Opioid Agonist/Antagonist Flashcards
What’s the most common thing that brings people in to see their provider?
pain
Does pain usually ascend the spinal cord on the same side or cross?
90% form synapse and cross, 10% on ipsilateral side
What are the 4 steps of pain pathway?
transduction, transmission, modulation, perception
Which pain fibers are sharp/well localized/fast?
delta, ex: glutamate, NMDA
Which pain fibers are dull/not localized/slower?
C fibers, ex: substance P, NK1, g-protein
Describe transduction.
When stimulus is converted to nerve signal. Occurs at end of nocioceptors. Tissue injured, chemicals released which activates peripheral nerves and immune cells. peripheral nerves transduce the chemicals into an action potential to be interpreted by the brain.
What is the difference between transduction and transmission?
transduction=chemical process, transmission=electrical component.
Define transmission.
signal relayed through 3 neurons in the afferent pain pathway along spinothalamic tract
Describe transmission through the neurons.
1st order periphery to dorsal horn, 2nd order dorsal horn to thalamus, 3rd order thalamus to cerebral cortex
Pain=SAD, define SAD
Sensory, afferent, Dorsal horn
What is the most important site to know for pain modulation?
substantia gelatinosa in the dorsal horn
Where do descending inhibitory pain pathways begin?
periaquaeductal grey and rostroventral medulla
What inhibits the descending pathway?
spinal neurons release GABA and glycine, descending pain pathway releases NE, 5-HT, and endorphins
Describe modulation.
the up or down regulation of pain signals throughout the brain and spinal cord
Why do many pain signals never reach consciousness?
they are dampened by intrinsic modulatory activity within the central nervous system
Describe perception.
Subjective, the processing of afferent pain signals in the cerebral cortex and limbic systems
True/false. The brain itself does not feel pain.
True, no nocioceptors, if headache it’s actually dura/pia pain
Define opiates/opioids.
all exogenous substances, natural and synthetic that bind specifically to any of the several opioid receptors and produce at least some agonist or morphine-like effects. Analgesic and hypnotic effects
What are opioids derived from?
juice of the opium poppy, oldest known pain agent
What are the 2 chemical classes of the alkaloids of opium?
phenanthrenes and benzylisoquinolines
Name examples of phenanthrenes.
morphine, codeine, thebaine
Name examples of benzylisoquinolines.
papaverine, noscapine (lack opioid activity)
How do you create semisynthetic opioids?
modification of morphine molecule
How does codeine differ from morphine?
sub a methyl group for the hydroxyl group on carbon 3
How many carbon atoms are in a phenanthrene ring?
14
How are synthetic opioids made?
contain the phenanthrene nucleus of morphine but are manufactured by synthesis rather than by chemical modification of morphine
Name phenylpiperidine derivatives.
meperidine, fentanyl, sufentanil, alfentanil, remifentanil
Name the phenylheptanones (dephenylheptanes).
methadone, propoxyphene, levomethadyl
What are the 3 classes of opioid analgesics?
phenanthrenes, phenylpiperidines, phenylheptanones
What are 2 things that cause additional responses to tissue damage/pain?
induction of cyclooxygenase-2, and synthesis of prostaglandins
What type of receptor are opioid receptors?
g-protein coupled receptor, inhibits adenylate cyclase
What changes happen at the opioid receptors?
intracellular cAMP is decreased, Ca conductance is decreased, K conductance is increased.
What does decreasing the Ca conductance do?
reduces neurotransmitter release from presynaptic neuron.
What does increasing K conductance do?
hyperpolarizes postsynaptic neuron moving trigger potential further from resting membrane potential making it more resistant to stimulation
Opioids are highly specific for which kind of receptors?
Mu
Where are Mu receptors located?
CNS
What are Mu1 effects?
supraspinal analgesia: euphoria, miosis, hypothermia, bradycardia, urinary retention, pruritis
What are Mu2 effects?
spinal analgesia: hypoventilation, physical dependence, ileus, constipation
What are the types of opioid receptors?
Mu, delta, kappa, sigma
Discuss delta receptors.
in dorsal root, modulate mu receptor activity
Discuss kappa receptors.
in dorsal root, opioid agonist-antagonists act here, very little respiratory depression. Sedation, dysphoria, miosis
Discuss sigma receptors.
