Analgesics

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Opioid receptors

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- 7 transmembrane family GPCR; inhibit adenylyl cyclase, increase K conductance, decrease Ca conductance
- µ, κ, and δ: analgesia (supraspinal and spinal)
- µ and δ: constipation (bowel)
- µ and κ: miosis
- µ only: nausea (area postrema of medulla), decreased respiration (decreased sensitivity of respiratory center of medulla to CO2), antitussive (cough center of medulla), euphoria (brainstem Da neurons?)
- κ only: psychotomimesis, dysphoria (Da neurons?)

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Endogenous opioids

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- β-endorphin: binds to µ and δ; located in arcuate nuc of hypothalamus, which projects to periaqueductal gray (PAG), etc.
- leu- and met-enkephalin: bind to µ and δ; located in inhibitory interneurons of spinal cord and PAG
- dynorphins A and B, α-neoendorphin: bind to κ; dynorphin A also binds to µ; located in spinal cord and PAG

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NSAIDs

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- non-steroidal anti-inflammatory drugs
- generally act by reversibly inhibiting COX (except for aspirin, which is irreversible)
- can also affect expression and function of leukocyte adhesion molec
- anti-inflammatory, antipyretic, and analgesic effects (but not as good for visceral pain)
- no tolerance/addiction
- “opioid-sparing” effect
- uses: MI/stroke prevention (aspirin), dysmenorrhea, patent ductus arteriosus, gout, FAP/colorectal ca

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Side effects of NSAIDs

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- GI, renal, allergic intolerance, bronchoconstriction, prolonged bleeding time, prolonged gestation, premature closure of ductus arteriosus, DDIs
- prevent gastric ulcers with misoprostol (PGE1 analogue) or PPIs

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Salicylates

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- NSAIDs that inhibit COX
- potent anti-inflammatory and analgesic properties, not entirely explained by COX inhibition
- aspirin and sodium salicylate also inhibit NF-κB (unlike other NSAIDs)
- dose-dependent kinetics: high doses --> saturation of liver glucuronidation mechanism --> more problematic in kids

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Salicylate side effects

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- GI: increased acid secretion, decreased mucus production
- salicylism: headache, dizziness, tinnitus, confusion, drowsiness, sweating, thirst, hyperventilation, nausea/vomiting
- severe salicylate intoxication: respiratory depression at v high doses --> acidosis
- indirect respiratory stimulation --> alkalosis
- renal, hepatic, CNS toxicity
- Reye’s syndrome: rare; fatal encephalopathy in kids; consequence of viral infection
- premature closing of ductus arteriosus

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Morphine

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- opiate analgesic; µ receptor agonist
- analgesia, euphoria, respiratory depression, miosis, nausea, constipation, antitussive effects
- causes release of histamine --> vasodilation, bronchoconstriction
- doesn’t penetrate BBB well due to polar hydroxyl groups
- more effective parenterally than orally due to first pass effect
- hepatic metabolism to active and inactive metabolites, which are excreted mostly in urine
- dependence, but withdrawal symptoms not hard to avoid

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Codeine

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- opiate analgesic; µ receptor agonist
= methylmorphine: lower affinity than morphine for µ receptor
- much analgesic activity results from demethylation to morphine
- less first pass effect than morphine
- greater antitussive action than morphine (mediated by binding to µ and non-opioid receptors)
- often used in combo with non-opioid analgesic (like aspirin or acetaminophen) to increase analgesic potency w/o side effects

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Methadone

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- opioid analgesic; µ receptor agonist
- good oral absorption
- slow onset and long duration of action
- use to treat severe chronic pain and opioid addiction (esp heroin)

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Meperidine (Demerol)

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- opioid analgesic; µ receptor agonist
- relative to morphine: similar binding and effects, more rapid onset, shorter duration of action, causes less constipation, no miosis
- also has some antimuscarinic activity
- preferred analgesic during labor
- should not be used in pts on MAOIs
- not recommended for long-term use due to possible toxicity

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Fentanyl

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- opioid analgesic; µ receptor agonist
- has 100X the analgesic potency of morphine
- relative to morphine: similar binding and effects, causes less constipation, no histamine release (so less CV effect)
- rapid and brief action --> used in general anesthesia and post-op pain
- readily crosses BBB
- potential for severe respiratory depression
- CYP3A4 metabolism

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Pentazocine

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- opioid analgesic; κ receptor agonist; partial agonist of µ receptor
- causes less respiratory depression than morphine
- dysphoria and psychotomimesis possible at high doses

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Nalbuphine

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- κ agonist; µ antagonist
- analgesic, but with lower ceiling effect than morphine
- causes respiratory depression (unknown mechanism)
- less potential for psychotomimesis than pentazocine
- structurally related to naloxone (pure µ antagonist)

