Pharmacology: Block 5: Drugs For Coagulation Disorders

Front 1

What are two different types of heparin?

Back 1

Unfractionated (UFH)
LMWH (enoxaparin, dalteparin)

Front 2

c/c heparin and warfarin: what do they do?

Back 2

Warfarin inhibits the synthesis of functional clotting factors

Heparin inhibits activated clotting factors.

Front 3

What "starts off" the clotting cascade?

Back 3

The binding of tissue factor and VIIa (in the presence of calcium)

Front 4

Warfarin: what exactly does it do?

Back 4

Blocks vitamin K dependent γ-carboxylation of prothrombin (II) and factors VII, IX, X in the liver.

Inhibits the formation of active, reduced form vitamin K by antagonizing hepatic epoxide and quinone reductases. Kind of blocks the "recycling of vitamin K"

Front 5

Warfarin: what if you are CYP2C9*2 or CYP2C9*3?

Back 5

Patients that are CYP2C9*2 or CYP2C9*3 require LOWER doses of warfarin.

Front 6

Warfarin: enantiomers

Back 6

S: more potent, metabolized via CYP2C9

R: less potent, metabolized via CYP1A2, CYP3A4

Front 7

Warfarin: what is a simple way to think about how drugs could increase the plasma concentrations of warfarin?

Back 7

Warfarin is 95-99% bound to albumin. Anything that "bumps off" warfarin from albumin will change the concentration.

Front 8

Warfarin: what is the active constituent?

Back 8

The free, unbound drug. Warfarin is highly bound to albumin, so this may account for the small volume of distribution and for the long plasma half life (36 hours)

Front 9

Warfarin: excretion

Back 9

hepatic, feces. Patients with liver dysfunction are at a greater risk of toxicity

Front 10

Warfarin: absorption

Back 10

in the gut

Front 11

Warfarin: when is its anticoagulant effect observed? Antithrombotic effect?

Back 11

The anticoagulant (due to degradation of factor VII, half-life: 6 hours) effect is seen in 8-12 hours.

The antithrombotic effect is seen 3-5 days after initiation (due to inhibition of prothrombin, half-life of 60 hours).

This delay is related to the half-lives of the various clotting factors.

Front 12

What effect does giving larger doses of warfarin have?

Back 12

It speeds the onset of anticoagulation, but beyond a certain dose there is no increase.

Front 13

What types of drugs interact with warfarin?

Back 13

Anything that inhibits CYP metabolism
(cimetidine, amiodarone, fluconazole, TMP/SULFA) --> less degradation of warfarin --> potentiation of anticoagulation.

Anything that induce hepatic microsomal enzymes:
Phenytoin, rifampin, alcohol --> increased degradation of warfarin --> procoagulant state

Front 14

Warfarin and valproic acid

Back 14

Valproic acid can "bump" warfarin off of albumin

But there is a compensatory increase in clearance of warfarin with increased plasma concentration.

Front 15

What foods are high in vitamin K?

Back 15

Green leafy vegetables.

Front 16

Warfarin: INR goal target. How is the INR calculated?

Back 16

2.0-3.0

(PTpatient/PTcontrol)^ISI

Front 17

Warfarin: FDA approved test looks for polymorphisms in what two genes?

Back 17

CYP2C9, VKORC1

Front 18

Warfarin: what would you say about the theraputic index?

Back 18

It's narrow

Front 19

Warfarin: AE

Back 19

- Teratogenicity: can cross plactena and cause hemorrhage in the fetus. Can also cause bone abnormalities in the fetus.

- Hemorrhage

Front 20

Warfarin: antidotes

Back 20

- vitamin K1 (phytomenadione)

- FFP

- Clotting factor concentrate containing factor IX

Front 21

warfarin: risk of hemorrhage depends on what?

Back 21

Intensity and duration of therapy.

Front 22

Heparin: MOA

Back 22

Heparin binds to antithrombin III (AT III) and increases its affinity for thrombin, IXa, Xa by 1000x. Heparin is a catalyst in this reaction.

Front 23

c/c unfractionated (high molecular weight) heparin with LMW heparin: effects on which clotting factors, efficacy, etc.

Back 23

HMWH binds to BOTH thrombin and antithrombin. Thrombin (IIa) > Xa + IXa


LMWH (enoxaparin, dalteparin) binds to ATIII and then selectively inactivates factor Xa. LMWH has much less affinity for thrombin. LMWH is four times more active than HMWH. Xa, etc >> thrombin (IIa)

Front 24

c/c unfractionated heparin vs. LMWH: protamine sulfate as an antidote

Back 24

Protamine sulfate (a basic substance) works well for unfractionated heparin, but not very well for LMWH.

Front 25

Heparin: AE

Back 25

Hemorrhage, especially in elderly and with heavy alcohol intake.