Activation causes excitation symptoms such as dysphoria, hypertonia, tachycardia, tachypnea, mydriasis
Discuss CV effects of opioid agonists.
minimal effect on BP, doesn’t decrease myocardial contractility, but lower BP could result from bradycardia and vasodilation, promotes CV stability compared to IV induction agents, drug dependent histamine release (morphine/demerol)
Discuss pulmonary effects of opioid agonists.
ventilation depression is dose-dependent, shifts CO2 curve to right (reduced response of ventilation to CO2, low RR, increased TV, increased PaCO2 increases ICP, prolonged inspiration, delayed expiration, apneic threshold elevated, hypoxic drive decreased.
Discuss nervous system effects of opioid agonists.
analgesia, drowsiness, euphoria, skeletal muscle rigidity with high doses, miosis, N/V CTZ stimulation and vestibular, cerebral vasoconstriction, decreased CBF, increase/decreased ICP, depression of cough reflex (codeine)
Discuss the GI effects of opioid agonists.
histamine release, spasm of biliary smooth muscle at sphincter of oddi, decreased GI motility and prolonged gastric emptying.
Discuss the GU effects of opioid agonists.
increased genitourinary tone and peristaltic activity of ureter
Other misc effects of opioid agonists:
placental transfer–fetal resp depression, reflexive coughing (fentanyl), dilation of cutaneous blood vessels–flushed/warm feeling, itching/redness
What is the concern with opioids and MAOIs?
increased amount of nor-epinephrine available for release in the CNS and systemically, exaggerated CNS depression and hyperpyrexia or hypertension/hyperthermia/seizures. 20% have excitatory response–muscle rigidity, hyperpyrexia, agitation & H/A
What drugs can cause serotonin syndrome when a patient is on SSRI’s?
Fentanyl, Demerol and its derivatives interact w/ MAOIs by enhanced serotonin inactivity in the brain because its uptake is inhibited
How long does it take for tolerance to occur?
2-3 weeks of continued use
How long does physical dependence take?
25 days but can be as fast as 48 hours.
What is hyperalgesia?
decrease in pain threshold in an area of inflammation, trivial stimuli cause pain, release of chemical mediators sensitize pain receptors especially in the peripheral nervous system
What drug can cause hyperalgesia?
Remifentanil at high doses.
What are the hypotheses for hyperalgesia?
1: Up-regulation of cAMP, increased endocytosis of receptors, decreased endocytosis receptors require reactivation by endocytosis, Opioid receptor changes or uncouples, Up-regulation of NMDA receptors, Changes in peripheral/central/endogenous systems, Spinal dynorphin release
What’s the solubility most to least of the opioids?
Sufentanil>Fentanyl>Alfentanil>Demerol>Remifentanil>Morphine
What’s the order of the lowest to highest pKa of the opioids?
Alfentanil
What’s the order of potency from least to most of opioids?
Demerol
When is morphine most effective?
when given BEFORE a painful stimulus
Does neuropathic pain respond to opioids?
no
Describe the pharmacokinetics of morphine.
mostly ionized, low protein binding, least lipid soluble, not very potent, does not undergo first pass uptake into lungs like fentanyl does.
What is a critical side effect (CSE) of morphine?
histamine release, caution in asthmatics resulting in bronchospasm/laryngospasm
Discuss metabolism of morphine.
rapid conjugation with glucouronic acid, liver and renal, active metabolite: morphine-6 glucuronide
True/false: Elimination of morphine may be impaired in patients with renal disease.
True, may cause accumulation of metabolites and respiratory depression.
What is meperidine derived from?
phenylpiperidine.
Discuss the pharmacokinetics of meperidine.
highly ionized, least potent, DOA 2-4 hours
When should you take caution in using meperidine?
In patients receiving MAOIs and SSRIs
What are the side effects of meperidine?
tachycardia, decreased myocardial contractility, histamine release, orthostatic hypotension, delirium and seizures with prolonged use.
anticholinergic effects like tachycardia, mydriasis and dry mouth
Does meperidine go through first pass metabolism?
yes, extensively if given orally
Discuss metabolism of meperidine.
90% metabolized by CYP450, active metabolite normeperidine
What are the analogs of meperidine?
fentanyl, sufentanil, alfentanil, remifentanil
What is the onset, DOA, and half life of fentanyl?
onset 2-5 min, DOA 0.5-1hr; half life 2-4 hours
Is fentanyl ionized or nonionized?
highly ionized, and potent–75-125x more potent than morphine, greater lipid solubility
Is there much first pass pulmonary intake of fentanyl?
yes, 75%. lungs act as a storage site of inactive drug, can cause respiratory depression
What are some side effects of fentanyl?
bradycardia leading to decreased SVR (BP), muscle rigidity (seizure activity). does not evoke histamine release. CSE–tachycardia because of circulation catecholamine-STOP fentanyl
Discuss pharmacokinetics of Sufentanil
most potent–5-10x more potent than fentanyl, most lipid soluble, highly protein bound, less ventilation depression and longer period of analgesia, decreases cerebral metabolic requirements of O2
What types of cases is sufentanil usually used for?
