Term
| sensation resulting from a NOXIOUS stimulus; associated with activation of AFFERENT A-DELTA AND C nerve fibers (nociceptor neurons) |
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Definition
nociception
pain sensing neurons (nociceptors) are of higher threshold than other sensory neurons; stimuli that can activate nociceptors include mechanical, temperature, or chemical |
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Term
| cause of neuropathic pain |
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Definition
neuropathic pain is caused by nociception resulting from NEURON DYSFUNCTION usually caused by tissue damage or disease
manifested by HYPERALGESIA (elevated pain sensation (hypersensitivity) in response to noxious stimuli) and/or ALLODYNIA (sensation of pain from a normally non-painful stimulus) |
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Term
| increased dose is required to maintain response level or response diminishes over time at constant dose |
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Definition
tolerance
a normal cellular response to opioids is decreased intracellular cAMP levels
over time tolerance may develop which correlates with return of cAMP to pretreatment levels
this is a biochemical basis/component for opioid tolerance
when drug is discontinued cAMP levels rise above pretreatment levels (this is associated with withdrawal symptoms
there are other intracellular mechanisms for tolerance |
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Term
| ascending and descending pathways in nociception |
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Definition
ASCENDING (AFFERENT) PATHWAY
the primary (first) afferent neuron is the nociceptor
the cell body of the nociceptor is in the dorsal root ganglia (DRG) and the nociceptors synapse with the secondary neuron in the dorsal horn (DH) of the spinal cord
the secondary neuron synapses with the tertiary neuron in the thalamus
the tertiary neurons go to the cortex where pain perception occurs
pain information is processed in cortex
DESCENDING (EFFERENT) PATHWAY
neurons beginning in the cortex make the first synapse in the brainstem
the next neuron in the descending pathway makes a synapse with the ascending pathway in the spinal cord
the descending neuron input modulates the ascending pain sensory pathway (modulation by descending pathways may result in enhancement or reduction in pain perception) |
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Term
| peripheral signal transduction of noxious stimuli |
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Definition
nociceptors (primary afferent pain conducting neurons) can be activated by 3 types of stimuli: chemical, mechanical, and thermal
CHEMICAL
there are receptors (ionotropic and metabotropic) for chemicals such as H+ (ASIC, acid sensing ion channel), ADP and adenosine (P2X, P2Y), and bradykinin (B1, B2)
MECHANICAL
certain ion channels are sensitive to force; mechanoreceptors are ion channels that open in response to force
THERMAL
certain ion channels are sensitive to temperature (transient receptor potential vanilloid receptors, TRPV); capsaicin, an active component in chili peppers, stimulate TRPV receptors
when one or more of these receptor types are activated, influx of sodium and/or calcium occurs (depolarization); if the nociceptor is depolarized enough to reach threshold an action potential is produced and pain is perceived in the cortex |
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Term
| synapse between primary and secondary neuron |
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Definition
the synapse is in the dorsal horn of the spinal cord
the terminus of the primary neuron releases glutamate and neuropeptides (calcitonin gene related peptide, substance P)
the ion channels (ionotropic receptors) mediate a fast response in the postsynaptic neuron
the metabotropic glutamate receptor and the receptors for the nuropeptides (also metabotropic) mediate a slow response in the postsynaptic neuron
the release of neuropeptides from the primary neuron is associated with high intensity pain (higher threshold) |
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Term
| 3 major subtypes of opioid receptors |
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Definition
there are at least 3 major subtypes: mu, kappa, delta (each subtype has subtypes)
opioid receptors are GPCRs
all of these receptor subtypes are linked to Gi (inhibits adenylyl cyclase) causing less conversion of ATP to cAMP
second messengers are linked to closing of Ca channels (presynaptic) and opening of K channels (postsynaptic) |
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Term
| actions of the mu opioid receptor |
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Definition
PRIMARY TARGET for opioid drugs
mediates analgesia, miosis, respiratory depression, dependence, euphoria, sedation, emesis |
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Term
| actions of the kappa opioid receptor |
