Opioids lecture part 2 Flashcards
What is the most widely used opioid analgesic in anesthesia?
fentanyl
What is significant about the structure of fentanyl?
phenlypiperdine ring
What is the potency of fentanyl?
75-125 times more potent than morphine
What is the liphophilicity of fentanyl?
Fentanyl is liphophilic b/c of its chemical structure
What is the pKa of fentanyl?
8.4
What is the pKa of morphine?
7.9
Discuss the pharmacokinetics of fentanyl?
rapid onset and shorter duration of action (1-3 minute onset)
lipid soluble
redistribution terminates effect of single dose
What is the elimination half-time of fentanyl?
longer than that of morphine
Large Vd- more than 80% leaves the plasma in less than 5 minutes
How is fentanyl metabolized?
N-dealkylation and hydroxylation
no active metabolites
Name 3 drugs that have a large first pass uptake in the lungs.
Propofol, fentanyl, & lidocaine
True or false: cirrhosis prolongs elimination half-time of fentanyl.
false
What is the context sensitive half-time like with fentanyl?
increases exponentially with infusions >2 hours
reflects redistribution and saturation into inactive
tissue sites
What patient population has implications with fentanyl?
elderly- prolonged elimination time due to decreased clearance
age-related decreases in hepatic blood flow, microsomal enzyme activity, and albumin production (highly protein bound)
What are the dosages for fentanyl?
induction/intubation: 1-3 mcg/kg
analgesia: 1-3 mcg/kg IV provide analgesia
sole anesthetic: 50-150 mcg/kg to produce surgical analgesia
What are the risks/benefits of fentanyl as sole anesthetic?
stable hemodynamics, lack of cardiac depressant effect, no histamine
recall?, respiratory depression post op, lack of response to surgical stim at any dose
Transdermal fentanyl
leave patch in place- reduces IV requirements
stable concentration for 3 days
Side effects of fentanyl:
similar profile to morphine
“secondary peaks” may reflect release from pulmonary uptake
Does NOT evoke histamine release; hypotension unlikely
bradycardia more prominent- carotid sinus baroreceptor control
Associated with modest increases in ICP
vasodilatory?
Seizure activity; myoclonus
Inhibition of inhibitory neurons
What does fentanyl have synergism with?
propofol and versed
What is the chemical structure of sufentanil?
Thienyl analogue of fentanyl
What is the potency of sufentanil?
potency is 5-10 times that of fentanyl
What are the clinical uses and dosages of sufentanil?
0.1-0.4 mcg/kg produces longer analgesia and less respiratory depression than fentanyl
induction-doses required for laryngoscopy may cause chest wall rigidity
Protein binding for sufentanil
significantly more than fentanyl
alpha 1 glycoprotein
enhanced effects in neonates
Comment on the Vd of sufentanil.
rapid distribution terminates effects- highly lipid soluble, increased Vd
Sufentanil has:
significant first pass pulmonary uptake
How is sufentanil different then fentanyl?
more potent, may contribute to chest wall rigidity, d/t high lipid solubility may see increased effects with liver disease
How is sufentanil metabolized?
rapidly metabolized by N-dealkylation and O-demethylation
N-dealylation metabolites are inactive
O-demethylation- desmethyl sufentanil- has activity and must be conjugated to be eliminated so renal function is important
Sufentanil clearance is sensitive to
hepatic blood flow
normal renal function is essential for clearance
What is the potency of alfentanil?
Alfentanil is less potent than fentanyl; shorter duration of action
What is the onset of alfentanil?
rapid onset after IV administration (redeeming quality)
high fraction of unionized drug (90% of the drug exists in nonionized form at physiological pH
What is the pKa of alfentanil?
6.5
What is the volume of distribution of alfentanil?
small Vd; less than that of fentanyl
What is alfentanil principally bound by?
alpha 1 glycoproteins
How is alfentanil metabolized?
metabolized by two independent pathways: piperdine N-dealkylation to noralfentanil & amide N dealkylation to N-phenyylpropionamide
What are the dosages of alfentanil?
15 ug/kg IV- blunts stimulation of laryngoscopy
30 ug/kg IV-catecholamine response to noxious stimulation
150-300 ug/kg IV- produces unconsciousness (induction)
combo w/ inhaled anesthetic 15-150 mcg/kg/hr
What are side effects associated with alfentanil?
decreased BP, diminished incidence of N/V
acute dystonia so avoid in pt’s with Parkinson’s
What is the mechanism of action of remifentanil?
selective mu agonist
potent like fentanyl
blood brain equilibration like alfentanil
What is significant about the structure of remifentanil?
it has an ester linkage so it allows for it to be broken down by nonspecific plasma esterases in the blood
What is remifentanil good for?
