1. excitatory neurotransmitters
    prostaglandins, nitric oxide, bradykinin, histamine
  2. neurotransmitters that inhibit pain
    • norepinephrine, dopamine, serotonin
    • endogenous morphines- can affect actual nerve excitation or the release of excitatory neurotransmitters
  3. 3 opioid receptors
    • main one is mu
    • other two are kappa and delta
  4. 4 classes of opioids
    • opioid receptor agonists
    • mixed agonist-antagonist
    • antagonists
    • central analgesics
  5. major ADR for opioids
    • sedation
    • respiratory depression
    • n/v
    • postural hypertension
    • constipation
    • urinary retention
    • pruritus
    • allergic reactions
  6. pharmacokinetics of opioids
    • phase 1 and phase 2 metabolism
    • some are active metabolites
    • metabolized in liver
    • fentanyl: CYP 450 metabolism
    • phenylpiperidine: phase 1 metabolism
  7. morphine
    • opioid agonist- everything is compared to morphine
    • t1/2: 2 hours
    • converted to active metabolite: 6 glucuronide, twice as potent
    • oral doses are higher than IV due to first pass
  8. meperidine
    • Demerol,opioid agonist
    • shorter duration of action than morphine
    • metabolite: normeperidine, excreted in urine, caution w/ renal failure
    • can cause CNS issues, leads to seizures, muscle tremors and twitches
    • rarely used continuously
  9. Fentanyl
    • most lipophilic, multiple formulations available
    • transdermal patch- replace every 72 hours, takes 24 hours to exert effects
    • lollipops used when you want to avoid IV route
    • metabolizd by CYP 3A4
    • opioid agonist
  10. methadone
    • main uses are pain, controlled withdrawal from heroin, morphine
    • has a long half life
    • very sedating, even with only 1 or 2 doses
    • opioid agonist
  11. Hydromorphone
    • opioid agonist
    • dilaudid
    • more potent, better oral absorption
  12. oxymorphone
    • opioid agonist
    • active metabolite of oxycodone
    • no pharmacologic advantages
  13. codeine
    • opioid agonist
    • prodrug of morphine, converted by CYP 2D6
    • often combined with other compounds
    • use for depression of cough reflex
  14. hydrocodone
    • opioid agonist
    • often used in combination products
    • very similar to morphine
  15. oxycodone
    • opioid agonist
    • good as analgesic when combined with peripherally acting non-opioid agent
  16. Mixed agonist/antagonist
    • stimulate one receptor and block another
    • has ceiling effect: at a certain dose, everything above that dose will have no effect
    • less abuse potential, less constipation
    • rarely used for pain, more for anesthesia b.c of CNS effects- anxiety, hallucinations
  17. opioid naive
    if you havent used opioids before, mixed agonist/antagonists will relieve pain, will have agonist activity
  18. opioid dependent
    if you have used opioids before mixed agonist/antagonists will block effects and will cause withdrawal symptoms, pain- you will see antagonist effects
  19. buprenorphine
    • for treatment of opioid addiction, similar to methadone
    • pentazocine and Nalbuphine have significant cardiovascular effects
  20. Antagonists
    • compete with endogenous and exogenous opioids at mu receptor sites
    • used to reverse side effects of opioids, usually in overdose situation
  21. Naloxene
    • most commonly used antagonist
    • IV, will bind to receptor but not produce any response
    • shorter t1/2, may need repeated dosing to maintain consciousness
  22. Central Analgesic
    • Tramadol: weak opioid receptor agonist, also inhibits NE and SE reuptake to decrease pain transmission
    • decreases seizure threshold,
    • option for people who dont want to take opioids
  23. acetaminophen
    • NSAID, tylenol
    • less side effects than aspirin
    • anti-pyretic, weak anti-inflammatory, no platelet effects
    • MOA: weak inhibitor of prostaglandins in CNS
  24. liver effects of acetaminophen
    in overdose, minor metabolism pathway that produces toxic metabolite, NAPQI, is overwhelmed by too much acetaminophen and too much NAPQI is produced for the body to excrete, not enough glutathione to metabolize NAPQI
  25. doses of acetaminophen
    • normal adult: 4000 mg/day
    • underlying liver disease: 2000 mg/day
  26. NSAIDs MOA
    • inhibition of 2 enzymes: COX-1 and COX-2
    • anti-inflammatory, analgesic, anti-pyretic and anti-platelet effects
    • response varies from patient to patient