Used as a drip for monitored spine cases started 0.5mcg/kg/mn once monitoring done turn off and get gas on
What’s the onset, DOA, and half life of Sufentanil?
onset 1-3 min; DOA dose dependent, half-life 6 hours
What is a potential side effect of sufentanil?
significant bradycardia causing decreased CO and decreased BP
Discuss the pharmacokinetics of alfentanil.
highly non-ionized, highly protein bound, low Vd, basic, high pKa, quick and short.
What’s the onset, DOA and half life of alfentanil?
onset immediate, DOA brief d/t rapid redistribution to inactive sites, half life 1.5 hours. eliminated faster than other opioids except remifentanil
What are the side effects of alfentanil?
bradycardia and hypotension
Why is the onset of Alfentanil instantaneous?
directly related to the pKa of the drug, it’s a base pKa 6.4 put into systemic circulation of 7.4 and you get more non-ionized portion
Discuss alfentanil metabolism.
CYP450 dependent (3A4), comparatively lower hepatic ER, erythromycin can inhibit metabolism and prolong action. renal failure doesn’t alter excretion–used in renal patients
Discuss the pharmacokinetics of remifentanil.
50/50 ionization, higher protein bound, lowest Vd, least lipid soluble and potent than all others except sufentanil
What is the metabolism of remifentanil?
hydrolysis by plasma esterases, noncumulative effects
What are the side effects of remifentanil?
skeletal muscle rigidity, hypotension, opioid induced hyperalgesia, bradycardia
What is the onset and DOA of remifentanil.
onset 1 min, DOA 5-10 min
Remifentanil reduced MAC and propofol needs by ___%.
50%
Reduce remi dose for elderly by ___-___%.
50-70%
In obese patients, calculate remi dose by ideal weight + __%
25%
How do you mitigate hyperalgesic effect of remifentanil?
bridge with another opioid, ketamine/mag
What are the doses for remifentanil?
ampule 1mg, dilute in 50mL of LR or NS for conc of 20mcg/mL, loading dose 1.5 mcg/kg, infusion dose 0.15mcg/kg/min or 0.1mcg/kg/min if hypotension/brady, sedation case use 0.06-0.08 with propofol and good LA
What is the onset, DOA, and half life of Hydromorphone?
onset 15-30 min, DOA 4-5 hours, half-life 1-3 hours
What are side effects of hydromorphone?
same as morphine but no histamine release
How do you make oxymorphone?
add hydroxyl group to hydromorphone
What are the side effects of oxymorphone?
more nausea and vomiting than other opioids, higher degree of physical dependence
Discuss codeine metabolism.
limited first pass hepatic metabolism due to substitution of a methyl group for the hydroxyl group on carbon 3 of morphine, 10% of codeine is metabolized or changed to morphine in liver
What are the side effects of codeine?
constipation (minimal sedation, N/V)
Where does methadone act on?
mu receptor agonist, NMDA receptor antagonist, inhibits reuptake of MAO in synaptic cleft
Discuss methadone metabolism.
high bioavailability 80%, metabolized by CYP450 to inactive metabolite, can increase QT interval
What is methadone used for?
suppression of withdrawal symptoms in physically dependent people
How do opioid agonist/antagonists work?
competitively inhibit mu receptors by displacing opioids off the receptor site, reversing resp depression, some weakly activate mu receptors, kappa and delta receptors stimulated/some analgesia will be maintained.
What is the dose, onset, DOA of nalbuphine?
dose 10-20mg IV, onset 15-20 min, duration 2-3 hours
What does nalbuphine do?
reverses resp depression from fentanyl but maintains analgesia
What are two pure mu opioid receptor antagonists with no agonist activity?
naloxone and naltrexone
Where is narcan metabolized?
primarily in liver, undergoes first pass, can cross placenta
What are side effects of narcan?
N/V, give slowly over 2-3 min, CV stimulation–may see increased HR, BP, pulmonary edema, and cardiac dysrhythmias
What is the dose of narcan?
0.4 mg, dilute and titrate
What is naltrexone used for?
ETOH withdrawal and recovering opioid abusers
Does naltrexone undergo first pass metabolism?
No.
