Pbl Exam 9 Case 5-2

Front 1

1. Apsirin

Back 1

MOA: Covalently inhibits platelet COX, thereby blocking TxA₂ generation and inhibiting platelet granule release reaction and platelet aggregation

PURPOSE: Prophylaxis against TIA, MI, and thromboembolic disorders; Treatment of acute coronary syndrome; Prevention of reocclusion in coronary revascularization and stent; Arthritis, juvenile arthritis, rheumatic fever; mild pain or fever

ADVERSE: GI bleeding, acute renal insufficiency, thrombocytopenia, hepatitis, angioedema, asthma, Reye's syndrome; tinnitus, dyspepsia, occult bleeding, prolonged bleeding time, rash

CONTRA: NSAID-induced sensitivity reactions; children with chickenpox of flu-like syndrome; G6PD deficiency; bleeding disorders such as hemophilia, vWF disease, or ITP.

Front 2

2. Therapeutic considerations for aspirin (5)

Back 2

1. Inhibits COX-1 and COX-2 nonselectively
2. Use cautiously in pts with GI lesions, impaired renal function, hypothrombinemia, vitamin K deficiency, TTP, or hepatic impairment.
3. Coadministration w/aminoglycosides, bumetanide, capreomycin, cisplatin, erythromycin, ethacrynic acid, furosemide, or vancomycin may potentiate ototoxic effects
4. Coadminstration with ammonium chloride or other urine acidifiers may lead to aspiring toxicity
5. Aspirin antagonizes uricosuric effects of phenylbutazone, probenecid, and sulfinpyrazone; avoid these combos.

Front 3

3. What is dipyridamole?

Back 3

Dipyridamole is an inhibitor of platelet phosphodiesterase that decreases platelet aggregability. Dipyridamole by itself has only weak antiplatelet effects, and is therefore usually administered in combo with warfarin or aspirin.

The combo of dipyridamole and warfarin can be used to inhibit thrombus formation on prosthetic heart vales, while the combo of it with aspirin can be used to reduce the likelihood of thrombosis in pts with a thrombotic diathesis.

*May paradoxically induce angina by causing the coronary steal phenomenon.

Front 4

4. Dipyridamole

Back 4

MOA: Inhibit platelet cAMP degradation and thereby decrease platelet aggregability

PURPOSE: Prophylaxis against thromboembolic disorders; alternative to exercise in thallium myocardial perfusion imaging

ADVERSE: Exacerbation of angina (IV route), rare MI, rare ventricular arrhythmia, rare bronchospasm, abnormal ECG, hypotension, abdominal discomfort, dizziness, headache

CONTRA: Hypersensitivity

NOTES: Weak antiplatelet effect; usually administered in combo with warfarin or aspirin; has vasodilatory properties; may paradoxically induce angina by causing the coronary steal phenomenon.

Front 5

5. What is ticlopidine and clopidogrel?

Back 5

Both ticlopidine and clopidogrel irreversibly inhibit the ADP dependent pathway of platelet activation and have antiplatelet effects in vitro and vivo.

They are thought to act by covalently modifying and inactivating the platelet P2Y (ADP) receptor, which is physiologically coupled to the inhibition of adenylyl cyclase.

Front 6

6. Ticlopidine

Back 6

MOA: Ticlopidine is a produg that requires conversion to become active. It covalently modifies platelet ADP receptor; thereby preventing receptor signaling and irreversibly inhibition ADP-dependent platelet activation pathway.

PURPOSE: Secondary prevention of thrombotic strokes in pts intolerant of aspirin; Prevention of stent thrombosis in combo with aspirin.

ADVERSE: Aplastic anemia, neutropenia, TTP; pruritus, rash, dyspepsia, abnormal LFTS, dizziness

CONTRA: Active bleeding disorder, neutropenia, thrombocytopenia; severe liver dyfunction

NOTES: ***Use is limited by associated myeloctoxicity; requires a loading dose to achieve immediate antiplatelet effect.

