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44 Cards in this Set

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Some local mediators of pain that directly or indirectly activate Adelta and C fibers?
histamine, serotonin, NE, substance P, CGRP, bradkinin, IL, Arachidonic acid metabolites.
What are arachidonic acid metabolites?
COX products: prostaglandins, thromboxanes.//

Lipoxygenase products: leukotrienes.//

NSAIDS block COX in peripheral tissues.
Afferent pain pathways?
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).
Descending Pain control pathways
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.
Major endogenous opiode peptides?
methionine-enkephaline, leucine-enkephalin; dynorphins, and beta-endorphins.
What gene is responsible for synthessis of endogenous opiodes, methionine-enkephaline, leucine-enkephalin. ?
pro-enkephalin gene, widely distributed in brain and peripheral NS. Rapidly degraded by peptidases. Tyr is always on end terminal of these peptides.
How about dynorphins?
synthesized from pro-dynorphin gene, found in brain, pituitary (SON, and PVN). Rapidly degraded by peptidases as well.
How about beta-endorphins?
co-synth with ACTH in POMC, found in HT, brain stem and pituitary. STABLE to degradation by peptidases.
Transcutaneous electrical nerve stimulation (TENS)...
TENS activates descending pain control pathways via opioids (enkephalins, dynorphins) and non-opiods (5-HT, NE). Pain relief beyond duration of stimualtion.
acupuncture
mech similar to TENS, relief extends beyond duration of use. Analgesia antagonized by opiate drug antagonist.
Pharmacological control of pain: aspirin, salicylates, NSAIDS, acetaminophen
action at sensory nerve ending by inhibition of COX. Acetaminophen has action on central sites as well.
Pharmacological control of pain: Opiates
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)
Pharmacological control of pain: local anesthetics
nerve trunks (precent conduction), spinal cord (nerve block).//

General anesthetics at central sites (via loss of conciousness).//
Treatment of acute pain: mild to moderate
NSAIDS if possible... otherwise combine with orally active opiates (codeine).//
Treatment of acute pain: severe pain
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.//
opiate drugs
derived from opium poppy, Papaver somniferum.
Some synthetic opiate drugs?
methadone, meperidine, fentanyl, propoxyphene, hydromorphone, oxycodone.
Opiate absorption properties?
alkaline drug so little stomach absorption, Great deal of first pass effect. SQ and IM, also patch (fentanyl) good ways of administering drug.
opiate distribution
partly protein bound, distribution to all tissues and organs. Brain gets relative small proportion of that.
Metabolism of opiates
mainly in liver.

Major route: glcuronic acid CONJUGATION, resulting in morphine 6-glucuronide metabolites which are acitve analgesic in CNS.
Opiate Metabolsim: minor route
N-demethylation to normorphine, a less active metabolite b/c poor cns penetration.
Codeine metabolism
metabolism leads to acive metabolite, Morphine. It is done by CYP2D6** If deficient in 2D6, the pt won't get analgesic effects from codeine.
excretion
URINE, free morphine and metabolites also excreted in feces via BILE
opiate structure
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.
Opioid receptors?
3 types: mu, delta, kappa
mu receptors?
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.
Kappa and delta receptors?
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.//
Opioid antagonists?
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.//
Opioid partial agonists
pentazocine, nalbuphine, buprenorphine.//

produce morphine like effects with lower max effect, analgestic for mild pain.//

When given with morphine, acts as an ANTAGONIST.
Cellular effects of opioid receptor activation?
-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).//
opioid effects on neurons?
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.//
action of opioids: analgesia
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.//
action of opioids: respiratory depression
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, //
action of opioids: anesthesia
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. //
advantages/disadvantages of opioid anesthetics?
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.//
opioid effects on CVS?
cardioprotective effects by opening K channels. Morphine better than short acting opiates.//
Other effects of opioids?
euphoria, miosis, stimulation of emesis center, constipation-- reduced gut motility, increased sphincter tone. Contraindicated in biliary colic b/c it constricts bile duct.//
most common complaint by pts taking opiates?
constipation... so give out laxation plus a surfactant combo.
Opiates as antidiarrheal agents
diphenoxylate and loperamide (imodium). Loperamide has high affinity for opiate-Rs but low CNS penetrance, so actions limited to GI.//
Opiate effects on hormones
PRL, GH increased. TSH, ACTH, and LH reduced.// The antagonist, naloxone, does the opposite.
opiates as antitussives (cough suppressants)
Codeine, Dextromethorphan.
Treatment for chronic pain
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).
How about Ziconotide?
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.//
See page 8, Lec 30 for list of drugs.
memorize those drugs.