Opioids

  • Created by: LBCW0502
  • Created on: 06-11-18 11:36
What are the biological activities of morphine?
Analgesia (decrease ability to perceive pain in CNS, interpretation/reaction to pain impulse diminished, reduced anxiety/sedation/euphoria). Narcotic. Cough suppression. Antidiarrheal
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What are the side effects of morphine?
Constipation, respiratory depression, tolerance, dependence
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What are the types of opioid receptors?
Mu (mediate analgesia at supra spinal level. Kappa (analgesia at the spinal level). Delta (analgesia in the periphery). Receptors found in brain and spinal cord
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Describe features of the mechanism of action for opioids (1)
Opioid receptors are G-protein coupled. Leads to a series of events which blocks neural pain transmission by: inhibition of Ca2+ channels to depress NT release, increase K conductance to cause hyperpolarisation of cell to reduce excitability
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Describe features of the mechanism of action for opioids (1)
Inhibit cAMP which inhibits phosphorylation of ion channels, prevents opening of channels
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Outline the process for the mechanism of action for endogenous opioids and morphine
Opioid binds to opioid receptor, Ca2+ channels close, block Ca2+ influx, cAMP levels decrease, K+ channels open, K+ efflux, hyperpolarisation of cell, dampen transmission of pain signals (analgesia)
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Outline the process for the mechanism of action for opioid antagonists e.g. naloxone
Naloxone binds to opioid receptor, opioid cannot bind to receptor, G protein not activated, cAMP levels/phosphorylation increases, no hyperpolarisation of cell/K+ channels not open/no K+ efflux, transmission of pain signal not dampened
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Describe features of endogenous opioid peptides
Endorphins (endogenous morphine peptides). b-endorphin (31 amino acids, Met Enkephalin). dynorphin A (17 amino acids, Leu Enkephalin)
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Where do opioids come from?
Opium (Greek work for juice of poppy). Papper somniferum. More than 20 distinct alkaloids present in opium. Morphine is the most active form (prototype opioid agonist). - Morpheus - Greek God of Dreams
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Outline the structure of morphine
Five rings. Function groups include: benzene, cyclohexane, cyclohexene, piperidine, tertiary amine (charged), quaternary C, 2C spaces between amine and quaternary C. 5 chiral centres (R,R,S,R,S). Only levorotatory (-) isomer is active
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Describe the use of morphine to treat pain
5-10 mg injection. Remains most valuable option for strong opioids for management of severe pain. Nausea/vomiting are frequent adverse effects. Feeling of detachment/euphoria (useful in management of anxiety in palliative care)
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What is the first line of treatment for moderate to severe cancer pain
Cochrane
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Describe features of codeine
Prodrug (metabolised in vivo into morphine). OH in morphine modified to OCH3 in codeine. Used for mild/moderate pain. Side effects (nausea/constipation - unsuitable for long term use). Codeine metabolised in liver to morphine (metabolism variation)
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Describe features of diacetylmorphine
OHs in morphine modified to form COOs. Increased lipophilicity, more rapidly penetrates BBB, converted in vivo into morphine, 2 fold increase in potency compared to morphine
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Describe features of hydrocodone
Modification of morphine (change groups to C=O, O-CH3). more potent than codeine. Semi-synthetic opioid derived from codeine and thebaine. Orally active narcotic analgesic and antitussive
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Describe features of oxycodone
Modification of hydrocodone (add OH group). Hydroxyl group increases potency. Potentially addictive opioid analgesic. Synthesised from thebaine. Effective orally. Post-operative pain. Moderate to severe pain (first line option for cancer)
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Which opioid is 8 fold more potent than morphine?
Oxymorphone
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Describe features of desmorphine
Codeine - a-Iodocodide - desmorphine. Krocodile. Similar effects of heroin synthesised from household chemical. Injection site turns flesh grey and scaly until gangrene skin peals away and the bond is exposed
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Describe the modification of thebaine
Diels alder reaction - react diel with alkene to form cycloalkene. Conversion of thebain to etorophine
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Outline the process for the dealkylation and alkylation of amines
Tertiary amine reacts with acyl chloride (dealkylation). Alkylation can lead to tertiary amine or reacting with acyl chloride leads to formation of amide
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Which synthetic opioid has a 10 fold increase in activity?
Phenylethyl
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What determines whether or not a structure is an agonist or antagonist?
