Download Opioids – anal-gesics (lol) ©2010 Mark Tuttle Mechanism of action

Opioids – anal-gesics (lol)
Mechanism of action/Uses
1. ↓voltage-gated Ca2+ channels
↓ NT release
2. ↑K+ channel conductance
Hyperpolarizes: IPSP
©2010 Mark Tuttle
Drugs
Pharmacodynamics
Pharmacokinetics
- Morphine
- Analgesia: ↑ threshold & alters subjective
- Well absorbed, but ↓ bioavailability
- Etrophine
- Sedation: qualitatively diff from other depress’s
- Distribution: crosses the blood-brain barrier
- Heroin (pro drug)
- Mood effects: euphoria (μ) or dysphoria (κ)
- Plasma t½: 2-3 hours
o More potent
- Respiratory depression: ↓ sensitivity to CO2
- Conjugated with glucuronic acid, and
- Codeine
o Usual cause of death in overdose
excreted mostly in the urine, primarily as 3↓ ascending pain transmission
o Selective antitussive
o ↑ brain blood flow can cause edema
glucuronide
- Spinal cord & thalamus
o CPY2D6  morphine
- Neuroendocrine / hypothalamic actions
o Metabolite can cause CNS stimulation
- Presynaptic μ,κ,δ: Ca2+ channels
- Dextromethorphan
o ↑ Prolactin and vasopressin (ADH)
- Morphine-6-glucuronide is also an active
- Postsynaptic: κ only: K+ channels
o Selective antitussive
 ↓ GnRH, CRH, LH, FSH, ACTH, β-endorphin
opioid, about 100 times as potent as
↓ descending pain modulation
- Meperidine
o ↓ set-point for thermoregulation
morphine.
- Periaqueductal gray + medulla
o Faster onset, ↓ t½
- Pupillary constriction (miosis) ↓ tolerance
o Crosses the blood-brain barrier poorly, but
- Disinhibit anti-pain GABA intern n.
o Interaction w/ MAO I’s - Nausea and vomiting - due to stimulation of CTZ
may account for some of morphine's
o Seizures
- Antitussive: cough reflex depressed in medulla
actions
μ receptors
- Fentanyl
- Cardiovascular actions: min effx w/usual doses
Antagonists
- Most effects, euphoria, sedation
o “Breakthrough pain”
- Relief of dyspnea: Mechanism is not known.
- Naloxone (IV)
κ receptors
- Methadone
- Morphine can release histamine from mast cells
- Naltrexone (Oral)
- Miosis, dysphoria, psychotic
o Acute/chronic withdr. - Gastrointestinal Tract (myenteric plexus):
Will precipitate abstinence (withdrawal)
δ , Σ receptors
o Longer t½
o ↑ tone, ↓peristalsis: constipation
syndrome if addict is not weaned first
- Propoxyphene
o ↑biliary Tone (colic possible)
Withdrawal
None are better at separating
o Weak agonist
o Tolerance to this effect does NOT readily dvlp
- Hyperactivity of autonomic nervous system
analgesia from the adverse effects
 ↓potency, ↓ abuse
- GU Tract: ↓renal function, uterus: ↑ labor
- Intense craving (Psychological withdrawl)
- Low PC  no BBB
o Can be worse than physical withdrawal
Tolerance is functional not metabolic
o Diphenoxylate
o Loperamide
Partial agonists & mixed agonist-antagonists
κ agonist, μ antagonist/weak agonist Pentazocine
- ↓ Analgesia & respiratory depression
Nalbuphine
- ↑ Dysphoria, psychomimetic from κ receptors
Will precipitate abstinence
- ↑ effect separation
(withdrawal) syndrome if addict is not Butorphanol
weaned first
- ↑ effect separation
Buprenorphine
- ↑ t½
- Resistant to naloxone
Endogenous opiopeptins: Actions of exogenously administered enkephalins and endorphins are similar to morphine, including tolerance and physical dependence
- Pro-opiomelanocortin
o β-endorphin, β-lipotropin, ACTH, and MSH
- Proenkephalin-derived peptides
o Met-enkephalin, Leu-enkephalin
- Prodynorphin-derived peptides
o Dynorphins A and B, and others, all of which include the leu-enkephalin sequence