opioids Flashcards
Where is opiates derived from? What is there structure? What are opioids?
Alkaloid product from the poppy-those are opiates
different from different plants
morphines and codeines-
opioids are anything with opiates like activity which opiates-naturally
structure-4 rings-one with tertiary nitrogen (important to allow receptor anchoring-lenght of that chain permits becoming being antagonist
Other side-2OH group-easily modified (heroin and codein (methyl morphine)-these are prodrugs realistically
What groups are important for moprhine binding? and lipophllic? and for its activity?
tertiary nitrogen
hydroxyl at position 3 OH attached to aromatic ring (heroin and codeine dont have that-prodrugs) +aromatic ring connected to it
The 6 position OH, if removed-becomes 10x more lipophillic (heroine very lipophillic)
quaternaty carbon isnt so important as though
What are different routes of administration of opioids? How does it ionisation affect its intake
Inegsted or injected
pKa usually above 8-so in low stomach pH-heavily ionised-poorly abosrbed
Illium-around 7-absorbed better as move down intestine
in Blood-least ionised
=> less than 20% ionised-cant diffuse well across membrane
compare the potency, duration of actions and lipid solubility of different opioids
Heroin 2x more potent than morphine -2/4h
codein 10x less -2/4h
methadone 4x more 24/32h
fentanyl 100x more 2-4h
lipid soluble-fentanyl VERY soluble, methadone quite a lot, codein and heroin just abit more than morphine
Which opioids produce active metabolites after liver metabolism? How fast are they cleared
Morphine-morphine 3 glucoronide and mophine 6 glucoronide-cause euphoria but not resp distress
all other dont really-heroine and codein are weird-their metabolite is MORPHINE -which targets receptors better
all clear around the same rate
except methadone—–0.5 ml/kg/min-why last 24h
How are opioids metabolised? How does that impact codeine
Most are done by p450
codeine needs to be activated to morphine by CYP2D6-activate (slow)
can gets deactivated VERY fast by-CYP3A4-
why codeine has low portency-90% doesnt become morphine and have an effect
What receptors do opioids bind to? What other compounds can bind to it
Opioids receptors-subtypes Mu, delta and Kappa
endogenous : ther things also-endorphines (Mu/delta), enkephalins (delta), dynorphins (Kappa)
euphoria and analgesia are Mu related-
Delta-motor cognitive, kappa-neuroendocrine
What do opiate receptors do in a cell?
Depressant-
hyperpolarise (sodium efflux)
Decrease Ca2+ influx-slow neurotransmitter release
Decrease adenylate cyclase activity-
What are the physiological effects of opiates receptors activating?
Anaglesia, Euphoria, depression of cough center
bad: depression of respiration, vomiting, pupillary constriction, GI effects
Describe the normal pain pathway and pain tolerance -neurological route
Normal: nociceptor in periphery link to dorsal horn-has mu and Kappa receptor
Then long tract (spinothallamic) to thalamus (distributes it)-mu receptor
From thalamus can go to cortex-mu and delta
PAIN TOLERANCE PATHWAY
PAG-periaquedecutal grey region-integrating center-receieve stimuli from brain (like thalamus, cortex, etc) and determine a response (up or down) (any pain will activate it a bit)
NRM-nucleus refe magnus-effector-signals back down to periphery (mainly spinal cord)-interfere with dorsal horn connection-percieve less pain)
NRPG-automatically pain tolerance-indeptendent of PAG and -nucleus reticularis paragianto_ ___ -feedback automatic
Hypothalamis samples current health and interfere with pain as well (if healthy, less pain)_
Locus correlius-sympatheric of brain-not part of pain pathway-but when on supresses stimuli at dorsal horn-fight or flight
What is the substanca gelatinosa
Region in spinal cord which recieve many singals-(from NRM and stuff)-modulate the pain tolerance very fast
inhbit stimuli
can happen automactically without it
but SG integrates all the signals-response from minute to minute
Where and how do opioids act on pain?
In spinal chord-connection between periphery and spinothallamic tract has mu-reduced actitivity
Increase activity by depressing GABA-release inhbition of NRPG-increase tolerance
Increase activity by depressing GABA-release inhbition of PAG
How do opioids lead to euphoria?
Act like cannabis-but with other receptor
Opiates act on gabanergic neuron
Reduce inhbition of dopanergic neuron in nucleus accumbens-release more
How does opioids affect cough?
COugh start from detection in airway of mechano/chemoreceptr
goes to cough center (medulla)-efferent impusle via parasympathetic to vagus
contraction
opioids interere with both pathways-up to medulla and down to muscle
How does opioids cause respiratory depression?
Decrease activity of central chemoreceptors-at very high dose
Conc of CO2 isnt being veryfied-urge to breath impaired
