Treatment of acute coronary syndromes week 2 Flashcards
Heparin
structure
MOA
onset of action, duration of action
site of action
clinical use
Toxicities
route of administration
antidote
blood monitoring
cross placenta?
Heparin
structure: Large, anionic, acid polymer of sulfated mucopolysaccharides
MOA: Activates antithrombin which inactivates thrombin and factor Xa
Onset of action: Rapid-seconds. Short half life-duration of action is acute (hours).
Site of action: Blood
Clinical use: Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT
Toxicities: Bleeding, heparain induced thrombocytopenia (HIT), osteoporosis, drug-drug interactions
HIT: development of IgG Abs againts heparin bound platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets–> Thrombosis and thrombocytopenia. rare toxicity.
Route of administration: Parenteral-IV, SC. Short half life-Continuous infusion or SC injection
Antidote: Protamine sulfate-positively charged molecule that binds negatively charged heparin
Blood monitoring: PTT (intrinsic pathway)
DOES NOT CROSS PLACENTA (too large) SAFE TO USE IN PREGNANCY
What are the low molecular weight heparins?
How do they compare to regular heparin?
Enoxaparin, Dalteparin, Fondaparinux
- shorter chain
- act more on factor Xa
- better bioavailability
- 2-4x longer half life
- can be adminstered SQ without laboratory monitoring
- not easily reversible
Direct factor Xa inhibitors
drugs in this class
MOA
clinical use
toxicities
form(s) of administration
blood monitoring
reversal agent
Apixaban, Rivaroxaban-factor Xa inhibitors
MOA: Bind to and directly inhibit factor Xa
Clinical use: Tx and prophylaxis for pts with DVT and PE (rivaroxaban), stroke prophlyaxis in pts with atrial fibrillation
Toxicities: Bleeding
Form of administration: PO, these oral agents do not usually require coagulation monitoring
No reversal agent available
Direct thrombin inhibitors
drugs in this class
MOA
clinical uses
forms of administration
Which must be adjusted for hepatic dysfunction?
Direct thrombin inhibitors
MOA: directly binds to active site of thrombin–>inhibits clotting
clinical uses: Alternatives to thrombin for anticoagulating pts with HIT (heparin induced thrombocytopenia). Remember that heparin is used for PE, ACS, MI, DVT
- Herudin (recombinant form Lepirudin leech saliva) used in heparin–induced thrombocytopenia (HIT)
- Bivalirudin – IV bolus and infusion, short half-life, also inhibits platelets and used in coronary stenting
- Argatroban – small molecular wt thrombin inhibitor used in HIT. Given IV, titrated to aPTT. Dosing adjustment required for hepatic fxn
- Dabagatran – oral direct thrombin inhibitor (approved in AF, may replace warfarin)
Warfarin
structure
MOA
onset of action, duration of action
clinical use
Toxicities
route of administration
onset and duration of action
site of action
antidote
blood monitoring, therapeutic range
cross placenta?
How do polymorphisms effect the action of this drug?
What drug is often administered with warfarin and why?
Warfarin
structure: small amphipathic molecule
MOA: Interferes with gamma carboxylation of vitamin K dependent clotting factors II, VII, IX, X, and proteins C and S by inhibiting C1 subunit of vitamin K epoxide reductase. Vitamin K epoxide reductase reduces vitamin K so it can act as a cofactor for gamma carboxylation. (note these factors need gamma carboxylation bc they are Ca2+ dependent, negatively charged carboxyl groups interact with Ca2+). Metabolism affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1)
Clinical use: chronic anticoagulation (eg. venous thromboembolism prophylaxis, prevention of stroke in A-fib.
Toxicities: Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions. Proteins C and S have shorter half-lives than clotting factors II, VII, IX, and X, resulting in early transient hypercoagulability with warfarin use. (Proteins C and S gone–> no inhibition of V and VIII—> continued activation of factors IX and X–> hypercoagulability)
Skin/tissue necrosis believed to be due to small vessel microthromboses.
