Nitrates, Viagra/CHF/Antiarrhythmics Flashcards
Low Dose Aspirin/NSAID Interaction
- Concomitant NSAID intake may reduce ____ effects of low dose aspirin.
- Both ASA and NSAID compete for ____ in the platelet.
- NSAID effect on inhibiting platelet aggregation is only ____
- ASA not binding to platelet is converted to salicylic acid which lacks ____ activity.• Aspirin inhibits COX and so does NSAID > blunting of the antiplatelet effects
○ Platelet cannot regenerate ____, while other cells can
○ Accept that the binding of aspirin to COX is an irreversible chemical bond (whether it’s COX1/2); while the endothelial cells can regenerate
• Taking an NSAID for chronic TMJ, while on cardioprotective doses of aspirin > clinically important
cardioprotective COX1 short lived antiplatelet COX1
ASA
T1/2 = ____; ____
SA
T1/2 = ____; as active as ____, inactive as ____
Conjugated metabolite
____
• Aspirin has an active metabolite > SA > every bit as active as aspirin as a pain reliever, but lacks \_\_\_\_ activity ○ Give an NSAID and low dose aspirin, there will be competition for COX1 in the platelet, and some of COX1 will be occupied instead of \_\_\_\_, it will be with ibuprofen - only reversibly binds (a couple of hours) § By this time, aspirin that hasn't bound > SA > lacks antiplatelet activity • Trying to stagger to maintain cardioprotection ○ Take first dose of aspirin early in the morning, then wait an hour until you start dosing with a \_\_\_\_ ○ Doing this over months, do not know how effective this strategy will be ○ On the package insert > aspirin/NSAID > both used at same time4 may inhibit cardioprotective use • 81mg of aspirin (low dose) > there's a tiny chance of \_\_\_\_ (1:4000)
1 hour active 3 hours analgesic antiplatelet inactive antiplatelet NSAID GI bleed
Antithrombotics
• aspirin
- blocks ____ (salicylic acid lacks antiplatelet)
• dipyridamole
- ____ inhibitor
- decreases ____ uptake
• ticlopidine (Ticlar®) • clopidogrel (Plavix®) • prasugrel(Effient®) - prodrugs - metabolized to active form by CYP - \_\_\_\_ receptor inhibitor - \_\_\_\_ outlasts t1/2 - clopidogrel most dependent on metabolism by \_\_\_\_ – potency subject to individual patient distribution of CYP2C19 isozymes - all used to for \_\_\_\_ with or without aspirin, \_\_\_\_ angina, and before PCTA during MI
• Ticagrelor( Brilinta®)
- ____ receptor inhibitor
• Aspirin is targeting thromboxane • See a lot of clopidogrel ○ ADP receptor antagonist on platelets ○ Inhibits activation ○ People at serious risk of an MI, or had one before and have unstable angina may be on this durg w/wo aspirin • 10% of individuals are aspirin \_\_\_\_ ○ Put on clopidogrel • Ticlopidine first on market, Clop has fewer drug interactions • Ticagrelor ○ Same mechanism as clopidogrel
CO PDE adenosine irreversible ADP P2Y12 action CYP2C19 MI prevention unstable reversible ADP P2Y12
resistant
Abciximab (ReoPro)
• t1/2a = ____ min; t1/2b = 30 min
• Platelet function recovers over ____ hours
• Low levels of IIb/IIIa blockade present for up to ____ days
Also: ____ (Integrilin®), tirofiban (Aggrastat®)
Indication: to reduce ____ complications to PTCA and ____. Given by ____ infusion.
