A 53-year-old man is brought to the emergency department because of wheezing and shortness of breath that began 1 hour after he took a new medication. Earlier in the day he was diagnosed with stable angina pectoris and prescribed a drug that irreversibly inhibits cyclooxygenase-1 and 2. He has chronic rhinosinusitis and asthma treated with inhaled β-adrenergic agonists and corticosteroids. His respirations are 26/min. Examination shows multiple small, erythematous nasal mucosal lesions. After the patient is stabilized, therapy for primary prevention of coronary artery disease should be switched to a drug with which of the following mechanisms of action?

Blockage of P2Y12 component of ADP receptors

Potentiation of antithrombin III

Inhibition of vitamin K epoxide reductase

A 14-year-old boy is brought to the emergency department because of a 4-hour history of vomiting, lethargy, and confusion. Three days ago, he was treated with an over-the-counter medication for fever and runny nose. He is oriented only to person. His blood pressure is 100/70 mm Hg. Examination shows bilateral optic disc swelling and hepatomegaly. His blood glucose concentration is 65 mg/dL. Toxicology screening for serum acetaminophen is negative. The over-the-counter medication that was most likely used by this patient has which of the following additional effects?

Irreversible inhibition of cyclooxygenase-1

Increased partial thromboplastin time

Decreased uric acid elimination

Decreased expression of glycoprotein IIb/IIIa

Irreversible inhibition of ATP synthase

A 61-year-old woman comes to the physician because of a 6-month history of left knee pain and stiffness. Examination of the left knee shows tenderness to palpation along the joint line; there is crepitus with full flexion and extension. An x-ray of the knee shows osteophytes with joint-space narrowing. Arthrocentesis of the knee joint yields clear fluid with a leukocyte count of 120/mm3. Treatment with ibuprofen during the next week significantly improves her condition. The beneficial effect of this drug is most likely due to inhibition of which of the following?

Conversion of arachidonic acid to prostaglandin G2

Conversion of hypoxanthine to urate

Conversion of phospholipids to arachidonic acid

Conversion of prostaglandin H2 to thromboxane A2

Conversion of dihydroorotate to orotate

A 48-year-old woman presents to the emergency room because of severe back pain after a fall. She says that she was walking home from work when she slipped on a patch of ice on the sidewalk. Since she did not have anything to hold onto, she fell backwards and landed on her posterior iliac crests bilaterally. Immediately after the fall, she started experiencing back pain and tenderness that concerned her enough to call for an ambulance. Her past medical history is significant for arthritis, diabetes, and hypertension. On arrival, her temperature is 99°F (37.2°C), blood pressure is 129/86 mmHg, pulse is 112/min, respirations are 19/min. Physical exam reveals tenderness to palpation over the middle of her lower back. A drug that may have predisposed this patient to this outcome most likely has which of the following mechanisms?

Stimulation of adipocyte transcription factor

Inhibition of leukotriene and prostaglandin production

Inhibition of circulating cytokine

Inhibition of folate processing

Inhibition of prostaglandin production alone

A 19-year-old woman with a history of poorly controlled asthma presents to her pulmonologist for a follow-up visit. She was recently hospitalized for an asthma exacerbation. It is her third hospitalization in the past five years. She currently takes inhaled salmeterol and medium-dose inhaled budesonide. Her past medical history is also notable for psoriasis. She does not smoke and does not drink alcohol. Her temperature is 98.6°F (37°C), blood pressure is 110/65 mmHg, pulse is 75/min, and respirations are 20/min. Physical examination reveals bilateral wheezes that are loudest at the bases. The patient’s physician decides to start the patient on zileuton. Which of the following is the most immediate downstream effect of initiating zileuton?

Decreased production of leukotrienes

Decreased signaling via the leukotriene receptor

Decreased signaling via the muscarinic receptor

Decreased mast cell degranulation

Decreased IgE-mediated pro-inflammatory activity

A 42-year-old woman comes to her primary care physician because of an irritating sensation in her nose. She noticed recently that there seems to be a lump in her nose. Her past medical history is significant for pain that seems to migrate around her body and is refractory to treatment. She has intermittently been taking a medication for the pain and recently increased the dose of the drug. Which of the following processes was most likely responsible for development of this patient's complaint?

Increased lipoxygenase pathway activity

Decreased lipoxygenase pathway activity

Decreased prostaglandin activity

Increased allergic reaction in mucosa

Eicosanoid synthesis and function for USMLE Step 1: High-Yield Biochemistry Lessons

Arachidonic Acid Metabolism - The Inflammatory Cascade

Source: Arachidonic Acid (AA) is released from membrane phospholipids by Phospholipase A₂ (inhibited by corticosteroids).
Pathways: AA is metabolized via two main pathways: Cyclooxygenase (COX) and Lipooxygenase (LOX).