Front 7

7. Clopidogrel

Back 7

MOA: Prodrug that requires P450 2A4 to the active drug form; covalently modifies platelet ADP receptor, thereby preventing receptor signaling and irreversibly inhibiting ADP-dependent platelet activation pathway

PURPOSE: Secondary prevention of atherosclerotic events in pts with MI, stroke, or peripheral vascular disease; Acute coronary syndromes; Prevention of stent thrombosis in combo with aspirin

ADVERSE: Afib, heart failure, erythema multiforme, GI hemorrhage in combo with aspirin, very rare anemia or neutropenia, rare intracranial hemorrhage, abnormal renal function; chest pain, edema, hypertension, purpura, rare LFTs, GI discomfort, arthralgia, dizziness

CONTRA: Active bleeding disorder

NOTES: *More favorable adverse effect profile that ticlopidine; significantly less myelotoxic than ticlopidine; requires a loading dose to achieve immediate antiplatelet effect.

Front 8

8. What is eptifibatide?

Back 8

Eptifibatide, the GPIIb-IIIa receptor antagonist, is a highly efficacious inhibitor of platelet aggregation. A synthetic peptide, eptifibatide antagonizes the platelet GPIIb-IIIa receptor with high affinity.

This drugs has been used to reduce ischemic events in pts undergoing percutaneous coronary intervention and to treat unstable angina and non-ST elevation MI.

Front 9

9. Eptifibatide

Back 9

MOA: Bind to platelet receptor GPIIb-IIIa and thereby prevent binding of fibrinogen and other adhesive ligands.

PURPOSE: Acute coronary syndromes; percutaneous coronary intervention

ADVERSE: Major bleeding, intracerebral hemorrhage, thrombocytopenia; hypotension, bleeding

CONTRA: History of bleeding diathesis or recent abnormal bleeding; concomitant administration of a secondary glycoprotein IIb-IIIa antagonist; recent major surgery, recent stroke or history of hemorrhagic stroke, Intracranial hemorrhage, mass, or AV malformation; severe uncontrolled hypertension

NOTES: Avoid coadmin w/other GPIIb-IIIa antagonists; minimize use of arterial and venous punctures, urinary catheters, and nasotracheal and nasogastric tubes

Front 10

10. What is abciximab?

Back 10

Chimeric mouse human monoclonal antibody directed against human GPIIb/IIIa receptor.

Binding is essentially irreversible w/dissociation half time of 18-24 hrs.

Reduces both long term/short term ischemic events in patients undergoing high risk percutaneous surgery (i.e. coronary artery)

Front 11

11. Abciximab

Back 11

MOA: Chimeric mouse human monoclonal antibody directed against human GPIIb/IIIa receptor; prevents binding of fibrinogen and other adhesive ligands

PURPOSE: Same as eptifibatide

CONTRA: Same as eptifibatide

NOTES: Same therapeutic considerations as eptifibatide; Adding abciximab to conventional antithrombotic therapy reduces both long-term and short-term ischemic events in pts undergoing high risk coronary angioplasty

Front 12

12. What is tirofiban?

Back 12

Tirofiban is a nonpeptide tyrosine analogue that reversibly antagonizes fibrinogen binding to the platelet GPIIb-IIIa receptor.

Approved for use in patients w/acute coronary syndromes.

Front 13

13. Tirofiban

Back 13

MOA: Bind to platelet receptor GPIIb-IIIa and thereby prevent binding of fibrinogen and other adhesive ligands

PURPOSE: Acute coronary syndromes in pts undergoing angioplasty or atherectomy or managed medically

ADVERSE: Same as eptifibatide; additionally, coronary artery dissection is rarely observed

CONTRA: Same as eptifibatide

NOTES: Same therapeutic considerations as epitifibatide, except tirofiban is a nonpeptide tyrosine analogue

Front 14

14. What are the four main anticoagulant classes?

Back 14

1. Warfarin
2. Unfractionated and LMW heparins
3. Selective Factor 10a inhibitors
4. Direct thrombin inhibitors

Bleeding is an adverse effect common to all anticoagulants

Target various factors in the coagulation cascade thereby interrupting the cascade and preventing the formation of stable fibrin meshwork

