Heme/onc pharm – Anti-platelet agents, NSAIDs, aspirin

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HY points followed by a quiz at the end

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• The highest yield point to note from this diagram is that aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) cause shunting of arachidonic acid down the lipoxygenase pathway. The USMLE loves to assess aspirin-/NSAID-induced asthma.
  • 16M + went snowboarding for 8 hours + next day has sore muscles + took aspirin for pain relief + now has wheezing; which agent should be avoid in the future? –> answer = ibuprofen (an NSAID); wrong answer = acetaminophen (not an NSAID; acts centrally).

Aspirin (salicylate) + other NSAIDs

• Other HY NSAIDs: diclofenac, ketorolac, ibuprofen, indomethacin, naproxen, mesalamine.
• Acetaminophen is not an NSAID (discussed later).
• I lump aspirin + other NSAIDs together because of their considerable overlap. But important differences are noted.

MOA of aspirin?

• Irreversible inhibition of cyclooxygenase 1 and 2 (COX1/2).

MOA of other NSAIDs?

• Reversible inhibition of COX1/2.

Physiologic effects of COX inhibition by aspirin + other NSAIDs:

• Results in ↓ production of prostaglandins and platelet thromboxane.
• ↓ platelet thromboxane means ↑ bleeding time (NR 2-7 minutes, so >7 minutes; no change in platelet count).
• ↓ prostaglandins (vasodilators) means ↓ diameter of arterioles (i.e., less vasodilation of afferent arterioles of the kidney → ↓ renal perfusion).
• ↓ COX1/2 activity means a shunting of arachidonic acid down the lipoxygenase pathway → ↑ leukotriene production → bronchoconstriction → asthma in some patients.

What’s the difference between COX1 and 2?

• COX1 is found in gastric mucosa and platelets. Thromboxane A2 is the major product of COX1 in platelets.
• COX2 is found in vascular endothelium and inflammatory cells; inhibition of COX2 is the primary mechanism for ↓ pain.

HY answers for aspirin on USMLE:

• The agent given in acute MI.
  • After aspirin is administered, give an ADP P2Y12 blocker (i.e., clopidogrel) for dual anti-platelet therapy.
• Atrial fibrillation (AF) in patients who have a low CHADS2 score.
  • CHADS2 score is used to assess whether patients with AF need anti-platelet (aspirin) or anti-coagulation therapy (usually warfarin).
  • Congestive heart failure, Hypertension, Age >75, Diabetes, Stroke/TIA (each worth 1 point; the latter is worth 2 points).
  • If 0 or 1 points, give aspirin to AF patients.
  • If 2+ points, give warfarin (anticoagulation answer on USMLE). Patients who have valvular AF (i.e., AF in the setting of, e.g., mitral regurg) must receive warfarin. Patients with non-valvular AF (i.e., idiopathic or, e.g., in the setting of hyperthyroidism) can receive other anticoagulants such as apixaban.
• Angina (ischemic heart disease) to decrease risk of MI.
  • Stable angina: used instead of daily baby aspirin in patients who can’t take the latter (e.g., because of renal insufficiency).
  • Unstable angina: added to daily baby aspirin. The combo of aspirin + clopidogrel is superior to aspirin alone in unstable angina; this relationship has not yet been proven for stable angina.
• Cerebrovascular disease or carotid stenosis to prevent ischemic stroke (three acceptable regimens are: aspirin alone; aspirin + dipyridamole; or clopidogrel alone).
• Kawasaki disease (+/- IVIG).
  • 4M + five days of fever + cervical lymphadenopathy + edema of the dorsum of the hands + red lips + red eyes; Tx? –> answer = aspirin + IVIG.

HY uses of other NSAIDs:

