Opioids Flashcards
Give an overview on opioids
– Opioid actions include analgesia, respiratory depression, euphoria and sedation…
• Led to discovery of receptor subtypes.
– Morphine analogues…
• Agonists - morphine, diamorphine (heroin), codeine.
• Antagonists – naloxone. Also used in the treatment of addiction.
– Synthetic derivatives: pethidine, fentanyl, methadone.
– Opioid applies to any drug (natural or synthetic) that mimics endogenous opioid peptides by causing prolonged activation of opioid (usually m receptors). Opiate refers to synthetic morphine-like drugs without a peptide structure.
what are pethidine and fentanyl?
phenylpiperidine derivatives
what are endogenous opioids?
Endogenous opioids are derived from large precursor molecules – encoded for by different genes: β-endorphin, enkephalins, dynorphins.
Describe opioid receptors
Opioid receptors are G-protein coupled linked to opening K+ channels which cause hyperpolarization and closing Ca2+ channels inhibiting transmitter release.
Receptors were postulated to mediate the dysphoric (anxiety, hallucinations, bad dreams) produced by some opiates but they are not true opioid receptors as not blocked by naloxone and acted on by other psychotomimetic drugs.
How do opioids produce their effect?
Most of the clinically relevant opioid agonists bind to the mu-opioid (MOP) receptors, within the central and peripheral nervous system. This subsequently induces cellular hyperpolarisation and prompts analgesia, by blocking pain signals travelling to the brain
Agonists: Bind to the receptor and stimulate physiological activity.
Partial agonists: Bind to the receptor but do not produce maximum stimulation.
Antagonists: Have no intrinsic pharmacological effect, but bind to the receptor and can block the action of an agonist.
name the 4 opioid receptor types
Three classical receptors mu, delta and kappa and a forth.
It not only shared homology but was also a classical Gi/Go coupled 7 transmembrane spanning receptor and it turned out to have an endogenous ligand that shared sequence homology with classical endogenous opioid peptide ligands that had already been identified as acting at the mu, delta and kappa opioid receptors - MOP, DOP, KOP and NOP.
The four receptors have four families of endogenous ligands that act at them. Describe them
POMC that gives rise to b-endorphin, Proenkephalin producing at least four distinct enkephalins, Prodynorphin producing two dynorphins and two neo-endorphins and pronociceptin that produces nociceptin and two other biologically active compounds, one nocistatin which is an antagonist at the NOP receptor.
where are opioid receptors found in the brain?
There is widespread expression in many brain regions, including the rostral to caudal cortex, motor regions such as the caudate, limbic structures such as the amygdala, stria terminalis, reward areas such as the nucleus accumbens and of course pain processing structures such as the thalamus and the colliculi.
name the pharmacological effects of opioids
Analgesic euphoria respiratory depression pupil constriction cough reflex GI tract nausea and vomiting (Caused by stimulation of chemoreceptor trigger zone on d (CTZ) and vomiting centre (m) – often need to give an anti-emetic alongside opioid analgesics)
Morphine can also cause histamine release from mast cells with vasodilation and itching (often needing an antihistamine to be prescribed).
describe how opioids mediate analgesic effects
- Opioids effective in acute and chronic pain although of limited use in neuropathic pain (neurological disease of sensory pathways).
- They can block pain at 3 different levels; supraspinal, spinal and peripheral.
- Supraspinal effect probably reflects an effect on the limbic system – reduces the perception of pain (this area would also be responsible for euphoria).
- Morphine antinociceptive and reduces affective component of pain. Action at limbic system (which part of brain?)
how can opioids cause respiratory depression?
- Mediated by m receptors.
- Decrease in sensitivity of respiratory centre to PCO2 levels.
- Commonest cause of death in acute opiate poisoning.
what is a diagnostic feature in opiate poisoning?
pupil constriction which gives rise to “pinpoint” pupils.
Other causes of respiratory depression & coma cause pupil dilatation.
what do opioids do to the GI tract?
- Reduced motility therefore constipation and reduced absorption of other drugs.
- Contraction of gall bladder and constriction of biliary sphincter – can increase pain in patients with gall stones.
describe tolerance
– Higher dose needed to exert same effect
– Tolerance rapidly develops to most pharmacological effects. However, there is less tolerance to GI effects.
Tolerance and dependence are problems in addicts but not in clinical situation. In terminally ill patients increased dose is usually required because of increasing pain and not tolerance.
what happens when morphine is abruptly withdrawn
Due to physical dependance, abrupt withdrawal of morphine after chronic ingestion causes increased irritability, loss of weight, body shakes, writhing, jumping & aggression.
– Gradual withdrawal less intense reaction.
– Physical dependence rarely progresses to addiction (psychological dependence).
describe the pharmacokinetic properties of morphine
– Morphine slowly and erratically absorbed.
– Slow release preparations to action.
– Patient controlled, pumps to allow infusion ‘on demand’ - upper dose set.
describe the mechanism of action of opioids
Opioid receptors m, d, k cause inhibition…
- K+ channel opening, hyperpolarization.
- ¯ opening of voltage-gated Ca2+ channels.
- Reduce neuronal excitability (K+) and reduce neurotransmitter release (Ca2+).
- Inhibition of adenylyl cyclase, decrease cAMP, PKA.
Acts both postsynaptically and presynaptically to block pain signals from going to the brain by reducing glutamate as well as hyperpolarising neurones to block the signal.
give an overview on diamorphine (MOP)- STRONG
- Used as analgesic in UK
- Tissue injury, tumour growth
- More lipid soluble than morphine and has more rapid onset when given IV.
- Small epidural doses of diamorphine are being used to control severe pain.
give an overview of pethidine (MOP)- STRONG
- Favoured for analgesia during labour as no ¯ in uterine contraction.
- Rapid onset of action but short duration of action.
- Pethidine slowly eliminated in the neonate, naloxone may be needed to reverse respiratory depression.
- Metabolized by liver – at high doses a toxic metabolite is formed (norpethidine) which can cause convulsions.
- Pethidine interacts with MAOIs – delirium, convulsions & respiratory depression.
describe fentanyl (MOP)-STRONG
- More rapid onset and shorter duration than morphine.
- Can be given transdermally for chronic pain.
- Main uses: anaesthesia, patient-controlled infusion, severe pain.
describe buprenorphine- STRONG
- Partial agonist at m receptors.
- Slow onset of action but greater duration of action than morphine – may cause prolonged vomiting.
- Given sublingually.
- Difficult to antagonise effects with naloxone as dissociates very slowly from receptors.
describe codeine- WEAK
- Readily absorbed, only 20% potency of morphine.
- Used as oral analgesic for mild pain.
- No euphoria, constipation.
- Low affinity for opioid receptors but about 10% of the drug is demethylated to morphine which is responsible for analgesic effect.
describe dextropropoxyphene- WEAK
• Half as potent as codeine often used in conjunction with paracetamol and aspirin although little evidence that combination is better than NSAID alone.
describe dihydrocodeine- WEAK
Useful in 10% of population who are resistant to codeine – lack demethylating enzyme converting codeine to morphine.
