Pharm 19: Opioids Flashcards
Opioids are weak acids / bases
weak bases
describe whether opioids will be unionized / ionized in the
a) stomach
b) s. int
describe whether opioids will be unionized / ionized in the
a) stomach –> ionized –> poor absorption
b) s. int –> unionized –> more absorption
What does the potency of opiates generally depend on?
lipid solubility
–> more lipid soluble = more potent
(except codeine - less potency despite great lipid solubility)
note:
- morphine 6-glucuronide = most potent active metabolite
in terms of metbolism, compare between fentanyl + Methadone
Fentanyl (fast metabolism)
- Fentanyl metabolised quickly by CYP3A4 –> cleared quite quickly
Methadone (slow metabolism):
- Methadone metabolised by multiple enzymes slowly –> poor clearance –> accumulates in fat
describe the pharmacodynamics of opioids
- They act via specific opioid receptors
- then acts on endogenous opioid peptides
What are the 3 endogenous opioid peptides?
what are they mostly mediated by?
- Endorphins (Mu or delta) –> mostly Mu
- Mu = important in pain suppression
- -> central motor function - Enkephalins (delta)
- -> motor + cognitive - Dynorphins/Neoendorphins (kappa)
- have neuroendocrine effects by affecting hypothalamus
- -> neuronal function
describe the different mechanism of action of opiate receptors.
- general depressant effect
action 1. can cause Hyperpolarisation ( K+ efflux) –> function impaired
action 2. Can lower Ca2+ inward current –> less NT release
action 3. can decrease Adenylate cyclase (AC) activity
List the main effects of opioids
- Analgesics
- Euphoria
- Depression of cough centre (anti-tussive)
- Depression of respiration (medulla) - WORST + most dangerous SE
- Stimulation of chemoreceptor trigger zone (nausea/vomiting)
- Pupillary constriction
- GI effects
Describe how opioids can have analgesic effects .
periatjkfjkal grey region
2 ways:
- decreases pain perception + increases pain tolerance
- pain travels up spinothalamic tract –> thalamus –> cortex –> PAG –> NRM (effector arm of PAG) –> suppresses neurotransmission at dorsal horn
- NRPG????
- LC???
- damage sensed peripherally –> relayed to dorsal horn –> relayed up to brain via spinothalmic tract –> thalamus receives info –> sends signal up cortex + also PAG
- PAG integrates info (modulated by cortex) –> activates NRM –> sends descending fibres + interferes with pain transmission (method 1 = direct suppression of spinothalmic / method 2 = substantial gelatinosa) –> causes suppression of pain via dorsal horn
NRPG = nucleus reticular para (independent) –> on higher centre directly activates tolerance
hypothalamus –> constantly relays info to PAG about general state of health
(unhealthy = interferes with PAG)
LC –> SNS directly inputs into the dorsal horn
when SNS witched off –> painful stimulus = starts to be perceived
when you are in poor state of health you are more / less sensitive to pain
when you are in poor state of health you are more sensitive to pain
Opioids act at ______ to:
a) dorsal horn
b) PAG
c) NRPG
Opioids act at ______ to:
a) dorsal horn
- -> prevent pain info transmission up SL tract by directly depressing firing rate + thus pain sensation // or via substantia gelatinosa
b) PAG
- enhances pain tolerance
- -> switching off GABA neurones –> less inhibition of firing –> more active descending inhibition
c) NRPG
- -> (same as NRPG)
- -> switching off GABA neurones –> less inhibition of firing –> more active descending inhibition
How does opioids cause euphoria?
opiates= acts on mu receptors –> more inhibition of GABA neurones –> less inhibition of VTA –> more DA secreted onto NAcc –> euphoria
How does opioids have an anti-tussive (anti-cough) effects of opioids ?