Good for surgeries where we can’t paralyze because it is very synergistic with propofol
What are the benefits of remifentanil
brief action, titratable, does not accumulate, rapid recovery
What are the dosages of remifentanil?
analgesia: 0.5-0.2 mcg/kg/min
anesthesia induction: 1 mcg/kg bolus followed by infusion of 0.1-0.3 mcg/kg/min for 10 minutes prior to induction agent
sedation: 0.05-0.1 mcg/kg/min in combination with midazolam 2 mg
What is a negative aspect of remifentanil?
it is abrupt–> can get hyperdynamic responses if you don’t give some type of long term coverage
What is the Vd of remifentanil?
small Vd
What is the context sensitive half-time of remifentanil?
4 minutes
What is significant about the metabolism of remifentanil?
metabolized by non-specific plasma esterases- no active metabolites, not affected by pseudocholinesterase deficiency, pK unchanged by renal or hepatic failure
What are side effects of remifentanil?
can induce “seizure like” activity, N/V, depress ventilation, decrease BP, hyperalgesia secondary to acute opioid tolerance (can give ketamine or mag to block this)
Discuss hydromorphone
main long-acting opioid
consistent, reliable, 5x more potent than morphine, shorter duration of action than morphine
less hydrophillic than morphine so faster onset, more sedation, less euphoria
can cause agitation and myoclonus
What is methadone?
synthetic opioid used in chronic pain settings
attractive for withdrawal and drug suppression
long terminal half-life- 12 hours so need to be prepared for long-term management
need to go to pulse ox floor
Side effects of methadone
similar to morphine: depression of ventilation, miosis, constipation, biliary tract spasm
sedative and euphoric effects less
Opioid withdrawal use of methadone dose
can substitute for morphine at 1/4th the dosage
20 mg IV, produces postop analgesia >24 hours
Methadone is used to treat chronic pain because
low abuse potential
NMDA antagonist activity may be beneficial for neuropathic pain
disadvantage is prolonged and unpredictable half-life
drug can accumulate and cause depression of
ventilation
What is tramadol?
synthetic codeine analog
given PO, IM, or IV
weak moderate Mu agonist
less potent than morphine
useful for chronic treatment-less addictive
enhances function of descending inhibitory pathways
What is the metabolism of tramadol?
CYP 450 in the liver
active metabolite O-desmethlytramadol has modest analgesic effects
What are the disadvantages of tramadol?
interacts with coumadin anticoagulants
drug-related seizures (may lower seizure threshold and not in a good way)
high incidence of N/V
Zofran may interfere with analgesic component d/t reuptake of 5-hydroxytryptamine
What is heroin?
synthetic opioid
differs from morphine in that it rapidly penetrates the CNS where it is hydrolyzed to active metabolites
monacetylmorphine, morphine
Compared to morphine: more rapid onset, less nausea, greater liability for physical dependence
Opioid agonist-antagonist
these bind to mu receptors but produce limited responses or no effect
What are the advantages of opioid agonist-antagonist?
produce analgesia
limited depression of ventilation
Have a ceiling effect- reserved for patients who can’t tolerate a pure agonist
What is butorphanol?
limited intraoperative use
agonist-antagonist so not 100% efficacy
affinity for kappa receptors
given for analgesia and anti-shivering
resembles pentazocine
agonist effects are 20x greater
antagonist effects are 10-30x greater
low affinity for mu receptors
produces antagonismWhere is butorphanol metabolized?
metabolized in liver and excreted primarily in the bile
inactive metabolite-hydroxybutorphanol
What is the half-time of butorphanol?
2.5-3 hours
What are the side effects of butorphanol?
sedation, nausea, diaphoresis, dysphoria, depression of ventilation, increase in catecholamine response (increased HR, BP, PAP, CO), mild biliary and GI tract symptoms, limits effects of concomitant opioid agonists, withdrawal following acute discontinuation in chronic therapy
What drug classification is nalbuphine?
agonist-antagonist
What is significant about the chemical structure of nalbuphine?
it’s related to oxymorphone and naloxone
Where is nalbuphine metabolized and what is the elimination half time?
liver
3-6 hours
Where does antagonism occur with nalbuphine?
mu receptors
if given before an opioid it may diminish effects of morphine-like drugs preop
if given after opioid it can reverse (2-3 hours) depression of ventilation effects but maintain analgesia
When is the best time to give nalbuphine?
after an opioid because it can reverse depression of ventilation while maintaining analgesia
What are the side effects of nalbuphine?
sedation
less dysphoria than pentazocine & butorphanol
depression of ventilation has ceiling effect (30 mg)
catecholamine stimulation effects
may be beneficial in cardiac patients needing
sedation and analgesia (doesn’t produce
hypotension or bradycardia)
What is buprenorphine derived from?
derived from thebaine
potent analgesic
What is the dosing of buprenorphine and its relationship to morphine?
