M5: Basic Pharmacology- Anesthesia Adjuncts – Flashcards
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What is the alpha phase?
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the initial drop in a drug's plasma concentration after administration. Due to distribution/redistribution
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What is beta phase?
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drop in drug's plasma concentration due to metabolism?
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Which of the following are hydrophilic? lipophilic?: - Opioids - Muscle relaxants
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Muscle relaxants are hydrophilic so they have a smaller volume of distribution. Opioids (fentanyl) are lipophilic so they have a larger volume of distibution
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What percent of body mass do vessel-rich organs account for?
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10%
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How is fentanyl metabolized?
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By the liver. Into inactive metabolites?
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What do fentanyl's metabolites do?
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nothing. They are inactive.
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Is fentanyl lipid solubule? water solubule?
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VERY lipid solubule. This means it has immediate effects on brain/cord.
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Compare fentanyl and morphine: - Lipid solubility - Onset time - Duration - Half life
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Fentanyl is more lipid solubule, so fentanyl has faster onset time but redistributes... so duration is shorter. HOWEVER, because fentanyl is all over the place, the terminal half life (time it takes to leave the body) is prolonged compared to morphine, even though the actual duration is less.
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The slope of a dose-response curve is determined by _______________
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The receptor binding characteristics.
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What does binding at an opioid receptor due to the cell?
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Increases K+ and Ca2+ current --> hyper-polarization of cell --> reduced neurotransmitters
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What opioid receptors mitigate pain in the -Brain -Spinal cord
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Brain: Mu1 Spinal Cord: Kappa
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Which opioid receptors cause: - Respiratory depression - Muscle rigidity - Dysphoria/hallucinations
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Respiratory depression: Mu 2 Muscle rigidity: Mu1 Dysphoria/hallucinations: sigma
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How is morphine metabolized? Into what? active or inactive?
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Metabolized by the kidneys into Morphine-3-glucoronide (inactive) and Morphine-6-glucoronide (active... actually even more potent than morphine itself! Causes lots of respiratory depression)
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What opioids are associated with histamine release?
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Morphine Meperedine
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Meperedine has a very special structure, and it has 3 VERY UNIQUE characteristics...
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Meperedine has an atropine like structure. It causes: 1. Decreased contractility 2. Increased heart rate 3. Mydriasis
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When does chest wall rigidity happen?
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With large doses of opioids, especially lipid-solubule ones like fentanyl. It's a centrally mediated process, so it can be prevented by using neuromuscular blockers
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Meperedine stops shivering by...?
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agonism of kappa receptors.
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What features of opioids are resistant to tolerance?
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-Constipation - Myosis (i.e. it never takes *more* of opioids to cause constipation or myosis)
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Which opioid can cause seizures, in which patients?
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Meperedine can cause seizures if in RENAL FAILURE, as normeperedine can build up
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Which opioid must be dosed renally?
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Meperedine
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Meperedine has a unique feature, what is it?
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It not only is an opioid, it also inhibits serotonin reuptake (think serotonin syndrome in patients taking MAOIs)
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Which medications, beside MAOIs inhibit serotonin reuptake?
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-Methadone - Tramadol - Meperedine
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Are these lipid solubule or lipid insoluble? - Fentanyl - Sufentanil
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Both lipid soluble.
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Which has longer context sensitive half-life, Fentanyl or Sufentanil? WHY?
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Fentanyl does. They are both lipid soluble, but when Fentanyl is turned off it quickly redistributes from vessel poor back into the vasculature, causing a longer duration of effect. Sufentanil hangs in the vessel-poor group for much longer, meaning duration of effect is over.
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What is alfentanyl's reputation compared to Fentanyl?
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Quick onset time, short terminal excretion time.
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What can remifentanil cause?
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Opioid tolerance
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How do you dose narcan in an over-narcotized patient to ONLY reverse respiratory depression (and not touch analgesia)
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0.04-0.08mg is the treatment to reverse: -Resp. depression -pruritus -sedation -nausea DOES NOT TOUCH ANALGESIA AT SUCH SMALL DOSES.
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What does benzodiazapine bind to? How does it work? Where are the receptors located?
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It binds to the alpha subunit of GABA-A. The GABA-A receptors are only located in the CNS. Not in the body.
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Which benzo has the shortest half-life?
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midazolam.
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When benzos bind to their site (_________), what do they do?
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They bind to GABA-A alpha subunit and augment the binding of GABA
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What does baclofen do?
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It is a GABA-B agonist (contrast with benzos, which are GABA-A)
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What is Samster's Triad?
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- Aspirin Sensitivity - Nasal Polyps - Asthma These patients often have a genetic defect leading to leukotriene overproduction when COX1 is blocked --> bronchospasm
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If you have a patient with genetic defect in COX1, why can't they get Ketorolac?
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They have a genetic defect which leads to leukotriene overproduction when a COX1 inhibitor is used --> bronchospasm
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Why are COX1 inhibitors potentially dangerous to the kidney?
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Decreased prostaglandins means decreased pain/inflammation but also decreased afferent arteriole flow at the level of the kidney
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Does Dexmedetomidine have cross-reactivity with any receptor?