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Definition
| mediates analgesia, DYSPHORIA, miosis, and sedation |
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Term
| actions of delta opioid receptors |
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Definition
| mediates analgesia, reduces GI motility, respiratory depression |
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Term
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Definition
| peptides: endorphins, enkephalins, and dynorphins |
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Term
| sites of opioid analgesic action |
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Definition
ASCENDING PATHWAY
3 possible sites:
1) at the site of noxious stimuli in the periphery
2) at the synapse in the spinal cord
3) at the synapse in the thalamus
the result of opioid analgesic action at these sites is to block or reduce pain transmission to the cerebral cortex
DESCENDING PATHWAY
the descending pathway connects with the primary afferent nociceptor in the spinal cord
the descending pathway inhibits pain transmission at the spinal cord synapse
the descending pathway normally releases endogenous opioids at the spinal cord to modulate pain input
exogenous administered opioid analgesics also work at this site |
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Term
| mechanism of analgesia through stimulation of opioid receptors |
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Definition
can occur in the synapse between the primary sensory neuron terminal and the secondary neurons in the spinal cord
normally the descending neuron terminus can release endogenous opioid peptides onto presynaptic and postsynaptic nerve terminals of the ascending pathway
exogenous administered opioid analgesics also act at this site
opioid receptors (mu subtype) are located presynapically and postsynaptically
delta and kappa are also present
endogenous opioid peptides or an opioid drug bind to these receptors
in the presynaptic terminal activation of the opioid receptor cuases closing of Ca channels
in the postsynaptic terminal activation of the opioid receptor causes opening of K channels |
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Term
| receptor activity classification of opioid drugs: agonists |
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Definition
agonists have agonist activity only, and are usually selective for MU RECEPTORS
minor activity at delta and kappa receptors
SIGNAL THROUGH ADENYLYL CYCLASE
activation is associated with Gi-GTP production, inhibition of AC, and consequently, decreased intracellular cAMP concentration
examples: morphine, methadone, codeine, fentanyl, meperidine, etorphine (has agonist activity at all 3 receptor types; used to immobilize large animals) |
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Term
| receptor activity classification of opioid drugs: mixed |
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Definition
mixed have antagonist activity at one receptor type and agonist activity at another receptor type
these drugs activate one receptor subtype (agonists or partial agonists) and are antagonists at another receptor subtype
most of the drugs of this group are mu antagonists and kappa agonists
CAN BLOCK ACTIVITY OF FULL AGONISTS
examples: pentazocine, nalbuphine, buprenorphine |
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Term
| receptor activity classification of opioid drugs: antagonists |
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Definition
antagonists have antagonist activity only
block action of agonist drugs or in some cases may block action of endogenous opioid peptides
some drugs from this group may have minor inverse agonist activity
giving an antagonist or even a mixed agonist can cause withdrawal symptoms (also known as abstinence syndrome)
examples: naloxone, naltrexone |
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Term
| pheysiologic effects of opioid analgesics |
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Definition
ANALGESIA
effective for most acute pain and chronic pain signaling through C FIBERS
less effective against neuropathic pain
less effective against A-DELTA
EUPHORIA
sense of wellbeing, contentment, comfort, associated with MU RECEPTOR ACTIVATION
COMPONENT OF ANALGESIA
SEDATION
drowsiness, clouding of mentation, little or no amnesia
RESPIRATORY DEPRESSION
most TROUBLESOME ADVERSE EFFECT
occurs at therapeutic doses
decreased sensitivity to pCO2
cause of death in overdose
cannot separate from analgesic potency (CONSTANT RATIO - high analgesic potency = high respiratory depression effects)
COUGH REFLEX DEPRESSION (antitussive)
therapeutic value
DOES NOT CORRELATE with respiratory effect
EMESIS
common
direct activation of the chemoreceptor trigger zone (CTZ); CTZ located in the medulla; bypasses the BBB; this area can "sample" the blood for toxins and other substances; 5HT-3 receptor antagonists are useful in treating this ADR
tolerance occurs
