Module 4 Pharmacology

Front 1

What type of cmpds do the endothelial cells of a normal vascular wall produce?

Back 1

1. Nitric oxide, PGI2 and PGE2 -- inhibit platelet aggregation and relax vascular smooth muscle to maintain smooth blood flow

2. COX-1

Front 2

What cmpds do the endothelial cells of a vascular wall experiencing hypoxia, inflamm, and shear stress produce?

Back 2

1. COX-1 and COX-2

2. PGI2 - antithrombotic

3. heparan - inhibits factors IIa and Xa, and tPA which cleaves plasmin from plasminogen
--- plasmin dissolves blood clots by destroying the cross-linked fibrin which maintains the structural integrity in this clot

3. Also present a negative external charge which repels the negatively charged platelets.

Front 3

What happens when the vascular wall is damaged?

Back 3

1. positively charged collagen is exposed which attracts negatively charged platelets
2. platelets bind to collagen of the damaged vascular wall via their glycoprotein Ia receptor (GP Ia)
3. Circulating von Willebrand's factor binds platelets to the damaged vascular wall via the platelet's GP Ib receptor
4. Interaction btwn platelets and collagen activates platelets which then release TXA2, ADP, and 5-HT
5. Platelet aggregation occurs b/c fibrinogen molecules cross-link platelets via the platelet IIb/IIIa receptor
6. TXA2 and 5-HT contract the vascular smooth muscle of the damaged area, and TXA2 enhances expression of the IIb/IIIa receptor
7. TXA2 and ADP induce further platelet adhesion, activation and aggregation

Front 4

The formation of a platelet plug "white clot" is followed by...

Back 4

activation of the intrinsic clotting cascade
-- factors XII, XI, IX, X, and II

Lipid surface of the platelet serves as the organizing surface for partial proteolysis and sequential activation of the clotting sequence w/ ultimate conversion of prothrombin (II) to thrombin (IIa)

Front 5

What is activated thrombin's fxn?

Back 5

Activated thrombin (IIa) converts fibrinogen to water soluble fibrin and activates factor XIII (fibrin stabilizing factor)

Facror XIIIa covalently cross lings water-soluble fibrin to form a "fishing net" of water insoluble fibrin

This "fishing net" catches the red blood cell "fish" to form a "red" clot

Fibrin net eventually contracts to form a solid, fibrin-encased "red" clot.

Front 6

Aspirin's effect on bleeding/coagulation?

Back 6

1. Increases bleeding time

2. NO effect on activated partial thromboplastin time (aPTT) or the prothombin time (PT)

3. VERY large doses ASA (6+ g/d) can increase the aPTT by inhibiting the hepatic synth of clotting factors

Front 7

Aspirin metabolism?

Back 7

Enters hepatic portal circulation, and almost all of a small dose (325mg) is converted to salicylate by first pass metabolism.

Front 8

Aspirin MOA?

Back 8

--In the hepatic portal circulation, aspirin irreversibly inhibits the COX-1 of platelets by acetylating the active site of the enzyme

-- Platelets attacked by aspirin can never again synthesize TXA2 (prothrombic prostaglandin) b/c they do not have nuclei and cannot synth new COX-1

-- platelets have life span of 9-14 days, but body makes millions of new platelets each day, thus have to take aspirin each day to exert antithrombotic effect

-- 160mg ASA/day completely inhibits all platelet TXA2 in most patients

Front 9

What about the salicylic acid that ASA is converted to via first-pass metabolism?

Back 9

Salicylate reversibly inhibits COX-1 and COX-2, including the COX-1 in platelets, but the half-life of salicylate is only 2-3h, so platelet aggregation is impaired for only 8-12h

Front 10

What if you take a large dose of aspirin?

Back 10

-- If a large dose ingested, significant quantity can escape hepatic first-pass metabolism and enter the peripheral circulation as acetylsalicylic acid which irreversibly inhibits COX-1 and COX-2 of the vascular endothelial cells that normally synth and release PGI2 and PGE2

-- BUT, vascular endothelial cells DO have nuclei, and thus can synth new COX-1 and COX-2

-- Production of PGE1 and PGE2 resumes w/in 6-12h

Front 11

Take home message about ASA?

Back 11

Single, small daily dose of aspirin (325mg) produces a persistent antithrombotic effect b/c it irreversibly inhibits production of TXA2 by platelets w/out affecting synth of PGI2 (another antithrombotic) by vascular endothelial cells

Front 12

Antagonists of the IIb/IIIa receptor (glycoprotein integrin receptor)?

Back 12

1. ABCIXIMAB -- monoclonal Ab which irreversibly binds to the IIb/IIIa receptor; antiplatelet effect lasts 24h

2. EPTIFIBATIDE -- a competitive inhibitor

3. TIROFIBAN -- a competitive inhibitor

Front 13

IIb/IIIa receptor antagonists' MOA?

Back 13

-- blocks the IIb/IIIa receptors by which fibrinogen binds platelets together, so platelet aggregation is blocked

-- blocks the platelet aggregation caused by any factor (collagen, TXA2, thrombin)

Front 14

Medical uses of the IIb/IIIa receptor antagonists?

Back 14

1. Percutaneous intervention (PCI): angioplasty, stent, or combo of the two

2. Acute coronary syndrome = acute MI, unstable angina
-- chest pain
-- abnormal ECG: depressed ST segment
-- elevated cardiac enzymes

Front 15

Adverse effects of the IIb/IIIa receptor antagonists?

Back 15

bleeding

Front 16

Antagonists of purinergic (ADP) receptors?

Back 16

toclopidine
clopidogrel

**both given p.o.

Front 17

ticlopidine, clopidogrel MOA?

Back 17

1. platelet activation and aggregation caused by ADP requires stimulation of two different purinergic receptors

2. ADP stim of the P2Y(1) receptor of the platelets activates phospholipase C leading to the synth of IP3, the release of Ca from the sarcoplasmic reticulum and a change in the shape of platelets

3. ADP stim of P2Y(12) receptro of platelets inhibits the activity of adenyl cyclase leaing to decreased cAMP (increased cAMP) inhibits platelet activation and aggregation by lowering the free intracellular Ca conc)

3. blockade of either the P2Y(1) or the P2Y(12) receptor inhibits platelet activation/aggregation

4. Both meds block the P2Y(12) purinergic receptor of paltelets and thus block platelet aggregation

Front 18

Medical uses of ticlopidine, clopidogrel?

Back 18

1. decrease incidence of MI and stroke in patients w/ atherosclerotic vascular disease
2. prevent thrombosis in patients w/ previous ischemic stroke (secondary prevention); work as well as ASA in this prevention
3. prevent MI in patients w/ unstable angina
4. used w/ aspirin during PCI and placement of coronary stents
5. treat patients who cannot take aspirin or have failed therapy on aspirin
6. Ticlopidine myst be given for 10 days to achieve its full antiplatelet effect

Front 19

Adverse effects ticlopidine, clopidogrel?

Back 19

TICLOPIDINE = neutropenia (1%), thrombocytopenia, agranuocytosis

CLOPIDOGREL = much lower incidence of neutropenia and agranulocytosis

Front 20

BJE question: A woman has had an MI or stroke but has hypersensitivity rxns to ASA? What do you give her to prevent future MI/stroke?

Back 20

ticlopidine or clopidogrel

Front 21

Heparin MOA regarding its use as an antiplatelet drug?

Back 21

1. blocks adhesion of platelets by maintaining the electronegativity of the damaged vascular wall

2. prevents platelet adhesion, aggregation, and the "release" reaction