Opioids Flashcards
1
Q
What is an opiate?
A
Alkaloid derived from the poppy, Papaver somniferum
2
Q
Main opioids
A
- morphine
- codeine
- papaverine
- thebaine
3
Q
Morphine structure
A
- tertiary nitrogen for analgesic effect of morphine (quarternary nitrogen would decrease analgesic effect since cannot pass into CNS)
- tertiary nitrogen permits receptor anchoring
- change to methyl group on nitrogen (extension o side chain to 3+ carbons) decreases analgesic effect also, generating antagonists
4
Q
Structure activity relationship: morphine vs heroin
A
- hydroxyl group at position 3 on morphine required for binding
- Codeine must undergo metabolism to become activated and reveal hydroxyl group=prodrug
- hydroxyl group at position 6 on morphine=oxidise OH group so lipophilicity of the drug increases 10-fold
5
Q
Structure activity relationship: morphine vs methadone/fentanyl
A
- methadone conforms to morphine rule of tertiary nitrogen, quaternary carbon and phenyl group
- fentanyl moves away from morphine rule and has generated more potent opioids=tertiary carbon instead of quarternary
6
Q
Pharmacokinetics of opioids
A
Route of administration=oral or I.V.
- opioids are weak bases (pKa>8) so more likly to be ionised in acidic stomach and blood(blood pH=7.4)=poor absorption results
- typically <20% of opioids unionised in the blood thus, only <20% can access tissues
- opioids unionised in small intestine so more readily absorbed here=first pass metabolism will decrease bioavailability here
7
Q
Lipid solubility of opioids
A
- determined by octanol-water partition coefficient at pH 7.4
- codeine more lipid soluble than morphine but less potent due to metabolism
- methadone/fentanyl more lipid soluble than heroin which is more lipid soluble than morphine
8
Q
Morphine metabolism
A
- morphine 6-G glucuronide (M6G) is a μ-opioid receptor agonist with potent analgesic activity
- morphine has greater affinity than M6G for μ2-opioid receptor=responsible for adverse effects of μ-receptor agonists
- in some patients=most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism
- fentanyl=predominantly metabolised (fast) by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
- methadone undergoes slow metabolism compared to fentanyl=6 CYP enzymes
9
Q
Codeine metabolism
A
- 5 to 10% of codeine metabolised to produce morphine by activating and deactivating enzymes in the liver
- slow activation via CYP2D6=converting codeine to morphine in O-dealkylation
- CYP3A4 enzyme metabolises and deactivates codeine=thus only 10% codeine metabolised to morphine=responsible for codeine analgesic property
- some individuals have CYP-2D6 polymorphism so won’t respond well to codeine
- morphine metabolised by uridine 5 diphospate glucoronsyltransferase
10
Q
Opioids pharmacodynamics
A
- act via specific opioid receptors
- endogenous opioid peptides include endorphins, enkephalins and dynorphins/neoendorphins
- endorphins act on mu or delta receptors
- enkephalins act on delta receptors
- dynorphins act on kappa receptors
11
Q
Opiate receptors cellular mechanism of action
A
DEPRESSANT ACTIONS
- hyperpolarisation=increasing potassium efflux
- reduces inward current calcium for neurotransmitter exocytosis
- reduces adenylate cyclase activity for general cell activity
12
Q
Opioid effects
A
- analgesia
- euphoria
- depression of cough centre=anti-tussive (prevent coughing)
- depression of respiration in medulla (dangerous)
- stimulation of chemoreceptor trigger zone to give nausea and vomiting
- pupillary constriction
- GI effects
13
Q
Opioid effects: analgesia
A
-analgesic effects mediated by decreased pain perception and increased pain tolerance
Mechanism:
14
Q
Tissue tolerance of opioids
A
/
15
Q
Opioid dependency
A
Withdrawal associated with:
- psychological craving
- physical withdrawal (resembling flu)