Heparin “bridging”: heparin frequently used when starting warfarin. Heparin’s activation of antithrombin enables anticoagulation during initial, transient hypercoagulable state caused by warfarin. Initial heparin therapy reduces risk of recurrent venous thromboembolism and skin/tissue necrosis.
Route of administration: PO
Onset and duration of action: onset of action is slow, limited by half-lives of normal clotting factors. duration of action is chronic (days)
Site of action: Liver (where clotting factors are synthesized)
Antidote: Vitamin K. Fresh frozen plasma (FFP) for rapid reversal
Blood monitoring: PT/INR (extrinsic pathway). The EX-PresidenT went to war(farin). INR range 2-3.5 is therapeutic.
WARFARIN CROSSES THE PLACENTA-TERATOGEN. Warfarin starts a war with the fetus.
How does warfarin travel in the blood?
How is warfarin metabolized?
Polymorphisms of what enzymes require modification of dosing warfarin? How does the dose need to be modified?
What drugs interfere with warfarin’s action?
What body factors interfere with warfarin’s action?
Separate the effects of drugs and body factors into those that increase and those that decrease prothrombin time.
Protein bound, displaced easily so increased free drug causes more adverse effects results in multiple drug interactions, problematic.
Metabolized by CYP3A4 and CYP2C9 (CYP450 substrates-Anti-epitleptics, Theophyllines, Warfarin, OCPs-Always Think When Outdoors)
Phamacogenomics: increased bleeding risk for patients with CYP2C9*2 or CYP2C9*3 alleles.
- CYP2C9*2 needs 17% less drug
- CYP2C9*3 needs 37% less drug
see pg 49 of course notes for drugs and body factors that interfere with warfarins action.
Thrombolytics
LIST drugs in this class
MOA
clinical use
toxicity
Contraindications
reversal agents
What blood values change with administration of these drugs?
Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA), urokinase
MOA: Directly or indirectly aid in the coversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots.
Increase in PT and PTT, no change in platelet count
Clinical use: Early MI, early ischemic stroke (NON HEMORRHAGIC), direct thrombolysis of severe PE
Toxicity: Bleeding
Contraindicated in pts with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe HTN.
Reversal agent: Aminocaproic acid-inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
State the differences in activity/potentcy and where they are isolated/how they are made of the following fibrinolytic drugs:
streptokinase
urokinase
alteplase
reteplase
tenecteplase
Streptokinase
- Facilitates plasminogen to plasmin
- From strep bacteria & thus antigenic
- Given by IV infusion
- Was the first thrombolytic agent tested
Urokinase –
- Facilitates plasminogen to plasmin
- From humans, synthesized by kidney, isolated from urine
- Loading & IV infusion
Alteplase – human t-PA manufactured by recombinant DNA technology
- IV infusion
- More potent than streptokinase & Urokinase
- Fibrin specific binding
Reteplase – recombinant human t-PA, several human amino acids deleted, less fibrin specific
- two IV boluses separated by 30 min
Tenecteplase – mutant form of t-PA, longer half-life
- single bolus (may be an advantage)
Aspirin (ASA)
MOA
clinical use
Toxicities
effects on blood values
ASA-antiplatelet
MOA: Irreversibly inhibits both COX1 and COX2 enzyms by covalent acetylation. Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced.
increased bleeding time, decreased TXA2 and prostaglandins. No effect on PT or PTT.
Clinical use: Antipyretic, analgesic, anti-inflammatory, antiplatelet (decreased aggregation). Primary prevention and secondary MI therapy after stent.
Toxicity: Gastric uleraction, tinnitis (CNVIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Reye syndrome in children with viral infection (acute brain damage and liver function problems, has occurred in children who were given aspirin when they had chickenpox or the flu-see below for more info). Overdose initially causes hyperventilation and respiratory alkalosis, but transitions to mixed metabolic acidosis-respiratory alkalosis.
