Transcript Opioider

Centrally acting analgesics
Opioids
Biomedicine spring 08
Year 2 no 2
Frågor till [email protected]
Pain medication
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Paracetamol
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NSAIDs
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Opioids
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Steroids, radiation, TENS, acupuncture
Physiology
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Afferent, peripheral nerves C and Ad
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C-fibres 0,5-1,5 mm, <1 m/s,
unmyelinated
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Ad-fibrer
1-5 mm, 5-35 m/s, myelinated
(larger Ab touch, vibration, proprioception)
Pain pathways
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Tissue damage releases bradykinin, serotonin,
histamin, lactate, ATP, ADP, potassium (among
others)
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Glutamate (excitatory) transmittor in dorsal horn
synapse
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GABA (inhibitory) transmittor interneuron
Pain, pathways
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Nociceptive neurons in dorsal root ganglion
Relays via tractus spinothalamicus,
spinomesencephalicus and spinoreticularis
Reaches thalamus and pons
Connects to cortex
Inhibitory neurons
Inhibitory mechanoreceptors
Pain, pathways
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Brain - upwards probably glutamat main
transmittor
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Downwards neurons GABA, ACh,
monoamines (serotonin, NA, DA).
Endogenous opioids
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Endorphin, enkephalin, dynorphin
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Spinal tract dynorphin interneuron,
enkephalin downward inhibitory neurons.
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In brain around ”pain centre” but also in
areas not involved in nociception and nonneuronal tissues
Opioid receptor
Receptors in brain and spinal cord
 4 subtypes: m(my), d, k and NOP (ORL-1)
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Opioid receptor
G-protein
 Intra/extracellular, intramembranous
 Pre- and postsynaptic membranes
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NMDA-receptor
N-metyl-D-Aspartate
 Learning
 Activation makes spinal neurons more
sensitive to pain stimulus
 Long-term C-fiberstimulation activates
NMDA  central sensitisation
 NMDA-antagonists
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Glutamat
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Presynaptic ion channel calcium influx 
glutamat release
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Crosses synapse and binds to NMDAreceptors postsynapticly  depolarisation
 hyperexcitability in nociceptive neurons
Pre- and postsynaptic binding
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G-protein inhibits adenylate cyclase
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Lower content intracellular cAMP
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Opens K+, inhibits Ca2+
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Inhibits pre-synaptic release of glutamat
The opioid receptor
The opioid receptor
m, d, k
 identical around 70%
 G-protein binds to 3rd receptor loop
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The opioid receptor m (mu)
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Mainly analgesic effects
Respiratory depression
Nausea / vomiting
Constipation
Cough reflex
Euphoria
Addiction
Sedation
Most analgesic opioids are m-agonists
The opioid receptor d (delta)
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Probably effects outside the CNS
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Some analgetic effekts
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Seizures?
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Least knowledge
The opioid receptor k (kappa)
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Analgesia on mainly spinal cord level
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Nausea and dysphoria
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Psychotomimetic effects – limits abuse
potential
Side effects - mechanisms
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Respiratory depression
Respiratory centre (medulla oblongata)
Less CO2 stimulation
Decreased respiratory rate
Nausea / vomiting
Area postrema (medulla oblongata)
(triggerzone vomiting reflex)
Stimulation of DA-receptors
Stimulation mechano/chemoreceptors GI
tract
Side effects - mechanisms
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Constipation
peripheral and central affection
less GI movement and increased tonus
No tolerans
Laxatives necessary
Peroral naloxone possible
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Itching
Histamine release or centrally mediated
Side effects - Mechanisms
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Sedation
Overdose
Wrong strategy
Sleep dept
Drugs
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Agonists (m-receptors)
morphine, metadon, fentanyl, heroin
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Partial agonists
buprenorfin, kodein, tramadol
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Antagonist
naloxone
What is an opioid?
