Drugs for Thromboembolic Disorders Flashcards
Heparin: Mechanism of Action
- Prepared from lungs of cattle and intestines of pugs, units/mL can vary widely
- Long polysaccharide chains
- Pentasaccharide sequence found randomly that binds to/activates ANTITHROMBIN III to inhibit factor Xa, and, via formation of a ternary complex, THROMBIN
Heparin: Effects
- Blocks the generation of thrombin and inactivates thrombin
- Prevents formation of RED CLOTS
Heparin: Clinical Applications
- Used when there is a need for RAPID ONSET anticoagulant effects including PULMONARY EMBOLISM, evolving STROKE, massive DEEP VEIN THROMBOSIS, treatment of DISSEMINATED INTRAVASCULAR COAGULATION and as adjunct to thrombolytic therapy for ACUTE MI
- used in PREGNANCY since it doesn’t cross the placenta
- Used to prevent coagulation in extracorporeal circuits
- Antidote: Protamine (protein with many positive charges)
Heparin: Pharmacokinetics
- Given parenterally (IV or SC) since highly negatively charged and cannot readily cross membranes
- Binds nonspecifically. Gives highly variable plasma levels which requires intensive monitoring via aPTT assay
- Half-life of ~1.5 hours but value can vary widely
Heparin: Toxicities
- Contraindicated for patients with THROMBOCYTOPENIA and uncontrollable bleeding, and avoid use during any surgery or procedure involving brain, eye, or spinal cord
- Bleeding is a big concern and develops in 10% of patients; must be used with extreme caution in all patients with a high likelihood of bleeding
- Bleeding can occur at any site and can be fatal so need to monitor
- Pose a risk of spinal or epidural hematoma that can cause paralysis
- Heparin- induced thrombocytopenia ***
- Potentially fatal immune-mediated disorder characterized by reduced platelet counts with a paradoxical increase in thrombotic events
Low molecular weight Heparin: Enoxaparin
MOA?
- Heparin molecules of shorter length
- Because of short length, they cannot form the ternary complex with antithrombin III and thrombin that is needed to inactivate this enzyme… but, factor Xa is inhibited
Low molecular weight Heparin: Enoxaparin
Effects?
- Selectively blocks factor Xa
- Prevents formation of RED CLOTS
Low molecular weight Heparin: Enoxaparin
Clinical Applications?
- prevention of deep venous thrombosis after abdominal surgery or hip/knee replacement surgery
- treatment of established DVT without/with pulmonary embolism
- prevention of ISCHEMIC COMPLICATIONS in unstable angina, non-Q-wave MI, STEMI
- Safe in pregnancy
Low molecular weight Heparin: Enoxaparin
Pharmacokinetics
- Easier to use because dosing is predictable, can be used at home
- First choice for treatment and prevention of DVT **
- Much longer half-lives
Low molecular weight Heparin: Enoxaparin
Toxicities?
- Bleeding is major. Antidote: Protamine
- can cause heparin-induced thrombocytepenia
- Like heparin, can cause severe neurologic injury in spinal puncture or spinal or epidural anesthesia
Fondaparinux: MOA
- synthetic pentasaccharide identical to antithrombin-binding structure of heparin
- selectively inhibits factor Xa without affecting thrombin
Fondaparinux: Effects
- Blocks coagulation but preventing conversion of prothrombin to thrombin
- Slightly more effective than enoxaparin, but also has increased risk of bleeding
Fondaparinux: Clinical Applications
- preventing deep venous thrombosis
- treatment of acute pulmonary embolism in conjunction with warfarin
- treatment of acute deep venous thrombosis in conjunction with warfarin
Fondaparinux: Pharmacokinetics
- administered subQ as a fixed daily dose
- predictable pharmacokinetics
- half-life of 17-21 hrs, longer if renal impairment… too long?
Fondaparinux: Toxicities
- bleeding is biggest concern. NOT reversible with protamine
- does NOT cause heparin-induced thrombocytopenia
Hirudin analogs: Bivalirudin
MOA?
synthetic 20 aa peptide similar to hirudin (anticoagulant of leeches), directly blocks thrombin
Hirudin analogs: Bivalirudin
Effects?
reversibly inhibits thrombin
Hirudin analogs: Bivalirudin
Clinical Applications?
can be given in combination with ASPIRIN to patients undergoing coronary ANGIOPLASTY
Hirudin analogs: Bivalirudin
Pharmacokinetics?
