Week 8 Opioid Analgesics and Antagonists Flashcards
What are the 3 families of endogenous opiates? What are the 3 families of receptors?
- beta-endorphin
- enkephalins
- dynorphins
RECEPTORS - mu
- kappa
- delta
List the precursor molecules for:
- beta-endorphin
- enkephalins
- dynorphins
- POMC–>beta endorphin
- preprodynorphin–>dynorphins
- preproenkeplin–>met-enkaphalin and leu-enkephalin
What is the distribution of opioid system?
- Very wide distribution
- endorphins synthesized in arcuate nucleus of the hypothalamus and nucleus tracts solitaries (NTS)
- enkephalins distributed in central and peripheral nervous systems, adrenal gland, enteric nervous sytem
- dynoprhins in certain CNS structures
What are the actions of opioid receptors?
- G protein coupled, lead to inhibition of adenylyl cyclase and decreased cAMP production
- inhibit presynaptic voltage gated Ca2+ channels and inhibit efflux of K+ from post synaptic neuron
- lead to inhibition of neurotransmitter release and postsynaptic hyper polarization and decreased neuronal excitability
Describe the effect of opioids on the DA release from the VTA.
- activation of opioid receptors in VTA–>increase DA release by inhibiting release of GABA from local inhibitory neurons
- opioids target mu receptors on GABAergic interneurons, inhibiting it–>disinhibition, releases its inhibition of VTA DA neurons
Describe the role of opioids in modulation of pain pathways in the spinal cord by higher order centers in the brain.
- opioid receptors found on dendrites of dorsal horn projection neurons and presynaptic termination of nociception neurons
- activation of nociceptors release glutamate and sub P–>STT activation and transmission of pain signals to thalamus
- NE and 5HT from brain stem can stimulate enk neurons and inhibit release of glutamate and sub P. Blocks pain signals to thalamus.
- NE and 5HT synapse on ENK neurons and STT projection neurons
- mechanism for brain to over ride pain info in times of extreme stress or injury
What are the natural opiates?
Morphine and codeine (weak agonist)
-all other opioids are prepared from morphine
What types of activity result from mu receptor activation by opioids?
Analgesia, euphoria, and respiratory depression
-kappa and delta receptors do more spinal analgesia
What is the mechanism of action of morphine?
-binds to opioid receptors in CNS, GI, and urinary bladder
-normally: activated nociceptive pain fibers leads to release of glutamate at presynaptic terminal and activation of neurons of nucleus proprious in dorsal horn of spinal cord when encephalin is inactive
-presynaptic: decreases Ca2+ influx, inhibits glutamate release on presynaptic opioid receptors
-postsynaptic: increase K+ conductance, causes hyper polarization
-acts at opioid receptors in dorsal horn of spinal cord to decrease release of Sub P (modulates pain perception in cord)
-
What are the physiological effects of opioids in the CNS?
- Analgesia-dull pain blocked more than sharp pain
- sedation, esp with morphine
- antitussive effect-suppresion of cough
- dysphoria
What are the physiological effects of opioids on emotions?
morphine produces powerful sense of well being and contentment by causing dish inhibition of DA release of the VTA neurons and drug addiction
What are the physiological effects of opioids on respiration?
- respiratory depression by reducing the sensitivity of respiratory center neurons to carbon dioxide
- pontine and medullary respiratory centers may also be depressed
- most common cause of death in acute morphine overdose
What are the physiological effects of opioids on the eye?
- causes pinpoint pupils due to activation of neurons of the Edinger-Wesphal nucleus of CN III and enhanced parasympathetic stimulation of the eye
- little tolerance to the effect
What are the physiological effects of opioids on emesis, renal system, bronchial effects, skin?
- emesis: stimulates neurons in chemoreceptor trigger zone of area postrema of medulla, causing vomiting and nausea
- renal system: depression, elevated ADH release, urinary retention
- bronchial: histamine release form heparin histamine complex in mast cell resulting in bronchoconstriction, depression of reparatory drive and cough reflex
- skin: vasodilation and flushing, itching and uricaria, due to histamine release, following displace from heparin in the mast cell
What are the physiological effects of opioids on the GI tract?
- causes constipation by increasing tone of the intestinal circular smooth muscles, decreases peristaltic waves
- delayed stomach emptying and decreased stomach utility
- reduction in gastric acid secretion
What are the physiological effects of opioids on cardiovascular system?
- therapeutic doses have little effect on heart rate or blood pressure in supine patient
- in standing position, orthostatic hypotension or fainting can occur
- hypotensive response partly due to release of histamine dn partly due to depression of vasomotor center.
Describe the pharmacokinetics of opioids.
- Metabolism and excretion: most metabolized in liver. 4-6 hrs if given systematically.
- Absorption: im, iv, sc admin of drug most reliable because of first pass metabolism Absorption generally good.
- Distribution: heroin and codeine pass BBB much more easily than morphine.
Summarize clinical uses of morphine, fentanyl (sublimaze), Zohydro ER.
- morphine: more effective b parenteral vs. oral, main use for severe acute pain, long duration of action due to active metabolite
- Fentanyl: very high potency, short duration. Useful in anesthesia due to fast induction and emergence. Use for severe chronic pain too (intrathecal, epidural, transdermal).
- Zohydro ER: for daily severe pain, oral formulation of hydrocodone, but pill form can be abused
Summarize the toxic effects of opioids.
- respiratory depression, coma, miosis
- nausea and vomiting
- addiction
- constipation
- urinary retention
- dysphoria in some cases, marked by hyperactivity
- postural hypotension
Describe the pharmakinetics of opioid antagonists Naloxone, naltrexone, nalmefene.
Competitive antagonists of mu, k, and d receptors
- absorption:
- naloxone has low oral bioavail, short duration of action (1-2 hr) parenterally.
- Naltrexone: good oral bioavail, but undergoes first past metabolism. t1/2 10 hrs
- nalmefene: for acute opiate overdose, longer half life 8-10 hrs than naloxone - Distribution: pass BBB more easily than morphine
- Metabolism and excretion: metabolized in liver microsomal fraction via glucuronidation
What are the effects of opioid antagonists?
- reverse the effects of morphine in 1-3 mins. Opiate effects are normalized, including reparatory depression, euphoria, pupils
- withdrawal symptoms immediately precipitated in opiate users
- tolerance doesn’t develop to antagonists
Describe the clinical usage of naloxone, nalmefene, and naltrexone.
- naloxone: choice treatment for acute opiate overdose. dosing may be repeated due to short duration of action.
- nalmefene: for acute opiate overdose, has long duration
- naltrexone: maintenance drug for addicts. blocks heroin effects up to 2 days.