Front 15

15. Warfarin

MOA, PURPOSE, ADVERSE

Back 15

MOA: Inhibit hepatic epoxide reductase that catalyzes the regeneration of reduced vitamin K, which is required for synthesis of biologically active coagulation factors 2, 7, 9, 10, and anticoagulant proteins C and S

PURPOSE: Prophylaxis and treatment of pulmonary embolism, DVT, systemic embolism after MI, or systemic embolism associated with Afib, rheumatic heart disease

ADVERSE: Cholesterol embolization syndrome, skin and other tissue necrosis, hemorrhage, hepatitis, hypersensitivity reaction

Front 16

16. Contraindications for warfarin

Back 16

1. Pregnancy
2. Hemorrhagic tendency
3. Bleeding tendency associated with active ulceration or bleeding due to mucosal lesions, cerebrovascular hemorrhage, cerebral or aortic aneurysm, pericarditis and pericardial effusion, bacterial endocarditis, recent eye, brain, or spinal surgery
4. Threatened abortion, eclampsia, preeclampsia
5. Regional or lumbar block anesthesia
6. History of warfarin-induced skin necrosis
7. Unsupervised pts with psychosis, senility, alcoholism, or lack of cooperation, and especially those with risk of falling

Front 17

17. Therapeutic considerations for warfarin

Back 17

1. Monitoring of PT requires
2. Drug-rug interactions must be considered; coadministration of warfarin with other albumin-bound drugs can increase the free (unbound) plasma concentrations of both drugs; coadministration of drugs that induce and/or compete for P450 metabolism can affect the plasma concentrations of both drugs
3. Warfarin should never be given to pregnant women b/c it can cause a hemorrhagic disorder and/or congenital defects in the fetus
4. Warfarin can cause skin necrosis as a result of widespread thrombosis in the microvasculature
5. For severe hemorrhage due to warfarin, pts should promptly receive fresh frozen plasma

Front 18

18. Review - again, how does warfarin work?

Back 18

Warfarin acts on the carboxylation pathway, not by inhibiting the carboxylase directly, but by blocking the epoxide reductase that mediates the regeneration of reduced vitamin K.

Because depletion of vitamin K in the liver prevents the carboxylation reaction required for synthesis of biologically active coagulation factors the onset of action of the oral anticoagulants parallels the half-life of these coagulation factors in the circulation.

Thus, the pharmacological effect of a single does of warfarin is not manifested for approx 18-24 hours.

Front 19

19. What is heparin?

Back 19

Heparin is a sulfated mucopolysaccharide stored in the secretory granules of mast cells. It is a highly sulfated polymer of alternating uronic acid and D-glucosamine.

Heparin molecules are highly negatively charged; indeed, endogenous heparin is the strongest organic acid in the human body.


Unfractionated heparin, which is often prepared from bovine lung and porcine intestinal mucosa, ranges in molecular weight from 5 to 30 kDA.

LMW heparins are prepared from standard heparin by gel filtration chromatography; their molecular weight range from 1 to 5 kDA

Front 20

20. How does heparin work?

Back 20

Depends on the presence of a specific plasma protease inhibitor, antithrombin III.

ATIII is essentially a suicide trap for serine proteases, and prevents the proteases from further participation in the coagulation cascade.

In the absence of heparin the binding reaction between the proteases and ATIII proceeds slowly.

Heparin, acting as a cofactor, accelerates the reaction by 1,000x.

Front 21

21. What are 2 important physiologic functions of heparin?

Back 21

1. It serves as a catalytic surface to which both ATIII and the serine proteases bind

2. It induces a conformational change in ATIII that makes the reactive site of this molecule more accessible to the attacking protease.

