Basic Principles of Clinical Pharmacology
Anesthetic drugs are administered with the goal of rapidly establishing and maintaining a therapeutic effect while minimizing undesired side effects (Gupta DK, Henthorn TK. Basic principles of clinical pharmacology. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Ortega R, Stock MC, eds. Clinical Anesthesia. Philadelphia: Lippincott Williams & Wilkins; 2013: 156–188).
I. Pharmacokinetic Principles: Drug Absorption and Routes of Administration
Transfer of Drugs across Membranes. Even the simplest drug that is directly administered into the blood to exert its action must move across at least one cell membrane to its site of action.
Because biologic membranes are lipid bilayers composed of a lipophilic core sandwiched between two hydrophilic layers, only small lipophilic drugs can passively diffuse across the membrane down its concentration gradient.
For water-soluble drugs to passively diffuse across the membrane down its concentration gradient, transmembrane proteins that form a hydrophilic channel are required.
Intravenous (IV) administration results in rapid increases in drug concentration. Although this can lead to a very rapid onset of drug effect, for drugs that have a low therapeutic index (the ratio of the IV dose that produces a toxic effect in 50% of the population to the IV dose that produces a therapeutic effect in 50% of the population), rapid overshoot of the desired plasma concentration can potentially result in immediate and severe side effects.
Bioavailability is the relative amount of a drug dose that reaches the systemic circulation unchanged and the rate at which this occurs. For most intravenously administered drugs, the absolute bioavailability of drug available is close to unity, and the rate is nearly instantaneous.
The pulmonary endothelium can slow the rate at which intravenously administered drugs reach the systemic circulation if distribution into the alveolar endothelium is
extensive such as occurs with the pulmonary uptake of fentanyl. The pulmonary endothelium also contains enzymes that may metabolize intravenously administered drugs (propofol) on first pass and reduce their absolute bioavailability.
Oral administration is not used significantly in anesthetic practice because of the limited and variable rate of bioavailability.
Because of this extensive first-pass metabolism, the oral dose of most drugs must be significantly higher to generate a therapeutic plasma concentration.
Highly lipophilic drugs that can maintain a high contact time with nasal or oral (sublingual) mucosa can be absorbed without needing to traverse the gastrointestinal (GI) tract. Sublingual administration of drug has the additional advantage over GI absorption in that absorbed drug directly enters the systemic venous circulation, so it is able to bypass the metabolically active intestinal mucosa and the hepatic first-pass metabolism.
Transcutaneous Administration. A few lipophilic drugs (e.g., scopolamine, nitroglycerin, fentanyl) have been manufactured in formulations that are sufficient to allow penetration of intact skin.
Intramuscular and Subcutaneous Administration. Absorption of drugs from the depots in the subcutaneous tissue or in muscle tissue directly depends on the drug formulation and the blood flow to the depot.
Intrathecal, Epidural, and Perineural Injection. The major downside to these three techniques is the relative expertise required to perform regional anesthetics relative to oral, IV, and inhalational drug administration.
Inhalational Administration. The large surface area of the pulmonary alveoli available for exchange with the large volumetric flow of blood found in the pulmonary capillaries makes inhalational administration an extremely attractive method (approximates IV administration) by which to administer drugs.
II. Drug Distribution
The relative distribution of cardiac output among organ vascular beds determines the speed at which organs are exposed to drug. The highly perfused core circulatory components (the brain, lungs, heart, and kidneys) receive the highest relative distribution of cardiac output and therefore are the initial organs to reach equilibrium with plasma drug concentrations. Drug transfer to the less well-perfused, intermediate-volume muscle tissue may take hours to approach equilibrium,
and drug transfer to the poorly perfused, large cellular volumes of adipose tissue does not equilibrate for days.
and drug transfer to the poorly perfused, large cellular volumes of adipose tissue does not equilibrate for days.
Redistribution
As soon as the concentration of drug in the brain tissue is higher than the plasma concentration of drug, a reversal of the drug concentration gradient takes place so that the lipophilic drug readily diffuses back into the blood and is redistributed to the other tissues that are still taking up drug.
Although single, moderate doses of highly lipophilic drugs have very short central nervous system (CNS) durations of action because of redistribution of drug from the CNS to the blood and other less well-perfused tissues, repeated injections of a drug allow the rapid establishment of significant peripheral tissue concentrations.
III. Drug Elimination
Drug elimination is the pharmacokinetic term that describes all the processes that remove a drug from the body. Although the liver and the kidneys are considered the major organs of drug elimination, drug metabolism can occur at many other locations that contain active drug metabolizing enzymes (e.g., the pulmonary vasculature, red blood cells), and drugs can be excreted unchanged from other organs (e.g., the lungs).
Elimination clearance (drug clearance) is the theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time.
Biotransformation Reactions. Most drugs that are excreted unchanged from the body are hydrophilic and therefore readily passed into urine or stool. Drugs that are not sufficiently hydrophilic to be able to be excreted unchanged require modification (enzymatic reactions) into more hydrophilic, excretable compounds.
Phase I reactions may hydrolyze, oxidize, or reduce the parent compound.
Cytochrome P450 enzymes (CYPs) are a superfamily of constitutive and inducible enzymes that catalyze most phase I biotransformations. CYP3A4 is the single most important enzyme, accounting for 40% to 45% of all CYP-mediated drug metabolism.
CYPs are incorporated into the smooth endoplasmic reticulum of hepatocytes and the membranes of the upper intestinal enterocytes in high concentrations (Table 7-1).
Phase II reactions are known as conjugation or synthetic reactions. Similar to the cytochrome P450 system, the enzymes that catalyze phase II reactions are inducible.
Genetic Variations in Drug Metabolism. Drug metabolism varies substantially among individuals because of variability in the genes controlling the numerous enzymes responsible for biotransformation.
Chronologic Variations in Drug Metabolism. The activity and capacity of the CYP enzymes increase from subnormal levels in the fetal and neonatal period to reach normal levels at about 1 year of age. Neonates have a limited ability to perform phase II conjugation reactions, but after normalizing phase II activity over the initial year of life, advanced age does not affect the capacity to perform phase II reactions.
Renal Drug Clearance. The primary role of the kidneys in drug elimination is to excrete into urine the unchanged hydrophilic drugs and the hepatic derived metabolites from phase I and II reactions of lipophilic drugs. In patients with acute and chronic causes of decreased renal function, including age, low cardiac output states, and hepatorenal syndrome, drug dosing must be altered to avoid accumulation of parent compounds and potentially toxic metabolites (Table 7-2).
Hepatic Drug Clearance. Drug elimination by the liver depends on the intrinsic ability of the liver to metabolize the drug and the amount of drug available to diffuse into the liver (hepatic blood flow) (Table 7-3).
Table 7-1 Substrates for CYP Isoenzymes Encountered in Anesthesiology | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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