B-15. Natural opiates, opioid receptors Flashcards
What makes up the ascending pain conducting pathway?
Via the 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
What makes up the descending pain inhibitory pathway ?
STT sends pain and temperature 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 VP
what are the receptors involved in pain inhibition
Mu (μ) - pre- and postsynaptic; postsynaptically stimulates K+ channel
Delta (δ) - presynaptic
Kappa (κ) - presynaptic
How do the pain receptors work?
All the 3 receptor types: are Gi coupled - usually inhibit, sometimes “disinhibit”
inhibit adenylate cyclase → ↓ cAMP
direct inhibition of calcium channels (L, N, P/Q and T-type) → ↓ Ca → ↓ NT release
facilitate opening of inwardly rectifying K+ channel → K+ efflux → hyperpolarization
What are the endogenous opioids and their receptors ? When are they released?
They are during during pain or trauma and after exercise.
Endomorphin 1 + 2 - mu-selective
Leu + Met Enkephalin - delta-selective
β Endorphin - both mu and delta
Dynorphin - kappa agonist
types of analgesics?
Major - opioids
Minor - NSAIDs
Adjuvant - compounds which increase the effects of other analgesics / treat special types of pain
Glucocorticoids - ↓ swelling
TCA or Anti-epileptics - for neuropathic pain
Gabapentin, Carbamazepine (CN V neuralgia), Amitriptyline, etc.
General indications of analgesics
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
Common central effects of exogenous 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
Common peripheral effects of exogenous 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
Tolerance and dependence of exogenous opioids
Tolerance - higher dose is needed over time to reach same effect
Strong tolerance to analgesia, euphoria, respiratory depression + sedation
No tolerance to constipation + miosis
Dependence - both psychological and physical
Psychological - cravings; obtaining and using the drug becomes a priority
Physical - withdrawal symptoms upon discontinuation of drug
Pharmacokinetics of exogenous opioids
Absorption?
Distribution?
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)
what are the natural opioids?
found in poppy seed pod “milk”; contains 42 alkaloids including morphine, codeine, papaverine
What type of drugs are morphine and codeine?
phenanthrene
Dosage of morphine
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 of morphine
glucuronidation forms M-3-G and M-6-G, mentioned above
Other metabolites are normorphine, morphine-3-ether-sulfate, and codeine
