opioid and non opioid analgesics Flashcards
4 steps for pain
transduction
transmission
modulation
perceptioin
transduction
injured tissues release a variety of chemicals that cause proimflammatory compounds. This is transduced into an AP via either A delta fibers (fast pain, sharp, well localized) or C fibers (slow pain, dull and poorly localized)
drugs that target transduction (5)
NSAIDS
LA’s
steroids
antihistamines
opioids
transmission
the pain signal is relayed through 3 neuron afferent pain pathway along spinothalamic tract
review of spinothalamic tract
first order neuron: periphery to dorsal horn (cell body in dorsal root ganglion)
second order neuron: dorsal horn to thalamus (cell body in dorsal horn)
third order neuron: thalamus to cerebral cortex (cell body in thalamus)
(can synapse at dorsal horn or go up/down tract of lesseiuer? and synapse somewhere else)
drugs that target transmission
LA’s
modulation and where it most frequently takes place
pain signal is modified (inhibited or augmented) as it advances to the cerebral cortex.
-takes place mostly in dorsal horn of SC
most important site of pain modulation
substantia gelatinosa in dorsal horn (rexed lamina 2 and 3)
descending inhibitory pain pathway begins in the ____________________ and __________________. it projects to the ____________________-
descending inhibitory pain pathway begins in the periaqueductal grey and rostroventral medulla. it projects to the substantia gelatinosa
pain is inhibited (modulated/augmented) when
spinal neurons release GABA and glycine (inhibitory neurotransmitters)
descending pain pathway release NE, serotonin, endorphins
modification: pain is augmented by (increase or decrease)
central sensitization
wind up
drugs that target modulation (5)
neuraxial opioids
NMDA antagonists
alpha 2 agonists
AchE inhibitors (apparently Ach helps with analgesia)
SSRI’s, SNRI’s
perception
describes processing of pain signals in cerebral cortex and limbic system
drugs that target perception (3)
GA
opioids
alpha 2 agonists
MOA of opioid receptors in order (6)
- opioid binds to receptor
- GPCR is activated
- adenylate cyclase is inhibited
- less cAMP is produced
- Ca2+ conductance is decreased
- K conductance is decreased
where are opioid receptors located in the brain? (3)
periaqueductal grey, locus coreuleus, rostral ventral medulla
where are opioid receptors located in SC?
primary afferent neurons in the dorsal horn and interneurons
where are opioid receptors located in periphery?
sensory neurons and immune cells
endogenous ligands of Mu
endorphins (beta endorphin, endo morphin)
endogenous ligands of delta
enkephalins (leu and met enkephalin)
endogenous ligands of kappa
dynorphins (A B and neo dynorphin)
physiologic functions of Mu (13)
supra spinal and spinal analgesia
resp depression
bradycardia
sedation
euphoria
prolactin release
mild hypothermia
mitosis
urinary retention
n/v
increased biliary pressure
peristalsis
pruritis
physiologic functions of delta (4)
supra spinal and spinal analgesia
respiratory depression
urinary retention
pruritis
physiologic functions of kappa (9)
supra spinal and spinal analgesia
plausible resp depression????
sedation
dysphoria
hallucinations
delirium
miosis
diuresis
anti shivering effect
Mu1 specific effects (7)
supra spinal and spinal analgesia*
bradycardia
euphoria
low abuse potential
miosis
hypothermia
urinary retention
Mu2 specific effects (5)
analgesic* (spinal only)
bradycardia*
resp depression*
constipation*
physical dependence*
Mu3 specific effects
immune suppression
ventilatory effects of opioids
shifts CO2 response curve to right and reduces ventilatory response to CO2
decrease RR and increase Vt
increased PaCO2 increases ICP if ventilation is not maintained
pupillary effects of opioids
edinger westphal nucleus stimulation –PNS stimulation of ciliary ganglion oculomotor nerve (CN3)- pupil constriction
tolerance does not develop to miosis
n/v and opioids
CTZ stimulation (in area postrema of medulla)
possible interaction with vestibular apparatus
SSEP and opioids
minimal effects on evoked potentials
BP and opioids
(is baroreceptor reflex affected)
minimal effects on BP in healthy patients
deceased BP with morphine and meperidine is likely the results of histamine
dose dependent vasodialtion
baroreceptor reflex not affected
myocardial function and opioids
myocardial contractility not affected (myocardial depression can occur if combined with N2O)
biliary pressure and opioids
