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3-22 Mild and Strong Analgesics 2
n/a
123
Pharmacology
Graduate
03/28/2010

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Term
what medically relevant alkaloids come from the papaver somniferum plant?
Definition
morphine, codeine, papaverine
Term
how does papaverine work and what is it used for?
Definition
direct SM cell relaxant

used to treat pain due to spasms (intestinal, etc)
Term
drugs derived from opium are known as
Definition
opiates
Term
what are oiopid (opium-like) analgesics?
Definition
narcotic analgesics like morphine that produce analgesia without loss of consciousness
Term
what are the receptors for opioids?
Definition
3 classic - MOP (mu), DOP (delta), KOP (kappa)
1 novel - NOP (orphanin FQ/nociceptin)
Term
which receptor do opioid drugs act mostly on?
Definition
MOP (mu) receptor
Term
location of opioid receptors involved in pain?
Definition
dorsal horn, PAG, thalamus
Term
location of opioid receptors for respiration, coughing, vomiting, myosis?
Definition
ventral brain stem
Term
what is a good sign of opioid toxicity?
Definition
pinpoint pupils

CN 3 Edinger-Westfall nucleus that controls pupil diameter has opioid receptors
Term
unconscious patient with pinpoint pupils. almost always due to what?
Definition
opioid overdose - heroin or morphine
Term
location of opioid receptors involved in neuroendocrine effects?
Definition
hypothalamus
Term
location of opioid receptors mediating mood and behavior?
Definition
limbic structures
Term
which opioid receptor is the only one responsible for sedation and respiratory depression?
Definition
MOP (mu)
Term
which receptor(s) cause spinal and supraspinal analgesia?
Definition
all - MOP, DOP, KOP
Term
what is the most important side effect clinically of opioid use?
Definition
respiratory depression
Term
what are the 3 endogenous ligand for opioid receptors?
Definition
endorphins
enkephalins
dynorphins
Term
endogenous ligand affinity for MOP?
Definition
endorphins > enkephalins > dynorphins
Term
endogenous ligand affinity for DOP?
Definition
enkephalins > endorphins and dynorphins
Term
endogenous ligand affinity for KOP?
Definition
dynorphins >> endorphins and enkephalins
Term
historically, morphine has been used to treat?
Definition
diarrhea - causes constipation
Term
opioid receptors are what type?
Definition
G protein coupled receptors
Term
effect of activation of opioid receptors on adenylyl cyclase and cAMP?
Definition
DECREASE
Term
effect of activation of opioid receptors on receptor-operated K channels?
Definition
activated/opened

hyperpolarizes the cell - blocks NT release and pain transmission
Term
2 effects of activating opioid receptors that leads to the final blockade of NT release and pain transmission?
Definition
1. activation of receptor operated K channels
2. suppression of voltage gated Ca channels
Term
what is the mechanism of acute tolerance at the molecular level?
Definition
1. agonist binding to opioid receptors (GPCR)
2. phophorylation by GPCR kinases
*3. binding of B-arrestins to receptors
4. interference with G-protein binding
5. receptor internalization
6. decrease in effectiveness (Acute tolerance)
Term
what protein stops the actions of morphine?
Definition
B-arrestin
Term
how does B-arrestin cause acute tolerance?
Definition
internalizes the receptor; stops signal production

requires more and more drug for effect = tolerance
Term
are all symptoms of opioids subject to mechanism of tolerance?
Definition
NO
Term
what effects have no tolerance development to opioid use?
Definition
1. miosis
2. constipation
3. convulsions
Term
what evidence is there for an endogenous ligand for the morphine receptor?
Definition
analgesia induced by electrical stimulation of brain was blocked by naloxone (morphine antagonist)
Term
what are the 3 families of endogenous opioid peptides?
Definition
endorphins, enkephalins, dynorphins
Term
what is the smallest endogenous opioid peptide?
Definition
enkephalin (5 aa)
Term
pro-opiomelanocortin (POMC) is a precursor of what?
Definition
*b-endorphin (endogenous peptide)
Term
what can be made from POMC?
Definition
MSH, ACTH, lipotropin, CLIP, endorphin and enkephalin
Term
where does the descending endogenous analgesic anti-nociceptive pathway originate?
Definition
aquductal sylvia (PAG) with enkephalin neurons
Term
in the descending endogenous anti-nociceptive system, first order neurons from the PAG go where?
Definition
raphe magnus nucleus in the brain stem