Size of group on nitrogen (N-substituents)
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Describe features of naloxone and naltrexone
Naloxone - allyl group on N, ketone at C6, OH at C14, C6-C7 reduced, pure antagonist. Naltrexone - cyclopropyl group on N, ketone at C6, OH at C14, C6-C7 reduced, pure antagonist
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Describe features of synthetic analogues
4 major chemical classes of synthetic analgesics, simpler structures than morphine. Pharmacophore. Tertiary N with small substituent, quaternary C, phenyl group, 2 C spacer between the quaternary C and tertiary N
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Give examples of synthetic modifications of morphine
Morphinans, benzomorphin, phenyl piperidines, oxycodone, pentazocine, pethidine
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Describe features of buprenorphine (1)
Longer duration of action than morphine, sublingually for 6-8 hr. Less effective than morphine (need higher concentration). High incidence of vomiting (both agonist/antagonist properties). Can precipitate withdrawal symptoms
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Describe features of buprenorphine (2)
High affinity for mu receptor, effects partially reversible by naloxone, fourth line option for cancer related pain
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Describe features of phenylproprylamines
Strong agonist, R>S, long-half life, longer duration of action than morphine, prescribed 1 OD (risk of accumulation), less sedating (for patients who have poor pain control/adverse effects), opioid dependence e.g. methadone used to treat addicts
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Describe features of pentazocine
Benzomorphan, 25% activity of morphine, for mild to moderate pain, oral/injection
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Describe features of tramadol
Weaker opioid than morphine. Step down analgesic from morphine. Minimum sedative effect/abuse potential. Agonist at opioid receptor/also effect on NA pathway. Inhibits uptake of NA. Oral/parenteral forms
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Describe features of pethidine
4-phenylpiperidine derivative of morphine. Weak mu receptor agonist. 20% of morphine activity. Doesn't inhibit cough. Rapid onset of action, high first pass metabolism. Used in obstetrics, administered in small doses to mother
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Does pethidine cause respiratory depression a newborn?
No - opioid metabolism not fully developed but pethidine can be metabolised by MAO
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Describe features of meptazinol
Agonist - antagonist. 10% activity of morphine. Selective agonist mu 1 receptor. Central cholinergic activity
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Describe features of phenylpiperidines
Morphine - weak agonist, antidiarrheal, CNS effects/high doses. Fentanyl - strong agonist, rapid onset, short duration, doesn't cause histamine release on IV injection, dose 0.01-0.04 mg. Sufentanil - strong agonist, rapid onset, short duration
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Which phenylpiperidine is 3000 times more potent than morphine?
3-methylfentanyl
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Describe features of MPPP
Easy to make. 25 x more potent than pethidine. Poor batch control led to ester elimination. Gives PD symptoms. MPTP. Penetrates BBB, induces tremors
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What are the four main mechanisms involved in the metabolism of analgesics?
N-dealkylation of alkyl amines. O-dealkylation of methoxyethers. Hydrolysis of esters. Conjugation of alcohols
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Describe features of neuropeptides (1)
40 peptides. Endorphins and Enkephalins. Opioid receptors found in brain stem, spinal cord, thalamus, mu, kappa, delta
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Describe features of neuropeptides (2)
Involved in emotion/hearing/motor co-ordination, pain processing, taste/vision. Similar activity to opioids/addition/withdrawal effects. Enkephalins antagonised by opioid antagonists (same receptor), inactivated by specific peptidases in brain
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State details of the enkephalin mechanism
Enkephalinergic system exists to modulate pain. Neurons have 'auto-receptor' that can bind enkephalin/exogenous opioids. Opioid binding to auto-receptor decreases enkephalin release - results in tolerance
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Describe features of opioid receptors and binding model
Leu-enkephalin contains structures from morphine and pethidine. Has anionic bind region and lipophilic binding sites (aromatic). Morphine binding to mu opioid receptor which has tyrosine, lysine and aspartic acid on the receptor binding site
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What are the three families of opioid peptides
Endorphin (released when stressed), enkephalin and dynorphin
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Which amino acid is essential for opioid activity?
Tyrosine
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What are the different types of analgesic drugs?
Local anaesthetics (e.g. lidocaine), NSAIDs (e.g. aspirin, ibuprofen, paracetamol), opioids (morphine, codeine), miscellaneous drugs (nitrates/angina, triptans/migraine, carbamazepine/trigeminal neuralgia, TCAs, gabapentin/pregablin/neuropathic pain)
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What are the different types of pain?
