all exogenous substances both natural & synthetic binding to opioid receptors producing “morphine-like” effects
What is the EFFECT of opioids?
Opioids produce analgesia without loss of touch (which make it different than local anesthetics), proprioception, or consciousness (except in large doses)
*operate on different receptors than local anesthetics
What are the 3 classifications of opioids?
What is a common antagonist of opioids?
naloxone most used and most familiar with
TRUE or FALSE. We give as much opioids as we want because we can reverse it.
FALSE! we don’t generally give an agonist
thinking we can reverse it w/antagonist
*Much more likely to reintubate if apnic in PACU than to give opioid antagonist.If we were to give it we’d dilute it down significantly.
What are some hazards involved w/using an opioid antagnonist.
can cause SNS stimulations as result of reversal of analgesia, get HTN, tachycardia, arrhythmias (VF) and pulmonary edema.
What drug is the the Phenanthrene (T shaped) structural class of drugs?
What drugs are in the Phenylpiperidines structural class of drugs
Fentanyl and Meperidine
What does Hemming's refer to Morphine's structure as?
Semisynthetic opioids result from substitution of the morphine molecule (give an example)
i.e. Codeine = methylmorphine
TRUE or FALSE. Synthetic opioids are completely synthesized not just morphine modified
TRUE! (ex: fentanyl family)
What are the 4 classifications of opioid receptors?
Mu 1, Mu 2
Sigma (probably not an opioid receptor)
Where are the receptors that opioids act on?
CNS, mostly brainstem & spinal cord
(pre and post synaptic areas in CNS)
What are the endogenous ligands of the opioid receptors?
How do we get the analgesic effect of the opioids?
come from ability to directly inhibit the ascending transmission of info from spinal cord, interrupting the pain circuits
Hemming's says they inhibit release of substance P from primary sensory neurons in the dorsal horn. This mitigates the transfer of painful sensations to the brain. Change the affective response to pain, they don’t complete block the pain but make the patient care less about the pain.
How do opioids work once they attach to the receptor?
Part of the guanine (G) protein-coupled receptors (like muscarinic Ach, GABA, adrenergic, etc)
Inhibition via adenyl cyclase decreasing conductance of voltage-gated calcium channels or opening outward flowing potassium channels
Receptor activation causes:
--↓ neurotransmission 2° presynaptic inhibition of neurotransmitters including Ach,dopamine, norepi, substance P
--Postsynaptic inhibition of evoked activity
--↑ potassium conductance → hyperpolarization, calcium channel inactivation, or both → mediate ↓ in neurotransmitter release
Which two receptors cause depression of ventilation? (This was highlighted in a chart on her slide)
Mu2 and Delta
What is the only receptor that does not cause supraspinal analgesia?
*They all cause spinal analgesia
Which receptors have low abuse potential?
Which receptor causes sedation?
Which receptor causes dysphoria and sedation?
Which receptor causes Euphoria?
Which two receptors cause miosis?
Which receptors cause marked constipation?
Which two receptors cause physical dependence?
What receptor causes bradycardia and hypothermia?
Which two receptors cause urinary retention?
Endorphins act as an agonist on what receptor (s)?
Mu1 and Mu2
Morphine acts as an agonist on what receptor(s)?
Mu1 and Mu2
Synthetic opioids act as an agonist on what receptor(s)?
Mu1 and Mu2
The antagonists act on what receptor (s)
All of them!
What are the 4 clinical effects of the Mu receptor and the 4 agonist
What are the 2 clinical effects of the Kappa receptor and the 5 agonists?
What are the 3 clinical effects of the Delta receptor and the 2 agonists?
Although Stoelting does not include the Sigma receptor is not a true opioid receptor, what are the clinical effects and agonists of the Sigma receptor?
List the following drugs in order of pKa (lowest to highest):
Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil
What are the ONLY TWO drugs with pka less than pH and what does this mean for the pharmokinetics?