- Must be given by IV
- Expensive
Hirudin analogs: Bivalirudin
Toxicities
- doesn’t require antithrombin and causes less bleeding
- NO antidote
Argatroban: MOA
directly binds to CATALYTIC SITE OF thrombin (like hirudin analog but doesn’t bind to substrate binding site of thrombin like them)
Argatroban: Effects
none emphasized
- reduces development of new thrombosis
- permits restoration of platelet counts in those with HIT
Argatroban: Clinical Applications
- prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia
- efficacy of treatment is monitored by aPTT
Argatroban: Pharmacokinetics
- given IV
- Short half-life
Argatroban: Toxicities
none emphasized
- Risk for hemorrhage
- 12% develop hematuria
Warfarin: MOA
- vitamin K antagonist
- ORAL
Warfarin: Effects
- Decreases production of biologically active forms of calcium-dependent clotting factors II, VII, IX and X, as well as Protein C and Protein S
Warfarin: Clinical Applications
• Drug most widely used for long-term prophylaxis of thrombosis… especially for:
- prevention of venous thrombosis
- prevention of thromboembolism in patients with mechanical heart valves
- prevention of thrombosis in patients with atrial fibrillation
- not useful in emergencies since effects are delayed
Warfarin: Pharmacokinetics
- Orally active, 100% bioavailability
- eliminated by liver in bile
- slow onset
- slow offset
- monitored with prothrombin time ratio, patients value to control value… now normalized (INR), must be monitored frequently, aim for INR = 2-3
- monitor more frequently whenever a drug is added or subtracted
Warfarin: Toxicities
• bleeding is major complication
- If bleeding occurs, discontinue warfarin immediately:
- warfarin effects can be reversed by administering vitamin K
- can quickly raise clotting factors levels with fresh whole blood, plasma or plasma concen
- liver disease increases risk
- crosses the placenta
- has many drug interactions:
- drugs that INCREASE effects of warfarin
- drugs that PROMOTE BLEEDING
- drugs that DECREASE effects of warfarin
Rivaroxaban: MOA
direct inhibitor of activated factor X
Rivaroxaban: Effects
- directly inhibits the production of thrombin
- advantages over warfarin:
- rapid onset
- fixed dosage
- lower bleeding risk
- fewer drug interactions
- no need for INR monitoring
Rivaroxaban: Clinical Applications
• Has 2 approved uses:
1. Prevention of deep venous thrombosis and pulmonary embolism after hip or knee replacement
- prevention of STROKE in patients with NONVALVULAR ATRIAL FIBRILLATION
• But..
- Dosing on time is important
- no antidote for overdose (but andexanet alfa recently approved)
Rivaroxaban: Pharmacokinetics
- administered ORALLY and has a high bioavailability
Rivaroxaban: Toxicities
• Bleeding is the major concern and has caused:
- epidural hematoma
- major intracranial/retinal bleeds
- adrenal bleeding
- GI bleeding
- should be avoided in patients with significant renal or hepatic impairment
- unsafe in pregnancy
- should not be combined with other anticoagulants
- interacts with CYP3A4
What is a recombinant form of hirudin, no longer available in US?
desirudin
What drugs are similar to Enoxaparin with similar indications?
delteparin, tinazeparin
Other drugs besides Rivaroxaban?
others include apixaban and edoxaban
Dabigatran: MOA
Reversible direct thrombin inhibitor
Dabigatran: Effects
- Directly blocks thrombin
- Has 5 advantages over Warfarin:
- rapid onset
- no need to monitor
- few drug or food interactions
- lower risk of bleeding
- same dose is used for all patients
Dabigatran: Clinical Applications
- approved for use in prevention of STROKE and SYSTEMIC EMBOLISM IN patients with NONVALVULAR ATRIAL FIBRILLATION
- recently given a contraindication for therapy of those with mechanical heart valves
Dabigatran: Pharmacokinetics
- Pills are unstable
Dabigatran: Toxicities
- Bleeding is the major concern
- antidote recently approved: idarucizumab
Aspirin: MOA
- irreversibly inhibits cyclooxygenase (thereby blocks synthesis of TXA2)
- see benefits since low dose aspirin (≤325 mg/day) preferentially blocks COX-1
Aspirin: Effects
- blocks formation of TXA2
- Because platelets have no ability to synthesize new COX-1, this blockade persists for the LIFETIME of the platelet
Aspirin: Clinical Applications
- transient ischemic attacks
- ischemic stroke
- chronic stable angina
- unstable angina
- Acute MI
- Previous MI
- Primary prevention of MI
- coronary stenting
Aspirin: Pharmacokinetics
none emphasized
- ORAL
- Doses need to be low
Aspirin: Toxicities
none emphasized
• Even at low doses, increases risk of: - peptic ulcer - GI bleeding - hemorrhagic stroke … so benefits must be weighed against risks
Clopidogrel: MOA
- irreversible blockade of P2Y12 receptors on platelets
- blocking the P2Y12 receptor prevents its Gi-protein driven decreases in platelet cAMP
Clopidogrel: Effects
- inhibits platelet aggregation
- like aspirin, has effects of platelet for its lifetime
Clopidogrel: Clinical Applications