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Alkaloid (plant) or synthetic
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Morphine like effekts, inhibited by naloxon
Opium
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Narcotic resin from opium poppies:
morphine 10%, noskapin 6%, papaverin 1%, kodein
0,5%
History
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3400 BC
Opium puppies grown in Mesopotamia
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460 BC
Hippocrates medicine (psychiatric disease
and epidemies)
History
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330 BC
Alexander the Great introduces opium to Persia
and India
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400 AD
Opium with traders to China
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Parcelsus (1490-1541) opium as medicine
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Laudanum (opium, sherry, cinnamon, clove bud
oil, saffron) 17th century
History
Morphin 1806
 Kodein 1832
 Heroin 1832
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Morphin
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C17H19NO3
Greek. Morpheus (God of dreams)
1806 from opium
1956 chemical structure
Morphine
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Half life 2-4 hours
Bioavailability 10-50% (30%)
Distribution volume 3L/kg
Bioaactive morphine-6-glucuronid (kidneys)
M6G half life 4-15 hours
Heroin
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C21H23NO5 (morphin
C17H19NO3)
Higher fat solubility
Produced 1874
Bayer 1899
Drug Sweden until
1964
Half life 30 minutes
Morphine
Kodein
C18H21NO3 (morfin C17H19NO3)
 Produced 1832
 Low receptor affinity
 10% into morphine  M6G
 7-10% non-responders
 Half life 2-4 hours.
 10 mg morfin  Kodein 60mg
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Dextropropoxifen
Half time 8-18 (90) hours
 Active metabolite norpropoxyfen
 Metabolite half life 30-45 (100) hours
 Alcohol enhances respiratory inhibition
 10mg morfin  100mg Dextropropoxifen
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Tramadol
Halflife 4-6 hours
 Active metabolite D-desmetyltramadol
 Halflife metabolite 9-12 hours
 5-10% non-responders
 Inhibits reuptake NA / 5-HT
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Fentanyl
”Complicated kinetics”
 Halflife 1 min, 8 min, 8 tim
 Active metabolites unknown
 10mg morfin  0,05 mg fentanyl (iv)
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Pethidine
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synthetic opioid
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Most histamine release. Seizures.
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100mg  10mg morphine
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Shivering
Ketogan
Ketobemidon(hydroklorid)
 NMDA – receptor antagonist?
 Halflife 2-4 hours
 Unknown metabolite activity
 Abuse risk
 ”Less documented morphine alternative”
 ”only” indication  renal failure (+NMDA?)
 10mg morphine  10mg ketobemidon
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Oxicodon
Halflife 2-4 timmar
 Probably inaktiva metaboliter
 10mg morfin  5mg oxikodon
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Metadon
NMDA-receptor antagonist ?
 Halflife 15-40 hours
 ”Bad reputation”
 Advanced pain treatment
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Clinical use
Cancer pain
 Postoperative pain
 Long-term pain ?
 Neurogenic pain?
 ”Always” in combination with paracetamol
and NSAID
 Elderly ?
 Try not to mix different opioids
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Intoxication
Mios (small pupils)
 Lower conscience
 Breathing
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Antidote – Naloxone (Narcanti)
opioid antagonist
 reverses endogenous and exogenous
substanses and acupuncture
 effect within 2 minutes
 Iterated
 iv + im when abuse overdose
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Abstinence
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sweating, fever (”cold turkey”), shakings,
muscular cramps, itching, diarrhea,
nausea, vomiting (the flu)
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At pain treatment because of to quick
withdrawal  re-medicate!
Cold Case
Cancer
 Current medication:
Tb. Dolcontin (longacting morphine)
60mgx2
Tb. Morphine (shortacting) 20mg as req.
inj. Ketogan 5mgvb
Tb. Tramadol 100mgx2
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Pain. What to do?
Patientfall
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Patient insatt på Ketogan tablett 5mgx6
med god effekt. Översatt till Dolcontin
20mgx2. Inkommer efter 1 vecka till
akuten: illamående, kräkning
Diffdiagnos (opioidrelaterat) ?
 Ytterligare status etc?
 Vad göra?
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Afterlife …..
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Morphina is currently Golden Standard
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Renal failure
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Treat pain!