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106 > Pharmacology - Antiplateltes & Anticoagulants > Flashcards

Pharmacology - Antiplateltes & Anticoagulants Flashcards

1
Q

Platelet activation, aggregation and thrombus formation - 7

A
  1. Damage to vascular endothelium exposes collagen & releases von Willebrand factor (VWF), facilitating platelet adhesion by bridging between sub endothelial macromolecules & platelet GPIb receptors.
  2. Platelets change shape to spiny spheres with pseudopodia, driven by P2Y1 receptors, which require concurrent activation of P2Y12 receptors (both activated by ADP) for full aggregation.
  3. Platelet secretion:
    Dense granules release ADP, ATP, calcium, 5-HT, & histamine.
    Alpha granules release IGF-1, PDGF, TGF-β, platelet factor 4, & coagulation factors.
  4. Platelets synthesize & release platelet-activating factor & TXA2 (thromboxane A2), promoting platelet activation.
  5. Agonists (e.g. collagen, thrombin, ADP, 5-HT & TXA2), promote aggregation, followed by expression of GPIIb/IIIa receptors that bind fibrinogen, linking adjacent platelets to form aggregates.
  6. Exposure of acidic phospholipids on platelet surface promotes thrombin formation, producing fibrin mesh.
  7. Can form thrombus
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2
Q

Antiplatelet agents - 4

A
  1. COX Inhibitors (Aspirin): Inhibits platelet aggregation by blocking COX enzymes.
  2. P2Y12 Receptor Antagonists: Block receptors involved in platelet activation.
  3. Glycoprotein IIb/IIIa Receptor Inhibitors: Prevent platelet aggregation by inhibiting receptors that bind fibrinogen.
  4. Phosphodiesterase Inhibitors: Affect platelet activation & aggregation.
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3
Q

ANTIPLATELET AGENTS: Mode of action of ASPIRIN
- 5

A
  1. Aspirin is non-selective inhibitor of COX, blocking both COX-1 (expressed in platelets) & COX-2. Results in prevention of production of TXA2.
  2. Inhibiting TXA2 production, aspirin prevents platelet aggregation by blocking activation of surface receptors (GPIIb/IIIa), essential for forming blood clots.
  3. Aspirin inhibits production of prostacyclin, promoting vasodilation & having antithrombotic effect.
  4. Platelets lack nuclei & cannot regenerate COX-1, meaning new platelets needed.
  5. Requires a new platelet cycle (about a week), making aspirin effective for long-term prevention.
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4
Q

Mechanism of Action of P2Y12 Receptors & inhibitors: - 5

A
  1. P2Y12 receptors on platelets are G-coupled & important for activation & aggregation.
  2. Activation of P2Y12 stabilizes P2Y1 receptor (causes platelet shape change), promoting platelet activation through calcium influx, granule secretion, and receptor synthesis.
  3. P2Y12 antagonists block this pathway, preventing excessive platelet aggregation & blood clot formation.
  4. Also inhibit amplification of platelet activation that occurs when both P2Y1 & P2Y12 receptors are active.
  5. Reduce breakdown of cAMP (helps maintain platelet homeostasis, preventing unnecessary platelet activation.
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5
Q

ANTIPLATELET AGENTS: P2Y12 RECEPTOR ANTAGONISTS:
Irreversible 2 vs reversible 2

A

Irreversible Antagonists (e.g., Clopidogrel & Prasugrel):
1. prodrugs requiring activation in the liver via CYPP450 enzymes.
2. Activation process makes them slower-acting & prone to DDI.

Reversible Antagonists (e.g., Ticagrelor & Cangrelor)
1. Provide quicker therapeutic effects with less dependency on liver metabolism.
2. They are effective for more immediate platelet inhibition

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6
Q

ANTIPLATELET AGENTS: P2Y12 RECEPTOR ANTAGONISTS:
First vs. Second Generation:

A

First-generation drugs (e.g., Clopidogrel):
Require liver activation, making them slower & subject to variable metabolism (e.g., CYP polymorphisms).

