opioids Flashcards
1
Q
what is an opiate?
A
- alkaloid derived from poppy
- e.g. morphine, codeine
2
Q
describe the structure of morphine
A
- tertiary nitrogen: permits receptor anchoring, essential for analgesic effect
- has methyl group on nitrogen but extending side chain can produce anatagonist
3
Q
where are the hydroxyl groups in morphine? what are they needed for?
A
- at position 3 and 6
- position 3: required for binding
- position 6: when in oxidised form, lipophilicty of drug inc. 10 fold
4
Q
why is codeine not active compared to morphine?
A
- codeine must undergo some metabolism to become activated
- to reveal hydroxyl group
5
Q
what are the different routes of admin of opioids?
A
- oral
- IV
6
Q
are opioids acids or bases?
A
- weak bases (pKa >8)
- more readily ionized in stomach and blood so poorly absorbed
7
Q
rank the opioids in terms of lipid solubility?
A
most lipid soluble:
- methadone/fentanyl
- heroin
- morphine
8
Q
what is the link between lipid solubility and potency?
A
more lipid soluble, more potent
9
Q
describe the metabolism of morphone
A
- 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
10
Q
describe the metabolism of fentanyl
A
- fast metabolism
- CYP3A4 enzymes
11
Q
describe the metabolism of methadone
A
- slow metabolism
- 6CYP enzymes
12
Q
what are the best tolerated opioids?
A
one that undergoes CYP-mediated metabolsim
13
Q
describe the metabolism of codeine
A
- 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
14
Q
what are the examples of opioid peptides?
A
- endorphins
- enkephalins
- dynorphins/neoendorphins
15
Q
what opioid receptors do endorphins act on? causing what effect?
A
- mu/delta receptors
- pain/mood/CVS
16
Q
what opiod receptors do enkephalins act on? causing what effect?
A
- delta
- pain/mood/CVS
17
Q
what opioid receptors do dynorphins act on? causing what effect?
A
- kappa
- appetite
18
Q
what are the opiate receptors cellular MoA?
A
depressant actions
- hyperpolarisation (inc. K efflux)
- reduce Ca influx (for NT exocytosis)
- reduce adenylate cyclase acticity (general cell activity)
19
Q
what are the opioid effects?
A
- analgesia
- euphoria
- anti-tussive (anti-cough)
- resp depression
- stimulation of CTZ (nausea/vomiting)
- pupillary constriction and GI effects
20
Q
what are the analgesic effects mediated by?
A
- dec. pain perception
- inc. pain tolerance
21
Q
what is the mechanism of analgesia?
A
- 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
22
Q
what is the NPRG?
A
- negative feedback centre of brain
- independent of thalamus
- automatically suppresses pain before brain has had a chance to process it
23
Q
how does the hypothalamus input to pain pathway?
A
- constantly signals PAG independent of pain sensation
24
Q
what is the LC? how does it input into the pain pathway?
A
- 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
25
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
26
what is the substantia gelatinosa?
- mini brain in spinal cord
| - can modulate/determine level of inhibition necessary on sensory neurones from NRM
27
which receptors impact the analgesic effect the most?
Mu receptors
28
what are the main targets of opioids in pain pathway?
- dorsal horn and periphery = inc. inhibition
- PAG = enhance firing
- NRPG = activates
29
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
30
how do opiods cause euphoria?
- opiates bind to Mu receptor and dec. GABA exocytosis
| - reduced inhibition on VTA so more DA release from NA
31
what are the 2 central ways that opioids cause anti-tussive effects?
1. 5HT1A receptor antagonist (5HT1A is -ve feedback receptor for serotonin, suppression of serotonin and activation of cough reflex)
2. medulla direct depression
32
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
33
how do opioids cause resp depression?
- depression of pre-botzinger complex (less rhythm)
| - central chemoreceptors inhibited by opioids, dec. firing rate of central chemoreceptors
34
how do opioids cause nausea and vomiting?
- activate Mu receptors in CTZ and stimulate vomiting
| - Mu receptor stimulated disinhibition by switching off GABA secretion
35
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
36
how do opioids cause miosis?
- activation of Mu receptors causes dis-inhibitory effct by dec. GABA secretion
- stimulates pupil constriction in EW nucleus
37
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
38
due to this, what do opioids cause?
- dec. in gastric emptying
- dec. GI motility
- inc. in water reabsorption
- so CONSTIPATION
39
how do opioids cause urticaria (local inflammation)?
- hydroxyl group found on some opioids causes mast cell degranulation
40
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
41
what is withdrawal associated with?
- psychological craving
| - physical withdrawal (resembling flu)
42
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
43
what are the features of an overdose?
- coma
- resp depression
- pin point pupils
- hypotension (due to histamine release)
44
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