• First-line for pain relief in rheumatoid arthritis; steroids are used for pain if NSAIDs are insufficient. For RA, there are two arms of pharmacologic management:
  • Symptom management only: NSAIDs first; if insufficient, add steroids. NSAIDs + steroids do not alter the course of the disease.
  • DMARDs (disease-modifying anti-rheumatic drugs); not used for symptoms; these slow the course of the disease –> methotrexate first almost always; if insufficient, add other agents like anti-TNF-alpha drugs.
• Toxic synovitis (aka transient synovitis) –> hip pain in a kid after a viral infection. Sounds weirdly specific, but it’s on the NBME.
  • 6M+ runny nose for 3 days + now has hip pain + low-grade fever; Tx? –> answer = ibuprofen (NSAIDs)
  • Septic arthritis, in contrast, will present in peds as a kid who has history of juvenile rheumatoid arthritis, and is almost always the knee, not the hip. Plus, if the USMLE wants toxic synovitis, they’ll always mention viral infection preceding the hip pain.
• Subacute granulomatous (de Quervain) thyroiditis –> tender/painful thyroid + hypo- or hyperthyroidism, usually after viral infection (but the USMLE will frequently not mention the infection).
  • 28M + tender thyroid + HR 92 + a bit tremulousness; Dx + Tx? –> deQuervain; NSAIDs +/- steroids (but choose NSAIDs first on USMLE).
• Pain relief in general (e.g., sore muscles, headache).
• Can be used in osteoarthritis after acetaminophen (i.e., choose acetaminophen first on USMLE if NSAID also listed).
  • If patient is overweight, always choose weight loss first as the treatment ( obesity = biggest risk factor for OA).
  • But if question asks for first-line pharmacologic management, answer = acetaminophen first, not NSAIDs. If acetaminophen alone is insufficient, NSAIDs can be added.
  • Osteoarthritis is degenerative joint disease. The pain will never go away. So if the patient takes chronic NSAIDs for pain, he or she is prone to renal damage (i.e., peripheral edema in someone taking naproxen for OA).
• Anti-pyretic (fever reduction).
• Indomethacin is first-line for acute gout.
  • If patient has renal insufficiency, choose corticosteroids over indomethacin.
  • If indomethacin and steroids are both not listed but patient has acute attack, answer = colchicine.
• Pseudogout –> NSAIDs, then steroids, then colchicine (same as acute gout, but NSAID need not be indomethacin).
• Pericarditis –> NSAIDs, then steroids, then colchicine (same as acute gout and pseudogout; NSAID need not be indomethacin).

Notable time to NOT give aspirin specifically:

• Viral infection in children → aspirin can cause Reye syndrome (cerebral edema, liver damage) due to inhibition of mitochondrial beta-oxidation enzymes.
  • 8M + viral infection + fever + given drug by mom to treat fever + now has confusion and papilledema + LFTs are increased.

Notable time to NOT give NSAIDs in general (including aspirin):

• Hx of peptic ulcer disease, gastritis, or upper GI bleeding → prostaglandins normally protect the mucosal barrier of the stomach by increasing production of alkaline mucous in the stomach.
• Renal insufficiency → vasodilating prostaglandins maintain patency of the renal afferent arterioles → NSAIDs decrease renal blood flow by decreasing prostaglandin synthesis.
  • 82F + taking naproxen for 6 weeks for pain relief + now has peripheral edema; why? –> answer = “decreased renal excretion of sodium,” or “increased renal retention of sodium”; ↓ renal blood flow means kidney attempts to ↑ fluid retention; it accomplishes this by reabsorbing sodium in the PCT, since water follows sodium → edema + FeNa <1% (fractional excretion of sodium).
  • In pre-renal etiologies of renal insufficiency – i.e., in the setting of decreased renal perfusion – a HY detail is that you know urinary FeNa is <1%, which would be seen with NSAID use.
• History of aspirin-/NSAID-induced asthma → knocking out COX causes shunting of arachidonic acid down lipoxygenase pathway → leukotriene synthesis → bronchoconstriction.

Adverse effects unique to aspirin:

• Reye syndrome (as mentioned above).
• Tinnitus (ringing of the ears); first symptom of salicylate (aspirin) toxicity (i.e., what the patient reports subjectively).
• Tachypnea (↑ respiratory rate); first sign of salicylate toxicity (i.e., what we notice on examination objectively; the patient doesn’t report tachypnea).
• Acid-base disturbance (discussed below).

Acid-base disturbance caused by aspirin (exceedingly HY for all Steps):

• Respiratory alkalosis early (i.e., first 20 minutes, answer = ↓ pCO2; normal HCO3^–;↑ pH); bicarb does not change in acute respiratory acid-base disturbances; it takes minimum 24 hours to really move (e.g., with altitude sickness).
• Mixed respiratory alkalosis-metabolic acidosis late (i.e., after 20 minutes, answer = ↓ pCO2; ↓ pH 80% of the time; 20% of the time it’s in the normal range; ↓ HCO3^–). Student says, “Wait, I thought you just said it takes ~24 hours for bicarb to really move, so how is it down already?” Because aspirin itself causes a metabolic acidosis (↓ HCO3^–) that is now superimposed on the respiratory alkalosis (↓ pCO2). It’s coincidental that the aspirin-induced metabolic acidosis that occurs with slight delay happens to look like metabolic compensation for the respiratory alkalosis, but this is NOT compensation. Aspirin directly upregulates respiratory centers (tachypnea) + is an acid itself (salicylic acid).

Adverse effects of NSAIDs (including aspirin):

• Gastric ulcers, gastritis, GI bleeding.
• Various renal pathologies:
  • Analgesic nephropathy (any adverse change in the kidney due to NSAIDs); can present as renal papillary necrosis (dark urine) or interstitial nephropathy (eosinophils in the urine).
  • Pre-renal azotemia –> starts off as patients getting peripheral edema due to NSAIDs because of decreased renal blood flow (as discussed above); the edema is not a renal pathology in and of itself, but reflects pre-renal changes in the kidney that may eventually cause elevations in creatinine and BUN. Once the renal function tests change, the patient now has pre-renal azotemia.
• Aspirin-/NSAID-induced asthma (Samter triad = NSAID hypersensitivity, NSAID-induced asthma, nasal polyps).

