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Block V, Pharmacology


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Function of VonWillebrand factor?
mediates platelet adhesion to endothelial wall; mediates platelet aggregation
Function of tissue plasminogen activator?
mediates fibrinolysis and clot degradation
Function of protein C and protein S?
inhibit thrombin activation
Currently, what is the main target of anticoagulation therapy?
direct thrombin inhibition
lepirudin (Refludan)
bivalirudin (angiomax)
Lovenox is an example of what kind of drug?
What is it's generic name?
low molecular weight heparin
generic = enoxaparin
What is important in order for heparin to have anticoagulant activity?
a unique pentasaccharide sequence - this is the antithrombin binding site.
general mechanism of action for heparin?
binds to antithrombin III and CATALYZES the inactivation of thrombin (IIa) and factor Xa (mainly, also inactivates IXa and XIIa)
Inactivation of IIa occurs by formation of a ternary complex (heparin, ATIII and IIa).
what effect does heparin have on platelets?
binds to platelets inhibiting platelet function.
How long must a heparin molecule be to form a ternary complex with ATIII and IIa?
at least 18 saccharides long
Are heparin molecules that are shorter than 18 saccharides long functional?
Yes, they still retain anti-Xa activity.
How does heparin have an influence at the very top of the clotting cascade?
it induces the secretion of tissue factor pathway inhibitor by vascular endothelial cells.
Why does heparin have decreased anticoagulant activity at low concentrations?
it is bound to plasma proteins, endothelial cells and macrophages. (there is no free heparin left to form the ternary complex)
What is the most effective method of dosing heparin?
weight based dosing (better than traditional "bolus" dosing)
Why is it important to overlap heparin therapy with warfarin 4-5 days before discontinuing heparin?
warfarin has a very long 1/2 life: therefore it takes about 4-5 days for it to reach therapeutic strength. When therapy is overlapped it ensures there will be no breaks in anticoagulation therapy.
How do you monitor heparin activity?
What else do you need to monitor during heparin therapy?
with a PTT
platelet activity needs to be monitored to prevent thrombocytopenia.
What are the 3 major adverse effects of heparin therapy?
1. Bleeding
2. Osteoporosis (due to decr. osteoblast activity)
3. heparin induced thrombocytopenia
What can you administer to counteract the effects of heparin?
protamine sulfate
What is the mechanism of heparin induced thrombocytopenia, and what are the therapeutic options?
HIT is immune-mediated. therapeutic options include lepirudin and argatroban (direct thrombin inhibitors)
Enoxaparin, Tinzaparin and Dalteparin belong to which drug class?
low molecular weight heparins
What are two major advantages of LMWH?
1. smaller, more consistent size gives a more reliable half-life
2. decreased plasma protein, endothelial cell and macrophage binding.
Why does LMWH not inactivate factor IIa as much as unfractionated heparin?
LMWH is smaller (<18 saccharides), therefore it cannot form the ternary complex with IIa like unfractionated heparin can.
Clinical indications of LMWH? (3)
1. tx. of DVT/PE
2. unstable angina, non ST segment elevation MI
3. Prophylaxis (surgery, acute medically ill pts.)
1. How would you monitor LMWH for renal toxicity?
2. What is renal dosing of LMWH?
1. do anti-Xa assays to measure the activity of LMWH.
2. Renal dosing is once per day, not BID as usual
What are some advantages of LMWH over unfractionated heparin? (6)
1. predictable dose-dependant response
2. increased bioavailability
3. longer duration of action
4. dose independent clearance
5. decr. incidence of thrombocytopenia
6. no lab monitoring required
What is the major drawback to fondparinux?
no reversal agent is available and bleeding is a major complication due to it's long 1/2 life.
What is the general MOA of Warfarin?
Binds to and inhibits all vitamin K dependant enzymes resulting in loss of production of II, VII, IX, X; proteins C and S.
How does warfarin inhibit recycling of vitamin K?
it inhibits KO reductase, therefore reduction of vitamin K cannot occur
What are the two main clinical indications for Warfarin?