contraction of sphincter of oddi–> increased biliary pressure
reversed by naloxone or glucagon
meperidine causes lowest increase
gastric emptying and opioids
prolonged
peristalsis and opioids
slowed (constipation)
urinary retention and opioids
detrusor relaxation (contraction needed to pass urine into urethra)
urinary sphincter contraction
immunologic response and opioids (3)
histamine release (morphine, meperidine, codeine)
inhibition of cellular and humoral immune function
suppression of NK cell function
thermoregulation and opioids
resets hypothalamic temperature set point (decrease in core body temp)
in women, morphine is associated with a (4)
greater analgesic potency
slower onset of action
longer DOA
lower postop opioid consumption
give examples of semi synthetic morphine derivatives (4)
hydromorpone, heroine, naloxone, naltrexone,
give an example of semi synthetic thebaine derivative
oxycodone
give an example of synthetic piperdine
meperidine
give an example of synthetic drug class we use every day
phenylpiperdines
give an example of synthetic diphenylpropylamines
methadone
relative potency to 10mg of morphine: meperidine
.1 (100mg is equivalent dose)
relative potency to 10mg of morphine: hydromophone
7x, (1.4mg is equivalent dose)
relative potency to 10mg of morphine: alfentanil
10x (1000mcg is equivalent dose(
relative potency to 10mg of morphine: remifentanil
100x more potent (100mcg is equivalent dose)
relative potency to 10mg of morphine: fentanyl
100x more potent (100mcg is equivalent dose)
relative potency to 10mg of morphine: sufentanil
1000x more potent (10mcg is equivalent dose)
what are tolerance and physical dependence likely attributed to
receptor sensitization and increased synthesis of cAMP
s/sx of withdrawal
diaphoresis, insomnia, restlessness (early)
n/v, abdominal cramping (late)
except for fentanyl, all opioids are metabolized how
hepatic transformation
morphine is conjugated into
morphine 3 glucuronide (inactive) and morphine 6 glucoronide (active)
morphine 6 glucoronide is a concern in which patient population
renal failure patients- cannot excrete without HD
metabolism of meperidine
demethylated in the liver to normeperidine byCYP450
caution with meperidine
reduces seizure threshold and increases CNS excitability (myoclonus and seizures are 2 significant side effects of meperidine active metabolite)
should be avoided in patients on HD and used with caution in the elderly
how is remifentanil metabolized
hydrolyzed in the plasma by erythrocyte and tissue esterases (NOT pseudocholinesterase)
-metabolized this way because of an ester linkage
how to dose remi, solubility
acts like a hydrophillic drug with low Vd but is very lipophilic. dose on lean body weight
which drug is associated with anticholinergic side effects
meperidine (structurally related to atropine)
MOA of meperidine
synthetic phenylpiperdine opioid that stimulates Mu and Kappa receptors
SE of meperidine metabolite normeperidine (3)
causes myoclonus, reduces seizure threshold, increases CNS excitability
co administration of meperidine with what is contraindicated
its a weak serotonin reuptake inhibitor, do not administer with MAOI’s for risk of serotonin syndrome
s/sx serotonin syndrome (5)
(also compare and contrast with MH and neuroleptic malignant syndrome)
hyperthermia, mental status changes, hyperreflexia, seizures, death
does meperidine cause histamine release from mast cells
yes
alfentanil
pKa
% non ionized (at physiologic pH)
% protein binding
Vd (mL/kg)
pKa: 6.5
% non ionized (at physiologic pH): 89
% protein binding: 92
Vd (mL/kg): 0.6
remifentanil
pKa
% non ionized (at physiologic pH)
% protein binding
Vd (mL/kg)
pKa: 7.2
% non ionized (at physiologic pH): 58
% protein binding: 93
Vd (mL/kg): 0.39
morphine
pKa
% non ionized (at physiologic pH)
% protein binding
Vd (mL/kg)
pKa: 7.9
% non ionized (at physiologic pH): 23
% protein binding: 35
Vd (mL/kg): 2.8
sufentanil
pKa
% non ionized (at physiologic pH)
% protein binding
Vd (mL/kg)
pKa 8
% non ionized (at physiologic pH) 20
% protein binding 93
Vd (mL/kg) 2
fentanyl
pKa
% non ionized (at physiologic pH)
% protein binding
Vd (mL/kg)
pKa 8.4
% non ionized (at physiologic pH) 8.5
% protein binding 84
Vd (mL/kg) 4
meperidine
pKa
% non ionized (at physiologic pH)
% protein binding
Vd (mL/kg)
pKa: 8.5
% non ionized (at physiologic pH) 7
% protein binding 70
Vd (mL/kg) 2.6
alfentanil effect site equillibration
~1.4m (fent and sufent are 6.8 and 6.2m)
metabolism of alfentanil
