ANALGESICS - Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Drug Class: antipyretics, analgesics, anti-inflammatory, anti-platelets

Drugs:

• ASA
• Non-selective NSAIDs—diclofenac [Voltaren], ibuprofen [Advil, Motrin], indomethacin [Indocin], naproxen [Anaprox, Naprosyn]
• COX-2 selective NSAIDs—celecoxib [Celebrex]

Mechanism of Action & Indications

• All act by inhibition of prostaglandin formation by cyclooxygenase (COX), which converts the substrate arachidonic acid. COX-1 is present in gastric mucosa and platelets, while COX-2 is present in inflamed tissue and the afferent arteriole of the kidney.
• For the treatment of mild to moderate pain and fever. Also for inflammation associated with non-infectious causes, usually of MSK origin, but also of pericarditis or pleuritis. Other specific indications include the use of low dose ASA for platelet inhibition.

Common Dosages

• Celecoxib 100-200mg PO BID
• Diclofenac 50mg PO BID-TID
• Diclofenac topical 1.5, 2, or 5% apply BID over affected area
• Ibuprofen 300-800mg PO TID-QID
• Indomethacin 25-50mg PO BID-TID

Adverse Effects & Contraindications

• Gastric ulcer, gastritis, or GI discomfort. The degree of GI side effects variesdepending on which class of NSAID drug is used (i.e. indomethacin>ASA>ibuprofen).
• Hypertension, fluid retention, renal dysfunction, interstitial nephritis.
• Impaired platelet function.
• Hypersensitivity with angioedema, hives, and bronchospasm.
• Less commonly causes abnormal liver function tests.
• Recent reports of COX-2 selective inhibitors and other NSAIDs increasing cardiovascular risk. Use with caution in patients at risk of cardiovascular diseases. Benefits of these agents should to be weighed against the potential adverse effects.

      Contra-indications include:

• Hypersensitivity (ASA sensitivity): severe reactions to one are frequentlyassociated with cross reaction to all NSAIDs, particularly in asthmatics.
• Significant renal impairment, hypertension, or CHF. All may lead to an increase in creatinine, increase in blood pressure, fluid and salt retention, and hyperkalemia, particularly at higher doses.
• Active acid peptic disease.

Practical Tips

• ASA is the prototype. It has unique, irreversible effects at low doses on platelets. Other non-specific NSAIDs (diclofenac, naproxen, and indomethacin) have reversible platelet effects. COX-2 selective inhibitors (celecoxib, valdecoxib) do not cause platelet inhibition, and less risk for gastric ulceration.

• Topical diclofenac is safer than oral as only a small quantity is systemically absorbed.

Interactions:

• May reverse the therapeutic effect of some anti-hypertensive medications (thiazide, β-blockers, ACE inhibitors, ARBs). With concurrent ACE inhibitor use,there is also a risk of hyperkalemia and acute renal failure.
• Increased risk of bleeding with anti-coagulants.
• Increased risk of lithium toxicity

Written by Stephen Aaron; reviewed by Raj Padwal and Jeff Whissell

Drug Guide 12:33 AM No comments Read More

ANALGESICS - Acetaminophen

Acetaminophen

Drug Class: antipyretics, analgesics
Drug: acetaminophen [Tylenol], acetaminophen with codeine [Tylenol #1, #2, #3, #4]

Mechanism of Action & Indications

• Inhibits synthesis of prostaglandins in the central nervous system and peripherally, blocking pain impulse generation.
• Antipyretic action by inhibition of hypothalamic heat-regulating center.

Common Dosage

• Acetaminophen 325-650mg PO q4-6h, maximum dose 4g/day
• Acetaminophen extra-strength 500-1000mg PO q4-6h, maximum dose 4g/day

Adverse Effects

• Generally a well-tolerated medication with minimal side effects if used appropriately.
• The toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is normally inactivated by glutathione (sulfhydryl donor). In the setting of large amount of this toxic
  metabolite (≥4g daily), glutathione conjugation becomes insufficient. NAPQI then
  binds covalently with cellular macromolecules, causing potential hepatic cell
  necrosis and acute renal failure. N-acetylcysteine, the antidote, regenerates hepatic
  glutathione stores.
• Acute overdose with a single dose of >10g (twenty 500mg tablets) can produce liver injury. Fulminant hepatic failure is associated with ingestion >25g.
• Chronic liver damage has been reported with long term use in adults of 5-8g/day for several weeks, or 3-4 g/day for one year.

Practical Tips

• For patients with liver disease/cirrhosis or malnutrition, limited low-dose therapy is usually well tolerated. However, hepatotoxicity at dosages <4 g/day have been reported. Avoid chronic use if hepatic impairment or heavy alcohol use.
• Caution in patients with alcoholic liver disease (≥3 drinks/day), as this may increase the risk of hepatotoxicity.
• Metabolized by the liver and excreted in urine. For patients with renal failure, consider dosing interval adjustment as metabolites may accumulate (q6h if creatinine clearance 10-50ml/min, and q8h if creatinine clearance <10ml/min).
• Unlike ASA or NSAIDs, acetaminophen does NOT have anti-inflammatory effect.
• Acetaminophen is combined with codeine in Tylenol #1 (300mg/8mg) and Tylenol #2 (300mg/15mg), Tylenol #3 (300mg/30mg) and Tylenol #4 (300mg/60mg) for better pain control. However, in patients with severe pain, the amount of codeine is limited by the maximum dose of acetaminophen. Consider replacing Tylenol #1- 4 with acetaminophen plus an opioid (e.g. morphine, codeine) as separate prescriptions.
• Caution in patients with febrile neutropenia or severe infections as acetaminophen may mask the fever, leading to delayed treatment of life-threatening infections. If symptomatic relief needed, consider a single dose at a time after fever documented and appropriate actions taken (blood cultures, antibiotics). 
• Treatment of acetaminophen overdose with N-acetylcysteine: 150mg/kg (~60ml) in 200cc D5W over 1hr, then 50mg/kg (~20ml) in 500cc D5W over 4hr, then 100mg/kg (~40ml) in 1L D5W over 16hr. Alternatively, N-acetylcysteine 140mg/kg PO/NG, followed by 70mg/kg q4h for 17 doses.

Drug Guide 12:24 AM No comments Read More