Pharmacology of Opioids Flashcards
what are opioids?
Any substance (natural or synthetic) that mediate an analgesic effect through opioid receptors that can be blocked by naloxone
- natural
- semi synthetic
- synthetic
what are natural opioids?
isolated
0 Endogenous
0 Morphine, codeine (Papaver somniferum)
what are semi-synthetic opioids/
modelled on the structure of opioids
0 Derivatives of morphine
0 Diamorphine, dihydrocodeine, buprenorphine, naloxone
what are synthetic opioids?
separate classes of chemical structures name of series comes from that chemical structure 0 Phenylpiperidine series 0 Pethidine, fentanyl, alfentanyl, remifentanyl 0 Diphenylpropylamine series 0 Methodone, dextropropoxyphene 0 Benzomorphan series 0 Pentazocine 0 Thebaine derivatives 0 Buprenorphine
what are the clinical effects of opioids?
Help control pain and reduce pain.
what other effects om the body do opioids have?
But as opioids have effects on other systems, they have effects on GI, endocrine, autonomic and cognition. We cannot easily get away from the two. They come as one.
Different opioids will have different effect on different pathways.
what are endogenous opioids?
• Enkephalins Met-enkephalin Leu-enkaphalin • Endorphins a-neoendorphin b-neoendorphin g-neoendorphin • Dynorphins Dynorphin A Dynorphin B • Endomorphins Endomorphin 1 Endomorphin 2
what are the different opioids receptors?
MOP: m1; m2; m3
DOP: d1; d2
KOP: k1a; k1b; k2a; k2b; k3
which opioids bind to MOP?
B-endorphins
Endomorphin 1
Endomorphin 2
which opioids bind to KOP?
Dynorphin A
Dynorphin B
which opioids bind to DOP?
Met-enkephalin
Leu-enkephalin
which opioids bind to KOP?
nociceptin
what is the opioid receptor mechanism?
- G coupled receptors have 7 transmembrane structure. G protein is within the cytoplasm which associates with the pre and post synaptic membrane
- this inhibits adenlyate cylase which decreases production of cAMP and neurotransmitter release
- this activates the voltage-gated inward K+ channels
- hyperpolarisation of the cell (no more excitation)
- decreases the responsiveness of the stimuli
- reducing the neurotransmitter release
where are the opioid receptor locations?
- vagal centres
- chemoreceptors of area postrema
- antinociceptive system
- smooth muscle
- bladder
what is pain?
- naturla defence to response of a stimuli
- higher centre of processing signals which allow the body to minimise exposure to the damage of the stimuli
- psychological factors will influence the extent to which an individual will feel suffering and distress
what is nocicpetion?
- The sensory processing associated with firing of small diameter nociceptive afferents
- Activated by different stimuli
- Chemical
- Mechanical
- Thermal – could be cold or hot - C-fibres – unmyelinated; dull, diffuse burning pain
- Ad fibres – myelinated; sharp localised pain
what are nociceptive fibres?
0 The sensory processing associated with firing of small diameter nociceptive afferents
0 Activated by different stimuli
0 Chemical
0 Mechanical
0 Thermal – could be cold or hot
0 C-fibres – unmyelinated; dull, diffuse burning pain
0 Ad fibres – myelinated; sharp localised pain
what are nociceptors?
Nociceptors are out in the periphery, present In the skin, organs, muscles, EVERYWHERE. Why we feel pain when we damage a part of our body – nerve signal sent to the brain.
Peripherally, we can get lots of different stimulus that will cause pain.
what causes stimulation of nociceptors?
- Cancer cells, tissue injury, osteolysis, inflammatory cells will cause release of noxius factors which act on receptors on the free nerve endings on the nociceptors to then trigger the action potential which will travel to the cell body in the dorsal root and dorsal ganglion and then go up to the doral horn and transmitted up to the brain
- Can also get an exacerbation of the peripheral signal by release of certain neurotransmitters which can cause release of more inflammation which can then also trigger chemical stimuli
- Prostaglandins don’t tend to cause stimulus on their own, they tenf to bind to a nociceptor and sensitise it and make it more susceptible to detecting changes of other substances
what is the ascending pain pathway?
0 Nociceptor is stimulated
0 Action potential travels along axon to cell body in dorsal ganglion (first order afferent)
0 Action potential potentiated along to dorsal horn
0 Signal transferred to next nerve: crosses over to other side of spinal cord (second order afferent)
0 Action potential travels to thalamus
0 Signal transferred to next nerve (third order afferent) which terminates in somatosensory cortex
what happens when a signal is detected?
