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Cardio II Final > Drugs used in Thromboembolic Disorders - DSA > Flashcards

Drugs used in Thromboembolic Disorders - DSA Flashcards

1
Q

Parenteral anticoagulants - indirect thrombin and factor Xa (FXa) inhibitors

A

• Unfractionated heparin
– Heparin sodium

• Low molecular weight heparins
– Enoxaparin
– Tinzaparin
– Dalteparin

• Synthetic pentasaccharide
– Fondaparinux

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2
Q

Parenteral anticoagulants - direct thrombin inhibitors

A

Lepirudin
Bivalirudin
Argatroban

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3
Q

Oral anticoagulants

A

Coumarin anticoagulatns - warfarin

Novel oral anticoagulants (NOAC):
• Factor Xa inhibitors
– Rivaroxaban 
– Apixaban 
– Edoxaban

• Direct thrombin inhibitor
– Dabigatran

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4
Q

Inhibitors of thromboxane A2 synthesis

A

Aspirin (acetylsalicylic acid)

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5
Q

ADP receptor blockers

A

Clopidogrel
Prasugrel
Ticlopidine
Ticagrelor

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6
Q

Platelet glycoprotein receptor blockers

A

Abciximab
Eptifibatide
Tirofiban

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7
Q

Inhibitors of phosphodiesterases

A

Dipyridamole

Cilostazol

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8
Q

Tissue-type plasminogen activator drugs (fibrinolytic)

A

Alteplase
Reteplase
Tenecteplase

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9
Q

Urokinase-type plasminogen activator (fibrinolytic)

A

Urokinase

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10
Q

Streptokinase preparations (fibrinolytic)

A

streptokinase

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11
Q

HMW vs LMW heparin

A

– Have practically equal efficiency in several thromboembolic conditions
– LMWs have increased bioavailability from the SC injection site and allow
for less frequent injections and more predictable dosing

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12
Q

Clinical use of heparins

A

• Very hydrophilic; must be given IV or SC

• Used to treat disorders secondary to red (fibrin-rich) thrombi and reduce the risk
of emboli
– Protects against embolic stroke, pulmonary emboli
– Administer to patients with deep vein thrombosis, atrial arrhythmias and
other conditions that predispose towards red thrombi
– Prevention of emboli during surgery or in hospitalized patients (reduces
risk of emboli)
– Heparin locks: prevents clots from forming in catheters

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13
Q

Activated Partial Thromboplastin Time (aPTT)

A

used primarily for HMV heparin
– Measures the efficacy of an intrinsic (contact activation) pathway and a common pathway
– In order to activate the intrinsic pathway, phospholipids, activator (kaolin or silica), and Ca2+ are mixed with patient’s plasma
– Evaluates serine protease factors (II, IX, X, XI,XII) affected by heparin

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14
Q

Anti-Xa assay

A

Designed to examine proteolytic activity of factor Xa

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15
Q

Adverse effects of heparin

A

– Bleeding

– Heparin-induced thrombocytopenia (HIT)

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16
Q

Heparin-induced thrombocytopenia (HIT)

A

• Mechanism: immunogenicity of the complex of heparin with platelet
factor 4 (PF4)
• A systemic hypercoagulable state
• Characterized by venous and arterial thrombosis
• Related to the immune response to heparin
• Treatment: to discontinue heparin and administer DTI

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17
Q

Contraindications to the use of heparin

A

– Severe hypertension
– Active tuberculosis
– Ulcers of GI tract
– Patients with recent surgeries

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18
Q

Reversal of heparin action

A

protamine sulfate

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19
Q

Fondaparinux

A

• Synthetic pentasaccharide (administered s.c.)