  27. COX-1 effects
    produce cytoprotective prostaglandins, maintain kidney function, protect gastric mucosa and aid in platelet aggregation
  28. COX-2 effects
    recruit inflammatory cells, sensitize skin pain receptors, regulate hypothalamic temperature control
  29. NSAID Adverse drug reactions
    • GI irritation, promote gastric ulcers, worsen pre-existing ulcers
    • renal insufficiency
    • rash
    • bronchospasm in asthma patients
    • long term use: fluid retention and edema, hypertensive effects
  30. NSAID contraindications
    history of peptic ulcer disease, pre-existing kidney disease, dehydrated patients, allergies, surgery associated with high blood loss
  31. Ketorolac
    • acute pain reliever that can be used after surgery, can avoid taking opioids
    • more potent than NSAID, can cause liver dysfunction, limited to 5 days use
  32. COX-2 inhibitor
    • Celebrex: only inhibition of bad prostaglandins, allows COX-1 pathway to be unaffected
    • contraindicated in patients with sulfa allergy
    • increased risk for cardiovascular effects
  33. Aspirin
    • own class of NSAID
    • causes irreversible inhibition of both COX-1 and COX-2 pathways
    • need to generate new enzymes once drug is out of body
  34. aspirin side effects
    • GI,more pronounced renal disease
    • high doses can cause "salicylism"- dizziness, deafness, tinnitus,
    • reye's syndrome: not for kids with viral infections, can cause liver disorder or encephalopathy
  35. abortive headache therapy
    • can use NSAIDs, opioids
    • for mild to moderate pain, wont work for severe migraines
  36. Ergots
    specific for migraines, antagonist effects at serotonin, dopamine and NE receptors- end effect is venous and arterial vasoconstriction
  37. ergots ADR
    • CNS effects: hallucinations, alter pituitary gland prolactin release
    • constrict blood vessels in rest of body as well, can raise BP
    • affect uterine smooth muscle- category X
    • N/v, diarrhea
    • hard drugs to tolerate
  38. contraindications
    • cant combine with triptans
    • not for cardiac or peripheral vascular disease
  39. Triptans
    • first line therapy for migraines, use at any time during migraine
    • relieve pain by constricting intracranial blood vessels
    • also suppress release of inflammatory neuropeptides
    • specific to serotonin receptors- type 1B and 1D agonists
    • all have different T1/2 and dosing regimens
    • can cause rebound headaches
  40. triptans ADR
    • well tolerated generally
    • chest pressure or tightness due to constriction of cardiac blood vessels
    • N/V, dizziness
    • need different formulation for patients who already have nausea
  41. triptan contraindications
    • uncontrolled BP, peripheral or cardiac pre-existing issues
    • previous MI, angina
  42. Gout
    • build up of uric acid- deposition of crystals at joint causes terrible pain
    • uric acid is from over-production or under-excretion- end product of purine metabolism
  43. NSAIDs for gout
    • will work at any max prescription dose
    • indomethacin is most commonly used
    • ADR are same as all NSAIDs
  44. corticosteroids for gout
    • for patients who can take colchicine or NSAIDs
    • systemically or injected directly at site of pain
    • short term effects, taper when finished
    • complications: altered mood, increase BP, glucose control problems
  45. Colchicine
    • for patients with NSAID allergy
    • anti-inflammatory effects, decrease leukotrienes
    • give until pain is gone or until diarrhea is intolerable
    • max dose is 8 mg- will usually get about half way through 8 hours before diarrhea becomes intolerable
  46. colchicine ADR
    • N/V, intolerable diarrhea
    • bone marrow suppression
  47. probenicid
    • for preventative gout therapy- to get uric acid out of the body
    • increases renal clearance of uric acid
  48. probenicid ADR
    • GI, rash, hypersensitivity
    • uric acid crystals in kidney, ureters- need to stay hydrated
    • blocks reabsorption of drugs in renal tubule, interacts with PCN, cephalosporins, prolongs the half life in the system
  49. allopurinol
    • inhibits xanthine oxidase which inhibits uric acid synthesis
    • well tolerated, builds up over time, has active metabolite
  50. allopurinol ADR
    • rash, GI, leukopenia
    • can worsen attacks with start of therapy, but will decrease over time
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