Drugs Used In Thromboembolic Disorders Flashcards by Sarah Gillen

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

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Coumarin anticoagulants: warfarin

Direct oral anticoagulants (DOAC): factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), direct thrombin inhibitor (dabigatran)

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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

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Tissue-type plasminogen activator drugs:
Alteplase
Reteplase
Tenecteplase

Urokinase-type plasminogen activator:
Urokinase

Streptokinase preparations:
Streptokinase

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Which category of drugs is primarily used to prevent clots from forming in the arteries (aka white thrombi)?

Antiplatelet drugs

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Which category of drugs is primarily used to prevent clots from forming in the venous system and heart (red thrombi)?

Anticoagulants

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MOA of indirect thrombin and FXa inhibitors

Bind plasma serine protease inhibitor ANTITHROMBIN III

Antithrombin III inhibits several clotting factor proteases, especially thrombin IIa, IXa, and Xa

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In the absence of _______, protease inhibition reactions are slow, when it is present it increases antithrombin III activity by 1000-fold

Heparin

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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

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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

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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

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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

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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

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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]

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T/F: unlike heparins, fondaparinux does not inhibit thrombin activity, rarely induces HIT, and is not reversed by protamine sulfate

True

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Clinical indications for fondaparinux use

Prevention of DVT

Tx of acute DVT (in conjunction with warfarin)

Tx of PE

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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)

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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

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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

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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

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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

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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

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)