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)
argatroban
ximelegatran -
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?
- 2.0-3.0
- 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?
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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?
- streptokinase
- 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?
-
LOOP DIURETIC
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?
-
antipsychotic
used to treat psychosis