Thrombotic Drugs Study Guide (Bleeding Disorders Pre-Work) Flashcards
Broadly, what are main uses of antithrombotic agents?
Used as both prevention of thrombosis in high-risk patients as well as treatment of acute & symptomatic thrombotic events.
Compare the typical composition of venous thrombi with arterial thrombi.
Venous: RBCs enmeshed in fibrin (“red thrombi”)
Arterial: Platelets with little fibrin or white cells (“white thrombi”)
Is a DVT of the distal or proximal larger leg veins worse?
Proximal (at or above the knee) is worse, due to icnreased odds of PE
When does arterial thrombosis typically occur?
What are the most severe clinical manifestations of this?
When: After erosion or rupture of an atherosclerotic plaque
Cardiac ischemia & stroke are the severe possibilities
What are some shared risk factors for both venous and arterial thrombosis?
- Advanced age
- Obesity
- Infection
- Metabolic syndrome
What are some classic risk factors for **venous **but not arterial thrombosis?
- Cancer
- Surgery
- Catheters
- Immobilization
- Fractures
- Pregnancy
- Estrogen Use
- IBD
- SLE autoantibodies
What are some classic risk factors for **arterial **but not **venous **thrombosis?
- Smoking
- Hypertension
- Diabetes
- Hyperlipidemia
NOTE: I think this is bullshit. The study guide later contradicts itself and lists these same things as venous thrombosis risk factors as well. I mean, it seems pretty obvious.
Common gain-of-function gene mutations, including Factor V Leiden and Prothrombin G20210A are mainly risks for (arterial/venous) thrombosis.
Venous
Name the function of the following platelet receptors:
- GP Ib/IX/V
- GP Ia/IIa
- GP IIb/IIIa
- Binds vWF
- Binds matrix collagen
- Allows platelet-to-platelet aggregation
Name two factors, released or produced by platelets, that serve to recruit additional platelets to a site of vascular injury?
ADP and thromboxane A2
Heparin
Mechanism of Action
Heparin
No instrinsic anticoagulant activity. Binds antithrombin (AT), making it up to 1000x more potent. Heparin must bind both AT and thrombin to be effective. Heparin chains must be at least 18 saccharide units long to accomplish this linking action.
Heparin
Pharmakokinetics
Heparin
Given by continuous IV or SubQ. Immediate onset when given IV, 1-2hr delay with SubQ. t1/2 varies with dose.
Heparin
Adverse Effects
Heparin
- Bleeding
- Heparin-induced thrombocytopenia
Enoxaparin & Dalteparin
Mechanism of Action
Enoxaparin & Dalteparin
Low Molecualr Weight Heparins (LMWH). More effective at inactivating Factor Xa than thrombin as compared to heparin. Otherwise, same mechanism as heparin.
Enoxaparin & Dalteparin
Pharmakokinetics
Enoxaparin & Dalteparin
Given parenterally. More uniform absorption with SubQ than heparin. Longer t1/2 than heparin. Cleared by kidneys.
Enoxaparin & Dalteparin
Adverse Effects
Enoxaparin & Dalteparin
- Bleeding (less than heparin)
- Kidney clears LMWHs
- Mostly a concern in pts with renal impairment
- Thrombocytopenia (less often than heparin) but still important to monitor
Lepirudin & Bivalirudin
Mechanism of action
Lepirudin & Bivalirudin
- Direct thrombin inhibitors
- Synthetic polypeptides that bind both the catalytic and extended recognition site (exosite I) of thrombin
Lepirudin & Bivalirudin
Pharmacokinetics
Lepirudin & Bivalirudin
- Given IV
- Excreted by kidneys
- t1/2 is 1.3hrs for lepirudin & 25min for bivalirudin
- Thrombin slowly cleaves the bond within the peptide drug that holds it’s catalytic site and regains activity
Lepirudin & Bivalirudin
Adverse Effects
Lepirudin & Bivalirudin
- Use w/ caution in pts with renal failure - may accumulate and cause bleeding
Fondaparinux
Mechanism of Action
Fondaparinux
- “Direct” Factor Xa inhbitor
- Causes an AT-mediated selective inhibition of Xa
- Synthetic pentasaccharide
Fondaparinux
Pharmacokinetics
Fondaparinux
- SubQ
- Reaches peak plasma levels in 2hrs
- Excreted in urine, t1/2 ~17hrs
- Do not use in pts w/ renal failure
Fondaparinux
Adverse Effects
Fondaparinux
- Much less likely than heparin or LMWH to trigger the syndrome of heparin-induced thrombocytopenia
[Easy to remember considering it doesn’t have heparin in it’s name…]
Warfarin
Mechanism of Action
Warfarin
- Inhibits hepatic vitamin K reductase (VKORC1), which is used to recycle the active form of vitamin K, vitamin K hydroxyquinone.
