Opioids Flashcards
what is an opiate?
natural alkaloid derived from the papaver samniferum plant
examples of opiates
morphine
codeine
papaverine
thebaine
what are opioids?
these are synthetic molecules that mimic natural opiate activity
what is the function of the tertiary nitrogen of morphine? what is the effect of a quaternary nitrogen?
important for the analgesic effect
helps anchor morphine to opioid receptor
a quaternary nitrogen decreases the analgesic effect greatly
how can morphine become an antagonist?
extension of the side chain to 3+ carbons
changing side chains to methyl groups (this also decreases the analgesic effect)
how does the structure of morphine compare to codeine and heroin?
- The hydroxyl group at position 3 (required for binding) Codeine undergoes metabolism to become activated and reveal its hydroxyl
- The hydroxyl group at position 6 – when in oxidised form, the lipophilicity of the drug increases 10-fold
heroin is a diacetyl morphine
codeine is a methyl codeine
how does the lipid solubility of heroin compare to morphine?
much higher
what type of drug is codeine?
a prodrug
how do the structures of methadone and fentanyl compare to morphine?
o Methadone – tertiary nitrogen.
o Fentanyl – 2x tertiary nitrogen’s
therefore great analgesic effects
what are the important structures required for opiate activity?
aromatic ring base
tertiary nitrogen
spacer
quaternary carbon centre
how are opioids generally administered?
oral
IV
how well are opioids absorbed in the stomach?
not well due to pKa> pH so predominantly in ionised state
absorption is better further down the GIT
what is the pKa of opioids?
weak bases pKa>8
what is the order in potency of the opioids from least potent to most potent?
codeine< morphine< heroine< methadone< fentanyl
what is the order of lipid solubility of the opioids from least soluble to most soluble?
morphine< codeine< heroine< methadone< fentanyl
not the same as for potency
what is the relationship between lipid solubility and potency?
the more lipid soluble, the greater the potency
what are is an example of an active metabolite created from morphine? what effects does it have and what effect does it fortunately not have?
Morphine-6-glucuronide (M6G)
creates euphoria
does not lead to cardio-respiratory failure
what receptor does morphine have an affinity to?
Mu
what are the active metabolites of fentanyl and methadone?
sike!
they don’t have active metabolites
which drugs produce morphine as an active metabolite?
heroin and codeine
what mediates metabolism of fentanyl and at what rate?
fast metabolism by CYP3A4
what mediates methadone metabolism and at what rate?
slow metabolism by six CYP enzymes
why does codeine have a low potency?
only 5-10% of codeine is metabolised to produce morphine
there is the involvement of slow (activating) and fast (inactivating) acting enzymes
what are the enzymes involved in codeine metabolism and what are their products? what is the rate of each enzyme?
CYP2D6- slow therefore activating- produces the low proportion of morphine
CYP3A4- fast therefore inactivating- produces the inactive normorphine metabolite.
ie. slow metabolism of codeine produced the active metabolite morphine
i. e. fast metabolism of codeine produced the inactive metabolite normorphine
why may some people not respond to codeine?
CYP-2D6 (O-dealkylation) can have a polymorphism so don’t respond to codeine
this is the slow metaboliser of codeine that produces the active morphine metabolite
what are most opioids metabolised by?
CYP-2D6 (slow) and CYP-3A4 in the liver.
what are the endogenous molecules that bind to opioid receptors?
Endorphins
Enkephalins
Dynorphins/Neoendorphins.
what are the opioid receptors?
Mu
Delta
Kappa
which endogenous molecule binds to Mu and what body functions does it affect?
endorphins (binds to delta also) pain/sensorimotor - pain - mood - CVS
what parts of the brain have Mu receptors?
thalamus
amygdala
nucleus accumbens
PAG (periaqueductal grey matter)
what endogenous molecule binds to Delta and what body functions does it affect?
enkephalins (endorphins can bind to) motor cognitive function - Pain - mood - CVS
what parts of the brain have Delta receptors?
nucleus accumbens
cerebral cortex
amygdala
what endogenous molecule binds to Kappa and what bodily functions does it affect?
dynorphins
neuroendocrine
- appetite
what part of brain have Kappa receptors?
hypothalamus
what is the main action of opiate receptors?
depressant
what are the 3 mechanisms of the depressant action of opioid receptors?
o Hyperpolarisation – increase potassium efflux. o Reduce Ca2+ influx – for NT exocytosis. o Reduce Adenylate Cyclase activity – for general cell activity.
what are the effects of opioids?
o Analgesia. o Euphoria. o Anti-tussive. o Respiratory depression (at medulla) o Stimulation of CTZ (Chemoreceptor Trigger Zone) – nausea/vomiting. o Pupillary constriction and GI effects.
how is the analgesic effect of opioids mediated?
o Decreased pain perception.
o Increased pain tolerance.
receptors in the pain perception and tolerance pathway are targeted by opioids
what is the pain perception pathway from the periphery?