Front 22

22. Unfractionated heparin

Back 22

MOA: Combines with ATIII and inhibits secondary hemostasis via nonselective inactivation of thrombin (factor 2a), factor 10a, factor 9a, factor 11a, and factor 12a

PURPOSE: Prevention and tx of PE, DVT, cerebral thrombosis, or left ventricular thrombus; prevention of systemic embolism associated with MI; unstable angina; open heart surgery; DIC, maintain patency of IV catheters

ADVERSE: Hemorrhage, heparin-induced thrombocytopenia, hypersensitivity reactions including anaphylactoid rections; overly prolonged clotting time, mucosal ulceration, hematoma

Front 23

23. What are the contraindications for unfractionated heparin?

Back 23

1. Heparin-induce thrombocytopenia
2. Active major bleeding
3. Bleeding tendencies such as hemophilia, thrombocytopenia, or hepatic disease with hypoprothrombinemia
4. Suspected intracranial hemorrhage
5. Open ulcerative wounds, extensive denudation of skin
6. Conditions that cause increased capillary permeability
7. Bacterial endocarditis
8. Severe hypertension

Front 24

24. Unfractionated heparin therapeutic considerations

Back 24

1. There is a higher incidence of heparin-induced thrombocytopenia in pts receiving unfractionated heparin than in those getting LMW heparin
2. Antihistamines, cardiac glycosides, nicotine, and tetracyclines may partially counteract anticoagulant effect
3. Cephalosporins, penicillins, oral anticoagulants, and platelet inhibitors may increase anticoagulant effect
4. Discourage concomitant use of herbs such as dong quai, garlic, ginger, ginkgo, motherwort, and red clover due to increased risk of bleeding.

Front 25

25. What is LMW heparin?

Back 25

Have an avg of only 3-4 kDa, and contain fewer than 18 monosaccharide units.

They efficiently catalyze the inactivation of factor 10a by ATIII but less efficiently catalyze the inactivation of thrombin by ATIII.

LMW heparin has a 3x higher ratio of anti-10a to anti-thrombin activity than does unfractionated heparin.

LMW heparin is therefore a more selective therapeutic agent than unfractionated heparin.

Front 26

26 LMW heparins
(Enoxaparin, Dalteparin, Tinzaparin)

Back 26

MOA: Combine with ATIII and inhibit secondary hemostasis via relatively (3-fold) selective inactivation of factor 10a.

PURPOSE: Prevention and treatment of DVT (all LMW heparins); Treatment of acute coronary syndromes and adjunct to percutaneous coronary intervention

ADVERSE: Hemorrhage, thrombocytopenia, abnormal LFTs, anaphylactoid reaction, spinal hematoma; Edema, diarrhea, nausea, hematoma, normocytic hypochromic anemia, confusion, pain, dyspnea, fever, local irritation

CONTRA: Active major bleeding, heparin-induced thrombocytopenia; hypersensitivity

NOTES: Administered as weight-based subcutaneous injection; avoid excessive anticoagulation in pts with renal insufficiency

Front 27

27. How do you monitor LMW heparin therapy?

Back 27

These agents are relatively selective for anti-10a compared to anti-2a (antithrombin) activity.

They have higher therpeutic index than unfractionated heparin, especially when used for prophylaxis.

For this reason it is generally not necessary to monitor blood activity levels of LMW heparins; instead use a specialized assay for anti-factor 10a actvitiy.

Front 28

28. What is fondaparinux?

Back 28

Fondaparinux is a synthetic pentasaccharide molecule that contains the sequence of five essential carbs necessary for binding to ATIII and inducing the conformational change in antithrombin required for conjugation to factor 10a.

This agent is therefore a specific inhibitor of 10a, with negligible anti-2a (anti-thrombing) activity.

Approved for prevention and treatment of DVT and is available as a once daily subcutaneous injection.

It is excreted via the kidneys and should not be administered to patients with renal insufficiency.

Front 29

29. Fondaparinux

Back 29

MOA: Combine with ATIII and inhibits secondary hemostasis via highly selective inactivation of factor 10a

PURPOSE: Prophylaxis and treatment of DVT; prophylaxis and treatment of PE

ADVERSE: Hemorrhage, thrombocytopenia, abnormal LFTs, anaphylactoid rection, spinal hematoma, edema, diarrhea, nausea, hematoma, normocytic hypochomic anemia, confusion, pain, dyspnea, fever, local irritation

CONTRA: Active major bleeding; severe renal impairment; bacterial endocarditis

NOTES: Avoid excessive anticoagulation in pts with renal insufficiency; Fondaparinux use has not been associated with heparin induced thrombocytopenia

Front 30

30. What are the direct thrombin inhibitors?

Back 30

1. Lepirudin
2. Desirudin
3. Bivalirudin
4. Argatroban

These agents are specific inhibitors of thrombin, with negligible anti-factor 10a activity.