- Without active vitamin K, clotting factors II, VII, IX, and X are not carboxylated and remain inactive
Warfarin
Pharmacokinetics
Warfarin
- The S-enantiomer is most active
- Metabolized by CYP2C9
- Common genetic polymorphisms in 2C9 affect metabolism rate
- Metabolized by CYP2C9
- Minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4
- Polymorphisms in VKORC1 affect its susceptibility to warfarin
- Affects dosing
Warfarin
Adverse Effects
Warfarin
- Bleeding: Risk increases w/ intensity and duration of therapy & use of other hemostasis-affecting drugs
- Serious cases arise when bleeding results in:
- Compression of vital structures
- e.g. PNS, CNS, Pericardium
- Massive internal blood loss that is not rapidly diagnosed
- e.g. GI, intra- & retroperitoneal
- Compression of vital structures
- Serious cases arise when bleeding results in:
- Rare: warfarin-induced skin necrosis
- Purple toe syndrome
- Reversible, sometimes painful, blue-tinged discoloration of plantar and side surfaces of toes. Blanches w/ pressure, fades w/ leg elevation. Develops 3-8 weeks into therapy.
Warfarin
Contraindications
Warfarin
- Pregnancy - causes birth defects & abortion
Dabigatran etexilate
Mechanism of action
Dabigatran etexilate
- Prodrug: converted in vivo to the active dabigatran
- Specific, reversible direct thrombin inhibitor
-
Inhibits both free and fibrin-bound (clot-bound) thrombin
- Heparin and LMWHs cannot inhibit fibrin-bound thrombin
-
Inhibits both free and fibrin-bound (clot-bound) thrombin
Dabigatran etexilate
Pharmacokinetics
Dabigatran etexilate
- Orally available prodrug
- Rapidly converted into active form by esterases
- Peak plasma levels in 2hrs
- t1/2: 14-17hrs
- Eliminated mainly via kidneys
- >80% of drug is excreted in the urine unchanged
Dabigatran etexilate
Drug Interactions
Dabigatran etexilate
- The prodrug but not the active form is a P-glycoproteins substrate in the gut and kidneys. Recall: Pgp pumps drugs out of cells. Thus:
- Inducers of Pgp (e.g. rifampin) will decrease plasma concentration of dabigatran
- Inhibitors of Pgp (e.g. ketoconazole, amiodarone, verapamil) will increase plasma concentration of dabigatran
Dabigatran etexilate
Adverse Effects
Dabigatran etexilate
- Comparable rates of serious bleeding vs. warfarin
- Monitor renal function to prevent accumulation that can lead to bleeding events
- Esp. important in elderly pts or those with renal impairment
Rivaroxaban
Mechanism of Action
Rivaroxaban
- Selective, direct-acting factor Xa inhibitor
- Binds the S1 and S4 active site pockets
Rivaroxaban
Pharmacokinetics
Rivaroxaban
- Given orally (F > 80%)
- Peak plasma levels at 2-4hrs
- t1/2: 5-9 hours
- Dual elimination
- 1/3 eliminated unchanged by kidneys
- 2/3 by liver
- CYP3A4/5 and CYP2J2
Rivaroxaban
Drug Interactions
Rivaroxaban
- Like dabigatran, rivaroxaban is a Pgp substrate, so use with caution in pts receiving Pgp inducers or inhibitors
Rivaroxaban
Adverse Effects
Rivaroxaban
- Bleeding events possible, but lower than other anticoagulants
Alteplase
Mechanism of Action
Alteplase
- Thrombolytic
- A naturally occuring plasminogen activator
- Results in a ~50% reduction in circulating fibrinogen
- Initiates local fibrinolysis by binding to thrombus-bound fibrin and converting entrapped plasminogen to plasmin
-
Thus, works on free and thrombus-bound fibrin
- “Alteplase activates plasminogen in all-the-places”
Alteplase
Pharmacokinetics
Alteplase
- Given IV.
- Administer a bolus dose over 1min, then follow with infusion.
- t1/2: About five minutes. >80% cleared in 10min. Fast-acting, fast to be cleared.
Alteplase
Adverse Effects
Alteplase
- Major bleeding in up to 5% of pts
- Most serious: intracranial hemorrhage
- Risk factors:
- >65yrs age
- HTN, esp. when severe
- Low body weight (<70kg)
- Risk factors:
- Most serious: intracranial hemorrhage
Aspirin
Mechanism of Action
Aspirin
-
Irreversible inhibition of COX via acetylation
- Blocks thromboxane A2 production
- Inhibits platelet aggregation
- Blocks thromboxane A2 production
Aspirin
Pharmacokinetics
Aspirin
- Orally available. Effects seen within an hour.
- Peak plasma levels in ~4hrs
- t1/2 is only 20min, but the effect is irreversible so it doesn’t really matter
Aspirin
- What is the life span of a platelet?