Sensory via nociceptors from the periphery into the thalamus via the spinothalamic tract.
Thalamus distributes the signals to the extra-cortical regions
Cortical inputs activate the PAG (co-ordinates pain).
what is the pain tolerance pathway from the Periaqueductal grey?
PAG (the integrating centre for pain tolerance) activates the NRM
- PAG can be activated by thalamus too before the cortex “thinks about” the pain and processes it
NRM (Nucleus Raphe Magnus) increases pain tolerance.
- sends inhibitory descending signals to the dorsal horn (spinal cord)
where else does NRM get its inputs from apart from PAG?
NPRG (Nucleus Reticularis Paragigantocellularis)
o The negative-feedback centre of the brain.
o Independent of the thalamus.
what is the function of the NRPG?
automatically supresses pain before the brain has had a chance to process it.
the feedback centre involved in pain tolerance
what is the cortex’s influence (inputs) to PAG?
memories etc
what does greater PAG stimulation mean?
greater pain tolerance
what is the the role of the hypothalamus in pain perception?
Constantly signals PAG independent of pain sensation. This updates it with the current health status
what is the role of the Locus Coeruleus (LC) in pain perception?
provides the spinal cord with SNS outflow which is activated in response to stress so the pain response does not interfere with fight or flight.
Hence an injury is worse after an event than during
how can the spinal cord modulate pain tolerance?
some inhibitory input from the NRM enters the substantia gelatinosa in the spinal cord
(other inputs go directly into decreasing pain)
the SG can modulate/determine level of inhibition necessary on the sensory neurones from the NRM
which receptors mediate the analgesic effect the most?
Mu
what are the main targets of opioids (pain perception and tolerance pathways)?
o Dorsal horn and periphery – increase inhibition (substantia gelatinosa)
o PAG – enhance firing into NRM
o NRPG – enhances firing into NRM
what do opioids do at their targets?
switch off GABA
what does GABA normally do in the pain tolerance pathway? what is the effect of switching it off?
has an inhibitory effect on many of the pain tolerance centres so blocking GABA activates the pain tolerance centres.
how do opioids create euphoria?
- Opiates bind to the Mu receptor on GABA neurones
- decrease GABA exocytosis.
- reduces the inhibition on the VTA
- more DA is released.
how can opioids suppress coughing centrally? 2 methods
1) act as 5HT1A-receptor antagonist
2) direct depression at the medulla
how can opioids suppress coughing peripherally?
ACh and NK (Neurokinin) release inhibition so less transmission down the sensory nerves to the vagus afferents
how can opioids leads to respiratory depression?
- Depression of the Pre-Botzinger complex in the ventrolateral medulla
- Central chemoreceptors are inhibited, so depress the firing rate of the central chemoreceptors.
what does the Pre-Botzinger complex do and what is the effect of its depression?
generates respiratory rhythm so less rhythm with depression
how does antagonising 5HT1a receptors suppress cough?
- 5HT1A-receptor is a negative feedback receptor for serotonin
- Firing leads to suppression of serotonin and activation of the cough reflex.
how do opioids lead to nausea and vomiting at low doses?
opioids activate Mu receptors in the CTZ (Chemoreceptor Trigger Zone) and stimulate vomiting
disinhibition switches off GABA
how do opioids cause miosis (pupillary constriction) at high doses?
Activation of the Mu receptors causes a dis-inhibitory effect by decreasing GABA secretion and thus stimulates the pupil constriction in the Edinger-Westphal nucleus.
how does the effect of high dose opioids on the eye differ to other drug overdoses?
Most overdoses exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction but opiates cause “pin-prick” eyes
where do opioids bind in the GIT?
opioid receptors (kappa and Mu) are found in the myenteric plexus.
what do motor neurones in the GIT release and what effect do they have on smooth muscle?
release Ach or substance P to contract SM release VIP (vasoactive intestinal peptide) or NO to relax SM
what effects do opioids have on the GIT?
- Decrease in gastric emptying
- Decreased GI motility.
- Increase in water reabsorption.
- constipation
“SNS” like effect
what is urticaria?
local inflammation caused by histamine release from mast cells under the skin
how may some opioids cause urticaria? how can this be avoided?
hydroxyl group found on some opioids that cause mast cell degranulation (non-IgE-mediated) [like cannabis can]
You can switch people to different opioids if they display this response (one without the OH group)
what is the difference in urticaria as an effect of opioids compared to the other effects mentioned?
reaction is PKA mediated i.e. the opioids themselves (not receptor-mediated)
how does chronic usage of opioids induce tissue tolerance?
