Module 4 Pharmacology

Front 1

What is the main goal of anticoagulant therapy?

Back 1

prevent the activation of prothrombin (II) to thrombin (IIa)

Front 2

Source and size of heparin?

Back 2

-- commercial preps from porcine intestinal mucosa and bovine lung
-- naturally occurring infractionated heparin is a mixture of high molecular weight molecules (5,000-30,000 Daltons)
-- Low Molecular Weight (LMW) heparins which are isolated by fractionatin of naturally occuring heparin, have avg MW of 5,000D

Front 3

Heparin anticoagulant MOA?

Back 3

1. Circulating pritein antithrombin III is a weak inhibitor of activated clotting factors in the absence of heparin
2. When protease activity of the activated clotting factors attacks a specific peptide bond on ATIII, the clotting factor becomes irreversibly bound to ATIII. Thus ATIII is a "suicide" inhibitor of the activated clotting factors.
3. Binding of heparin to ATIII induces conformational change which makes this critical peptide bond of ATIII more accessible to the protease site of the activated clotting factor. Causes 1000x increase in rate of interaction btwn ATIII and the activated clotting factors
4. After ATIII-heparin cmplx is attacked by a clotting factor, the heparin is able to bind to another molec of ATIII; thus acts as catalyst in rxn
5. Heparin inhibits protease activity of clotting factors 2, 9, 10, 11, and 12.

Front 4

In which circumstances does heparin's anticoagulant effect occur?

Back 4

It exerts an anticoagulant effect in vivo AND invitro, and the effect in either case is IMMEDIATE.

Front 5

How do we guage the pharmacodynamic effect of heparin?

Back 5

We measure the actiated partial thromboplastin time (aPTT) which measeures the activity of clotting factors that are intrinsic to plasma (primarily thrombin, factor IIa)

Front 6

Does Heparin normally affect the value of prothrombin time?

Back 6

It normally does not affect PT, so the anticoagulant activity of warfarin can be quantified in the presence of heparin

Front 7

How do we reverse the effects of heparin?

Back 7

Its ability to inhibit the intrinsic clotting pathway is reversed by PROTAMINE SULFATE.

- binds avidly to heparin and prevents its interaction w/ ATIII
- protamine sulfate itself possesses some anticoagulant activity, so no more than 50mg should be given
- dose given by slow IV injection, and the antiheparin effects are immediate

Front 8

Name the LMW heparins?

Back 8

ardeparin
dalteparin
enoxaparin

Front 9

LMW heparin MOA?

Back 9

-- They primarily inhibit activatied factor 10 (Xa)

-- exert little effect against thrombin (IIa)

-- normal heparin is sufficient molec size to bind both ATII and IIa simltaneously, but LMW heparin are too small to do this

Front 10

LMW heparin reversal?

Back 10

The effects of LMW heparins are only partially reversed by protamine sulfate

Front 11

Pharmacokinetics and pharmacodynamic of heparin?

Back 11

1. Cannot be given p.o.
2. is given i.v. by bolus injection, constant infusion, or by s.c. injection
3. is cleared by the reticuloendothelial system
4. half life increases as dose is increased -- HL of 100U dose is 1h, vs HL of 800U dose is 5h.
5. Goal of therapy is to increase the aPTT to 1.5-2.5 the normal value
6. Goal achieved by giving i.v. loading dose followed by i.v. infusion of maintenance dose
7. The aPTT should be meas every 6h and infusion rate adjusted until desired steady-state increase in the aPTT is achieved
8. Heparin is given s.c. every 8-12h during long-term trtmt
9. The LMW heparins have little effect on aPTT, so the aPTT is not measured during their use

Front 12

Heparin resistance -- causes?

Back 12

1. Increased heparin clearance -- occurs in pulmonary embolism

2. Genetic antithrombin deficiency

3. Acquired antithrombin deficiency = nephrotic syndrome, hepatic cirrhosis, DIC

4. Acute phase proteins can bind to heparin to render it inactive

Front 13

Other pharmacologica effects of heparin?

Back 13

1. Antiplatelet effect -- blocks platelet adhesion by maintaining the electronegativity of the damaged vascular wall; may increase bleeding time and has additive effect w/ aspirin

2. Releases lipoprotein lipase into circulation -- hydrolyzes TGs to glycerol and free f.a., thus it "clears" the postprandial hyperlipidemia caused by chylomicrons rich in TGs

Front 14

Therapeutic uses of UNfractionated heparin?

Back 14

1. prophylaxis of post-op DVT

2. Trtmt of DVT and PE

3. Prophylaxis during PTI

4. Relief from chest pain in pts w/ unstable angina

5. Anticoag for i.v. caths, hemodialysis and cardiopulmonary bypass (need BIG dose for CP bypass)

6. If anticoag must be used during pregnancy, heparin is the DOC b/c it does NOT cross the placental barrier, have teratogenic effects or cause premature labor or fetal death. D/C 24h before delivery

Front 15

Therapeutic uses of LMW heparins?

