Pharm 14- Platelet Inhibitors, Thrombolytics, AT-III Flashcards
Many functions are mediated by what ability of aspirin?
Irreversibly bind (and inactivate) the enzyme cyclooxygenase-1 (COX-1) and modify the activities of COX-2; inhibition lasts for the entire life of the platelet
How does aspirin affect platelets?
Platelets release of ADP is inhibited
Ability to synthesize Thromboxane A2 and Prostaglandin E2 from Arachadonic Acid is inhibited
What do the thromboxanes produced by platelets do?
Tend to help induce clot formation while the prostaglandins tend to be pro-inflammatory
What does COX-2 produce once its been modified by aspirin?
Lipoxins; once its been modified by aspirin
What’s the effect of Lipoxins?
Anti-inflammatory
What does the blocking of thromboxanes do to platelets?
Platelets won’t aggregate for the life of the platelet (a good thing in places like coronary or carotid arteries)
Why don’t platelets just make more thromboxane?
They don’t have a nucleus so they are unable to make more. Once you have it commited and already programmed
RBCS live how long
100 days
How long to platelets live?
About a week
3-10 days
What is the effect of having prostaglandins blocked?
Inflammation decreased
Nerve endings’ thresholds for pain is increased
Anterior pituitary’s thermostat is reset at a lower level (hence the aspirin’s antipyretic effect)
What are the four major clinical applications for aspirin?
Antiplatelet
Antiarthritic
Reduce inflammation
Antipyritic
Aspirin Side Effects
Bleeding (Hemorrhagic strokes)
GI (such as gastric ulcers)
Kidney damage
What does aspirin help prevent?
TIAs
Embolic strokes
At what dose of aspirin does complete platelet inactivation occur?
160 mg
Why does aspirin have GI effects (such as gastric ulcers)?
PGI2 prevents gastric parietal cells from secreting HCL
PGE2 and PGF2-alpha cause the stomach and SI to create surface-protective mucus
Aspirin thins the layer of slime becuase it produces more acid and stomach is exposed to the effects of the acid
Why don’t “coated” and “enteric” acid actually accomplish much?
GI effects occur on cellular biochemical level
Why does aspirin have a kidney damaging side effect?
Prostaglandins are largely responsible for maintaing adequate renal blood flow; by blocking prostaglandin synthesis salts and fluid start to be retained, K+ isn’t excreted properly and the kidneys are scarred “Interstitialneprhritis”
What does PGF2-alpha do?
Massive uterine contractions
How is aspirin cleared?
Conjugated by the liver, cleared by the kidneys
What is the half-life of aspirin?
3.5 hours
What happens to the half-life of aspirin as higher doses are given?
Conjugation stage is very saturable
Higher doses over several days the half-life increase 4-5x; increased half-life dramatically increases renal toxicity causing a vicious cycle
How are Thienopyidines like and unlike aspirin?
Like aspirin: Block platelet aggregation
Unlike aspirin: different MOA
What are some examples of Thienopyridines?
Ticlopidine (Ticlid)
Clopidogrel (Plavix)
Prasugrel (Effient)
How do Thienopyridines work?
Irreversibly inhibit the ADP pathway of platelets
Blocks platelets GP IIb/IIA receptors
Affected plts cant bind to each other or fibrinogen
When is Ticlopidine (Ticlid) approved for use?
Prevention of TIAs and strokes
With aspirin post-stent placement to prevent thrombi formation
What is the black box warning for Ticlopidine (Ticlid)?
Hematological disorders:
Aplastic anemia
Neutropenia
Thrombotic Thrombocytopenia Purpura
Thrombotic Thrombocytopenia Purpura
Rash; platelets get used up, purple blotches because of the thrombi
Clopidogrel (Plavix) Use
used for more cardiac “issues” (MI prevention, ACS, post-PTCA) than Ticlopidine (Ticlid)
How does Clopidogrel (Plavix) compare to Ticlopidine (Ticlid)?
Like it, but less side effects
Although thrombotic thrombocytopenia purpurea can still occur
Prasugrel (Effient) Good and Bad news
Good news: more effective in treating thrombotic-related events than other thienopyridines
bad news: Black box warning for hemorrhagic stroke, excessive hemorrhage, and negative sequelae resulting form sudden discontination from Prasugrel tx
What is used to monitor antiplatelet therapy?
TEG
What is the actual clinical response to antiplatelet therapies?
varies wildly
What drugs are Glycoprotein IIb/IIIa blockers?
Abciximab (Reopro)
Eptifibatide (Integrilin)
Tirofiban (Aggrastat)
How are Glycoprotein IIb/IIIa blockers administered?
All given parenterally
What are Glycoprotein IIb/IIIa blockers used extensively for?
ACS and in cath labs to make your life more miserable when they finally decide to send the pt to surgery
How does Dipyridamole (Persantine) work and what is it used for?
