Coagulation Disorder Drugs - Sweatman 03.27.15

Question 1

What are the antiplatelet drugs? List their categories and names.

Answer 1

• COX inhibitors: aspirin, ibuprofen (reduce TxA2 production)
• ADP P2Y12 inhibitors: clopidogrel, ticlopidine, prasugrel
• Phosphodiesterase inhibitor: dypiridamole (reduces hydrolysis of cAMP and cGMP)
• Gp2b3a inhibitors: abciximab, eftifibatide, tirofiban
• Inhibitors of PAR-1: vorapaxar (blocks thrombin-induced platelet aggregation)

Question 2

What two processes does stimulation of platelet receptors trigger?

Answer 2

1. Activation of internal signaling pathways that lead to further activation and granule release
2. Capacity of the platelet to bind to other adhesive proteins/platelets

NOTE: both of these factors contribute to the formation of a thrombus

Question 3

What is Gp2b3a? How does it work?

Answer 3

• Major platelet integrin maintained in inactive conformation in unstimulated platelets -> functions as low-affinity adhesion receptor for fibrinogen
• Only expressed on platelets
• Ca-sensitive conformational change in EC domain => high-affinity binding of soluble plasma fibrinogen via complex network of inside-out signaling events
• Gp2b3a receptor a bidirectional conduit w/signaling (outside-in) occurring immediately after binding of fibrinogen -> platelet aggregation

Question 4

What are the contraindications to the use of platelet inhibitors?

Answer 4

• PMH incl. active pathological bleeding
• Use w/caution in pts who may be at risk of increased bleeding from trauma, surgery, or o/pathological conditions (especially GI or intraocular)
• If pt is to have elective sx, and antiplatelet effect not desired, drugs should be discontinued sufficient period of time to allow effects to dissipate (interval depends on persistence of antiplatelet action of the drug in question)

Question 5

What is the difference between the actions of ibuprofen and aspirin?

Answer 5

• Aspirin: irreversibly acetylates COX, rendering it inactive for the life of the platelet
  1. Platelet can’t recover functionality because no nucleus, but endothelial cells can recover and continue to release PGI2 (PLT aggregation INH)
  2. Very low doses will produce desired effect, and only risk of AEs is increased with higher dose, not clinical activity
• Ibuprofen: reversible inhibition

NOTE: both INH COX1 at low doses + 2 at high doses

Question 6

Do aspirin and ibuprofen affect PT and/or PTT?

Answer 6

No

Question 7

What is aspirin indicated for? What are its contraindications?

Answer 7

• Widely used for secondary prevention of CV events in pts with coronary artery, cerebrovascular, or peripheral vascular disease
• Contraindications: PMH of aspirin-induced bronchospasm

Question 8

What are the adverse effects of aspirin and ibuprofen?

Answer 8

• Dose-related effects in GI due to importance of PGs in homeostatic mechs in stomach and intestines
  1. Dyspepsia, erosive gastritis, ulcers w/bleeding and perforation
• Hepatic and renal toxicity with aspirin overdose (i.e., in attempted suicide
  1. Customary doses of 75-325mg once daily

Question 9

What is the MOA of Clopidogrel, Ticlopidine, and Prasugrel?

Answer 9

• Close structural congeners that inhibit binding of ADP to P2Y1 and P2Y12 receptors on platelets (GPCRs) via steric hindrance
  1. When activated by ADP, these receptors inhibit adenylyl cyclase, reducing cAMP, and inhibition of platelet activation
  2. Inhibition of EITHER receptor sufficient to block activation (don’t need to block both)
• Also inhibit Gp2b3a receptor activation, preventing fibrinogen binding)

Question 10

What are the clinical uses for Clopidogrel?

Answer 10

• Post-MI
• Stroke
• Established PAD
• Percutaneous coronary intervention (PCI): coronoary angioplasty to treat atherosclerosis
• PREFERRED AGENT IN ISCHEMIC HEART DISEASE

Question 11

What are the clinical uses for Ticlopidine?