Back 15

1. prophylaxis of post-op DVT

2. Trtmt of ischemic stroke

3. Acute coronary syndrome

4. Anticoag during hemodialysis

Front 16

Contraindications for heparin and LMW heparins?

Back 16

1. spinal anesthesia or lumber puncture

2. bleeding

Front 17

Adverse effects of heparins

Back 17

1. Bleeding: less incidence w/ LMW
2. reversible heparin-induced thrombocytopenia (HIT)
-- caused by IgG Ab that recog platelet factor 4 bound to heparin
-- lack of platelets puts patients at risk
-- occurs in 1-5% of patients after 1-2wks of heparin therapy
-- monitor platelet count during heparin trtmt (<150,000 means trouble)
-- incidence much less w/ LMW heparins

3. Osteoporosis w/ fractures after continuous trtmt or 3+ months

4. Slight elevation of plasma K from inhibition Aldo synth; may be problem if patient taking ACE inhibitor

Front 18

Advantages of LMW over unfractionated?

Back 18

1. kinetics not altered by binding to plasma proteins, acute phase proteins, endothelial cells, or macrophages; removes one major cause heparin resistance

2. increased s.c. F and longer half-life

3. cleared by kidney and not RE system

4. cause less thrombocytopenia b/c fewer antiheparin Ab formed

5. use decreases length of hospitalization after surgery b/c patients can admin s.c. from home

6. When given s.c. q12h or qd, they produce a predictable reproducible antigoag effect w/out need for lab monitoring of hemostasis*****

DRAWBACK: expensive and not yet covered by Medicare

Front 19

Danaproid properties and MOA?

Back 19

1. Consists of the non-heparin glycosaminoglycan heparan extracted from porcine intestinal mucosa

2. An indirect factor Xa inhibitor -- promotes binding of ATIII to factor Xa, bit does not affect aPTT or PT

Front 20

Danaproid therapeutic use?

Back 20

1. Used in patients w/ heparin-induced thrombocytopenia

2. Approved for trtmt of DVTs

Administered s.c. and half-life 24h and is increased in patients w/ renal failure

NO ANTIDOTE

Front 21

Fondaparinux properties and MOA?

Back 21

1. a small synthetic pentasaccharide

2. An indirect factor Xa inhibitor -- requires presence of ATIII

3. Mimics site on heparin which binds ATIII to produce a predictable, stable antithrombotic effect

Front 22

Admin, F, half-life, effect on aPTT/PT, antidote?

Back 22

-- Injected s.c. w/ 100% F

-- half-life 17-21h and increases in pts w/ renal dysfxn

-- Little effect on aPTT, so aPTT cannot be used to monitor its effects on clotting

-- No effect on PT

-- NO ANTIDOTE

-- Appears to be superior to LMW heparins in the trtmt of ACS-similar risk reduction, but substantially less bleeding, re-infarction, and morbidity/mortality

Front 23

How do we monitor the effect of antifactor Xa cmpds?

Back 23

Antifactor Xa cmpds: LMW heparins, danapriod, fondaparinux

Point-to-care assay for Xa activity to monitor the effects of the cmpds

Front 24

Lepirudin properties and MOA?

Back 24

A direct inhibitor of thrombin (IIa) which is found in the salivary gland of the medicinal leech.

DOES NOT depend on presence of ATII!!

Front 25

Therapeutic use of lepirudin?

Back 25

Used in pts w/ heparin induced thrombocytopenia (HIT)

Front 26

Lepirudin admin, half-life, antidote?

Back 26

-- Admin i.v. at a dose which increases the aPTT to 1.5-2.5 the normal value

-- half-life is 1.3h and is increased in pts w/ renal failure

-- NO ANTIDOTE

Front 27

Argatrobin properties, MOA?

Back 27

-- Small, synthetic molec which is a direct, competitive, reversible inhibitor of thrombin

-- inhibits soluble, fibrin-bound and clot-bound thrombin

-- inhibits platelet aggregation and TXA2 release in the presence of both free and clot-bound thrombin

Front 28

Argatrobin admin, half-life, aPTT/PT effect, antidote?

Back 28

-- given by i.v. loading dose followed by constant i.v. infusion

-- half-life of 40-50minutes

-- exhibits predictable dose-response curve and no dosage adjustment reqd for age, sex, or renal dysfxn

-- produces predictable increase in aPTT, and then the aPTT returns to normal w/in 1-2h after d/c the drug

-- It increases the PT and this fact complicates the interpretation of the INR in the presence of therapy w/ warfarin - if INR w/ warfarin alone is 2-3, it will be 4 if pt trtd w/ argatrobin

-- NO ANTIDOTE

Front 29

Therapeutic use argatrobin?

Back 29

used as anticoagulant in pts w/ DVTs and HIT

Front 30

Warfarin MOA?