--this means the % ionized is lower than the rest, (they are basic drugs) so these drugs have a quick onset!
List the following drugs in order of % ionized (lowest to highest): Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil
Hint: it's the same order as pKa!
All the opioids are acidic or basic?
List the following drugs in order of partition coefficient (lowest to highest): Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil
What does the partition coefficient of opioids relate to?
refers to lipid solubility
List the following drugs in order of protein binding: Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil
(++, +++, or ++++)
+++Meperidine, Fentanyl, Remifentanil
++++Sufentanil & Alfentanil
List the following drugs in order of the non-ionized fraction (+, ++, +++, ++++)
+ Meperidine & Fentanyl
++ Morphine & Sufentanil
Which drug is highly non-ionized?
Alfentanil has a more rapid onset & shorter duration of action than Fentanyl even though it is less lipid-soluble because of….(what two things)
High non-ionized fraction at physiologic pH
Significant amounts of lipid-soluble opioids can be retained by the lungs (first-pass uptake) & amount of uptake depends on… (what 3 things)
*this is very true for fentanyl
Prior accumulation of another drug - ↓ uptake
History of tobacco use - ↑ uptake
Inhalation anesthesia -↓ uptake
Describe this picture
See a delay in onset of action at effect site (Brain) w/regard to fentanyl as opposed to alfentanil.
Hemming's: refers to this as latency to peak effect. (new terminology in that text).
Describe this picture
Time to equilibration between brain and effect site (which produces rise in effect site concentration)
Alfentanil, Fentanyl, and then Sufentanil is last.
List the following drugs in order of clearance (ml/min): Morphine, meperidine, Fentanyl, Sufentanil, Alfentanil, & Remifentanil
(lowest to highest)
List the following drugs in order of Vd (low to high): Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, & Remifentanil
Describe the biotransformation of the opioids
Morphine conjugated with glucuronic acid to active metabolite
Meperidine is de-methylated to normeperidine (active metabolite)
Fentanyl, sufentanil, alfentanil, to inactive
Remifentanil by ester hydrolysis
What are the drugs w/active metabolites
Morphine (glucoronic acid)
Clearance of most opioids is dependent on what?
hepatic blood flow
Why is there a short elimination 1/2 life of alfentanil?
Morphine is principally metabolized by conjugation in the liver into what?
the resulting water-soluble glucuronides (morphine 3-glucuronide & morphine 6
glucuronide) which are excreted via the kidneys.
Morphine 6 glucuronide is more potent and long lasting than Morphine itself.
What happens if a patient has renal failure and received meperidine?
If pt. as renal failure (normeperidine not eliminated) then can have seizure activity.
List the following drugs in order of elimination 1/2 time (hours)---from lowest to highest:
Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, and Remifentanil
List the following drugs in order of context-sensitive 1/2 time (4 hr infusion) in minutes: (Low to high)
Fentanyl, Sufentanil, Alfentanil, Remifentanil
List the effect site (blood/brain) equilibration in minutes for the following drugs (From low to high): Fentanyl, Sufentanil, Alfentanil, Remifentanil
What is the advantage to Remifentanil?
Rapid biotransformation. (Esters)
Terminal elimination ½ life is less than 10min.
Remifentanil is great because you can titrate but need analgesia on board in PACU so it requires a bit of a plan. (give Morphine or Fentanyl towards end of case for adequate pain control post-op)
Remifentanil metabolized by ester hydrolysis.
Pseudocholinesterase deficiency does not effect its metabolism
For Fentanyl and Morphine, the Vd is pretty much the same, what is very different?
huge difference in protein binding and partition coefficient.
Protein binding (Fentanyl 84 & Morphine 35)
Partition coefficient (Fentanyl 955 & Morphine 1)
What are the effects of opioids on the CV system?
Morphine & meperidine cause histamine release so ↓BP & ↓ SVR
Fentanyl family associated with vagus mediated bradycardia (high doses)
What are the effects of opioids on the respiratory system?
