Opioids, Opioid Agon-Antag, Opioid Antag Flashcards
butorphanol MOA
MOA: low affinity for mu receptors (produces antagonism for mu receptors), moderate affinity for kappa receptors (to produce analgesia and anti-shivering)
I don’t trust him that we don’t need to know PK/PD but I have no capacity to remember more shit.
SE’s: causes sedation, nausea, diaphoresis. Also can have dysphora “don’t feel well” – kappa receptors, depression of ventilation, ↑ catecholamine response, mild biliary/GI tract sx’s.
Limits effects of concomitant opioid agonists given (need to give ketamine, NSAIDS, peripheral nerve blocks to target other receptors).
nalbuphine MOA
MOA: chemically related to oxymorphone and naloxone. Antagonist at mu receptors, and agonist at kappa receptors (dr. google). If given before an opioid, it diminishes the opioid’s effects. If given after an opioid, it can reverse respiratory depression without affecting their analgesia. (depression of ventilation returns after ~2-3 hours).
Equal analgesic potency of morphine, ¼ antagonist potency as nalorphine (which we never talked about).
SE’s: sedation, less dysphoria than butorphanol, depression of ventilation has a ceiling effect (any dose higher than 30 mg of nalbuphine and you no longer have depression of ventilation), catecholamine stimulation
naloxone (opioid antagonist)
MOA: pure mu antagonist (but apparently blocks all of the receptors)
PK: metabolized by glucuronidation – phase II, metabolite Naloxone-3-glucuronide
PD: SEs are reversal of analgesia – aka PAIN. N/V. ↑ SNS activity – bc PAIN. Fetal withdrawal.
Dose: 1-4 mcg/kg IV
T 1/2: 30-45 minutes. Effects of the reversal agent don’t last as long as the narcotic.
opioids in general
- Lipophilic
- CNS - Decreased responsiveness to CO2
- CV - Cardiac protectant – enhances myocardial resistance to oxidative/ischemic stress, Cause bradycardia,↓ SNS, orthostatic hypotension
- OD sx’s: pinpoint pupils (miosis = Edinger-Westphal), slow deep breaths, coma/unresponsive
- Resp - Increase AW resistance, histamine release, cause slow, deep breaths (dose-dep depression of ventilation)
- Pain - Inhibit transmission of ascending nociceptive info
- Activate descending modulating pathways
- GI/GU – constipation, N/V (stimulation of chemoreceptor trigger zone in the medulla – 5HT3 and DA2), ↑ PO secretions and delayed emptying, ↑ detrusor muscle tone (urgency) but ↑ sphincter tone (difficulty)
- Narcan works everywhere, methylnaltrexone if you want to target GI tract only.
- Glutamate and substance P continue the neurotransduction of pain
- Rexed lamina I, II (substantia gelatinosa), V
morphine (MOA, PK/PD, Vd, Dosing, T1/2)
MOA:
▾Opioid receptors are G-protein coupled receptors. Principle effect is to decrease neurotransmission through synaptic inhibition of neurotransmitter release of pain causing substances, does not block nerve impulses, does not alter responsiveness of afferent nerve endings to noxious stimulation
▾Mimic the actions of endogenous ligands (enkephalins, endorphins, and dynorphins)
▾Receptors located in the spine, brain, periphery (pre-synaptic inhibit the release of ACH, Dopa, Norepi, Substance P. Post-synaptic increase K+ conductance= decreased fxn)
▾May regulate fxn of other ion channels (NMDA)
PK:
• Onset is 15-30 minutes
▾Small portion reaches CNS: Poor lipid solubility, high degree of ionization at physiologic pH, protein binding, rapid conjugation by the liver
▾CO2 induced increases in CBF and enhanced delivery of morphine to the brain are more important than the fraction of drug that exists in either ionized or nonionized fraction (hypoventilation increases CO2 causes vasodilation ↑ effect of morphine, despite more nonionized form in acidosis. This is more important than the increased nonionized fraction that hyperventilation/alkalosis causes).
▾Accumulates rapidly in the kidneys, liver, muscle
▾Does NOT undergo 1st pass uptake in the lungs
▾Primary metabolism is by conjugation w/ glucuronic acid, “renal metabolism is significant”
▾Impaired renal fxn can result in accumulation and resp depression
▾Metabolites: Morphine-6-Glucuronide 5-10% active, 65x more potent that morphine, longer duration of action [75% morphine-3-Glucuronide (inactive), nomorphine]
▾Decrease in plasma concentration through metabolism (higher in elderly and neonate)
• Rapidly crosses the placenta (morphine > meperidine causes neonatal depression). Chronic use causes neonatal physical dependence, and neonatal abstinence syndrome.
