Musculoskeletal, Skin, and Connective Tissue - Pharmacology

Question 1

Arachidonic acid products (439)

• Lipoxygenase
• LTB4
• LTC4, D4, and E4
• PGI2

Answer 1

• Lipoxygenase pathway yields Leukotrienes.
  
  • L for Lipoxygenase and Leukotriene.
• LTB4 is a neutrophil chemotactic agent.
  
  • Neutrophils arrive “B4” others.
• LTC4, D4, and E4 function in bronchoconstriction, vasoconstriction, contraction of smooth muscle, and increased vascular permeability.
• PGI2 inhibits platelet aggregation and promotes vasodilation.
  
  • Platelet-Gathering Inhibitor.

Question 2

Aspirin

• Mechanism
• Clinical use
  
  • Low dose
  • Intermediate dose
  • High dose
• Toxicity

Answer 2

• Mechanism
  
  • Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by covalent acetylation, which decrease synthesis of both thromboxane A2 (TXA2) and prostaglandins. 
  • Increased bleeding time until new platelets are produced (~ 7 days).
  • No effect on PT, PTT.
  • A type of NSAID.
• Clinical use
  
  • Low dose (< 300 mg/day): decrease platelet aggregation.
  • Intermediate dose (300–2400 mg/day): antipyretic and analgesic.
  • High dose (2400–4000 mg/day): anti-inflammatory.
• Toxicity
  
  • Gastric ulceration, tinnitus (CN VIII).
  • Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding.
  • Risk of Reye syndrome in children treated with aspirin for viral infection.
  • Also stimulates respiratory centers, causing hyperventilation and respiratory alkalosis.

Question 3

NSAIDs

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 3

• Examples
  
  • Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac.
• Mechanism
  
  • Reversibly inhibit cyclooxygenase (both COX-1 and COX-2).
  • Block PG synthesis.
• Clinical use
  
  • Antipyretic, analgesic, anti-inflammatory.
  • Indomethacin is used to close a PDA.
  • Acute gout drugs
• Toxicity
  
  • Interstitial nephritis, gastric ulcer (PGs protect gastric mucosa), renal ischemia (PGs vasodilate afferent arteriole).

Question 4

COX-2 inhibitors (celecoxib)

• Mechanism
• Clinical use
• Toxicity

Answer 4

• Mechanism
  
  • Reversibly inhibit specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain
  • Spares COX-1, which helps maintain the gastric mucosa.
  • Thus, should not have the corrosive effects of other NSAIDs on the GI lining.
  • Spares platelet function as TXA2 production is dependent on COX-1.
• Clinical use
  
  • Rheumatoid arthritis and osteoarthritis
  • Patients with gastritis or ulcers.
• Toxicity
  
  • Increased risk of thrombosis.
  • Sulfa allergy.

Question 5

Acetaminophen

• Mechanism
• Clinical use
• Toxicity

Answer 5

• Mechanism
  
  • Reversibly inhibits cyclooxygenase, mostly in CNS.
  • Inactivated peripherally.
• Clinical use
  
  • Antipyretic, analgesic, but not anti-inflammatory.
  • Used instead of aspirin to avoid Reye syndrome in children with viral infection.
• Toxicity
  
  • Overdose produces hepatic necrosis
  • Acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue adducts in liver.
  • N-acetylcysteine is antidote—regenerates glutathione.

Question 6

Bisphosphonates

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 6

• Examples
  
  • Alendronate, other -dronates.
• Mechanism
  
  • Pyrophosphate analogs
  • Bind hydroxyapatite in bone, inhibiting osteoclast activity.
• Clinical use
  
  • Osteoporosis, hypercalcemia, Paget disease of bone.
• Toxicity
  
  • Corrosive esophagitis (patients are advised to take with water and remain upright for 30 minutes), osteonecrosis of the jaw.

Question 7

Allopurinol

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 7

• Type of drug
  
  • Chronic gout drug (preventive)
• Mechanism
  
  • Inhibits xanthine oxidase, decreases conversion of xanthine to uric acid.
  • Increases concentrations of azathioprine and 6-MP (both normally metabolized by xanthine oxidase).
• Clinical use
  
  • Also used in lymphoma and leukemia to prevent tumor lysis–associated urate nephropathy. 
• Toxicity
  
  • Do not give salicylates
  • All but the highest doses depress uric acid clearance.
  • Even high doses (5–6 g/day) have only minor uricosuric activity.

Question 8

Febuxostat

• Type of drug
• Mechanism

Answer 8

• Type of drug
  
  • Chronic gout drug (preventive)
• Mechanism
  
  • Inhibits xanthine oxidase.

Question 9

Probenecid

• Type of drug
• Mechanism

Answer 9

• Type of drug
  
  • Chronic gout drug (preventive)
• Mechanism
  
  • Inhibits reabsorption of uric acid in PCT
  • Also inhibits secretion of penicillin

Question 10

Glucocorticoids

• Type of drug
• Administration

Answer 10

• Type of drug
  
  • Acute gout drug
• Administration
  
  • Oral or intraarticular.

Question 11

Colchicine

• Type of drug
• Mechanism
• Toxicity

Answer 11

• Type of drug
  
  • Acute gout drug
• Mechanism
  
  • Binds and stabilizes tubulin to inhibit microtubule polymerization, impairing leukocyte chemotaxis and degranulation.
  • Acute and prophylactic value.
• Toxicity
  
  • GI side effects

Question 12

TNF-α inhibitors

Answer 12

• All TNF-α inhibitors predispose to infection, including reactivation of latent TB, since TNF blockade prevents activation of macrophages and destruction of phagocytosed microbes.

Question 13

Etanercept

• Type of drug
• Mechanism
• Clinical use

Answer 13

• Type of drug
  
  • TNF-α inhibitor
• Mechanism
  
  • Fusion protein (receptor for TNF-α + IgG1 Fc), produced by recombinant DNA.
  • Etanercept** is a TNF decoy receptor.**
• Clinical use
  
  • Rheumatoid arthritis, psoriasis, ankylosing spondylitis

Question 14

Infliximab, adalimumab

• Type of drug
• Mechanism
• Clinical use

Answer 14

• Type of drug
  
  • TNF-α inhibitor
• Mechanism
  
  • Anti-TNF-a monoclonal antibody
• Clinical use
  
  • IBD, rheumatoid arthritis, ankylosing spondylitis, psoriasis