ANALGESIA Flashcards
circulating beta-endorphin is derived predominantly from the __________ where it is released
pituitary
circulating proenkephalins are derived from the ___________ and exocrine glands of the stomach and intestine
adrenal medulla
what is the precursor molecule for beta-endorphin?
proopiomelanocortin (POMC)
which type of analgesics modulate initial signal transduction for pain?
NSAIDs
which type of drugs blocks signal conduction in nociceptive fibers?
Na+ channel blockers (local anesthetics)
how do opioids antidepressants, NSAIDs and alpha-adrenergic agonists all modulate transmission of pain?
modulate transmission of pain sensation in the spinal cord by decreasing the signal relayed from peripheral to central pain pathways
activating a peripheral nerve leads to influx of what two cations which results in depolarization of the polarized nerve membrane and generation of an action potential?
influx of sodium & Calcium
sensitizing agents act via what two intracellular signaling systems can modulate both the extent of originating ion influx and the sensitivity of the voltage-gated sodium channels to increase the likelihood of propagation and conduction of the pain impulses?
G-proteins coupled receptor either activates Phospholipase C to increase Ca2+ release from intracellular stores and activates protein kinase C, OR increases cAMP, activates protein kinase A and phosphorylates sodium channels
What effect do Norepinephrine (acting via alpha-2 receptors), GABA (acting via GABAb receptors) and endogenous opiates, endorphin and encephalin have on the pre synaptic terminal in the spinal cord?
Norepinephrine, GABA, endogenous opiates, endorphin and encephalin all inhibit calcium entry to teh pre-synaptic terminal
what effect do norepinephrine, GABA, endogenous opiates, endorphin and encephalin have on the post-synaptic membrane in the spinal cord?
activate potassium channels, leading to an increase in K+ conductance and hyperpolarization of the cell
(reduces the likelihood of the depolarization and the onward transmission of the pain signal is interrupted)
what effect does activating mu opiate receptors have on the presynaptic terminal?
decreases calcium influx
what effect does activating mu opiate receptors have on the post-synaptic membrane?
increases potassium efflux
how do NMDA receptors cause sustained or intense activation of central transmission?
activating NMDA receptors leads to postsynaptic calcium influx (Ca2+ influx activates signal transduction ascades that can enhance both short-term and long term excitability of the synapse)
what are the two drugs that block NMDA receptors?
ketamine
dextromethorphan
how can ketamine and dextromethorphan be used to prevent surgery-induced sensitization?
preemptive block of NMDA receptors
what are some of the adverse effects of ketamine?
hallucinations, amnesia, CV pressor, increased ICP
what are some of the adverse effects of dextromethorphan?
dizziness, confusion, fatigue
what is allodynia?
normally innocuous stimuli are now painful
what is hyperalgesia?
high intensity stimuli perceived as more painful
what are some of the extra-neuronal inflammatory components?
bradykinin, protons, histamine, PGE2, Nerve growth factor (NGF)
how do the extra-neuronal inflammatory components (bradykinin, protons, histamine, PGE2, NGF) cause increased pain perception?
G-protein coupled effects
reduced activation threshold
increased current conducted
what are the intra-neuronal mechanisms that increased the pain perception?
Substance P & CGRP (released from termini of primary afferents)
how do the intra-neuronal molecules like substance P & CGRP increase pain perception?
stimulates inflammatory cells to release histamine and TNF-alpha, recruits granulocytes to the site of inflammation
what is neuropathic pain?
pain arising from transection of mechanical damage to the nerve axon
explain how neuropathic pain lead to the continued perception of injury
loss of neurotrophic support alters gene expression in the injured nerve fiber
-inflammatory cytokines alter gene expression in both injured and adjacent uninjured nerve fibers (changes in gene expression lead to altered sensitivity and activity of nociceptive fibers)
what Na+ channel blocking drug is used to treat trigeminal neuralgia?
