Pharmacology of Selected Opioids.txt

• Agonist: strong, mild-to-moderate
• Opioids with mixed actions: agonist-antagonist (Ag-Antag); partial agonist
• Antagonist: .

• Morphine
• Heroin
• Hydromorphone (Dilaudid)
• Oxymorphone (Numorphan)
• Methadone (Dolophine)
• Meperidine (Demerol)
• Fentanyl (Sublimaze)
• Levorphanol (Levo-Dromoran)

• Heroin is biologically inactive
• In the body it is converted to MAM (monoacetylmorphine) and then to morphine: MAM and morphine are responsible for the effects elicited upon injection of heroin

• Mu agonist
• similar to morphine
• prolonged use fives rise to tolerance
• Oral efficacy!

• relief of pain
• treatment of opioid abstinence syndrome
• treatment of opioid dependence

• within hours of missing first dose of morphine: sense of intense fear (can be alleviated by placebo)
• 8-16 hrs: lactation, rhinorrhea (as in a severe head cold), yawning, sweating, mydriasis, anorexia, nervousness, irritability, tremors, increased anxiety and fear, restless sleep
• within 36 hrs: skeletal muscle fasciculation and twitch, severe/painful cramps develop in legs and stomach
• intense/uncontrolled vomiting, salivation, diarrhea, and urination
• weakness, depression, chilliness/sweating, gooseflesh, muscle spasms, kicking movements
• patient is unable to sleep: increased respiratory rate, increased blood pressure, increased temperature, increased blood sugar, increased basal metabolic rate
• 48-72 hours: Reaches it's peak; subsides over net 10 days
• Withdrawal reaction: is evidence for physical dependence

• half-life of drug being used: for morphine, with a short half-life, symptoms of abstinence are intense but brief
• for methadone, with a long-half-life, symptoms are less intense but more prolonged
• degree of physical dependency: withdrawal syndrome of methadone and codeine qualitatively the same but less intense than for morphine

• Why is it used in treatment of opioid dependence?
• Methadone withdrawal is: *
• slower in onset
• longer in duration
• much less intense
• Why don't opioid addicts like it?

• methadone keeps plasma concentration in a narrow range
• but methadone has a wide range, get highs and lows

• does what morphine does, but - has a problem
• Mu-Agonist
• In equianalgesic doses produces as much sedation, respiratory depression, and euphoria as does morphine
• the rise in bile duct pressure - thought to be less than that caused by morphine
• constipation, urinary retention: less common than with morphine

• can use it for a day or 2 but NOT for a week or 2
• Large, repeated doses can lead to an
• excitatory syndrome: hallucinations; tremors; muscle twitches; dilated pupils; hyper-reflexia; convulsions
• Due to the accumulation of normeperidine
• half time 15-20 house (meperidine = 3 hours)
• Not drug of choice for treatment of severe prolonged pain

• Mu agonist
• 80 times more potent than morphine: as an analgesic

• For anesthesia and post-op analgesia
• Duragesic: (transdermal patch) releases fentanyl over a period of 72 hours (for treatment of chronic pain; cancer pain)
• Patient controlled anesthesia (Actiq) - lollypop

• Codeine
• Oxycodone (Oxycontin)
• Hydrocodone (Vicodin)

• metabolizes to norpropoxyphene: 1/2 life ~30 hrs; accumulates and causes cardiotoxicity
• prolonged PR and QT intervals and widened QRS complex

• high oral/parenteral ratio: partially protected from conjugation by the methyl group at C3
• Has very low affinity for opioid receptors
• Analgesic efficacy is due to its conversion to morphine: polymorphisms in cytochrome P450 isoform CYP2D6
• Dispensed alone or in combination with aspirin or acetaminophen

very important enzyme in metabolizing drugs in the liver

• Caucasians (7%) - poor metabolizers
• Saudi Arabia, 20% , Ethiopia, 29% - Ultra-rapid metabolizers

• Hydrocodone: dispensed in combination with other drugs
• Acetaminophen - norcet, vicodin, lortab
• Ibuprofen - vicoprofen
• Oxycodone: Oxycontin - dispensed alone or in combination with
• Aspirin - percodan
• Acetaminophen - percocet
• Ibuprofen - combunox

• Rapid, progressive, and profound (> 83%) sensorineural hearing loss in patients taking Vicodin: successful rehabilitation with cochlear implants
• Hearing loss reported with propoxyphene
• Oxycodone (vicodin) gets concentrated in inner ear: when combine with other drugs, leads to hearing loss, tinnitus and 1st sigh of autotoxicity

• substances that appear to be agonists at some receptors but antagonists at others: pentazocine; butorphanol
• Partial agonists: buprenorphine

• intrinsic Mu antagonistic activity is sufficient to afford advantages over morphine as analgesic
• 20 mg -> decreased respiration = 10 mg morphine
• increased doses do not cause proportionate depression of respiration
• But high doses -> increased BP; increased HR
• Increased cardiac work in patients with coronary artery disease
• May precipitate withdrawal when given to Mu-opioid dependent individual

• Talwin-NX (50mg Talwin + 0.5mg naloxone)
• Oral pill laced with naloxone, to prevent abuse potential through injection
• The added naloxone is degraded in liver
• If oral pill is powdered for injection naloxone produces aversive effects in individuals dependent on opioids

• Butorphanol (Stadol)
• More potent that morphine (on a per weight basis)
• 2-3mg -> 10mg morphine
• Onset, peak activity, duration ~ morphine
• lowest abuse potential
• Actions similar to pentazocine
• increased pulmonary arterial BP -> increases work of heart
• thus, less useful in patients with CHF or MI

• on a per weight basis - better in longer duration of action: !
• Highly lipophilic opioid derivative of thebaine
• Partial Mu agonist; 25-50-fold more potent than morphine
• Produces analgesia and other CNS effects ~ to those of morphine
• Duration of analgesia is longer than that of morphine

• Opioid antagonists produce few effects unless opioid agonists have been administered previously
• Naloxone
• Naltrexone

In treatment of opioid toxicity, especially respiratory depression: In patients with respiratory depression small doses IM or IV promptly reverse effects of Mu opioid agonists in 1-2 minutes!

• Efficacious by the oral route
• Duration of action 24-48 hours
• Used in long-term management of opioid addiction
• the long duration of action serves as a safety valve after detoxification for patients with high motivation to remain opioid-free
• if a pt injects themselves with morphine or opioid, blocks the high of the drug..