Pharm I - Hefnawy

Question 1

what does GP2b/3a bind to?

Answer 1

-vWF and fibrinogen

Question 2

COX1

Answer 2

• synthesizer for TXA2
• inhibited by aspirin
• no drugs that target TXA2R

Question 3

ADP receptors

Answer 3

• binds to P2Y-1,12

- only have drugs that target P2Y-12

Question 4

inhibitors of the TXA2 pathway (synthesis, not receptor)

Answer 4

1. aspirin** - inhibits COX1
2. nitro aspirin
3. dipyradimole - stops platelet aggregation

Question 5

why give baby aspirin instead of full dose?

Answer 5

• baby aspirin –> targets COX1, not COX2 –> prevents TXA2 synthesis
• full dose aspirin –> targets/inhibits COX2 - inhibits prostacyclin (PGI2) –> more platelet aggregation/clotting (counterproductive)
• full dose aspirin also GI/stomach upsets

Question 6

aspirin

Answer 6

• irreversible inhibition of COX1 –> prevents synthesis of TXA2**
• deficit lasts until new platelets are synthesized (reason for stopping 1-2 weeks before surgery)
• used as prophylaxis against MI or ischemic attacks/stroke of brain
• low dose (75-100mg/day)

Question 7

pharmacokinetics of aspirin

Answer 7

• exaggerated stomach irritations due to pKa 3.5 –> accumulate in gastric mucosa cytoplasm (pH7) causing toxicity and degrading PGE2
• inclusion of alkali reduces absorption
• metabolized to salicylic acid

Question 8

why do you not use low dose aspirin with gout?

Answer 8

• interferes with uric acid excretion
• low dose aspirin (<2g) –> uric acid retention**
• high dose aspirin (>5g) –> uric acid excretion**
• reason for not giving low dose with gout

Question 9

drug interactions of aspirin

Answer 9

• displaces warfarin from protein –> toxicity
• displaces T4 from protein –> iodine deficiency
• interferes with diuretic action of furosemide, thiazides, and spironolactone
• spirolactone won’t have K+ sparing effect if used with aspirin –> hypokalemia

Question 10

contraindications of aspirin

Answer 10

1. peptic ulcer –> bleeding
2. flu or chicken pox in children –> Reyer’s syndrome
3. chronic liver disease –> hepatic necrosis increasing half-life of aspirin
4. teratogen in pregnancy –> closure of DA –> post-partum blood loss
5. high doses with G6PD –> hemolysis

Question 11

dipyridamole

Answer 11

• inhibits adenosine uptake by RBCs –> vasodilation*
• build up of adenosine –> inhibit ADP binding –> slows down platelet aggregation*
• increases platelet cAMP/cGMP
• glucuronidation in liver like aspirin*

Question 12

P2Y12 inhibitors

Answer 12

1. Clopidogrel
2. Prasugrel
3. Ticagrelor
4. Cangrelor
5. Ticlopidine

“grel” –> P2Y12 inhibitors
“or” –> reversible

Question 13

clopidogrel

Answer 13

• need enzymes for activation** –> CYP2C19 for 1st step, CYP2C19, CYP2C9, CYP3A4 for 2nd step**
• irreversibly binds P2Y12 receptor (lifespan of platelet)
• not good drug to use with CYP polymorphisms/mutations
• helpful if given before surgery, but not during bc it is slow acting* (need time to become active)*
• prevent platelet aggregation, not DVT/PE/valve replacement (coagulation)
• used if aspirin is contraindicated*
• side effects: bleeding*
• decreases warfarin metabolism increasing toxicity by keeping the CYP enzymes busy*
• clearance: 50% renal, 45% feces

Question 14

prasugrel

Answer 14

• prodrug (1 step activation) –> CYP3A4 and CYP2C19*
• irreversible binding to P2Y12* (last platelet lifetime)
• fast acting (peak [] 30 min.)**
• discontinued 7 days before coronary surgery
• opiods delay absorption

Question 15

ticagrelor

Answer 15

• already active (not prodrug) –> fast action** and greater inhibition of platelets –> bleeding, dyspnea, heart problems (tachycardia, arrhythmia, ventricular pauses)
• reversible inhibition of P2Y12**
• metabolized/eliminated by CYP3A4*
• inhibits P-glycoprotein –> increase serum digoxin –> toxicity**
• exacerbate hyperuricemia
• renal filtration

Question 16

cangrelor

Answer 16

• only one administered by IV infusion** –> short term effects - half life 2-3 min. (ex. during surgery)
• reversibly binds P2Y12 receptor
• not prodrug –> immediate effects
• no ventricular pauses or digoxin toxicity

Question 17

ticlopidine

Answer 17

• 1st generation thienopyridine*
• irreversible inhibition of P2Y12*
• not administered right before/during surgery –> required 3-7 to be active**
• metabolized by CYP2C18, CYP2B6
• need to monitor theophylline and phentynoin*
• side effects: neutropenia, thrombocytopenia, leukopenia*

Question 18

drugs targeting GP2b/3a

Answer 18

1. Abciximab
2. Eptifibatide
3. Tirofiban

all of them given parentally

Question 19

Abciximab

Answer 19

• monoclonal antibody (Fab) against GP2b/3a* –> irreversible action*
• only has variable regions –> reduces risk of opsonization/autoimmune rxn
• infused, not used daily
• fast action on platelets (10-30 min.*) and long action (15 days or more in circulation)
• good prior to/during surgery - ex. percutaneous coronary intervention aka PCI (stents)*
• bridge therapy with warfarin bc warfarin can give you hyper coagulation by itself*

Question 20

Eptifibatide and Tirofiban

Answer 20

• bind reversibly to GP2b/3a as fibrinogen fragments**
• peptide –> cannot give orally; must be transfused/parental
• reversal in 6-10hr (by dissociation from platelets)**
• removed by renal filtration (small peptides)**
• used with acute coronary syndrome (ACS) and PCI, heparin, and aspirin
• eptifibatide is peptide from rattlesnake venom

Question 21

drugs that inhibit the PAR-1 receptor (receptor for thrombin)

Answer 21

1. vorapaxar

Question 22

vorapaxar

Answer 22

• reversible, competitive antagonist of PAR-1 (competes with thrombin binding)**
• given orally
• not a prodrug –> fast action
• long time in circulation (4 weeks)** –> 90% bioavailable
• used to reduce thrombotic cardiovascular events (MI or PAD)*
• CYP3A4 needed for metabolism/excretion –> lead to toxicity if used in liver failure**
• no problem if used in renal failure*