Drugs in thromboembolic disorders - Konorev Flashcards
_ thrombus forms high pressure arteries and is the result of platelet binding to the damaged endothelium and aggregation with little involvement of fibrin.
White
Pathologic condition associated with white thrombi include_
local ischemia due to arterial occlusion (in coronary arteries: MI/unstable angina etc)
Red thrombus are made of _
fibrin-rich with trapped RBCc
Red thrombus forms in _ pressure areas such vein and in the heart; result of platelet binding and aggregation followed by formation of bulky fibrin tails in which red blood cells become enmeshed.
low pressure
Pathologic conditions associated with red thrombi include _
pain and severe swelling, embolism and distal pathology (embolic stroke)
Anticoagulants functions to _ and used in what kind of thrombi?
regulates clotting factors (both the intrinsic and extrinsic factors).
- used to prevent red thrombi (veins and in heart)
Antiplatelet drugs functions to inhibit _ and are used to prevent _
platelet aggregation
- prevents white thrombi in arteries
Anticoagualants drugs prevents thrombus formation, but once the thrombus has already formed, anticoagulants are useless. In this case _ class of drugs are useful.
Thrombolytic drugs. Acts on fibrin and is able to restore blood flow into previously ischemic areas.
Anticoagulants are divided into parenteral and oral anticoagulants. Parenteral anticoagulants are further divided into Indirect thrombin inhibitors and direct thrombin inhibitors. What drugs are found in the indirect and direct thrombin inhibitor category?
- Indirect thrombi and Factor Xa (FXa) inhibitor: A) unfractionated heparin (UFH or HMW): heparin sodium; B) low molecular wt heparin (LMH): Enoxaparin, tnzaparin, dalteparin; C) Synthetic pentasaccharide: Fondaparinus
- Direct thrombin inhibitor: Lepirudin, bivalirudin and argatroban
what is the MOA of indirect thrombin and FXa inhibitors?
Bind antithrombin III (serine protease inhibitor) which then inhibits thrombin (IIa), IXa, and Xa.
Normally these reactions are slow, but heparin increases the antithrombin III activity by 1000-fold
HMW, LMW heparin and fondaparinux all inhibit activity of Xa, but they do have slight differences. What are their specific differences?
A. HMW: Inhibits the activity of both thrombin and factor Xa
B. LMW: inhibits factor Xa with little effect on thrombin
C. Fondaparinux inhibits factor Xa activity with no effect on thrombin
What is the MOA of parenteral direct thrombin inhibitors?
- Direct inhibition of protease activity of thrombin
Lupirudin and bivalirudin and argatroban all are parenteral direct thrombin inhibitors that which inhibit protease activity of thrombin. what are their specific difference in MOA?
Lupirudbin and bivalrudin are bivalrent direct thrombin inhibitors–they bind at both the active site and substrate recognition site.
Argatroban binds only at the thrombin active site
What are the oral anticoagulants available?
- Coumarin anticoagulants: warfarin
- Novel oral anticoagulants: A)Factor Xa inhibitors (Rivaroxaban, apixaban, edoxaban); B) Direct thrombin inhibitor: Dabigatran
what is the MOA of warfarin?
inhibits reactivation of vitamin K, by inhibiting enzyme Vit K epoxide reductase
- Inhibits carboxylation of glutamate residues by GGCY (y-glutamyl carboxylase) in prothrombin and factors VII, IX, and X, making them inactive
Why is warfarin a difficulty drug to dose?
- High individual variability in optimal dose (genetic make up, disease state, drug drug interactions, diet)
- Narrow therapeutic window.
Warfarin dose is tirated on lab testing measuring _
Prothrombin time INR..
what is the rationale for using LWMs vs HMW?
They both have equal efficiency in several thromboembolic conditinos but LMW have increased bioavailability from the SC injection site and allow for less frequent injections and more predictable dosing
What are the clinical indications for Heparin?
- used to treat red (fibrin-rich) thrombi reduces the risk of emboli in cases like embolic stroke, PE.
- Used in pts with DVT, afib,
- used during surgery to prevent emboli or in hospitalized patients
- Used as heparin locks to prevent clots from forming in catheters.
How can heparin dosing be monitored?
- activated partial thromboplastin Time, (mainly for HMV). this measures efficacy of an intrinsic pathway and a common pathway and thsu evaluates protease factors II, IX, X, XI, XII.