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Yes. It primarily is an alpha 2 agonist, but it also has some cross-reactivity at the alpha 1 receptor which can lead to hypertension and reflex bradycardia. This ONLY happens during the initial infusion, as during an infusion you USUALLY SEE DECREASED SVR AND HR
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Dextromethorphan has NMDA antagonistic actions (like ketamine and methadone), it has SSRI actions (like meperedine)... so what should you NOT use dextromethorphan with?
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Just like meperedine, avoid Dextromethorphan in patients also taking MAOIs as it can cause a serotonin syndrome
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There are two drugs that can cause rebound hypertension when discontinued. What are they? 1) _________________ after what period of time? 2) __________________ after what period of time?
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Discontinuation of prolonged use of alpha-2-agonists can cause rebound hypertension. 1) Clonidine after using for > 1 month 2) Dexmedetomidine after using after using for several days
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GABA binding at GABA-A receptor causes what?
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Hyperpolarization of cells via chloride channels making nernst potential more negative in the cerebral cortex
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What are benzo's effects?
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Sedative, Anxiolytic, Hypnosis, Antegrade amnesia, muscle relaxant
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Where do benzos work?
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cerebral cortex neurons
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Do benzos have effects on opioid receptors?
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Weak agonism of opioid receptors
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Do benzos have respiratory depressive effects?
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No. But if administered with opioids they greatly potentiate opioid's respiratory depressant effects
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How do benzos cause muscle relaxation?
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Gamma subunit of GABA-A receptor
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What does the Gamma subunit of the GABA-A receptor cause - In the brain? - In the spinal cord?
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Brain: anxiolysis Spinal cord: muscle relaxation
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Dexmedetomidine: what is its effects on CMRO2 and ICP
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Dex resembles normal sleep. no change to CMRO2 or ICP
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What does each opioid receptor do? Mu1: Mu2: Kappa: Delta:
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Mu1: Euphoria, miosis, bradycardia Mu2: Respiratory depression, constipation Kappa: Sedation, miosis Delta: Possibly respiratory depression, constipation
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What does morphine's metabolite Morphine-6-glucoronide do?
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It is a Mu2 agonist so it causes a lot of respiratory deprssion
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Prolonged opioid use causes what with regards to opioid receptors?
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Opioid receptors are downregulated, so there are less opportunities for hyperpolarization of pain/fibers
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Prolonged opioid use causes what with regards to G-protein coupling to receptors?
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Opioid prolonged use causes decoupling of G-proteins from their respective opioid receptors, so now you have LESS receptors, and LESS receptors that do anything.
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Prolonged opioid use causes what with regards to Glutamate receptors?
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Cause downregulation of glutamate receptors in the spinal cord causing hyperalgesia
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Prolonged opioid use causes what with regards to NMDA receptors?
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Opioids have weak NMDA receptor AGONISTIC effects, leading to wind-up and hyperalgesia
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So to wind up chronic opioid use... what is the pharmacologic approach to treating someone with hyperalgesia from chronic opioid use? What medications exactly do the strategy you are describing
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Attack NMDA receptors! Use concurrent NMDA antagonists such as: - Dextromethorphan - Ketamine - Methadone
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By what percent can Opioids decrease MAC requirement?
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Up to 60%. They used to use high-dose morphine and nitrous in the good ol' days, but this could lead to intra-op awareness.
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Untoward effects of opioids, and their antidotes: - Urinary - GI - Lower esophageal sphincter tone - Sphincter of oddi - Chemotactic trigger zone
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Urinary: urinary retention. Reversed by naltrexone (opioid antagonist) GI: Decrease motility, decrease gastric secretions, decrease pancreatic secretions. Reversed by methylnaltrexone (opioid antagonist that does NOT cross the blood-brain-barrier) LES: decreases tone --> GERD. Sphincter of oddi: causes increase in tone, can lead to severe abdominal pain, increases in amylase/lipase Chemotactic trigger zone: stimulate --> nausea
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Which opioids can stimulate histamine release
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Morphine, meperedine
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What opioid works for post-op shivering, why?
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Meperedine. Mediated by kappa agonism by meperedine
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What is butorphanol?
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Also a kappa agonist. Can be used in place of meperedine for post-op shivering.
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Put these in order from shortest to longest half life - Alfentanil - Remifentanil - Morphine - Sufentanyl - Methadone - Meperedine - Fentanyl
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- Remi (10 minutes) - Alf (1.5 hours) - Morphine - Sufentanyl - Meperedine - Fentanyl - Methadone (34 hours)
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Why does fentanyl have a short clinical effect time but a very long terminal excretion half life?
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Lipid solubility. Fentanyl is very lipid soluble, so it distributes to the periphery (large Vd)
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Relative potency to morphine: - Meperedine - Morphine - Alfentanil - Fentanyl - Remifentanil - Sufentanyl
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Meperedine: 0.1 Morphine 1 Alfentanil 10 Fentanyl 100 Remifentanyl 300 Sufentanyl 1000
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What has quicker onset, Fentanyl or Alfanentanil
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Alfentanil is much quicker onset compared to fentanyl
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What does increasing age do to Remi?
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It decreases the volume of distribution --> more potent at a given dose
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What does increasing age do to terminal excretion half life in opioids?
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Increasing age increases the time it takes to excrete opioids.
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How long will naloxone work?
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About 2 hours. After that, respiratory depression can re-occur.
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What can reverse opioid respiratory depression, pruritus, nausea/vomiting and sedation but not touch analgesia???
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Mini-dose naloxone: 0.4-1mg!