VESTIBULAR COMPONENT - emetic effect worsened during ambulation
MIOSIS
result of parasympathetic pathway input to eye
diagnostic value
LITTLE OR NO TOLERANCE
blocked by atropine
mydriasis during severe respiratory depression - increased input to the eye from the parasympathetic nervous system
GASTROINTESTINAL
decreased gastric emptying
increased smooth muscle tone (PERSISTENT - by contrast, normal peristalsis is wave of smooth muscle contraction)
decreased intestinal motility
constipation (little tolerance)
biliary tract and gall bladder contraction
CARDIOVASCULAR
no direct cardiac effects
can cause blood vessel dilation (hypotension) |
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Term
| general definition of tolerance |
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Definition
after repeated dose tolerance may develop
tolerance is defined as an increased dose required to produce the same response as in control (curve shift to right)
sensitization is reduced dose required to produce the same response as in the control
tolerance may also result in lower maximal response
sensitization may result in >100% response |
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Term
| metabolic mechanism of tolerance |
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Definition
[image]
tolerance can occur b/c of increased metabolic rate of the drug
plasma concentration falls at a faster rate with accelerated metabolism |
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Term
| intracellular signaling mechanism of tolerance |
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Definition
[image]
this mechanism is more specific to opioids than accelerated metabolism
the tolerance to the effects of opioids correlates with the cAMP intracellular signaling system
the above graph shows levels of adenylyl cyclase and cAMP over time
recall that opioid receptors are linked to Gi which inhibits AC; cAMP is a second messenger that has many different effects
baseline AC and cAMP is 100
the immediate effect of morphine administration is drop in cAMP with no effect on AC levels
binding of morphine to the opioid receptor causes direct inhibition of AC and opening of K channels through Gi
low AC activity causes low intracellular cAMP, low PKA activity, and decreased transcription of CREB-responsive genes
CREB regulates AC gene transcription
other downstream effects of low PKA is closed Na channels (threshold is elevated)
over continued administration of morphine, AC and cAMP levels rise (this return of cAMP levels toward baseline correlates with development of tolerance)
after longer term use of morphine tolerance developes and CREB becomes activated (phosphorylated) which increases levels of AC above baseline (activated CREB causes transcription of AC gene)
as a result of increased levels of AC, levels of cAMP return toward baseline
the activity of PKA also returns toward baseline
PKA activity open Na channels (neuron can reach threshold easier)
K channels are not affected
when morphine is discontinued there is a sharp spike in cAMP levels (the spike in cAMP levels above baseline correlates with withdrawal symptoms)
recovery from withdrawal correlates with return to baseline |
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Term
| NMDA receptor signaling mechanism of tolerance |
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Definition
[image]
activation of the NMDA receptor by glutamate induces the activation of NO synthase, which in turn synthesizes NO
NO cannot be stored and immediately diffuses through membranes (has local effects)
NO will complex with heme-containing proteins such as guanylyl cyclase causing guanylyl cyclase activation
NO will also S-nitrosylate proteins
NO may be converted to peroxynitrite, which will nitrate tyrosine residues within proteins
these mechanisms of NO action are thought to be involved in the development of opioid tolerance |
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Term
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Definition
agonist
REFERENCE DRUG for comparison of other opioids
first pass metabolism (~25% oral bioavailability)
for moderate to severe pain
RELATIVELY hydrophilic
slower to cross BBB compared to other more lipophilic drugs (i.e. fenanyl)
MU RECEPTOR selectivity
analogs have higher analgesic potency: oxymorphone and hydromorphone
naturally occurring (an opiate) alkaloid from opioid plant |
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Term
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Definition
agonist
more selective for ANTITUSSIVE ACTIVITY
less analgesic potency but higher antitussive activity compared to morphine
higher oral bioavailability than morphine
DEMETHYLATED to morphine = analgesic effect
genetic polymorphisms exist
naturally occurring
analogs are MORE POTENT analgesics compared to codeine: oxycodone and hydrocodone
the analogs retain antitussive activity
cough suppression mediated by receptors in medulla (receptors activated by codeine) |
