Nonopioid Analgesics: NSAIDs and Acetaminophen Flashcards
Pain source
- Somatic (nociceptive): prostaglandin mediated, typically responds to NSAIDs
- Visceral (nociceptive): responds to opioid analgesics
- Neuropathic (deafferentiated): poor response to analgesics- better response to adjuvant Tx
Prostaglandin’s role in pain and inflammation
- Prostaglandins act at prostaglandin (G-protein coupled) receptors on cell membranes to cause pain and inflammation
- Dorsal Horns: PGs increase sensitivity of adenylate cyclase to stimulation by pain mediators
- PGs enhance neurotransmitter release and act post synaptically
NSAIDs: MOA
- Inhibit both peripheral and central cyclooxygenase (COX)
- COX-1: Constitutive, Physiologic (increases TXA, PGE, PGI)
- COX-2: Inducible, Inflammatory (increases PGI & PGE)
NSAIDs: Indications
- Inflammation (surgery, arthritis- symptomatic relief)
- Pain in multiple disease states (cancer, muscle, bone pain, menstrual pain)
- doses for inflammation are higher than those for pain
NSAIDs: Effectiveness
-All NSAIDs have a ceiling effect on analgesia (increasing the dose will not increase analgesic efficacy, but will increase incidence of side effects)
NSAIDs: Non Analgesic uses
- Antipyretic
- Antiplatelet/Cardioprotection
- Gout, cancer chemoprevention, systemic mastocytosis, Alzheimer’s
NSAIDs ADRs
Gastrointestinal (GI bleeds) Renal Cardiovascular Bleeding Hepatic CNS Impairment of Joint Healing?
NSAIDs: ADE with GI
- Mediated through both COX inhibition and local irritation
- Increased risk: age, concurrent GI problems, smoking, alcohol use, steroid use
- Reduced by proton pump inhibitors, misoprostol (replenishes PG), and possibly high dose histamine 2 blockers
- Increases Ketorolac (increases risk of GI bleed)
NSAIDs: ADE with Renal
- Renal toxicity may only be important in patients with reduced renal function, CHF, hepatic cirrhosis
- NSAIDs can cause salt retention, hyperkalemia, and edema
- Reduce GFR and can precipitate renal failure of: repeated or long term dosing, concomitant nephrotic therapy, dehydration, CHF, diabetes, hypertension, elderly
NSAIDs: Drug interactions
- ACEI inhibitors
- Corticosteroids
- Warfarin
- Sulfonylureas
- Methotrexate
Acetaminophen: MOA
- Peripherally blocks pain impulse generation
- Inhibition of hypothalamic heat regulating center
- Selective COX 2 inhibitor
Acetaminophen: Indications
- Analgesic for mild to moderate pain, headache
- Minimal anti-inflammatory activity
- Antipyretic
Acetaminophen: ADE
- Hepatotoxicity
- Overdose: stores of GDH depleted, NAPQI binds covalently to cell macromolecules, leads to dysfunction and apoptosis
Acetaminophen: Precautions
- Liver Disease
- Alcoholics
- Max dose: 4g/day
Aspirin
- Analgesic, anti inflammatory and antipyretic
- Antiplatelet effect: irreversible inhibition of platelet aggregation (thromboxane)
Traditional NSAIDs: PK and PD
- Well absorbed orally
- Peak concentrations with 1-4 hrs
- Accumulate at sites of inflammation
- Metabolized in liver
- Excreted in kidneys by glomerular filtration and tubular secretion
- Extensively protein bound
COX 2 Inhibitors (Coxibs) MOA
- COX 2 selective inhibitors (coxibs) designed to preserve COX 1 activity
- Beneficial anti inflammatory, analgesic, and antipyretic effects without the GI and platelet effects mediated through COX 1 inhibition
Pros and Cons of Coxibs
Coxibs may reduce GI complications, but increase cardiovascular events versus traditional NSAIDs
Thromboxane activities
- Exclusive COX 1 product in platelets
- Promotes platelet aggregation
- Vasoconstriction
- Vascular proliferation
Prostacyclin (PGI2)
- Predominant COX 2 product in endothelium
- inhibits platelet activation
- vasodilation
- prevents proliferation of vascular smooth muscle cells
COXIBs Place in Therapy
- Perioperative or acute setting
- chronic pain
Celecoxib
- Half life: 11 hours
- contraindicated for sulfa allergy
- metabolized by cytochrome P450 enzyme 2C9
- African Americans and elderly often deficiency in 2C9, which could lead to elevated levels of drug
Prostaglandin “Housekeeping” activities
- Gastrointestinal Cytoprotection (PGE)
- Renal Vasodilation (PGE2, PGI2)
- Fever (PGE2)
- Uterine Contraction (PGE2)
Thromboxane
- Exclusive COX-1 product in platelets
- Promotes platelet aggregation
- Vasoconstriction
- Vascular proliferation
Prostacyclin (PGI2)
- Predominant COX-2 product in endothelium
- Inhibits platelet aggregation
- Vasodilation
- Prevents proliferation of vascular smooth muscle cells
