Opioid receptors - morphine Flashcards
Naturally occurring opioids from the opium poppy:
Morphine
Codeine (Weak)
Simple chemical modifications to naturally occurring one:
Diamorphine
Oxycodone
Dihydrocodeine
Synthetic opioids
Pethidine
Fentanyl
Alfentanil
Remifentanil
Synthetic partial opioid agonists
Buprenorphine
What is the antagonist for opioids?
Naloxone
Routes of administration for morphine
Oral - bioavailability is reduced.
First pass metabolism by the liver - 50% is metabolised.
Single dose lasts for ~3-4 hours.
Slow release preparations for palliative care - continuous.
How does morphine dosing differ if its given orally vs S/C; IM or IV?
50% of oral dose is metabolised by the liver thus parenteral administration requires half the oral dose.
10mg orally is equivalent to 5mg s/c; IM; IV.
What are the parenteral routes for morphine administration?
S/C (third fastest)
IM (second fastest)
IV (fastest)
IV PCA (patient controlled)
Epidural/CSF
Transdermal patches for lipid soluble drugs= fentanyl.
Morphine problems
Serious problems with addiction,
the drug companies started
trying to develop non-addictive
(and non-respiratory depressant)
versions of morphine
Diamoprhine
Simple chemical transformation to diacetylmorphine.
More potent and faster acting (crosses BBB quickly)
Controlled drug legislation
Started in the 1920s
Current legislation:
Misuse of Drugs Act 1971
Class A drugs
Secure storage
CD books (2 signatures needed)
How do opioids work?
Review of pain pathways - opioid drugs simply use the existing pain
modulation system.
Natural endorphins (endogenous morphine) and enkephalins.
G protein coupled receptors - act via second messengers.
Inhibit the release of pain transmitters at spinal cord and midbrain - and modulate pain perception in higher centres - euphoria - changes the
emotional perception of pain
What do opioids inhibit?
Descending inhibition of pain
Part of the fight or flight response
Never designed for sustained activation
Sustained activation leads to tolerance and
addiction
Opioid receptors
MOP, KOP, DOP and NOP (nociceptin opioid-like receptor)
- Receptors now sequenced, all vertebrates have copies of the
main opioid receptors - unchanged in evolutionary terms for
millions of years
Importance of opioid receptors?
- MOP, KOP, DOP and NOP - what do you need to know?
- Aim remains to develop opioid analgesics without the side
effects of respiratory depression or addiction - Kappa agonists cause depression instead of euphoria
- At the moment all the drugs that we use are µ agonists
Potency
Whether a drug is ‘strong’ or ‘weak’ relates to how well the drug binds to the receptor,
the binding affinity
Efficacy
Is it possible to get a maximal response with the drug or not?
Or even if all the receptor sites are occupied do you get a ceiling response?
The concept of full or partial agonists
Relative potencies
Diamorphine 5 mg
Morphine 10 mg
Pethidine 100 mg
Tolerance
Down regulation of the receptors with prolonged use
Need higher doses to achieve the same effect
Dependence
Psychological - craving, euphoria
Physical
Opioid withdrawal
Starts within 24 hours, lasts about 72 hours.
Side effects
Opioid receptors exist outside the pain system
e.g.: digestive tract, respiratory control centre
- We can sometimes deliver opioids epidurally, but for the most part we have to
give them systemically
Respiratory Depression
Sedation
Nausea and Vomiting
Constipation
Itching
Immune Suppression
Endocrine Effects
- Different patients have quite a range of sensitivity to opioids - start with a small
dose and titrate up as necessary
Opioid induced respiratory depression
Call for help
- ABC
- Naloxone
- IV is fastest route
- Titrate to effect - don’t have to give it all once - once you’ve injected a drug you
can’t get it back! - Short half-life of naloxone - beware drug addict overdoses in A&E
How to titrate naloxone to effect?
Titrate to effect - dilute 1ml in
10ml saline
One ampoule of a drug is
usually about the right adult
dose - if you think you need to
open more than one - check
with a colleague first!
Opioid use in chronic non-cancer pain (AVOID if possible)
Opioids for non-cancer pain start to lose effectiveness fairly quickly (within
weeks)
Addiction to the drug leads to manipulative behaviour - easy to start, but can be
very difficult to get patients off them.
- Before prescribing opioids, discuss with the patient the risks and features of
tolerance, dependence, and addiction - use short term courses. - Agree a treatment strategy and plan for end of treatment.
- Warnings have been added to the drug labels and packaging of opioids to
support patient awareness. - At the end of treatment, taper dosage slowly to reduce the risk of withdrawal effects - may take weeks.
What metabolises codeine (prodrug) to morphine?
CYP2D6 enzyme.
CYP2D6 activity is decreased in 10-15% of the Caucasian population
- CYP2D6 is absent in a further 10% of this population
- Codeine will have a reduced or absent effect in these individuals
- CYP2D6 is overactive in 5% of this population - these individuals may be at
increased risk of respiratory depression with codeine - not licensed for
children under 12
Morphine metabolism
Metabolised to morphine-6-glucoronide (more potent and is renally excreted).
Careful use in patients with renal function <30%.
Tramadol
Weak opioid agonist - slightly stronger than codeine.
Prodrug - CYP2D6
It has a secondary effect in analgesia as a serotonin and nor-epinephrine reuptake inhibitor
- So it interacts with SSRIs, tricyclic antidepressants and MAOIs, sometimes fatally - take care prescribing it to patients on antidepressants
