1. The nonionized form of a drug commonly crosses the cell membrane because it is more lipid-soluble. Ion trapping occurs when there is a pH gradient across a membrane. The drug will be trapped on the side that has the higher ionized fraction. For weak base drugs, for example, local anesthetics (LAs) and narcotics, this will be on the low pH side, whereas for weak acidic drugs, for example, Pentothal, this will be on the high pH side.

2. Sublingual administration has the least first-pass effect. It is limited by the small surface area available for absorption. It is only efficacious for nonionized, highly lipid-soluble drugs. The first-pass effect is less evident also after rectal administration because more drug is absorbed into systemic circulation, although absorption is often irregular and incomplete.

3. Redistribution is the rapid entry and exit of lipophilic drugs from richly perfused organs (brain, heart).

4. Drugs distribute across the placenta by simple distribution. Regardless of effects and protein binding, the concentration of free, nonionized drug will be the same on both sides of the placenta once equilibrium is reached.

5. Competitive antagonists compete with the receptor agonists for the receptor site. The drug that has the higher concentration will occupy the receptor site. Therefore if you increase the concentration of the agonist it will displace a competitive antagonist from the receptor. The significance of this is that all competitive antagonists are reversible. Nondepolarizing muscle relaxants are a good example of competitive antagonists.

1. Drug clearance is the theoretic volume of blood from which drug is completely removed in a given time interval. It depends on three biologic factors:

2. First-order elimination is the constant fraction of drug eliminated per unit of time. Therefore, hepatic clearance is a function of hepatic blood flow and the ability of the liver to extract drug from blood perfusing the liver.

3. A low extraction ratio (30%) is due to intrinsic clearance that is small in relation to hepatic blood flow. Therefore, the clearance is independent of changes in liver blood flow but very sensitive to the liver’s ability to metabolize the drug. With a high extraction ratio (>70%), clearance is determined primarily by liver blood flow rather than the activity of drug metabolizing enzymes → extensive first-pass metabolism.

4. Liver disease decreases drug clearance by:

5. All volatile anesthetic agents decrease liver blood flow: isoflurane (Forane) < halothane (Fluothane) or enflurane (Ethrane).

1. Only unbound drug passes through the glomerular membrane to be filtered or reabsorbed. These are reabsorbed by passive diffusion, which is determined by lipid solubility and degree of ionization.

2. Renal blood flow (RBF) and glomerular filtration rate (GFR) are autoregulated at a mean arterial pressure (MAP) between 70 and 160 mm Hg.

3. Drugs commonly used in anesthesia with significant renal excretion include the following:

4. The two main plasma proteins responsible for drug binding are as follows:

1. Volume of distribution is a numeric index of the extent of drug distribution. (It does not have any relationship to the actual volume of any tissue or group of tissues.)

If one drug has a larger apparent distribution volume than another with similar pharmacologic activity, it will take a larger loading dose to “fill up the box” and achieve the same concentration. Various pathologic conditions alter the volume of distribution, necessitating therapeutic adjustments; for example, hypovolemia requires a smaller dosage of drug. Drug clearance is the ability of the system to irreversibly eliminate a drug. It is the portion of the volume of distribution from which the drug is completely removed in a given time interval.

2. The two-compartment model assumes a central compartment and a peripheral compartment. The first phase after injection represents drug redistribution from central to peripheral compartments (rapid decrease in plasma concentration due to passage of drug from plasma to tissues). This is followed by a slower decline of concentration owing to drug elimination.

3. The dose-response curves provide information regarding four aspects of the relationship of dose and pharmacologic effect:

The disadvantage of dose-response curves is the inability to determine whether variations in pharmacologic responses are due to differences in pharmacokinetics, pharmacodynamics, or both.

