Opioid analgesics lecture part 1 Flashcards
Who was the first individual to hypothesize that perception of pain comes from the brain instead of the heart as previously believed?
Renee de Clarks with his drawing of Treatsy of Man
In general, where are opioid receptors located?
Centrally (brain & spinal cord)
can be located in periphery but not primary location!
What happens to pain receptors in patients with chronic pain?
pain receptors can be located peripherally at the site of pain and pain can be initiated anywhere along the pathway thus opioids are not best drugs for chronic pain
Why wouldn’t we inject an opioid at the surgical site?
there’s nowhere for the opioid to work on because our opioid receptors are not located there
What substances are released that send a pain signal when we have destruction of cells?
Substance P, calcitonin gene related peptide, serotonin, histamines; these cause neuroelectrical stimulation which create a nerve impulse
Why do we have endogenous pain modulation?
It is a survival benefit
Describe the transmission of pain/ pain pathway
we have injury to the phospholipid bilayer and substances are released (substance P, calcitonin gene related peptide, serotonin, & histamines)–> these substances create a nerve impulse along first order neuron–> synapse in the spinal cord at second order neuron in the dorsal root ganglion–> transmission to midbrain (3rd order neuron)–> brain sends signal to part of brain that is experiencing the pain via the 4th order neuron
Additionally have spinal reflex arc
What substances does the body release to modulate pain?
Endorphins, enkephalins, dynorphins, norepinephrine
What are the distinct classes of opium?
Phenanthrenes (morphine, codeine, & thebaine)
Benzlisoquinolines (papaverine, noscapine)
What is the role of opioid agonists (and what do they not do)?
Produce analgesia! analgesia is the lack of perception of pain
They do not produce loss of touch, loss of proprioception, or loss of consciousness (in appropriate dosages)
Semi-synthesized opioids are:
Modifications to the morphine molecule which result in heroin
What are naturally occurring opiates?
morphine & codeine
What is a synthetic opioid?
Not modified from a naturally occurring drug; created in a lab
-they do contain a phenanthrene nucleus but they are created rather than modified
What are the most common synthetic opioids?
Methadone (recent resurgence due to prolonged half-life) and phenylpiperidine- meperidine, fentanyl, sufentanil, alfentanil, and remifentanil
Where are our pain fibers located?
Rexed lamina 1, 2, and sometimes 5 in the dorsal horn
What is the mechanism of action for opioids?
Opioid receptors are G-protein-coupled receptors
Their principle effect is to decrease
neurotransmission
Mimic the actions of endogenous ligands- such as
enkephalins, endorphins, dynorphins, and
norepinephrine
Where do endogenous substances work to prevent pain?
They were pre-synaptically to inhibit release of acetylcholine, dopamine, norepinephrine, and substance P
they include: enkephalins, dynorphins, and endorphins
Where do exogenous substances work to modulate pain?
Endogenous substances work postsynaptically by attaching to GCPRs in which the second messenger causes increased K+ conductance and decreased function
What is another site of action for opioids?
NMDA receptors
In regards to their mechanism of action, opioids do not…
block nerve impulses (only way to do this is with LA)
alter responsiveness of afferent nerve endings to noxious stimulation
Where specifically in the brain are opioid receptors found?
periaqueductal gray- recognizes pain and tells body to limit it endogenously
locus coeruleus- related to alertness (dex also acts on this)
rostral ventral medulla
Where specifically in the spinal cord are opioid receptors found?
Primary afferent and interneurons of the dorsal horn
target rexed lamina 1, 2, and 5
What are the names of the opioid receptors?
Kappa, Sigma, Mu, & Delta
What do the Mu1 receptors cause?
BEAMU
Bradycardia, euphoria, analgesia (spinal & supraspinal), miosis, and urinary retention
What do the Mu2 receptors cause?
ALL THE BAD THINGS… ventilatory depression, physical dependence, constipation, analgesia (spinal)
What do the Kappa receptors cause?
activation results in the inhibition of neurotransmitter release
analgesia (supraspinal & spinal), dysphoria, sedation,
miosis, diuresis, lesser extent (hypoventilation & high-
intensity pain), agonist-antagonist often act principally
on K receptors (low abuse potential)
If we wanted to give an opioid that resulted in the least amount of respiratory depression and was less likely to cause urinary retention, what receptor would this opioid be acting on?
Kappa receptors…. kappa receptors also cause the least amount of pain control
Why don’t Kappa receptors have full efficacy when modulating pain?
Because they are agonist-antagonists
What do the Delta receptors cause?
it’s your typical opioid: physical dependence, reduced ventilation, constipation, analgesia (supraspinal & spinal) & urinary retention
Delta receptors respond to endogenous ligands known as enkephalins & they may also serve to modulate Mu receptor activity
What opioids are not metabolized in the liver?
