B-15. Natural opiates, opioid receptors Flashcards
Pain transmission
- Ascending pain conducting pathway - spinothalamic tract (STT): anterior and lateral pathways for sensation of pain and temperature.
sends signals to the ventroposterolateral nucleus (VPL) of thalamus which projects to cortex. - Descending pain inhibitory pathway - STT: sends pain/temp signals to “periaqueductal grey” (PAG) in midbrain via spinomesencephalic tracts → enkephalin-producing PAG neurons project to “raphe nuclei” in brainstem → nucleus raphe magnus transmit signals to dorsal horn inhibitory interneurons (substantia gelatinosa) using 5-HT → interneurons release enkephalin and dynorphin to inhibit C / Aδ pain fibers of the STT via μ receptors → ↓ substance P release from pain fibers → ↓ transmission of pain to VPL.
3 receptor types involve in pain transmission and MOA
receptor types:
- Mu (μ) - pre- and postsynaptic, postsynaptically stimulates K+ channel.
- Delta (δ) - presynaptic.
- Kappa (κ) - presynaptic.
MOA :
(all are Gi coupled - usually inhibit, sometimes “disinhibit”)
1. inhibit adenylate cyclase → ↓ cAMP
2. direct inhibition of calcium channels (L, N, P/Q and
T-type) → ↓ Ca → ↓ NT release
3. facilitate opening of inwardly rectifying K+ channel → K+ efflux → hyperpolarization.
Endogenous opioids
released during pain/trauma, after exercise.
- Endomorphin 1 + 2 (mu-selective)
- Leu + Met Enkephalin (delta-selective)
- β Endorphin (both mu and delta)
- Dynorphin (kappa agonist)
Analgesics
- Major - opioids
- Minor - NSAIDs
- Adjuvant - compounds which increase the effects of other analgesics / treat special types of pain:
a. Glucocorticoids - ↓ swelling
b. TCA or Anti-epileptics - for neuropathic
pain. (Gabapentin, Carbamazepine (CN V neuralgia), Amitriptyline, etc).
General Indications for opioids
- Pain - severe pain, either acute or chronic; often used for cancer-related pain.
- Anxiety - in life-threatening states (MI, hematemesis, shock).
- Lung Edema - as in LV failure; as an adjuvant.
- Perioperative - in combo with anesthetics; for pre- / post-op pain.
- Diarrhea - opiates ↓ intestinal motility.
- Terminal States - palliative / hospice care.
Central effects of opioids
- Analgesic - relieve both sensory + “affective”/emotional components of pain; sensory inhibition occurs via stimulation of the descending pain inhibitory pathway mentioned above.
- Euphoria - via disinhibition of dopamine release in limbic system; occurs less in chronic pain patients (probably via limbic neuronal changes in these pts)
- Sedative / Anxiolytic - potentiated in combo with BZDs etc. (common pre-surgical combo).
- Respiratory Depression - via ↓ CO2 sensitivity of brainstem respiratory center → ↓ frequency + amplitude of breath → may be fatal in OD; given in MI to ↓ pain, anxiety and rapid breathing.
- Cough Suppression - inhibit cough reflex; usually codeine is used, only for dry cough, otherwise atelectasia can develop via secretion accumulation
- Miosis - via central vagus stimulation; no tolerance to this effect → useful in dx of OD
- Truncal Rigidity - supraspinal effect → ↑ tone of skeletal muscles → further breathing difficulty.
- Nausea - stimulates chemoreceptors
Peripheral effects of opioids
- CV - ↓ BP via vasomotor center inhibition + histamine release (HA release is morphine-specific); direct inhibitory effect on heart + vagal stimulation → ↓ HR / CO
- GI - constipation (both central + peripheral mechanisms; inhibit release of ACh in GI tract); no tolerance to this effect; biliary cramps via ↑ SM tone
- Urogenital - urinary retention via ↑ sphincter tone and ADH ↑; relax uterus - prolong labor
- Neuroendocrine - ↑ ADH, PRL, ACTH, GH; ↓ LH / FSH.
- Bronchoconstriction - via HA release; CI in COPD / asthma.
- Pruritus - via HA release
Opioid tolerance
need higher dose over time to reach same effect.
Strong tolerance to analgesia, euphoria, respiratory depression + sedation.
No tolerance to constipation + miosis.
Opioid dependence
- Psychological - cravings. obtaining + using the drug becomes a priority.
- Physical - withdrawal symptoms upon discontinuation of drug.
a. Acute Phase - 5-10 days
* anxiety, anger, aggression, hallucination; no directly fatal effects, but suicide risk increases.
* increased secretions: sweat, lacrimation, rhinorrhea, salivation, diarrhea, vomit.
* yawning, tremor, bone/joint pain; ↑ BP, fever, hyperpnea, mydriasis.
b. Chronic Phase
bradycardia, hypotension, hypothermia, mydriasis.
Pharmacokinetics of opioids
generally good oral absorption; oral, IM, IV, nasal, transdermal administration.
- Oral morphine → strong first-pass, low bioavailability; oxycodone / codeine → better oral bioavailability
- Distribution - distributed widely; enter brain well (lipophilic)
- Metabolism:
a. Glucuronidation - morphine-3- (can cause seizures) and -6-glucuronide (active metabolite, analgesic)
* maternal morphine use → immature glucuronidation in child → respiratory depression
b. Tissue esterases - degrades diacetyl morphine (heroin) into monoacetyl- and then morphine (active metabolite)
c. Oxidation - fentanyl and derivatives are oxidized
Natural Opioids
Natural Opioids - found in poppy seed pod “milk”. contains 42 alkaloids incl.
Morphine, Codeine, Papaverine.
Morphine (dose, kinetics, indications, CI)
a phenanthrene.
- Dose: on mandatory doses list
Morphine sulfate - oral; 2 x 30-100 mg (slow-release oral form)
Morphine HCl - s.c. 10-20 mg; i.v. 1 mg repeated up to 10 mg
There is no “maximum dose” for opiate analgesics, since some patients may have tolerance; dose can be increased to meet analgesic need, with close monitoring of respiratory function, etc. - Kinetics: glucuronidation forms M-3-G and M-6-G.
Other metabolites are normorphine, morphine-3-ether-sulfate, and codeine - Indications:
MI - to decrease pain, anxiety, tachypnea / -cardia
Pulmonary edema - as adjuvant
Any moderate-severe acute pain
Cancer-related or severe rheumatic pain (oral, especially in arthritis when NSAIDs ineffective) - Contraindications:
Obstructive pulmonary disease - i.e. asthma; HA release → bronchoconstriction
Liver and kidney dysfunction
Pregnancy - not an absolute CI + often used perinatally
Head injuries - respiratory depression → ↑ CO2 → cerebral vasodilation → ↑ ICP
Codeine (indications, SE, dependence)
a phenanthrene. less analgesic + antitussive effect than morphine.
- Indication: anti-tussive for irritative, dry cough.
- Side Effects: mainly constipation
higher doses can have a ‘disinhibitory’ stimulant effect → seizures. - Dependence: causes less euphoria → less dependence; weak dependence known as “codeinism”.