Front 31

31. What is Lepirudin?

Back 31

Lepuridin is a recombinant 65 AA derived from the medicinal leech protein hirudin.

It binds w/high affinity to two sites on the thrombin molecule, the enzymatic active site and a region of the thrombin protein that orients substrate proteins.

This binding prevents the thrombin mediated activation of fibrinogen and Factor 13.

***It is a highly effect anticoagulant because it can inhibit both free and fibrin-bound thrombin in devloping clots, and because lepirudin binding to thrombin is essentially irreversible.

Front 32

32. What is Desirudin?

Back 32

This is another recombinant formulation of hirudin, and has been approved for prophylaxis against DVT in patients undergoing hip replacement.

Front 33

33. What is Bivalirudin?

Back 33

Bilvalrudin is a synthetic 20 AA peptide that binds to both the active site and exosite of thrombin and thereby inhibits thrombin activity. Thrombin slowly cleaves an arginine-proline bond in bivalirudin, leading to reactivation of the thrombin. (Has a short half life - 25 min)

Approved for anticoagulation in patients undergoing coronary angiography and angioplasty, and may reduce rates of bleeding relative to heparin.

Front 34

34. Hirudin-related agents:
Lepirudin, Desirudin, Bivalirudin

Back 34

MOA: Bind directly to thrombin and thereby inhibits secondary hemostasis

PURPOSE: Heparin-induced thrombocytopenia (lepirudin); prophylaxis against DVT (desirudin); anticoagulation in pts undergoing coronary angiography and angioplasty (bivalirudin)

ADVERSE: Heart failure, GI hemorrhage; bleeding, abnormal LFTs, anaphylaxis, hypertension, hypotension, cerebreal ischemia, intracranial hemorrhage, peripheral nerve paralysis, facial nerve paralysis, hematuria, renal failure, extrinsic allergic respiratory disease, penumonia, sepsis, cutaneous hypersensitivity, anemia, fever

CONTRA: Active major bleeding, pregnancy, severe uncontrolled hypertension; severe renal impairment

NOTES: Dose adjustment is required in pts w/renal insufficiency b/c these agents are excreted via the kidneys

Front 35

35. What is argatroban?

Back 35

Argatroban is a small molecule inhibitor of thrombin that is approved for the treatment of patients with heparin induced thrombocytopenia (HIT).

Unlike other direct thrombin inhibitors, argatroban binds only to the active site of thrombin, and it also is excreted by biliary secretion.

Thus, it is safe to administer argatroban to patients with renal insufficiency.

Front 36

36. Argatroban

Back 36

MOA: Bind directly to thrombin and thereby inhibit secondary hemostasis

PURPOSE: Coronary artery thrombosis; prophylaxis in percutaneous coronary intervention; heparin-induce thrombocytopenia

ADVERSE: Cardiac arrest, cerebrovascular disorder, ventricular tachycardia, sepsis, hypotension

CONTRA: Active major bleeding, severe liver impairment

NOTES: Bind to active site but not exosite of thrombin; dose adjustment is required in pts with liver disease b/c argatroban is excreted in the bile.

Front 37

37. What is recombinant activated protein C (r-APC)?

Back 37

Endogenously activated protein C (APC) exerts an anticoagulant effect by proteolytically cleaving factors 5a and 8a. APC also reduces the amount of circulating plasminogen activator inhibitor 1, thereby enhancing fibrinolysis. Also, APC reduces inflammation by inhibiting the release of TNF-α by monocytes.

r-APC has been found to significantly reduce mortality in patients at high risk of death from septic shock, and the US FDA has approved r-APC for the treatment of patients with severe sepsis who demonstrate evidence of acute organ dysfunction shock, oliguria, acidosis, and hyoxemia.