Back 30

1. Clotting factors are not biologically active after they are formed by translation of mRNA in the liver
2. Clotting factors 2,7,9, and 10 require a post-transl gamma-carboxylation of 9 to 12 glutamate residues which is coupled to the oxidative metab of reduced VitK to its epoxide. Extra carboxyl gros needed to bind Ca for activation
3. Reduced VitK is regenerated from VitK epoxide via the enzyme VitK epoxide reductase, and warfarin inhibits this enzyme
4. depletion of reduced VitK eventually stops the post-transl modification of clotting factors 2, 7, 9, 10.

Front 31

How do we guage warfarin anticoag action?

Back 31

The half-life of factor 7 is the shortest (6h) of the four clotting factors affected, so we measure PT to guage clotting efficiency since this test measures the efficiency of clotting via the extrinsic pathway

-- PT is normalized to an international standard, so the value can be reported as the PT in seconds or as the International Normalized Ratio (INR) which is a number w/out units

Front 32

Conditions in which warfarin works?

Back 32

Only works in vivo -- NO ability to inhibit clotting in vitro

ONLY orally active drug that inhibits clotting!!!

Front 33

Warfarin effect on aPTT and PT(INR)?

Back 33

Therapeutic doses usually do not prolong the pTT

Overdose increases both the aPTT and the PT (INR) -- want INR around 2-3

Heparin does not normally affect PT(INR), so the anticoag effect of warfarin can be meas in presence of heparin

Front 34

How do we reverse the anticoag affect of warfarin?

Back 34

1. Phytonadione (reduced VitK)
-- can be admin i.v., s.c., or p.o.
-- effect is not immediate; reversal of anticoag effect appears after several hours
-- may take 24h for full reversal of the anticoag effect
-- repeated doses VitK req'd to produce normal hemostasis after overdose w/ warfarin

2. fresh frozen plasma -- provides fully-fxnal clotting factors

3. factor 9 concentrate -- contains large amts clotting factors 2, 7, 9, 10

Front 35

Pharmacokinetics, pharmacodynamics of warfarin?

Back 35

-- is 99% bound to plasma proteins, and numerous drug-drug interactions w/ warfarin involve its displacement from plasma proteins
-- biotransformed by CYP2C9, and drugs that induce CYP2C9 increase the clearance of warfarin and thus reduce its anticoag activity
-- drugs which inhibit CYP2C9 decrease the clearance of warfarin and thus increase its anticoag activity
-- crosses placental barrier and is teratogenic (X)
-- Onset of action is slow (2-3d) and max effect achieved at 5 days

Front 36

Goal of warfarin therapy?

Back 36

Increase INR to 2-3, and the INR should be measured monthly after patients are titrated to the desired value of INR

Front 37

Causes of warfarin resistance?

Back 37

1. Induction of CYP2C9

2. Hypoalbuminemia caused by hepatic dyxfxn or the nephrotic syndrome shortenbs the half-life of warfarin b/c more free drug avb in plasma for hepatic extraction and metabolism

-- cotreatment w/ anion exchange resins like cholestyramine and colestipol which bind warfarin and thus prevent its GI absorption

-- increased VitK intake

Front 38

Causes of increased anticoag response to warfarin?

Back 38

1. Inhibition CYP2C9

2. Destruction of gut bacteria w/ antibiotic drugs (gut flora produce 50% of the VitK we use to synth clotting factors)

3. cephalosporin antibiotic drugs partially inhibit VitK epoxide reductase, but this does not seem to be a problem clinically

4. decreased synth clotting factors due to hepatic dysfxn

Front 39

Therapeutic indications for use of warfarin?

Back 39

1. prophylaxis for DVTs -- espec after orthopedic surgery

2. prophylaxis of thromboembolism in pts w/:
-- atrial fib
-- prostetic cardiac valves
-- rheumatic mitral valve disease
-- unstable angina

Front 40

How do we transition from "in house" treatment w/ heparin to outpatient treatment with warfarin?

Back 40

1. a period of 4-5 days of overlapping therapy w/ heparin and warfarin is req'd before you can discharge the patient on p.o. therapy w/ warfarin

2. After initiating therapy w/ p.o. warfarin, it takes several days for the INR to increase to a value of 2-4 b/c the PT depends on factor 7 which has the shortest half-life of the 4 clotting factors

3. despite relative suppression of factor 7 after a few days, factors 10 and 2 have half-lives of 40 and 60 hours, respectively

4. Therefore, a pt could STILL be at risk for thromboembolism if heparin was d/c only two days after therapy w/ warfarin was started

5. recall that LMW heparin given s.c. q12h or qd produces a predictable and reproducible anticoag effect w/out need for lab monitoring, thus pts treated w/ LMW can be discharged sooner on p.o warfarin by allowing self-admin of LMW at home

Front 41

warfarin adverse effects?

Back 41

1. bleeding

2. teratogenesis and fetal death
-- ingestion by mother during first trimester pregnancy causes abnormal bone growth and nasal hypoplasia w/ stippled epiphyseal calcifications
-- adversely effects VitK-dependent synth of protein osteocalcin impt for mineralization of bone
-- abnormalities of CNS may also occur
-- intrauterine or neonatal death result from hemorrhage

3. cutaneous necrosis