Opiates Flashcards
Around what % of codeine is converted to morphine?
5-10%
What are mu opioid receptors important for?
Nociception
Sensorimotor function
What are the chemical names for heroin and codeine?
Heroin = diacetylmorphine Codeine = Methyl morphine
Where are mu opioid receptors located?
Cerebellum, caudate, NA
Which of the synthetic opiates has the highest lipophilicity?
Fentanyl
What is the most potent active metabolite of morphine?
Morphine-6-glucuronide
Recall 2 synthetic opiate drugs
Methadone
Fentanyl
What is naxolone?
Antagonist of opioid receptors - due to extended side chain on tertiary nitrogen
Recall the 3 types of opioid receptor and the types of opioid that act on them?
Mu - endorphins
Delta - Enkephalins
Kappa - Dynorphins
Recall 5 side effects of opiate use
- Depression of respiration (medulla)
- Stimulation of CTZ
- Miosis
- GI effects
- Urticaria
What is the most significant between synthetic opiates and natural opiates?
Synthetic drugs have a much higher lipophilicity
What chemical group determines the efficacy of an opiate drug?
OH groups bound to nitrogen
Recall the sites of conversion to morphine of heroin and codeine
Heroin - brain (can cross the BBB)
Codeine - outside brain
Recall 3 mechanisms by which endogenous opioids have a depressive effect on cells
- Increase K+ efflux to cause hyperpolarisation
- Decrease Ca++ efflux
- Decrease AC activity
Describe the structure activity relationship of opiate action
Tertiary nitrogen permits receptor anchoring
Extension of side chain changes the drug from an agonist to an antagonist
Compare the lipophilicity of heroin, methadone and fentanyl to morphine and explain the consequences of this
Number of times more soluble = number of times more potent
Heroin = 2 x
Methadone = 4 x
Fentanyl = 100 x
Describe the metabolism and clearance of fentanyl
Quickly metabolised and cleared - therefore fast effect but quickly lost
How do opiates lead to miosis?
Switch on PNS
GABA disinhibited in EW nucleus
How do opiates interact with the CTZ?
Inhibit GABA leading to DISINHIBITION
Why do opiates affect the GIT?
Several opioid receptors on myenteric neurons
What is the main mechanism driving opiate tolerance?
Receptor endocytosis driven by arrestin
Describe 2 ways in which opioids affect the cough centre
- Between cough receptors and medulla (cough centre) are C fibre receptors - these are inhibited by opioids
- Receptors in cough centre = 5HT1A which are negative feedback receptors for serotonin (which inhibits cough) - opiates inhibit 5HT1A receptors so more serotonin in cough centre
Recall 3 useful effects of opioid drugs
- Analgesia
- Euphoria
- Anti-tussive
Compare the effects of morphine and Morphine-6-glucuronide
Morphine is more likely to cause adverse side effects
Why does methadone act as an effective morphine replacement?
Persists in the body for a long time due to accumulation in fat so effect more sustained
Explain the rebound effect of cells in opiate withdrawal
Depressant drugs decrease cellular activity
Cells increase AC in response
When you remove opiate - overactive AC
–> muscle cramping and diarrhoea
What is the effect of opiates on the GIT?
Severe constipation
How can heroin have efficacy if it doesn’t have any OH groups bound to the tertiary nitrogen?
It is converted to morphine within the brain
Describe the metabolism and clearance of methadone
Much slower than fentanyl as many more enzymes involved
Likely to accumulate in fat due to slow clearance and high lipophilicity
How does heroin’s structure differ from that of morphine?
Replace the 2 OH groups on the tertiary nitrogen with acetyl groups
What is the pKa of opiate drugs, and what does this indicate about site of absorption?
8
Small intestine
Which enzyme is responsible for the conversion of codeine to morphine?
CYP2D6
Recall the 2 mechanisms by which a respiratory rhythm is generated and how opiates interact with these
- Central chemoreceptors give tonic drive to resp centre
- Pre-botzinger complex generates rhythm
Both inhibited by opiates
How can opiates result in urticaria?
Bond to receptors on mast cells to stimulate histamine release
What treatment is given in opiate overdose?
Naxolone
How does opiate overdose affect blood pressure?
Hypotensive crisis
Due to excessive histamine release
How does the pKa of opiates affect their bioavailability
Blood pH = 7.4. pKa = 8, therefore only about 20% of drug is unionised (bioavailable)
Compare the enzymes that metabolise fentanyl and methadone
Fentanyl = just CYP450 3A4 Methadone = 6 or 7 different enzymes
