Opioida Flashcards
What is meant by an opioid
An alkaloid derived from the poppy, Papaver somniferum
Opiate- nautral product – alkaloids that come from poppy
Give some examples of opiates
Morphine
Codeine
Thebaine
Papaverine
What is meant by an opioid
Opiod- anything with opiate like activity- synthetic
Describe the importance of the tertiary nitrogen in the opiate structure-activity relatiobship
Tertiary nitrogen = analgesia Permits receptor anchoring Extend side chain to 3+ carbons and you generate antagonist
The tertiary form of the nitrogen appears to be crucial to the analgesia of morphine; making the nitrogen quaternary greatly decrease the analgesia, since it cannot pass into the central nervous system. Changes to the methyl group on the nitrogen will decrease analgesia as well, creating antagonists
Tertiary nitrogen- important for affinity
Extend this chain- determines whether its agonist or antagonist
Afiinity and efficaycy- need teriary niterogen and short side chain
Describe the importance of the hydroxyl groups at position 3 and 6 in morphine
Hydroxyl groups- sites for modification
Heroin- is di-acetyl morphine- hydroxyl groups replaced by acetyl groups
Hydroxyl group at position 3: Required for Binding i.e. codeine is a prodrug
What is important for the activity of morphine
Aromatic ring- all 3 parts of molecule interacting with receptor- vand der waals forces
Morphine best at bidnign to receptor- all 3 compnents, hydroxyl group, aromatic ring and 3 nitrogen
How is the structure of codeine different to morphine
Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)
Describe the hydroxyl group at position. 6 in morphine
Hydroxyl group at position 6: Oxidise the OH group and lipophilicity Increases 10-fold
Heroin most lipid soluble
Di-acetyle instead of two hydroxyl groups
Describe methadone and fentanyl
Methadone conforms to the ‘Morphine Rule’ – tertiary nitrogen, quarternary carbon, phenyl group.
Fentanyl – moving away from the morphine rule has generated even more potent opioids i.e. fentanyl has a tertiary carbon NOT a quarternary carbon.
Morphine rulep- gap between aromatic ring and teriary nitrogen, also quaternary cartbon
Need to look like morphine to have an effect
Rule has broken down
2 other similar drugs to morphine include – methadone and fentanyl.
o Methadone – tertiary nitrogen.
o Fentanyl – 2x tertiary nitrogen’s?
They are extremely lipid soluble
Describe the key pharmacokinetic properties of opiates
Opioids are weak bases and thus are likely to be ionised in the acidic stomach and poorly absorbed from this site.
In the small intestine, they will be unionised and more readily absorbed. However, first pass metabolism will decrease the bioavailability.
Blood pH = 7.4. Therefore most opioids will be largely ionised in the blood. Usually <20% unionised. This is the component that can access tissues.
S.I- 5-7
Opioids are weak bases – mostly pKa > 8
Why is the comparison of potency of the opiates complex
Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.
How is the lipid solubility of the opiates determined
Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.
Describe the lipid solubility of the different opiates
morphine - 1 heroin- 2.3 codeine- 1.2 methadone - 116 fentanyl - 816
Lipid Solubility: Methadone/Fentanyl»_space; Heroin > Morphine
General rule of thumb – More lipid soluble, more potent - except for codeine
potency: morphine 1:1 heroin 2:1 codeine 1:10 methadone 4:1 fentanyl: 100:1
Describe the active and inactive metabolites of the opioids
Morphine:
Inactive metabolite - normorphine
Active metabolites - Morphine 3-G glucuronide
Morphine 6-G glucuronide (10%)
Heroin:
Inactive metabolites- normprphine
Active metabolites- Morphine
Codeine:
Inactive metabolite- nor codeine
Active metabolite- codeine
Methadone
inactive - EDDP
Active- none
Fentanyl
inactive - norfentanyl
active- none
Describe the metabolism of morohine, methadone and fentanyl
Like morphine, M6G is a μ-opioid receptor agonist with potent analgesic activity. However, morphine has greater affinity than M6G for the μ2-opioid receptor thought to be responsible for many of the adverse effects of μ-receptor agonists
In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism. For example, in a 2001 clinical trial, 50 patients with cancer who did not respond to morphine or were unable to tolerate it were switched to methadone, which undergoes complex metabolism involving up to 6 CYP enzymes.
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
Active metabolites- cxaude euophori but not respiratory depression
Compare the rate of metabolism of fentanyl and methadone
Fentanyl is metabolised rapidly (it can be broken down by cholinesterases in the blood)
Methadone is metabolised slowly so remains in the blood for longer
What is a use of methadone based on its metabolism
It is used to wean people off heroin and morphine – as methadone remains in the blood for longer, it can reduce cravings
Describe the metabolism of codeine
Metabolism 2: Codeine morphine – only 5-10% of codeine is metabolised to produce morphine as there are activating (slow) and inactivating enzymes found in the liver:
o Activation (slow) via CYP-2D6 (O-dealkylation) – can have a polymorphism so don’t respond to codeine.
o Deactivation via CYP-3A4.
Most opioids are metabolised by CYP-2D6 and CYP-3A4 in the liver.
Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.
Essentially, how do opioids work
They act via specific ‘opioid’ receptors
Endogenous opioid peptides:
Endorphins
Enkephalins
Dynorphins/neoendorphins
What do endorphins act on
Mu or delta receptors
Cerebellum Caudaute Nucleus accumbent PAG All mu-mediated
Pain/Sensorimotor