Second-generation drugs (e.g., Prasugrel):
Fewer metabolic steps, offering faster onset & more predictable effects.

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7
Q

Role of Glycoprotein IIb/IIIa Receptors Inhibitors - 3

A
  1. Expressed on surface of activated platelets & provide binding sites for fibrinogen, enabling platelets to link together & form aggregates.
  2. Process is driven by platelet activation via agonists like thromboxane A2 & thrombin.
  3. Glycoprotein IIb/IIIa inhibitors mimic fibrinogen & occupy its binding site, preventing platelet aggregation even when platelets are activated.
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8
Q

ANTIPLATELET AGENTS: P2Y12 RECEPTOR ANTAGONISTS: Clinical uses 2 & Advantages 2

A

Clinical Use:
1. Manage ACS & prevent thrombotic events.
2. Combining with aspirin can significantly reduce vascular events.

Advantages:
Faster acting (second-generation), predictable effects
Effective prevention of thrombus formation in high-risk patients.

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9
Q

Drugs Targeting Glycoprotein IIb/IIIa: Abciximab (Monoclonal antibody) - 2

A
  1. Short plasma half-life but long-acting effect.
  2. Potently binds to the receptor, effectively inhibiting platelet aggregation.
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10
Q

Drugs Targeting Glycoprotein IIb/IIIa: Eptifibatide (Synthetic cyclic heptapeptide) - 2

A
  1. Contains RGD sequence responsible for receptor binding.
  2. Reversible inhibitor with short antiplatelet effect.
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11
Q

Phosphodiesterase (PDE) inhibitors: Mechanism of Action - 4

A

1.Inhibition of PDE prevents breakdown of cAMP in platelets, leading to increased cAMP levels.
2. Higher cAMP levels reduce platelet activation & aggregation
3. PDE inhibitors also act on blood vessels, causing vasodilation by increasing cGMP levels, improving blood flow.
4. Additional: PDE inhibitors increase [adenosine], further stimulating production of cAMP in platelets & blood vessels. Increase in cAMP aids in platelet inhibition & vasodilation, enhancing blood flow.

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12
Q

ANTIPLATELET AGENTS: THERAPEUTIC APPLICATIONS:
Stable angina & primary prevention of ACS - 2

A
  1. ASPIRIN Low-dose (75-150 mg/day)
  2. A P2Y12 ANTAGONIST CLOPIDOGREL (if intolerance to aspirin)
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13
Q

ANTIPLATELET AGENTS: THERAPEUTIC APPLICATIONS:
Unstable angina (NSTEMI & STEMI) - 2

A
  1. ASPIRIN High-dose (150-300 mg/day)
  2. ASPIRIN + P2Y12 ANTAGONIST + TIROFIBAN + HEPARIN
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14
Q

ANTIPLATELET AGENTS: THERAPEUTIC APPLICATIONS:
Secondary prevention of MI

A

Low-dose ASPIRIN + P2Y12 ANTAGONIST (for 12 months)

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15
Q

ANTIPLATELET AGENTS: THERAPEUTIC APPLICATIONS:
In PCI (angioplasty) - 2

A
  1. ASPIRIN + IIb/IIIa INHIBITOR (short term treatment) + HEPARIN
  2. Low-dose ASPIRIN + reversible P2Y12 ANTAGONIST (in preparation for & after PCI)
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16
Q

ANTIPLATELET AGENTS: ADVERSE REACTIONS
- 8

A
  1. GI bleeding (ASPIRIN)
  2. Bronchospasm (ASPIRIN)
  3. Hypersensitivity (ASPIRIN)
  4. Low platelet count
  5. GI discomfort, diarrhoea (CLOPIDOGREL)
  6. Rashes (CLOPIDOGREL, PRASUGREL)
  7. Thrombotic Thrombocytopenic Purpura (with thienopyridines) – microscopic clots form
  8. Neutropenia (low neutrophils) (with TICLOPIDINE)
17
Q

