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1
Q

Heparin

structure

MOA

onset of action, duration of action

site of action

clinical use

Toxicities

route of administration

antidote

blood monitoring

cross placenta?

A

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

2
Q

What are the low molecular weight heparins?

How do they compare to regular heparin?

A

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
3
Q

Direct factor Xa inhibitors

drugs in this class

MOA

clinical use

toxicities

form(s) of administration

blood monitoring

reversal agent

A

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

4
Q

Direct thrombin inhibitors

drugs in this class

MOA

clinical uses

forms of administration

Which must be adjusted for hepatic dysfunction?

A

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)
  • BivalirudinIV 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
  • Dabagatranoral direct thrombin inhibitor (approved in AF, may replace warfarin)
5
Q

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?

A

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.

6
Q

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.

A

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.

7
Q

Thrombolytics

LIST drugs in this class

MOA

clinical use

toxicity

Contraindications

reversal agents

What blood values change with administration of these drugs?

A

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.

8
Q

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

A

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

Alteplasehuman t-PA manufactured by recombinant DNA technology

  • IV infusion
  • More potent than streptokinase & Urokinase
  • Fibrin specific binding

Reteplaserecombinant human t-PA, several human amino acids deleted, less fibrin specific

  • two IV boluses separated by 30 min

Tenecteplasemutant form of t-PA, longer half-life

  • single bolus (may be an advantage)
9
Q

Aspirin (ASA)

MOA

clinical use

Toxicities

effects on blood values

A

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.

10
Q

ADP receptor inhibitors

LIST drugs in this class

MOA

clinical use

toxicities

A

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.

11
Q

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).

A

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
12
Q

GP IIb/IIIa inhibitors

drugs in this class

MOA

clinical use

toxicities

A

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

13
Q

Cilostazol, dipyradimole

MOA

clinical use

toxicities

What is the diffence in use btwn these two drugs? How are they administered?

A

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.

14
Q

Vitamin K1: forms of administration, onset and duration of action

Protamine sulfate: dose, toxicities, clinical use

A

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