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Pharmacology 344 > Anti-platelet, anti-coagulant & fibrinolytic drugs > Flashcards

Anti-platelet, anti-coagulant & fibrinolytic drugs Flashcards

1
Q

Describe platelet formation.

A
  1. Vasuclar injury leads to platelet adhesion in the damaged tissue.
  2. Platelets begin to agregate.
  3. Fibrin forms through activation of II to IIa (throbin). Thrombin activates fibrinogen into fibrin as part of the coagulation pathway.
  4. Fibrinolysis is them performed to break down the clot. In this pathway tPA enzyme cleaves plasminogen into plasmin.
  5. Vascular repair.
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2
Q

What is thrombosis?

A
  • Pathological formation of hemostatic plug,
    often occurring in absence of bleeding.
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3
Q

What are white clots?

A
  • Location: arterial. Rapid blood flow (arteries of heart and brain).
  • Composition: mainly platelets with some fibrin.
  • Main risk factor: rupture atherosclerotic plaque.
  • Clinical presentation: Myocardial infracture, cerebrovascular stroke.
  • Treatment: Anti-platelet drugs (prevention; can’t be treated after it occurs.
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4
Q

What are red clots?

A
  • Location: venous. Relative stasis (veins, chambers of heart).
  • Composition: Fibrin and erythrocytes, few platelets.
  • Main risk factor: Slow/disturbed blood flow. Hypercoagulable state.
  • Clinical presentation: Venous thromboembolism, cardioembolic stroke.
  • Treatment: Anticoagulant drugs.
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5
Q

What are the preventative treatments for blood clots?

A
  • Anti-platelet drugs.
  • Anti-coagulant drugs.
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6
Q

What are anti-platelet drugs?

A
  1. Acetylsalicylic acid.
  2. Thienopyridines: Ticlopidine, Clopidogrel, Prasugrel.
  3. Non-thienopyridine P2Y12 antagonist: Ticagrelor.
  4. Dipyridamole.
  5. GP IIb/IIIa Receptor Antagonists: Abciximab, Epifibatide, Tirofiban.
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7
Q

What are the treatments for blood clots?

A
  • Thrombolytic/Fibrinolytic drugs.
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8
Q

Describe the essence of anti-platelet drugs.

A
  1. Anti-platelet drugs prevent platelets from sticking together (aggregating).
  2. Consequently, an;-platelet drugs prevent adverse cardiovascular events such as myocardial infarction or stroke from occurring.
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9
Q

Anti-platelet drugs inhibit platelet aggregation
by targeting _________.

A

Anti-platelet drugs inhibit platelet aggregation
by targeting platelet pathways.

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10
Q

What are the unwanted effects of ASA?

A
  • Gastrointes;nal – ulcer formation, bleeding.
  • Decreased hemostatic function (bleeding).
  • Hypersensitivity – patients with asthma and nasal polyps.
  • Reye’s syndrome in children with or after a viral
    infection.
  • Decrease glomerular filtration rate in patients with renal disease.
  • Mild hepatitis.
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11
Q

What is ASA?

A
  • Non-selec;ve non-steroidal an;-inflammatory drug (NSAID).
  • Also has anti-platelet effects.
  • Orally active, low dose enough to inhibit platelet function.
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12
Q

Describe the mechanism of action of ASA.

A
  • Irreversibly acetylates and inhibits Cyclooxygenase-1 (COX-1) thereby preventing thromboxane-A2 (TXA2) synthesis.
  • TXA2 is a potent platelet aggregation
    stimulator.
  • Inhibition lasts for life span of platelets
    (7-10 days).
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13
Q

What are the thienopyridines?

A

a. Ticlopidine.
b. Clopidogrel.
c. Prasugrel.

  • Orally active, prodrugs requiring hepatic conversion to active metabolites.
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14
Q

Describe the mechanism of action of thienopyridines.

A
  • Irreversible, non-competitive antagonists of ADP binding to P2Y12 receptors.
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15
Q

What is ticlopidine?

A
  • First thienopyridine introduced.
  • Can cause neutropenia and thrombocytopenia has unwanted effects.
  • Largely replaced by clopidogrel.
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16
Q

What is clopidogrel?

A
  • Fewer serious unwanted effects than ticlopidine, but still can cause dyspepsia, rash, diarrhea.
  • Usually used by ASA intolerant individuals.
  • Fairly quick metabolism after oral administration (~ 5 hrs with loading dose).
  • Problem: some patients with variant alleles of CYP2C19 are poor metabolizers; hence, clopidogrel is not efficiently converted into active metabolite.
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17
Q

What is prasugrel?