COAGULATION CASCADE: Extrinsic pathway - 7

A
  1. Tissue Factor released by leukocytes when endothelial layer is damaged.
  2. TF binds to Factor VII, activating it through interaction with Factor IIa (Thrombin) & Factor Xa.
  3. The TF:FVIIa complex cleaves & activates Factor X to Factor Xa.
  4. Factor Xa (assisted by: Factor Va, phospholipids & Ca), cleaves Prothrombin (II) to Thrombin (IIa).
  5. Thrombin converts Fibrinogen to Fibrin, initiating formation of a fibrin clot.
  6. Thrombin activates Factor XIII, which cross-links fibrin strands, stabilizing the thrombus.
  7. Results in formation of stable blood clot to seal the site of injury.
18
Q

Prevention of thrombosis -2

A
  1. Antithrombin III & Heparin act as natural anticoagulants, preventing excessive coagulation.
  2. They inhibit components of the coagulation cascade, e.g. Factor Xa & Thrombin, which helps regulate blood clot formation & prevents thrombosis under normal conditions.
19
Q

Anticoagulants - 6

A

INHIBITORS OF FACTOR Xa:
1. HEPARIN & LMWHs
2. FONDAPARINUX

DIRECT INHIBITORS OF FACTOR Xa:
3. RIVAROXABAN
4. APIXABAN

DIRECT THROMBIN INHIBITORS:
5. HIRUDIN ANALOGUES
6. DABIGATRAN ETEXILATE

20
Q

HEPARINS: Mechanism of UFH & LMWH (e.g. ENOXAPARIN, DALTEPARIN) - 6

A
  1. Both UFH & LMWHs bind to antithrombin III (ATIII) & enhance ATIII binding activity to Factor Xa
  2. UFH also inhibits thrombin (IIa)
  3. To inhibit factor Xa, heparin needs to bind only to ATIII
  4. To inhibit Factor IIa (Thrombin), heparin needs to bind with both the ATIII + Factor IIa (exosite 2)
  5. Most of LMWHs are too short to bind to exosite 2 of thrombin
  6. Longer the inhibitor, the more effective
21
Q

PROTAMINE SULFATE: MoA as an antidote for UFH bleeding - 3

A
  1. It binds to negatively charged UFH forming stable inactive ion pairs
  2. Can cause hypersensitivity and anaphylactic reaction
  3. Less effective against LMWHs
22
Q

Mode of Anticoagulant Action - 4
Fondaparinux

A
  1. Mimics the unique binding sequence of heparin to ATIII
  2. Enhance interactions of ATIII with active site of the Factor Xa
  3. Does not cause immune thrombocytopenia (low platelet count)
  4. Does not have an antidote
23
Q

Mechanism of Anticoagulant Action: - 4 NOAC: Apixaban, Rivaroxaban

A
  1. Selective direct inhibitors of the Factor Xa
  2. Block conversion of prothrombin to thrombin
  3. Pros: Long-lasting anticoagulants
  4. Antidote available

NOAC / DOAC
Novel oral anticoagulants

24
Q

ANTICOAGULANTS: DIRECT THROMBIN INHIBITORS: Dabigatran - 6

A
  1. Given as a pro-drug Dabigatran Etexilate Mesylate (substrate of P-gp transporter in GIT)
  2. Is hydrolysed to active DABIGATRAN
  3. Rapid & reversible thrombin inhibitor
  4. Inhibits both free and fibrin-bound forms of thrombin
  5. Inhibits thrombin-induced platelet aggregation
  6. Antidote available
25
Q

Vitamin K Epoxide Reductase Inhibition - 4

A
  1. Warfarin inhibits Vitamin K epoxide reductase (VKOR), which reduces vitamin K.
  2. Reduced vitamin K essential for enzyme gamma-glutamyl carboxylase, which carboxylates clotting factors to make them active.
  3. Inhibition of Vitamin K epoxide reductase prevents the reduction of vitamin K, limiting activation of clotting factors.
  4. Thus, inhibits clotting
26
Q

Warfarin Pharmacokinetics - 3

A

Pharmacokinetics:
1. Warfarin exists as a racemic mixture of two isomers: R and S, metabolised by different enzymes.
2. S more potent
3. Difference in enzymes in populations causes difference in race.

