Chapter 5

General Principles, Pharmacodynamics, and Drug Receptor Concepts

The practice of anesthesia requires a full spectrum of drugs from which an anesthetic plan can be implemented to achieve the desired level of surgical anesthesia, analgesia, amnesia, and muscle relaxation. In addition to surgical anesthesia, pain medicine has evolved as a significant clinical practice component.1,2 Now that the human genome has been mapped and the field of molecular and cellular proteomics is exploring new concepts, specific receptor-targeted drugs are envisioned, as is a revolution in the way health care is delivered. Likewise, the methods used to provide anesthesia care will undergo a profound change based on this new knowledge. Already, studies are challenging long-held concepts of pharmacodynamics and pharmacokinetics that guide the clinical use of anesthetic agents. Target-controlled drug administration that factors in clinical pharmacodynamic and pharmacokinetic information is already being applied.^3,4

Although the mechanism of action of the general anesthetics remains unknown, the primary site of anesthetic action is now considered to be membrane receptors and not the lipid bilayer surrounding the nerve cells.5–7 Spinal cord receptors are being differentiated from receptors in the brain and targeted with specific drugs. A more in-depth knowledge of the concept of minimum alveolar concentration, which is used to define inhalation anesthetic dosing, is now coming to light.^8,9 Receptor super families with definable amino acid subunits are the targets of new classes of anesthetic drugs such as α₂-agonists and analgesics.¹⁰ The potentiation of the inhibitory γ-aminobutyric acid (GABA) receptors is considered a primary mechanism of action of inhalation and intravenous anesthetics.¹¹ The recovery from intravenous anesthesia is described in terms of context-sensitive half-time, which in addition to the usual concept of drug half-life takes into consideration the duration of anesthetic administration rather than just drug redistribution and elimination profiles.^12–14

The importance of the individual, with his or her unique genetic profile, is surfacing as a major determinant of anesthesia outcome.15,16 The number of patients who now make up the portion of the population classified as elderly—those age 60 years and above—is ever increasing. Clinical experience has shown that the response to anesthetic drugs in elderly patients differs from that in younger patients. Age-related changes in drug pharmacokinetics do not totally explain the differences in drug dosing necessary to achieve anesthetic end-points in elderly patients. Studies to date in elderly patients, although limited, demonstrate an age-related decline in most receptor populations and an overall decrease in pharmacodynamic responses.^17–20 Preoperative assessment may soon take on an entirely different meaning as patient information becomes more genetically oriented. The choice of anesthetic agents will be based on age-related receptor profiles and the patient’s genetic ability to rapidly clear and recover from anesthetic drugs once their administration has been terminated.^21–24 Until that time, anesthetists will continue to administer anesthesia based on age-indexed population drug profiles adjusted for individual pathologies (i.e., general principles of pharmacology).

The current medical economic climate necessitates the optimum selection and use of anesthetic drugs based on their pharmacologic profiles. The term pharmacology refers to the study of processes by which a drug produces one or more measured physiologic responses. The concept of a drug-induced tissue response has changed little since Ehrlich first proposed it (circa 1905). What has changed, and continues to change, is our understanding of the processes involved in drug-receptor interactions.25–27 Recent attention has focused on the biosphere, or the protein receptor site, as not only the locus of drug binding but also a primary regulator of the measured pharmacologic response. Secondary processes, including drug absorption, distribution, biotransformation, and excretion, also influence the pharmacologic response.²⁸

Receptor Structure

A receptor is a protein or other substance that binds to an endogenous chemical or a drug. This coupling causes a chain of events leading to an effect. Receptors have three common properties: sensitivity, selectivity, and specificity. These properties are characterized by the fact that a drug response occurs from a low concentration (sensitivity) produced by structurally similar chemicals (selectivity), and the response from a given set of receptors is always the same because the cells themselves determine the response (specificity). The bonds that form between drugs and receptors typically fall into these categories from weakest to strongest: van der Waals, hydrophobic, hydrogen, ionic, and covalent.

Drug Receptors

The historic concept of a drug receptor complex considered the receptor to be a single protein to which the drug aligned and attached itself. We now have identified multiple mechanisms by which an endogenous substance or drug may complex with a receptor and transmit a signal. There are seven classes of drug receptor proteins based on genetic characterization and similarity of structure and functions.²⁹ Some examples of different types of receptors are given in Box 5-1.

BOX 5-1 Receptor Classification

• 7-Transmembrane receptors

• Ligand-gated ion channels

• Ion channels

• Catalytic receptors

• Nuclear receptors

• Transporters

• Enzymes

Data from: Guide to receptors and channels (GRAC), 4th ed. Br J Pharmacol 2009; 158(Suppl 1):S1-S254.