Tx for aspirin toxicity?

• Sodium bicarbonate → alkalinity traps the salicylic acid as the oxalate (O^–) form → kidney cannot reabsorb charged species as well as neutral ones → increased urinary excretion.
• If the USMLE asks you the mechanism for how sodium bicarb works for aspirin toxicity, the answer = “increased excretion through urinary alkalinization.”
• Do not confuse this mechanism with sodium bicarb in the treatment of TCA toxicity. TCAs cause cardiotoxicity by binding to myocardial sodium channels. If the USMLE asks you the answer for the mechanism in this case, the answer = “increased dissociation from myocardial sodium channels”; the wrong answer is “increased excretion through urinary alkalinization,” which is aspirin. Students fuck this up and choose the latter because they’ve memorized it as HY for aspirin, but don’t realize it’s wrong for TCAs.

Acetaminophen

MOA of acetaminophen?

• Inhibits COX in the CNS; inactivated peripherally.
• Not considered an NSAID → does not act as an anti-inflammatory agent peripherally. The ability to decrease pain is linked to ↓ prostaglandin effects in the CNS, not at peripheral tissues.

When is acetaminophen the answer on USMLE?

• First-line pharmacologic treatment for osteoarthritis (second-line is NSAIDs). Should be noted that USMLE likes simple “weight loss” as the first treatment overall for osteoarthritis, but if a drug is given, choose acetaminophen over NSAIDs.
• Pain relief in patients with renal insufficiency (does not act peripherally so does not kill the kidneys like NSAIDs do).
• Febrile non-hemolytic transfusion reaction (most common type of transfusion reaction). Sounds weirdly specific, but it’s on the NBME.
  • Mechanism is antibodies against donor leukocyte antigens.
  • 30F + fever 2 hours after receiving blood transfusion + Coombs test is negative; Tx? –> answer = acetaminophen.
• Can be used safely in children to avoid Reye syndrome caused by aspirin.

Adverse effect of acetaminophen?

• Severe hepatic necrosis. Acetaminophen is metabolized into a toxic metabolite called NAPQI that is immediately neutralized by reduced glutathione in the liver. If the patient overdoses on acetaminophen, the reduced glutathione is depleted and then the NAPQI oxidizes and diffusely kills the hepatocytes.
• In short, whilst NSAIDs and aspirin kill the kidneys, acetaminophen kills the liver.

Treatment for acetaminophen toxicity?

• N-acetylcysteine.
• USMLE wants you to specifically know the reason N-acetylcysteine works is because it regenerates reduced glutathione in the liver.
• Species with thiol (-SH) groups are in the reduced form and can act as reducing agents (i.e., can act as anti-oxidants).
• Species with disulfide bonds (-S–S-) are in the oxidized form.
• Hepatic glutathione has a thiol (-SH) group. So does N-acetylcysteine. After glutathione neutralizes a toxin, it becomes oxidized and inactive.
• The thiol group on N-acetylcysteine then binds to and frees up the sulfurs on glutathione so that they can once again neutralize toxins.
• This mechanism may sound cumbersome, but it’s HY for USMLE. Probably because N-acetylcysteine is such an important antidote used clinically.
• Activated charcoal can be used in select acute circumstances. There’s a Qbank Q floating around where activated charcoal is the answer over N-acetylcysteine. On the USMLE, however, always choose N-acetylcysteine for acetaminophen.

Celecoxib

MOA of celecoxib?

• Selective COX2 inhibitor.
• Considered to be an NSAID.
• Called a COX2-selective NSAID.

When is it used?

• In patients who have contraindications to NSAIDs (i.e., peptic ulcer disease, gastritis, GI bleeding, renal insufficiency) but who need pain relief (e.g., in rheumatoid arthritis).

Adverse effects of celecoxib?

• Increases risk of MI and thrombosis → selective inhibition of COX2 decreases vasodilatory effects of prostaglandins and prostacyclins without inhibiting thromboxane A2 in platelets (COX1).
• USMLE vignette will mention specifically that a physician is apprehensive about giving celecoxib to a patient because of increased MI risk with this drug; then they’ll ask why this is the case –> answer on NBME = “inhibition of prostacyclin (PGI2) formation without inhibition of thromboxane A2 in platelets.”
• Similar risk of renal complications as non-selective NSAIDs.

