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44 Cards in this Set
- Front
- Back
Some local mediators of pain that directly or indirectly activate Adelta and C fibers?
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histamine, serotonin, NE, substance P, CGRP, bradkinin, IL, Arachidonic acid metabolites.
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What are arachidonic acid metabolites?
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COX products: prostaglandins, thromboxanes.//
Lipoxygenase products: leukotrienes.// NSAIDS block COX in peripheral tissues. |
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Afferent pain pathways?
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via Adelta fibers (myelinated) and C fibers (unmyelinated). //
Spinothalamic pathway: rapid, facilitates localization (discriminative pain).// Sprinoreticular/spinomesencephalic tracts: slow conducting, involved in alerting, arousing (affective pain). |
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Descending Pain control pathways
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from midbrain (PAG region) via Raphe magnus, to dorsal horn of spin. Cord. //
descending activity reduces activation of pain pathways by afferents in the sp. cord. // i.e. electrical stimulation of PAG reduces pain. |
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Major endogenous opiode peptides?
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methionine-enkephaline, leucine-enkephalin; dynorphins, and beta-endorphins.
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What gene is responsible for synthessis of endogenous opiodes, methionine-enkephaline, leucine-enkephalin. ?
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pro-enkephalin gene, widely distributed in brain and peripheral NS. Rapidly degraded by peptidases. Tyr is always on end terminal of these peptides.
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How about dynorphins?
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synthesized from pro-dynorphin gene, found in brain, pituitary (SON, and PVN). Rapidly degraded by peptidases as well.
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How about beta-endorphins?
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co-synth with ACTH in POMC, found in HT, brain stem and pituitary. STABLE to degradation by peptidases.
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Transcutaneous electrical nerve stimulation (TENS)...
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TENS activates descending pain control pathways via opioids (enkephalins, dynorphins) and non-opiods (5-HT, NE). Pain relief beyond duration of stimualtion.
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acupuncture
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mech similar to TENS, relief extends beyond duration of use. Analgesia antagonized by opiate drug antagonist.
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Pharmacological control of pain: aspirin, salicylates, NSAIDS, acetaminophen
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action at sensory nerve ending by inhibition of COX. Acetaminophen has action on central sites as well.
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Pharmacological control of pain: Opiates
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Spinal cord, Thalamus (via hyperpolarization, and inhibit transmitter release).//
PAG, Raphe Magnus (via activation of descending pain control pathway). // central, cortex (thru loss of conciousness) |
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Pharmacological control of pain: local anesthetics
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nerve trunks (precent conduction), spinal cord (nerve block).//
General anesthetics at central sites (via loss of conciousness).// |
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Treatment of acute pain: mild to moderate
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NSAIDS if possible... otherwise combine with orally active opiates (codeine).//
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Treatment of acute pain: severe pain
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opiates by mouth, skin patch (fentanyl) or i.m. injection, in combo with NSAID. Keep pain reduced b/c if recurs, hard to then supress.//
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opiate drugs
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derived from opium poppy, Papaver somniferum.
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Some synthetic opiate drugs?
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methadone, meperidine, fentanyl, propoxyphene, hydromorphone, oxycodone.
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Opiate absorption properties?
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alkaline drug so little stomach absorption, Great deal of first pass effect. SQ and IM, also patch (fentanyl) good ways of administering drug.
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opiate distribution
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partly protein bound, distribution to all tissues and organs. Brain gets relative small proportion of that.
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Metabolism of opiates
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mainly in liver.
Major route: glcuronic acid CONJUGATION, resulting in morphine 6-glucuronide metabolites which are acitve analgesic in CNS. |
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Opiate Metabolsim: minor route
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N-demethylation to normorphine, a less active metabolite b/c poor cns penetration.
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Codeine metabolism
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metabolism leads to acive metabolite, Morphine. It is done by CYP2D6** If deficient in 2D6, the pt won't get analgesic effects from codeine.
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excretion
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URINE, free morphine and metabolites also excreted in feces via BILE
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opiate structure
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hydroxyl at 3 position most potent (i.e morphine); if OCH3 at 3 position (ie codeine), less potent.//
Part of ring structure can be superimposed on Tyrosine. The full morphine ring not required for acitivty. |
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Opioid receptors?