CARBAMAZEPINE
The rewiring of the peripheral and central pain pathways following nerve damage involves changes in expression of what ion channel?
Na+
what are the adverse effects of opioids?
Sedation Resp. depression N/V increased ICP Constipation Urinary Retention Itching around nose, urticaria postural hypotension behavioral restlessness
opioids act mainly as an agonist on what receptor?
mu-receptor agonist
what are the adverse effects of acetaminophen?
hepatic toxicity and liver failure at high doses, hypersensitivity
what are the main adverse effects of NSAIDs?
GI irritation, platelet inhibition, renal insufficiency or failure, cardiovascular hypersensitivity
what is the MOA of the gabapentinoids?
inhibition of voltage gated Ca2+ channels
how are the gabapentinoids (gabapentin, pregabalin) administered?
PO
what are the main adverse effects of the gabapentinoids?
sedation, peripheral edema, GI, decrease dose for renal insufficiency
what is the MOA for clonidine and dexmedetomidine?
alpha-2 receptor agonist
what are the adverse effects of clonidine?
sedation, hypotension, bradycardia
what are the functions of the Mu opioid receptor (OP-3)?
supraspinal & spinal analgesia; sedation; decrease respiration; decrease GI transit; modulation of hormone & NT release
what are the functions of the delta opioid (OP-1) receptors?
supraspinal & spinal analgesia; modulation of hormone and NT release
what are the functions of the kappa opioid (OP-2) receptors?
supraspinal & spinal analgesia; psychotomimetic effects; decrease GI transit
Name the opioid receptor type: endorphins> enkephalins> dynorphins
mu opioid receptor (OP-3)
name the opioid receptors type: enkephalins > endorphins & dynorphins
delta opioid receptors (OP-1)
name the opioid receptor type: dynorphins»_space; endorphins & enkephalins
kappa opioid receptor (OP-2)
what are the american pain society and the american academy of pain medicine’s five MAIN recommendations?
- Try other treatments first
- assess the risk for abuse
- Keep expectations realistic
- Start w/ a short term trial
- Weight individuals potential harm / benefit ratio
for the opioids that are considered full agonist, which receptor do they mostly act on?
OP-3
which 4 full agonist (at the mu receptor) opioids have a low oral:IV potency ratio?
morphine
hydromorphone
oxymorphone
fentanyl
which full agonist at the mu receptor opioid drug has a high oral:IV potency ratio?
methadone
Name the 7 opioids that are considered full agonists at the mu receptor?
Morphine hydromorphone oxymorphone methadone meperidine fentanyl
which drug is the only full agonist opioid that also has some activity on kappa receptors?
morphine
name the 7 opioids that are only partial agonists at the mu receptor
codeine hydrocodone oxycodone pentazocine nalbuphine buprenorphine butorphanol
which two opioids that are partial agonists at the mu receptor are only available in IV form?
Nalbuphine
Butorphanol
which opioid is often given as a patch to provide 48-72 hours of relatively stable drug delivery?
fentanyl
what is the benefit to the peripheral analgesia devise (PCA)?
the dose rate and max delivery/hr dose is set by te nurse or physician and the controls locked to prevent tampering
why does oral morphine have a low bioavailability?
it has a high first pass metabolism
which organ serves as the main reservoir for opiate distribution because it has greater relative bulk?
skeletal muscle
what can happen with frequent high dose administration or continuous infusion of highly lipophilic & slowly metabolized opioids (e.g. fentanyl)?
can lead to accumulation (depot storage site, can release drug slowly, once dosing is terminated)
opiates would really like to accumulate in what kind of tissue, but is limited by the poor blood supply to this tissue?
adipose tissue
explain how enkephalin signaling can persist, yet morphine has a loss of drug activity?
Enkephalin has a relative balance b/w desensitization and resensitization.