Primarily used as a coronary vasodilator
Blocks cAMP
After a chain of thromboxane A2 synthesis is blocked
(No prostaglandin effect)
cAMP
ubiquitous intracellular messenger chemical derived form that ubiquitous cellular energy currency ATP
What is Dypyridamole (Persantine) usually administered with?
Rarely used by itself
Usually as adjunt with warfarin (coumadin) or aspirin for anticoagulation post-prosthetic heart valve implanation or for a-fib
What are dextrans?
Heavily-branched complex glucose-based polymers
Who discovered Dextrans?
Louis Pasteur as a component of wine
What are Dextrans used as?
Volume exanders, particularly when albumin is available
Pump prime protocol maybe
Anti-thrombotic functions (ill-defined)
One gram of Dextran binds with how much water?
20-25 ml of H20
What are the two kinds of Dextrans?
Dextran 70 (Macrodex) Dextran 40 (Rheomacrodex)
How are Dextrans administered?
Parenterally
How does Dextran 70 compare to Dextran 40?
Dextran 70 has somewhat greater osmotic capabilities than Dextran 40?
How are both kinds of Dextran excreted?
By kidneys over several hours and the rest metabolized
What does Dextran do?
Binds RBCs, platelets and vascular endothelium making them all less “sticky”
Decreases FV, VIII, and IX functionality
clots formed in the presence of dextrans are “less sturdy” and more easily lysed
What are some concerns and side effects with Dextrans?
- Intra-op and post-op bleeding
- Volume overload, particularly in heart failure and anuric renal failure patients**
- Anaphylaxis (within minutes)
What is the max Dextran dose?
2g/kg (20ml/kg)
How does Hespan compare to Dextran?
Made with a mixture of starch polymers instead of glucose polymers; volume expander like Dextran; cleared similarly but has real tendency to hang around
What factors does Hespan effect?
Reduces Factor VIII casing elevated aPTT values
What is Hespan usage associated with?
Acute renal failure
coagulopathies
anaphylaxis
How long is Hespan found in the plasma?
Months after administration
What is the max daily dose for Hespan?
20ml/kg; but this seems to be more dogma than evidence based
What are some thrombolytic drugs?
Ateplase/tPA (Activase)
Reteplase (Retavase)
Streptokinase (Streptase)
Urokinase (Kinlytic)
When do perfusionists give thrombolytics?
Perfusionists will never give these particularly on bypass
How do thrombolytics work?
These drugs actually dissolve (“lyse”) clots that are already present in the critter
What is Streptokinase (Streptase) and what does it do?
Not really an enzyme, but it attaches to plasminogen and this complex acts to convert plasminogen into plasma
this complex also destroys fibrinogen and Factors V and VII
Made from bugs
What is Streptokinase (Streptase) approved for?
Pulmonary emboli, DVTs, AMIs and thrombosed shunts
What is the half life of Streptokinase (Streptase)
<30 minute half life
When is Streptokinase (Streptase) given?
Within 4 hours of an MI via slow infusion
How is Streptokinase (Streptase) monitored?
Thrombin Time (TT)
What do Urokinase (Kinlytic) do?
Directly converts plasminogen into plasma to dissolve clots
What is the half-life of Urokinase (Kinlytic)?
20 minutes
What is Urokinase (Kinlytic) approved for?
Use in PE
What is Urokinase (Kinlytic) made from?
Urine
What do certain malignant tumors produce and how does it work?
Urokinase (kinlytic) to help “invade” tissues
Mesupron acts as a uPA inhibitor
non-cytotoxic chemotherapeutic effects
What is Alteplase/tPA (Activase) and how does it work?
Naturally occuring enzyme form human cancer cells, tPAs selectively and directly binds with plasminogen that is bound to fibrin (as in a clot)
In low doses, free plasminogen is hardly affected but bound fibrinogen is selectively targeted so you get more clot lysis and less diffuse hemorrhagic problems as compared to streptokinase
What is Alteplase/tPA (Activase) used for?
aMIs
Thrombotic strokes
PE
What is the half life of Alteplase/tPA (Activase)?
5-30 minutes
What is Reteplase (Retavase)?
A synthetic close relative of tPA
Cheaper than tPA
Less fibrin-specific than tPA
What is antithrombin?
Antithrombin (AT) is a small protein made in the liver
What is the half-life of antithrombin?
0.5-3 days
What is antithrombin referred to as?
Antithrombin III (ATIII)
What does ATIII work with to effect anticoagulation?
Heparin
What does normal ATIII have an effect on?
Thrombin and Factors IXa and Xa; that effect is multipled by thousands to millions of times when combined with heparin
What are the two types of antithrombin available?
- Thrombate (Made from pooled human plasma)
2. Atryn (Made form milk genetically modified goats)
Atryn vs Thrombate
Atryn is 40% cheaper to use than thrombate
Atryn’s half life is 9 hours/ thrombates 3 days
Atryn must be refrigerated, thrombate room temp
Recent perfusion trend is toward using which antithrombin?
Away from thrombate and more toward atryn
What is ATIII used to treat?
Tx of acquired or congenital ATIII deficiency