enkephalin neurons stimulate 2nd order neuron (serotonergic)
Term
NT of 3rd order neuron of descending endogenous anti-nociceptive system?
Definition
enkephalin
Term
what type of synapse is the final synapse in descending endogenous anti-nociceptive path?
Definition
axo-axonic in the spinal cord; secretes enkephalin in response to a stimulus
Term
how does the endogenous anti-nociceptive pathway affect the perception of pain?
Definition
inhibitory enkephalin interneurons have axoaxonic synapse with DRG nociceptor neuron terminal fibril and block the release of NT to second order neuron

blockade is caused by hyperpolarization from opening K channels
Term
why is effect of pain different from person to person?
Definition
due to endogenous analgesic systems - hard to predict how much will be activated and its effect in blocking pain pathways
Term
which receptors does morphine act on at normal doses?
Definition
mostly MOP, some KOP

no DOP
Term
sustained release morphine?
Definition
MS-contin
Term
what MOP strong agonist is most potent?
Definition
hydromorphone
Term
what MOP strong agonist is short acting?
Definition
meperidine
Term
how is fentanyl administered?
Definition
patch or parenteral

not oral
Term
MOP strong agonists (4)
Definition
1. morphine sulfate
2. hydromorphone
3. meperidine
4. fentanyl
Term
what is important to remember when you switch from IM to tablet form of morphine in a post-operative patient?
Definition
the dose must be increased
Term
what is important to remember about partial agonists?
Definition
even with a good dose of drug, never achieve full effect
Term
what are partial MOP agonists?
Definition
codeine
oxycodone
hydrocodone
propoxyphene
Term
what is important to remember in dosing with morphine vs. a partial agonist?
Definition
partial agonist is not as potent and requires a much higher dose
Term
what is the mechanism of a mixed strong analgesic?
Definition
it is an agonist for one receptor type and an antagonist for another
Term
example of mixed strong analgesic?
Definition
buprenorphin

*potent; partial MOP agonist; DOP and KOP antagonist
Term
mixed analgesics are used to treat?
Definition
opioid dependence - treat withdrawal effects
Term
morphine administration form(s)?
Definition
oral and parenteral
Term
codeine admin?
Definition
ORAL only
Term
what is the mechanism of opioid and NSAID synergy?
Definition
1. NSAIDs block COX
2. more AA available for lipoxygenase
3. lipoxygenase products facilitate opening of K channels by opioids
Term
benefit of adding NSAID to post-op treatment with opioid?
Definition
synergism allows for less frequent dosing
Term
why do you need 30 mg orally after 10 mg IM dose of morphine in the post-op period?
Definition
oral has first pass in the liver and therefore needs higher doses to be as effective
Term
morphine is converted to what in liver?
Definition
morphine-6-glucuronide (twice as potent as morphine) and morphine-3-glucuronide
Term
why is morphine 2-6 fold less potent orally than parenterally?
Definition
due to first pass metabolism
Term
when must be done to the dose when switching patients from parenteral to oral morphine?
Definition
INCREASED
Term
individual response to morphine is ____
Definition
variable
Term
standard dose of morphine is effective in how many patients?
Definition
2/3
Term
what is the standard dose of morphine?
Definition
morphine sulfate 10 mg IM Q3h
Term
when a higher dose of morphine is required what should be done?
Definition
a more potent drug should be used
Term
when should long acting drugs be used in place of morphine?
Definition
when less frequent dosing required