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Buprenorphine

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- partial µ agonist; κ antagonist
- more potent (higher affinity) than morphine at µ receptor but only a partial agonist --> can reduce effects of more efficacious agonists --> possible use in treatment of heroin addiction

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Dextromethorphan

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- cough suppressant; binds to non-opioid receptors
- structurally related to codeine

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Naloxone

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- µ and κ antagonist (competitive)
- liver metabolism; administered parenterally
- fast acting --> used to diagnose and treat opioid overdose

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Naltrexone

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- µ and κ antagonist (competitive)
- slow acting, but higher oral efficacy and longer-lasting than naloxone --> used to treat addiction and prevent relapse in addicts

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Heroin

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- morphine with the hydroxyls replaced by acetyls --> penetrates BBB well

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Oxycodone

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- opiate analgesic; binds to µ receptor
- high oral/parenteral ratio of potency
- often used in combo w/ aspirin (Percodan) or acetaminophen (Percocet)
- Oxycontin: timed release form
- high potential for abuse

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Acetaminophen (Tylenol)

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- NSAID analgesic, antipyretic; only weakly anti-inflammatory
- weak nonselective COX inhibitor
- inhibits COX in the brain, not at peripheral sites of inflammation
- little/no effect on GI mucosa or in platelet function
- use in pts for whom aspirin is contraindicated
- liver metabolism yields active metabolite (AM404) which inhibits COX
- large doses (10-15 g) --> hepatic toxicity (treat with N-acetylcystein)

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N-acetylcystein

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- antidote to acetaminophen overdose
- repletes intracellular glutathione levels that were depleted by metabolite of acetaminophen

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Aspirin

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= acetylsalicylic acid (ASA)
- salicylate NSAID; only one that irreversibly inhibits COX (duration of action exceeds half-life)
- also inhibits NF-κB
- low doses to prevent MI (≤325 mg/day)
- large doses for anti-inflammatory effects (>4 g/day)
- even low doses increase GI blood loss; enteric-coated tablet provides some protection

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Salsalate

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- salicylate NSAID; weakly inhibits COX
- less GI irritation; minimal inhibition of platelet function

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Sodium salicylate

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- salicylate NSAID; weakly inhibits COX
- also inhibits NF-κB

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Mesalamine

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- salicylate NSAID; nonselective COX inhibitor
- used to treat inflammatory bowel disease—main effect in colon (no need for systemic absorption)
- similar to sulfasalazine

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Sulfasalazine

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- salicylate NSAID; nonselective COX inhibitor
- used to treat inflammatory bowel disease—main effect in colon (no need for systemic absorption)
- similar to mesalamine

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Diflusinal

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- salicylate NSAID; nonselective COX inhibitor
- used as analgesic
- more potent than aspirin as an analgesic and anti-inflammatory agent, but no antipyretic effect and less GI irritation

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Ibuprofen

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- NSAID; nonselective COX inhibitor
- anti-inflammatory, analgesic, antipyretic
- less GI effects than aspirin
- uses: chronic treatment of RA and OA, dysmenorrhea, fever
- most common side effects are GI; also CNS effects
- same class as naproxen

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Naproxen

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- NSAID; nonselective COX inhibitor
- considered by some as one of the safest NSAIDs
- same class as ibuprofen

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Indomethacin

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- NSAID; nonselective COX inhibitor
- very potent --> toxic
- CNS disturbances common in addition to usual GI side effects and impaired platelet function
- uses: acute gout, ankylosing spondylitis, RA/OA, patent ductus arteriosus, suppression of pre-term labor

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Diclofenac

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- NSAID; nonselective COX inhibitor
- more potent than indomethacin or naproxen
- accumulates in synovial fluid --> use to treat OA, RA, ankylosing spondylitis

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Ketorolac

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- NSAID; nonselective COX inhibitor
- given IM or IV as post-op analgesic; oral admin also, but can only be used for a limited time (5 days) due to GI and renal toxicity
- no tolerance, respiratory depression, or withdrawal effects
- inhibits platelet function

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Celecoxib (Celebrex)

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- NSAID; selective COX-2 inhibitor
- less GI irritation than aspirin
- CYP2C9 metabolism; CYP2D6 inhibition
- less selective for COX-2 than rofecoxib
- no increased risk of MI (maybe protective effect?)

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Rofecoxib (Vioxx)

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- NSAID; selective COX-2 inhibitor
- more selective for COX-2 than celecoxib
- pulled from market due to 3X increased risk of MI

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Sulindac

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- NSAID; nonselective COX inhibitor
- metabolized to active sulfide form; undergoes enterohepatic cycling --> prolonged duration of action
- uses: OA, RA, ankylosing spondylitis, acute gout
- closely related to indomethacin (but less potent)