• Binds to antithrombin to indirectly inhibit Factor Xa
– High-affinity reversible binding to antithrombin III
– Conformational change in the reactive loop greatly enhances antithrombin
basal rate of factor Xa inactivation
– Fondaparinux acts as an antithrombin III catalyst

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20
Q

Difference of fondaparinux from heparins

A

– Does not inhibit thrombin activity
– Rarely induces HIT
– Its action is not reversed by Protamine sulfate

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21
Q

Clinical indications of fondaparinux

A

– Prevention of deep vein thrombosis
– Treatment of acute deep vein thrombosis (in conjunction with Warfarin)
– Treatment of pulmonary embolism

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22
Q

Lepirudin

A

– Recombinant form of hirudin (which was originally purified from medicinal
leeches)
– Lepirudin is identical to natural hirudin except for substitution of leucine for
isoleucine at the N-terminal end of the molecule and the absence of a
sulfate group on the tyrosine at position 63
– Irreversible inhibitor of thrombin

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23
Q

Bivalirudin

A

– A synthetic, 20 amino acid peptide
– Reversible inhibitor of thrombin
– Also inhibits platelet aggregation

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24
Q

Argatroban

A

– A small molecular weight inhibitor

– Short-acting drug – used intravenously

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25
Q

Clinical indications for parenteral direct thrombin inhibitors (DTIs)

A 
HIT
Coronary angioplasty (bivalirudin and argatroban)
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26
Q

Adverse effects of parental DTIs

A

– Bleeding (should be used with caution as no antidote exists)
– Repeated lepirudin use may cause anaphylactic reaction

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27
Q

MOA of warfarin

A

– Inhibits reactivation of vitamin K, by inhibiting enzyme vit K epoxide
reductase
– Inhibits carboxylation of glutamate residues by GGCX (-glutamyl carboxylase) in prothrombin and factors VII, IX, and X, making them inactive

28
Q

Proteins affected by carboxylation

A

– Factor II (protrombin)
– Hemostatic Factors VII, IX, and X
– Other proteins that function in apoptosis, bone ossification, extracellular
matrix formation, etc.

29
Q

Carboxylation of glutamate residues

A

common mechanisms of post translational modification of proteins

converts hypo functional hemostatic factors into functional ones

30
Q

Pharmacokinetics of warfarin

A

– Two stereoisomers: R and S
• S-isomer is 3 to 5-fold more potent
– R-warfarin is metabolized by CYP3A4, and some other CYP isoforms
– S-warfarin is metabolized primarily by CYP2C9
– OH-derivatives are pumped out of hepatocytes by ABCB1 transporter into
bile, excreted with bile
– Administered orally
– Has 100% bioavailability
– Delayed onset of action (12 h)
– Long half-life (36 hr)
– 99% of it is bound to plasma albumin (responsible for its small volume of
distribution and a long half-life)
– Correct warfarin dose varies widely from patient to patient
• Significant individual variability based on disease states and genetic make-up
• Multiple drug interactions

31
Q

Clinical use of warfarin

A

– Used to prevent thrombosis or prevent/treat thromboembolism
– Atrial fibrillation
– Prosthetic heart valves

32
Q

Adverse effects of warfarin

A

– Teratogenic effect (bleeding disorder in fetus, abnormal bone formation)
– Skin necrosis, infarction of breasts, intestines, extremities
– Osteoporosis
– Bleeding

33
Q

PT/INR

A

– Prothrombin time (PT) – time to coagulation of plasma after the addition of
a Tissue Factor (TF or factor III) – used for the evaluation of the extrinsic
pathway

– International normalized ratio (INR)
• 0.9-1.3 – normal
• 0.5 – high chance of thrombosis
• 4.0-5.0 – high chance of bleeding
• 2.0-3.0 – range for patients on warfarin
34
Q

Pharmacokinetic drug interactions with warfarin increasing PT

A 
Amiodarone
Cimetidine
Disulfiram
Fluconazole
Metronidazole Phenylbutazone
Sulfinpyrazone Trimethoprim-sulfamethoxazole
35
Q

