Opiods Flashcards
What is an opiate?
An alkaloid derived from the poppy, palaver somniferum
What are the most common opiates?
Morphine Codeine Thebaine Papaverine (All natural)
What do all opiates have in common structurally?
Tertiary nitrogen which is essential for its role as an analgesic
It is important in permitting receptor anchoring- the side chain that the tertiary nitrogen is on is extended to 3+ carbons, you can generate an antagonist
What is heroin?
Synthetic opiod- derivative of morphine
What do the side chains of opioids determine?
How active and effective these drugs are
How does codeine exist?
It exists as a prodrug- it needs to be converted to morphine before it can have an effects
What effect did substituting the OH groups of morphine with acetyl groups to form heroin cause?
It meant that heroin is much more lipid soluble so can have more profound effects on the brain
What is the structure of methadone and fentanyl like?
They aren’t very similar to morphine but are very lipid soluble and very powerful opiod drugs
Opioids are weak bases, how does this affect their pharmacokinetics?
They are ionised in the stomach so poorly absorbed from this site
Unionised in the small intestine- more readily absorbed
First pass metabolism will decrease bioavailability
Blood has a pH of 7.4 so most opioids are ionised in the blood
What percentage of opioids are unionised in the blood?
<20%- this is the component that can access tissues
What do you need for a drug to be heavily unionised?
You need the pH of the environment to be roughly the same as the pKa of the drug
What is the order of lipid solubility from most soluble to least?
- Methadone/Fentanyl
- Heroin
- Morphine
How does lipid solubility link to potency?
More lipid soluble = more potent
How is morphine different from other opioids?
It is metabolised in liver and regularly excreted in the bile
What is the main metabolite of morphine?
Morphine-6-Glucoronide (10% of metabolites)- this is an active metabolite
What happens to morphine-6-glucoronide?
The active metabolite is excreted in the bile into the intestines where it undergoes enterohepatic cycling and returns to the blood to have more of an effect
How are most opioids excreted?
By the kidneys
What is the metabolism of fentanyl like?
Incredibly quickly so it has a fast onset of effects and fast loss of effects- highly addictive
Fentanyl is broken down so quickly because it’s broken down in the blood (by plasma cholinesterase)
What is the metabolism of methadone like?
It is a poor substrate for CYP450 so it is metabolised very slowly and remains in the blood for a very long time
What is methadone commonly used for?
It used to wean people off heroin or morphine as it has a slow metabolism and low addictive potential but reduces craving for opioids as methadone remains in the blood for longer
What percentage of a dose of codeine is activated into morphine?
5-10%
Which two enzymes are involved in metabolism of codeine?
CYP2D6- performs O-dealkylation and activates codeine (slow)
CYP3A4- deactivates codeine (fast)
What is the effect of a common polymorphism in the 2D6 enzyme?
They don’t really have the capacity to activate the codeine so it doesn’t have much effect
What are the specific opiod receptors?
Endorphins
Enkephalins
Dynorphins/Neoendorphins
What are the 4 main parts of the brain that mu receptors are expressed in abundance?
Thalamus
Amygdala
Nucleus accumbent
Periaqueductal grey matter
What type of drug are opiates and what are the three mechanisms by which they have this effect?
Depressants- slow down cellular activity
Three mechanisms:
Hyperpolarisation (increased potassium efflux
Reduce Ca2+ influx (important for neurotransmitter exocytosis)
Reduce adenylate cyclase activity (general reduction in cellular activity)
What are the main effects of opioids?
Analgesics
Euphoria
Depression of cough centre
Depression of respiration- worst and most dangerous
Stimulation of chemoreceptor trigger zone (nausea/vomiting)
Pupillary constriction
GI effects
What are the main methods of analgesia?
Decrease pain perception
Increase pain tolerance
What detects painful stimuli?
Sensory neurones in periphery
What do sensory neurones do once detecting pain?
Conduct the action potential to the dorsal horn of the grey matter in the spinal cord
What happens at the dorsal horn?
The sensory neurone synapses with a neurone of spinothalamic tract
What is the role of the thalamus in detecting pain?
It is the gate keeper which receives the painful information and distributes it to multiple sites
What does the thalamus do once it receives painful information?
It activates the periaqueductal grey matter (PAG)- the central pain coordinating region of the brain
What else converges on the PAG?
Cortical inputs
What does the PAG do once it has received the inputs?
It will activate the nucleus raphe magnus (NRM) which projects down the spinal cord and sends down descending inhibitory neurones to the dorsal horn
What is the role of the NRM?
Start reducing painful sensation- pain tolerance
What is the nucleus reticular paragigantocellularis? (NRPG)
Negative feedback centre for pain perception- independent of the thalamus
As soon as you sense pain it is activated which activates the NRM- you’re trying to automatically suppress painful feelings before even your brain has processed it
What role does the hypothalamus have in pain sensation?