Answer 11

• Generally used as second line treatment due to hematologic toxicities:
  1. Agranulocytosis, neutropenia, TTP, anemia, and thrombocytopenia
• Severe hematologic events most commonly during 1st 3 months of treatment
  1. These effects are not seen with the other purinergic receptor (P2Y1, 12) blocking agents

Question 12

What are the clinical uses for Prasugrel?

Answer 12

• Acute MI
• Arterial thromboembolism prophylaxis
• PCI
• Unstable angina

Question 13

How are Clopidogrel, Ticlopidine, and Prasugrel administered and metabolized?

Answer 13

• Oral drugs
• Clop and Pras are pro-drugs that require intestinal and hepatic metabolism for activation
• Poor 2C19 metabolizers at risk of reduced response to Clop -> genetic test available
• Ticlop active, but a metabolite is 5-10x more potent
• Hepatic/renal elim of products

Question 14

What is the MOA and clinical use of dypiridamole?

Answer 14

• MOA: phosphodiesterase inhibitor -> induces INC in cAMP concentration, blocking release of AA from membrane phospholipids, and reducing TxA2 activity
  1. Also directly stimulates release of prostacyclin, which induces adenylate cyclase activity, raising intraplatelet cAMP level, inhibiting aggregation
  2. Vasodilation of coronary vessels via accumulation of adenosine
• Clinical use: prophylaxis of thromboembolic event in pts with prosthetic heart valves (with warfarin)

Question 15

How is Dipyridamole metabolized? What are its contraindications/AEs?

Answer 15

• Oral/IV drug w/extensive hepatic glucuronidation and fecal elimination
• Contraindicated in hypotension (may exacerbate) and asthma (causes bronchospasm)
• Dose-related transient AEs resolve with continued therapy -> generally well tolerated

Question 16

What are the MOAs of Abciximab, Eptifibatide, and Tirofiban?

Answer 16

• All IV administered Gp2b3a receptor antagonists (max INH when >80% of receptors blocked by drug)
• Abciximab: humanized form of mAb binding arginine-glycine-aspartic acid (AGA) sequence (steric hindrance or conformational effect); only this one is Ab-based
• Epitifibatide: synthetic, cyclic heptapeptide derived from snake venom binding lysine-glycine-aspartic acid (LGA) sequence
• Tirofiban: nonpeptide inhibitor derived from tyrosine that is similar to, and binds like, abciximab

Question 17

What are the utility, onset, and persistence of Abciximab, Eptifibatide, and Tirofiban?

Answer 17

• Utility: unstable angina, percutaneous transcutaneous coronary angioplasty
• Onset: rapid, following IV admin
• Persistence: whereas Eptifibatide and Tirofiban actions are over 4-hrs after stopping admin, abciximab-bound platelets persist for up to 2 weeks
• NOTE: Gp2b3a binding fibrinogen results in cross-linking between platelets, and is final common pathway of platelet aggregation

Question 18

What are the major issues with Abciximab, Epitifibatide, and Tirofiban?

Answer 18

• Major issue for all 3 drugs -> RISK OF BLEEDING, especially in susceptible individuals
  1. Low risk of anaphylaxis with all 3
• Human anti-chimeric Ab formation to abciximab could cause thrombocytopenia (<5% incidence); lesser incidence (<1-2% with the other drugs)

Question 19

What is Vorapaxar?

Answer 19

• Oral drug w/slower onset than Gp2b3a inhibitors
• Antagonizes protease-activated receptor-1 (PAR-1), which is stimulated by thrombin
• Elimination T(1/2) of 8 days
  1. Significant platelet inhibition persists for up to 4 weeks (effectively irreversible) -> holding a dose will do nothing to correct bleeding event or reduce risk
• Hepatic metabolism (3A4): fecal elim of products
• Major AE increased risk of bleeding

Question 20

Why are herbal product interactions important? List some.