methadone
Term
quick acting, fast dissipating drugs (remifentanil) are used for what?
Definition
short, painful procedures
Term
what are additional routes of admin of opioid analgesics?
Definition
1. rectal transmucosal
2. epidural
3. subarachnoid
4. oral transmucosal
5. transdermal patch
6. iontophoresis
7. inhalation
Term
epidural access for admin of opioid analgesics
Definition
direct access to DRG neurons using very low doses

usually admin as an infusion
Term
subarachnoid route of admin of opioid analgesics
Definition
spinal or CSF

direct access to dorsal horn neurons and brain structures

much longer acting by direct access
Term
fentanyl patch for cancer pain mechanism
Definition
after permeation, drug forms a depot in stratum corneum

unlike scopolamine patches for nausea which permeates best over the mastoid process, fentanyl patches can be applied anywhere on the skin

12 hour onset
Term
what is iontophoresis?
Definition
transport of soluble ions through the skin by using mild electric current
Term
what are the modes of control of infusion analgesia?
Definition
1. patient controlled analgesia (PCA)
2. computer-assisted continuous infusion (CACI)
Term
what is patient-controlled analgesia (PCA)?
Definition
patient has limited control of dosing from infusion pump within tightly mandated parameters

short acting drugs are used

addiction does not develop

preferred over IM injections
Term
what is computer-assisted continuous infusion (CACI)?
Definition
needs continuous measurement of plasma opioid levels with indwelling sensors

only used for patients emerging from unconsciousness in ICU
Term
what are the non-analgesic use of opioids?
Definition
dyspnea and central antitussives
Term
what is dyspnea due to?
Definition
acute left ventricular failure and pulmonary edema
Term
what opioid is given for improvement of dyspnea?
Definition
IV morphine
Term
what is the mechanism of morphine treatment of dyspnea?
Definition
not entirely clear - decreased peripheral resistance and increased capacity of peripheral vascular compartments may be involved
Term
when is morphine contraindicated in the treatment of dyspnea?
Definition
pulmonary edema due to resp disease
Term
what can be used as antitussives?
Definition
codeine - 10-20 mg - ineffective as analgesic; also hydrocodone

dextromethorphan - isomer of codeine analog methorphan; no analgesic or addictive properties; 10-30 mg 3-6 times daily; OTC drug
Term
what is a main opioid adverse effect?
Definition
resp depression
Term
what is the mechanism of resp depression with opioid use?
Definition
opioid directly inhibit 5HT4a receptors in the rhythm-generating respiratory center neurons in the pre-boetzinger complex of the brain stem --> leading to decreased rate and tidal volume

resp center is less sensitive to CO2 but sensitivity to O2 is unaltered
Term
what can happen with oxygen admin to a patient with opioid induced resp depression?
Definition
apnea because sensitivity to oxygen is unaltered
Term
what increases the risk of resp depression in a patient taking opioids?
Definition
drug interactions with anesthetics, tranquilizers, alcohol, sedatives
Term
what can be done to avert opioid induced respiratory depression without loss of analgesia?
Definition
concurrent activation of 5-HT4a receptors
Term
opioid adverse effects (10)
Definition
1. sedation
2. cough reflex depression
3. miosis
4. truncal rigidity
5. nausea and vomiting
6. euphoria
7. convulsion
8. endocrine changes
9. constipation
10. CV effects
Term
what effect do opioid have on sedation?
Definition
drowsiness; loss of concentration and recent memory
Term
what effect do opioid have on the cough reflex?
Definition
depress the cough center in the medulla
Term
how do opioid cause miosis?
Definition
stimulation of Edinger-Westphal nucleus of oculomotor nerve - leads to pinpoint pupils

no tolerance develops to this effect
Term
what is the mechanism for truncal rigidity as an adverse effect to opioid use?
Definition
increased tone in the large trunk muscles from an action at supraspinal levels

