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90 Cards in this Set

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Physiology of pain
nociceptor neurons activated by pressure, heat, cold, stretch, or chemical stimuli
Local mediators
monoamines
peptides
arachidonic acid metabolites
(MA)- Histamine, serotonin, NE
(Peptides)-Substance P, CGRP, kinins(bradykinin) interleukins
(ARA)- Cyclooxygenase products: prostaglandins, thromboxanes Lipoxygenase products: leukotrienes
Afferent Pain pathway
Primary Adelta and C fibers--Spinothalamic tract (STT)--Spinoreticular and spinomesencephalic tracts
STT vs. Spinoreticular/mesencephalic tracts
Discriminative vs affective pain
Desending Pain Control
Signal from PAG via Raphe Magnus (ventral medulla) to Dorsal horn, reduces activation of pain primary afferents
Endogenous opoid peptides are derived from three gene products, what are they
Beta endorphin, methionine-enkephalin/leucine-enkephalin (by pro-enkephalin gene), dynorphins (pro-dynorphin gene)
B-endorphin is found...
Hypothalamus, brain stem, and pituitary
B-endorphin cosynthesized with...
ACTH or alpha-MSH in pro-opiomelanocortin (POMC)
What happens to enkephalins in the PNS
Rapidly degraded by peptidases
Where is dynorphin found
Brain, pituitary, neurons of supraoptic and paraventricular
What happens to dynorphin
Rapidly degraded by peptidases
TENS
Transcutaneous electrical stimulation. Patient controlled electrical stimulation of sensory neurons
What TENS MA?
Enhances descending pain control pathway both opiod and non-opiod (NE, 5HT)
What's the TENS effect?
Pain controlled at and below level of stimulation and last beyond stimulation
Acupuncture
Electrical or mechanical stimulation of needles placed at specific sites
What is the effect of acupuncture?
Pain relief beyond stimulation and analgesia is antagonized by opiate drug antagonists.
PAG electrical stimulation
Experimental stimulation of electrodes in the PAG to activate descending pain control pathways
Is PAG electrical stimulation antagonized?
Yes, by opoid antagonist release, release of enkephalins and Beta endorphin into CSF occurs.
What are the agents that act at sensory nerve endings?
Aspirin, salicylates(derivative of aspirin), NSAIDs, acetaminophen, bradykinin antagonists, and opiates
What is the MA of aspirin, salicylates, NSAIDs, and acetaminophen
Inhibition of cycloooxygenase
What is the MA of opiates?
hyperpolarization?
What agents act at nerve trunks? How?
local anesthestics, prevention of nerve conduction
What agents work at the spinal cord, how?
local anesthetics-nerve block
Opiates- hyperpol., (-)NT release
Sub P antagonists- decrease substance P
What agents act at the thalamus? How
Opiates- inhibit NT release
What agents act at the PAG, ventral medulla?
Opiates- activate descending pain control pathways
What agents act at central cites?
Acetaminophen
Aspirin?
What agents act at the cortex?
Opiates- cause loss of consciousness
General anesthetics
Ziconotide (Prialt)
Approved for neuropathic pain that responds to nothing else. Blocks N-type Ca channels.
Where does opium come from?
Opium poppy- papaver somniferum
What are the opiates?
Morphine
Codiene (weak analgesic)
What are the synthetic opiate drugs?
methadone
meperidine
fentanyl
propoxyphene
hydromorphone
oxycodone
How are opiates absorbed?
Readily by subcu,i.m, and from G.I.*
*significan first-pass effect
Fentanyl can be transdermal
Are opiates protein bound?
Partly, they are distributed to all tissues, mainly in kidney,liver,lungs, and spleen. Small amount to brain
Where is the major site of metabolism for morphine
Mainly in liver: major route by glucoronic acid conjugation
minor route by N-demethylation to normorphine(less active)
Metabolism of Codeine
Mainly in liver, converted to morphine.
Which enzyme determines codeine metabolism?
CYP2D6
*not anaglesic in patients deficient in 2D6
Excretion of opiods
Most polar metabolites (conjugates) in urine, free morphine also in feces via bile
What are the critical features of opiate activity?
Aromatic ring with 3 position substituent
Hydroxyl @ 3 position is most potent
Tertiary nitrogen
Size of nitrogen substituent-larger groups confer antagonism
What are the 3 kinds of opiate receptors?
mu (m), delta (&), and kappa (k)
Function of m receptors
Mediate analgesia, anesthesia, sedation, miosis, euphoria, constipation, respiratory depression
Do m receptors have low or high affinity for morphine-like drugs?