Answer 20

• # of herbal products possess antiplatelet activity or induce platelet aggregation -> careful monitoring of clinical/lab data
• Ginkgo biloba: antiplatelet properties
• Ginger: inhibits thromboxane synthetase, a platelet aggregation inducer

Question 21

What are the anticoagulant categories and drugs?

Answer 21

• Indirect thrombin inhibitors: heparin (protamine sulfate antidote)
• Direct thrombin inhibitors: dabigatran, bivalirudin, lepirudin
• Factor Xa inhibitors: enoxaparin, apixaban, rivaroxaban, fondaparinux
• Inhibitors of clotting factor synthesis: warfarin (prothrombin complex, phytonadione, Vit K1 antidotes)

Question 22

What is the MOA of heparin?

Answer 22

• 1/3 w/unique pentasaccharide seq w/high affinity binding to ATIII -> conformational change in ATIII, accelerating inactivation of thrombin (most sensitive to INH by heparin; 2a), 10a, and 9a
• Heparin a template to which thrombin and ATIII bind to form ternary complex
• Inactivation of Xa doesn’t require heparin/ATIII complex formation and occurs via binding of ATIII to factor Xa

Question 23

Why is the size of the heparin molecule important?

Answer 23

• Must be > 18 monosaccharides to bind thrombin and ATIII simultaneously
• Low molecular weight heparin (LMWH), enoxaparin, differs from heparin b/c unable to accelerate inactivation of thrombin by ATIII, but retains ability to catalyze the inactivation of factor Xa by ATIII
• This discussion only includes enoxaparin, but other preparations, such as dalteparin, are available

Question 24

What is heparin?

Answer 24

• Glycosaminoglycan chains of alternating residues of D-glucosamine and uronic acid
• 5K-30K Daltons
• Derived from porcine or bovine tissue, and available as Ca or Na salt

Question 25

What are the similarities/differences b/t heparin and LMWH in regards to half-life, effects, major events, and when they are used?

Answer 25

• IV T(1/2): H- 2 hrs, L- 4 hrs
• Effects: H- variable, L- predictable
• Major events: H- frequent bleeding, L- possibly less frequent bleeding
• Used in: H- hospital, L- hospital/outpatient

NOTE: numerous studies show no significant reduction in risk of thromboembolism or mortality in LMWH vs. heparin

Question 26

How is heparin metabolized and eliminated?

Answer 26

• Depolymerization and desulfation to inactive products -> longer T(1/2) with hepatic cirrhosis
• Products and some parental drug eliminated renally
  1. Renal insufficiency increases T(1/2)

Question 27

What are the major AEs produced by heparin products?

Answer 27

• Chief complaint is bleeding
• May be antigenic b/c obtained from animal sources: chills, fever, urticaria, anaphylactic shock
• Thrombocytopenia (HIT) common in hospitalized patients (30% of pts on unfractionated heparin; rarely observed with enoxaparin)
  1. Discontinue if problems become severe and substitute another anticoagulant
• Abnormal liver function tests and osteoporosis reported w/long-term treatment

Question 28

How is heparin monitored and dosed?

Answer 28

• Monitoring: aPTT test: goal is 1.5-2.5x normal value
  1. If too high, slow infusion rate or briefly discontinue (short T(1/2), so drug levels decline rapidly)
  2. Extreme circumstances: protamine sulfate or whole body plasma given to block action
• Dosing: Q6 hr first day, and after dose change (prolonged aPTT does not occur w/LMWH)

Question 29

Why does LMWH have a lower impact on aPTT?

Answer 29

• Because it ony inhibits Xa, while heparin acts at several points in the intrinsic pathway by inactivating thrombin, including: VIII, V, and prothrombin
• NOTE: LMWH effect can be monitored via Xa assay, a chromogenic test

Question 30

What is protamine?

