Opiates/Opioids Flashcards
Give examples of opiates
Morphine
Codeine
Thebaine
Papaverine
Describe the hydroxyl structure of morphine
2 Altered hydroxyl groups
Hydroxyl group at position 3 = binding site
Hydroxyl group at position 6 = oxidise this OH and lipophilicity increases 10 fold
Describe the nitrogen structure of morphine
Tertiary nitrogen
Permits receptor anchoring for the analgesic effect
Affinity is dependent on the tertiary nitrogen
What do changes to the methyl group on nitrogen in morphine cause
Extending the side chain to 3+ carbons -> antagonists
Which structural elements are necessary for activity of morphine accord to the morphine rule
Aromatic Ring
Basic (tertiary) nitrogen
Quaternary carbon centre
Phenyl group
Describe the pharmacokinetics of opioids (admin and absorption in the gut)
IV or oral
Opioids are weak bases and thus are likely to be ionised in the acidic stomach and poorly absorbed
Unionised in the SI - more readily absorbed
First pass metabolism decreases the bioavailability
Describe the ionisation of opioids in the blood
Blood pH = 7.4.
Therefore most opioids will be largely ionised in the blood
Usually <20% unionised
This is the component that can access tissues.
Describe the lipid solubility of opioids and its general rule
Methadone/Fentanyl»_space; Heroin > Morphine
More lipid soluble, more potent
Describe the metabolism of opioids
Morphine – Morphine-6- glucuronide (10% - active metabolite)
Fentanyl - fast metabolism
Methadone - slow metabolism
How do opioids work
Action via specific opioid receptors
Give examples of endogenous opioid peptides
Endorphins
Enkephalins
Dynorphins/neoendorphins
Which receptors do endorphins bind to and what is the result of this
Mu or Delta
Pain/sensorimotor
Which receptors do enkephalins bind to and what is the result of this
Delta
Motor/cognitive function
Which receptors do dynorphins bind to and what is the result of this
Kappa
Neuroendocrine
Describe the cellular mechanism of action of opiate receptors
Depressant
Hyperpolarisation (increase in K+)
Decrease in Ca2+ inward current
Decrease in adenylate cycles activity
What are the effects of opioids
Analgesia
Euphoria
Depression of cough centre (anti-tussive)
Depression of respiration (medulla)
Stimulation of chemoreceptor trigger zone (nausea/vomiting)
Pupillary Constriction
G.I. Effects
What are the 2 main things that analgesia causes
Decrease in pain perception
Increase in pain tolerance
Describe the pain perception pathway and its receptors
- Peripheral tissue
- Dorsal horn (mu or kappa receptors) -> spinothalamic tract
- Thalamus (mu)
- Cortex (mu or delta)
Describe the pain tolerance pathway and its receptors
- +ve effect on PAG from cortex and thalamus (mu or kappa)
- +ve effect on NRM from PAG (delta)
- +ve effect on NRPG (mu, delta) from the post ganglionic neurone
- +ve effect on NRM (delta) form NRPG
- -ve effect on dorsal horn from NRM
Describe the role of the hypothalamus and LC on the pain pathway
Hypothalamus (kappa) - +/- effect on PAG
LC - Sympathetic arm of the brain. Not part of the pain pathway. An activated sympathetic nervous system will suppress painful stimuli
substantia gelatinosa?
-
Where are the sites of opioid action
Dorsal horn
PAG
NRPG
Peripheral tissue
Explain how opioids induce euphoria
- Opiates bind to mu receptors on GABAminergic neurones
- Reduced GABA release
- VTA
- NAcc
- Dopamine release
Describe the neural pathway involved in the cough reflex
- Stimulation of mechano/chemoreceptors
- Afferent impulses to cough centre in medulla
- Efferent impulses via parasympathetic and motor nerves to the diaphragm, intercostal muscles and lung
- Increased contraction of diaphragmatic, abdominal and intercostal muscles
- Noisy expiration / cough
