Opiods Flashcards
(56 cards)
What is an opiate
An alkaloid derived from the poppy, Papaver somniferum
What is an opoiod
Anything that has opiate activity, be it natural or synthetic
Give examples of opiates
Morphine and codeine
thebaine and papaverine
Structure of opiate (morphine in this case…. the others are modifications mostly)
Tertiary nitrogen… important for analgesic activity (binds mostly strongly to receptor)
OH groups (at C3 and C6)
Quaternary carbon
What determines whether an opiate is an agonist or antagonist
Whether the tertiary nitrogen has a long or short side chain….
if just 1 or 2 carbons on the side chain, still an agonist
if lots, then antagonist
If you make it quarternary it will not get into the CNS
The tertiary nitrogen impacts the efficacy of the natural opioid for the receptor. What is important for affinity?
- Tertiary nitrogen)- important for both efficacy and affinity. Because tertiary nitrogen allows the molecule to bind the receptor (gives it its affinity and permits receptor anchoring)
- The hydroxyl groups at the C3 and C6 positions (especially C3…which is required for binding)
What is the difference between heroin and morphine
Heroin is di-acetyl morphine (has 2 acetyl groups instead of 2 OH groups at C3 and C6)
This makes it MORE LIPID SOLUBLE (but as there are no OH, it doesn’t have any activity in this form… heroin is prodrug)
What is the difference between codeine and morphine
methyl-morphine
Also more lipid soluble than morphine. but not as much as heroin which has OH groups removed for acetyl (but again not much effect because the C3 is required for opiate receptor binding)….. codeine also a prodrug
Give 2 examples of synthetic opioids and their structures
So morphine, and codeine are natural opioids (i.e. opiates). Heroin is a synthetic opioid but with a traditional morphine structure
Fentanyl and methadone are both synthetic opioids.
They don’t look like morphine (they are ‘open chain opioids’), but still have the tertiary nitrogen/aromatic ring which is important for opioid activity.
Fentanyl has tertiary carbon not quaternary though
What is necessary for an opioid to work on the receptor
Methadone and fentanyl
- Tertiary nitrogen
- Central quaternary carbon
- Aromatic ring
- Spacer (gap between carbon and nitrogen)
How are opiates given
Oral or IV
What is the pKa of opiate
They are weak bases
So pKa>8 (this makes no sense as pKa is for acid but go with it)
(if pH and pKa are the same, then good absorption..)
Outline the absorption of opiates
In stomach, where pH is 2 then the drug is ionised and poorly absorbed (pKa above pH so poor absorption)
in intestine, less ionised so better absorbed (as pH more similar to the pKa)
Note there is HIGH FIRST PASS METABOLISM which affects bioavailability (IV provides 100% BA)
What proportion of opioid is ionined in the blood
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
How is morphine metabolised
Morphine 3-G glucuronide
Morphine 6-G glucuronide (also a mu-opioid receptor agonist like morphine)
M6G is ACTIVE METABOLITE (but only 10% of the metabolites of morphine are the active forms)
Outline the lipid solubility of
morphine heroin codeine methadone fentanyl
Methadone/Fentanyl»_space; Heroin > codeine>Morphine
What can be said to determine potency of opioid? What is the exception
General rule of thumb – More lipid soluble, more potent.
EXCEPTION: codeine more lipid soluble than morphine but less effective
What are the metabolites of heroin and codeine
The active metabolites of heroin and codeine are MORPHINE
The heroin and codeine are lipid soluble, but not active at opioid receptor as they do not have the critical C3 OH group until converted into morphine
Why is codeine less potent than morphine and heroin
Less potent than morphine because morphine gets into CNS and binds effectively to opioid receptor
Codeine and heroin have to be broken down to morphine (their metabolites) to become active. They are otherwise inactive at opioid receptor (or 300x less active)
The reason codeine is less effective than morhine, but heroin is more effective:
Heroin is more lipophilic than morphine. Passes through the BBB and into the CNS. Then, when in the CNS, can be converted into morphine, and have morphine effects.
However codeine cannot be metbaolised in the CNS. It must be metabolised by the liver. Only 10% max is metabolised to morphine, whilst the rest is inactivated (see next card)
Give more detail on codeine metabolism
and metabolism of opioids generally
5-10% goes via slow route to produce morphine… CYP2D6… o-dealkylation
The rest goes through fast route CYP3A4, which deactivates the codeine so it doesn’t even become morphine
GENERAL: The majority of opioids are metabolised in the liver by either CYP3A4 and CYP2D6
Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.
What makes a drug really addictive
Rapid clearance
Why is methadone used in addiction recovery
It has really slow clearance, so it will last for ages rather than keep needing to take heroid
fentanyl has similar clearance to morphne (only slightly less) so not used in addiction recovery
What produces the negative effects like respiratory depression with opioids and who is most likely to get them
Morphine (not M6G)… (individuals who don’t metabolise morphine very well are more likely to have negative side effects)
Because 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
Differentiate the metabolism of fentanyl and methadone and their active metabolites
Fentanyl fast metabolism
Methadone slow metabolism
No active metabolites (they are really active themselves at the opioid receptor)
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