Answer 30

• Highly basic, + charged peptide (derived from fish sperm) combines with (-) charged heparin as ion pair to form stable, inert complex -> fish hypersensitivity
• Admin IV; activity up to 2 hrs -> avoid excess b/c it also has anticoagulant effect
• Incompletely neutralizes LMWH, and won’t reverse action of Fondaparinux
• Indicated for heparin OD & commonly used to neutralize it during extracorporeal circulation after dialysis, or arterial/cardiac sx
• Acutely, may cause protamine rxn

Question 31

What is the protamine rxn?

Answer 31

• Predisposing factors: insulin-dependent diabetes, fish allergy, vasectomy, prior exposure, infusion rate
• Self-limiting duration (1 hr-ish)
• Signs: shaking, flushing, chills, back, chest, flank pain, vasomotor collapse, sinus bradycardia, pulmonary HTN (also reported to cause systemic HTN, N/V, fatigue)
• Tx: morphine or meperidine, diphenhydramine, salline, support of low blood pressure
• Protamine has also been associated w/some severe anaphylactic rxns

Question 32

What is the MOA of Warfarin?

Answer 32

• Inhibits hepatic syn of Vit K dependent factors 2, 7, 9, 10, and anticoagulant proteins C and S (reduced at rate proportionate to their half-lives -> prolongs PT)
  1. Inhibits C1 subunit of Vit K epoxide reductase (VKORC1), reducing regeneration of Vit K epoxide
  2. VK is cofactor for carboxylation of glutamates to gamma-carboxyglutamates at N-terminal end; carboxylation necessary for activation
• Possibly inhibits VK reductase
• Degree of effect dose-dependent, and affected by pt’s VKORC1 genotype

Question 33

How is warfarin metabolized?

Answer 33

• S-enantiomer more potent, and metabolized by C29
• R redundant metabolism by other CYPs
• Anticoagulant effects are stereoselective: S 3-5x more potent

Question 34

Describe the differences between heparin and warfarin.

Answer 34

• H- large, anionic and acidic; W- small amphipathic
• H- IV, SC; W- oral
• Site of action: H- blood; W- liver
• Onset: H- rapid; W- slow, limited by T(1/2) of cofactors
• Mech: you know these - review in your head
• Duration: H- acute (hrs); W- chronic (days)
• H- inhibits in vitro; W- does not
• Reversal agent: H- protamine suflate; W- prothrombin complex, VK, fresh frozen plasma
• Monitoring: H- aPTT (intrinsic); W- PT (extrinsic)
• Teratogenic: H- NO; W- YES (crosses placenta)

Question 35

What are some pharmacokinetic, pharmacodynamic, and body factors that affect PT (i.e., Warfarin)?

Answer 35

• Increase PT:
  1. PK (via 2C9): cimetidine, fluconazole, trimeth-sulfa, disulfiram, phenylbutazone
  2. PD: aspirin, cephalosporins, heparin, dabigatran, rivaroxaban, chronic large daily doses of acetaminophen also INC INR
  3. BF: hepatic disease, hyperthryoidism
• Decrease PT:
  1. PK: barbiturates, cholestyramine, rifampin
  2. PD: Vit K
  3. BF: hereditary resistance, hypothyroidism

Question 36

What are the diet recommendations for patients on Warfarin?

Answer 36

• No major changes, esp. in things with Vit K
• Asparagus, basil, beef, pork liver, black eyed peas, broccoli, brussel sprouts, cabbage, chick peas, cucumber with peel, green onions, green tea, okra, parsley, peas, thyme, and green, leafy veggies like beet greens

Question 37

What is important when considering Warfarin pharmacogenetics?

Answer 37

• Variability in pt response can be attributed to genetic differences in CYP2C9 and VKROC1
• Controversy as to clinical value of these test b/c only about 40% of Warfarin variability can be attributed to these 2 gene products
• Potential danger of current commercial testing for AA b/c they may harbor a 2C9 allele not currently tested for -> could lead to undertreatment
• 1 of most difficult drugs to titrate for individual pt

Question 38

Why are the cofactor half-lives important when considering the effects of Warfarin?

