Opioids Flashcards
2 opioid structures
phenanthrene
benzylisoquinolines
Opiate
term used to designate drugs derived from opium
Opioid
all substances;
natural & synthetic
that bind to opioid receptors and produce agonist effect
Opioid classification
Natural occurring
–Morphine
Semisynthetic analogs of morphine
- –Heroine
- –codeine
- –Hydromorphone [[Dilaudid]]
Synthetic
–Exogenous [[4 groups]]
4 types of synthetic opioids
[[exogenous]]
Morphinan derivatives
Diphenyl derivative
Benzomorphans
**Phenylpiperdines
believed that synthetic opioids; [[exogenous]] mimic the activity of endogenous [[naturally occurring; enkephalins, endorphins and dynoprhins]] at the opioid receptors
Morphinan derivative
type of synthetic opioid [[exogenous]]
- Levorphenol
- Butorphenol
becoming popular to use for withdrawal
Diphenyl Derivative
type of synthetic opioid [[exogenous]]
- METHADONE
used for withdrawal; but can get addicted to methadone
Benzomorphans
type of synthetic opioid
[[exogenous]]
- Phenazocine
- Pentazocine
PHENYLPIPERDINES
type of synthetic opioid [[exogenous]]
OR DRUGS
- Meperidine [[demerol]]
- Fentanyl
- Alfentanil
- Sufentatil
- Remifentanyl
Opioid receptor activity classification
Agonist
Partial Agonist
Mixed agonist/ antagonist
Antagonist
Agonist
full mu receptor effects
partial agonist
Regardless of dose can not produce full mu receptor effects like morphine
Buprenorphine
mixed agonist/ antagonist
agonist at other opioid receptor [[kappa or delta]] but antagonist at mu receptor
ex. Nalbuphine ; reverses resp. depression
[[agonist at kappa; antagonist at mu]]
Antagonist
inhibits mu receptor activity
ex. Naloxone [[Narcan]]
reverses opioid
Opiate Receptors
mu [[mu1 and mu2]]
kappa
delta
3 endogenous agonists
[[naturally occurring]]
Enkephalins
endorphins
dynorphins
Opioid and pain modulating systems
- ANTInociceptive; down regulates pain receptors
- Inhibits excitatory neurotransmitters [[Substance P]]
Mu 1
Supraspinal [[BRAIN]] Analgesia
Euphoria
Miosis [[pupil constriction]]
Bradycardia [[DIRECT action on vagus nerve]]
Urinary Retention
ALL endogenous and exogenous [[synthetic]] opioids work on Mu1
Mu 2
SPINAL analgesia
Physical Dependence
hypoventilation
Constipation
All endogenous [[natural]] and exogenous [[synthetic]] agonists act on Mu2
Mu receptors
Primarily in the CNS;
Brain and Spinal cord
some periphery
Mu1
Mu2
ALL endogenous [[naturally occurring]] and exogenous [[synthetic]] agonists act on Mu receptors
Bradycardia
Mu1 effect
DIRECT effect on Vagus nerve
Kappa receptors
ONLY Dynorphins work on KAPPA
Supraspinal[[Brain]] and spinal Analgesia
Dsyphoria [[Dynorphins, kappa]]
Sedation
Miosis [[constricted pupils]]
Diuresis
Delta
ONLY Enkephalins work on DELTA
Supraspinal [[Brain]] and spinal Analgesia
hypoventilation
physical Dependance
constipation and urinary retention
Opioids on G coupled opioid receptors
-Suppression/ inhibition of neurotransmitter [[substance P]]
-decreases adenylyl cyclase; cAMP
presynaptic
postsynaptic
G alpha i; decreases cAMP
[[increased conductance of K –> hyperpolarizes; decreases Ca into cell]]
Fentanyl in your epidural
makes a denser block
2 mechs of action
LA; block transmission via VGNaC
opioid activity on Mu receptors but mostly Mu2 [[ spinal analgesia; M2]]
Explain the mechanism of action of Opioids
opioids work on G alpha i opioid receptors
G alpha i
decreased cAMP
increases K conductance
[[hyperpolarizes]]
increased K out of the cell
hyper polarizes the cell and inhibits VGCa and decreases Ca into the cell
*when you have pain Ca is sent into the cell and releases NT [[substance P]] signals pain
by increasing K conductance and hyperpolarizing the cell it decreasing Ca into cell and decrease the release of pain NT
decreasing nociceptive [[pain]] receptor activity
Activation of Receptors can be
Direct; directly decreases neurotransmission
[[decreases Ca into cell]]
inhibits the release of excitatory NT [[substance P]]
Opioids onset of action
higher % not protein bound
higher % unionized
^faster onset of action
all opioids are weak bases
B + B = nonionized!