- Anti-Xa assay (examines proteolytic activity of Xa)
What is the indication for oral Anticoagulants?
- prevent thrombosis or prevent/treat thromboemoblism
- Afib
- Prostehtic heart valves
Indicate what each of these is an antidote of: A. Protamine sulfate B. Vit K, C. Idaruzicumab Andexanet alfa
A. HMV, LMV heparins
B. warfarin (competitive antagonism of Vit K)
C. NOAC- DTI
D. NOAC- FXa inhibitors
How is NOAC-FXa inibitors (Rivaroxban, apixaban, edoxaban) and dabigatran levels monitored?
NOAC- FXa inhibitors - blood test for anti-Xa
Dabigatran - blood test for diluted thrombin time (TT)
what AE are associated with heparin?
- bleeding
- Heparin-induced thrombocytopenia (HIT)
What is heparin-induced thrombocytopenia?
Formation of abnormal antibodies that activate platelet factor 4 (PF4).
If a pt receiving heparin develops a new or worsening thrombosis, or if the platelet count falls, suspect HIT.
HIT should be suspected in a patient when the patient develops 1 and 2 after receiving heparin.
- New and/or worsening thrombosis
2. Thrombocytopenia
What contraindications are associated with heparin use?
- severe HTN
- Active TB
- Ulcers of GI
- Pts with recent surgeries
if a patient receiving heparin develops HIT, what other drugs can be given instead?
Dabigatran
_ is a synthetic pentasaccharide that is usually administered subcutaneously.
Fondaparinux
What is the MOA of fondaparinux?
- high affinity reversible binding to antithrombin III and enhances antithrombin’s basal rate of factor Xa inactivation.
How is fondaparinux different from Heparin?
- Fondaparinux does not inhibit thrombin activity
- Fondaparinux does not induce HIT
- Fondaparinux’s actions are NOT reversed by protamine sulfate
What are the clinical uses of fondaparinux?
- prevent DVT
- treat acute DVT in conjunction with warfarin
- treatment PE
Lepirudin, bivalirudin and argatroban all belong to what class of drugs?
Direct thrombin inhibitors (parenteral)
_ parenteral drug that is a irreversible direct inhibitor of thrombin
Lepirudin (recombinant form of hirudin (leeches))
which direct thrombin is a small molecular weight inhibitor that has a short half life and is used intravenously only.
Argatroban
Which direct thrombin inhibitor is also known to inhibit platelet aggregation?
Bivalirudin
What are the clinical uses of Direct thrombin inhibitors?
- HIT
- Coronary angioplasty (bivalirudin and argatroban)
which Direct Thrombin inhibitor is associated with anaphylactic reaction with repeated use?
Lepirudin
what are the clinical uses of warfarin?
- prevent /treat thrombosis/thromboembolism
- Afib
- Prosthetic heart valves
what adverse effects are associated with warfarin?
- teratogenic effects (avoid in pregnant woman)
- skin necrosis, infarction of breasts, intestines, extremities
- osteoporosis
- bleeding
What is the implication of the each of the following INR levels: A. 0.5 B. 0.9-1.3 C. 2-3 D. 4-5
A. high chance of thrombosis
B. Normal
C. normal range for patients on warfarin
D. high chance of bleeding
_ is responsible for 30% variation in dose of warfarin (low and high dose haplotypes)
Vit K epoxide reductase complex subunit 1 (VKORC1)
- High dose haplotype in Blacks (more resistant to warfarin thus needs a high dose)
- low dose haplotype in asians (less resistant to warfarin thus needs a lower dose)
10% variation of doses of warfarin in Caucasian is due to variability of what enzyme?
CYP2C9
which factors are inhibited by warfarin?
Prothrombin (II) , VII, IX, X
Notable PK of warfain include _
Oral, 100% bioavailability, delayed onset, long half life, 99% bound to albumin
When you want to start a patient on warfarin, what test should you do to decide what dose to start them at?
- Prothrombin time.
- VKORC1 haplotype
- CYP2C9
What diseases should you be cautious of when giving warfarin?
- liver disease (clotting factors are made here)
- thyroid status
what the pros and cons of warfrain?
Pros: oral, long duration, renal function not important, can reverse it
Cons: high dosing variability, hard to maintain concentration, bleeding complications, requires INR monitoring
what are the clinical uses of Direct thrombin inhibitor (DTI)?
- reduce risk of stroke and systemic embolism in pts with non valvular afib
- tx venous thromboembolism
Compared to warfarin, what advantages do DTI’s have?