A
  • Newest thienopyridine.
  • Faster biotransforma;on (30 min) to ac;ve metabolite.
  • More efficacious as an;-platelet drug, but also more bleeding.
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18
Q

What is ticagrelor?

A
  • Non-thienopyridine P2Y12 antagonist.
  • Cyclo-pentyl-triazolo-pyrimidine.
  • Not a pro-drug, has direct action.
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19
Q

Describe the mechanism of action of ticagrelor.

A
  • Orally active, reversible allosteric P2Y12 antagonist.
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20
Q

What are the adverse effects of ticagrelor>

A
  • Dyspnea, bradyarrhythmia (more likely to discontinue use than clopidogrel).
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21
Q

What is Dual Anti-Platelet therapy (DAPT)?

A
  • ASA is often combined with P2Y12 inhibitors (Clopidogrel and Ticagrelor) as part of Dual Anti-
    Platelet Therapy (DAPT)
  • Usually up to one year following MI and one month following cerebrovascular stroke
  • Depending on the indication – different combinations of P2Y12 inhibitors recommended with ASA.
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22
Q

Describe dipyridamole’s mechanism of action.

A
  • Cyclic nucleotide phosphodiesterase (PDE) inhibitor.
  • Blocks adenosine (a weak platelet inhibitor) uptake.
  • May decrease platelet TXA2 / or increase
    endothelial PGI2 synthesis.
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23
Q

Is dipyridamole used alone?

A
  • Not effective alone; used with ASA to prevent transient ischemic attacks and stroke.
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24
Q

What are glycoprotein IIb/IIa?

A
  • GPIIb/IIIa (integrin αIIbβ3) – receptor for fibrinogen.
  • Fibrinogen cross-links platelets upon aggregation.
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25
Q

What are the glycoprotein IIb/IIIa antagonists?

A

a. Abciximab.
b. Eptifibatide.
c. Tirofiban.

26
Q

Describe the mechanism of action of glycoprotein IIb/IIIa antagonists

A
  • GPIIb/IIIa antagonists block receptor or compete for receptor occupancy with fibrinogen.
  • Inhibit the final common step leading to platelet aggregation.
27
Q

What is abciximab?

A
  • Glycoprotein IIb/IIIa Antagonist.
  • Mouse/human chimeric monoclonal Ab vs. GPIIb/IIIa.
28
Q

What is eptifibaide?

A
  • Glycoprotein IIb/IIIa Antagonist.
  • Synthetic cyclic heptapeptide.
29
Q

What is tirofiban?

A
  • Glycoprotein IIb/IIIa Antagonist.
  • Synthetic non-peptide.
30
Q

What are the similarities of eptifibatide and tirofiban?

A
  • Both are based on Arg-Gly-Asp (RGD) sequence that is common to GPIIb/IIIa ligands.
  • Not selective for fibrinogen.
31
Q

How are glycoprotein IIb/IIIa antagonists administered?

A
  • All are administered iv (can only be given in a hospital setting).
  • Used to prevent thrombosis in patients with acute coronary syndromes or undergoing coronary angioplasty.
32
Q

What are the unwanted effects of glycoprotein IIb/IIIa antagonists?

A
  • Bleeding.
  • Thrombocytopenia.
33
Q

What is blood coagulation?

A
  • Blood coagulation = secondary hemostasis.
  • Clotting = Coagulation (Blood converted into solid gel called clot or thrombus).
  • Occurs around platelets and reinforces plug.
  • Vital hemostatic defence mechanism.
34
Q

What are the anti-coagulants?

A
  1. Warfarin
  2. Heparins: Unfractionated heparin or Low molecular weight heparin.
  3. Direct oral Anti-coagulants (DOACss): Rivaroxaban (and Apixiban & Edoxaban) or Dabigatran etexilate.
  4. Hirudins.
35
Q

What is Virchow’s Triad?

A
  • Factors that increase the risk of blood clots: Circulatory stasis, Hypercoagulable state, Endothelial injury.
36
Q

What is circulatory stasis?

A
  • Atrial Fibrillation.
  • Immobilization.
  • Deep Vein Thrombosis.
37
Q

What is hypercoagulable state?

A
  • Malignancy.
  • Deficiencies in anti-clotting factors.
  • Pregnancy.
38
Q

What is EC injury?

A
  • Trauma.
  • Fractures.
  • Surgery.
  • Heart valve replacement.
39
Q

What is coagulation?