Front 38

38. r-APC

Back 38

MOA: Proteolytically inactivates factors 5a and 8a, may also exert anti-inflammatory effect by inhibiting tumor necrosis factor production and blocking leukocyte adhesion to selectins

PURPOSE: Severe sepsis with organ dysfunction and high risk of death

ADVERSE: Hemorrhage

CONTRA: Active internal bleeding, intracranial mass, hemorrhagic stroke w/in 3 months, recent intracranial or intraspinal surgery or severe head trauma w/in 2 months; present of an epidural catheter; major trauma w/an increased risk of life-threatening bleeding

NOTES: Prolongs PTT but has little effect on PT.

Front 39

39. What is streptokinase?

Back 39

Streptokinase is a protein produced by β-hemolytic streptococci as a component of that organisms' tissue destroying machinery.

The pharmacologic action of streptokinase involves two steps: complexation and cleavage.

In complexation reaction, streptokinase forms a stable, noncovalent 1:1 complex with plasminogen which produces a conformational change in plasminogen that exposes this protein's proteolytically active site.

This complexed plasminogen can then proteolytically cleave other plasminogen molecules to form plasmin.

Front 40

40. Stroptokinase

Back 40

MOA: Proteolytically activate plasminogen to form plasmin, which digests fibrin to fibrin degradation products

PURPOSE: ST elevation MI, arterial thrombosis; DVT, PE, Intra-arterial or IV catheter occlusion

ADVERSE: Cardiac arrhythmia, cholesterol embolus syndrome, major bleeding, anaphylactoid reaction, polyneuropathy, non-cardiogenic pulmonary edema, hypotension, fever, shivering

CONTRA: Active internal bleeding or known bleeding diathesis; intracranial or intraspinal surgery or trauma w/in 2 months; cerebrovascular accident w/in 2 months; intracranial mass; severe uncontrolled hypertension

Front 41

41. What are some therapeutic considerations for streptokinase?

Back 41

Streoptokinase is a foreign bacterial protein that can elicit antigenic responses in humans upon repeated administration; *prior administration of streptokinase is a contraindication to use due to the risk of anaphylaxis.

Thrombolytic actions of streptokinase are relatively nonspecific and can result in systemic fibrinolysis.

Front 42

42. What is recombinant tissue plasminogen activator (t-PA) or (alteplase)?

Back 42

Generically referred to as alteplase approved for use in those with ST elevation MI or life threatening pulmonary embolism.

Also approved for the treatment of acute ischemic stroke.

Its use is contraindicated in patients who have had a recent hemorrhagic stroke.

Front 43

43. Alteplase (t-PA)

Back 43

MOA: t-PA binds to newly formed thrombi with high affinity, causing fibrinolysis at the site of a thrombus. Once bound to the thrombus, t-PA undergoes a conformational change that rends it a potent activator of plasminogen.

PURPOSE: Acute MI; acute cerebrovascular thrombosis; PE, central venous catheter occlusion

ADVERSE: Cardiac arrhythmia, cholesterol embolus syndrome, GI hemorrhage, rare allergic reaction, intracranial hemorrhage, sepsis

CONTRA: Same as streptokinase

NOTES: as with other thrombolytic agents, t-PA can generate a systemic lytic state and cause unwanted bleeding.

Front 44

44. Tenecteplase and reteplase

Back 44

MOA: Genetically engineered variants of t-PA with increased specificity for fibrin

PURPOSE: Acute MI

ADVERSE: Cardiac arrhythmia, cholesterol embolus syndrome, major bleeding, allergic reaction, anaphylaxis, intracranial hemorrhage, cerebrovascular accident

CONTRA: Same as streptokinase

NOTES: Longer half-life than t-PA; *tenecteplase is administered as a single weight-based bolus; *reteplase is administered as a double bolus.