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3 types: mu, delta, kappa
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mu receptors?
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mediate analgesia, anesthesia, sedation, miosis, euphoria, constipation, resp depression.//
High affinity for endogenous opioids ie enkephalins and beta-endorphins.// Current opiate analgesic drugs activate this receptor.// chronic use may lead to tolerance and physical dependance. |
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Kappa and delta receptors?
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less important.
kappa: mediates analgesia, miosis, sedation but also DYSPHORIA, high affinity for dynorphin.// delta-r: influence affective behavior, CV reg, high affinity for enkephalin and Beta endorphins.// |
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Opioid antagonists?
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naloxone and naltrexone.//
These are morphine derivatives with LARGER N-POSITION SUBSTITUENTS. // Both useful in acute opioid OD.// Naltrexone, longer duration, used in tx for opioid addictions.// |
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Opioid partial agonists
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pentazocine, nalbuphine, buprenorphine.//
produce morphine like effects with lower max effect, analgestic for mild pain.// When given with morphine, acts as an ANTAGONIST. |
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Cellular effects of opioid receptor activation?
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-increased K conductance via Gi-mediated.//
-reduce Ca conductance, Go mediated.// -inhibition of AC, Gi mediated. > lower cAMP (short term effect) and cAMP expression altered (long-term effect).// |
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opioid effects on neurons?
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inhibition of NT release ie. ACh, NE, GABA, substance P.//
activations of neurons in PAG and Raphe Magnus by reducing GABA.// Modification of gene expression via AC inhibition > tolerance, dependance.// |
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action of opioids: analgesia
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reduction in pain w/out loss of conciousness. pain relief selective, so touch, temp, sight and sound not affected.//
Anatgonize analgesia completely by Naloxone.// Sites of action: spinal cord dorsal horn, raphe magnus, PAG, thalamus.// |
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action of opioids: respiratory depression
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most common cause of death in opiate OD.// use naloxone (t1/2 2 hours), multiple doses since opiates have longer half lives.//
depress all phases of resp acitivity, irregular breathing, reduced PCO2 sensitivity in resp center, // |
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action of opioids: anesthesia
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with high doses, ie Fentanyl.//
high dose cause gradual loss of conciousness, will require artificial ventilation. LITTLE muscle relaxation, so those are required in conjuction with opiates. // |
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advantages/disadvantages of opioid anesthetics?
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advantages: no peripheral vasodilation unlike volatile anesthetics, so good in CARDIAC surgery, rapidly reversed if needed.//
Disadvantages: little musc relaxation, conciousness may not be fully lost, so used with N2O.// |
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opioid effects on CVS?
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cardioprotective effects by opening K channels. Morphine better than short acting opiates.//
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Other effects of opioids?
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euphoria, miosis, stimulation of emesis center, constipation-- reduced gut motility, increased sphincter tone. Contraindicated in biliary colic b/c it constricts bile duct.//
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most common complaint by pts taking opiates?
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constipation... so give out laxation plus a surfactant combo.
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Opiates as antidiarrheal agents
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diphenoxylate and loperamide (imodium). Loperamide has high affinity for opiate-Rs but low CNS penetrance, so actions limited to GI.//
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Opiate effects on hormones
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PRL, GH increased. TSH, ACTH, and LH reduced.// The antagonist, naloxone, does the opposite.
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opiates as antitussives (cough suppressants)
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Codeine, Dextromethorphan.
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Treatment for chronic pain
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treated in conjunction with anti-convulsants (carbamazepine, gabapentin) as if the Sp. Cord is having epilepsy ;). Also, NMDA-R anatgonist (dextramethorphan) Na Channel blockers. //
If pain associated w/ sympathetic activity, use clonidine (alpha 2 activation). |
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How about Ziconotide?
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Ziconotide is given when pain responds to nothing else. It is given directly into spinal cord, which blocks N-type calcium channls in nerves transmitting pain.//
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See page 8, Lec 30 for list of drugs.
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memorize those drugs.
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