• \_\_\_\_ ○ Has to be given IV, will not see someone walk into your practice and that they're on this • Used in the \_\_\_\_ to prevent complications form PTCA (percutaneous transluminal coronary angioplasty - this was a balloon, now it's a stent) • Atherectomy - endo on the carotid arteries; carotids are blocking with occlusive strokes, and CV surgeons will rotoruter the carotid artery > risk ○ During the procedure you may slightly injure the BV, or you dislodge platelet material > you can throw a clot which can go to your lungs or your brain ○ Given the drug during the procedure to prevent a clot from forming • T1/2a and t1/2b - add them up and total half life ○ Alpha - 50% of cleared blood ○ Beta - taking into account elimination of the drug ○ Example of the drug where the half-life is short, but the actions are very long • Iib/IIIa - bridge receptors between platelets
10 48 10 eptifibatide atherectomy IV
monoclonal ab
hospital
Role of ADP receptors in platelet activation and aggregation
• Platelet aggregation involves lots of chemicals ○ Can block \_\_\_\_, ADP receptors, \_\_\_\_ receptors § Rheopro does all of this
TXA
IIb, IIIa
Anticaoagulants
Intravenous
• heparin - binds to ____ - complex binds and inhibits ____
• enoxaparin - ____ molecular weight heparin (LMWH) Decrease in immune mediated ____
• Work on the clotting cascade, can have platelet effects but not directly; thrombin stimulates platelet aggregation (cross-talk) • No-one is coming in on these • When taking blood samples for a study - flush the catheter with \_\_\_\_, which prevents blood coagulation > binds to something that opposes one of final steps in the clotting cascade > antithrombin III > opposes thrombin ○ Makes antithrombin III \_\_\_\_ more powerful ○ Large molecule; issue with all these drugs > enhance bleeding • Enoxaparin ○ Smaller version of heparin § Lower \_\_\_\_ with it; one of immune mediated responses that you saw with heparin, you can get severe bleeding: thrombocytopenia (very lower platelets) § See this less with low MW heparin; typically a \_\_\_\_ drug > knee-replacement surgery
antithrombin III thrombin thrombocytopenia heparin 100x antigenicity hospital
Anticoagulants
Oral
• ____
• dicumarol
•Reduces liver synthesis of
Factors ____ by 30-50%
•Reduces activity of Factors by 10-40%
• You will see people on these ○ Classic oral anticoagulant • Inhibit the synthesis of \_\_\_\_ dependent clotting factors ○ Active form of vitamin-K is reduced vitamin K ○ Antidote for someone bleeding in stomach/brain from warfarin is \_\_\_\_ (IV) § Competitive inhibition • Warfarin hits multiple clotting factors ○ TI of \_\_\_\_ (5x the effective dose is lethal - may be even lower) ○ Has such a low TI and how it behaves in body [???]
warfarin II, VII, IX and X vitamin-K vitamin-K 5
Warfarin: Pharmacokinetic and Pharmacodynamic Pathways
• Warfarin is a \_\_\_\_ compound ○ Exists as L and R handed isomer ○ The \_\_\_\_ isomer is 5x more potent as an anticoagulant ○ The S isomer is only processed by a single cyto p450, while the weaker is detoxified by multiple isoforms • If block \_\_\_\_ with grapefruit/erythromycin - 1A1 and 2 ar eopen and it's the weaker isomer • If you knock of \_\_\_\_ > then the S warfarin has nowhere to go and it cannot be processed ○ \_\_\_\_ and metronidazole inhibits 2C9 § Fluconazole is a major antifungal; also penetrates the BBB - people with opportunistic fungal infections § Metronidazole > major antibiotic for anaerobic infections, and combined with amox/penicillin (punches holes in wall) • \_\_\_\_ is the ultimate site of warfarin ○ \_\_\_\_ ○ Left with hypofunctional factors, but there are other proteins involved in this clotting cascade that remain hypofunctional
racemic S 3A4 2C9 fluconazole VKORC1 vitamin-K epoxide receptor complex 1
Plasma protein binding characteristics of various drugs and the potnetial result of their displacement
Wafarin
% protein bound: ____
Displacement result: ____
Tolbutamide, chlorpropamide, glyburide
% protein bound: ____
Displacement result: ____
Phenytoin
% protein bound: ____
Displacement result: ____
• Warfarin is one of highly protein bound drugs ○ When drugs are bound to plasma proteins > not free to interact with receptors ○ If you decrease binding by giving a displacer like an \_\_\_\_, chloral hydrate > decrease plasma protein binding of warfarin to 96% > now you have \_\_\_\_% free (increasing it 4x) • Prescribing ibu/naproxen > already on a drug that inhibits vitamin K dependent clotting factors, now you're gonna give something that temporarily wacks the platelets > increase risk of \_\_\_\_ two additive by distinct mechanisms of action, regardless of protein binding ○ Can also thin the blood via other mechanisms