B + A = ionized
[[pt is acidotic pH under 7.35; will need a larger dose; more ionized]]
only unionized and not protein bound can diffuse
Anomaly Opioid
Sufentanil
20% nonionized
93% protein bound
NOT Highly nonionized and highly protein bound
[[would think it would be a weaker; slow onset]]
BUT 1000x stronger than morphine
VERY diffuse-able [[partition coeff. 1727]]
*attributed to molecule size/ structure
Drugs in potency order
most potent to least
Sufentanil
Remifentanil
Fentanyl
Alfentanil
Dilaudid
Morphine
Demerol
more potent; smaller dose
Factors that alter pharmacokinetics of Opioids
Age
-neonates; give less [[decrease rate of elimination; bc immature CYP 450]]
-elderly; give less
[[weaker BBB]]
Weight
dose based on ideal body weight [[not actual]]
Renal Failure
decrease dose
Hepatic failure
decrease dose
^both kidney and liver failure will effect metabolism and elimination oof opioid
DECREASE DOSE
Spinal Analgesia
analgesia produces by receptor activation in the spinal cord and dorsal root ganglion
pain [[sensory; afferent; approaching; dorsal root ganglion to the dorsal horn of gray matter –> laminae II and III]]
pain signals synapses in the substantial gelatenosa [[laminae II & III]]
Direct stimulation of these receptors produces intense analgesia [[pain relief]]
how?
Gi; decrease cAMP; increase K conductance; decrease Ca into cell decrease/ inhibit release of substance P [[pain NT]]; decreases activity at nociceptive [[pain]] receptors
Mu2 and kappa and delta
Supraspinal [[BRAIN]] Analgesia
analgesia produced by receptor activation in the BRAIN [[periaquaductal/ periventricular gray matter]]
Mu1 and kappa and delta
Opioids in the Epidural space
more lipophilic drug will go right into venous system and you’ll have an immediate response; less lipophilic delayed response
less lipophilic drug more CEPHALAD movement; doesn’t diffuse right away so travels up
less lipophilic drug more cephalic movement
Morphine more cephalic movement than Fentanyl
CNS effects of Opioids
Analgesia
Euphoria
Sedation; Drowsiness/ sleepy
respiratory depression
miosis
nausea [[direct via chemoreceptors; indirect via GI]]
decrease in CBF and ICP [[modest]]
**NO AMNESIA or ANESTHESIA
[[big doses in cardiac OR can get anesthesia but NO amnesia –> give Benzes or gases
Cardiac effects of Opioids
ALL dose dependent
no impairment of CV function
-dose dependent Bradycarid
Cardiac effects of Opioids
ALL dose dependent
no impairment of CV function
-dose dependent Bradycardia
decreases workload and increases supply; decreases demand
[[except DEMEROL; tachycardia]]
- vasodilation
- decrease CO and BP
What opioid does not produce bradycardia
Meperidine [[DEMEROL]]
tachycardia
demerol structure similar to atropine; antimuscarininc effects
What opioid does not produce bradycardia
Meperidine [[DEMEROL]]
tachycardia and
DIRECT myocardial depression
demerol structure similar to atropine; antimuscarininc effects
What combination can cause CV depression
Morphine and Nitrous
**not with morphine alone
Ventilatory effects of Opioids
dose dependent respiratory depression
[[give more; more depression]]
**drop RR but increase TV
[[slower deeper breaths]]
hypoxia and hypercarbia
[[lower RR blowing off less C02]]
decrease chest wall compliance; muscle rigidity
[[think fent–> right chest]]
constricts pharyngeal and laryngeal muscles
NONtherapeutic ventilatory effects
decrease RR
increase TV
decrease hypoxic ventilation drive [[normal person its ok, C02 level is drive to breath; can become a problem in COPD patient]]
ventilatory response curve is shifted the the R