Pharmacokinetic drug interactions with warfarin decreasing PT

A

Barbiturates
Cholestyramine
Rifampin

36
Q

Pharmacodynamic drug interactions with warfarin increasing PT

A

Aspirin (high doses)
Cephalosporins, third-generation
Heparin, argatroban, dabigatran, rivaroxaban, apixaban

37
Q

Pharmacodynamic drug interactions with warfarin decreasing PT

A

diuretics

Vit K

38
Q

Body factors increasing PT with warfarin

A 
hepatic disease (reduced clotting factor synthesis)
hyperthyroidism
39
Q

Body factors decreasing PT with warfarin

A

hereditary resistance

hypothyroidism

40
Q

Pharmacogenomics of warfarin

A

– VKORC1 (vit K epoxide reductase complex subunit 1) – responsible for 30% variation in dose (low and high dose haplotypes)
• High dose haplotype is more common in African Americans, they are more resistant to warfarin
• Low dose haplotype is more common in Asian American patients, they are less resistant to warfarin

– CYP2C9 – responsible for 10% variation in dose, mainly among Caucasian patients

41
Q

Warfarin drug interactions - pharmacokinetic interactions

A

– CYP enzyme induction
– CYP enzyme inhibition
– Reduced plasma protein binding

42
Q

Warfarin drug interactions - pharmacodynamic interactions

A

Synergism with other antithrombotic drugs

Competitive antagonism (vit K)

Clotting factor concentration (diuretics)

43
Q

Advantages of warfarin

A

– Oral administration
– Long duration of action
– Drug clearance is independent of renal function
– Reversal of action strategy has been developed
• Vit K administration usually reverses Warfarin action in 12-24 hours
• If more rapid reversal is needed fresh frozen plasma or prothrombin
complex concentrate are given

44
Q

Drawbacks of warfarin

A

– Very high dosing variability, maintaining optimal drug concentration is difficult
– This may lead to bleeding complications, such as intracranial
hemorrhages
– Require INR monitoring

45
Q

Clinical use of NOAC - Factor Xa inhibitors

A

– Prevention of thromboembolism (Rivaroxaban and Apixaban)
– Treatment of thromboembolism
– Prevention of stroke in patients with atrial fibrillation

46
Q

Advantages of NOAC - Factor Xa inhibitors

A

– Given orally
– Administered at fixed doses and do not require monitoring
– Shown non-inferiority compared with Warfarin (efficacy and bleeding
complications)
– Rapid onset of action as compared to warfarin

47
Q

Drawbacks to NOAC - Factor Xa inhibitors

A

– No antidotes currently exist for direct Xa inhibitors
• In the Pipeline – Andexanet alfa (modified recombinant FXa with a higher affinity for FXa inhibitors as compared to natural FXa
– Excreted by kidneys; dose adjustment is needed in renal patients

48
Q

Clinical use of NOAC- direct thrombin inhibitor

A

– To reduce the risk of stroke and systemic embolism in patients with non-
valvular atrial fibrillation
– Treatment of venous thromboembolism

49
Q

Advantages of NOAC- direct thrombin inhibitor

A

– Predictable pharmacokinetics and bioavailability
– Fixed dosing and predictable anticoagulant action (no INR monitoring
required)
– Rapid onset and offset of action
– No interaction with P450-metabolized drugs
– Antidote approved by FDA in 2015
• Idarucizumab (Praxbind) – humanized antibody fragment that binds dabigatran with high affinity to prevent dabigatran inhibition of thrombin

50
Q

Drawbacks of NOAC- direct thrombin inhibitor

A

– 80% renal excretion – may not be suitable in renal patients

51
Q

MOA of aspirin

A

– Inhibition of cyclooxygenase

– Decreased TxA2 production

52
Q

Clinical use of aspirin

A

Primary and secondary prevention of a heart attack and other vascular
events (ischemic stroke, arterial thrombosis of the limbs resulting in
intermittent claudication)