• Avoid in elderly
PD:
• Act on mu opioid receptors
• Biliary tract spasm (spasm of biliary smooth muscle and at sphincter of Oddi), RUQ pain. Treat with 2mg glucagon. Also contracts pancreatic ducts ↑ amylase and lipase levels
• Histamine release – red eyes, pruritus or rash (esp intrathecal)
• CV – BVs dilate – warm, flushed skin
• Causes neonatal dependence. Narcan can cause acute w/d.
• Interaction: cholinergics enhance (physostigmine), anticholinergics antagonize (atropine, glycopyrrulate, scopolamine)
• Resp: reflex coughing, ventilatory depression can be exaggerated by amphetamines, phenothiazines, MOAs (MAOIs?) tricyclics, BZ’s
Vd: high, 1.7-3.3
Dosing: 1 mg IV
T1/2:
CS ½ time:
meperidine
phenylpiperdine ring
PKA: 8.5
MOA:
▾Opioid receptors are G-protein coupled receptors. Principle effect is to decrease neurotransmission through synaptic inhibition of neurotransmitter release of pain causing substances
▾Mu receptor agonist, also stimulates kappa receptors, used for anti-shivering effects
• Increases pain threshold, modified perception of noxious stimulation (great for visceral pain, or muscles/joints, when given preemptively)
• Produces analgesia, sedation, decreased concentration, nausea, body warmth, pruritus, dry mouth, and extreme heaviness
PK: 1/10th as potent as morphine, DOA 2-4 hours
• Extensive 1st-pass metabolism by liver, limits PO usefulness
• Extensive metabolism in liver (Phase I) – demethylation to normeperidine (active) and hydrolysis to meperidinic acid
• Normeperidine T1/2 15 hrs, >30 hours in renal failure, eventually goes through hydrolysis meperidinic acid
• Eliminated primarily through excretion – pH dependent, so acidic pH causes greater fx of drug to be excreted. Decreased renal fn can result in accumulation of metabolites.
o Avoid in elderly
• Crosses placenta, may exceed maternal [ ]s
PD: Act on opioid receptors
• In equianalgesic doses, similar effects to morphine (sedation, euphoria, N/V, depression of ventilation)
• Structurally similar to atropine, mild antispasmodic effects
• In high doses, negative cardiac inotropy, histamine release
• CNS – delirium and szs (reflect accum of normeperidine), common in elderly with renal failure
• CV - ↑ HR (modest atropine-like effects), mydriasis (dilation of pupils). High doses ↓ inotropy
• Interactions: may cause serotonin syndrome in pts taking MAOIs and fluoxetine
• Some biliary tract spasmDosing: 12.5 mg
Volume of Distribution (L/kg): 3-5
fentanyl
PKA: 8.4 (hardly any is nonionized, but the small amount of nonionized is SUPER lipophilic)
-basic drug, going into physiologic pH which is more acidic = LOTS OF IONS
MOA:
▾Opioid receptors are GPCRs. Principle effect is to decrease neurotransmission through synaptic inhibition of neurotransmitter release of pain causing substances
▾Mimic the actions of endogenous ligands (enkephalins, endorphins, and dynorphins)
▾Receptors located in the spine, brain, periphery (pre-synaptic inhibit the release of ACH, Dopa, Norepi, Substance P. Post-synaptic increase K+ conductance= decreased fxn) ▾May regulate fxn of other ion channels (NMDA)
PK:
• Quick onset, 1-3 minutes
• Highest lipophilicity of all the phenylpiperdines, 75-125x more potent that morphine
▾Rapid onset & shorter duration of action (lipid soluble, redistribution terminates effect of single dose)
▾Lungs responsible for large first pass uptake, “secondary peak” d/t release from pulm uptake
▾Extensively metabolized by N-dealkylation & hydroxylation (minimal metabolite activity – why we didn’t go over it) – PHASE I
▾Elderly (prolonged elimination time d/t decreased clearance, age-related decrease hepatic flow, microsomal enzyme activity, albumin production)
▾Cirrhosis does not prolong elimination 1/2 time
▾Context sensitive 1/2 time increases w/ infusion >2 hours (reflects redistribution & saturation into inactive tissue sites
PD: Act on opioid receptors
• CNS - Blocks SNS stimulation to surgical response, modest ↑ in ICP, sz activity/myoclonus (like etomidate) inhibition of inhibitory neurons
• No histamine response
