18. Opioids Flashcards
What is an opiate?
Alkaloid derived from the poppy - Papaver somniferum
Opioid = natural and synthetic
What are the 4 most common natural opiates?
- Morphine
- Codeine
- Thebaine
- Papaverine
What part of opiates’ structure makes it an analgesic?
- Tertiary nitrogen
- Permits receptor anchoring
- The side chain attached to the nitrogen determines the efficacy
What happens if you extend the tertiary nitrogen side chain of morphine (so it has 3+ carbons)?
Agonist => antagonist
How is the solubility of heroin and codeine different to morphine?
They are more lipid soluble (theoretically can pass the BBB easily)
Why are the hydroxyl groups at position 3 and 6 significant in morphine?
- Position 3 - required for binding
* Position 6 - oxidising this increases the lipophilicity by 10-fold
Where is codeine and heroin converted into morphine?
- Codeine - must happen outside the brain
* Heroin - can happen in the brain
What is heroin and codeine also known as?
- Heroin - diacetylmorphine
- Codeine - methylmorphine
(they are prodrugs of morphine)
Give 2 examples of synthetic opioids and their relationship with morphine
- Methadone and fentanyl
- Both have tertiary nitrogen and phenolic groups
- Fentanyl is less like morphine
- They are both more lipid soluble - more gets into the brain
How are opioids usually administered therapeutically?
Orally
What is bioavailability of IV administered opioids?
100%
Describe the absorption and metabolism of opioids administered orally?
- Weak bases - pKa > 8, not very unionised in the stomach
- Small intestine has alkaline environment - more unionised and well absorbed
- Heavily metabolised in liver - first pass (impacts bioavailability)
- Blood is pH7.4 - opioids largely ionised (20% remain unionised)
- You want pH=pKa, so at this point absorption is quite good
Compare the lipid solubility of methadone, heroin, codeine, fentanyl and morphine (in order starting with least soluble)
- Morphine
- Codeine
- Heroin
- Methadone
- Fentanyl
How does lipid solubility affect potency?
• More lipid soluble = more potent
• Exception: codeine
- codeine is a bit more soluble than morphine, but less potent
What is the most potent active metabolite of morphine and how do the side effects of the metabolites compare to morphine?
- Morphine-6-glucoronide (10% of active metabolite)
- Morphine seems more likely to cause negative side effects e.g. respiratory depression
- Therefore individuals who don’t metabolise morphine well are more likely to have negative side effects
How does the potency of heroin and codeine compare to morphine on its own?
200 times less potent than morphine at the receptor
Why is heroin more potent than codeine?
- More lipid soluble
- Converted in the brain so has more of an effect there
- Codeine is converted outside the brain - less potent
How does the speed of fentanyl metabolism compare to methadone?
- Fentanyl - fast metabolism (metabolised and cleared equally fast - effect is quickly lost - addictive)
- Methadone - slow metabolism (means it can accumulate in fatty tissues and prolong effect)
Describe the metabolism of codeine in the liver?
- CYP2D6 converts codeine to morphine (5-10% as it’s slow)
* CYP3A4 deactivates codeine => norcodeine (quicker)
What effect does the poor metabolism of codeine?
Causes codeine to have little effect
How can heroin be metabolised outside the liver?
Esterase enzymes in the blood converts heroin => morphine
What are the 3 main types of opioid receptors, where are they located and what are they functionally important for?
Mu (μ) receptors
• cerebellum, caudate nucleus, nucleus accumbens, PAG
• pain and sensation
Delta (δ) receptors
• nucleus accumbens, cerebral cortex, hippocampus, putamen
• motor and cognitive function
Kappa (κ) receptors
• hypothalamus, putamen, caudate
• neuroendocrine role
On which opioid receptors do the different endogenous agonists act?
- Endorphins - μ (or δ)
- Enkephalins - δ
- Dynorphins - κ
What effect do opioids have on cells?
- Depressant - slow cellular activity
- Hyperpolarisation - increase K+ efflux
- Reduce Ca2+ inward current - impacts exocytosis and NT release, impairs nerves
- Decrease adenylate cyclase activity - decreases cellular activity
What positive effects do opioids have?
- Analgesia
- Euphoria
- Depression of cough centres (anti-tussive)
What negative effects do opioids have?
- Depression of respiration (medulla) - easy to OD
- Stimulation of chemoreceptor trigger zone (nausea)
- Pupillary constriction
- GI effects
How do opioids act as an analgesic?
- Decrease pain perception - information relayed to brain
* Increase pain tolerance - brain suppresses signals
Which region in the brain is the integrating centre for the pain tolerance pathway?
PAG (periaqueductal gray region)
Where is information for pain tolerance and perception relayed to?
NRM (nucleus raphe magnus)
What does the NPRG (nucleus reticularis paragigantocellularis) do?
- Auto-feedback element of the brain
* Switches on pain tolerance without any higher centre functioning
What does the thalamus do in the pain pathway?
- Spinothalamic neurones relay pain to the thalamus
* Thalamus directs the information to the cortex
How is the hypothalamus involved in pain?