- Opioids upregulate levels of arrestin
- Arrestin promotes receptor internalisation
- Over-internalisation of receptors means the tissue becomes less receptive to opioids and so becomes tissue tolerant
what is the role of arrestin?
Arrestin promotes receptor internalisation
what is withdrawal of opioids associated with?
o Psychological craving.
o Physical withdrawal (resembling the flu)
how do withdrawal symptoms arise (AC)?
- Opioids normally depress cell activity by reducing AC activity
- Body responds by upregulating AC activity
- When the drug is removed the body is overstimulating AC
- General cell activity is greatly increased causing withdrawal
what are the features of an opioid overdose?
o Coma.
o Respiratory depression.
o Pin-point pupils.
o Hypotension (due to histamine release).
what is the treatment for overdose?
I.V. Naloxone (opioid antagonist)
how does naloxone’s structure enable it to work?
- Naloxone has a tertiary nitrogen, so can bind to the opioid receptors
- has a LONG side chain of carbons therefore has ANTAGONISTIC properties when bound
describe Heroin
- agonist drug IV injected
- travels to brain and binds to opioid receptor
- heroine is lipophilic therefore can cross BBB
why would heroin have greater selectivity to its receptors than alcohol? how does this impact side effects?
- heroine has more functional groups
- more complex in structure
- therefore greater selectivity
- fewer side effects
how is tolerance to e.g. heroin, induced?
- loss of receptors
- change in receptors
- loss in sensitivity
- change in internal mechanisms
- exhaustion of stores
how do the opioid agonists heroin and fentanyl cause different effect?
- heroine–> euphoria
- fentanyl–> unconciousness and respiratory depression
- Fentanyl is much more potent
- shifts the dose-response relationship to the left
- thus a much smaller dose is required to produce a euphoric effect.
what would be given to restore consciousness when fentanyl was taken?
naloxone
- opioid antagonist blocks receptors without efficacy itself
what are the principle types of drug antagonism?
- receptor blockage (e.g. antihistamine) is physiological
- chemical (anti-venom)
- pharmacokinetic (increased drug metabolism)
what is affinity and efficacy? how is this related to potency?
- affinity= ability of a molecule to bind to the receptor site
- efficacy= how much of an effect the drug will have once bound to the system
potency= affinity + efficacy
why would buprenorphine be given to ween someone off methadone?
methadone is a full agonist
buprenorphine is a partial agonist
you can’t OD on buprenorphine so same high is not achieved
the DR curve is suppressed and shifted right (more needed)
what drug activity does naloxone show?
antagonist
what drug activity does buprenorphine show?
partial agonist
what drug activity does methadone show?
full agonist
how well absorbed are opiates in the stomach and intestine?
as weak bases (pKa>8)
- in the stomach (pH low): more ionised, poorly absorbed
- in intestine (pH high): more unionised, well absorbed
why does IV administration only allow a small amount of heroin to get into tissue?
mostly ionised in the blood so little gets in
why does heroin have a more profound effect on the brain than morphine?
think about the structures of the molecules
heroine contains acetyl groups rather than hydroxyl groups like morphine
the acetyl groups make heroin more lipophilic so it is crossed into the brain better than morphine
where are opiates metabolised and excreted?
metabolised in the liver
excreted into bile
what is arrestin? what effect do opioids have on it?
opioids upregulate arrestin
this causes the increased ability for Mu receptor internalisation
what effect does mu receptor internalisation have?
tolerance
caused by arrestin activity due to long term opioid use
what are the mild side effects of opioids?
- nausea
- miosis (constriction, unlike many other ODs)
- constipation
- pruritus (itching) and urticaria (rash)
why do opioids cause nausea?
- decreased GABA release to CTZ
- stimulation of CTZ
- nausea
why do opioids cause miosis?
- decreased GABA release to Edinger Westphal nucleus
- increased oculomotor nerve firing
- pupil constriction
why do opioids cause constipation?
- binding to Mu and Kappa receptors located in GIT
- on myenteric neurones
- leads to reduced gut motility
why do opioids cause pruritus and urticaria?
stimulation of mast cell degranulation
what is the severe side effect of opioids?
Respiratory depression
why do opioids cause resp depression?
- inhibition of pre-Botzinger complex
- found in the ventrolateral medulla
- responsible for generating the respiratory rhythm
where is the substantia gelatinosa located?
in the spinal cord (dorsal horn)
what sends inhibitory signals to the sub gelatinosa to reduce pain sensation?
nucleus raphe magnus (receives inputs from NRPG and PAG)