COX Pathway (Prostanoids)
- Prostaglandins (PGI₂, PGE₂): ↑ Vascular permeability & vasodilation, pain, fever.
- Thromboxane A₂ (TXA₂): ↑ Platelet aggregation & vasoconstriction.
- Inhibited by NSAIDs, Celecoxib.
LOX Pathway (Leukotrienes)
- LTB₄: Neutrophil chemotaxis. (📌 Brings neutrophils to site).
- Cysteinyl-LTs (LTC₄, LTD₄, LTE₄): Bronchoconstriction, ↑ vascular permeability.
- Inhibited by Zileuton, Montelukast.

⭐ Aspirin irreversibly inhibits COX-1 and COX-2 via covalent acetylation, unlike other NSAIDs which are reversible inhibitors.

Arachidonic Acid Metabolism and Eicosanoid Synthesis

Cyclooxygenase (COX) Pathway - Prostanoid Production

Cyclooxygenase Pathway with COX-1/COX-2 and NSAID Inhibition

Precursor: Arachidonic Acid, released from cell membranes via Phospholipase A₂.
Key Enzyme: Cyclooxygenase (COX) converts Arachidonic Acid to Prostaglandin H₂ (PGH₂).
- COX-1 (Constitutive): "Housekeeping" roles like gastric protection, renal blood flow, and platelet aggregation.
- COX-2 (Inducible): Upregulated by inflammatory stimuli to produce prostaglandins that mediate pain, fever, and inflammation.

Products from PGH₂:
- Prostacyclin (PGI₂): Causes vasodilation and inhibits platelet aggregation.
- Thromboxane A₂ (TXA₂): Causes vasoconstriction and promotes platelet aggregation. 📌 Thromboxane Aggregates.
- Prostaglandins (PGE₂, PGD₂): Mediate inflammation, pain, and fever. PGE₂ maintains a patent ductus arteriosus (PDA).

⭐ Aspirin causes irreversible inhibition of COX-1 in platelets, thus blocking TXA₂ synthesis for the entire platelet lifespan (~7-10 days).

Lipoxygenase (LOX) Pathway - Leukotriene Lineage

Eicosanoid synthesis pathways and receptor interactions

Initiating Enzyme: 5-Lipoxygenase (5-LOX) acts on Arachidonic Acid.
Pathway Inhibitor: Zileuton blocks 5-LOX.

Key Products & Functions:
- LTB4: Neutrophil chemotaxis, adhesion, and activation. 📌 LTB4 is for Neutrophils (Brings them 4ward).
- Cysteinyl-LTs (LTC4, LTD4, LTE4):
  - Intense bronchoconstriction (asthma).
  - ↑ Vascular permeability & vasoconstriction.

⭐ Cysteinyl-leukotriene receptor antagonists (e.g., Montelukast, Zafirlukast) are mainstays in asthma therapy, specifically blocking the effects of LTC4, D4, and E4 on bronchial smooth muscle.

Pharmacologic Modulation - Taming the Flames

Corticosteroids (e.g., Prednisone): Inhibit Phospholipase A₂, blocking the entire cascade upstream. Halts all prostaglandin and leukotriene production.
NSAIDs: Inhibit cyclooxygenase (COX) enzymes.
- Non-selective (Aspirin, Ibuprofen): Block both COX-1 and COX-2.
- COX-2 Selective (Celecoxib): Target inflammation with less risk of gastric ulcers.
Leukotriene Pathway Inhibitors: Primarily for asthma & allergic rhinitis.
- Zileuton: Inhibits 5-Lipoxygenase enzyme.
- Montelukast, Zafirlukast: Block CysLT1 leukotriene receptors.

⭐ Aspirin irreversibly acetylates COX-1 and COX-2. Its effect on platelets is permanent for the platelet's lifespan (~7-10 days), crucial for its cardioprotective role.

Arachidonic Acid Pathway & Pharmacologic Inhibition

High‑Yield Points - ⚡ Biggest Takeaways

Eicosanoids are signaling molecules derived from arachidonic acid, released from membranes by Phospholipase A2.

The cyclooxygenase (COX) pathway produces prostaglandins (inflammation, gastric protection) and thromboxanes (platelet aggregation).

The lipoxygenase (LOX) pathway yields leukotrienes (bronchoconstriction, chemotaxis) and anti-inflammatory lipoxins.

NSAIDs inhibit COX enzymes; corticosteroids block Phospholipase A2 upstream, hitting both pathways.

Aspirin causes irreversible COX inhibition, crucial for its antiplatelet effect.

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