(enkephalins and B-endorphin)
High
What happens when m receptors are chronically activated
Dependence
What do k receptors do
Mediate analgesia, miosis, sedation, dysphoria.
What do k receptors have a high affinity for?
dynorphin
What do delta receptors mediate? What do they have an affinity for?
May influence behavior and central regulation of CV system
High affinity for Met/Leu-enkephalin, and B endorphin
Opioid Antagonists
Naloxone
Naltrexone
What Naloxone and Naltrexone good antagonists?
Large N-position substituents
How does Naltrexone differ from Naloxone?
Longer duration, used to treat addiction
Opioid Partial Agonists
Pentazocine
Nalbuphine
Buprenorphine
Why give partial antagonists with morphine?
Antagonize morphine lessening it's affects. Lower abuse potential
Cellular effects of opioid receptor activation
Increased K+ conductance
Reduced Ca conductance
Inhibition of adenylyl cyclase
What is the consequence of increased K+ conductance?
Membrane hyperpolarization, reduced excitability, reduced NT release
What is the consequence of reduced Ca conductance
Reduced signal for NT release
What are the short term consequences of inhibition of adneylyl cyclase?
Possible inhibition of NT release, lower cAMP, reduced activity of cAMP activated enzymes
What are the long term consequences of inhibition of adneylyl cyclase?
Altered expression of cAMP-regulated genes
Opioid affect on neurons
Inhibition of NT release, decreased Ach, NE, GABA, Sub P
Modification of gene expression
How much morphine to relieave moderate pain? Severe?
10mg
15-20mg
What are the side effects of large doses of morphine
drowsiness, nausea, vomiting, respiratory depression
Is pain relief from morphine selective?
Yes, touch, temp, sight, and sound senses are not affected
Analgesia can be rapidly and completely reversed by what drug?
Naloxone
How long does 10-15mg of morphine last?
2-5 hours
Can you give 10mg morphine with aspirin or NSAIDs?
Yes
What is the most common cause of death in opiate overdose?
Respiratory depression
How can you rapidly reverse respiratory depression
Naloxone i.v.
How long does Naloxone last?
about 2 hours, may need more than one dose
Characteristics of respiratory depression caused by analgesia
Depression of all phases
Irregular breathing
Reduced sensitivity to PCO2
Direct depression of pontine and medullary centers to electrical stimulation
Tolerance? (I assume for the antidote)
High dose opiates
Can produce generalized neural depression and anesthesia
Is morphine a good anesthetic
No
Use of Fentanyl
Used as a primary anesthetic
Features of opiate anesthetics
Higer dose
Severe resp. depression, artificial respiration required
little muscle relaxation- use other muscle relaxant
Advantages of opiate anesthetics
No peripheral vasodilation (good in cardiac surgery)
Rapidly reversible
Disadvantages of opiate anesthetics
Little muscle relaxation
Consciousness may not be fully lost
What are the stimulatory effects of opiods?
Miosis, nausea, emesis, rush
What is the major effect of opioids on the G.I. system
Constipation
reduced motility, increased H2O retention, increased sphincter tone (esp. pyloric)
When is morphine contraindicated?
In biliary colic, increases constriction of bile duct
Antidiarrheal agents
Diphenoxylate
loperimde (Imodium)
What is diphenoxylate with atropine?
Lomotil
Which hormones increase in respose to morphine and decrease in response to Naloxone?
Prolactin, GH
(acidophil secretions)
Which hormones decrease in response to morphine and increase in response to Naloxone?
TSH, ACTH, LH
(basophil secretions)
Antitussives
Codeine
Dextromethorphan
Morphine Duration
3-4 hours
Codeine: more or less potent than morphine, duration
less
3-4 hours
Heroin (diacetylmorphine)
enters CNS more rapidly than morphine
Hydromorphone (Dilaudid): more or less potent than Morphine, duration
more
3-5 hours
Methadone: more or less, duration, use
Equipotent to morphine
4-6 hours
Treatment of heroin addiction
Meperidine (Demerol): more or less, duration
less
2-3 hours
Oxycodone (Percodan): more or less, duration, use
less
3-4 hours
analgesic for mild pain
Fentanyl: potency, duration, delivery
very potent
1 hour
I.V. or transdermal patch
Loperamide characteristics
highly potent demerol analog, does not enter brain or cause analgesia, resp depression. No abuse ability
Naloxone (Narcan)
Antagonizes actions of all opiates
1-2 hours