Morphine has a slow persistent desensitization and little recycling, favoring loss of drug activity
which adverse effects of opioids have a minimal chance of tolerizing?
miosis
constipation
convulsions
which adverse effects of opioids have a high chance of tolerizing?
Analgesia euphoria, dysphoria mental clouding sedation resp. depression antidiuresis N/V Cough Suppression
what is the most common and persistent side effect from opioids?
CONSTIPATION
what is the prophylactic treatment for opioid-induced constipation?
stool softener & laxatives (also increased consumption of fluids and dietary fiber)
what class of drugs may be useful to treat refractory constipation due to opioid agonists?
opioid antagonists (avoid in the presence of bowel obstruction)
what is the mechanism behind opiates causing constipation?
opiates have direct & anticholinergic actions to reduce motility
what can be done to manage the somnolence caused by opioid therapy?
- reduce or eliminate non-essential centrally-acting drugs
- adjust analgesia dose-opioid rotation
- consider drug treatment directed at symptom (e.g. methylphenidate)
how can you help prevent persistent nausea in the context of opioid therapy?
gradual rather than rapid upward titration of the opioid dose (could also try changing the route of drug delivery)
what are the mechanisms that explain why opioids can cause emesis?
direct effect on the chemoreceptor trigger zone
enhanced vestibular sensitivity
delayed gastric emptying
when is there a major risk of respiratory depression with opioid therapy?
- if opioids are titrated too rapidly
- w/ sleep apnea syndrome (obesity, short neck, snoring)
- if combined w/ sedative hypnotic
what should you do if you start to see respiratory depression in a pt who is being treated with opioids?
withhold the dose until the respiration improves, or you can use naloxone
what drug can you give in the event of opioid abuse/overdose induced respiratory depression that will help reverse the respiratory depression?
naloxone (opiate antagonist)
what are the risks associated with use of naloxone with the treatment of opioid abuse induced respiratory depression?
risks of abstinence, aspiration, and severe pain
how do you treat the pruritis caused by opioid therapy?
antihistamine drugs
what is the classic triad of opiate overdose?
pinpoint pupils
coma
respiratory depression
other than the classic triad of opioid overdose, what are some other adverse effects of opioid overdose?
altered mental status, severe perspiration, sock, pulmonary edema, unresponsiveness
what are the 3 opiate antagonists?
Naloxone
Naltrexone
Nalmefene
which opiate antagonist has the shortest half life?
naloxone (used to treat opiate intoxication and has a short duration of action)
which opiate antagonist has the longest half life and is used to treat addiction?
Naltrexone
opiate antagonists work at which opiate receptors?
all 3: mu, delta, kappa
what is a major downside to using opiate antagonists?
can precipitate withdrawal in dependent pts
how does Naltrexone decrease alcohol craving in alcoholics?
decreasing baseline beta-endorphin release
what are the 3 major drug groups that can cause further CNS depression when used with opioids?
sedative-hypnotics
antipsychotic tranquilizers
MAO inhibitors
what happens if you use sedative-hypnotics with opioids?
increased CNS depression, particularly resp. depression
what happens if you use antipsychotic tranquilizers with opioids?
increased sedation
accentuation of CV effects (antimuscarinic and alpha-blocking actions)
what happens if you use MAO inhibitors with opioids?
relative contraindication to all opioid analgesics b/c high incidence of hyperpyrexic coma; HTN
codeine is converted to morphine by what enzyme?
CYP2D6 (normally accounts for up to 15% conversion of codeine to the more potent morphine)
what happens to a pt taking codeine if they have renal insufficiency?
metabolites accumulate
why is it a bad idea for nursing moms to be taking codeine?
mom can metabolize the drug to morphine and this morphine can accumulate in the neonatal system and prove fatal
what is the adverse effect associated with high first pass metabolism of meperidine to normeperidine?