Osteoporosis when taking heparin for several weeks. UFH > LMWH

Thrombocytopenia:
- Non-immune mediated (HAT)
- Immune mediated (HIT)

Front 26

HIT: pathogenesis

Back 26

Heparin --> antibodies to platelets --> thrombocytopenia

Heparin --> antibodies to platelets --> activation of platelets --> thrombosis

LMWH does not affect platelet aggregation!

Front 27

c/c LMWH and UFH: HIT

Back 27

LWMH does not affect platelet aggregation and therefore does not cause HIT!

HIT: 1-4% of patients on UFH for a minimum of 7 days will show signs.

If you see HIT, discontinue heparin and administer fondaparinux.

Front 28

Bivalirudin

Back 28

Anticoagulant: direct thrombin inhibitor

Synthetic 20 aa peptide

Reversible

Uses:
Unstable angina
Revascularization procedures.

AE: minor bleeding

"binds to thrombin and binds to receptor" (?)

Front 29

c/c Bivalirudin and heparin

Back 29

Bivalirudin:
+ Predictable anticoagulation effect (B doesn't bind to plasma proteins)
+ No HIT
- Excretion = urine, so half-life elimination increased as renal function diminishes. Renal dysfunction = reduction of dose needed.

Front 30

What is the most common thrombotic complication of heparin?

Back 30

Venous thrombosis

Front 31

The interaction between heparin and AT III is mediated by what structure/molecule?

Back 31

"By a unique pentasaccharide sequence"

Front 32

Fondaparinux, Idraparinux

Back 32

Have an identical sequence to heparin's unique pentasaccharide sequence.

MOA: indirectly inhibits thrombin generation/activity

Common AE: injection site hemorrhage

Serious AE: anemia, major bleeding.

Theraputic advantage: risk for heparin induced thrombocytopenia is greatly reduced.

Indraparinux has a longer half-life.

Uses: to prevent DVT (post orthopedic surgery), treatment of DVT, pulmonary embolism.

Front 33

Idraparinux: advantages

Back 33

Increased half-life
Once a week dosing regimen

Front 34

Name some anti-platelet agents and their MOAs

Back 34

Abciximab (REOPRO), Eptifibatide, Tirofiban: target the GPIIb/IIIa receptor complex to inhibit platelet aggregation.

Clopidogrel: ADP receptor antagonist

Aspirin: Irreversible inhibition of cyclooxygenase

Front 35

What are the drugs that are given for Acute coronary syndrome?

Back 35

Clopidogrel + aspirin.

Front 36

ASA inhibits COX leading to decreased production of what?

Back 36

Of thromboxane A2

Front 37

Clopidogrel: AE

Back 37

Pruritus, purpura, dyspepsia, rash.

Bleeding risk is low

Rates of minor and major bleeding were higher in patients treated with clopidogrel + aspirin vs. placebo + aspirin.

Can cause TTP (thrombic thrombocytopenic purpura)

Contraindicated in patients with peptic ulcer or intracranial hemorrhage.

Front 38

Clopidogrel: what type of drug, activated and metabolized where?

Back 38

Prodrug. Activated and metabolized in the liver via CYP2C19.

Dose adjustment may be needed for patients with hepatic disease.

Front 39

Clopidogrel: drug-drug interactions

Back 39

Any substrate of CYP2C19

Inhibitors of CYP2C19 metabolism: PPIs (lansoprazole, rabeprazole), chloramphenicol, cimetidine, fluoxetine, ketoconazole, ticlopidine

Other anticoagulants

NSAIDs - Aspirin, naproxen, ibuprofen

Herbals: Cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng

Front 40

Name some thrombolytic agents (recombinant tissue plasminogen activators). Where is their site of action?

Back 40

Alteplase (Activase)
Reteplase (RETAVASE)
Tenecteplase (TNKase)

Site of action = clot (fibrin)

Front 41

Tissue plasminogen activators: MOA

Back 41

cleaves plasminogen to active plasmin --> lysis of clot matrix.

Front 42

c/c Alteplase, Reteplase, Tenecteplase: half-lives, dosing, excretion

Back 42

Tissue plasminogen activator

Half-life: 5-10 min
Hepatic metabolism
Low antigenicity
High fibrin specificity
Low half-life


Reteplase and Tenecteplase: have a longer half life - allow for bolus dosing!

Front 43

What drug is used to inhibit fibrinolysis?

Back 43

Aminocaprocic acid (EACA)

Lysine analog that competes with lysine for binding sites on plasminogen and plasmin.

Blocks interaction of plasmin with fibrin

Main action mediated through inhibition of plasminogen activators rather than exerting antiplasmin activities.

If administered IV, need slow dosing to prevent hypotension.