Answer 38

• C and S have shorter half-lives than 2, 7, 9, and 10, so early, transient hypercoagulable state with Warfarin
• Resulting rare necrotic rxns -> seen most typically in obese, middle-aged women
• Heparin “bridging” used with initial Warfarin tx to reduce risk -> once 2, 7, 9, and 10 have been inhibited, can stop heparin

Question 39

What is cholesterol embolism?

Answer 39

• Anticoag therapy with Warfarin may enhance release of atheromatous plaque emboli, leading to systemic cholesterol microembolization
• Sequelae may include: livedo reticularis, rash, gangrene, hematuria, pancreatitis, HTN, and more
• Most commonly involved visceral organs are: kidneys, pancreas, spleen, liver -> some symptoms progress to organ failure and death
• Purple-toe syndrome (see image): mottled, pain, tenderness; < 0.1% of cases may lead debridement, amputation (discontinuation recommended when these conditions occur)

Question 40

What are the direct Xa inhibitors? Describe them.

Answer 40

• Apixaban, Rivaroxaban: oral admin
• MOA: bind to, directly inhibit Xa -> thrombin INH; inhibit free and clot-bound Xa, and prothrombinase activity
• Clinical utility: tx, prohpylaxis of DVT, PE; stroke prophylaxis
• Monitoring: not usually required
• Toxicity: BLEEDING; no reversal agent available

Question 41

What is the indirect factor Xa inhibitor? Describe it.

Answer 41

• Fondaparinux: copy of the ATIII binding region of heparin; administered IV or SC
• MOA: binds ATIII, eliciting permanent conformational change that INC affinity for factor Xa 300-fold -> thrombin inhibition
• Clinical utility: treatment and prophylaxis of DVT, PE
• Monitoring: usually not required; anti-cofactor Xa levels if abnormal coagulation parameters or bleeding during therapy
• Toxicity: bleeding; no reversal agent available

Question 42

What are the direct thrombin inhibitors? Describe them.

Answer 42

• Dabigatran (oral), Bivalirudin (IV), Lepirudin (IV)
• MOA: bind to and directly inhibit both free and clot-bound thrombin
• Clinical utility: tx and prophylaxis of DVT, PE; stroke prophylaxis -> useful for pts at risk of HIT
• Monitoring: not usually required
• Toxicity: bleeding; no reversal agent required

Question 43

Which drugs are metabolized by CYP?

Answer 43

• Apixaban: primarily 3A4; also a substrate for P-gp
• Rivaroxaban: CYP3A4 and 2J2; also a substrate for P-gp and BCRP
• Warfarin: 2C9 (S-Warfarin), 1A1, 1A2, and 3A4 (R-Warfarin); interactions with serum albumin binders and Vit K-rich foods too
• NOTE: each of these drugs therefore interacts with drugs that inhibit or induce these CYPs

Question 44

Which drug can interact with strong P-gp inhibitors or inducers?

Answer 44

Dabigatran

Question 45

What are the half-lives of Dabigatran, Apixaban, Rivaroxaban, Warfarin, Enoxaparin, Fondaparinux, Bivalirudin, and Lepirudin? More importantly, which ones are super long and which ones are super short?

Answer 45

• D: 16
• A: 12
• R: 7 (12 in geriatric pts)
• **Warfarin: 40 **
• E: 6
• F: 18
• Bivalirudin: 0.5
• Lepirudin: 1.5

Question 46

What is phytonadione?

Answer 46

• Vitamin K1: PO, IV, SC, IM
• Identical activity to natural K vitamins
• Used for prophylaxis or tx of hemorrhage, nutritional supplementaion, hemorrhagic disease of the newborn, hypoprothrombinemia, and VK deficiency (or to antagonize Warfarin)
• Fat-soluble vitamin, but ability of body to store VK much less than for other fat-soluble items
• Hemorrhage typically controlled w/in 3-8 hours of admin

Question 47

What is prothrombin complex concentrate?