Front 45

45. What are the 4 inhibitors of anticoagulation and fibrinolysis?

Back 45

1. Protamine
2. Aprotinin
3. Aminocaproic acid
4. Tranexamic acid

Front 46

46. Protamine

Back 46

MOA: Inactivates heparin by forming a stable 1:1 protamine:heparin complex

PURPOSE: Heparin overdose

AdVERSE: Bradyarrhythmia, hypotension, anaphylactoid reaction, circulatory collapse, capillary leak, noncardiogenic pulmonary edema, flushing, nausea, vomiting, dyspepsia

CONTRA: Hypersensitivity

NOTES: ***Protamine can also partially reverse the anticoagulant effect of LMW heparin, but it cannot reverse the anticoagulant effect of fondaparinux***

Front 47

47. Aprotinin

Back 47

MOA: Inhibits serine proteases, including plasmin, t-PA, and thrombin

PURPOSE: Reduce perioperative bleeding during coronary artery bypass graft surgery

ADVERSE: Heart failure, MI, shock, thrombotic disorder, anaphylaxis with re-exposure, cerebral artery occlusion, renal failure

CONTRA: Hypersensitivity

NOTES: ***At higher doses, aprotinin may also inhibit kallikrein and thereby paradoxically inhibit the coagulation cascade***; aprotinin may increase the risk of postoperative acute renal failure relative to other antifibrinolytic agents.

Front 48

48. Aminocaproic acid and tranexamic acid

Back 48

MOA: Analogues of lysine that bind to and inhibit plasminogen and plasmin

PURPOSE: Disorder involving the fibrinolytic system; hemorrhage from increased fibrinolysis, reduce perioperative bleeding during CABG

ADVERSE: Bradyarrhythmia, hypotension, thrombotic disorder, drug-induced myopathy (aminocaproic acid), rare renal failure

CONTRA: DIC; hypersensitivity

NOTES: May cause less acute renal failure relative to aprotinin

Front 49

49. What are the six statins?

Back 49

1. Lovastatin
2. Pravastatin
3. Simvastatin
4. Fluvastatin
5. Atorvastatin
6. Rosuvastatin

Front 50

50. Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, Rosuvastatin

Back 50

MOA: Inhibit HMG CoA reductase, the rate limiting enzyme in cholesterol synthesis; LDL ↓ 25-55%; HDL ↑ 5%; TAGS ↓ 10-25%

PURPOSE: Hypercholesterolemia; Familial hypercholesterolemia; Coronary atherosclerosis; Prophylaxis for coronary atherosclerosis

ADVERSE: Myopathy, rhabdomyolysis,hepatotoxicity, dermatomyositis; abdominal pain, constipation, diarrhea, nausea, headache

CONTRA: Active liver disease; pregnancy and lactation

NOTES: Statins are the DOC for lowering LDL

Front 51

51. Which statins are metabolized by P450 3A4?

Back 51

Lovastatin, simvastatin, and atorvastatin are metabolized by P450 3A4; inhibitors of P450 3A4 increase risk of myopathy.

Front 52

52. Which statins are not metabolized by P450 3A4?

Back 52

Fluvastatin is metabolized via a different cytochrome P450 system;

***Pravastatin and rosuvastatin are not metabolized by cytochrome P450s; consider choosing a statin not metabolized by P450s in pts who are concurrently taking drugs that are metabolized by P450s.

Front 53

53. Combination of statins with ________ results in an additive ↓ in LDL levels?

Back 53

Bile acid sequestrant or cholesterol absorption inhibitor results in additive decrease in LDL.

Examples are cholestyramine, colesevelam, colestipol, and ezetimibe.

Front 54

54. Combination of statins with _____ may be useful in pts with ↓LDL and ↑HDL?

Back 54

Combination of statins with niacin may be useful in pts with ↓LDL and ↑HDL; however, coadministration w/niacin increases the risk of myopathy.

Front 55

55. Coadministration of statins with ______ decreases statin clearance and raises plasma concentration of statins, which can induce rhabdomyolysis...?