↓response to CO2
↓ hypoxic drive
** chest wall rigidity: centrally mediated hypertonus of striated muscle
(more depression of RR than TV)
What are the effects of opioids on the CNS?
↓ CBF, ICP, CMRO2 but < barbs/benzos
Stimulate chemoreceptor trigger zone
What are the effects of opioids on the Endocrine system?
block stress hormone release > volatiles
Explain the chest wall rigidity caused by opioids
is a centrally mediated hypertonus of all striated muscle.
It can be severe enough to prevent ventilation
that you need neuromuscular blocker.
Most common w/highly lipid soluble opioids,
most assoc. w/fentanyl.
Dose related, more likely to occur the higher the dose (all at once)
It’s refered to as chest wall or truncal but involves all striated muscle (includes pharyngeal and laryngeal muscle—narrow)
What effect do opioids have on bile duct pressure?
they increase it
What drug increases HR because it's related to Atropine?
How do opioids compare to benzos and barbs for the cerebral effects (CBF, CMRO2, ICP)?
MUCH less of reduction
What is the prototype and standard drug upon which all other drugs are measured?
Name 2 kinetic key points regarding Morphine
1. Low lipid solubility
2. Metabolism to:
a) Morphine-3-glucuronide (75-85%) - inactive
b) Morphine-6-glucuronide (5-10%) – active with potency & duration greater than that of morphine
Sue said the metabolites were IMPT :)
TRUE or FALSE. Morphine is better at relieving continuous dull pain rather than sharp intermittent pain, works best if given preemptively.
How long does Morphine take to peak in CNS? Why does only 1/10th reach the CNS at time of peak?
Takes about 15-30min to peak in CNS (After IV injection).
Probably only a 1/10th (0.1%) reaches CNS at time of peak, because of lipid solubility as well as high degree of ionization.
What happens to morphine if we make the patient alkalotic by hyperventilating?
The non-ionized fraction will increase, and therefore passage of drug into CNS will be enhanced.
If resp acidosis (Flip side) then we would expect more ionized however w/resp acidosis what happens there will be increase CBF d/t hypercarbia, increase in CBF will deliver whatever non-ionized drug is there, better delivery to CNS. This is thought to be a more important factor (Inc. CBF) than the increase in ionization d/t hypercarbia.
What are the side effects of Morphine?
Histamine release – minimize by slow injection, IV fluids (preload)
Orthostatic hypotension → venous pooling
What are the uses of Morphine?
Acute pulmonary edema
--↓ perception of SOB
--↓ preload & afterload (because of venous pooling)
What is the dosing, onset, peak, and duration of Morphine?
--Analgesia: 1 -15 mg IV
--Induction: 1 mg/kg IV
Onset: less than 1 minute
Peak: 5-20 minutes
Duration: 2-7 hours
Analogs of Meperidine include what family?
the fentanyl family
What is Meperidine derived from?
TRUE or FALSE. Structurally similar to atropine & possesses a mild atropine-like anti-spasmodic effect
How potent is Meperidine compared to Morphine?
1/10th as potent as morphine so 75-100 mg = 10 mg morphine
What are the kinetic key points for Meperidine?
Metabolism by demethylation & hydrolysis to:
--Normeperidine which has elimination ½ life of 15 hours, is ½ as active as meperidine as
analgesic, produces CNS stimulation with toxicity & can cause seizures & myoclonus
What are the side effects of Meperidine?
↑ HR – remember structurally similar to atropine (rarely bradycardia)
*↓ myocardial contractility in large doses (unique among opioids)*
Delirium & seizures (2° normeperidine-metabolite)
What are the uses of Meperidine?
Suppressing postop shivering (kappa receptors)
Small doses 12.5mg will help w/that
What is a major drug interaction associated w/meperidine?
Contraindicated in patients on MAOIs (serotonin syndrome)
Serotonin syndrome: excess availability of serotonin in CNS characterized by confusion, fever, shivering*, diaphoresis, ataxia, hyperpyrexia, myoclonus, & diarrhea.