• CV - Bradycardia is prominent (carotid sinus baroreceptor control)
• Resp - Deep slow breathing
• Synergism with propofol and versed (opioids and benzos, and also prop)
Dosing:
▾Block sympathetic stimulation to surgical response and intubation- 1-3 mcg/kg prior to induction of anesthesia
▾Analgesia- 1-3mcg/kg
▾Surgical anesthesia as sole anesthetic- 50-150 mcg/kg
Volume of Distribution (L/kg): 335 L (anything over 42 L is big)
T ½: “longer than morphine” - 3.1-6.6 hours (St)
Context Sensitive ½ Time (4 hour infusion): 4.3 hours, dramatically increases after 2 hr gtt
sufentanil
PK:
• Extensive protein binding (to α1-glycoprotein, which ↑s after surg) compared to fentanyl enhanced effects in neonates
• Highly lipid soluble
• Significant 1st pass pulmonary uptae
• Phase I metabolism in liver → desmethyl sufentanil metabolite must be conjugated. Normal renal fn important to clearance
PD:
• 5-10x potency of fentanyl
• Produces longer analgesia and less respiratory depression than fentanyl
• Most likely of the phenylpiperidines to cause chest wall rigidity/laryngeal contracture
Vd:
Dosing: 0.1-0.4 mcg/kg
T1/2:
alfentanil
PKA: 6.5
MOA:
▾Opioid receptors are G-protein coupled receptors. Principle effect is to decrease neurotransmission through synaptic inhibition of neurotransmitter release of pain causing substances
▾Mimic the actions of endogenous ligands (enkephalins, endorphins, and dynorphins)
▾Receptors located in the spine, brain, periphery (pre-synaptic inhibit the release of ACH, Dopa, Norepi, Substance P. Post-synaptic increase K+ conductance= decreased fxn) ▾May regulate fxn of other ion channels (NMDA)
PK:
▾Rapid onset and offset d/t prompt on-sight equilibration (90% of the drug exists nonionized at physiologic pH, bound to alpha 1 glycoproteins) – higher fx of 90% nonionized but…
▾Metabolized by 2 independent pathways (piperdine N-dealkylation to noralfentanil, amide N-dealkylation to N-phenylpropionamide) - PHASE I
▾ Vd less than fentanyl, less potent that fentanyl
PD: Act on opioid receptors
• CV – more significant decrease in BP
• GI/GU - ↓ incidence of PONV
• MSK - Acute dystonia – avoid in untreated Parkinson’s pts
Dosing:
▾Blunts stimulation of laryngoscopy- 15mcg/kg IV
▾Catecholamine response to noxious stimulation- 30mcg/kg IV
▾Produces unconsciousness(induction): 150-300 mcg/kg IV
▾Combination w/ inhaled anesthetic 15-150 mcg/kg/hr
Volume of Distribution (L/kg): 1.4-1.5 SMALL Vd, only phenylpiperidine‼
Context Sensitive ½ Time (4 hour infusion): 60 minutes
remifentanil
PKA: 7.3
MOA: selective mu agonist, potent like fentanyl, blood-brain equilibrium like alfentanil
• Although a phenylpiperidine, it has an ester linkage – H2O-soluble
▾Opioid receptors are G-protein coupled receptors. Principle effect is to decrease neurotransmission through synaptic inhibition of neurotransmitter release of pain causing substances
▾Mimic the actions of endogenous ligands (enkephalins, endorphins, and dynorphins)
▾Receptors located in the spine, brain, periphery (pre-synaptic inhibit the release of ACH, Dopa, Norepi, Substance P. Post-synaptic increase K+ conductance= decreased fxn) ▾May regulate fxn of other ion channels (NMDA)
PK:
▾Small Vd
▾Rapid clearance (accumulate less than other opioids, similar in obese and IBW patients)
▾Metabolized by non-specific plasma esterases (no active metabolites, not affected by pseudocholinesterase deficiency, PK unchanged by renal or hepatic failure)
• CS ½ is 4 minutes (can contribute to hyperalgesia if not bridged with longer-acting opioid)
PD: Act on opioid receptors
• Very synergistic with propofol
• Must administer a long-acting opioid for postop analgesia
• GI/GU – N/V
• RESP – depress ventilation
• CV - ↓ SVR/BP
• Pain – hyperalgesia if acute opioid tolerance, ketamine and Mg++ can block this
Dosing:
▾Analgesia- 0.25-1 mcg/kg IV, 0.05-0.2 mcg/kg/min gtt
▾Sedation- 0.05-0.1 mcg/kg/min in combo with midazolam 2mg
▾Anesthesia Induction- ▾1mcg/kg bolus, then 0.05-0.2 mcg/kg/min gtt
Volume of Distribution (L/kg): 0.5 L/kg
Context Sensitive ½ Time (4 hour infusion): 4 minutes