99 bleeding 90-99 hypoglycemia 90 cns depression, ataxia
NSAID
4
GI bleeds
Dabigatran etexilate
Direct ____ inhibitor
Use: Stroke prevention in patients with ____
-European Approval, April, 2008: -Canadian Approval June, 2008 -US Approval, October 2010
MW: 627.7 (471.5) Route: Oral
t1/2: 8 h Bioavailability: %
• Flood of new oral anticoagulants • Instead of multiple CF, they tend to hit \_\_\_\_ ○ If only hit one, there's less bleeding • There has been bleeding episodes • With warfarin you have the INR; with these you don'y get an \_\_\_\_ ○ With a fib (2.2-2.5) ○ Surrogate measure of blood coagubility (consistency of cherry koolaid - 9) • Targets only thrombin ○ Essential for converting \_\_\_\_ (the clot) ○ NOTHING TO TREAT THE \_\_\_\_ ○ Used at high risk for heart attacks and strokes • Atrial fib: atria beating like jello and forms clots
thrombin atrial fibrillation one INR fibrinogen to fibrin fibrillation
Rivaroxaban (Xarelto®)
____ inhibitor Use:
- prevention of ____ and ____ after major orthopedic surgery -Stroke in patients with ____ -European Approval, July, 2008, 2011 -November, 2011 US Approval
MW: 435.9
Route: Oral
t1/2: 5.7 – 9.2 h Bioavailability: 60-80%
• Clot formed in leg and then it breaks off and it ends up in pulmonary vessel > becomes lethal ○ Concern after major orthopedic surgery, get them up quickly ○ Prevent DVTs from blood stagnation ○ Also treats a fib
factor Xa
DVT
pulmonary embolism
Apixaban (Eliquis®)
____ inhibitor Use:
-Stroke in patients with ____
-European Approval, May, 2012
-US Approval, Dec 2012
MW: 459.5
Route: Oral
t1/2: 9 – 14 h
Bioavailability: ~50%
Excretion: 75% billiary, 25% renal
• Can come in on these drugs and they're more likely to bleed ○ Won't give an advil, will give \_\_\_\_ § No antiplatelet effects
factor Xa
atrial fib
acetominophen and hydrocodone
Fibrinolytics (all given iv or through iv catheter)
Lyse thrombus in ____ or ____. Not employed for ____.
• tissue plasminogen activator (Alteplase®)
• streptokinase
• anistreplase
• Emergency drug administered in the hospital for a MI or an occlusive stroke ○ How to know occlusive and not bleeding stroke > take a \_\_\_\_ scan § Thread a catheter to blockage and locally deliver a drug • Strepokinase and anistreplase ○ Ani is streptokinase (product of a \_\_\_\_) and is tied to plasminogen, and \_\_\_\_ will lyse clots ○ Will activate plasmin wherever it is located > if plasminogen is buried in a clot and will lyse it, but if it's in the BS it will also activate it • The beauty of TPA ○ Need much less (\_\_\_\_ less) to activate plasminogen that's bound to fibrin (in a clot), then plasminogen that's floating around the plasma ○ Major problem with these two: you \_\_\_\_ out ○ TPA is highly \_\_\_\_ for activating plasminogen when it goes to plasmin and will lyse clots § Plasminogen that's already in a clot ○ No one will walk in on this; but if someone is having a heart attack you will take this > within first hour or two you will prevent major damage
MI occlusive stroke hemorrhagic stroke CAT fungus plasmin 400X bleed selective
VIAGRA
• Interaction between NG-like drugs, and sublingually you have the largest interaction; still can demonstrate with the oral ones • \_\_\_\_ inhibitors ○ \_\_\_\_ ○ Not only specific for male sexual organ
PDE-5
vasodilator
Risk factors for erectile dysfunction include many of the same risks for cardiovasuclar disease!!!
- ____
- High Cholesterol – High LDLs, low HDLs
- ____
- Smokers
Bottom line: Many patients with erectile dysfunction will also have ____ and may require acute or chronic nitrates to treat angina.
• Interaction between nitrates and male erectile dysfunction drugs • Why are people on both nitrates and ED drugs ○ The risks for male ED are seen to be some of the same risks as having CAD • People started looking > men on ED became sexually active, had chest pain and had a dose of nitro and their BP fell > organs were not perfused as well
hypertension
diabetics
CAD
How do these drugs work and why has the combo lead to severe hypotension?
Nitrates: ____ (Nitrostat®), isorbide dinitrate (Isordil®)
PDE5 Inhibitors: ____ (Viagra®), Tadalafil (Cialis®) Vardenafil (Levitra®)
• The nitrates are \_\_\_\_ > not just the coronaries, it's all over the place • Male ED drugs > work on the same pathway but a little differently > block \_\_\_\_ ○ The end result, one drug increases \_\_\_\_, and the other is blocking its breakdown > can get an \_\_\_\_ effect (vasodilation everywhere, and a drop in BP, with a \_\_\_\_)
nitroglycerin sildenafil NO donors cGMP additive reflex tachycardia