[[takes more C02 two get brain to breath; when waking pt up let C02 level rise; will need much higher C02 level to start breathing r/t opioids]]
Respiratory depression effects with different opioids
Peak of respiratory depression is slower with morphine than with Fentanyl
respiratory depression with morphine lasts longer than with fentanyl
Why? bc fentanyl is more lipophilic
respiratory depression right away
[[give morphine 30 min before bringing pat to pacu fentanyl you can give 5 min before bringing them to pacu]]
Factors that increase magnitude and duration of opioid induced respiratory depression
larger opioid dose
synergistic effect
[[opioid given with other anesthetic]]
*speed of injection
continuous vs intermittent injection
decreased clearance
liver and kidney failure pt
alkalosis
B + B = more nonionized
more crosses BBB
age
lower does in babies; immature CYP 450
lower dose in elderly; weaker BBB
secondary peak in plasma level from reuptake of opioid in muscle, fat, lungs and intestine
[[fentanyl first pass pulmonary; sits in lungs and comes back for second peak]]
Skeletal muscle effects of opioids
Skeletal muscle rigidity
^makes ventilation difficult and sometimes impossible
[[decrease chest wall compliance]]
*give some muscle relaxant
- laryngeal muscle
- inhibition of GABA
- increase in dopamine
Renal/ GI/ Liver effects of Opioids
increased peristaltic tone of ureters
[[Mu1, kappa and delta receptor activity cause s urinary retention; now they also have a sense of urgency]]
**blocked catecholamine release and cortisol
[[reduced stress response during surgery]]
spasm of sphincter of oddi [[spinchter between GI and gallbladder]]
constipation; decreased GI motility
[[Mu2, kappa and delta receptor activity]]
prolonged gastric emptying
[[indirect effect of Nausea]]
Nausea direct effect –> chemoreceptors
How do you treat spasm of sphincter of oddi
GLUCAGON
-reverses the spasm
Pruritis caused by opioids
‘fentanyl nose itch’
cause unknown
histamine release with demerol and morphine can cause the itch
occurs mostly on face and nose
Opioids that release Histamine
Morphine
Demerol
Neuraxial [[epidural]] effects of Opioids
opioids placed in epidural space can undergo uptake into
- fat
- systemic absorption
- diffusion into CSF
*diffusion into CSF depends on lipid solubility [[just like all diffusion]]
more lipid soluble drug faster diffusion into CSF; quicker peak CSF concentration
more lipid soluble less cephalad movement bc diffuses into CSF so quickly
less lipid soluble more cephalad movement bc doesn’t diffuse into CSF as quickly
morphine more cephalad movement than fentanyl
[[more less lipid soluble than morphine]]
Side effects of neuroaxial [[epidural]] opioid use
-purities
‘fentanyl nose itch’
-N/V
[[direct via chemoreceptors
indirect via prolonged gastic emptying GI]]
-urinary retention
-ventilatory depression
[[more rapid with lipophilic agents]]
cephalad migration
more pronounced in less lipophilic drugs
MORPHINE
natural occurring; endogenous
poorly lipid soluble; highly ionized and protein bound 23% nonionized 35% protein bound 1 potency E1/2 t 1.7 - 3.3 hours [[DOA 4 hours]]
Histamine Releaser
Active metabolite
Morphine-6-glucuronide
IM peak effect 45 min
IV effect 15-30 min
effects;
analgesia
euphoria
sedation
nausea
purities
dry mouth
ventilatory depression [[slower effect than fentanyl]]
Bradycardia [[direct effect of vagus and inhibition of SA node]]
metabolized by the liver
kidneys –> extra hepatic metabolism or morphine
Renal Failure don’t give morphine
