NSAID Uses and Classes Quiz

NSAID Uses and Classes

• NSAIDs are used for muscle pain, dysmenorrhea, arthritis, fever, gout, migraines
• Can be used as an opioid-sparing agent in acute trauma cases
• NSAIDs are divided into groups based on chemical structure and selectivity:
  • Acetylated salicylates (aspirin)
  • Non-acetylated salicylates (diflunisal, salsalate)
  • Propionic acids (naproxen, ibuprofen)
  • Acetic acids (diclofenac, indomethacin)
  • Enolic acids (meloxicam, piroxicam)
  • Anthranilic acids (meclofenamate, mefenamic acid)
  • Naphthylalanine (nabumetone)
  • Selective COX-2 inhibitors (celecoxib, etoricoxib)
• Non-selective NSAIDs include diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin
• COX-2 selective NSAIDs include celecoxib, rofecoxib, valdecoxib

NSAID Mechanism

• NSAIDs primarily work by inhibiting cyclooxygenase (COX)
• COX is responsible for converting arachidonic acid into thromboxanes, prostaglandins, and prostacyclins
• This inhibition prevents the production of these eicosanoids, which contribute to inflammation, pain, and fever
• Thromboxanes play a role in platelet adhesion
• Prostaglandins cause vasodilation, increase temperature, and contribute to pain relief
• There are two COX isoenzymes: COX-1 and COX-2
• COX-1 is constitutively expressed in the body and is involved in maintaining gastrointestinal lining, kidney function, and platelet aggregation
• COX-2 is not constitutively expressed but is inducibly expressed during an inflammatory response
• Most NSAIDs are nonselective and inhibit both COX-1 and COX-2
• COX-2 selective NSAIDs only target COX-2, leading to a different side effect profile
• COX-2 selective NSAIDs are thought to provide anti-inflammatory benefit without harming the stomach lining

Nifedipine Pharmacokinetics

• Nifedipine is readily absorbed from the GI tract after sublingual, oral, and rectal administration
• Bioavailability is approximately 56% to 77% due to presystemic metabolism
• Peak plasma concentration after oral administration of 10mg occurs between 30-60 minutes
• After intravenous administration, elimination is biphasic with a short alpha-phase half-life of 13 minutes and a longer beta-phase half-life of 1.26 hours
• A third phase with a half-life of 8 hours is observed after higher oral doses or continuous infusion
• Nifedipine undergoes hepatic metabolism into two main metabolites: 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid (M I) and 2-hydroxymethyl-pyridinecarboxylic acid (M II)

Aspirin Development

• Aspirin’s history dates back thousands of years with the use of willow bark and plants containing salicylates
• Synthetic salicylate was developed by Felix Hoffman at Bayer Company in Germany in 1897
• Aspirin became the most widely used medication globally
• In 1971, Vane discovered the mechanism of aspirin’s actions, proving that it inhibits cyclooxygenase (COX) leading to the formation of prostaglandins (PGs) which mediate inflammation, swelling, pain, and fever

Drug Elimination

• Medical absorption is the movement of a drug from its site of administration into the blood.
• Oral medications enter the stomach, where they are either dissolved and pass through epithelial cells or travel undissolved to the small intestine for absorption.
• Drugs pass through the intestinal wall and enter the portal venous system, leading to the first-pass effect in the liver.
• The liver metabolizes the drug, potentially inactivating it or excreting it into bile.
• The remaining active drug leaves the liver and enters the general circulation, reaching its target organs.
• Intravenous injection bypasses the first-pass effect in the liver.
• Drugs administered into muscle or subcutaneous tissue pass through gap junctions into capillaries and then into the bloodstream.
• Bioavailability refers to the fraction of a drug dose absorbed into the bloodstream.
• Bioavailability is less than 100% due to the first-pass effect but is 100% for intravenous administration.
• Different drugs have varying bioavailability because they are absorbed at different rates.

Ibuprofen

• Ibuprofen is sold under trade names like Nurofen and Advil.
• It’s a non-steroidal anti-inflammatory drug (NSAID) and a COX inhibitor.
• It is effective for headaches, fever, and pain.
• Ibuprofen has analgesic, antipyretic (fever-reducing), and anti-inflammatory properties.
• NSAIDs are FDA-approved for antipyretic, anti-inflammatory, and analgesic uses.