ADP P2Y12 blockers

• Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine
• ADP P2Y12 receptors are on platelets and lead to the expression of platelet glycoproteins IIb/IIIa, which enable platelet aggregation.
• Despite ADP P2Y12 agonism leading to increased expression of GpIIb/IIIa, do not confuse these with the actual GpIIb/IIIa inhibitors.
• Clopidogrel will almost always be agent mentioned / asked about on the USMLE in relation to this class of drugs.

When are these the answer on USMLE?

• Second drug given after aspirin for the acute treatment of MI (aspirin given first).
• Technically used for stenting procedures, and this is an important use that’s widely propagated in USMLE resources, but I’m yet to have seen this on any NBME assessment as an actual answer.
• Stable angina: used instead of daily baby aspirin in patients who can’t take the latter (e.g., because of renal insufficiency).
• Unstable angina: added to daily baby aspirin. The combo of aspirin + clopidogrel is superior to aspirin alone in unstable angina; this relationship has not yet been proven for stable angina.
• Cerebrovascular disease or carotid stenosis to prevent ischemic stroke (three acceptable regimens are: aspirin alone; aspirin + dipyridamole; or clopidogrel alone).

Adverse effects of ADP P2Y12 blockers?

• Clopidogrel and prasugrel can cause TTP (thrombotic thrombocytopenic purpura) – i.e., can precipitate the inactivation of ADAMTS13, leading to schistocytosis, thrombocytopenia, and renal insufficiency.
• Hemorrhagic stroke (prasugrel > clopidogrel).
• Ticlopidine can cause neutropenia (mouth ulcers, sore throat fever).

GpIIb/IIIa inhibitors

• Abciximab, Tirofiban, Eptifibatide
• GpIIb/IIIa on platelets enable platelet aggregation (i.e., platelets sticking to each other). Do not confuse this with platelet adhesion (i.e., platelets sticking to vascular endothelium) which is mediated by GpIb.
• Physiologically, fibrinogen is what bridges GpIIb/IIIa on adjacent platelets; therefore the GpIIb/IIIa inhibitors have been described as fibrinogen analogues on USMLE.

When is a GpIIb/IIIa inhibitor the answer on the USMLE?

• Can technically be used for stenting procedures, but I have not seen the USMLE specifically assess this. The exam cares more that you know the mechanism of action of these drugs. That is, know the drug names (especially abciximab) and that they simply inhibit GpIIb/IIIa, thereby decreasing platelet aggregation.

—

1. Complete the following diagram (all light blue rectangles):

 Ok, I think I got it.

 Sorta rough as fuck.

2. 16M + went snowboarding for 8 hours + next day has sore muscles + took aspirin for pain relief + now has wheezing; what happened?

Aspirin-/NSAID-induced asthma.

Knocking out COX causes shunting of arachidonic acid down the lipoxygenase pathway –> increased synthesis of leukotrienes –> bronchoconstriction.

Samter triad = NSAID hypersensitivity, NSAID-induced asthma, nasal polyps.

3. What’s the key difference between aspirin and other NSAIDs?

MOA of aspirin?

• Irreversible inhibition of cyclooxygenase 1 and 2 (COX1/2).

MOA of other NSAIDs?

• Reversible inhibition of COX1/2.

4. Name three products that are decreased as a result of COX inhibition (In other words, what does COX normally lead to the production of?)

Prostaglandins, Prostacylin, Thromboxane

—

Physiologic effects of COX inhibition by aspirin + other NSAIDs:

• Results in ↓ production of prostaglandins and platelet thromboxane.
• ↓ platelet thromboxane means ↑ bleeding time (NR 2-7 minutes, so >7 minutes; no change in platelet count).
• ↓ prostaglandins (vasodilators) means ↓ diameter of arterioles (i.e., less vasodilation of afferent arterioles of the kidney → ↓ renal perfusion).
• ↓ COX1/2 activity means a shunting of arachidonic acid down the lipoxygenase pathway → ↑ leukotriene production → bronchoconstriction → asthma in some patients.

5. What’s the difference between COX1 and 2?

What’s the difference between COX1 and 2?

• COX1 is found in gastric mucosa and platelets. Thromboxane A2 is the major product of COX1 in platelets.
• COX2 is found in vascular endothelium and inflammatory cells; inhibition of COX2 is the primary mechanism for ↓ pain.

6. a) What’s the first drug given to a patient who’s having an acute MI?

b) What’s the second drug?

Aspirin first.

After aspirin is administered, give an ADP P2Y12 blocker (i.e., clopidogrel) for dual anti-platelet therapy.

7. a) What is the CHADS2 score for atrial fibrillation?

b) What do we give to the patient based on the scoring?

(Variations of CHADS2 exist, e.g., CHADS2VASC, but on USMLE, a simplified CHADS2 always works).

—

 

CHADS2 score is used to assess whether patients with AF need anti-platelet (aspirin) or anti-coagulation therapy (usually warfarin).

Congestive heart failure, Hypertension, Age >75, Diabetes, Stroke/TIA (each worth 1 point; the latter is worth 2 points).