Drug receptor proteins may be located within the luminal membrane and at the surface of the ionic channel. They also occupy intracellular sites. The drug lidocaine and other amide and ester local anesthetics, for example, act at intracellular receptor sites near the sodium channel. Studies of acetylcholine and its receptor at the neuromuscular junction indicate that less than 1% of the cell surface binds drug to receptor protein to achieve the tissue response.³⁰ Complete saturation of available receptors with drug molecules is not necessary for a desired tissue response to be elicited. With recent advances in molecular biology, many receptors have been extensively characterized, amino acid sequenced, and cloned. This is leading to new and better understanding of receptor pharmacology and new approaches to drug discovery.31–34

For intravenously administered drugs, sufficient drug for a maximal tissue response is delivered to the receptor site within the time required for a single complete circulation (approximately 1 minute), provided an adequate drug dose was administered initially. Current understanding of molecular pharmacology suggests that the delay recorded from initial drug administration to the onset of the tissue response reflects the time required for molecular orientation and attachment to the receptor—that is, the time course of the receptor protein conformational change and the tissue response time.³⁵ As long as both the drug and the receptor are hydrophobic, bonding occurs.³⁶ Intravenous anesthetics act by binding to membrane receptor channel proteins. The GABA_A (ionotropic receptor family A) inhibitory receptor has been implicated and suggested as a primary site of intravenous anesthetic action, except in the case of ketamine.^37–39 Inhalation anesthetics have long been thought to produce their anesthetic action by dissolving in the lipid bilayer surrounding membrane ion channels and interfering with their ability to open and close. Recent electrophysiologic evidence, however, indicates that inhalation anesthetics, like intravenous anesthetics, bind to GABA_A receptor proteins and cause inhibition of signal transduction by increasing the influx of chloride ions through membrane channels.^11,37–39

Individual agonist drugs have at least three configuration points for attachment to their receptors. With more points of attachment, a more perfect drug-receptor fit occurs. Agonist drugs can induce receptor proteins to alter their topography to achieve a more exacting fit with the drug. The alignment of a drug with its receptor is aided by various bonding forces, of which van der Waals forces and ionic bonding are prominent. Volatile anesthetics (e.g., desflurane, sevoflurane, isoflurane, and nitrous oxide) bond to cell receptors by means of a nonspecific hydrophobic bonding mechanism.

Some endogenous proteins provide alternative drug-binding sites. These sites are more correctly termed acceptors; the acceptor reduces the amount of unbound drug available for receptor complexing. Albumin contains numerous acceptor sites and generally binds to acidic drugs. Alpha₁ acid glycoprotein and β-globulin favor basic drugs. Drugs bound to these proteins are unavailable to interact with receptors, therefore reducing the available active drug concentration.

Types of Receptors

As noted earlier, a variety of receptor types have been isolated and investigated, including GABA, opioid, alpha, beta, acetylcholine, histamine subtypes, and the pain-related capsaicin receptor, as well as numerous others.39–43 The nicotinic and muscarinic cholinergic receptors that bind acetylcholine have been extensively studied.^44–46 The acetylcholine receptor protein is a pentamer of five peptide subunits conceptually forming a five-sided ring, with the central portion serving as the transduction ion channel. Only two of the five subunits are involved in acetylcholine binding. The remaining three peptide subunits participate in the signal transduction process that involves a protein conformational shift, allowing inward movement of sodium ions through the opened ion channel. It is interesting to note that the GABA_A receptor also has been shown to be composed of five peptide subunits arranged to form a pentameric ring.^43,47–49

Signal Transduction

In biology, signal transduction refers to processes by which a cell converts one kind of signal or stimulus into another. Most often, these involve ordered sequences or cascades of biochemical reactions inside the cell. They are commonly referred to as second messenger pathways. An example of a G protein–coupled receptor (GPCR) and its second messenger system is shown in Figure 5-1.

FIGURE 5-1 G Protein–coupled receptors. Upon ligand binding, β-adrenergic receptors (β-AR) bind to the heterotrimeric guanine nucleotide–binding protein Gs, inducing the exchange of GTP for GDP on the Gα subunit. Guanine nucleotide exchange induces dissociation of the α subunits from βγ subunits, the former of which activates adenylyl cyclase and the production of the second messenger cyclic AMP (cAMP). Signaling is terminated by GTP hydrolysis by the Gα subunit, resulting in its occupation by GDP, promoting reassociation of the heterotrimeric αβγ complex and inactivation of adenylyl cyclase. Moreover, receptors are inactivated by phosphorylation by G protein–coupled receptor kinase (GRK) resulting in the binding of β-arrestin, producing receptor desensitization by preventing productive interaction with G proteins and inducing internalization. (From: Waldman SA, Terzic A: Pharmacology and Therapeutics: Principles to Practice. Philadelphia: WB Saunders, 2009:55.)