n dealkylation and o demethylation by CYP3A4
-because of its lower extraction ratio, it is more susceptible to alterations in CYP3A4 function
can you give alfentanil to renal patients
yes
what can you not co administer with alfentanil
erythromycin, inhibits alfents metabolism and prolongs resp depression
name each drug on this chart
postoperative hyperalgesia can be prevented with
ketamine or magnesium sulfate
methadone MOA
Mu agonist
NMDA antagonist
inhibits reuptake of monoamines in synaptic cleft
bioavailability of PO methadone
half life
metabolism
bioavailability 80%
half life 3-6h
metabolism CYP450
what can methadone do to EKG
can increase QT interval
-inhibits delayed rectifier potassium ion channel
-can lead to torsades
Oliceridine MOA and indication for use
IV opioid analgesic (Mu)- indicated for adults for pain when other opioid analgesics have not worked
Oliceridine dosing (bolus and PCA)
cumulative daily dose limit
bolus
-loading dose IV 1-2mg
-supplemental IV doses 1-3mg every 1-3h PRN
PCA
-leading dose 1.5mg
-demand dose .35-.5
-lockout 6 minutes
cumulative daily dose limit 27mg
Oliceridine dosage adjustment for renal patients?
no
contraindications to oliceridine (4)
can cause mild QT prolongation
risk of HoTN (d/t vasodilation) is increased with GA
increased risk of seizures in patient with seizure DO
patients on serotenergic drugs can be at greater risk of serotonin syndrome
best tx for opioid induced skeletal muscle rigidity and receptor believed to be the cause
paralysis and intubation
Mu receptor is cause
complications of skeletal muscle rigidity
ID drug categories outlined on this chart
common characteristics of partial agonists
produce analgesia with a reduced risk of resp depression
ceiling effect beyond which additional analgesia is not possible
reduce efficacy of previously administered opioids
can cause acute opioid withdrawal in the opioid dependent patient
can cause dysphoric reactions
carry low risk of dependence
are used in patients who cannot tolerate full opioid agonist
buprenorphine
MOA
analgesia compared to morphine
reversed by naloxone
key features
MOA: mu agonist (partial)
analgesia compared to morphine: greater
reversed by naloxone: difficult due to high affinity for mu receptor
key features: long duration (8h), avail via transdermal route
nalbuphine
MOA
analgesia compared to morphine
reversed by naloxone
key features
MOA: kappa agonist, mu antagonist
analgesia compared to morphine: similar
reversed by naloxone: yes
key features: does not increase BP, PAP, HR, RAP. useful with hx of heart disease
butorphanol
MOA
analgesia compared to morphine
reversed by naloxone
key features
MOA: kappa agonist, mu antagonist (weak)
analgesia compared to morphine: greater
reversed by naloxone: yes
key features: useful for postop shivering, avail via intranasal route
naloxone dose
DOA
metabolism
1-4mcg/kg (better to give 20-40mcg at a time)
DOA 45m
metabolism: liver (significant first pass metabolism)
how to cause less n/v with naloxone
slow titration over 2-3m
methylnaltrexone “difference”
has a quarternary amine group that prohibits passage across BBB
-since it does not enter the brain, it does not reverse respiratory depression
-useful for mitigating peripheral effects of opioids such as opioid induced bowel dysfunction
nalmefene dose, difference, use
0.1-0.5mcg/kg
-profile similar to naloxone but much longer DOA (10h)
-can be used to maintain recovering opioid abusers
naltrexone difference, uses
-unlike naltrexone, does not undergo significant first pass metabolism
-can be given PO, has DOA up to 24h
-ER may be used for ETOH withdrawal tx
-can be used to maintain recovering opioid abusers
incidence of resp depression with PCA is not higher at baseline but is higher with these risk factors
basal infusion rate
other sedatives administered
old age
pulmonary disease
OSA
3 patient populations that benefit from methadone therapy
chronic opioid abuse
chronic pain syndrome
cancer pain
name 4 disadvantages of using partial agonist opioids
- reduces efficacy of previously administered opioids
- can cause acute opioid withdrawal in opioid dependent patient
- can cause dysphoric reactions
- has ceiling effect beyond which additional analgesia is not possible
partial agonist that can be administered via intranasal route
butorphanol
partial agonist that can be administered via transdermal route
buprenorphine
2 partial agonists that provide better analgesia than morphine
buprenorphine, butorphanol