If 0 or 1 points, give aspirin to AF patients.

If 2+ points, give warfarin (anticoagulation answer on USMLE). Patients who have valvular AF (i.e., AF in the setting of, e.g., mitral regurg) must receive warfarin. Patients with non-valvular AF (i.e., idiopathic or, e.g., in the setting of hyperthyroidism) can receive other anticoagulants such as apixaban.

8. What is the role of aspirin in patients with angina?

Angina (ischemic heart disease) to decrease risk of MI.

• Stable angina: used instead of daily baby aspirin in patients who can’t take the latter (e.g., because of renal insufficiency).
• Unstable angina: added to daily baby aspirin. The combo of aspirin + clopidogrel is superior to aspirin alone in unstable angina; this relationship has not yet been proven for stable angina.

9. What are the three acceptable pharmacologic regimens for patients with ischemic stroke risk (i.e., cerebrovascular disease and/or carotid stenosis)?

The three acceptable regimens are: aspirin alone; aspirin + dipyridamole; or clopidogrel alone.

10. 4M + five days of fever + cervical lymphadenopathy + edema of the dorsum of the hands + red lips + red eyes; Tx?

Kawasaki disease Tx = aspirin + IVIG.

And yes, you can get coronary artery aneurysms. Most Qs won’t mention that detail, but students obsess over it.

11. What does the USMLE want you to know about NSAIDs in rheumatoid arthritis treatment?

First-line for pain relief in rheumatoid arthritis; steroids are used for pain if NSAIDs are insufficient. For RA, there are two arms of pharmacologic management:

– Symptom management only: NSAIDs first; if insufficient, add steroids. NSAIDs + steroids do not alter the course of the disease.

– DMARDs (disease-modifying anti-rheumatic drugs); not used for symptoms; these slow the course of the disease –> methotrexate first almost always; if insufficient, add other agents like anti-TNF-alpha drugs.

12. 6M+ runny nose for 3 days + now has hip pain + low-grade fever;

a) Diagnosis?

b) Treatment?

a) Toxic synovitis (aka transient synovitis) –> hip pain in a kid after a viral infection. Sounds weirdly specific, but it’s on the NBME.

b) Ibuprofen (NSAIDs)

—

Septic arthritis, in contrast, will present in peds as a kid who has history of juvenile rheumatoid arthritis, and is almost always the knee, not the hip. Plus, if the USMLE wants toxic synovitis, they’ll always mention viral infection preceding the hip pain.

13. 28M + tender thyroid + HR 92 + a bit tremulousness;

a) Diagnosis?

b) Treatment?

a) Subacute granulomatous (de Quervain) thyroiditis –> tender/painful thyroid + hypo- or hyperthyroidism, usually after viral infection (but the USMLE will frequently not mention the infection).

b) NSAIDs +/- steroids (but choose NSAIDs first on USMLE).

14. How is osteoarthritis treated on USMLE?

If patient is overweight, always choose weight loss first (also obesity = biggest risk factor).

But if question asks for first-line pharmacologic management, answer = acetaminophen first, not NSAIDs. If acetaminophen alone is insufficient, NSAIDs can be added.

Osteoarthritis is degenerative joint disease. The pain will never go away. So if the patient takes chronic NSAIDs for pain, he or she is prone to renal damage (i.e., peripheral edema in someone taking naproxen for OA).

15. When is indomethacin the answer on USMLE?

Indomethacin is first-line for acute gout.

If patient has renal insufficiency, choose corticosteroids over indomethacin.

If indomethacin and steroids are both not listed but patient has acute attack, answer = colchicine.

16. How is pseudogout treated?

NSAIDs, then steroids, then colchicine (same as gout acutely, but NSAID need not be indomethacin).

17. How is most pericarditis treated?

NSAIDs, then steroids, then colchicine (same as acute gout and pseudogout; NSAID need not be indomethacin).

18. 8M + viral infection + fever + given drug by mom to treat fever + now has confusion and papilledema + LFTs are increased; diagnosis?

Reye syndrome, caused by aspirin given to a kid for a viral infection –> causes cerebral edema and liver damage due to inhibition of mitochondrial beta-oxidation enzymes.

19. Why must NSAIDs not be given to patients with history of peptic ulcers, gastritis, and upper GI bleeding?

Prostaglandins normally protect the mucosal barrier of the stomach by increasing production of alkaline mucous in the stomach.

NSAIDs knock out COX –> decreased prostaglandins.

20. 82F + taking naproxen for 6 weeks for joint pain + now has peripheral edema; why does she have the edema?

Vasodilating prostaglandins maintain patency of the renal afferent arterioles → NSAIDs decrease renal blood flow by decreasing prostaglandin synthesis.

