Coagulation Disorder Drugs - Sweatman 03.27.15 Flashcards
1
Q
What are the antiplatelet drugs? List their categories and names.
A
- 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)
2
Q
What two processes does stimulation of platelet receptors trigger?
A
- Activation of internal signaling pathways that lead to further activation and granule release
- Capacity of the platelet to bind to other adhesive proteins/platelets
NOTE: both of these factors contribute to the formation of a thrombus
3
Q
What is Gp2b3a? How does it work?
A
- 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
4
Q
What are the contraindications to the use of platelet inhibitors?
A
- 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)
5
Q
What is the difference between the actions of ibuprofen and aspirin?
A
- 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
6
Q
Do aspirin and ibuprofen affect PT and/or PTT?
A
No
7
Q
What is aspirin indicated for? What are its contraindications?
A
- Widely used for secondary prevention of CV events in pts with coronary artery, cerebrovascular, or peripheral vascular disease
- Contraindications: PMH of aspirin-induced bronchospasm
8
Q
What are the adverse effects of aspirin and ibuprofen?
A
- 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
9
Q
What is the MOA of Clopidogrel, Ticlopidine, and Prasugrel?
A
- 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)
10
Q
What are the clinical uses for Clopidogrel?
A
- Post-MI
- Stroke
- Established PAD
- Percutaneous coronary intervention (PCI): coronoary angioplasty to treat atherosclerosis
- PREFERRED AGENT IN ISCHEMIC HEART DISEASE
11
Q
What are the clinical uses for Ticlopidine?
A
- 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
12
Q
What are the clinical uses for Prasugrel?
A
- Acute MI
- Arterial thromboembolism prophylaxis
- PCI
- Unstable angina
13
Q
How are Clopidogrel, Ticlopidine, and Prasugrel administered and metabolized?
A
- 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
14
Q
What is the MOA and clinical use of dypiridamole?
A
-
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)
15
Q
How is Dipyridamole metabolized? What are its contraindications/AEs?
A
- 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
16
Q
What are the MOAs of Abciximab, Eptifibatide, and Tirofiban?
A
- 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
17
Q
What are the utility, onset, and persistence of Abciximab, Eptifibatide, and Tirofiban?
A
- 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
18
Q
What are the major issues with Abciximab, Epitifibatide, and Tirofiban?
A
- 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)
19
Q
What is Vorapaxar?
A
- 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
20
Q
Why are herbal product interactions important? List some.
A
- # 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
21
Q
What are the anticoagulant categories and drugs?
A
- 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)
22
Q
What is the MOA of heparin?
A
- 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
23
Q
Why is the size of the heparin molecule important?
A
- 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
24
Q
What is heparin?
A
- 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
25
What are the similarities/differences b/t heparin and LMWH in regards to half-life, effects, major events, and when they are used?
- _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
26
How is heparin metabolized and eliminated?
- 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)
27
What are the major AEs produced by heparin products?
- 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
28
How is heparin monitored and dosed?
- _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)
29
Why does LMWH have a lower impact on aPTT?
- 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
30
What is protamine?
- 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
31
What is the protamine rxn?
- _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
32
What is the MOA of Warfarin?
- 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
33
How is warfarin metabolized?
- S-enantiomer more potent, and metabolized by **C29**
- R redundant metabolism by other CYPs
- Anticoagulant effects are _stereoselective_: S 3-5x more potent
34
Describe the differences between heparin and warfarin.
- 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)
35
What are some pharmacokinetic, pharmacodynamic, and body factors that affect PT (i.e., Warfarin)?
- _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
36
What are the diet recommendations for patients on Warfarin?
- 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
37
What is important when considering Warfarin pharmacogenetics?
- 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
38
Why are the cofactor half-lives important when considering the effects of Warfarin?
- _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
39
What is cholesterol embolism?
- 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)
40
What are the direct Xa inhibitors? Describe them.
- 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
41
What is the indirect factor Xa inhibitor? Describe it.
- **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
42
What are the direct thrombin inhibitors? Describe them.
- 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
43
Which drugs are metabolized by CYP?
- _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
44
Which drug can interact with strong P-gp inhibitors or inducers?
Dabigatran
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?
- D: 16
- A: 12
- R: 7 (12 in geriatric pts)
- **Warfarin: 40 **
- E: 6
- F: 18
- **Bivalirudin: 0.5**
- **Lepirudin: 1.5**
46
What is phytonadione?
- 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
47
What is prothrombin complex concentrate?
- 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
48
What is the MOA of Alteplase?
- t-PA (tissue plasminogen activator) that acts on endogenous fibrinolytic system to convert plasminogen to plasma by directly hydrolizing ariginine-valine bond in plasminogen
49
What is the mechanistic difference between Alteplase and Streptokinase?
- _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
50
What ARE each of the tPA's and Streptokinase?
- _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
51
What are the half-life and metabolism differences between the tPA's?
- 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
52
What are the indications (and contra-) for the thrombolytics?
- 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
53
What is the major AE associated with the thrombolytics?
- BLEEDING
1. Internal, intracranial, retroperitoneal, GI, GU, and respiratory
2. Superficial/surface, mainly at venous cutdowns, arterial punctures, and sites of recent surgical interventions
54
What are the potential drug interactions of the thrombolytics?
- _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
55
What is aminocaproic acid?
- _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