Morphine and Codeine ok, alfentanil and remifentanil are ok.
What is the dosing, onset, peak, and duration of Meperidine?
--Analgesia: 12.5-100 mg (0.5-2 mg/kg)
Onset: less than 1 minute
Peak: less than 1 hour
Duration: 2-4 hours
What is the chemical structure of Hydromorphone (Dilaudid)
Phenathrene (hydrogenated ketone of morphine)
What is the potency of Hydromorphone (Dilaudid) compared to morphine?
5 - 6 times as potent as morphine
Less opioid-related side effects than with morphine
May cause chest wall rigidity
Caution in the elderly
What are the kinetic key points of hydromorphone (dilaudid)
Vd: 4 L/kg
8-20% protein bound
Biotransformed in the liver
Active metabolites are:
Inactive metabolite is hydromorphone-3-glucoronide
Has been the preferred opioid for patients with renal impairment BUT hydromorphone-3-glucuronide can accumulate in renal failure & cause neuroexcitation & cognitive impairment
(caution is advised)
What does Hemming's say about Hydromorphone compared to Morphine?
Slightly more duration of action than morphine.
More sedation and less euphoria than morphine.
What is the dosing, onset, peak, and duration of Hydromorphone?
--Analgesia: 0.5-2 mg
Onset: 15 min
Peak: 30-60 minutes
Duration: 4-5 hours
(0.2mg incremental doses in 5min for total of 1mg) Small doses, received a lot of drugs in OR, don’t want to leave in PACU w/resp compromise.
What is the chemical structure of Fentanyl?
Phenylpiperidine derivative synthetic opioid structurally related to meperidine (w/out nasty effects)
What is the potency of Fentanyl compared to Morphine?
75-100 times more potent than morphine
What are the kinetic key points of Fentanyl?
Faster onset & shorter apparent duration than
morphine because it is more lipid soluble and larger Vd. Faster onset, lipid soluble can go across BBB fast
Lungs act as large & inactive store w/estimated 75% of initial fentanyl dose undergoing first-pass pulmonary uptake which limits the amount of initial dose reaching systemic circulation
Saturation of inactive tissue sites → ↑ duration of action & context-sensitive half time (Repeated boluses will stack and saturate fat stores. Similar to thiopental, not high clearance and very lipid soluble)
What should we know about the metabolism of Fentanyl?
Fentanyl is extensively metabolized to norfentanyl by N-dimethylation. Norfentanyl is structurally similar to normeperidine. It is excreted by the kidneys and has less analgesic potency than fentanyl.
** note longer elimination ½ time (3-6 hours) compared with morphine (1.7-3.3 hours) even with apparent shorter duration (short acting, but not d/t eliminatioin...highly lipid soluble)
What are the advantages of Fentanyl?
--No myocardial depression
--No histamine release
Suppression of stress response
What are the side effects of Fentanyl?
Carotid sinus reflex control of heart is depressed → ↓HR
Chest wall rigidity
----Because it is so highly lipid soluble
Why should we be cautious when giving Fentanyl to an Elderly patient?
prolonged elimination. ½ time, decreased clearance could be r/t hepatic blood flow
What is the dosing, onset, peak and duration of Fentanyl?
a) Premedication/analgesia: 25-100 mcg (1.5 – 5 mcg/kg) IV
--With hypnotic: 1.5-5 mcg/kg
--With 70% nitrous oxide: 8 -23 mcg/kg
--High dose opioid: 50 mcg/kg
c) Intermittent bolus: 25 -100 mcg
d) infusion: 0.05-0.2 mcg/kg/min (anesthesia
Onset: 30 sec
Peak: 5- 15 minutes
Duration 0.5-1 hour
How can we prevent apnea when giving Fentanyl?
spontaneous breathing, give small dose of opioid, give 25mcg of fentanyl decrease
RR but 50mcg will make them apnic.