- What percentage of a person’s platelet population is normally turned over in a day?
- Knowing this, about how long would it take for a person’s functional platelet population to recover following a single dose of aspirin?
Aspirin
- 7-10 days
- 10%
- 10 days
Aspirin
Adverse Effects
Aspirin
- Bleeding
- GI irritation
- Inhibition of GI COX1
- Dosing of 75-150mg appears to be as effective as higher doses
- Side effects increase with dosage, so low doses are favored
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Mechanism of Action
Which of the four is reversible?
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
- Inhibit binding of ADP to the platelet P2Y12 receptor
- Inhibits platelet aggregation
- All are irreversible, except for ticagrelor
- Reversibility of ticagrelor is useful in some circumstances, e.g. pts about to undergo surgery
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Pharmacokinetics
Which are prodrugs?
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
- Clopidogrel and ticlopidine are prodrugs
- Activated primarily by CYP2C19
- Prasugrel is also a prodrug
- First metabolized to an inactive thiolactone intermediate
- Then activated via CYP3A4 and 2B6
- Despite the two-step activation, prasugrel shows more extensive activation and more consistent activity (between pts) than clopidogrel
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Adverse Effects
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
- Bleeding risk
- Ticagrelor: dyspnea
-
Ticlopidine: severe neutropenia
- Ticlopidine has been largely replaced by the other 3 for this reason
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Which of the four has a notable drug interaction concern? What is the interaction?
Clopidogrel
- It’s activation by CYP2C19 can be inhibited by PPIs (e.g. omeprazole)
- Less active clopidogrel means a great risk for CV events
- Avoid concurrent use of moderate or strong PPIs
Dipyridamole
Mechanism of Action
Dipyridamole
- Inhibits adenosine deaminase & phosphodiesterase
- Causes accumulation of adenosine, adenine nucleotides, & AMP
- These inhibit platelet aggregation (opposite of ADP) and may cause vasodilation
- May also stimulate release of prostacyclin or PGD2
- coronary vasodilation
- Causes accumulation of adenosine, adenine nucleotides, & AMP
Dipyridamole
Pharmacokinetics
Dipyridamole
- Oral
- Peak plasma levels in ~75min
- t1/2: ~10hrs
- Highly bound to plasma proteins
- Metabolized in liver
- Conjugated as a glucuronide, excreted w/ bile
Dipyridamole
Adverse Effects
Dipyridamole
- Usually minimal and transient
- Headache
- GI upset
- Dizziness
Abciximab & Eptifibatide
Mechanism of Action
Abciximab & Eptifibatide
- Binds platelet GP IIb/IIIa receptors, preventing fibrinogen binding and platelet cross-linking
-
Abciximab is a chrimeric human-murine mAb
- Does not bind GP IIb/IIIa at the ligand-binding site
- Thus acts noncompetitively
- Does not bind GP IIb/IIIa at the ligand-binding site
-
Eptifibatide
- Competitive, reversible inhibitor
- A polypeptide derived from rattlesnake venom
- Critical sequence: Lys-Gly-Asp (KGD)
Abciximab & Eptifibatide
Pharmacokinetics
Abciximab & Eptifibatide
- Both given IV
-
Abciximab:
- Biological t1/2 is under 30min, but its slow clearance gives it a functional t1/2 of up to 7 days
-
Eptifibatide
- Maximal inhibition by 15min
- Reversible - platelet aggregation normalizes within 4-8hrs
- Renal clearance
- Use w/ caution in pts w/ renal dysfunction
Abciximab & Eptifibatide
Adverse Effects
Abciximab & Eptifibatide
- Bleeding
- Thrombocytopenia
- Hypotension
- Bradycardia
What drug(s) would you give for:
Acute venous thromboembolism
LMWH or fondaparinux
What drug(s) would you give for:
Surgical prophylaxis for venous thromboembolism
Like acute VTE, LMWH or fondaparinux
What drug(s) would you give for:
Long-term VTE prophylaxis
Warfarin or rivaroxaban
What drug(s) would you give for:
PE
Heparin, fibrinolytic drug
What drug(s) would you give for:
Unstable Angina and non-STE ACS
Aspirin + or - clopidogrel or prasugrel;
eptifibatide or tirofiban;
LMWH or fondaparinux
What drug(s) would you give for:
STEMI
Fibrinolytic drug, aspirin, and LMWH
What drug(s) would you give for:
Acute Thrombotic Stroke
Fibrinolytic drug or aspirin
What drug(s) would you give for:
Thrombotic Stroke & TIA Prophylaxis
Aspirin + dipyridamole;
clopidogrel or prasugrel
What drug(s) would you give for:
Afib
Heparin or LMWH, followed by warfarin, dabigatran, or rivaroxaban
What drug(s) would you give for:
Prophylaxis in a pt with an atificial heart valve
Warfarin, aspirin