Once we get the signal in the periphery from the nociceptor, it travels up to the dorsal root ganglion which lies just beside the dorsal horn in the spinal chord. Then get the signal sending the signal up through thr brain stem and up to cortex – where it decides how to interpret brain signal. Pain back out with motor nerves.
Ascending pathway – signal from periphery in to brain
what is the descending pathway?
- Somatosensory cortex connects with brain regions which co-ordinate the response
- The amygdala, anterior cingulate cortex, insular cortex and hypothalamus send projections to the periaqueductal grey (integrates response)
- PAG sends signal to rostroventral medulla
- RVM sends signal to dorsal horn, where nerve interacts with the ascending pathway
- When it travels to other side of dorsal horn: e.g. if you have pain in your left finger, it will go up to spinal chord and signal will be sent up the right hand side of your body.
- Dorsal horn up to other regions of brain, there are second order afferents
what are the pain transmitters?
0 Glutamate; substance P; CGRP (Calcitonin gene-related peptide); nitric oxide
what are analgesic transmitters?
Endogenous opioids; 5HT; noradrenaline; endocannibinoids
glycine; GABA
what is the transmitter process of the ascending pathway?
periphery to spinal chord. Glutamate, SP and CGRP released from a nerve ending and have receptors on the next nerve. When they bind to their receptors, they will cause signal transferred the next set of nerves up the brain and the cortex. When they activate this neurone, we also get a release of nitrous oxide. The NOS acts as a local transmitter and acts on the presynaptic nerve to further increase the release of glutamate, SP and CGRP.
what are the transmitters in the descending pathway?
descending pathway neurones that will come down from the brain to decrease the activity of the ascending pathway. Can have either presynaptic (first order afferent) or postsynaptic (dampen activity of the NEXT nerve), and some can dampen BOTH
where are the locations of the opioid receptors in pain pathways?
Dorsal root: spinal chord ‘
Dorsal ganglion lies alongside the spinal chord.
Free fibres in periphery
Cell body in spine
Different parts of the brain have different amounts of opioid receptors
Spinal effect: opioid receptors present within the dorsal horn
what is the role of MOPreceptors in pain?
0 MOP involved in motor and sensory processing
0 MOP also involved in integration and perception of pain
0 Located presynaptically on primary afferent neurones in the dorsal horn
0 Inhibit glutamate release and therefore transmission of nociceptive stimuli
MOP – associated with reception and understanding of pain, primarily located pre-synaptically on neurones in the dorsal horn – coming INTO horn from ganglion.
Inhibit glutamate release (main transmitter) – means the next neurone is not activated and you don’t get the signal sent upwards (stop ascedinng pathway so you don’t feel pain – analgesia)
what is the role of PAG receptors in pain?
MOP also in high concentrations in PAG.
In PAG: usually gaba as an inhibitory neurone, prevents the ascending pathway from being active. Don’t need it to be active if we have no stimuli coming up. Gaba stops release of 5HT (serotonin) and NA. when opiods act, they prevent gaba from being released, so the ascending pathway can work. Then descending pathway allows 5HT and NA to be released onto the ascending pathway and stop the ascending pathway from transmitting signals.
what is the role of GABA in pain?
0 Prevent GABA neurones inhibiting descending control pathway
0 GABA tonically inhibits 5HT and NA nerves that project from RVM to dorsal horn
Gaba acts as endogenous break on the descending pathway and stops it working when we don’t need it to be working. Opiods take the break off, to allow it to work
what is the role of DOP receptors in pain?
0 DOP receptors are located presynaptically on primary afferent neurones in the dorsal horn and secondary afferent neurones in the brain
what are opioids analgesics?
0 Full agonists
0 MOP receptors (weak KOP receptors)
0 Morphine, diamorphine, fentanyl, pethidine, dihydrocodeine, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, oxycodone, oxymorphone
0 Mixed agonist-antagonist
0 Pentazocine weak agonist KOP (k receptor); weak antagonist MOP (m receptor)
0 Mixed partial agonist-antagonist
0 Buprenorphine partial agonist MOP (m receptor); weak antagonist KOP (k receptor
what are the analgesic effects?
0 Most effective against chronic visceral pain
0 No anti-inflammatory effect
0 Tolerance and dependence can occur
0 Partial agonists or mixed agonist-antagonist at MOP (m) receptors can precipitate withdrawal
0 Short acting opioids fentanyl and remifentanil are used as analgesics during anaesthesia
what are the traditioanl classifications of opioids?
0 Strong 0 Morphine, pethidine, fentanyl, alfentanil, remifentanil 0 Intermediate 0 Buprenorphine, pentazocine, 0 Weak 0 Codeine
what is the pharmacokinetics of opiods
- weak bases
- in acid they would be highlu ionised so poorly absorbed
- extensive first pass metabolism
- high lipid solubility
- extensively disrupted
- small i/v dose is short acting
- larger dose is more in plasma threshold
what is the metabolism of opioids?