- Predictable PK and bioavailability
- Fixed dosing and predictable anticoagulant action
- rapid onset and offset of action
- No interaction with P450 metabolized drugs
- Antidote available (idarucizumab)
What is the single biggest disadvantage of DTI?
80% renal excretion thus not suitable in pt with renal issues.
What are the clinical uses of Factor Xa inhibitors?
- prevent thromboembolism (rivaroxaban and apixaban)
- treat thromboembolism
- prevent stroke in pts with afib
What are some pros and cons of Factor Xa inhibitors?
Pros: oral, fixed dose, no monitoring, seems equal to warfrain, rapid onset compared to warfain
Cons: no antidotes, dose ajdustment in real disease
What are the 4 classes of antiplatelet drugs?
- TxA2 synthesis inhibitors
- ADP receptor blockers
- Platelet glycoprotein receptor blocker
- Phosphodiesterase inhibitor
What drugs call under TxA2 synthesis inhibitors, what is the MOA, use and adverse effects?
Aspirin
MOA: COX inhibitor
Use: prevent MI and other vascular events
AE: peptic ulcers, GI bleeding
What drugs are ADP receptor blockers?
- Clopidogrel and ticlopidine
- Prasugrel
- Ticagrelor
What is the MOA of ADP receptor blockers?
Inhibit receptor –> activates AC –> increase cAMP
Clopidogrel is related primarily to metabolism by the hepatic enzyme _ which often is seen as an nonfunction allele in 50% of chinese, 34% of Africans, 25% of whites and 19% of Mexians
CYP2c19
What is ADP receptor blockers used for?
- prevent arterial thrombosis in stroke (Ticlopidine)
- Prevent thrombosis in pts with ACS and recent AMI, stroke and peripheral arterial disease (Clopidogrel, prasugrel, ticagrelor)
What adverse effects are associated with Ticlopidine?
- thrombotic thrombocytopenic purpura
- GI: nausea, dispepsia, diarrhea
- bleeding
- leukopenia
What AE are associated with Clopidogrel, prasugrel, ticagrelor?
- Bleeding
- dyspnea (ticagrelor)
- Less side effects than ticlopidine - they are preferred drugs over ticlopidine
what drugs are phosphodiesterase (PDE) inhibitors ?
- Dipyridamole
- cilostazol
What is the MOA of PDE inhibitors?
inhibition of cAMP degradation –> increase platelet cAMP
What are the clinical uses of PDE inhibitor?
- dipyridamole is used in combo with asipirin to prevent CV ischemia and in combo with warfain to prevent thromboemboli in pts with prosthetic heart valves
- Cilostazol is used to treat intermittent claudication
what drugs are platelet glycoprotein receptor anatagonists?
- Abciximab (anti 2b/3a monoclonal ab)
- Tirofiban (2b/3a antagonists)
- Eptifibatide (2b/3a antagonist)
what are the clinical uses of platelet glycoprotein receptor anatagonists?
- prevent thrombosis in unstable angian and other acute coronary syndromes
- in pts undergoing percutaneous coronary angioplasty
what AE are associated with platelet glycoprotein receptor antagonist?
- hypotension
- myalgia- abciximab
- thrombocytopenia (rare) - abciximab and tirofiban)
what are the three types of thrombolytic (fibrinolytic) drugs?
- tPA- cleaves plasminogen
- Urokinase - cleaves plasminogen
- Streptokinase - converts plasminogen to plasmin
What are the different tPA activator drugs?
- alteplase
- reteplase
- tenecteplase
what are the clinical uses of fibrinolytic drugs?
- embolic/thrombotic stroke
- MI
- PE
- DVT
- ascending thrombophlebitis
when should fibrinolytic drugs be used?
within 3 hours of clot formation
What AE are associated with fibrinolytic drugs?
bleeding from fibrinogenolysis
- allergic reactions (stretpkinase)
A 70-year-old Caucasian male presents to the emergency room following a fall. The patient’s past medical history is significant for myocardial infarction and atrial fibrillation. His home medications are unknown. The patient’s head CT does not show any acute bleeding. Laboratory results reveal an International Normalized Ratio (INR) of 6. Which of the following is the most appropriate pharmacologic therapy for this patient?
- Vitamin K
- Cryoprecipitate
- Protamine
- Platelet transfusion
- Fresh frozen plasma
- Vit K.
