Ten or more drugs (premedication, perioperative antibiotics, IV agents, inhalation anesthetics, opioids, muscle relaxants, reversal drugs, postoperative analgesics) may be given for a relatively routine anesthetic.

1. In vitro pharmaceutical (physiochemical) interactions can significantly alter drug bioavailability and produce unintended toxic byproducts.
   1. An example of a physiochemical drug–drug interaction that alters drug bioavailability is the formation of insoluble salts that precipitate when acidic drugs (thiopental) and basic drugs (opioids or muscle relaxants) are administered into IV tubing with an insufficient fluid flow rate.
   2. Commercial preparations of local anesthetic solutions that contain epinephrine have a lower pH than plain local anesthetic solutions to which epinephrine is added shortly before administration because of the high acidity of the antioxidant stabilizers used in commercial preparations (local anesthetic appears less effective caused by the increased concentration of the less permeable ionized form local anesthetic that exists in acidic environments).
   3. If conditions are correct, the halogenated volatile anesthetics can undergo degradation by the strong base (sodium or potassium hydroxide) contained in the carbon dioxide absorber (formation of compound A).
      1. Although the effects of compound A on human renal function are not of great clinical concern, the strong bases in some carbon dioxide absorbents can also degrade the difluoromethyl-containing halogenated volatile anesthetics (desflurane and isoflurane) to carbon monoxide.
      2. These patient safety concerns led to the development and the increased use of Amsorb, a carbon dioxide adsorbent that contains calcium hydroxide lime in place of sodium or potassium hydroxide and therefore causes minimal to no carbon monoxide or compound A formation.
2. In vivo pharmaceutical (physiochemical) interactions have been exploited to develop two novel approaches to antagonize neuromuscular junction blocking agents.
   1. Sugammadex irreversibly binding plasma rocuronium acts as a chelator that rapidly decreases the free plasma rocuronium concentration and promotes redistribution of rocuronium from the neuromuscular junction (extracellular space) to the intravascular space
   2. An alternative approach to neuromuscular blockade antagonism is to design a molecule that can be inactivated via nonbiological routes (molecules are rapidly inactivated by the nonenzymatic formation of cysteine adducts when combined with plasma cysteine).
3. Pharmacokinetic Interactions. Drugs can alter each other's absorption, distribution, and elimination.
   1. Pharmacokinetic Interactions: Absorption (Uptake)
      1. Drugs such as ranitidine, which alters gastric pH, and metoclopramide, which speeds gastric emptying, alter absorption from the GI tract.
      2. Vasoconstrictors that decrease local blood flow and decrease systemic uptake of drug can be beneficial when added to local anesthetic solutions.
   2. Pharmacokinetic Interactions: Distribution
      1. Drug-induced alterations of cardiac output and the distribution of cardiac output to tissues can change the distribution clearance of other drugs (vasoactive agents can alter tissue distribution by altering regional blood flow even if the total cardiac output is unchanged).
      2. The clinical importance of protein binding in anesthetic drugs is based on several common misconceptions regarding drug distribution. First, the number of unoccupied binding sites is several orders of magnitude higher than the number of molecules of anesthetic drug administered in clinical practice (hard to envision a scenario where a significant amount of displacement could occur). The theoretical argument supporting the importance of protein binding on highly lipophilic drugs ignores the fact that lipophilic drugs not only have flow-limited elimination clearance but also flow-limited tissue distribution. (There are no examples in the literature that drug–drug interactions that produce changes in protein binding of opioids and hypnotics are clinically relevant.)
   3. Pharmacokinetic Interactions: Metabolism (Table 7-5: Inducers and Inhibitors of Hepatic Drug Metabolism)
      1. Phenytoin shortens the duration of action of the nondepolarizing neuromuscular junction blocking agents by inducing CYP3A4 and therefore increasing elimination clearance of the drug.
      2. When CYP isozyme inhibition is present (protease inhibitors), it is more difficult to adjust the drug dose without achieving supratherapeutic and possibly toxic drug concentrations (opioids, warfarin, glyburide).
      3. Prodrugs that require CYP isozyme activity for conversion to active moieties may be difficult to titrate to adequate clinical effect. (The opioid prodrugs codeine, oxycodone, hydrocodone, and tramadol all require CYP2D6 for conversion to the biologically active opioid.)
      4. Because of the high polymorphic character of the CYP2D6 enzyme, it is difficult to determine which patients who are taking selective serotonin reuptake inhibitors, which also inhibit CYP2D6 activity, would receive adequate analgesia from these opioids. (Other opioids may have less variability in opioid dose response and be better choices than these prodrugs.)
4. Pharmacodynamic interactions fall into two broad classifications.
   1. Drugs can interact, either directly or indirectly, at the same receptors.
      1. Opioid antagonists directly displace opioids from opiate receptors.
      2. Cholinesterase inhibitors indirectly antagonize the effects of neuromuscular blockers by increasing the amount of acetylcholine, which displaces the blocking drug from nicotinic receptors.
   2. Interactions can also occur if two drugs affect a physiologic system at different sites.
      1. Mu-opioid receptor–mediated ventilatory depression can be selectively antagonized by ampakines that potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated glutamatergic excitation without mitigating opioid-induced analgesia.
      2. The pharmacodynamic interaction between two drugs can be characterized using response surface models.
   3. Serotonin Syndrome
      1. The more common use of medications that modulate the serotonergic pathway is the potentially fatal serotonin syndrome (syndrome toxicity).
      2. High CNS concentrations of serotonin can produce mental status changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering, and fever.
      3. Classically, excessive CNS serotonin levels are associated with inhibition of monoamine oxidase, an enzyme responsible for breaking down serotonin in the brain.
      4. The interaction of meperidine with monamine oxidase inhibitors is the most classic drug–drug interactions associated with serotonin syndrome.
      5. When methylene blue or phenylpiperidine opioids must be administered to patients taking serotonergic psychiatric medications, clinicians should have a high clinical suspicion for the development of serotonin toxicity.

Basic Principles of Clinical Pharmacology

1. Pharmacokinetic Principles: Drug Absorption and Routes of Administration
2. Drug Distribution
3. Drug Elimination
4. Pharmacokinetic Models
5. Compartmental Pharmacokinetic Models
6. Pharmacodynamic Principles
7. Drug–Receptor Interactions
8. Drug Interactions
9. Clinical Applications of Pharmacokinetic and Pharmacodynamics to the Administration of IV Anesthetics