- Gives information to the rest of the brain about current state of health
- Worse health => higher sensitivity to pain
- This prevents sick people from expending their energy on activities
How is the Locus Coeruleus involved in pain?
- It is a nucleus in the pons
- Symapathetic NS effector
- Stress => activates LC => signal to dampen down pain
- Reason for lack of pain during sports injury
What is the sustantia gelatinosa and why is it important in pain?
- When the brain senses pain it tries to suppresses it
- Certain amount of signal comes down the spinal cord
- SG is a collection of cells in the gray area (dorsal horns) at all levels of the spine
- Processing and modification of the signal takes place here
Which areas of the pain pathway do we want to activate and suppress for analgesic effects?
Activate (these parts suppress pain)
• PAG
• NPRG
• NRM
Suppress (involved in pain transmission) • Thalamus • Cortex • Hypothalamus • Periphery • Dorsal horn
How do opioids act in the pain pathway?
- Act in the dorsal horn
- Prevent information relay from the periphery to the spinothalamic tract (substantia gelatinosa)
- Enhance signals from PAG and NRPG - increase pain tolerance
- Do this by suppressing normal inhibitory signals to pain tolerance (by switching off GABA)
• Can also interfere with pain perception through sensory neurones
How do opioids cause euphoria?
- Enter brain and bind to their receptors
- Depress firing rate of GABA interneurons
- Less inhibition of dopaminergic neurones
- Dopaminergic neurones increase firing rate => increased dopamine secretion => feelings of reward
How does irritation in the lungs cause a cough?
- Mechno/chemoreceptor detection
- C-fibres send the information via the vagus nerve
- Information reaches medulla
- Effector arm stimulated - parasympathetic/motor nerves
- Reaches diaphragm, IC muscles and lung
- Increased contraction => cough
What are the 2 neurotransmitters involved in coughing?
ACh and neurokinin (NK)
Why are 5-HT1A receptors important in coughing?
- Negative feedback receptors for serotonin
- Reduce amount of serotonin
- Serotonin is anti-cough
- So stimulation increases the likeliness to cough
How do opioids act as anti-tussives?
- Decreases firing rate of C-fibres
- Directly depress the cough centre
- Inhibit 5-HT1A feedback receptors => more serotonin to inhibit cough
What are the 2 important parts of respiratory rhythm generation?
- Central chemoreceptors
* Pre-Botzinger complex
What do central chemoreceptors sense in respiratory rhythm generation and where do they relay this information?
- CO2 in blood
- CSF
- Information relayed to medullary control centre
- Provides a constant stimulus to breath
- Tells the brain the level of respiration needed
How do opioids depress respiration?
Inhibits the central chemoreceptors and pre-Botzinger complex
How is the pre-Botzinger complex involved in breathing?
- Provides constant tonic stimulus for breathing
* Mainly inspiration
Where is respiratory depression most commonly seen with reference to opioids?
- Heroin addicts
* Those who wean themselves off then go back to the same dose after losing tolerance
How do opioids cause nausea/vomiting?
- GABA keeps the chemoreceptor trigger zone (CTZ) suppressed
- Opioids switch off this inhibition
- CTZ signals to the medullary vomiting centre (CTZ is located right behind) - nausea
How do opioids cause miosis (constricted pupils)?
- Optic nerve relayed information to the pretectal nucleus
- Signals transmitted to parasympathetic nerve in the Edinger-Westphal nucleus
- GABA suppresses the parasympathetic nerves here - opioids switch inhibition off => miosis
(most other drugs cause pupil dilation as they become unconscious, but opioids cause constriction)
How does the presence of food in the gut cause contraction/relaxation in the enteric nervous system?
• Sensory neurone (connected to the mucosal chemoreceptors and stretch receptors) detect chemical substances or tension
• Information relayed to submucosal and myenteric plexus via interneurons
• Motor neurones release:
- ACh or substance P to contract smooth muscle
- Vasoactive intestinal peptide or nitric oxide to relax smooth muscle
How do opioids affect the GIT?
- Prevent sensory information from relayed into the enteric nervous system
- Also affects motor function => less gut contraction (heavy constipation) and fewer secretions
How do opioids cause urticaria?
- Opioids directly interact with mast cells under the skin
- Causes histamine release
- Involves PKA but not opioid receptors
- Caused mainly by morphine and codeine (OH position 6)
- Not allergic reaction
What causes opioid tolerance?
Tissue level (not liver) • Arrestin - drives receptor internalisation • Arrestin concentration increases => increase internalisation => tolerance
What causes withdrawal symptoms (and dependence) to opioids?
• Psychological
• Physical (flu-like)
- cells try to up-regulate activity while taking opioids (increased adenylate cyclase)
- once opioids are removed, adenylate cyclase is overactive
- muscular shakes, diarrhoea
What happens to the body if you OD on opiates?
- Respiratory depression
- Pin-point pupils
- Hypotension
- Coma
What is the treatment for opiate OD?
- Naloxone (opioid antagonist)
* Has 3 carbons on the tertiary nitrogen side chain