The patient has a supratherapeutic INR. Even though vitamin K is slower acting than fresh frozen plasma (FFP), it is most appropriate in this patient given his lack of acute bleed on head CT.
A 72-year-old woman with a history of atrial fibrillation on warfarin, diabetes, seizure disorder and recent MRSA infection is admitted to the hospital. She subsequently begins therapy with another drug and is found to have a supratherapeutic International Normalized Ratio (INR). Which of the following drugs is likely contributing to this patient’s elevated INR?
- Phenobarbital
- Glipizide
- Rifampin
- Carbamazepine
- Valproic acid
- Valproic acid
Warfarin is metabolized by the cytochrome P-450 pathway. Inhibitors of this pathway, such as valproic acid, decrease the metabolism of warfarin and increase a patient’s INR.
A 58-year-old Caucasian male with a history of peripheral vascular disease is admitted to the hospital with a painful, pulseless foot. He is prescribed antiplatelet and anticoagulant drugs. Which of the following matches a drug with its correct characteristic?
- Warfarin: directly inhibits thrombin
- Heparin: activates antithrombin 3
- Aspirin: reversibly inhibits COX-1
- Clopidogrel: antagonizes ADP receptors on endothelial cells
- Prasugrel: reduced risk of bleeding compared to other drugs in its class
- Heparin: activates antithrombin 3
A 66-year-old male with a history of deep venous thrombosis is admitted to the hospital with shortness of breath and pleuritic chest pain. He is treated with an anticoagulant, but he develops significant hematochezia. His BP is now 105/60 and HR is 117; both were within normal limits on admission. The effects of the anticoagulant are virtually completely reversed with the administration of protamine. Which of the following was the anticoagulant most likely administered to this patient? Topic Review Topic
QID: 1338
- Warfarin
- Enoxaparin
- Heparin
- Bivalirudin
- Dabigatran
- Heparin
Protamine sulfate is a large, positively charged protein molecule that binds to negatively charged unfractionated heparin and may be used to reverse the effects of heparin.
Drug A is an experimental compound being investigated for potential use as a protectant against venous thrombosis. Binding assays reveal that the drug’s primary mechanism of action is to block carboxylation of glutamic acid residues in certain serum proteins. Drug A is most similar to which of the following:
- Steptokinase
- Heparin
- Rivaroxaban
- Bivalirudin
- Warfarin
- Warfarin
Warfarin interferes with the synthesis and gamma-carboxylation of glutamic acid in the vitamin K-dependent factors II, VII, IX, and X and proteins C and S.
A 48-year-old woman is admitted to the hospital and requires anticoagulation. She is administered a drug that binds tightly to antithrombin III. Which of the following drugs was administered?
- Aspirin
- Warfarin
- Dabigatran
- Rivaroxaban
- Enoxaparin
- Enoxaparin
Unfractionated heparin and low-molecular weight heparin (LMWH) bind to antithrombin III. Enoxaparin (trade name Lovenox) is a LMWH.
A 63-year-old man is aiming to improve his health by eating a well balanced diet, walking daily, and quitting smoking following a 45-year smoking history. While on his daily walks he notices a strong cramping pain in his calves that consistently appears after a mile of walking. He sees his physician and a diagnosis of peripheral artery disease with intermittent claudication is made. To improve his symptoms, cilostazol is prescribed. What is the mechanism of action of this medication?
- Irreversible cyclooxygenase inhibitor
- Glycoprotein IIB/IIIA inhibitor
- Thromboxane synthase inhibitor
- Adenosine diphosphate receptor inhibitor
- Phosphodiesterase inhibitor
- PDE inhibitor
Cilostazol is a phosphodiesterase III inhibitor that leads to arterial vasodilation and decreased platelet aggregation. It is a first-line medication for the treatment of claudication caused by peripheral artery disease (PAD).
57 yr old man admitted to ED and diagnosed with unstable chest pain. Pt received an emergency therapy that included tirofiban. which steps, as it’s MOA, was most likely inhibited by this drug?
Binding of fibrinogen to platelet surface.
Tirofiban is a platelet glycroprotein receptor antagonist.
GP receptor is an a integrin which binds to fibrinogen in plasma for platelet aggregation to occur. Tirofiban blocks the site on the integrin to which fibrinogen binds.
Doc wants his pt to take aspirin to prevent future transient ischemic attacks, but pt is very sensitive to aspirin. what drug can the patient take instead to have the same affect?
Clopidogrel
