Drugs Used In Thromboembolic Disorders Flashcards Preview

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1

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

2

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

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

4

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

5

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

Antiplatelet drugs

6

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

Anticoagulants

7

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

8

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

Heparin

9

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

10

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

11

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

12

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

13

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

14

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]

15

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

True

16

Clinical indications for fondaparinux use

Prevention of DVT

Tx of acute DVT (in conjunction with warfarin)

Tx of PE

17

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)

18

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

19

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

20

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

21

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

22

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]

23

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

24

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

25

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

26

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

27

Pharmacokinetic factors that increase prothrombin time d/t interactions with warfarin

Amiodarone
Cimetidine
Disulfuram
Metronidazole*
Fluconazole*
Phenylbutazone*
Sulfinpyrazone*
TMP-SMX

[* = specific to S-warfarin]

28

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

29

Pharmacokinetic factors that decrease prothrombin time d/t interactions with warfarin

Barbiturates
Cholestyramine
Rifampin

30

Pharmacodynamic factors that decrease prothrombin time d/t interactions with warfarin

Drugs:
Diuretics
Vitamin K

Other factors:
Hypothyroidism