ANTICOAGULANTS, ANTIPLATELET DRUGS AND FIBRINOLYTIC AGENTS 2 Flashcards
1
Q
PLATELET ADHESION
- Platelets maintain the integrity of circulation
- A low platelet count results in _____
- Sequence of events –
- Adhesion following vascular damage (via _____ between subendothelial macromolecules and _____ receptors on the platelet surface
A
thrombocytopenic purpura
von Willebrand factor bridging
glycoprotein (GP) Ib
2
Q
PLATELET ACTIVATION
- Shape change (from smooth discs to spiny spheres with protruding pseudopodia)
- Secretion of _____ contents ( platelet agonists such as _____, 5-HT, coagulation factors and platelet derived growth factors )
- Biosynthesis of labile mediators such as platelet-activating factor and thromboxane (TXA2)
- _____ which is promoted by various agonists, such as _____, _____, _____ and _____ acting on specific receptors on the platelet surface
A
granule ADP Aggregation collagen thrombin ADP TXA2
3
Q
- Aggregation which is promoted by various agonists, such as collagen, thrombin, ADP and TXA 2 acting on specific receptors on the platelet surface
- Activation by agonist leads to expression of _____ receptors which bind _____ and this links adjacent platelets sticking them together (aggregation)
- Exposure of _____ on the platelet outer surface promoting thrombin formation (hence further platelet activation via _____ receptors and _____ formation via cleavage of fibrinogen) and this links adjacent platelets sticking them together (aggregation)
A
GPIIb/IIIa fibrinogen acidic phospholipids thrombin fibrin
4
Q
ANTIPLATELET DRUGS
- Aspirin
- Dipyridamole
- Thienopyridine derivatives –irreversible _____/_____ inhibitors Ticlopidine, Clopidogrel
- _____ receptor antagonists – Abciximab, Tirofiban, Epifibatide
- Other antiplatelet drugs – Epoprostenol
A
ADP receptor
P2Y12
Glycoprotein IIB/IIIA
5
Q
aspirin
- Alters the balance between TXA2 which promotes aggregation and PGI2 which inhibits it.
- Aspirin inactivates _____ – acting mainly on the constitutive form COX-1 by _____ acetylating a _____ residue in its active site
- This reduces both _____ synthesis in platelets and _____ synthesis in endothelium.
- Vascular endothelium can synthesize new enzyme whereas platelets cannot
A
cyclooxygenase irreversibly serine TXA2 PGIs
6
Q
aspirin
- After aspirin use, _____ cannot recover until the affected cohort of platelets is replaced in 7-10 days
- Higher doses of aspirin are needed to inhibit cyclooxygenase in _____ than in _____, especially when given by _____
- This is because platelets are exposed to aspirin in the portal blood, where as systemic vasculature is partly protected by presystemic metabolism of aspirin to salicylate by esterases in the liver
- Consequently _____ of aspirin given intermittently decrease the synthesis of _____ without drastically reducing _____ synthesis
A
TXA2 vascular endothelium platelets mouth low dose TXA2 PGI2
7
Q
DIPYRIDAMOLE
- A _____ inhibitor
- SE- Headache
- Unlike Aspirin – no excess risk of _____
A
phosphodiesterase
bleeding
8
Q
THIENOPYRIDINE DERIVATIVES
- Ticlopidine
- Inhibits ADP- dependent aggregation (_____ receptor/_____ inhibitor)
- Action is slow in onset takes 3-7 days to reach maximal effect
- Works through an active metabolite
- Idiosyncratic unwanted effects – severe blood dyscrasias (_____)
A
irreversible ADP
P2Y12
neutropenia
9
Q
IRREVERSIBLE ADP RECEPTOR /P2Y12 INHIBITORS
- CLOPIDOGREL
- _____
- Inhibits _____- induced aggregation through an active metabolite
- SE- like Ticlopidine can cause rash or diarrhea
- _____ effects with Aspirin (separate pathway of action)
- Pretreatment with Clopidogrel and Aspirin followed by long-term therapy is also effective in patients with ischemic heart ds undergoing percutaneous coronary interventions
A
Active metabolite
ADP
Additive
10
Q
GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONISTS
- All pathways of platelet activation converge on activation of GP IIb/IIIa receptors
- Abciximab is used in high risk patients undergoing _____ as an adjunct to _____ and _____
- It reduces the risk of _____ at the expense of an increased risk of bleeding
- Immunogenicity limits its use to a _____ administration
- Tirofiban and Eptifibatide – Given iv these agents reduce early events in unstable coronary syndrome patients treated invasively but long term oral therapy is not effective and may be harmful
A
coronary angioplasty heparin aspirin restenosis single
11
Q
OTHER ANTIPLATELET AGENTS
-Epoprostenol (PGI2) is sometimes administered into blood entering dialysis circuit to prevent _____ during _____ in patients in whom heparin is contraindicated.
A
thrombosis
hemodialysis
12
Q
CLINICAL USES OF ANTIPLATELET DRUGS
- Following _____ (PCI) +- stenting (iv Abciximab in addition to aspirin) and Clopidogrel can be added to aspirin reduces major cardiovascular events
- _____ (TIA) or _____) to prevent recurrence (Dipyridamole can be added to Aspirin)
- Atrial fibrillation, if oral anticoagulation is contraindicated
A
coronary artery angioplasty
Transient cerebral ischemic attack
thrombotic stroke
13
Q
FIBRINOLYSIS (THROMBOLYSIS)
- When coagulation system is activated, the fibrinolytic system is also set in motion via several endogenous plasminogen activators- t PA, urokinase-type plasminogen activator, kallikrein and neutrophil elastase
- T PA is inhibited by a structurally related _____, which is an independent risk factor for MI
- _____ is deposited on fibrin strands within a thrombus
A
lipoprotein(a)
Plasminogen
14
Q
- Plasminogen activators are serine proteases and are unstable in circulating blood
- They diffuse into thrombus and cleave _____ to release _____
- Plasmin digests _____, _____, factor _____, _____, _____ and many other proteins, generating fibrin degradation products (FDP) and lysing the clot
- Its action is _____ to the clot because plasminogen activators are effective mainly on plasminogen adsorbed to fibrin
- Any plasmin that escapes into circulation is inactivated by _____ which protect us from digesting ourselves from within
A
plasminogen plasmin fibrin fibrinogen II, V, VIII localized Plasmin inhibitors (PAI-1)
15
Q
FIBRINOLYTIC DRUGS
- Streptokinase – Protein extracted from cultures of streptococci
- It activates _____.
- Infused iv
- Its action is blocked by _____ antibodies which appear about 4 days or more after the initial dose
- At least 1 year must elapse before it is used again
- Alteplase and Duteplase – Both are _____ selective ( more active on _____ plasminogen than plasma plasminogen)
- Reteplase – similar but long elimination half life – allows for bolus admin and makes administration simple
A
plasminogen
antistreptococcal
Clot
fibrin bound