CNS toxicity
which opioid is was originally synthesized as an anticholinergic?
meperidine
which opioid can cause serotonin syndrome by inhibiting both 5-HT and NE reuptake?
meperidine
why is meperidine such a crappy opioid?
less effective analgesic than other drugs, and has peripheral anticholinergic effects and central anticholinergic effects
what factor facilitates increased fentanyl absorption?
increased skin temperature
what makes methadone a unique and useful opioid agonist?
has long elimination half life (used in the treatment of opiate withdrawal)
which opiate agonist is an aromatase inhibitor and has a long elimination half life?
methadone
meperidine and its active metabolite ___________ accuulates with renal dysfunction or prolonged use at high doses
normeperidine
morphine _________ are renally-excreted and can accumulate and lead to unanticipated changes in potency or side effects in pts with renal failure
glucuronides
which two opioid drugs lack active metabolites and could be considered safe in the setting of renal failure?
hydromorphone & fentanyl
why are adjuvant nonopioid agents used in the treatment for cancer pain?
to permit the lowest level of opiate dosing that can be effective and to maximize the pain relief
the onset of opiate withdrawal depends on what?
the half-life of the abused drug
opiate withdrawal peaks at what time and lasts for about how many days?
peaks at 36-48 hrs and lasts about 7-10 days
what are the first signs of opiate withdrawal?
craving and drug-seeking behavior
what are some of the symptoms and signs of opiate withdrawal that occur after the craving and drug-seeking behavior?
crawling sensation in skin, diaphoresis, rhinorrhea
Also, anxiety, fear, & sleep disturbance
fever, seizures, hallucination and delirium do not occur with what drug withdrawal?
opioid
the physical exam findings of agitation, diaphoresis, increased lacrimation, piloerection, and dilated pupils are all indicative of what?
opiate withdrawal
ethanol and sedative-hyponotic withdrawal produces what signs/symptoms?
seizures, hyperthermia, HTN, tachycardia
sympathomimetic intoxication may produce what symptoms and signs?
mydriasis, agitation, tachycardia, HTN
what are the signs/symptoms of cholinergic agent intoxication?
diarrhea, vomiting
how can you distinguish cholinergic intoxication from opioid withdrawal?
cholinergic intoxication has salivation, bradycardia & altered level of consciousness
what is the short term inpatient treatment for opiate withdrawal?
methadone
what is the outpatient treatment for opiate withdrawal?
clonidine (very effective for treating drug craving, sweating, piloerection, anxiety, and agitation)
clonidine is an ineffective treatment of what opiate withdrawal symptoms?
insomnia, muscle cramps, GI symptoms
term for physical dependence
dependence
term for psychological dependence
addiction
what defines dependence clinically?
once availability of the drug lapses and there is an appearance of withdrawal syndrome
________ consists of compulsive, relapsing drug use despite negative consequences (often triggered by cravings in response to contextual clues)
addiction
___________invariably occurs with chronic exposure, addiction does not
dependence
which drug is a long acting opiate and is formulated with the antagonist naloxone to prevent pts from shooting the drug up?
buprenorphine (if drug is taken as indicated the naloxone isn’t absorbed and so the pt gets what they need, however if the pt shoots the drug up then the naloxone blocks any euphoric feelings)
if you are in methadone maintenance therapy less than 180 days it is considered what?
detoxification
if you are in methadone maintenance therapy more than 180 days it is considered what?
maintenance
why can’t pts undergoing methadone maintenance therapy take additional opiates and experience euphoria?
the methadone has a very long half life and is preventing additional opioids from binding
what is the treatment of choice for opioid dependent pregnant women?
methadone
what are the adverse effects of methadone maintenance therapy?
constipation, mild drowsiness, excess sweating, peripheral edema reduced testosterone (reduced libido and sexual performance, erectile dysfunction) Prolonged QTc and arrhythmia
regarding buprenorphine: what is the result of very tight binding to opioid receptors?