53
Q

Adverse effects of aspirin

A

PUD

GI bleeding

54
Q

MOA of blockers of ADP receptors

A

– Inhibition of AC by αi is relieved

– Increased production of cAMP

55
Q

Pharmacogenomics of clopidogrel

A

– High variability of clopidogrel action
– Related primarily to metabolism by CYP2C19 isoenzyme
– Nonfunctional CYP2C19 allele is present in 50% Chinese, 34% African
Americans, 25% Caucasians, and 19% Mexican Americans
– Cytochrome P450 status does not affect the use of other ADP receptor antagonists

56
Q

Clinical use of ADP receptor blockers

A

– Prevention of arterial thrombosis in stroke patients (Ticlopidine)
– Prevention of thrombosis in patients with ACS and recent AMI, stroke and
peripheral arterial disease (Clopidogrel, Prasugrel, Ticagrelor)
– Patients undergoing PCI and stenting (Prasugrel, Ticagrelor)

57
Q

Adverse effects of Ticlopidine

A
  • Thrombotic thombocytopenic purpura
  • GI: nausea, dispepsia, diarrhea
  • Bleeding
  • Leukopenia
58
Q

Adverse effects of Clopidogrel, prasugrel, ticagrelor

A

• Bleeding
• Dyspnea – Ticagrelor
• Less side effects that ticlopidine – they are preferred drugs over
ticlopidine

59
Q

MOA of inhibitors of PDE

A

– Inhibition of cAMP degradation

– Levels of cAMP in platelets are increased

60
Q

Clinical uses of inhibitors of PDE (adjunct anti platelet agents)

A

– Dipyridamole is used in combination with aspirin to prevent
cerebrovascular ischemia, and in combination with warfarin to prevent
thromboemboli in patients with prosthetic heart valves
– Cilostazol is primarily used to treat intermittent claudication

61
Q

Clinical use of platelet glycoprotein (GP) receptor antagonists

A

– Prevention of thrombosis in unstable angina and other acute coronary
syndromes
– In patients undergoing percutaneous coronary angioplasty
– Often used in combination with other antiplatelet agents
– Administered by i.v. infusion because of short half-lives

62
Q

Adverse effects of platelet glycoprotein (GP) receptor antagonists

A

– Hypotension
– Myalgia – Abciximab
– Thrombocytopenia (rare) – Abciximab and Tirofiban

63
Q

Thrombolytic (fibrinolytic) drugs

A

Induce fibrinolysis (lyse fibrin in thrombi after they have formed)

General mechanism: activate endogenous fibrinolytic system by different mechanisms

Plasminogen – plasma zymogen that forms active enzyme upon cleavage of the peptide bond between Arg-560 and Val-561 by tPA or uPA

Plasmin – active serine protease that cleaves and degrades fibrin and other proteins (fibronectin, laminin, thrombospondin, vWf)

64
Q

Types of fibrinolytic drugs

A

• Tissue-type plasminogen activator (tPA) – endogenous protein that cleaves
plasminogen, released by endothelium, needs fibrin as coactivator
• Urokinase-type plasminogen activator (urokinase, uPA) – endogenous protein,
produced in kidneys; a human enzyme directly converting plasminogen to
plasmin
• Streptokinase – protein released by -hemolytic Streptococci, forms the complex
with plasminogen, converts it into plasmin by a non-proteolytic mechanism

65
Q

Clinical uses of thrombolytic drugs

A
  • Acute embolic/thrombotic stroke (within 3 h)
  • Acute myocardial infarction (within 3 to 6 h)
  • Pulmonary embolism
  • Deep venous thrombosis
  • Ascending thrombophlebitis
66
Q

Adverse effects of thrombolytic drugs

A
  • Bleeding from systemic fibrinogenolysis (streptokinase, urokinase)
  • Allergic reactions (streptokinase)

Cardio II Final (15 decks)

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