Beta-Lactamase

• Beta-lactamase is an enzyme produced by bacteria that breaks down the beta-lactam ring in antibiotics, rendering them ineffective.
• It is a significant factor in antibiotic resistance.

Uremic patients

• Are patients with kidney failure.
• Experience difficulty eliminating drugs from the body, leading to accumulation and potential toxicity.

Penicillin and Antibacterial Activity

• Some penicillins, such as procaine penicillin and benzathine penicillin, lack direct antibacterial activity.
• These are administered as pro-drugs.
• They require conversion to active metabolites within the body to exert their antibacterial effect.

MIC (Minimum Inhibitory Concentration)

• MIC is the lowest concentration of an antibiotic that inhibits the visible growth of a bacterium.
• It is crucial to maintain antibiotic concentrations above the MIC to effectively fight infection.

Daptomycin (Lipopeptide)

• Daptomycin shows concentration-dependent bactericidal activity.
• It is primarily excreted by the kidneys, with a longer half-life in patients receiving hemodialysis.

Broad Spectrum Antibiotics

• Broad-spectrum antibiotics are effective against a wide range of bacteria.
• They are used for infections where the specific pathogen is unknown or when the infection is caused by multiple organisms.

Time-Dependent vs Concentration-Dependent Antibiotics

• Time-dependent antibiotics: Effectiveness depends on maintaining drug concentrations above the MIC for a specific duration.
• Concentration-dependent antibiotics: Effectiveness depends on achieving high peak concentrations.
• Time>MIC is a critical factor for time-dependent antibiotics (like beta-lactams).
• Peak:MIC ratio is a critical factor for concentration-dependent antibiotics (such as aminoglycosides).

Pharmacodynamic Properties and Dose Adjustments for Kidney Disease

• Understanding an antibiotic's pharmacodynamic properties is crucial for adjusting dosages for patients with kidney disease.
• For time-dependent antibiotics (e.g., beta-lactams), it is often preferable to decrease the dose while maintaining the dosing interval.
• For concentration-dependent antibiotics, it might be better to keep the dose the same and prolong the dosing interval.

Beta-Lactam Antibiotics

• Penicillin, cephalosporin, and carbapenem antibiotics contain a beta-lactam ring.
• They inhibit the final step in bacterial cell-wall peptidoglycan synthesis, leading to bacterial cell death.

Nonlinear Pharmacokinetics

• Nonlinear pharmacokinetic models indicate that certain aspects of drug behavior, such as metabolism or absorption, can become saturated at higher doses.
• This saturation can lead to a greater than proportional increase in the area under the curve (AUC) with increasing dose.
• A common example is the saturation of metabolic pathways, resulting in decreased clearance and a higher AUC at higher doses.
• In some cases, shortening the infusion duration can also increase the AUC due to higher peak plasma concentrations and slower clearance.
• 5-Fluorouracil (5-FU) exhibits nonlinear pharmacokinetics due to saturation of its conversion to dihydrofluorouracil by dihydropyrimidine dehydrogenase.
• Doubling the dose of 5-FU can result in a 135% increase in AUC.
• Paclitaxel also demonstrates nonlinear pharmacokinetics, with shorter infusion durations (3 hours vs. 24 hours) leading to a higher AUC for a fixed dose. However, this does not result in increased toxicity.
• Alternatively, nonlinear pharmacokinetics can occur when a drug's absorption from the gastrointestinal tract or renal tubular reabsorption is saturable.
• This leads to a less than proportional increase in AUC with increasing dose.
• Drugs that resemble natural compounds and are absorbed through active transport processes often exhibit saturable absorption, such as folate analogs (methotrexate, leucovorin) and amino acid analogs (melphalan).
• Cisplatin exhibits nonlinear pharmacokinetics due to saturation of its renal tubular reabsorption.
• Continuous infusion of cisplatin leads to a 42% increase in free plasma platinum compared to a 20-minute infusion.
• Prolonged cisplatin infusion also results in a greater than threefold increase in the free platinum half-life.