reduces thoracic compliance --> interferes with ventilation

most apparent when high doses of the highly lipid-soluble opioids are rapidly administered IV
Term
what is an acute effect of rapidly administering highly lipid-soluble opioids (fentanyl, sufentanil, alfentanil, remifentanil) at high doses IV?
Definition
truncal rigidity
Term
how does opioid use lead to nausea and vomiting?
Definition
direct stimulation of chemoreceptor trigger zone

vestibular component may be involved because ambulation increases nausea
Term
what is euphoria?
Definition
decreased anxiety and pleasant floating sensation
Term
which receptors do not lead to euphoria with opioid use?
Definition
KOP - opposite effects
Term
what is the mechanism of convulsion due to opioid use?
Definition
due to inhibition of GABA release in interneurons
Term
what are the endocrine effects of opioid use?
Definition
1. decrease in secretion of LH, FSH
2. increased prolactin, ADH
3. decreased libido, sperm motility, ejaculate volume
4. anovulatory cycles; amenorrhea
Term
effects of opioid use in the GI tract?
Definition
constipation

historic use of opium poppy was for diarrhea
Term
what are the CV effects of opioid use?
Definition
decrease preload, inotropy, and chronotropy --> reduces oxygen consumption of myocardium

morphine is used in angina pectoris and acute MI
Term
what opioid is used in angina pectoris and acute MI?
Definition
morphine
Term
effects of opioid antagonists?
Definition
few effects unless agonists have already been administered
Term
what type of drug is naloxone?
Definition
opioid antagonist
Term
what is the IV 'coma cocktail'?
Definition
naloxone + thiamine + 50% dextrose
Term
what is the use of the 'coma cocktail'?
Definition
opioid antagonism

1 mg IV blocks 25 mg IV heroine
Term
admin of 'coma cocktail'
Definition
ONLY parenteral admin works

completely metabolized in liver; half life = 1 hour
Term
what are 2 opioid antagonists?
Definition
naloxone (coma cocktail) and naltrexone
Term
how is naltrexone admin?
Definition
ORAL admin effective (unlike naloxone)
Term
what tonic substance is released into the serum by clotting platelets?
Definition
serotonin
Term
what is the SM stimulant contained in enterochromaffin cells of intestinal mucosa?
Definition
enteramine
Term
where is 90% of 5-HT located in the body?
Definition
enterochromaffin cells of the intestine
Term
what is platelets role in serotonin mechanisms in the body?
Definition
platelets actively transport and store serotonin
Term
serotonin containing cell localization (4)
Definition
1. enterochromaffin cell of intestines
2. platelets
3. raphe magnus nuclei of brainstem
4. around BV
Term
serotonin in the raphe magnus nuclei in the brain stem is used in?
Definition
endogenous analgesic system
Term
which type of pain is mostly chronic pain?
Definition
neuropathic pain
Term
examples of neuropathic pain (5)
Definition
1. polyneuropathy
2. post-herpetic neuralgia
3. trigeminal neuralgia (tic doloreaux)
4. glossopharyngeal neuralgia
5. myelitis
Term
what 2 classes of drugs can be used to treat neuropathic pain?
Definition
1. tricyclic antidepressants
2. anticonvulsants
Term
how do tricyclic antidepressants work to treat neuropathic pain?
Definition
block serotonin re-uptake and facilitate the action of then endogenous opioid analgesic system
Term
examples of tricyclic antidepressants used to treat neuropathic pain?
Definition
imipramine
amitriptyline
doxepin
Term
how do anti-convulsants work to treat neuropathic pain?
Definition
block Na channel and prevent neuronal firing
Term
examples of anti-convulsant drugs used to treat neuropathic pain?
Definition
phenytoin
carbamazepine
gabapentin
levetiracetam
Term
what 3 classes of drugs are used to treat migraines?
Definition
1. 5-HT 1D/1B agonists
2. ergot alkaloids
3. NSAIDs or NSAIDs + combined opioid
Term
how do the triptans work in treating migraines?
Definition
agonists for 5-HT 1D/1B receptors in serotonergic pathway
Term
sumatriptan (all -triptans) used to treat?
Definition
migraines
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