PECCCCC
normal cough physiology
- chemo/mechoreceptor stimulated
- afferent impulse to cough centre in medulla
- efferent impish via PNS
- increases contraction of diaphragmatic / abdominal / intercostal muscles –> cough
serotonin = anti cough
- C-fibres (mediated by ACh + neurokinin) send irritation/information via Vagus to cough centre (medulla)
- Cough receptors in medulla = 5HT1a receptors = negative feedback receptors for serotonin (reduce serotonin levels), serotonin has anti-cough effect
Opioid action:
- Decrease firing rate of C-fibres
- Supress cough centre directly + supress 5-HT1a receptors –> increasing serotonin levels –> anti-cough
how can opioids cause respiratory depression at high dose?
- Respiratory control centre in medulla, central chemoreceptors detect CO2 levels in blood
- Pre-Bötzinger complex deals w/ rhythm generation of respiratory rate
- Opioids inhibit:
a) Central chemoreceptors (inhibit sensory arm)
b) Pre-Bötzinger complex –> and reduces appropriate rhythm generation –> low rate
both = key stimulus to breath
- common when addicts try to ween off –> then come back –> and administer the same amount as before –> cause resp depression –> they would ave lost tolerance to drug
how can opioids cause nausea + vomiting at low dose?
Opioids inactivate GABA-mediated inhibition in chemoreceptor trigger zone –> more firing to medullary vomit centre
how can opioids causes miosis of the eye?
Opioids inactivate GABA-mediated inhibition –> stimulate EW nucleus (start of parasympathetic nerve) –> switch on parasympathetic nerve –> cause pupil constriction
What effects can opioids have on GIT?
Opioid receptors all around enteric NS –> supress sensory + motor function causing:
- Constipation due to less gut contraction
- Fewer gastric secretions
opioids + Utricaria
- opiates –> if they have hydroxyl group –> activates mast cells under skin –>cause Utricaria
how can tolerance to opioids occur?
chronic opioid uptake –> up regulation go arrestin ( Arrestin protein drives this internalisation)
- Due to increased opioid receptor internalisation
- If opioids = constantly available + supressing cells –> cells become desensitised by decreasing no. of receptors
Opioids dependence
PECCCCCC
- no physical symptoms w withdrawal
- due to cells trying to compensate for the opiates (massive up regulation of adenylate cyclase / cAMP)
- over activation of cells –> diarrhea /
List features of opioid Overdose
- coma
- respiratory depression
- pinpoint pupils
- hypotension
How would you treat overdose of opioid ?
treatment = Naloxone (Opioid receptor antagonist)
Has tertiary N –> can bind opioid receptors, but its side chain has been extended (still a tertiary N) –> so ANTAGONIST rather than agonist
opiates = structure difference
- morphine
- codeine
opiates =
a) morphine
- has tertiary nitrogen –> which binds strongly to relevant receptors (for analgesic effect)
- methyl group on the end of nitrogen –> determines agonist (1/2 chain) / antagonists (>2 chains)
- has hydroxyl groups –> allows molecules to secure onto receptor
b) codeine
- methyl morphine
- don’t have both hydroxyl groups –>
- CODEINE = prodrug
c) heroine = di acetyl morphine
Note: heroine = more lipid soluble than morphine
what 4 key components allows action of different forms of opiates
(even if their structures are diff, as long as they have these components, they can have opiate actions)
- tertiary nitrogen
- central carbon = quaternary
- aromatic ring
- phenyl groups
morphine has 2 active metabolites =
- morphine 3-G glucuronide
- morphine 6 - G glucuronide
heroine + codeine active metabolites =
- morphine
what are clinical uses of
a) fentanyl
b) Methadone
what are clinical uses of
a) fentanyl - pain relief / analgesic effects
- -> slow clearance
b) Methadone - drug used to ween off heroine effects
- -> slow clearance
c) codeine more lipid soluble, less potent
- -> metabolism to morphine is slow
- -> mostly metabolized by fast CYP3A4 –> deactivated