4. Steady state is achieved in five elimination half-lives.

1. Alveolar partial pressure is determined by the following:

2. Uptake of agent is determined by the following:

3. The concentration effect consists of two phenomena: the concentrating effect and the augmentation inflow effect. Concentration is equal to the amount of gas over the total volume in the lung. The concentrating effect determines that at initial low concentrations of anesthetic gas, when a portion of that gas is taken up by circulation, the numerator (the amount of gas) decreases a lot more than the denominator (total volume in the lung), resulting in a lower concentration of the gas. However, at initial higher concentrations (when anesthetic gas makes up more of the total volume in the lung) when a portion of the gas is taken up, both the numerator and the denominator will decrease proportionally, and the resulting concentration will be higher. In the extreme situation, where the anesthetic gas makes up 100% of the total volume of the lung, when 50% of it is taken up, the resulting concentration is still 100%. The augmentation inflow effect is that the gas that comes in to fill the void of the anesthetic gas that has been taken up by the blood has a higher concentration, and therefore leads to a more rapid rate of rise of the alveolar concentration. With these two phenomena, by increasing the concentration of delivered anesthetic gas the rate of rise of the alveolar gas concentration can be increased exponentially.

In the second gas effect, if 50% of your total lung volume is nitrous oxide, and a portion of that gets taken up by the blood, a greater amount of the total volume (denominator) decreases and therefore the concentration of the second anesthetic gas will be higher.

4. The duration of anesthesia may prolong emergence.

5. MAC is the concentration of an inhaled anesthetic at 1 atm required to prevent skeletal muscle movement in response to a noxious stimulant in 50% of patients.

7.

1. Isoflurane decreases cerebral metabolic rate of oxygen (CMRO₂) the most and nitrous oxide (N₂O) the least.

2. Halothane, a potent cerebrovasodilator, increases cerebral blood flow (CBF) the most, and isoflurane the least.

3. Isoflurane best preserves the cerebral O₂ supply-demand relationship and best maintains autoregulation. It decreases cerebral metabolic rate (CMR), CBF, and blood pressure (BP). The greatly decreased CMRO₂ requirements may explain why CBF is minimally altered by this drug.

4. Enflurane causes a repetitive spiking pattern on the electroencephalogram (EEG).

5. Decreased BP is a dose-dependent response. N₂O alone has little effect on BP. Halothane, enflurane, and sevoflurane (Ultane) cause decreased myocardial contractility and decreased cardiac output. Isoflurane causes peripheral vasodilation and associated decreased systemic vascular resistance (SVR).

6. Heart rate (HR) effects of inhalation anesthetics include the following:

7. Halothane is most arrhythmogenic. It sensitizes the heart to catecholamines > enflurane > isoflurane (the least). This reflects the differences in the effects of these drugs on transmission of cardiac impulses. Halothane, enflurane, and isoflurane have a direct negative chronotropic effect on the sinoatrial node. They do not appear to alter cardiac-pacing stimulation thresholds. The cardiovascular (CV) effects can be altered by the concomitant administration of other drugs (i.e., epinephrine, calcium channel blockers, or thiopental sodium [Pentothal]). There may be a relationship between responsiveness of the alpha-adrenergic system and epinephrine sensitivity (mechanism is unclear).

8. Coronary steal is associated with isoflurane because it is the most potent coronary dilator. Myocardial ischemia may occur when isoflurane is used in circumstances of decreased perfusion pressure. Steal occurs when normal coronary arteries become even better perfused by vasodilation than diseased coronary arteries, which are already maximally dilated because they are relatively underperfused. Therefore, normal areas of the heart get increased blood flow, and the abnormal/ischemic areas get decreased flow → myocardial ischemia. In most patients, myocardial ischemia does not develop during administration of isoflurane, emphasizing the importance of avoiding drug-induced events that may alter the balance between myocardial O₂ requirements and delivery, regardless of the inhaled anesthetic being administered.

