Pharm 19 - Opiates/Opioids Flashcards
What is an opiate?
Alkaloid derived from Opiate poppy (Papaver somniferum)
What are the 4 most common opiates
Morphine
Codeine
Thebaine
Papaverine
Describe the structure of opiates
- Tertiary N present - this is what gives opiates an analgesic effect
- Hydroxyl groups on 3’ and 6’ positions - they help secure the molecule at the receptor
(OH group on 3’ is required for binding - hence
What happens if the side chain on the tertiary N has more than a 3 C side chain?
It becomes an antagonist
Heroin and codeine are what of morphine
Derivates/prodrugs
Heroin is much more soluble than morphine. Why?
Because the 3’ and 6’ OH group is replaced by acetyl groups
Fentanyl is a very potent opioid compared to morphine. One reason for this?
Morphine = quaternary carbon
Fentanyl = tertiary carbon
Methadone conforms to the morphine rule in what sense?
It has a tertiary N, quaternary C, Phenyl group
Opioids are weak bases. Where will they be most readily absorbed?
In the SI - as they are mainly unionised here.
In stomach, they are ionised so less absorption
What process decreases the bioavailability of opioids?
First pass metabolism
Blood has a pH of 7.4. Opioids have a pKa of >8. Therefore what state are they in the blood
Ionised
<20% of opioids are unionised in blood - it is these opioids that can access tissues
pKa and pH must be roughly the same in order for the drug to be…?
Heavily unionised
Rank the lipid solubility of the opioids
- Fentanyl
- Methadone
- Heroin
- Morphine
(more lipid soluble = more potent)
Morphine is metabolised in the liver and excreted in the …?
Bile - undergoes enterohepatic cycling - returns to blood to have more of an effect
What are the 2 main active metabolites of morphine?
- Morphine-3-Glucuronide (M3G)
2. Morphine-6-Glucuronide (M6G)
Most opioids aside from morphine are excreted by the…?
Kidneys
Fentanyl is very addictive because?
It has a very fast clearance (because it is broken down in the blood by plasma cholinesterase’s)
Why is methadone used to wean people off heroin?
It has a slow clearance - low addictive potential as it remains in blood for longer
Why is methadone metabolised very slowly?
It is a poor substrate for CYP450
Which 2 enzymes metabolise the majority of opioids in the liver.
In the case of codeine, what do these 2 enzymes do
- CYP2D6 -activates codeine into morphine (slow process)
- CYP3A4 - deactivates codeine into inactive metabolites (fast process)
Consequently, only 10% of codeine is converted into morphine - this is what gives codeine its analgesic effect
A polymorphism in the CYP2D6 means what for people who take codeine?
Codeine cant be activated - doesn’t have much effect
Name 3 types of endogenous opioid peptides (they act on opioid receptors)
- Endorphins
- Enkephalins
- Dynorphins / neoendorphins
Which type of opioid receptor do endorphins act on?
Mu receptors (or delta)
Pain/sensorimotor parts of the brain
Which type of receptor do enkephalins act on?
Delta
Motor/cognitive function parts of the brain
Which type of receptor do dynorphins act on?
Kappa
Neuroendocrine part of the brain
What are the 3 means through which opioids have a depressive effect?
- Hyperpolarisation - increased K efflux
- Reduce Ca influx - important for Neurotransmitter exocytosis
- Reduce adenylate cyclase activity - general reduction in cellular activity
What are the 7 main effects of opioids?
- Analgesic
- Euphoria
- Anti-tussive (depression of cough centre)
- Respiratory depression - most dangerous side effect
- Pupillary constriction
- Nausea/vomiting
- GI effects
Generally speaking, how do opioids have their analgesic effects?
Increase pain tolerance
Decrease pain perception
Where are the targets of opioids in terms of analgesia
- Dorsal horn - increases inhibition of sensory neurones
- PAG - enhances PAG firing
- NRPG - activates this
Opioids work by switching off GABA
How do opioids cause euphoria
- Binds to Mu receptors on GABA interneurones - inhibits GABA
- Less inhibitory GABA input on dopaminergic neurones of the VTA
- Increased dopamine release at the nucleus accumbens
What are the 2 means by which opioids exert an antitussive effect?
- Inhibits motor neurones linking the cough centre to the larynx. This Inhibition of 5HT1A receptor increases serotonin levels in the cough centre, decreasing cough reflex.
- Preventing transmission of information from sensory nerves to vagus
Where are 5HT1A receptors found?
Dorsal raphe nucleus
How do opioids cause nausea and vomiting
- Activate mu receptors in chemoreceptor trigger zone (CTZ)
- Activates medullary vomiting centre
- Stimulants from the stomach and intestines send signals to chemoreceptor trigger zone and medullary vomiting centre
- Opioids switch off GABA receptors which inhibit CTZ
Opioids cause pupil constriction. Why?
- Oculomotor nerve is preganglionic PNS nerve to the eye - causes pupil constriction (nerve originates from Edinger-Westphal nucleus)
- Opioid receptors present on GABA receptors on Edinger-Westphal nucleus
- Less GABA inhibition of oculomotor nerve
What is the pre-Botzinger complex and what does it do
Small area in the ventrolateral medulla - generates respiratory rhythm
How can opioids cause respiratory depression
- Inhibits pre-botzinger complex (which is active in inspiration)
- Inhibits central chemoreceptors (chemoreceptors which provide tonic drive to respiratory motor output - sense changes in pH)
Ultimately opioids depress firing rate of central chemoreceptors - interfering with ability of brain to control respiration
What are the main effects that opioids have on the GI tract
- Decreases gastric emptying
- Decreases gastric motility
- Less water absorption
ALL CAUSE CONSTIPTAION
Which opioid receptor types are found on myenteric neurones?
Kappa and Mu
Why are opioids good for preventing diarrhoea?
Depress intrinsic nervous system of GIT
Symptoms of opioid use include itching, hives, hypotension, though opioids do not cause an allergic response. Whats going on?
- Opioids bind to mast cells in skin - promote histamine release
- Hydroxyl group at position 6 vital in this - only if this present can histamine release occur
How does tolerance to opioids occur?
Receptor internalisation due to arrestin upregulation (if long term use)
Opioids have a powerful physical withdrawal. How?
Body compensates for decreased adenylate cyclase function (when opioids were used) by upregulating adenylate cyclase function ; leading to shakes, sickness, etc
- withdrawal symptoms resemble flu
What are features of opioid OD
- Coma
- Respiratory depression
- Pinpoint pupils
- Hypotension
What is the treatment for opioid OD and why
Naloxone - opioid receptor antagonist (it has a tertiary N with extended side chain)