1. Primary and secondary prevention of venous thromboembolism
2. prevention of systemic embolism in patients with prosthetic heart valves or A-fib.
*both indications are chronic disorders; warfarin is never used in an acute disorder.
How do you monotor Warfarin activity?
1. PT time - measures the activity of factors II, VII and X. An INR is then calculated to standardize the results
What is the target INR value that we shoot for in most of our patients?
What two factors would influence the dose of warfarin to initally begin with?
1. weight (<45 kg)
2. age (>75 yrs)
What dosage of warfarin do you start most patients on?
5.0 mg
What are the three main adverse effects of warfarin?
1. bleeding (mainly intracerebral)
2. skin necrosis (rare)
3. purple-toe syndrome (rare)
1.What would you do if your patient had an INR of 9.0?
2. What if the INR was >20?
1. Administer vitamin K PO
2. administer vitamin K IV (life-threatening)
Of the direct thrombin inhibitors, which are reversible and which aren't?
Lepirudin (refludan) is the only irreversible one.
bivalirudin (angiomax) and argatroban are both reversible inhibitors.
What is the MOA of direct thrombin inhibitors?
they bind with thrombin and form an inactive complex.
Do direct thrombin inhibitors have an effect on platelet function?
No direct effect, except for inhibition of thrombin-induced platelet activation.
What is the primary indication for direct thrombin inhibitors?
heparin induced thrombocytopenia.
What is scary about direct thrombin inhibitors?
there is no antidote or reversal agent if major bleeding occurs.
What are the four classes of antiplatelet agents?
1. Aspirin
2. Dipyridamole
3. Thienopyridines
4. IIb/IIIa antagonists
What is the MOA of aspirin?
irreversible inhibition of COX-1. This results in blockage of Thromboxane A2 (TXA2) and prostaglandin I2 (PGI2) production. End result - no platelet aggregation
What is the MOA of dipyridamole?
inhibits phosphodiesterase which increases intracellular concentrations of cAMP. The cAMP potentiates the effects of prostacyclin (platelet deaggregation).
What is done to make dipyridamole more effective?
it is combine with ASA or warfarin. (ie. Aggrenox - dipyridamole and ASA)
What are the two types of thienopyridines?
1. Ticlopidine
2. Clopidogrel (Plavix)
What is the MOA of thienopyridines?
Inhibition of ADP induced platelet activation
are tienopyridines reversible or irreversible?
irreversible (additive benefits when used with ASA)
Three adverse effects of thienopyridines?
1. diarrhea, rash
2. neutropenia
3. thrombocytopenia
Name three Glycoprotein IIb/IIIa inhibitors
1. abciximab (reopro)
2. tirofiban (aggrastat)
3. eptifibatide (integrilin)
What is the MOA of Glycoprotein IIb/IIIa inhibitors?
bind to IIb/IIIa receptor. this prevents fibrin from attaching, thereby preventing platelet aggragation. It does not prevent platelet attachment to the endothelium.
Three adverse effects of Glycoprotein IIb/IIIa inhibitors?
1. bleeding
2. thrombocytopenia
3. allergic reactions
physiology of physiologic thrombolysis? (3)
1. release of tissue plasminogen activatior (t-PA)
2. t-PA converts plasminogen to ploasmin. this results in fibrin lysis and degradation of factors V and VIII
3. a2-antiplasmin is activated: this inactivates circulating plasmin to prevent systemic lysis.
MOA of pharmacological thrombolytic agents?
exogenous plasminogen activator, causes fibrin clot breakdown.
Pharmacologic t-PA is known as?
alteplase (activase)
Which thrombolytic agent is the only indirect plasminogen activator?
Which of the thrombolytic agents is the most fibrin-specific? Which one is #2?
most: Tenecteplase
#2: Alteplase (t-PA)
Which of the thromblolytic agents...
1. is a naturally occuring plasminogen activator produced by the kidneys?