82F + taking naproxen for 6 weeks for pain relief + now has peripheral edema; why? –> answer = “decreased renal excretion of sodium,” or “increased renal retention of sodium”; ↓ renal blood flow means kidney attempts to ↑ fluid retention; it accomplishes this by reabsorbing sodium in the PCT, since water follows sodium → edema + FeNa <1% (fractional excretion of sodium).

In pre-renal etiologies of renal insufficiency – i.e., in the setting of decreased renal perfusion – a HY detail is that you know urinary FeNa is <1%, which would be seen with NSAID use.

21. a) What’s the first symptom of aspirin toxicity?

b) What’s the first sign of aspirin toxicity?

Symptom = what the patient reports.

Sign = what we observe but the patient doesn’t report.

—

a) Tinnitus (ringing of the ears); first symptom of salicylate (aspirin) toxicity (i.e., what the patient reports subjectively).

b) Tachypnea (↑ respiratory rate); first sign of salicylate toxicity (i.e., what we notice on examination objectively; the patient doesn’t report tachypnea).

22. 18F + consumed bottle of aspirin ten minutes ago.

a) What’s the name of the acid-base disturbance she is most likely to have?

b) What’s her pH, bicarb, pCO2?

a) Respiratory alkalosis.

b) This occurs early (i.e., first 20 minutes of aspirin toxicity). Answer = ↓ pCO2; normal HCO3^–;↑ pH); bicarb does not change in acute respiratory acid-base disturbances; it takes minimum 24 hours to really move (e.g., with altitude sickness).

23. 20F + consumed bottle of aspirin one hour ago.

a) What’s the name of the acid-base disturbance she is most likely to have?

b) What’s her pH, bicarb, pCO2?

a) Mixed respiratory alkalosis-metabolic acidosis.

b) This occurs late (i.e., after 20 minutes). Answer = ↓ pCO2; ↓ pH 80% of the time; 20% of the time it’s in the normal range; ↓ HCO3^–).

—

Acid-base disturbance caused by aspirin (exceedingly HY for all Steps):

• Respiratory alkalosis early (i.e., first 20 minutes, answer = ↓ pCO2; normal HCO3^–;↑ pH); bicarb does not change in acute respiratory acid-base disturbances; it takes minimum 24 hours to really move (e.g., with altitude sickness).
• Mixed respiratory alkalosis-metabolic acidosis late (i.e., after 20 minutes, answer = ↓ pCO2; ↓ pH 80% of the time; 20% of the time it’s in the normal range; ↓ HCO3^–). Student says, “Wait, I thought you just said it takes ~24 hours for bicarb to really move, so how is it down already?” Because aspirin itself causes a metabolic acidosis (↓ HCO3^–) that is now superimposed on the respiratory alkalosis (↓ pCO2). It’s coincidental that the aspirin-induced metabolic acidosis that occurs with slight delay happens to look like metabolic compensation for the respiratory alkalosis, but this is NOT compensation. Aspirin directly upregulates respiratory centers (tachypnea) + is an acid itself (salicylic acid).

24. 60F + taking high-dose naproxen for 4 weeks for joint pain + now has dark urine + elevated creatinine and BUN; diagnosis?

Renal papillary necrosis (sloughing of renal papillae due to low oxygen delivery).

—

Analgesic nephropathy (any adverse change in the kidney due to NSAIDs); can present as renal papillary necrosis (dark urine) or interstitial nephropathy (eosinophils in the urine).

Pre-renal azotemia –> starts off as patients getting peripheral edema due to NSAIDs because of decreased renal blood flow (as discussed above); the edema is not a renal pathology in and of itself, but reflects pre-renal changes in the kidney that may eventually cause elevations in creatinine and BUN. Once the renal function tests change, the patient now has pre-renal azotemia.

25. What is Samter triad?

Aspirin-/NSAID-induced asthma (Samter triad = NSAID hypersensitivity, NSAID-induced asthma, nasal polyps).

26. a) Treatment for aspirin toxicity?

b) What’s the answer on the USMLE for the mechanism of this treatment?

a) Sodium bicarbonate → alkalinity traps the salicylic acid as the oxalate (O^–) form → kidney cannot reabsorb charged species as well as neutral ones → increased urinary excretion.

b) If the USMLE asks you the mechanism for how sodium bicarb works for aspirin toxicity, the answer = “increased excretion through urinary alkalinization.”

Do not confuse this mechanism with sodium bicarb in the treatment of TCA toxicity. TCAs cause cardiotoxicity by binding to myocardial sodium channels. If the USMLE asks you the answer for the mechanism in this case, the answer = “increased dissociation from myocardial sodium channels”; the wrong answer is “increased excretion through urinary alkalinization,” which is aspirin. Students fuck this up and choose the latter because they’ve memorized it as HY for aspirin, but don’t realize it’s wrong for TCAs.