Answer 47

• Prepared from human plasma -> II, VII, IX, X, C, and S
• Preferred over fresh frozen plasma for rapid reversal of VK antagonist-associated major bleeding
  1. Resume anticoagulation after admin of PCC once risk of thromboembolic events outweighs risk of acute bleeding

​- More rapid action than plasma in trials

• Manufactured from human blood -> disease transmission possible despite manufacturing safeguards
• Contraindicated with PMH of angina, MI, peripheral vascular disease, stroke, and thromboembolic disease

Question 48

What is the MOA of Alteplase?

Answer 48

• t-PA (tissue plasminogen activator) that acts on endogenous fibrinolytic system to convert plasminogen to plasma by directly hydrolizing ariginine-valine bond in plasminogen

Question 49

What is the mechanistic difference between Alteplase and Streptokinase?

Answer 49

• Alteplase (reteplase, tenecteplase) are fibrin-specific plasminogen activators -> preferentially activate fibrin-bound plasminogen (activated plasminogen unfolds to expose potent enzymatic domains)
• Streptokinase: non-specific activator with no affinity for fibrin -> does not discriminate b/t fibrin-bond and circulating plasminogen
  1. Activation of circulating plasminogen generates activated plasmin that overwhelms alpha-2 antiplasmin, and can trigger systemic lytic state

Question 50

What ARE each of the tPA’s and Streptokinase?

Answer 50

• Alteplase: recombinant human tPA
• Tenecteplase (TNK-tPA): glycosylation site Y on K1 repositioned to endow it with longer half-life
• Reteplase (rPA): truncated variant lacking the F, EGF and K1 domains -> longer 1/2 life
• Streptokinase: EC protein purified from hemolytic streptococci

Question 51

What are the half-life and metabolism differences between the tPA’s?

Answer 51

• Alteplase: 30 min, hepatic
• Tenecteplase: 110, hepatic
• Reteplase: 170, hepatic and renal
• Streptokinase: 20, undefined
• NOTE: 1) dose adjustment may be necessary in pts w/severely compromised renal or hepatic function, 2) small risk of allergic rxn, so meds to treat anaphylaxis should be readily available

Question 52

What are the indications (and contra-) for the thrombolytics?

Answer 52

• Used in early MI, early ischemic stroke, direct thrombolysis of severe PE
• Contraindicated with: active internal bleeding, hx of cerebrovascular incident, severe uncontrolled HTN, intracranial neoplasm, aneurysm, and o/bleeding risks
• Hazardous with: a-fib, a-flutter, o/cardiac disease that INC likelihood for cerebral embolism; avoid if possible
• NOTE: cardiac arrythmias, incl. sinus bradycardia, premature ventricular depolarizations, and ventricular tachycardia can devo as result of reperfusion following coronary thrombosis

Question 53

What is the major AE associated with the thrombolytics?

Answer 53

• BLEEDING
  1. Internal, intracranial, retroperitoneal, GI, GU, and respiratory
  2. Superficial/surface, mainly at venous cutdowns, arterial punctures, and sites of recent surgical interventions

Question 54

What are the potential drug interactions of the thrombolytics?

Answer 54

• Agents affecting hemostasis: platelet INH, NSAIDs, anticoagulants (heparin and low dose aspirin freq used with thrombolytic agents w/o AE)
• Agents producing significant thrombocytopenia: antineoplastic agents, antithymocyte globulin
• Antifibrinolytics: aminocaproic acid
• Antibiotics: cephalosporins (w/methothiotetrazole) like cefotetan cause hypoprothrombinemia, and disturb syn of VK-dependent clotting factors in liver

Question 55

What is aminocaproic acid?

Answer 55

• Uses: hemorrhage and hyperfibrinolysis
• Binds lysine-binding sites in plasminogen/plasmin molecule, preventing fibrinolytic activity
• Oral/parenteral agent w/T(1/2) of 2hr (hepatic metabolism, and hep/renal elim)
• Issues: contraindicated in DIC or active IV clotting w/o concurrent use of heparin b/c thrombus formation can be potentiated
• Monitor cardiac pts; hypotension and bradycardia may occur if IV drug admin too rapid