ninds.nih.gov: Reye’s syndrome (RS) is primarily a children’s disease, although it can occur at any age. It affects all organs of the body but is most harmful to the brain and the liver–causing an acute increase of pressure within the brain (cerebral edema-encephalopathy) and, often, massive accumulations of fat in the liver and other organs. RS is defined as a two-phase illness because it generally occurs in conjunction with a previous viral infection, such as the flu or chicken pox. The disorder commonly occurs during recovery from a viral infection, although it can also develop 3 to 5 days after the onset of the viral illness. RS is often misdiagnosed as encephalitis, meningitis, diabetes, drug overdose, poisoning, sudden infant death syndrome, or psychiatric illness. Symptoms of RS include persistent or recurrent vomiting, listlessness, personality changes such as irritability or combativeness, disorientation or confusion, delirium, convulsions, and loss of consciousness. If these symptoms are present during or soon after a viral illness, medical attention should be sought immediately. The symptoms of RS in infants do not follow a typical pattern; for example, vomiting does not always occur. Epidemiologic evidence indicates that aspirin (salicylate) is the major preventable risk factor for Reye’s syndrome. The mechanism by which aspirin and other salicylates trigger Reye’s syndrome is not completely understood. A “Reye’s-like” illness may occur in children with genetic metabolic disorders and other toxic disorders. A physician should be consulted before giving a child any aspirin or anti-nausea medicines during a viral illness, which can mask the symptoms of RS.
ADP receptor inhibitors
LIST drugs in this class
MOA
clinical use
toxicities
Clopidogrel, Pasgurel, Ticagrelor, Ticlodipine
MOA: Inhibit platelet aggregation by irreversibly blocking ADP receptors (P2Y12 receptor) preventing expression of glycoproteins IIb/IIIa on platelet surface.
Clinical use: Acute coronary syndrome; coronary stenting. Decreased incidence or recurrence of thrombotic stroke.
Toxicities: Neutropenia (ticlodipine). TTP may be seen.
What activates the ADP receptor inhibitors? In what part of the body? What drug interactions can occur?
Explain the difference in activities and/or activation of the ADP receptor inhibitors (clopidogrel, ticlodpine, prasugrel, ticagrelor).
Clopidogrel
- Pro-drug activated via CYP2C19 hepatic enzyme pathway & lots of drug interactions
- Drugs that impair CYP2C19 function such as the proton pump inhibitor omeprazole can decrease clopidogrel action
- About 15% of population can’t activate pro drug
Ticlopidine - similar to clopidogrel,
- frequent leucopenia & blood dyscrasias (not used)
Prasugrel
- Activated faster in liver, multiple pathways for activation so less drug interactions, works like clopidogrel, more bleeding (toxicity)
Ticagrelor
- Newest antiplatelet agent
- Similar to adenosine in structure
- Inhibits ADP induced platelet aggregation
- Active drug, not a pro-drug, so less drug interactions & more reliable action
GP IIb/IIIa inhibitors
drugs in this class
MOA
clinical use
toxicities
Abciximab, eptifibatide, tirofiban
MOA: Bind to glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abcixmab is made from monoclonal antibody Fab fragments
Clinical use: Unstable angina, percutaenous transluminal coronary angioplasty
Toxicities: Bleeding, thrombocytopenia
Abciximab given IV, very expensive
Cilostazol, dipyradimole
MOA
clinical use
toxicities
What is the diffence in use btwn these two drugs? How are they administered?
MOA: phosphodiesterase III inhibitor; increase cAMP in platelets resulting in inhibition of platelet aggregation; vasodilators
Clinical use: Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with ASA), angina prophylaxis
Toxicities: nausea, headache, facial flushing, hypotension, abdominal pain
Dipyradimole: Available IV & oral. Used with ASA in pts with prosthetic heart valves
Cilostazol: used in pts who fail ASA and clopidogrel or cant tolerate clopidogrel and/or therapy for claudication. Oral only.
Vitamin K1: forms of administration, onset and duration of action
Protamine sulfate: dose, toxicities, clinical use
Antidotes
Vitamin K1 – phytonadione available in oral and parenteral forms
- onset 6 hrs, duration 24 hrs
Protamine sulfate
- For every 100 units heparin 1 mg protamine can be given for reversal of effect
- hepatic & thrombotic toxicity & paradoxical bleeding
- may cause anaphylaxis
- used in cardiac cath lab to quickly reverse anti-coagulation by heparin
