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.
BDZ binds to
Alpha subunits of GABA-A then it facilitates GABA-GABA receptor binding leading to Cl- conductivity across the membrane leading to hyperpolarization and reduced excitability of post-synaptic neurons
What alpha subtype receptor responsible for transit hypertension caused by precedex?
Dexmedetomidine is more selective for the alpha-2 receptor than clonidine (about 1600:1 alpha-2:alpha-1). There are three alpha 2 receptor sub-types: alpha-2A, alpha-2B, and alpha 2C. Dexmedetomidine binds to all three subtypes (although higher affinity for alpha -2A and alpha-2C). During administration of dexmedetomidine, especially at high doses, alpha-2B agonism can lead to a transient hypertensive phase. Later hypotension can develop from alpha-2A agonism.
Some other board relevant trivia:
- sedation effects: primarily alpha-2 receptors in the locus coreruleus
- sedation mimics non-REM sleep
- reduced opioid needs while on dexmedetomidine
- Reduces cerebral blood flow and cerebral O2 consumption
Dextromethorphan
Dextromethorphan is a complex drug with many active metabolites. Primarily used as an antitussive agent, it (or its metabolites) also have NMDA antagonistic qualities (like methadone and ketamine), local anesthetic effects, and SSRI effects. Like meperidine (also having SSRI qualities), it should not be used with MAOIs due to serotonin syndrome (see question 13). Discontinuation of prolonged use of alpha-2 agonists such as clonidine (about a month) or dexmedetomidine (a few days) can lead to rebound hypertension (NOT dextromethorphan)
Clonidine Patch
Clonidine is an alpha-2 agonist, which easily crosses the blood brain barrier to decrease sympathetic outflow from the brain stem. Additionally, alpha-2 agonism of pre- (and probably also post-) synaptic nociceptive transmission is reduced. Low doses of clonidine transdermal can lead to improved pain control often without significant hypotension and sedation. Lidocaine patches have less effect treating pain when the patch does not cover either the painful area or the nerve transmission to that area (very challenging to do with a post-operative back!). Furthermore, Lidoderm is probably less effective than clonidine in treating patients with chronic pain syndromes.
What is the “Nernest potentials” caused by BDZ?
Benzodiazepines bind to the GABA-A receptor that increases the affinity of GABA for the GABA-A receptor. This interaction opens a chloride channel which hyperpolarizes the membrane, making action potentials more difficult to propagate. The Nernst potential, when applied to cell membranes, describes the potential difference between the extracellular and cytosol side of the cell. With more chloride passing through the membrane, the intracellular concentration of this ion changes and therefore changes the potential difference across the cell (Nernst potential), with the end result being hyperpolarization.
How do BDZs causes muscle relaxation?
Benzodiazepine mediated muscle relaxation is mediated through the gamma-subunit agonism of the GABA-A receptor, specifically in the spinal cord.
In the brain, gamma-subunit agonism is responsible for anxiolysis.
Alpha-subunit agonism is responsible for anticonvulsant effects.
Therefore, benzodiazepines have sedative, anxiolytic, hypnotic, amnestic effects as well as muscle relaxation (often used for muscle spasms).
Opioid receptors and their effects
Mu1 …
Mu2
Kappa
Delta
Mu-1 – Euphoria, miosis, bradycardia
Mu -2 – Respiratory depression, constipation
Kappa – Sedation, miosis
Delta – Respiratory depression (maybe), constipation
Morphine metabolite morphine-6-glucuronide is though to have increased potency for the mu-2 receptor, explaining its respiratory depressive effects.
Mechanism of opioid intolerance and hyperalgesia
Prolonged opioid exposure leads to down-regulation and internalization of opioid receptors, leading to less membrane hyperpolarization (of pain fibers/ pathways).
Opioid receptors are G-proteins with secondary messaging mechanisms , and “decoupling” the receptor from the messenger explains another mechanism of this process. In other words there are fewer opoiods receptors, and the receptors that are left have less of a response.
Prolonged opioid exposure also leads to down-regulation of glutamate receptors in the spinal cord, ultimately leading to hyperalgesia.
In the same vein, opioids have weak NMDA agonistic properties, leading to wind-up and hyperalgesia (see the chronic pain section). The significance of this is that patients with long standing opioid tolerance and hyperalgesia are typically responsive to adjuvant therapy with NMDA antagonsism.
How much high opioids decrease MAC%?
~ 60%
There is a lot of variation for this answer, I’d suggest you just remember that the MAC is reduced by a little more than half.