1. Most inhaled anesthetics increase the frequency of breathing and decrease the tidal volume as the anesthetic concentration increases. PaCO₂, the partial arterial pressure of carbon dioxide (CO₂), will change minimally unless other factors occur. As anesthetic concentration is increased, PaCO₂ will increase.

3. Apnea results if the anesthetic dose is high enough. If apnea occurs, the apneic threshold is approximately 4 to 5 mm Hg below the PaCO₂ maintained during spontaneous breathing, regardless of the depth of anesthesia.

4. Anesthetics depress the hypoxic ventilatory drive in humans. In addition, all anesthetics produce an anesthetic dose-related depression of the ventilatory response to CO₂. High doses can obliterate the response.

5. Hypoxic pulmonary vasoconstriction is the diversion of blood away from atelectatic lung. Inhaled anesthetics depress the response in animals in a dose-related manner. However, these findings have not been found in humans undergoing one-lung ventilation. Neither halothane nor isoflurane decreased the partial arterial pressure of oxygen (PaO₂) during one-lung ventilation.

1. There is concern that since N₂O can interfere with methionine synthase and cell division, its use in pregnancy may be associated with an increased incidence of fetal abnormalities. However, there is currently no evidence to suggest that this is the case.

There is increased risk of spontaneous abortion for all types of anesthetics, particularly after the first trimester. No particular anesthetic agent or technique has been implicated. It seems that the condition that necessitated surgery is the most relevant factor.

2. Uterine relaxation for replacement of an inverted uterus requires rapid-sequence induction with cricoid pressure and then high-flow halothane.

1. The first stage of anesthesia is a stage of sensory and gentle mental depression. Patients in this state open their eyes on command, breathe normally, and tolerate mild painful stimuli such as skin suturing or superficial debridement.

2. The second stage of anesthesia is marked by muscle movement, retching, heightened laryngeal reflexes, disconjugate pupils, tachycardia, hypertension, and hyperventilation. The goal should be to pass through this stage quickly by increasing the inspired concentration of the inhaled drug or eliminate it all together with an intravenous agent.

3. MAC awake is described as the anesthetic dose at which subjects begin to respond to commands; it also defines a dose of anesthetic at which most patients lose consciousness and recall.

4. MAC is the concentration at which 50% of patients do not move when a noxious stimulus (skin incision) is applied. At an MAC of 1.25% to 1.30%, the vast majority of patients will not move in response to skin incision. This level of anesthesia is associated with depression of the four elements of nervous system (NS) function: motor, sensory loss, loss of recall, and reflex depression (absence of increases in HR or BP in response to surgical stimulation). Although a patient may not move in response to surgery, there may be inadequate relaxation for abdominal or thoracic surgery.

5. MAC-BAR is the MAC required to block the adrenergic and CV response to incision. At this dose, you would not expect to see tachycardia or hypertension in response to surgical stimulation or endotracheal intubation.

6. Signs of anesthesia include changes in the following:

1. The blood-to-gas coefficient is 0.6, which means that sevoflurane is NOT very soluble in blood. This is associated with both a rapid induction of anesthesia and a rapid emergence from anesthesia. This effect is the same in both pediatric and adult patients, in contrast to halothane and isoflurane, which are less likely to have this effect in the very young.

2. Sevoflurane is degraded by soda lime. One of the degradation products from the interaction of sevoflurane with soda lime is called Compound A. The amount of Compound A formed is dose and time dependent. Levels are higher with baralyme than with soda lime. Compound A may be nephrotoxic at high levels, but it is unknown how high these levels need to be before causing renal injury. To avoid this, it is recommended that sevoflurane not be used for prolonged periods of time in patients with preexisting renal dysfunction, and that fresh gas flows remain above 1 L/min or higher, if used for prolonged periods of time.

3. The MAC of sevoflurane is 1.71, and it is 0.66 when combined with 60% to 70% of N₂O in O₂.

4. Sevoflurane is 2% to 3% metabolized. The major metabolite is fluoride. Sevoflurane decreases the synthesis of all serum proteins produced by the liver. Hepatic blood flow is maintained.