All of them except remifentanil are metabolized in the liver
Opioids are primarily excreted ______
by the kidneys
Small dose effects of opioids are terminated by ____ whereas effects of multiple doses and infusions are terminated by ____
redistribution; metabolism
Pharmacogenetics
we have genetic variation in each one of us which determines our responsiveness to opioids
What are common CV side effects of opioids?
-In healthy patients, bradycardia w/ sustained BP
-Impairment of SNS response (orthostatic hypotension)… venous pooling & histamine release
-Does not sensitize the heart to catecholamines
does not affect hearts ability to be affected by
endogenous substances
Opioids are _____ with these drugs____ to cause myocardial effects
synergistic; with benzodiazepines & nitrous oxide
What is a positive CV side effect of opioids?
Sigma & Kappa receptors produce a cardiac protectant effect by enhancing myocardial resistance to oxidative and ischemic stresses
How do opioids affect the oxyhemoglobin curve?
They shift the curve to the right by making us less responsive to changes in CO2
Opioids act on Mu and Delta receptors in the brainstem…
to produce a dose-dependent depression of ventilation
What are common respiratory effects of opioids?
-interfere with pontine & medullary ventilatory centers- regulate rate and rhythm of breathing
-decreased responsiveness to CO2
by decreasing acetylcholine release in the medullary
center of the brain
Shift the CO2 response curve to the right
-Produce a dose-dependent depression of ventilation
What are additional respiratory effects of opioids?
- decreased RR accompanied by compensation in TV (think slow, deep breaths)
What are some bronchial effects of opioids?
Decreased ciliary action
Increased airway resistance
bronchial smooth muscle & histamine release
Factors that affect depression of ventilation:
advanced age or extremes in age
Natural sleep
amount of and tolerance to pain
What opioid is used for cough suppression?
Codeine is used for depression of medullary cough centers
Dextromethorphan- also has cough suppression component without analgesia or respiratory depression
What are common CNS effects?
- awareness possible
- sedative and euphoric effects; a sedated patient is not pain free
- decreased cerebral blood flow & possibly ICP
Opioids are most effect for what kind of pain?
acute, visceral, and dull
Anesthetic effects of opioids are two fold:
Inhibit ascending transmission of nociceptive information
activate descending pathways
Why would we use opioids cautiously with head trauma patients?
Opioids alter wakefulness, cause miosis, depression of ventilation, and increased sensitivity when BBB is compromised
Why do opioids cause miosis?
they act on autonomic nervous system component of Edinger-Westphal nucleus of oculomotor nerve
this can be antagonized by atropine
Muscle rigidity
-Opioids have no effect on nerve conduction (can’t cause muscle contraction)
-skeletal muscle hypertonus “truncal rigidity”
following large doses of opioid
related to mu receptors acting on dopamine &
GABA channels
evidence supports resistance due to laryngeal
musculature contracture (treat with naloxone or
NMB)
If you give an induction dose of a drug & you go to ventilate & cannot…
1st- stick in an oral airway (rules out masking issues)
2nd- If it’s an airway issue based on the drug, give a drug to combat the issue
In up to 60% of patients, morphine….
induces sedation that precedes analgesia
assumption that sleep occurs when pain is relieved
What do opioids do to the biliary tract?
Opioids cause spasm of biliary smooth muscle and the sphincter of Oddi
-Morphine can contract pancreatic ducts which can increase amylase and lipase levels and mimics acute pancreatitis
How would you reverse the smooth muscle spasm that opioids can cause in the biliary tract?
Give 2 mg Glucagon IV
It will not antagonize analgesic effects
How do opioids affect the GI tract?
-cause decreased gastric motility, propulsive activity, and emptying time
can increase risk of aspiration or delay drug
absorption
-Opioid-induced constipation
What can antagonize GI effects?
Methylnaltrexone is an opioid antagonist that only works in the gut
Why do opioids cause nausea & vomiting?
- stimulation of chemoreceptor trigger zone in the medulla (serotonin type 3 receptors & dopamine type 2 receptors)
- Increased GI secretions and delayed gastric emptying
What types of patients have reduced NV?
recumbent patients
What causes the genitourinary side effects of opioids?
opioid induced augmentation of detrusor muscle tone results in urgency but tone of urinary sphincter is enhanced making voiding difficult
Why might people receiving opioids have cutaneous changes?
Histamine release (not an allergy) which results in conjunctivial erythema & pruritis Morphine causes blood vessels to dilate resulting in warm, flushed skin
What opioid is the biggest culprit that causes pruritis?