Back 55

Gemfibrozil

Front 56

56. Cholestyramine, Colesevelam, Colestipol

Back 56

MOA: Bind to bile acids, preventing enterohepatic circulation - ↓ LDLs (8-24%) and ↑ HDLs (5%)

PURPOSE: Hypercholesterolemia; Pruiritus (cholestyramine only)

ADVERSE: ↑ TAG levels; bloating, dyspepsia, flatulence, bleeding diathesis secondary to vitamin K deficiency

CONTRA: Complete biliary obstruction; Hyperlipidemia types 2, 4, or 5 (hypertriglyceridemia)

NOTES: Lower LDL levels dose-dependently; increase HDL modestly

Front 57

57. Therapeutic considerations for cholestyramine, colesevelam, and colestipol

Back 57

1. ***Second line agents for lipid reduction; used mainly to treat hypercholesterolemia in young pts and pts for whom statins alone do not provide sufficient LDL reduction
2. Raise TAG levels
3. Significant bloating and dyspepsia limit pt compliance
4. Decrease absorption of fat soluble vitamins; bleeding may result due to vitamin K deficiency; bind certain drugs, such as digoxin and warfarin

Front 58

58. What is ezetimibe?

Back 58

Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver.

It does this by inhibiting its uptake thru the brush border protein NPC1L1.

This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

It ↓ LDL cholesterol by 19% and TAGs by 6% and ↑ HDL by 1.3%.

Front 59

59. Ezetimibe

Back 59

MOA: Decrease cholesterol transport from micelles into the enterocyte by inhibiting uptake thru brush border protein NPC1L1 - ↓ LDL cholesterol 19%; ↓ TAGs 6% ;↑ HDL 1.3%.

PURPOSE: Primary hypercholesterolemia; Familial hypercholesterolemia; Sitosterolemia (very rare)

ADVERSE: Elevated LFTs, myopathy, Dyspepsia, arthralgia, myalgia, headache

CONTRA: Active liver disease, persistently elevated LFTs when co-administered with a statin

Front 60

60. Therapeutic considerations for ezetimibe

Back 60

1. Modest LDL reduction; small effect on HDL and TAGs
2. Inhibition of cholesterol absorption by ezetimibe leads to a compensatory increase in hepatic cholesterol synthesis, partially offsetting the benefits of reduced cholesterol absorption; *By combining with a statin, this compensatory increase can be prevented.***
3. Ezetimibe is rapidly absorbed by enterocytes and circulates enterohepatically
4. Ezetimibe levels are increased by cyclosporine and fibrates

Front 61

61. Gemfibrozil and fenofibrate

Back 61

MOA: Agonists of peroxisome proliferator-activated receptor α(PPARα). ↓ TAGs and ↑ HDLs

PURPOSE: Isolated hypertriglyceridemia; hypertriglyceridemia w/low HDL, Type 3 dysbetalipoproteinemia

ADVERSE: Elevated LFTs, myopathy when coadministered w/a statin, arrhythmias, dyspepsia, myalgia, gallstones, xerostomia

CONTRA: Concomitant gemfibrozil and vervastatin; preexisting gallbladder disease; hepatic dysfunction; severe renal impairment

NOTES: DOC for ↑ TAGs; ***Fenofibrate has fever GI and myopathy adverse effects than gemfibrozil***

Front 62

62. When are gemfibrozil and fenofibrate used in combo with statins?

Back 62

Used in combo with statins for combined hyperlipidemia or when HDL cholesterol is decreased.

However, there is an increased risk of myopathy when combined with statins.

Also, fibrates increase warfarin levels.

Front 63

63. Niacin

Back 63

MOA: Niacin reduces free fatty acid release from adipose tissue (lypolysis) and increases plasma residence time for ApoAI; ↓ LDL and TAGs, ↑ HDLs

PURPOSE: Isolated low HDL; Low HDL with mildly elevated LDL or TAGs; Familial combined hyperlipidemia

ADVERSE: Hepatotoxicity, GI bleeding, Flushing, pruritus, hyperuricemia and gout, impaired insulin sensitivity, myopathy

CONTRA: Active liver disease, active peptic ulcer, arterial bleeding

NOTES: *Flushing occurs during first few weeks of use and can be prevented with aspirin; *Hyperuricemia occurs in 20% of pts and may precipitate gout; *Niacin use is associated with impaired insulin sensitivity.