It constantly signals into PAG independent of pain and is constantly telling the PAG about general state of health
What is the locus coeruleus?
The major sympathetic outflow that is affecting pain perception- it is activated during a stress response
Why is the locus coeruleus activated during stress?
At time of stress, you don’t want your fight or flight response to be interfered with by painful stimuli
What part of the spinal cord behaves like a mini brain in terms of pain tolerance?
Substantia Gelatinosa- it processes information coming down from the NRM and then determines the level of inhibition on the sensory neurones
What is the most important target of opioids in terms of analgesic effect?
Mu receptors
What are the main targets of opioids?
Dorsal horn- increase inhibition
PAG- enhance PAG firing
NRPG- activates this
What are opioids very good at switching off and what effect does this have?
Switching off GABA- GABA has an inhibitory effect on many of these pain tolerance centres so knocking out GABA will activate these
How do opioids cause euphoria?
They work via the same mechanism as cannabis in causing euphoria but via a different receptor
Opioids act on mu receptors on GABA interneurones and switches off the GABA activity. This means that the inhibitory input of GABA on dopaminergic neurone in VTA is removed hence there is increased dopamine release at nucleus accumbens leading to euphoria
What is the 5HT1a receptor the negative feedback receptor for?
Serotonin
What does the firing of 5HT1A receptors in DRN lead to/
Suppression of serotonin which leads to activation of cough centre
How do opioids centrally have an anti-tussive effect?
They desensitise this receptor so serotonin levels in the cough centre increase and this has an anti-jussive effect as it inhibits motor neurones that connect the cough centre to the larynx
How do opioids peripherally have an anti-tussive effect?
It occurs via action on sensory neurones that relay to the vagus
The two main neurotransmitters that activate vagus are acetylcholine and neurokinin- an irritant will activate sensory nerves which release neurotransmitters and activate vagus nerve which activates the cough centre
Opioids stop the transmission of information from sensory nerve to vagus
Which aspect of respiration is the most opiod sensitive?
Rhythm generation
What generates respiratory rhythm?
The pre-Botzinger complex, a small area in ventrolateral medulla
When is the pre-Botzinger complex active?
During inspiration
What do opiod receptors inhibit to do with respiration?
Prebotzinger complex and central chemoreceptors which provide a tonic drive to the respiratory motor output by sensing changes in pH
How do opioids stimulate nausea/vomiting?
Low doses of opioids activate mu receptors in the chemoreceptor trigger zone stimulating vomiting as it activates the medullary vomiting centre
Opioids switch off GABA which is normally suppressing the chemoreceptor trigger zone
How can you tell if a patient that has overdoses and is comatose has overdosed on opioids?
Majority of unconscious patients will have dilated pupils- because normally the pupils are held partially constricted but if they are comatose, their brain function is depressed and their pupils will dilate however opioids cause constriction of the pupil
How do opioids cause miosis?
Oculomotor nerve in the pre-ganglionic parasympathetic nerve to the eye which causes pupil construction and originates in the Edinger-Westphal nucleus and there are lots of opiod receptors on GABA neurones in Edinger-Westphal nucleus and the removal of the inhibitory input of GABA stimulates firing of oculomotor nerve leading to miosis
What do kappa and mu receptors regulate in GI tract?
Cholinergic transmission in the myenteric plexus
What are opioids good for preventing in GI tract?
Diarrhoea because they depress the intrinsic nervous system of the GI tranct
What are the main effects of opioids on the GI tract?
Decrease in gastric emptying
Decreased GI motility
Increase in water absorption
Result= constipation
How do opioids cause what looks like an allergic response?
They bind to mast cells in the skin and promote histamine release, this is not an allergic response but the skin mast cells appear to be particularly sensitive to this opiod mediated degranulation- hydroxyl group 6 seems to be vital to this
What symptoms are due to histamine release?
Itching (pruritus)
Hives (urticaria)
Hypotension
What happens with prolonged treatment with opioids?
Tolerance develops due to receptor internalisation- receptors are removed from tissue so the tissue is less responsive so you need more of the drug to have the same effect
What proteins are important in receptor internalisation and how?
Arrestins- long term use of opioids will lead to up regulation of arresting in tissues which increases the ability of the tissue to internalise receptors
What is opioid withdrawal associated with?
Psychological craving
Physical withdrawal
Resembles flu
How does opioid withdrawal lead to these effects?
Depression of adenine cyclase function so long term use of opioids will lead to compensatory up regulation of adenylate cyclase in an attempt to regain normal function so stopping will result in increased adenylate cycle activity in tissues leading to shakes, sickness and headaches
What are the features of opioid overdose?
Coma
Respiratory depression
Pinpoint pupils
Hypotension
How is opioid overdose treated?
Naloxone
What is naloxone?
Opioid receptor antagonist- has a tertiary nitrogen which allows it to bind to opioid receptors but side chain has been extended meaning it is an antagonist not an agonist