A
  • A proteolytic cascade involving serine proteases.
40
Q

Describe the Coagulation pathway.

41
Q

What is warfarin?

A
  • Derived from sweet clover.
  • Oral anticoagulant, one of the oldest anticoagulants.
  • Initially developed as rat poison (rats would bleed out).
42
Q

Describe warfarin’s mechanism of action.

A
  • Vitamin K reductase antagonist
  • Interferes with carboxylation of glutamic acid residues in clotting factors II, VII, IX, and X.
  • Leads to accumulation of inactive clotting factors that cannot bind to negatively charged surfaces via Ca2+.
43
Q

What are the issues with warfarin?

A
  • Peak blood concentration < 1hr after ingestion; peak
    pharmacological effect > 48 hrs later.
  • Wide individual variation; therefore, treatment a highly
    individualized matter.
  • Teratogenic.
  • Need for monitoring – International Normalized Ratio (INR).
  • MANY drug interactions (also with natural health products & certain foods).
  • Increase risk of bleeding –narrow therapeutic window.
44
Q

What are the unwanted effects of warfarin?

A
  • Bleeding.
  • Liver damage.
45
Q

What are heparins?

A
  • First extracted from liver.
  • Administered intravenously or subcutaneously.
  • Negatively charged sulfated glycosaminoglycans (3 – 40 KDa MW).
  • Contain unique pentasaccharide sequence responsible for mechanism of action.
  • Rapid onset of action.
  • Used to bridge warfarin therapy.
46
Q

Describe the mechanism of action of heparins.

A
  • Bind antithrombin III (ATIII) – an endogenous
    anticoagulant- via pentasaccharide sequence.
  • Induce conformational change in
    antithrombin III which increases affinity for
    active site of serine proteases of coagulation
    cascade.
  • UFH particularly good at inhibiting thrombin
    (IIa).
  • LMWH particularly good at inhibiting Xa.
47
Q

Do LMWH or UF heparin have better pharmacokinetics?

A
  • LMWH have more favorable pharmacokinetics – longer
    elimination half-life – dosing less frequent and anticoagulation effects more predictable.
48
Q

What are the unwanted effects of heparin?

A
  • Bleeding.
  • Heparin-induced thrombocytopenia (HIT)/thrombosis.
49
Q

What is rivaroxaban?

A
  • Orally active drug.
  • Once daily dosing.
50
Q

Describe the mechanism of action of rivaroxaban.

A
  • Reversible, direct competitive inhibitor of Fxa.
  • > 10,000-fold selectivity for FXa than other serine proteases of coagulation pathway.
51
Q

What are the unwanted effects of rivaroxban?

A
  • Bleeding.
  • Contraindicated in pa;ents with renal failure (66% of absorbed drug excreted by kidneys).
52
Q

What other drugs are similar to rivaroxaban?

A
  • Apixiban and Edoxaban.
53
Q

What is dabigatran etexilte?

A
  • Orally active prodrug.
  • Once/twice daily dosing (short half-life).
  • Rapidly converted by plasma esterases to dabigatran.
54
Q

Describe the mechanism of action of dabigatran etexilate.

A
  • Reversible, direct compe;;ve inhibitor of thrombin.
55
Q

What are the unwanted effects of dabigatran etexilate.

A
  • Bleeding.
  • Contraindicated in patients with renal failure (80% of absorbed drug excreted by kidneys).
56
Q

What are hirudins?

A
  • Anticoagulant from medicinal leech.
  • Specific inhibitor of thrombin.
  • 7 KDa protein (65 amino acids).
  • Does not need ATIII.
  • Slowly reversible.
57
Q

What is lepirudin?

A
  • Recombinant hirudin.
58
Q

What is bivalirudin?

A
  • 20 amino acid hirudin-based synthetic peptide.
59
Q

What are the thrombolytic (fibrinolytic) drugs?

A
  1. Recombinant tissue-Plasminogen Activator (r-tPA).
  2. Streptokinase.
60
Q

what is r-tPa?

A
  • Alteplase, duteplase, reteplase.
  • Administered intravenously.
  • Convert plasminogen to plasmin.
  • Plasmin breaks down fibrin resulting in clot lysis.
61
Q

What is streptokinase?

A
  • Non-enzymatic protein (47KDa) from hemolytic
    streptococci.
  • Forms stable complex with plasminogen inducing a conformational change which allows plasminogen to gain enzymatic activity.
  • Inactivated by anti-streptokinase antibodies.
  • Not used as frequently.

Pharmacology 344 (24 decks)

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