = anti-Xa
DOAC-DTI = diluted thrombin time (TT)
Aspirin MOA
Inhibition of cyclooxygenase
Decreased TxA2 production
Clinical use and AEs associated with ASA
Clinical use: primary and secondary prevention of a heart attack and other vascular events (ischemic stroke, arterial thrombosis of the limbs reulting in intermittent claudication)
AEs: peptic ulcer, GI bleeding
MOA of clopidogrel, ticlopidine, and prasugrel
Block ADP receptors — inhibition of AC by alpha-i is relieved —> increased production of cAMP
MOA of dipyridamole
Inhibits PDE — thus inhibits cAMP degradation —> levels of cAMP in platelets are increased
There is a high variability to clopidogrel action, related primarily to its metabolism by _____ isoenzyme. A non-functional version of this allele is present in 50% of ______, 34% of african americans, 25% in caucasians, and 19% of mexican americans. Cytochrome p450 status does not affect the use of other ADP receptor antagonists
CYP2C19; chinese
MOA of abciximab, tirofiban, and eptifibatide
Antagonists of platelet glycoprotein (GP) IIb/IIIa, which is an integrin that binds extracellular ligands: fibrinogen, vitronectin, fibronectin, and vWF
They specifically target the Arg-Gly-Asp (RGD) sequence and prevent binding of ligands to the GP IIb/IIIa receptor to inhibit platelet aggregation
Clinical use of antiplatelet drugs
Prevention of thrombosis in unstable angina and other acute coronary syndromes
Prevention of ischemic stroke and arterial thrombosis in peripheral vascular disease
In pts undergoing percutaneous coronary angioplasty and stenting
Inhibitors of phosphodiesterase are considered adjunct anti-platelet agents and used in combination with other antiplatelet agents or anticoagulants. One example is:
______ with ______ to prevent cerebrovascular ischemia
Dipyridamole; ASA
Inhibitors of phosphodiesterase are considered adjunct anti-platelet agents and used in combination with other antiplatelet agents or anticoagulants. One example is:
______ with ______ in pts with prosthetic heart valves
Dipyridamole; warfarin
______ is an antiplatelet drug primarily used to treat intermittent claudication
Cilostazol
MOA of thrombolytic (fibrinolytic) drugs
Activate endogenous fibrinolytic system by converting plasminogen to palsmin
[plasminogen is a plasma zymogen that forms active enzyme upon cleavage of the peptide bond between Arg-560 and Val-561 by tPA or uPA
Plasmin is an active serine protease that cleaves and degrades fibrin and other proteins (fibronectin, laminin, thrombospondin, vWF)
All fibrinolytic drugs activate plaminogen to plasmin; what are the 3 types of fibrinolytic drugs?
Tissue-type plasminogen activator (tPA) —endogenous protein that cleaves plasminogen released by endothelium; needs fibrin as coactivator (includes alteplase, reteplase, tenecteplase)
Urokinase-type plasminogen activator (uPA) — endogenous protein, produced in kidneys; a human enzyme directly converting plasminogen to plasmin (includes Urokinase)
Streptokinase — protein released by beta-hemolytic streptococci, forms the complex with plasminogen, converts it into plasmin by non-proteolytic mechanism (includes Streptokinase)
Clinical uses for thrombolytic drugs
Acute embolic/thrombotic stroke (w/i 3 hrs)
Acute MI (w/i 3-6 hrs)
Pulmonary embolism
DVT
Ascending thrombophlebitis
[tx with t-PA to break down the clot and open up artery; most effective w/i 3 hrs after embolic and thrombotic stroke. Can exacerbate the damage produced by hemorrhagic stroke]
AEs of fibrinolytic drugs
Bleeding from systemic fibrinogenolysis (streptokinase, urokinase)
Allergic reactions (streptokinase)