• Used to:
- prevent stenosis of coronary stents
- secondary prevention of MI and ischemic stroke
Clopidogrel: Pharmacokinetics
- PRODRUG must be converted to active form by CYP2C19…
* some people have CYP2C19 variant enzyme that cannot activate clopidogrel (certain races)
Clopidogrel: Toxicities
- generally well-tolerated
- carries a risk of bleeding, but risk is lower for GI bleeding and intracranial hemorrhage than for aspirin
another prodrug that is a close relative of clopidogrel, more effective with fewer drug interactions, but also causes more major bleeding
prasugrel
reversible P2Y12 blocker that is not a prodrug, more effective than clopidogrel but increased risk of hemorrhagic stroke
ticagrelor
Dipyridamole: MOA
none emphasized
Uncertain
Dipyridamole: Effects
somehow suppresses platelet aggregation
Dipyridamole: Clinical Applications
Used in a fixed-dose combination with aspirin to prevent recurrent ischemic stroke
Dipyridamole: Pharmacokinetics
none emphasized
ORAL
Dipyridamole: Toxicities
- BLEEDING is a concern
- most common adverse effects are:
- headache
- dizziness
- nausea
- vomiting
- dyspepsia
- diarrhea
Cilostazol: MOA
type 3 phosphodiesterase inhibitor … i.e., prolongs life of cAMP in platelets and cells
Cilostazol: Effects
- platelet aggregation inhibitor
- vasodilator
Cilostazol: Clinical Applications
claudication
Cilostazol: Pharmacokinetics
none emphasized
- ORAL tablet
- Metabolized by CYP3A4
Cilostazol: Toxicities
none emphasized
- headache (~34%)
- diarrhea/abnormal stools
- palpitations
- dizziness
- peripheral edema
Abciximab: MOA
purified Fab fragment of monoclonal antibody
Abciximab: Effects
• Blocks the final common pathway of platelet aggregation
- Thus inhibits aggregation caused by all factors
•most effective of antiplatelet drugs
Abciximab: Clinical Applications
• used short-term to prevent ischemic events in:
- acute coronary syndromes
- percutaneous coronary intervention
Abciximab: Pharmacokinetics
Administered IV
Abciximab: Toxicities
none emphasized
- doubles risk of major bleeding
* also may cause GI, urogenital and retroperitoneal bleeds
SMALL PEPTIDE INHIBITOR of GP IIb/IIIa, also approved for ACS and PCI; Integrilin(TM), recently available as generic
eptifibatide
NON-PEPTIDE INHIBITOR of GP IIb/IIIa modeled from venom of saw-scaled viper, also used for ACS and off-label for PCI, patent expired Jan 2019 but no generics yet
tirofiban
alteplase (tPA): MOA
• purified glycoprotein of 527 amino acids
- AA sequence is identical to HUMAN TISSUE PLASMINOGEN ACTIVATOR
- generated in Chinese hamster ovary cells by recombinant DNA technology
alteplase (tPA): Effects
catalyzes the conversion of clot-bound plasminogen to plasmin, the major enzyme responsible for clot breakdown
alteplase (tPA): Clinical Applications
3 main indications:
- acute myocardial infarction
- acute ischemic stroke
- acute massive pulmonary embolism
alteplase (tPA): Pharmacokinetics
- large molecule that must be administered parenterally, almost always IV
- very short half-life
alteplase (tPA): Toxicities
bleeding is the major complication
- INTRACRANIAL HEMORRHAGE is the most serious concern
Occurs for 2 reasons:
1. DESTROYING PREEXISTING CLOTS CAN promote re-occurrence of bleeding at that site
- By degrading clotting factors, interferes with clot formation
tPA variant (3 aa) with longer half-life (20-24 min), can be given as IV bolus, approved only for MI; recent data –> 2X more effective than alteplase for stroke
tenectaplase
355 aa tPA derivative, has half-life of 13-16 min, approved only for MI
reteplase
alteplase (tPA): Absolute contraindications
- any prior intracranial hemorrhage
- know structural cerebral vascular lesion
- ischemic stroke with past months, unless has occurred within past 4.5 hrs*
- active internal bleeding (other than menses)
- suspected aortic dissection
alteplase (tPA): Relative Contraindication
- severe uncontrolled hypertension on presentation (BP > 180/110 mm Hg)
- history of prior ischemic stroke, dementia or known intracerebral pathology not covered in absolute contraindications
- traumatic or prolonged CPR (> 10 min) or major surgery (< 3 weeks ago)
- noncompressible vascular punctures
- active peptic ulcer
- history of chronic, severe, poorly-controlled hypertension
- current use of anticoagulants in therapeutic doses (INR 2-3 or greater); known bleeding diathesis
- recent internal bleeding (< 4 weeks ago)
- pregnancy
urokinase (uPA): MOA
second physiologic plasminogen activator, present in high concentration in the URINE
urokinase (uPA): Effects
the major activator of fibrinolysis in the fluid phase / extravascular compartment
urokinase (uPA): Clinical Applications
pulmonary embolism
urokinase (uPA): Pharmacokinetics
injected IV slowly
urokinase (uPA): Toxicities
- potentially fatal hemorrhage
- anaphylactic shock
similar/classic systemic non-proteolytic activator of plasminogen purified from bacteria, appears to no longer be available in the US
streptokinase