So give 25 and then another 25 a few min. later, achieve same analgesic effect without knocking out their RR.
What is Innovar?
Fentanyl and droperidol
(Referred to as neurolept anesthesia) because of issues w/droperidol (prolonged QT) inobar is no longer used
What is Sufentanil? What is it's potency compared to Fentanyl?
Fentanyl derivative, 10 times as potent as fentanyl
What are the key kinetic points about sufentanil?
Similar to fentanyl
Higher degree of ionization & protein binding than fentanyl so smaller Vd & shorter elimination ½ life
Metabolism by dealkylation & demethylation in the liver
*More lipophilic than fentanyl, 93% protein bound, as apposed to 80% of fentanyl (makes Vd smaller than fentanyl)*
What is the major side effect of Sufentanil?
sympatholysis with vasodilation but hemodynamic stability prevails
What is dosing, onset, peak and duration of Sufentanil?
--With hypnotic: 0.1 – 1 mcg/kg
--With 70% nitrous oxide 1.3 – 2.8 mcg/kg
--High dose opioid: 10 – 30 mcg/kg
b) Intermittent bolus: 5 -20 mcg
c) Infusion: 0.005 – 0.015 mcg/kg/min (anesthesia supplement)
Onset: 1-3 minutes
Peak: 3-5 minutes
Duration: 30 minutes – 1 hour
What is the potency of Alfentanil compared to Fentanyl?
1/5th as potent
(Derivative of fentanyl)
What are the kinetic key points of Alfentanil?
Peak brain effect in less than 1 minute
pKa of 6.8 so almost 90% is non-ionized at
Moderate lipid solubility but less than fentanyl so…
---Vd is smaller than fentanyl
---Highly protein bound (92%)
Metabolized by dealkylation & demethylation to inactive metabolites
What are the side effects of Alfentanil?
Chest wall rigidity in 90-100% of pts at dose of 150-175 mcg/kg (high dose)
? More hypotension & bradycardia than fentanyl or sufentanil
? More N/V
What is the dosing, onset, peak and duration of Alfentanil?
--With hypnotic: 10 - 50 mcg/kg
--High dose opioid: 120 mcg/kg
--Intermittent bolus: 250-500 mcg (5-10 mcg/kg)
b) Infusion: 0.5-1.5 mcg/kg/min (anesthesia
Onset: less than 1 min
Peak: 1-2 min
Duration: 10-15 min
When was Remifentanil approved? (it was on Sue's slide...)
Ultra short acting approved for use in 1996
What are the kinetic key points for Remifentanil?
Short duration of action due to metabolism (not redistribution)
Metabolism by blood & tissue esterases (not pseudocholinesterase)
Rapid recovery with return of spontaneous
ventilation in 2-5 minutes
No lingering analgesia (great for cases that need analgesia intraop but not a lot of pain post-op. Need to give another opioid prior to discontinuing infusion. Want to stay ahead of pain.)
What is the dosing of Remifentanil?
Induction: not suitable alone
Analgesia: intraop as continuous infusion 0.3-1 mcg/kg/min
What are the 4 partial agonist & mixed agonist-antagonist?
What partial agonist (or mixed agonist/antagonist) works on the Mu receptor?
What partial agonist (or mixed agonist/antagonist) works on the kappa receptor?
What is the advantage of the partial agonist (or mixed agonist/antagonist)
They don’t cause significant respiratory depression (ceiling effect) increasing dose doesn’t increase the response.
Stoelting: should be reserved for pt. that can’t tolerate the opioid agonist.
Hemming's: most common use periop is to
reverse resp depression from other opioids while maintaining analgesia.
** not commonly used in practice
How does the context sensitive half time of fentanyl compare to remifentanil?
fentanyl, as tissue stores get saturated, its different than remifentanil which is completely independent of infusion duration.
So the context sensitive 1/2 time of Fentanyl is very long (especially w/a long infusion) and Remifentanil, infusion time doesn't really matter