Many of the actions of the common anesthetic drugs are transduced through cell-surface receptors that are linked to GPCRs. Receptor signaling translates changes to G proteins that are then linked to a second messenger such as cyclic AMP (adenosine monophosphate) or cyclic GMP (guanosine monophosphate). These second messengers regulate enzymes such as protein kinases and phosphatases, which drive their ultimate intracellular actions.

Signal transduction for the GABA_A receptor, for example, involves inward chloride ion movement through the opened central channel. The protein compositions of acetylcholine and GABA receptors are remarkably similar, despite their functional differences—specifically, acetylcholine and sodium ion transduce an excitatory signal, and GABA and chloride ion transduce an inhibitory signal.50,51

For many drugs, the composition of the receptor protein and the signal transduction process may be identical, even though the drug-induced tissue response is not. The primary difference among drug receptor proteins may be only the selective binding subunits and the ion species moving through the channel.37,39,41,52,53 The specific peptide subunits are ultimately responsible for the pharmacologic properties of specificity, affinity, and potency.

In addition, specific isomers that have fewer side effects than the racemic mixture have been marketed. Drugs such as dexmedetomidine, ropivacaine, and cisatracurium are selective in their receptor binding and thus achieve a better clinical side effect profile.54,55

Drug Response Equation

The drug response equation is fundamental to pharmacologic principles.³⁵ It is derived from the law of mass action and is shown in the following equation, where drug (D) combines with receptor (R) to form a drug receptor complex (DRC) that elicits a tissue response (TR).

What remains unique about this equation is that in most cases, the drug receptor complex represents a highly selective process. Yet the resultant tissue response tends to vary from individual to individual, reflecting each individual’s receptor and genetic profile and physiologic state. The basic drug response relationship conceptually depends on a common pharmacologic theory of drug action. This is the occupancy theory. Simply stated, the magnitude of a drug’s effect is proportional to the number of receptors occupied. Although it is understood that drug receptor interactions have more complexity than this theory accounts for, it serves as a useful background for many pharmacologic concepts.

Population Variability

Because the objective of pharmacologic intervention is to achieve a desired therapeutic response, anesthetists recognize that a range of responses to a given drug and dosage is possible within a patient population. Therapeutic drug doses reflect average doses of a “normal” population of individuals. Specific therapeutic doses for population subsets (e.g., pediatric, neonatal, geriatric, patients with cardiac or other chronic diseases) are available, thereby narrowing the degree of response variability for a given drug and clinical population. The age, sex, body weight, body surface area, basal metabolic rate, pathologic state, and genetic profile of an individual directly influence the pharmacologic response.

Given the increasing median age of the population in the United States, studies of the influence of age on the responses to anesthetic drugs have increased. Steady-state plasma concentrations of hypnotic drugs such as midazolam and propofol and minimum alveolar concentrations (MAC) for inhaled anesthetics (e.g., desflurane, isoflurane, or sevoflurane) required to achieve desired anesthetic end-points decrease as age increases, independent of any age effect on drug pharmacokinetics.56,57–59 In addition, the effective plasma concentration 50 (median effective concentration [EC₅₀]) needed to achieve sedation with midazolam infusion is reported to be decreased by 50% in elderly volunteers.^57,60 Unfortunately, the specifics responsible for the observed age-related decrease in effective dose of anesthetic drugs is not presently known. Receptor changes associated with aging and kinetic differences in the elderly are in part responsible for the variation in response. Until a better understanding of the age-related changes exists, empirical dose reduction or the use of dosing algorithms for the elderly patient population is indicated.

Mean, Median, and Mode

A graphic description of the dose-response relationship is displayed in Figure 5-2. The theoretic normal distribution of quantal (desired) responses to increasing drug dose takes the shape of a Gaussian curve. Theoretically, the numbers of respondents on both sides of the mean (average dose) are equal, with the greatest percentage of individuals responding near the center of the curve. In a Gaussian distribution curve, the mean, median, and mode are equidistant from the two extremes.⁶¹ Atypical responders fall at each end of the curve.

FIGURE 5-2 The theoretic normal frequency distribution of a drug response in a normal population.

On the curve, the mean dose is the arithmetic average of the range of doses that produce a given response. The median dose is that dose on either side of which half of the responses occur. The mode dose is the dose representing the greatest percentage of responses. The mean, median, and mode doses are often close but are rarely the same in actual dose-response curves.

Standard Deviation

The terms standard deviation (SD) and standard error of the mean (SEM) describe population response variability.⁶² The SD provides information regarding the actual responses measured and their difference from the calculated mean. In Figure 5-3, 1 SD makes up 68% of the responses (34% to the left and 34% to the right of the mean value); 2 and 3 SDs constitute 95% and 99.7% of the responses, respectively. The greater the SD, the less the mean reflects the central tendency of responses.