opioids Flashcards
what is an opiate?
- alkaloid derived from poppy
- e.g. morphine, codeine
describe the structure of morphine
- tertiary nitrogen: permits receptor anchoring, essential for analgesic effect
- has methyl group on nitrogen but extending side chain can produce anatagonist
where are the hydroxyl groups in morphine? what are they needed for?
- at position 3 and 6
- position 3: required for binding
- position 6: when in oxidised form, lipophilicty of drug inc. 10 fold
why is codeine not active compared to morphine?
- codeine must undergo some metabolism to become activated
- to reveal hydroxyl group
what are the different routes of admin of opioids?
- oral
- IV
are opioids acids or bases?
- weak bases (pKa >8)
- more readily ionized in stomach and blood so poorly absorbed
rank the opioids in terms of lipid solubility?
most lipid soluble:
- methadone/fentanyl
- heroin
- morphine
what is the link between lipid solubility and potency?
more lipid soluble, more potent
describe the metabolism of morphone
- morphine –> morphine-6-glucuronide (M6G)
- mui receptor agonist = potent analgesic activity
- morphine has greater affinity for mui 2 receptors than M6G, related to adverse side effects
describe the metabolism of fentanyl
- fast metabolism
- CYP3A4 enzymes
describe the metabolism of methadone
- slow metabolism
- 6CYP enzymes
what are the best tolerated opioids?
one that undergoes CYP-mediated metabolsim
describe the metabolism of codeine
- codeine –> morphine
- only 5-10% of codeine is metabolized to produce morphine as they are activating and inactivating enzymes in liver
- activation via CYP-2D6
- deactivation via CYP-3A4
what are the examples of opioid peptides?
- endorphins
- enkephalins
- dynorphins/neoendorphins
what opioid receptors do endorphins act on? causing what effect?
- mu/delta receptors
- pain/mood/CVS
what opiod receptors do enkephalins act on? causing what effect?
- delta
- pain/mood/CVS
what opioid receptors do dynorphins act on? causing what effect?
- kappa
- appetite
what are the opiate receptors cellular MoA?
depressant actions
- hyperpolarisation (inc. K efflux)
- reduce Ca influx (for NT exocytosis)
- reduce adenylate cyclase acticity (general cell activity)
what are the opioid effects?
- analgesia
- euphoria
- anti-tussive (anti-cough)
- resp depression
- stimulation of CTZ (nausea/vomiting)
- pupillary constriction and GI effects
what are the analgesic effects mediated by?
- dec. pain perception
- inc. pain tolerance
what is the mechanism of analgesia?
- sensory info from periphery into thalamic via spinothalamic tract
- thalamus and extra-cortical and cortical inputs activate PAG (co-ordinates pain)
- PAG activated NRM
- NRM sends inhibitory signals to dorsal horn
- NRM inc. pain tolerance
what is the NPRG?
- negative feedback centre of brain
- independent of thalamus
- automatically suppresses pain before brain has had a chance to process it
how does the hypothalamus input to pain pathway?
- constantly signals PAG independent of pain sensation
what is the LC? how does it input into the pain pathway?
- locus coeruleus
- major SNS outflow
- activated during stress response
- fight/flight don’t want pain response interfering
- inputs directly into dorsal horn to prevent pain pathway
describe the 2 ways the spinal cord can modulate pain tolerance
- descending inhibition from NRM
- some go directly in to dec. pain transmission in spinothalamic tract
- some project into substantua gelatinosa
what is the substantia gelatinosa?
- mini brain in spinal cord
- can modulate/determine level of inhibition necessary on sensory neurones from NRM
which receptors impact the analgesic effect the most?
Mu receptors
what are the main targets of opioids in pain pathway?
- dorsal horn and periphery = inc. inhibition
- PAG = enhance firing
- NRPG = activates
how do opioids affect GABA?
- very good at switching off GABA
- GABA has inhibitory effect on many pain tolerance centres
- blocking GABA activated pain tolerance centres
how do opiods cause euphoria?
- opiates bind to Mu receptor and dec. GABA exocytosis
- reduced inhibition on VTA so more DA release from NA
what are the 2 central ways that opioids cause anti-tussive effects?
- 5HT1A receptor antagonist (5HT1A is -ve feedback receptor for serotonin, suppression of serotonin and activation of cough reflex)
- medulla direct depression
what is the peripheral way in which opioids are anti-tussive?
- Ach and neurokinin release inhibition so less transmission down sensory nerves to vagus afferents
how do opioids cause resp depression?
- depression of pre-botzinger complex (less rhythm)
- central chemoreceptors inhibited by opioids, dec. firing rate of central chemoreceptors
how do opioids cause nausea and vomiting?
- activate Mu receptors in CTZ and stimulate vomiting
- Mu receptor stimulated disinhibition by switching off GABA secretion
what effect does opioid overdose have on the eyes? how is this different from most overdoses?
- opioid overdose = miosis
- most overdoses = dilated pupils (mydriasis)
- dec. brain function reduces level of constriction
how do opioids cause miosis?
- activation of Mu receptors causes dis-inhibitory effct by dec. GABA secretion
- stimulates pupil constriction in EW nucleus
how do opioids cause GI disturbances?
- many opioid receptors found in myenteric plexus
- motor neurones release Ach or substance P to contract SM
- motor neurones release vasoactive intestinal peptide or NO to relax SM
due to this, what do opioids cause?
- dec. in gastric emptying
- dec. GI motility
- inc. in water reabsorption
- so CONSTIPATION
how do opioids cause urticaria (local inflammation)?
- hydroxyl group found on some opioids causes mast cell degranulation
how do opioids cause tissue tolerance?
- opiods upregulate levels of arrestin in tissues
- arrestin promotes receptor internalization
- over internalization of receptors –> tissues become less receptive to opioids
- tissue becomes tissue tolerant
what is withdrawal associated with?
- psychological craving
- physical withdrawal (resembling flu)
what causes the physical withdrawal?
- opioids normally depress cell activity by reducing AC acticity
- body responds by upregulating AC activity
- when remove opioid drug, body is overstimualting AC
- general activity is inc. for few weeks after = withdrawal
what are the features of an overdose?
- coma
- resp depression
- pin point pupils
- hypotension (due to histamine release)
what is the treatment of an overdose?
- I.V. naloxone (opioid antagonist)
- naloxone also has tertiary nitrogen chain so can bind to opiod receptors
- naloxone has long side chain of Carbons so has antagonistic properties once bound to opioid receptors