0.3 mg IM= 10 mg morphine so very potent
What are the clinical uses of buprenorphine?
postop pain related to cancer, renal colic and MI
What are the side effects of buprenorphine?
drowsiness, n/v, and depression of ventilation- similar to morphine but may be prolonged, resistant to antagonism by naloxone
pulmonary edema
dysphoria unlikley
low abuse risk
can precipitate withdrawal in patient taking morphine
What is the chemical structure of an opioid antagonist like?
opioid agonists with mild structural changes to the substitution of an alky group for a methyl group
What are examples of opioid antagonists?
pure Mu antagonist receptors include: naloxone, naltrexone, nalmefene
What is the dosage of naloxone?
dose 1-4 mcg/kg IV; don’t ever give a whole vial typically will se 40 mcg given
5 mcg/kg/hr can fix depression of ventilation without affecting analgesia
What is naloxone used for?
opioid induced hypoventilation, depression of ventilation in the neonate d/t maternal administration, treat deliberate drug overdose, detect suspected physical dependence
What is the half-life of naloxone?
30-45 minutes
the oral route of naloxone is
1/5th as potent due to first pass hepatic metabolism
How is naloxone metabolized?
by liver conjugation with glucoronic acid
naloxone-3-glucuronide
What are side effects of naloxone administration?
reversal of analgesia (can be possible to titrate to maintain analgesia and reverse hypoventilation)
N/V
increased sympathetic nervous system activity- sudden onset of pain, tachycardia, hypertension, pulmonary edema, cardiac dysrthythmia- vfib
administration to the opioid dependent parturient may result in fetal withdrawal
Role of naloxone in shock
in animals large doses of naloxone (>1 mg/kg) have shown to improve myocardial contractility and outcomes
What is naltrexone and when is it used?
opioid antagonist
used in treatment of alcoholism; has sustained effects >24 hours
What is nalmefene?
pure opioid antagonist
What is the dosing for nalmefene?
15-25 mcg IV until effect achieved (max dose 1 mcg/kg)
What is the potency of nalmefene?
Equally potent to naloxone
If nalmefene is given prophylactically,
it decreases N/V and pruritis in patient with IV PCA
What is the primary advantage of nalmefene?
longer duration of action than naloxone so doesn’t need to be re-dosed in 30 minutes
How is nalmefene metabolized?
metabolized in the liver by hepatic conjugation
What are the side effects of nalmefene?
pulmonary edema
What is methylnaltrexone?
quaternary opioid receptor agonist
doesn’t penetrate the CNS b/c it is highly ionized
attenuates morphine induced delayed gastric emptying
decreases incidence of nausea
True or false: If you have an allergy to fentanyl, you’re allergic to morphine.
False they do not cross-react
also true opioid allergies are very rare- mostly histamine release, orthostatic hypotension, and N/V
Opioid immune modulation
chronic opioid use can compromise immune function
opioid receptors are present on immune cells & allows for immunosuppression-depression of NK cell
following prolonged exposure or abrupt withdrawal
pain itself can also impair immune function
Opioids are shown to decrease
the amount of anesthetic gas required
What are the advantages of PCAs?
decreased healthcare provider workload, increased patient satisfaction, lower opioid consumption, inherent safety
What PCA in the first stage of labor has been shown to provide good analgesia while minimizing neonate effects?
remifentanil
Post surgery we tell moms to
dump for 24 hours even though concentration of fentanyl & sufentanil is negligible in breast milk
Where do neuraxial opioids target?
placed intrathecally to target Mu receptors in the substantia gelatinosa in the spinal cord
Unlike local anesthetics, neuraxial opioids
do not result in sympathectomy, sensory block or weakness
epidural placement of opioids results in:
Mu receptors and systemic absorption
offers minimal to no over IV administrtion
uptake into fat, systemic absorption, and diffusion across dura
With neuraxial opioids,
epinephrine can enhance intrathecal effects of morphine
Epidural injection of neuraxial opioids results in
similar blood concentrations produced by IM injection
Pharmacokinetics of neuraxial opioids:
uptake into fat, systemic absorption or diffusion across dura
dependent on liphophilicity, only 3% of epidural
morphine crosses the dura to enter the CSF
Less lipid soluble drugs more likely to stay in CSF
morphine movement can result in delayed
depression of ventilation
coughing and straining can facilitate this
lumbar to cisterna magna (1-2 hours) 4 and lateral
ventricles (3-6 hours)
What are the side effects of neuraxial opioids?
Dose dependent
Pruritis- related to cephalad migration and interaction with trigeminal nucleus
N/V
urinary retention- common in young males d/t interaction of opioid with spinal cord receptors in the sacrum
depression of ventilation- CSF migration and interaction with ventral medulla (morphine)
pulse ox, oxygen
Additional side effects of neuraxial opioids
sedation
myoclonus rare
reactivation of herpes virus (trigeminal nucleus)
miosis, nystagmus, and vertigo (reversible with naloxone), delay in gastric emptying, priapism
spinal cord damage (needs to be preservative free!)