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Term
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Definition
agonist
HIGHER ORAL BIOAVAILABILITY
LONGER T1/2
means less severe withdrawal symptoms (less magnitude) but more prolonged
this property makes methadone good for detoxification of heroin addicts
high tissue and protein binding may act as a reservoir for methadone and contribute to its long duration of action (methadone can act very similar to effects of morphine when given as a large single dose) |
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Term
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Definition
less analgesic potency than morphine
for moderate to severe pain
metabolite (normeperidine) CAN CAUSE SEIZURES
note: al opioids have convulsive effect at very high doses, however meperidine metabolite is concern at therapeutic doses
SEROTONIN REUPTAKE blocking activity
caution with MAOI USE |
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Term
| comparison of heroin (IV) to methadone (oral) |
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Definition
[image]
the plasma concentration of fast acting opioids such as heroin rises rapidly after IV administration, generating a "high", but also falls quickly, producing withdrawal symmptoms
the plasma concentration of a slow acting, long t1/2 drug such as methadone, remains in the asymptomatic range for a period of over 24 hours, so that the patient does not experience either the "high" or the withdrawal symptoms
moreover, b/c of its long plasma t1/2, methadone needs to be administered only once daily |
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Term
| properties of fentanyl and congeners (sufentanil, remifentanil, alfentanil) |
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Definition
agonists
POTENT SYNTEHTIC ANALGESICS (10-1000 x morphine)
more lipid soluble than morphine
FASTER ONSET AND RECOVERY
probably higher mu receptor affinity than morphine and higher lipid solubility
similar ADRs as morphine
for moderate to severe pain
remifentanil is unique in that it is metabolized by plasma esterases instead of by liver enzymes
this property ALLOWS FOR CONTINUOUS INFUSION WITHOUT ACCUMULATION IN LESS PERFUSED TISSUES
the recovery is very rapid after stopping infusion b/c of plasma esterase activity
properly speaking, these drugs are not opiates |
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Term
| opioid drugs with agonist and antagonist activity (mixed) |
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Definition
pentazocine: (-) mu; (+) kappa
nalbuphine: (-) mu; (+) kappa
butorphanol: (-) mu; (+) kappa
buprenorphine: (+) mu; (-) kappa
(+) = agonist
(=) = antagonist or partial agonist
INTENTION WAS TO MAKE opioid analgesics without unwanted effects
create opioids that possess analgesic activity with less abuse potential and respiratory depression
unfortunately drugs that have high analgesic potency have high potential for abuse and have ADRs
this is b/c analgesia, abuse potential, and respiratory depression are mediated through the mu receptor
these drugs have little delta receptor activity
DYSPHORIA mediated through kappa
may cause withdrawal |
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Term
| properties of pentazocine and butorphanol |
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Definition
analgesia mediated by kappa receptors
effective for moderate to severe pain
higher doses increase BP AND HR (PENTAZOCINE)
pentazocine is different from other opioids in that it may increase blood pressure |
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Term
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Definition
mixed
kappa agonist
similar analgesic potency as morphine
CEILING reached for analgesia and respiratory depression
for moderate to severe pain |
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Term
| properties of buprenorphine |
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Definition
mixed
kappa antagonist and mu partial agonist
OPIOID ADDICTION management
SLOW RECEPTOR DISSOCIATION
dissociation t1/2 for buprenorphine is 160 minutes (fentanyl is 7 minutes) |
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Term
| properties of naloxone, naltrexone, and nalmefene |
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Definition
antagonists
also, reverse (INVERSE) agonist activity
naloxone and naltrexone are inverse agonists (bind a receptor and turn it off); pure antagonists bind to receptor and block the binding of agonists
FEW EFFECTS when administered alone
causes withdrawal
reverses toxicity
USED FOR OVERDOSE |
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Term
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Definition
non-opioid
for severe chronic pain
25 amino acid peptide
blocks N-type Ca channel, a type of HVA channel found presynaptically
ziconotide is derived from a peptide found in the cone snail
delivered intrathecally via pump system |
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