27
Q

Warfarin Pros 2 vs Con 2

A

Pros:
1. Cost effective,
2. Antidote, Vitamin K
Cons:
1.Complex pharmacokinetics & liver metabolism (CYP450 dependent)
2. Polymorphism in enzymes makes does different in populations

28
Q

FACTORS WHICH CAN AFFECT ACTION OF WARFARIN - 4

A
  1. DRUGS THAT REDUCE GI ABSORPTION (e.g. colestyramine)
  2. ALCOHOLISM (increases activity of P450 enzymes)
  3. DISEASES (e.g. Hypothyroidism)
  4. Polymorphism of enzymes
29
Q

Common therapeutic applications - 4

A
  1. Unstable angina & prevention of STEMI (with aspirin + antiplatelets)
  2. Prophylaxis of stroke & TIA (e.g. in patients with non-vulvar AF)
  3. Prophylaxis & treatment of DVT & PE
  4. Thromboprophylaxis (e.g. in heart surgeries & in rheumatic heart disease)
  5. a) WARFARIN; in haemodialysis patients
    4.b) HEPARINs; after hip/knee replacement surgeries)
30
Q

ANTICOAGULANTS: COMMON ADVERSE REACTIONS
- 7

A
  1. IMMUNE THROMBOCYTOPENIA
    (Heparin & PF 4 complex)
  2. Hyperkalaemia (suppression of aldosterone production)
  3. Osteoporosis (chronic use of HEPARIN)
  4. Hypersensitivity & anaphylactic reactions
  5. Teratogenicity (Warfarin)
  6. Nausea, GI discomfort
  7. Anaemia
31
Q

MoA of Fibrinolytic (THROMBOLYTIC) Agents & Their Antidotes - 5

A
  1. Body regulates clot formation & dissolution through plasminogen system.
  2. Plasminogen, produced by liver, circulates in blood & is converted into plasmin, (breaks down fibrin & dissolves blood clots).
  3. Process initiated by tissue plasminogen activator (tPA), released by endothelial cells.
  4. Plasminogen activator inhibitor-1 (PAI-1) released when endothelial cell injured, inhibiting tPA & preventing excessive fibrinolysis.
  5. Recombinant tPA (e.g., alteplase) administered to stimulate breakdown of clots.
32
Q

FIBRINOLYTIC (THROMBOLYTIC) AGENTS: Therapeutic uses
- 4

A
  1. In Acute Myocardial Infarction (to dissolve thrombus & prevent further ischaemic damage)
  2. In acute thrombotic stroke (recombinant tPA)
  3. In life-threatening thromboembolisms
  4. S/E Bleeding
33
Q

FIBRINOLYTIC (THROMBOLYTIC) AGENTS: An antidote
MoA - 2

A

e.g. Tranexamic acid
1. Competitive inhibition of plasminogen activation by blocking the lysine binding sites on plasminogen, preventing activation.
2. Also, can block plasmin noncompetitively at [high]

34
Q

TRANEXAMIC ACID
Therapeutic uses - 3

A
  1. In haemorrhage complications associated with thrombolytic therapy
  2. For prophylaxis & treatment in patients at high risk of pre- & post-operative haemorrhage (e.g. in dentistry, in patients with haemophilia, prostatectomy, & in cervical cancer biopsies)
  3. Heavy menstrual bleeding
  4. S/Es Nausea, vomiting & diarrhoea (dose-dependent

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