0 Metabolism occurs in the liver
0 Main mechanism is conjugation with glucuronide
0 Neonates lack glucuronide
0 Pethidine not conjugated with glucuronide
0 Therefore, preferred in labour
0 Entero-hepatic recirculation can occur
0 Glucuronides metabolised by gut flora back to parent opioid
what are the active metabolites of opioids?
morphine .> morphine
diamorphine > 6-methylmorphine> morphine
codeine > codeine-6-glucuronide
what is tolerance?
decrease effect despite maintaining a given conc of a drug
what is dependence?
exists when the sudden withdrawal of an opioids after repeated use over a prolonged ttime causes physical and psychological signs
what are side effects of MOPs?
analgesia depression euphoria physical dependence respiratory depression sedation
what are the side effects od Dops/
analgesia
inhibition of dopamine release
modulation of MOP receptors
what are the side effetcs of KOP
analgesia
diuresis
dysphoria
what are the side effects of NOP?
analegsia
sedation
what causes nausea and vomiting?
0 Opioids stimulate chemoreceptor trigger zone
0 Worse in ambulatory patients
0 For equi-analgesia codeine > morphine for vomiting
0 Blocked by dopamine antagonists
0 Similarity in structure for morphine and apomorphine
what causes euphoria and dysphoria?
0 Euphoria, elevated feeling of well-being
0 MOP receptors
0 Contributes to analgesic effect
0 Alters perception of pain
0 Dysphoria, feeling of restlessness and agitation
0 KOP receptor
what causes convulsions?
0 High doses excite hippocampal pyramidal neurones
0 Inhibition of GABA release
0 Blocked by opioid antagonists
0 Pethidine is metabolised to norpethidine
0 Norpethidine is proconvulsant
0 Blocked by anti-convulsant not opioid antagonist
what causes respiratoyr effects?
0 Action at medullary respiratory centre
0 MOP receptors (m2)
0 m1-receptor selective less depression (meptazinol)
0 Decreases response to increased pCO2
0 Decreases respiratory rate
0 Decreases FEV1
0 Usually equal analgesia and respiratory depression
what causes gastrointestinal effects?
0 Increased tone in propulsive muscle
0 Decreased contractions in propulsive muscle
0 Contracts GIT sphincters
0 Increase pain in biliary colic (sphincter of Oddi)
0 Leads to decreased water movement into lumen
0 Likely to result in constipation
0 Act on MOP, DOP and KOP receptors on myenteric plexus
0 Reduced ACh release from nerves
what are agonists that are used to treat diarrhoea?
0 Kaolin and morphine 0 Has abuse potential 0 Morphine in very small dose 0 Loperamide 0 Not absorbed, reduced abuse risk 0 Diphenoxylate 0 Contains atropine in ratio 1:100
what is the treatment of opioid induced diarrhoea?
0 Methylnaltrexone
0 Opioid antagonist
0 Poor penetration of CNS
0 Does not affect central analgesic action
what are the endocrine effects?
0 Opioids lead to suppression of hypothalamic-pituitary-adrenal axis
0 Leads to decline in plasma cortisol
0 Opioids also cause
0 An increase in prolactin release
0 A decrease in luteinising hormone release
0 Testosterone and oestrogen deficiencies
what are the occular effects?
0 Mediated via MOP opioid receptors and KOP opioid receptors on the Edinger-Westphal nucleus of occulomotor nerve (3rd cranial nerve)
0 Increases parasympathetic outflow to iris sphincter
0 miosis
0 Increases parasympathetic outflow to ciliary body
0 accommodation for near vision
0 Pinpoint pupils (+ coma, slow respiration) are signs of overdose
what is the suppression of cough reflex?
0 Suppress activity of the cough centre in medulla
0 MOP and DOP receptors
0 Increase threshold for stimulation
0 Anti-tussive action due to large substituent at position 3 of morphine molecule
0 Codeine, pholcodine
0 (Dextromethorphan)
what is the histamine release and itchin?
0 Basic nature of morphine greater than histamine
0 Displaces histamine from histamine-heparin complex in mast cells
0 Causes urticaria, itching, bronchospasm, hypotension
0 More pronounced on face, nose, torso
what are the other side effects of opioids?
0 Sedation 0 Interfere with sleep cycle 0 Relief of pain allows sleep? 0 Cardiovascular effects (high doses) 0 Bradycardia and hypotension 0 Immunity 0 Immune response decreased with long term use 0 Greater risk of infection