27. a) MOA of acetaminophen?

b) Is it an NSAID?

a) Inhibits COX in the CNS; inactivated peripherally.

b) Not considered an NSAID → does not act as an anti-inflammatory agent peripherally. The ability to decrease pain is linked to ↓ prostaglandin effects in the CNS, not at peripheral tissues.

28. 30F + fever 2 hours after receiving blood transfusion + Coombs test is negative;

a) Diagnosis?

b) Mechanism for this condition?

c) Treatment?

a) Febrile non-hemolytic transfusion reaction (most common type of transfusion reaction)

b) Antibodies against donor leukocyte antigens

c) Acetaminophen

29. What is the role of acetaminophen in osteoarthritis treatment?

First-line pharmacologic treatment for osteoarthritis (second-line is NSAIDs).

Should be noted that USMLE likes simple “weight loss” as the first treatment overall for osteoarthritis, but if a drug is given, choose acetaminophen over NSAIDs.

30. a) What’s the main toxicity of acetaminophen?

b) How is it treated?

c) What’s the mechanism for the treatment?

a) Severe hepatic necrosis. Acetaminophen is metabolized into a toxic metabolite called NAPQI that is immediately neutralized by reduced glutathione in the liver. If the patient overdoses on acetaminophen, the reduced glutathione is depleted and then the NAPQI oxidizes and diffusely kills the hepatocytes. Whilst NSAIDs and aspirin kill the kidneys, acetaminophen kills the liver.

b) N-acetylcysteine

c)

USMLE wants you to specifically know the reason N-acetylcysteine works is because it regenerates reduced glutathione in the liver.

Species with thiol (-SH) groups are in the reduced form and can act as reducing agents (i.e., can act as anti-oxidants).

Species with disulfide bonds (-S–S-) are in the oxidized form.

Hepatic glutathione has a thiol (-SH) group. So does N-acetylcysteine. After glutathione neutralizes a toxin, it becomes oxidized and inactive.

The thiol group on N-acetylcysteine then binds to and frees up the sulfurs on glutathione so that they can once again neutralize toxins.

This mechanism may sound cumbersome, but it’s HY for USMLE. Probably because N-acetylcysteine is such an important antidote used clinically.

Activated charcoal can be used in select acute circumstances. There’s a Qbank Q floating around where activated charcoal is the answer over N-acetylcysteine. On the USMLE, however, always choose N-acetylcysteine for acetaminophen.

31. a) MOA of celecoxib?

b) When is it used?

c) Adverse effects of celecoxib?

a) MOA of celecoxib?

• Selective COX2 inhibitor.
• Considered to be an NSAID.
• Called a COX2-selective NSAID.

b) When is it used?

• In patients who have contraindications to NSAIDs (i.e., peptic ulcer disease, gastritis, GI bleeding, renal insufficiency) but who need pain relief (e.g., in rheumatoid arthritis).

c) Adverse effects of celecoxib?

• Increases risk of MI and thrombosis → selective inhibition of COX2 decreases vasodilatory effects of prostaglandins and prostacyclins without inhibiting thromboxane A2 in platelets (COX1).
• USMLE vignette will mention specifically that a physician is apprehensive about giving celecoxib to a patient because of increased MI risk with this drug; then they’ll ask why this is the case –> answer on NBME = “inhibition of prostacyclin (PGI2) formation without inhibition of thromboxane A2 in platelets.”
• Similar risk of renal complications as non-selective NSAIDs.

32. A physician is apprehensive about giving celecoxib to a patient because of increased MI risk with this drug; why this is the case?

Answer = “inhibition of prostacyclin (PGI2) formation without inhibition of thromboxane A2 in platelets.”

—

Celecoxib is a COX2-selective inhibitor.

Increases risk of MI and thrombosis → selective inhibition of COX2 decreases vasodilatory effects of prostaglandins and prostacyclins without inhibiting thromboxane A2 in platelets (COX1).

33. a) Name four ADP P2Y12 blockers.

b) What is ADP P2Y12 agonism do?

ADP P2Y12 blockers

• Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine
• ADP P2Y12 receptors are on platelets and lead to the expression of platelet glycoproteins IIb/IIIa, which enable platelet aggregation.
• Despite ADP P2Y12 agonism leading to increased expression of GpIIb/IIIa, do not confuse these with the actual GpIIb/IIIa inhibitors.
• Clopidogrel will almost always be agent mentioned / asked about on the USMLE in relation to this class of drugs.

34. When is clopidogrel the answer on the USMLE? (treatment-wise)

• Second drug given after aspirin for the acute treatment of MI (aspirin given first).
• Technically used for stenting procedures, and this is an important use that’s widely propagated in USMLE resources, but I’m yet to have seen this on any NBME assessment as an actual answer.
• Stable angina: used instead of daily baby aspirin in patients who can’t take the latter (e.g., because of renal insufficiency).
• Unstable angina: added to daily baby aspirin. The combo of aspirin + clopidogrel is superior to aspirin alone in unstable angina; this relationship has not yet been proven for stable angina.
• Cerebrovascular disease or carotid stenosis to prevent ischemic stroke (three acceptable regimens are: aspirin alone; aspirin + dipyridamole; or clopidogrel alone).

