Pharmacology: Test 2 Treatment Of Pain: Opiate Drugs

Front 1

Some local mediators of pain that directly or indirectly activate Adelta and C fibers?

Back 1

histamine, serotonin, NE, substance P, CGRP, bradkinin, IL, Arachidonic acid metabolites.

Front 2

What are arachidonic acid metabolites?

Back 2

COX products: prostaglandins, thromboxanes.//

Lipoxygenase products: leukotrienes.//

NSAIDS block COX in peripheral tissues.

Front 3

Afferent pain pathways?

Back 3

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).

Front 4

Descending Pain control pathways

Back 4

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.

Front 5

Major endogenous opiode peptides?

Back 5

methionine-enkephaline, leucine-enkephalin; dynorphins, and beta-endorphins.

Front 6

What gene is responsible for synthessis of endogenous opiodes, methionine-enkephaline, leucine-enkephalin. ?

Back 6

pro-enkephalin gene, widely distributed in brain and peripheral NS. Rapidly degraded by peptidases. Tyr is always on end terminal of these peptides.

Front 7

How about dynorphins?

Back 7

synthesized from pro-dynorphin gene, found in brain, pituitary (SON, and PVN). Rapidly degraded by peptidases as well.

Front 8

How about beta-endorphins?

Back 8

co-synth with ACTH in POMC, found in HT, brain stem and pituitary. STABLE to degradation by peptidases.

Front 9

Transcutaneous electrical nerve stimulation (TENS)...

Back 9

TENS activates descending pain control pathways via opioids (enkephalins, dynorphins) and non-opiods (5-HT, NE). Pain relief beyond duration of stimualtion.

Front 10

acupuncture

Back 10

mech similar to TENS, relief extends beyond duration of use. Analgesia antagonized by opiate drug antagonist.

Front 11

Pharmacological control of pain: aspirin, salicylates, NSAIDS, acetaminophen

Back 11

action at sensory nerve ending by inhibition of COX. Acetaminophen has action on central sites as well.

Front 12

Pharmacological control of pain: Opiates

Back 12

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)

Front 13

Pharmacological control of pain: local anesthetics

Back 13

nerve trunks (precent conduction), spinal cord (nerve block).//

General anesthetics at central sites (via loss of conciousness).//

Front 14

Treatment of acute pain: mild to moderate

Back 14

NSAIDS if possible... otherwise combine with orally active opiates (codeine).//

Front 15

Treatment of acute pain: severe pain

Back 15

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.//

Front 16

opiate drugs

Back 16

derived from opium poppy, Papaver somniferum.

Front 17

Some synthetic opiate drugs?

Back 17

methadone, meperidine, fentanyl, propoxyphene, hydromorphone, oxycodone.

Front 18

Opiate absorption properties?

Back 18

alkaline drug so little stomach absorption, Great deal of first pass effect. SQ and IM, also patch (fentanyl) good ways of administering drug.

Front 19

opiate distribution

Back 19

partly protein bound, distribution to all tissues and organs. Brain gets relative small proportion of that.

Front 20

Metabolism of opiates

Back 20

mainly in liver.

Major route: glcuronic acid CONJUGATION, resulting in morphine 6-glucuronide metabolites which are acitve analgesic in CNS.

Front 21

Opiate Metabolsim: minor route

Back 21

N-demethylation to normorphine, a less active metabolite b/c poor cns penetration.

Front 22

Codeine metabolism

Back 22

metabolism leads to acive metabolite, Morphine. It is done by CYP2D6** If deficient in 2D6, the pt won't get analgesic effects from codeine.

Front 23

excretion

Back 23

URINE, free morphine and metabolites also excreted in feces via BILE

Front 24

opiate structure

Back 24

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.

Front 25

Opioid receptors?

Back 25

3 types: mu, delta, kappa

Front 26

mu receptors?

Back 26

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.

Front 27

Kappa and delta receptors?

Back 27

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.//

Front 28

Opioid antagonists?

Back 28

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.//

Front 29

Opioid partial agonists

Back 29

pentazocine, nalbuphine, buprenorphine.//

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

When given with morphine, acts as an ANTAGONIST.

Front 30

Cellular effects of opioid receptor activation?

Back 30

-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).//

Front 31

opioid effects on neurons?

Back 31

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.//

Front 32

action of opioids: analgesia

Back 32

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.//

Front 33

action of opioids: respiratory depression

Back 33

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, //

Front 34

action of opioids: anesthesia

Back 34

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. //

Front 35

advantages/disadvantages of opioid anesthetics?

Back 35

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.//

Front 36

opioid effects on CVS?

Back 36

cardioprotective effects by opening K channels. Morphine better than short acting opiates.//

Front 37

Other effects of opioids?

Back 37

euphoria, miosis, stimulation of emesis center, constipation-- reduced gut motility, increased sphincter tone. Contraindicated in biliary colic b/c it constricts bile duct.//

Front 38

most common complaint by pts taking opiates?

Back 38

constipation... so give out laxation plus a surfactant combo.

Front 39

Opiates as antidiarrheal agents

Back 39

diphenoxylate and loperamide (imodium). Loperamide has high affinity for opiate-Rs but low CNS penetrance, so actions limited to GI.//

Front 40

Opiate effects on hormones

Back 40

PRL, GH increased. TSH, ACTH, and LH reduced.// The antagonist, naloxone, does the opposite.

Front 41

opiates as antitussives (cough suppressants)

Back 41

Codeine, Dextromethorphan.

Front 42

Treatment for chronic pain

Back 42

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).

Front 43

How about Ziconotide?

Back 43

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.//

Front 44

See page 8, Lec 30 for list of drugs.

Back 44

memorize those drugs.