Fentanyl Effects | Lecture Note

University:
The University Of Western Ontario
Course:
Pathology 3500B | Human Pathology
Academic year:

2023
Views:

264

Pages:

6
Author:

Kyuwon J.

Fentanyl ● Clinical significance ○ Synthetic phenylpiperidine opioids ○ Extreme lipophilic ■ Entry to CNS rapid ○ ~50-100x potency to morphines ○ Short redistribution half-life ■ Prolonged effect of repeated dosing ● Fat storage ● BBB dynamics ○ Crosses BBB through passive diffusion ○ High lipid solubility ■ Fast onset of CNS actions ○ Quick accumulation on… ■ brain stem ■ Limbic system ■ Spinal dorsal horns ○ Fast CNS equilibration compared to hydrophilic opioids Rapid CNS penetration increases overdose risk prior to compensatory mechanisms becomes activated u-Opioid Receptor interaction ● Primarily targets u1 and uz opioid receptors ● Gi/o protein-coupled receptor ○ Periaqueductal gray ■ Pain modulation ○ Thalamus ■ Sensory integration ○ Ventral tegmental areas = reward mechanisms ○ Medullary respiratory centers Intracellular signal transduction ● Once fentanyl binds ○ GI protein activates ■ Decrease in adenylate cyclase activity ■ Decrease in cAMP level ■ Decrease in Protein Kinase A activity ● PKA ○ Ion channel effects ■ Increase in K+ efflux ● Membrane hyperpolarizations ■ Decrease in Ca2+ influx ● Happens in presynaptic terminal ● Reduction on neurotransmitter release ○ Glutamate ○ Substance P ○ GABA Neural Circuit-Level Effects ● Pain pathways ○ Nociceptive transmission inhibited ○ Descending inhibitory pathway enhanced ○ Perception reduced ○ Less emotional response to pain ● Euphoria ○ GABA interneurons in VTA ○ Disinhibition in dopamine neurons ○ Increase in dopamine release ● Respi center ○ Medullary chemoreceptors ○ Decrease in sensitivity on CO2 + hypoxia ○ Decrease in respiratory rate Cause of fatal overdoses ● Fentanyl entry ○ lipophilic synthetic opioids ■ administered via IV ■ transdermal ○ Strong lipid solubility ■ able to cross membrane efficiently ● BBB Penetration of BBB ● BBB responsible for restricting entry ○ CNS protection against foreign body, chemicals ● lipophilicity of fentanyl will allow passive diffusion across the BBB ○ rapid accumulation to brian tissue ○ morphine on the other hand, a will have lesser rate opioid ■ less lipophilic ● Rapid CNS penetration ○ fast onset analgesia ○ High potency ○ Higher risk of CNS toxicity u-Opioid receptors ● U-opioid receptors ○ MORS ○ G-protein coupled receptors ■ expressed in… ● brainstem ● thalamus ● limbic sys ● spinal cord ● intracellular signalling ○ u-opioid activation pathway ■ inhibition of adenylate cyclase ● decrease in cAMP productions ■ opening of K+ channels ● hyperpolarization on neuron ■ Closing of Ca2+ channel ● neurotransmitter reduction ● lesser release ○ suppress neuronal excitability Functional effects on NS ● Neuronal inhibition ○ Analgesia ■ pain reduction on spinal cord + brain ○ sedation ○ Euphora ■ limbic sys ○ Respiratory depressions ■ brainstem respi ○ cough reflex ● respiratory depression happens on primary life threatening CNS effects ○ these are due to reduction responsiveness on medulla ⇒ carbon dioxides