35. What are three acceptable pharmacologic regimens used in patients with cerebrovascular disease or carotid stenosis to prevent ischemic stroke?

Aspirin alone; aspirin + dipyridamole; or clopidogrel alone.

USMLE expects you to know this, yes.

36. What are the high-yield adverse effects of ADP P2Y12 blockers for USMLE?

Clopidogrel and prasugrel can cause TTP (thrombotic thrombocytopenic purpura) – i.e., can precipitate the inactivation of ADAMTS13, leading to schistocytosis, thrombocytopenia, and renal insufficiency.

Hemorrhagic stroke (prasugrel > clopidogrel).

Ticlopidine can cause neutropenia (mouth ulcers, sore throat fever).

37. a) Name three GpIIb/IIIa inhibitors.

b) What’s the normal, physiologic role of GpIIb/IIIa?

a) Abciximab, Tirofiban, Eptifibatide

b) GpIIb/IIIa on platelets enable platelet aggregation (i.e., platelets sticking to each other). Do not confuse this with platelet adhesion (i.e., platelets sticking to vascular endothelium) which is mediated by GpIb. Physiologically, fibrinogen is what bridges GpIIb/IIIa on adjacent platelets; therefore the GpIIb/IIIa inhibitors have been described as fibrinogen analogues on USMLE.

38. MOA of clopidogrel?

ADP P2Y12 blockers

• Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine
• ADP P2Y12 receptors are on platelets and lead to the expression of platelet glycoproteins IIb/IIIa, which enable platelet aggregation.
• Despite ADP P2Y12 agonism leading to increased expression of GpIIb/IIIa, do not confuse these with the actual GpIIb/IIIa inhibitors.
• Clopidogrel will almost always be agent mentioned / asked about on the USMLE in relation to this class of drugs.

39. MOA of celecoxib?

MOA of celecoxib?

• Selective COX2 inhibitor.
• Considered to be an NSAID.
• Called a COX2-selective NSAID.

40. MOA of abciximab?

GpIIb/IIIa inhibitors

• Abciximab, Tirofiban, Eptifibatide
• GpIIb/IIIa on platelets enable platelet aggregation (i.e., platelets sticking to each other). Do not confuse this with platelet adhesion (i.e., platelets sticking to vascular endothelium) which is mediated by GpIb.
• Physiologically, fibrinogen is what bridges GpIIb/IIIa on adjacent platelets; therefore the GpIIb/IIIa inhibitors have been described as fibrinogen analogues on USMLE.

41. MOA of ticlopidine?

ADP P2Y12 blockers

• Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine
• ADP P2Y12 receptors are on platelets and lead to the expression of platelet glycoproteins IIb/IIIa, which enable platelet aggregation.
• Despite ADP P2Y12 agonism leading to increased expression of GpIIb/IIIa, do not confuse these with the actual GpIIb/IIIa inhibitors.
• Clopidogrel will almost always be agent mentioned / asked about on the USMLE in relation to this class of drugs.

Ticlopidine causes neutropenia.

42. MOA of tirofiban?

GpIIb/IIIa inhibitors

• Abciximab, Tirofiban, Eptifibatide
• GpIIb/IIIa on platelets enable platelet aggregation (i.e., platelets sticking to each other). Do not confuse this with platelet adhesion (i.e., platelets sticking to vascular endothelium) which is mediated by GpIb.
• Physiologically, fibrinogen is what bridges GpIIb/IIIa on adjacent platelets; therefore the GpIIb/IIIa inhibitors have been described as fibrinogen analogues on USMLE.

43. MOA of ticagrelor?

ADP P2Y12 blockers

• Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine
• ADP P2Y12 receptors are on platelets and lead to the expression of platelet glycoproteins IIb/IIIa, which enable platelet aggregation.
• Despite ADP P2Y12 agonism leading to increased expression of GpIIb/IIIa, do not confuse these with the actual GpIIb/IIIa inhibitors.
• Clopidogrel will almost always be agent mentioned / asked about on the USMLE in relation to this class of drugs.

44. MOA of eptifibatide?

GpIIb/IIIa inhibitors

• Abciximab, Tirofiban, Eptifibatide
• GpIIb/IIIa on platelets enable platelet aggregation (i.e., platelets sticking to each other). Do not confuse this with platelet adhesion (i.e., platelets sticking to vascular endothelium) which is mediated by GpIb.
• Physiologically, fibrinogen is what bridges GpIIb/IIIa on adjacent platelets; therefore the GpIIb/IIIa inhibitors have been described as fibrinogen analogues on USMLE.

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