displaces other opioids from receptors
triggers withdrawal in pts physically dependent on opioids
blocks the analgesic action of other opioids
regarding buprenorphine: what is the result of slow dissociation from opioid receptors?
long duration of action, relieves withdrawal and cravings for greater than 24 hrs
regarding buprenorphine: what is the result of no bioaccumulation?
allows quick titration to effective dose
regarding buprenorphine: what is the result of the fact that it is a partial agonist with celiing effect?
has a very low risk of overdose, might be less effective than higher doses of methadone
regarding buprenorphine: what is the result of Sublingual and IV absorption; poor oral absorption?
can be abused intravenously
what is the test used to identify morphine, heroin, hydrocodone, and codeine in urine?
antibody-based enzymatic immunoassays
if you want the exact drug and concentration of morphine, heroin, hydrocodone, and codeine what test do you have to perform?
GC-MS
which metabolite of heroin is definitive evidence of heroin use?
6-MAM
what does it mean if you have a morphine: codeine ration > 2:1?
indicates heroin or poppy seed use (if ratio is less than 2:1 then think codeine use)
Synthetic opiates (fentanyl, meperidine, methadone) are ______________ negative
Enzymatic immunoassays (EIAs)
which antibiotics can produce false-positive EIAs?
fluroquinolones (ciprofloxacin)
how does gabapentin (pregabalin) work?
drugs bind to alpha2-delta subunit, preventing trafficking to cell surface (upreg. of voltage-gated Ca2+ channels occurs in hypersensitization)
what is the pharmacological effect of gabapentin in dense synaptic connectionsn of neocortex, amygdala, & hippocampus?
inhibition of neuronal excitability
how is gabapentin (pregabalin) excreted?
renal
what are the 2 most common adverse effects of gabapentin-pregabalin?
dizziness & drowsiness
how does lamotrigine-carbamazepine work?
blocks sodium channel function
Lamotrigine-Carbamazepine has a BB warning fr what?
rash-Stevens Johnson syndrome
what are the most common adverse effects of lamotrigine-carbamazepine?
diplopia, blurred vision
anticonvulsants carry an increased risk for what adverse effect?
suicidal ideation
regarding lamotrigine-carbamazepine: you need ot adjust the dose in __________ failure
hepatic
both ketamine and dextromethorphan are limited by what adverse effect?
psychomimetic effects
hepatic metabolism of tricyclic antidepressants with what CYP enzyme could cause drug interactions?
CYP2D6
what are the adverse effects of TCAs?
dizziness headache fatigue drowsiness lethargy uneasiness hypersomnia difficulty concentrating memory impairment
TCAs work by blocking reuptake of what two molecules?
norepinephrine and 5-HT
TCAs work on serotonin and norepinephrine in ________________ pathways
cortciospinal monoamines
what are the adverse effects of dextromethorphan if they are abused?
hallucinogenic and habit forming
name the drug: nonprescription opioid agonist that has no analgesia or potential for addiction (no BBB) access
Loperamide
name the drug: prescription opioid agonist that is used as an antidiarrheal and contains atropine to discourage abuse
diphenoxylate
which drug is used to treat alcohol dependence and craving by blocking? the elevation of dopamine levels arising from signals in the ventral tegmental area in the arcuate nucleus
naltrexone
what is the toxicity associated with capsaicin?
increased pain, burning of eyes or mucus membrnaes
what is the benefit of cod-liver oil?
alleviates musculoskeletal & osteoarthritic pain
what is the toxicity associated with cod-liver oil?
increased bleeding risk oral anticoagulants, additive w/ antihypertensives, increased blood sugar
what is the toxicity associated with devil’s claw?
adversely affects acid-inhibiting, BP & CV drugs
what is the toxicity associated with epsom salts?
GI irritation, interacts with drugs affecting excretion and skeletal muscle relaxants
what is the toxicity associated with white willow?
contains salicylates; potential interaction with anticoagulants, antiplatelet & oral drugs