Intrathecal morphine
Given the hydrophilicity of opioids, how does this effect placental transfer?
opioids readily cross the placenta which results in neonatal depression
-morphine has a greater effect than meperidine (think about potency)
Chronic use can cause neonatal physical dependence & naloxone may precipitate neonatal abstinence syndrome
Ventilatory effects of opioids act synergistically with which drugs?
benzodiazepines, amphetamines, phenothiazines, MAO’s, tricyclics
What effect does physostigmine and atropine have on opioids & why?
physostigmine- enhances & atropine-antagonizes b/c cholinergic system is a positive modulator of opioid analgesia
What is the triad of an overdose?
miosis, hypoventilation, coma (hypotension & seizures develop if arterial hypoxemia persists)
What is the treatment for an opioid overdose?
Mechanical ventilation, supplemental oxygen, antagonist
What opioids cause reflex coughing?
seen more so with fentanyl, sufentanil, and alfentanil
-not seen with morphine or hydromorphone
What are the two thoughts behind reflex coughing with administration of fentanyl, sufentanil, and alfentanil?
- imbalance of sympathetic and vagal nerve innervation
- Stimulation of juxtacapillary irritant receptors
Explain the relationship with tolerance & dependence?
We can develop tolerance without physical dependence but we cannot develop physical dependence without tolerance
What kind of tolerance can develop between all opioids?
Cross-tolerance b/c they are chemically related/act on similar receptors
Describe what happens with pharmacodynamic tolerance.
Since opioids are agonists we have desensitization and down-regulation; up regulation of cAMP
-can develop in 2-3 weeks… much quicker with more potent drugs
What are some s/s that don’t go away even when we develop a tolerance?
Constipation & miosis
What is a consideration with ketamine use in long-term chronic opioid abusers?
long-term opioid use activates NMDA receptors down regulating spinal glutamate receptors which may make them less responsive to ketamine
What are the symptoms of withdrawal abstinence syndrome?
Initial symptoms: yawning, diaphoresis, lacrimation, insomnia, & restlessness
Cramps, N/V, diarrhea peak at 72 hours then decline in 7-10 days
Tolerance is quickly lost
What is the onset of morphine?
15-30 minutes which is slow compared to other opioids making it not as useful in anesthesia
Describe the pharmacokinetics of morphine related to lipid solubility
only a small portion reaches the CNS d/t poor lipid solubility, high degree of ionization at physiologic pH, protein binding, and rapid conjugation in the liver
What does morphine do?
Produces analgesia, euphoria, sedation, and decreased concentration, nausea, body warmth, pruritis (nose), dry mouth, extreme heaviness
When should you give an opioid?
Preemptively before the pain pathway is activated
What kind of pain is morphine best for?
Slow, dull pain
Describe the metabolism of morphine
Morphine is primarily metabolized through conjugation with glucuronic acid via both the liver & kidneys; ok to give in liver patients but has significant renal metabolism so be careful
Due to Co2 changes…
there is increased cerebral blood flow b/c of vasodilation
What active metabolite of morphine are we concerned with?
morphine 6-glucuronide b/c it is more potent than morphine itself & has a longer duration of action
other metabolites include morphine 3-glucuronide (inactive), normorphine, and codeine
With morphine impaired renal function can result in
accumulation and unexpected respiratory depression
What is the clinical use of meperidine (demerol)?
anti-shivering postoperatively through activation of kappa receptors
Meperidine is structurally similar to
atropine & produces mild antispasmodic effects
Meperidine acts on what receptor site?
Mu-receptor agonist & kappa receptors
Meperidine’s potency related to morphine is
1/10th as potent
The duration of action of meperidine is
2-4 hours
Extensive first pass metabolism by the liver limits the oral usefulness of
meperidine
Meperidine has extensive metabolism to
Normeperidine (active metabolite) & meperidinic acid
What is the primary route of elimination for meperidine?
Renal excretion- pH dependent so the more acidic, the greater fraction of drug excreted unchanged
decreased renal function can result in accumulation of metabolites
What are side effects of meperidine?
may cause increase in heart rate, mydriasis (atropine like effects d/t structural similarity), high doses decrease myocardial contractility
delirium & seizures
can elicit serotonin syndrome in patients taking MAOI or fluoxetine
Crosses the placenta
less biliary tract spasm
withdraw develops more rapidly & is shorter in duration
Pearls of Meperidine:
structurally related to atropine & the implications of this are increased HR & mydriasis, clinical use 4.5 mg for shivering, don’t give in 80 year old pts. on dialysis
What is the elimination half-time of normeperidine?
15 hours and can exceed 30 hours in renal failure
Why are elderly patients more sensitive to normeperidine?
decreased plasma protein= increased circulating volume= exaggerated response
How is normeperidine excreted?
eventually undergoes hydrolysis to meperidinic acid