1. The MAC of desflurane is 7.25% in healthy individuals aged between 10 and 30 years and 6.0% in those aged between 31 and 65 years. When mixed with 60% to 70% of N₂O in O₂, the MAC is 2.83%. Desflurane is resistant to degradation both by soda lime and the liver. Fluoride level is nearly unmeasurable in humans. Virtually all elimination is through the lung.

2. Cerebral effects include the following:

See Table A-4 for the effects of the different inhalation agents on the EEG.

Mental function returns more quickly following desflurane anesthesia.

3. CV effects of desflurane include the following:

4. Potential benefits of desflurane include the following:

1. The mechanism of potent inhalation agent metabolism is an oxidative metabolism. It is dependent on the P-450 system, genetic factors, chemical structure, and alveolar concentration. Halothane is the only inhalation agent with reductive metabolism.

2. N₂O undergoes reductive metabolism (0.004%) of an absorbed dose by anaerobic bacteria such as Pseudomonas → nitrogen in the gastrointestinal (GI) tract.

4. The main metabolites of inhalation agents include the following:

The amount of volatile anesthetic degraded or metabolized depends upon a number of factors: alveolar concentration, lipid solubility, and presence of disease states. The effects of the different factors are listed below:

5. Although not exactly known, mechanisms for halothane hepatitis include the following:

6. In nephrotoxicity from inhalation agents, damage depends on the duration of exposure of the renal tubules to fluoride and the absolute increased concentration of fluoride (>50 μmol/L in plasma):

7. N₂O inhibits the vitamin B₁₂—dependent enzymes (methionine synthase and thymidylate synthase) by irreversibly oxidizing the cobalt atom of B₁₂. It manifests as anemia and polyneuropathy. It resembles pernicious anemia and bone marrow suppression.

1. The prototypical mu-receptor agonist is morphine.

2.

3. Effects from stimulation of mu-receptors:

4. A smaller dose of fentanyl is required to produce analgesia equivalent to that with morphine sulfate. This may be due to activation of the delta or epsilon receptors, which may explain the difference in the potency of different opioids.

5. The opioid receptors are found in the brain and spinal cord (substantia gelatinosa) and possibly in the periaqueductal gray area.

6. Opioid analgesia is produced through the following actions:

7. Opioids affect nausea/vomiting through the following actions:

Higher plasma concentrations may overcome the effects on the chemoreceptor trigger zone.

1. Bradycardia induced by opioids is probably caused by stimulation of the vagal nucleus in the medulla. It can be attenuated or blocked by atropine sulfate.

2. Tachycardia is associated with meperidine (Demerol) and its congener alphaprodine in high doses, and the association is presumably related to their atropine-like structure.

3. Meperidine may directly depress myocardial contractility at clinically useful doses.

4. Morphine-induced hypotension is due to arteriolar-venous dilation, which is primarily due to histamine release. It also has a direct action on vascular smooth muscle and may selectively block the venous vascular response to alpha-adrenergic stimulation.

Data are controversial on fentanyl, sufentanil, and alfentanil (Alfenta) regarding vasodilatory effects at high doses. It may be the result of direct action on smooth muscle of the peripheral arterial system, a neurologic mechanism, or both.

1. Opioids cause a decrease inrespiratory rate. There is no change in tidal volume except at high doses (decreased tidal volume). PaCO₂ increases with a shift to the right and a decreased slope on the PaCO₂ curve.

2. The mechanism of opioid-induced respiratory depression is mediated by the mu₂ receptor.

3. GI effects of opioids include the following:

4. Meperidine is best for a cholecystectomy. Naloxone (Narcan) is the best drug to use to reverse spasm of the sphincter of Oddi, but the spasm can also be reversed with glucagon, nitroglycerin, or atropine.

1. The elimination half-life of morphine