Morphine Active Metabolite
Morphine-6-glucuronide
** active metabolite stronger than morphine
Morphine and Bradycardia
DIRECT effect of the vagus nerve and inhibition of SA node
What patient should morphine be avoided in
RENAL FAILURE
Meperidine [[Demerol]]
synthetic [[exogenous]]
-Phenylpiperdine
Only Opioid with DIRECT cardiac depressant effects
ACTVIE metabolite;
normeperidine
^lasts ups to 3 days [[can cause seizures]]
only 1/2 as potent as meperidine
structurally similar to atropine
[[exhibits anti-muscarinis effects]]
blocks VGNaC [[like Locals]]
potent alpha 2 receptors agonist
[[calms patient; sedation]]
1/10th as potent as morphine 7% nonionized 70% Protein bound E1/2t 3-5 hours [[DOA 2-4]]
produces the same amount of euphoria, sedation and analgesia as morphine; but 1/10th as potent
used to treat post shivering
[[kappa and alpha 2 receptor activity]]
Meperidine is the only opioid with
DIRECT cardiac depressant activity
Active metabolite of meperidine
normeperidine
lasts up to 3 days but only half as potent as meperidine
long duration of active metabolite can cause seizures
What another use for meperidine
treats post op shivering
[[activity on kappa and alpha2]]
What patient do you avoid meperidine in
Seizure patient
active metabolite hangs around a long time [[risk for seizures]]
Hydromorphone [[Dilaudid]]
Semisynthetic; analog [[derived]] from morphine
5 potency
[[5 x as potent as morphine]]
DOA [[4 hours]]
need q 4 hour dosing
rapid elimination and redistribution
more sedation
less euphoria
^compared to morphine
Fentanyl
synthetic [[exogenous]]
-Phenylpiperdine
more lipid soluble than morphine *faster onset 100 potency [[100 x more potent than morphine]] 8.5% nonionized 84% protein bound
shorter DOA than morphine
[[but DOA can be longer with multiple doses or infusion]]
Very CV stable [[hemodynamic stability]]
**good for helping with HR and BP changes with intubation
75% of initial dose undergoes first pass pulmonary uptake into the lungs
rapid redistribution to inactive tissue;
fat
muscles
lungs
multiple IV doses OR continuous IV infusion can SATURATE inactive tissue
**shut off infusion 45 min- 1 hour before case ends
plasma concentration DOES NOT decrease rapidly
DOA is prolonged
[[2nd peak plasma concentration]]
Fentanyl is unique by
75 % of initial dose undergoes first pass pulmonary uptake
plasma concentration does NOT decrease rapidly and DOA is prolonged
^2nd peak plasma concentration
large Vd because more lipid soluble
Whats causes 2nd peal plasma concentration of Fentanyl
75% of initial dose goes to the lungs [[inactive tissue]]
then mobilized from lung
can saturate your reserve [[accumulate in the lungs]] with multiple doses or continuous infusion
DOA can be prolonged from this second peak
**turn infusion off 45 min -1 hour before the case
Clinical uses of Fentanyl
PAIN
analgesia adjunct for surgery
Blunts stimulation of incision; intubation
[[prevent the SNS response]]
very CV stable
[[large dose can be sole anesthetic]]
wide range of doses
1 - 20mcg/kg
cardiac can be 50 mcg/kg
*fentanyl lollipop for pediatrics
5-20 mcg/kg
*45 min prior to induction
Sufentanil
Syntheic [[exogenous]]
-Phenylpiperdine
–Fentanyl Analog
[[also undergoes first pass pulmonary effect]]
–CV stable [[like fentanyl]]
[[helps decrease SNS stem with intubation/ incision]]
**most potent
1000 x more potent than morphine
and
10 x more potent than fentanyl
2x more lipid soluble than Fentanyl
20% nonionized
Highly protein bound 93%
ACTIVE metabolite;
Desmethylsufentanil
rapidly metabolized by the liver
E1/2t 2 - 5 hours