2. made from streptococci?
3. the lease expensive?
4. the only one indicated for inschemic stroke?
1. Urokinase
2. Streptokinase
3. Streptokinase
4. Alteplase
1. What are the similarities and differences between reteplase and tenecteplase regarding administration?
2. What are the indications for both?
1. reteplase - given as 2 IV boluses 30 min. apart
tenecteplase - given as a single IV bolusf
2. Acute MI
Hemorrhage is a major adverse effect of thrombolytics. What are the causes of this? (2)
1. Lysis of physiological thrombi
2. Systemic lytic state
What would systemic a2-antiplasmin depletion result in?
a systemic lytic state (excess plasmin degrades coagulation factors)
How would you treat a life-threatening hemorrhage caused by thrombolytics?
you would administer:
1. aminocaproic acid (an antifibrinolytic agent)
2. a competitive inhibitor of plasminogen activators
MOA of nitroglycerin?
forms NO which activates guanylyl cyclase which increases cGMP leading to vasodilation
MOA of lidocaine hydrochloride?
antiarrythmic, analgesis
blocks Na+ ion channels required for initiation and conduction of neuronal impulses (and decreases phase 4 depolarization)
MOA of sodium bicarbonate?
buffers H+ excess and raises pH.
MOA of digoxin?
inhibits Na+/K+ activated ATP, thereby promoting mvmt of Ca++ from extracellular to intracellular cytoplasm - this strengthens myocardial contraction.
- also acts on CNS to enhance vagal tone - this slows conduction through the SA and AV nodes and provides an antiarrhythmic effect.
MOA of Dopamine?
dose dependant action
- low doses stimulate dopaminergic and alpha and beta receptors of the sympathetic nervous system
- large doses: mainly alpha stimulation
what is estrogel?
transdermal estrogen gel for vulva and vaginal atrophy
what is Climera and ClimeraPro?
transdermal patch to relieve postmenopause symptoms
Climera - estradiol
ClimeraPro - estradiol/levonorgestral
What class of drug are Flutamide(Eulexin) and Bicalutamide(Casodex)?
androgen receptor antagonists
what is the MOA of Cyproterone acetate-progestin?
prevents transcription of genes involved in androgen synthesis
what is Spironolactone?
Aldosterone inhibitor and inhibits androgen biosynthesis
What is Ketoconazol (Nizoral)?
antifungal agent that blocks P450 enzymes involved in steroid biosynthesis
what is Finasteride and what is it prescribed for?
5-alpha reductase inhibitor, prescsribed for prostate cancer (Proscar) and male pattern baldness (Propecia).
what is Leuprolide acetate (Leupron)
analog of GnRH
continuous administration suppresses gonadal steroidogenesis. (negative feedback lowers FSH and LH production, thereby lowering steroidogenesis)
what is Raloxifene and what is it prescribed for?
SERM that acts like estrogen on bone and lipids but has anti-estrogenic effects on the breast and endometrium
MOA of lisinopril?
inhibits ACE, results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion.
MOA of Claforan (Cefotaxime Sodium)
Cephalosporin antibiotic:
inhibits cell wall synthesis
highly stable in the presence of beta-lactimases
Effect of Dextromethorphan (DM)?
elevates cough threshold
Found in OTC cough medication
MOA of Azithromycin (Zithromax)
binds to 50S ribosomal subunit interfering with microbial protien synthesis. Nucleic acid synthesis not affected.
MOA of hydrochlorothiazide?
inhibits reabsorption of Na+ and Cl- in thick ascending limb of the Loop of Henle and early distal tubules. This increases urinary excretion of NaCl.
What is atenolol?
differences between hi and lo doses?
beta blocker
low dose: B1 selective
high dose: B1 and B2 action
What would I prescribe Tegretol (Carbamezapine) for?
its an anticonvulsant, I would prescribe it for seizures
What is Mellaril (Tioridazine Hydrochloride) and what is it used for?
used to treat psychosis

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