Acute pain (responds well to all three types of analgesic). Chronic pain (pain of more than 3-6 months duration - due to chronic nociceptive activation/responds well to opioids, neuropathic pain due to adaptive changes/responds poorly to opioids)
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Outline features of the WHO stepladder for pain control
Mild pain (NSAIDs), persistant pain (codeine/tramadol), moderate-severe pain (morphine, fentanyl)
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State which molecules bind to the opioid receptors
Morphine binds to mu, enkephalin binds to delta and dynorphin binds to kappa - all have the same effect e.g. increase K+ conductance/inhibit cAMP production, inhibit neurotransmitter release
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Which fibres are involved in sharp pain and throbbing pain?
Sharp pain is due to A fibres (myelinated) and throbbing pain is due to C fibres (unmyelinated)
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Outline the organisation of dorsal horn lamina (1)
A beta fibres (mechanoreceptors in lamina 3,4,5). A delta fibres (mechanoreceptor in lamina 2,3, nociceptor in lamina 1,4). C fibres (nociceptor/thermoceptor/mechanoceptor in lamina 1,2). Lamina II is substantia gelatinosa
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Outline the organisation of dorsal horn lamina (2)
Noxious stimuli activate nociceptive primary afferents (C delta/C fibres). Primary afferents activate projection neurons in dorsal horn. Projection neurons travel to brain in spinothalamic tract
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Outline the organisation of dorsal horn lamina (3)
Record firing of dorsal horn neurones, opioids inhibit firing and stop transduction of the spinal to the brain via the spinothalamic tract
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Outline the ascending pathway of pain
Nociceptor detects stimulus, sensory nerve in dorsal root (C fibre), into dorsal horn, up to medulla, to midbrain and then to forebrain in the thalamus (process information)
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Outline the descending pathway of pain
Impulse in midbrain sent to nucleus raphe magnus in medulla and then into spinal cord through motor neurones in the ventral root to produce response
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Describe opioid receptors found in the CNS
High concentrations in the brain, areas involved in pain control have high levels of receptors/opioid peptides. Brain (PAG, NRM, NRPG), dorsal horn of spinal cord (lamina II, substantia gelatinosa)
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Describe features of opioids and pain control (1)
Activation of PAG and NRM by morphine causes increased firing of descending pathway to dorsal horn. Involves serotonergic neruons and depletion of 5HT/antagonists decrease anti-nociceptive effect of morphine
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Describe features of opioids and pain control (2)
Effect in PAG/NRM due to inhibition of release of GABA from local interneurons. Leads to disinhibition of descending serotonergic pathway which decreases transmission of nociceptive information through dorsal horn
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What are the effects of morphine (selective agonist at mu receptors)?
Analgesia, euphoria, respiratory depression (sensitive to partial pressure for CO2), miosis (pin-point pupils), emesis, constipation, opioid induced hyperalgesia, cough suppression, histamine release, hypotension, tolerance, dependence
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Give examples of withdrawal symptoms
Yawning, runny rose, perspiration, tachycardia, tremor, muscle spasm, nausea, vomiting, diarrhoea, abdominal cramps
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What are the routes of administration for opioids?
Oral, IV, IM, IT, epidurally, transdernal, sublingual, nasal
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Give examples of strong opioids which are mu agonists
Diamorphine, hydromorphone, buprenorphine, fentanyl, pethidine, methadone, oxycodone
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Give examples of mixed opioid/uptake inhibitors
Tramadol, tapentadol - inhibit NA/5HT uptake
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Give examples of weak opioids (used for mild pain)
Codeine, dihydrocodeine
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Give examples of antagonists - used to treat opioid overdose
Naloxone, naltrexone (longer duration of action). Used to treat addicts - methadone (mu agonist), buprenorphine (partial mu agonist), naltrexone (mu antagonist), lofexidine (alpha 2 - agonist), suboxone (sublingual film)
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Give an example of a peripherally active antagonist
Alvimopam - paralytic ileus, counter opioid-induced constipation
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Give examples of antagonists for opioid induced constipation
Alvimopam, methylnaltrexone, pruclopride, lubiprostone, 5HT4 agonist, PG1 analog agonist at CIC-2 chloride channels
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Describe features of biased agonism
Aim for morphine to bind to opioid receptor to activate mechanism for analgesia but prevent activation of beta arrestin (causes respiratory depression, constipation, tolerance)
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Card 5

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