Active metabolite of Sufentanil
desmethylsufentanil
**weak
Clinical uses for Sufentanil
adjunct for surgery and induction
used as infusion for OUTpatient surgery
*turn off 30 min before; as opposed to 45- 60 with fentanyl
[[QUICK on QUICK off]]
compared to morphine and fentanyl;
produces quicker induction
earlier emergence
earlier extubation
Alfentanil
synthetic [[exogenous]]
–Phenylpiperdine
–Fentanyl Analog
[[blunt SNS stim]]
10 - 20 x more potent than morphine
1/5th as potent as fentanyl
RAPID onset [[1.4 min]]
89-90% in nonionized state
fent [[6.8 min]]
sufentanil [[6.2 min]]
Highly protein bound 92%
*even though more protein bound than fentanyl; greater diffusion than fentanyl
Onset of action
Fentanyl
6.8 min
onset of action
Sufentanil
6.2 min
Onset of action
Alfentanil
1.4 min
Clinical uses of Alfentanil
RAPID onset [[1.4 min]]
90% nonionized
useful for blunting hemodynamic responser to noxious stim [[intubation; incision]]
used for infusion in OUTpatient surgery
Remifentanil
synthetic [[exogenous]]
- -Phenylpiperdine
- -chemically similar to fentanyl
- *unique r/t ester linkage
- -chemically similar to fentanyl
100 x more potent than morphine
[[slightly more potent than fentanyl]]
-metabolized by tissue/ plasma esterase
- rapid onset
- short DOA [[plasma esterase]]
Small Vd
minimal accumulation in tissues even with infusion
Clinical uses of Remifentanil
blunt noxious stim
[[just like fentanyl and other analogs]]
infusion for intermediate/ long surgeries; where rapid recovery is desired
- neurosurgery [[scoliosis]]
- outpatient surgery
- great for extracting eggs
[[very painful procedure but once procedure is over pain is gone and patient goes home]]
Why is Remifentanil good for neurosurgery
able to quickly wake patient up halfway through case to check motor movement/ reflex
Agonit/ Antagonist
ANTAGONIST at Mu
Agonist at Kappa
NO ventilatory depression !!
less physical dependance
Analgesia with little ventilatory depression
side effects similar to opioid agonist
can have some dysphoria from kappa receptor
[[Kappa receptor effects]] analgesia [[supraspinal and spinal]] dysphoria sedation mitosis diuresis
ex. Nalbuphine [[Nubain]]
Butorphenol [[Stadol]]
Nalbuphine [[Nubain]]
Agonist/ Antagonist
analgesia = to morphine
works on Kappa
[[and sigma]]
antagonizes opioid induced respiratory depression
**analgesia with no ventilatory depression
no adverse CV problems
**reverses spasm of sphincter of Oddi [[antagonizing]]
Butorphenol [[Stadol]]
Agonist/ Antagonist
agonist on Kappa
weak antagonist or partial agonist of Mu [[dose dependent]]
5 x more potent than morphine for analgesia
**nasal spray for migraines
Naloxone [[Narcan]]
Antagonist
Pure opioid antagonist
Blocks receptor site;
reverses analgesia and respiratory depression
Competitive antagonist for Mu, Kappa and Delta
[[can be overcome with higher opioid doses]]
DOA less than opioids
[[use trip bc shorter acting than the opioid your reversing]]
Titratable
[[dilute give slowly and tribute drip to effect]]
onset 1-2 min
reversal is dose dependent
Reversal is NOT benign
Reversal effects with Narcan
tachycardia
HPTN
ventricular dysrhymias
severe pain
pulmonary edema in patient with CV disease
[[pulmonary HPTN, hydrostatic pulmonary edema]]
pulmonary edema in healthy patient
[[catecholamine release, increased SNS activity; that you blunted with opioid, increased preload]]
Catecholamines
epinephrine
norepinephrine
Which opioids produce active metabolites
moprhine
[[morphine-6-glucuronide]]
meperidine
[[normeperidine]]
sufentanil
[[desmethylsufentanil]]
