Opioids (musculoskeletal pain) Flashcards
What are natural opiates? Give an example.
These are alkaloids found in opium
e.g. morphine.
What are semi-synthetic opioids? Give an example.
They are derivatives of natural opiates
e.g. heroin, oxycodone, diamorphine.
What are synthetic opioids? Give an example.
These are synthetic compounds
e.g. methadone, tramadol.
What are opiate peptides? Give an example.
These are endogenous peptides (naturally occurring within body)
e.g. endorphins, enkephalins.
What is the difference between opioids and opiates?
Opiates occur naturally
What are all the effects of opium/morphine?
Major effects: analgesia, nausea/vomiting, dependence Reduced GI motility Respiratory depression Cough suppressant Pupil constriction Formication (feeling insects crawling over you) Sedation/anaesthesia Euphoria/dysphoria
How does taking opioids decrease GI motility?
Opioid receptors are found in the GI tract - individuals who overuse opioids suffer from severe constipation.
Describe the structural morphology of morphine (4 points).
- Contains 5 rings.
- Basic due to the tertiary amino group (alkaloid) - will be inactive if removed.
- Contains a phenolic group at position 3 - will be inactive if removed.
- Contains a benzene aromatic ring.
List the 5 functional regions of morphine.
phenol ether alcohol tertiary amine aromatic benzene ring
What is the effect of removing the OH/alcohol group at position 3?
This group influences the lipophilicity of the drug - removing it will make molecule more lipophilic so can cross the blood brain barrier and cause CNS effects.
What is the main route of metabolism for morphine?
Via glucuronidation.
What is the enzyme involved in the metabolism of morphine?
UGT
= UDP-glucronosyl transferase.
How are conjugates excreted after metabolism of morphine?
Mostly excreted in urine - glucuronic acid conjugate
Describe morphine-3-glucuronide.
Made by altering the phenol group on position 3 by adding glucuronic acid group - this makes it inactive.
It is an inactive toxic metabolite - 60% of this will be made.
Describe morphinr-6-glucuronide.
Made by altering the alcohol group on position 6 by adding glucuronic acid - makes it more lipophilic - increases transport of drug across BBB = increases relative potency of drug by 50 fold.
This is the active metabolite and only 6-10% of this is made.
What is morphine-3,6-diglucuronide?
This is the resultant metabolite of morphine after morphine-3-glucuronide and morphine-6-glucuronide are continued to metabolise by UGT enzyme. It is an inactive metabolite.
Codeine is a prodrug of morphine. What is a prodrug?
Means that drug is modified after administration to exert its effects.
Describe how codeine converts to morphine.
Codeine is produced by methylation of the phenolic OH at position 3. This reduces the activity of morphine.
Metabolism causes demethylation of the phenol group resulting in the potent morphine.
Describe conversion of heroin to morphine.
Heroin is produced when the phenol and alcohol group become acetylated (diacetylation) - results in diacetylmorphine = heroin.
Heroin is more active than morphine as acetyl group is more lipophilic hence crosses the BBB. Once it has crossed the BBB, both acetyl groups are removed by esterase enzymes within the brain. Removal results in morphine and can start to exert effects.
Heroin is a prodrug of morphine. What are the metabolites and how are they formed?
Metabolites are 3-monoacetylmorphine (3-MAM), 6-monoacetylmorphine (6-MAM) and morphine.
Formed by the action of carboxylesterases.
Are the metabolites of heroin active?
Heroin and 3-MAM are inactive at the mu receptors.
Morphine and 6-MAM are active at the mu receptors.
What are two mu receptor/opioid receptor antagonists?
Naloxone and Naltrexone
- can be used reverse effects of morphine.
What is naloxone?
- used to overcome respiratory depression post surgery
- rapid onset post iv administration
- is a complete antagonist of morphine (no analgesia or respiratory)
- used to treat morphine or diacetylmorphine overdose
What is naltrexone?
- not commonly used
- used as an antidote in morphine overdose
- used to assist rehabilitation of opioid-dependent patients
What is nalorphine?
- strong antagonist of morphine
- no major analgesic properties but has weak analgesic effects without unwanted side effects
Name the 3 opioid receptors.
mu, kappa, delta
- all are GPCRs = G-Protein Coupled Receptors
What is the endogenous agonist for delta receptor?
Enkephalins
What happens when opioid agonists bind to GPCRs?
They cause a decrease in adenylyl cyclase activity which causes a reduction in cyclic AMP thereby inhibiting the likelihood of neurotransmission. Pain feeling will be absent.
- link this to how beta gamma subunit prevent influx of calcium hence no HT released into synaptic cleft so no neuronal transmission.
Describe how the opioid receptors are distributed with respect to analgesia.
Widely distributed in the brain - found in periaqueductal gray, nucleus raphe magnus, thalamus and brainstem.
Found in the spinal cord in the substantia gelatinosa.
Found in the periphery - nociceptors, Ad/C fibres, gut myenteric plexus
