Pharmacology Adjuncts Flashcards
Redistribution vs Clearance of drug affect on diminishing it clinical effect?
As the concentration of the drug decreases in vessel-rich areas (such as brain), its clinical effect may diminish. Propofol, thiopental, and fentanyl (for example) all have their termination of effects after single bolus through redistribution. Subsequent doses increase plasma levels at equilibrium, and once the vessel-poor and vessel-rich compartments equilibrate (more-or-less, simplifying things here!), termination of effect becomes a function of clearance (not redistribution).
Volume of distribution is thought of as the theoretical volume in which a drug distributes and is smaller for hydrophilic drugs (muscle relaxants) than lipophilic drugs (fentanyl), because lipophilic drugs can better distribute into vessel-poor organs (again, a simplification). Highly metabolized drugs may have their duration of clinically significant action limited by metabolism, but distribution still determines initial plasma concentrations of the drug.
Alpha vs Beta phase pharmacokinetic
The initial drop in plasma concentration after administration is known as the alpha phase (or distribution), whereas the continual drop due to metabolism is called the beta phase (or elimination).
Relationship of half life and rate of clearance and volume of distribution:
The half-life of any drug is inversely proportional to its rate of clearance. Said another way, the faster the rate of clearance, the shorter the half-life.
Volume of distribution, on the other hand, is proportional to half-life (the bigger the volume of distribution, the longer the half life – assuming the same rate of clearance!!!).
The dose response curve is determined by … what would mean a steep slope for a drug on the dose-response curve?
The dose-response curve looks at the clinical effect of a drug at varying doses (such as change in blood pressure). The rate of increase in clinical effect from one dose to the next higher is due to how avidly the additional drug will bind to the receptors.
A drug that binds to many more receptors following a small dose increase will have a steep slope.
Activation of Opioid receptors results into …
Decreased release of neurotransmitters.
By increasing potassium and decreasing calcium conductance, neuronalmembranes in pain pathways become hyperpolarized, decreasing the release of neurotransmitters. Additionally, post-synaptically, the opioid receptors can produce inhibitory postsynaptic potentials, making action potentials more difficult to generate.
Opioid receptors, do not in themselves, lead to opening of voltage gated sodium channels (such as those used for action potentials), but may indirectly decrease their firing (see above). cAMP levels may decrease, not typically increase cAMP levels.
Opioid receptor responsible for respiratory depression is
mu 2 = respiratory depression,
mu 1 = muscle rigidity, and sigma = hallucinations/ dysphoria.
μ (mu if the character doesn’t show up right for you): Most anesthetic opioids bind to this receptor fairly specifically. It is found spinal, supra spinal and peripheral. It leads to respiratory depression, decreased GI motility, skeletal muscle rigidity, prolactin release, probably bradycardia, pruritus, biliary spasm, and maybe urinary retention.
κ (kappa): Various subtypes spinal, supra spinal and peripheral. May be responsible for sedation.
δ (delta):Various subtypes spinal, supra spinal and peripheral. May also be involved in respiratory depression, GI motility, antidiarrheal (actually includeμ here too), perhaps urinalysis ry retention, pupillary constriction, and nausea and vomoting.
The morphine metabolite that responsible for respiratory depression is ..
M6G
M3G is inactive form
the only opioid decreased cardiac contractility is
Meperidine
it has atropine-like structure causing decreased contractility, mydraisis, and increased HR.
Opioids cause respiratory depression through …
blunting CO2 responsiveness (in the medulla), resulting in an increased apneic threshold.
PaCO2 rises due to decreases in ventilation , causing a decrease in serum pH. Even though minute volume decreases, tidal volume increases (it is the decrease in respiratory rate that decreases overall ventilation).
At extremely high PaCO2s, the A-a gradient can decrease, especially at low FiO2s (due to the alveolus being filled with CO2), decreasing the P/F ratio.
The main point here is that respiratory drive is less responsive to CO2 with opioids (hello mu receptor!) leading to a decreased minute volume. Remember, these effects are through the CNS (decreased central drive to breath).
Meperidine treates shivering by acting on which opioid receptor?
agonisim at kappa receptors
what are the 2 side effects of opioids that will occur despite tolerance to opioid?
Constipation & Myosis
all others: nausea, RS depression, analgesia, sedation, and ms rigidity develop tolerance with increasing opioid doses.
Normeperidine can cause seizures in …
Meperidine’s metabolite normeperidine accumulates with repeated doses of meperidine in patients with renal failure leading to CNS stimulation and possibly seizures.
Opioids that has SSRI activity and if given to patients on MOI might cause serotonin syndrome.
Meperidine, Tramadol, and methadone
Fentanyl and sufentanil are both highly lipid soluble synthetic opioids. Sufentanil is more potent, has about an equipotent tendency to depress ventilation but which one has more likely to cause bradycardia? and which one has longer Context-sensitive t1/2?
Sufentanil
When the infusion is stopped, fentanyl redistributes from the peripheral to the central compartment, leading to a prolongation in plasma levels. Sufentanyl slightly differs from fentanyl in that even after long infusions there remains a movement from central to peripheral compartments and increased rate of clearance. The net result of this is that the context-sensitive half time for fentanyl greatly exceeds sufentanil for infusions greater than 2 hours.
Alfentanil has a very fast onset and relatively short terminal elimination half-life as compared to fentanyl. Remifentanil has a very short half life (~9 minutes adults, less in children).
Can remifentanil be used as a sole anesthetic? And would it’s metabolism be affected in patients with 20% dibucaine number?
Remifentanil is a very short acting opioid typically used by infusion. Its ester linkage is metabolized by nonspecific esterases in red blood cells (and tissues). Abnormalities in pseudocholinesterase (as this patient with a 20% dibucaine number, see MUS 7) do not affect remifentanil metabolism. Opioids do not reliably produce amnesia, and should not be used as sole anesthetics. In general, it is theorized that opioids can reduce the MAC of a volatile agent by only 50%, even at very high doses. High doses of remifentanil may induce an acute opioid tolerance, making pain control difficult in the PACU; although some of the data conflicts regarding this point.
