KEY POINTS

1. The fundamental pharmacokinetic processes are dilution into volumes of distribution and clearance. These processes are governed by the physical properties of the drug and the metabolic capacity of the patient. Anesthetic drugs tend to be highly bound to protein in plasma and highly bound to lipid in peripheral tissues. Most anesthetic drugs are metabolized in the liver.
2. The pharmacokinetic actions of anesthetic drugs are typically described by mathematical models with a central compartment and one or two peripheral compartments. These compartments do not directly correspond to any anatomic or physiologic structures. Computer simulations can be used to predict the time course of plasma concentration and drug effect.
3. Drugs exert their effects through binding to receptors. The fraction bound is determined by the law of mass action, which yields a sigmoidal relationship between fractional occupancy and drug concentration.
4. Drugs can be agonists, partial agonists, neutral antagonists, or inverse agonists. Receptors exist in activated and inactivated states, and the intrinsic efficacy of a drug is determined by the extent to which it stabilizes the active form of the receptor (i.e., agonists), the inactive form (i.e., inverse agonists), or displaces agonists from the binding site without favoring either form (i.e., neutral antagonists).
5. The four main receptor types are G protein-coupled receptors (e.g., opioids, catecholamines), ligand-gated ion channels (e.g., hypnotics, benzodiazepines, muscle relaxants, ketamine), voltage-gated ion channels (e.g., local anesthetics), and enzymes (e.g., neostigmine, amrinone, caffeine). The first three types are located in cell membranes. Enzymes can be located anywhere.
6. Many drugs act through second messengers, which amplify drug action. Common second messengers are G proteins, which can release stimulating or inhibitory subunits in response to drug binding at the receptor; c-AMP, which is frequently a target of G-protein stimulation or inhibition; IP3 and DAG, also targets of G-protein regulation; and intracellular ions, especially calcium.

---

103

7. Advances in molecular pharmacology are helping to identify the specific function of individual receptors and the role of individual amino acids in mediating receptor action. Specific tools include site-directed mutagenesis to create designer receptors and knock-out or knock-down (underexpressed) or transgenic (overexpressed) murine models to understand the physiologic action of individual receptors.
8. The fundamental properties of the concentration versus response relationship are potency and efficacy. Potency is the concentration associated with a 50% drug effect. Efficacy is the maximal possible drug effect.
9. Drugs can interact pharmacokinetically through enzymatic induction or inhibition or pharmacodynamically through synergy or antagonism. Anesthetic techniques typically take advantage of the synergy between hypnotics and opioids to produce the anesthetic state at far lower doses of each drug than would be required if they were used alone.
10. Pharmacogenetics is gradually explaining some of the variability in response to drugs. Genetic variability in pharmacokinetics can be attributed to variability in hepatic cytochromes (e.g., CYP2D6, CYP2C19), circulating enzymes (e.g., pseudocholinesterase), or transporters. Genetic variability in pharmacodynamics can be attributed to alterations in receptors, as has been demonstrated for multiple adrenergic-receptor variants. Malignant hyperthermia has been clearly linked to variability in the ryanodine receptor.
11. Variability in response to drugs can also be attributed to nongenetic causes, such as aging, disease, exposure to environmental toxins, and the pharmacokinetic or pharmacodynamic influence of other drugs. Variability is also introduced through continuous exposure to a single drug, which can trigger desensitization (tolerance) or, if the drug is an antagonist, increased receptor sensitivity to the agonist.