Drug Absorption and Routes of Administration PDF

Authors: Cullen, Bruce F.; Stock, M. Christine; Ortega, Rafael; Sharar, Sam R.; Holt, Natalie F.; Connor, Christopher W.; Nathan, Naveen Title: Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition Copyright ©2024 Lippincott Williams & Wilkins > Table of Contents > Section 2 - Basic Sci...

Authors: Cullen, Bruce F.; Stock, M. Christine; Ortega, Rafael; Sharar, Sam R.; Holt, Natalie F.; Connor, Christopher W.; Nathan, Naveen Title: Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition Copyright ©2024 Lippincott Williams & Wilkins > Table of Contents > Section 2 - Basic Science and Fundamentals > 11 - Basic Principles of Clinical Pharmacology > Pharmacokinetic Principles > Drug Absorption and Routes of Administration Drug Absorption and Routes of Administration Transfer of Drugs across Membranes Even drugs that are administered directly into the bloodstream must move across at least one cell membrane to get to their 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 their concentration gradients. For water-soluble drugs to passively diffuse across the cell membrane down a concentration gradient, a hydrophilic channel formed from transmembrane proteins is required. Nonspecific hydrophilic channels are abundant in the capillary endothelium of all organs except for the central nervous system (CNS). As a result, passive transport of drugs from the intravascular space into the interstitium of various organs is limited by blood flow, not by the lipid solubility of the drug.5 In the CNS, the blood-brain barrier capillary endothelial cells have very limited numbers of transmembrane hydrophilic channels. Hydrophilic drugs can only enter the CNS after binding to drug-specific transmembrane proteins that actively transport the hydrophilic drug across the capillary endothelium into the CNS interstitium. When these transmembrane carrier proteins require energy to transport the drug across the membrane, they are able to shuttle compounds against their concentration gradients, a process called active transport. In contrast, when these carrier proteins do not require energy to shuttle drugs, they cannot overcome concentration gradients, a process called facilitated diffusion. Active transport is not limited to the CNS; it is also found in the organs related to drug elimination (e.g., hepatocytes, renal tubular cells, pulmonary capillary endothelium), where the P.227 ability to transport drugs against the concentration gradient has specific biologic advantages. Both active transport and facilitated diffusion of drugs are saturable processes that are primarily limited by the number of carrier proteins available to shuttle a specific drug.5 For lipophilic compounds, transporters are not needed for the drug to diffuse across the capillary wall into tissues, but the presence of transporters does affect the concentration gradients that exist. For instance, some lipophilic drugs are transported out of tissues by adenosine triphosphate (ATP)-dependent transporters such as p- glycoprotein (P-gp). The lipophilic potent µ-opioid agonist, loperamide, used for the treatment of diarrhea, has limited bioavailability because of P-gp transporters at the intestineportal capillary interface. What does reach the circulation has its CNS penetrance limited by P-gp at the blood-brain barrier.6 Conversely, lipophilic compounds can be transported into tissues, increasing the tissue concentration of the drug beyond what would be accomplished by passive diffusion. The class of transporters called organic anion polypeptide transporters (OATPs) is located in the microvascular endothelium of the brain and transports endogenous opioids into the brain.7,8 These OATPs also transport drugs. The degree to which transporter proteins may account for intra- and interindividual responses to anesthetic drugs has not been well-studied to date.9 Intravenous Administration In order for a drug to be delivered to the site of drug action, it must be absorbed into the systemic circulation. Therefore, IV administration results in immediate delivery of a drug with 100% bioavailability. This can lead to rapid overshoot of the desired plasma concentration which can potentially result in immediate and severe side effects for drugs that have a low therapeutic index (defined as the ratio of the blood concentration that produces a toxic effect in 50% of the population to the blood concentration that produces a therapeutic effect in 50% of the population). Except for IV administration, the absorption of a drug into the systemic circulation is an important determinant of the time course of drug action and the maximum drug effect produced. As the absorption of drug is slowed, the maximum plasma concentration achieved—and therefore the maximum drug effect achieved—is limited. However, as long as the plasma concentration is maintained at a level above the minimum effective plasma concentration, the drug will produce a drug effect.10 Therefore, non-IV methods of drug administration can produce a sustained and significant drug effect that may be more advantageous than IV administration.11 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 is close to unity and the rate is nearly instantaneous. However, 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 it is with fentanyl. The pulmonary endothelium also contains enzymes that may metabolize intravenously administered drugs (e.g., propofol) on first pass.12 Oral Administration For almost all therapeutic agents, oral administration is the safest and most convenient method of administration. However, this route is not utilized significantly in anesthesia practice because of the limited and inconstant rate of bioavailability. The absorption rate in the gastrointestinal tract is highly variable because the main determinant of the timing of absorption is gastric emptying into the small intestines, where the surface area for absorption is several orders of magnitude greater than that of the stomach or large intestines. In addition, the active metabolism of drug by the small intestine mucosal epithelium, and the obligatory path through the portal circulation before entering the systemic circulation, contribute to decreased bioavailability of drugs administered via the oral route.13 In fact, the metabolic capacity of the liver for drugs is so high that only a small fraction of most orally administered lipophilic drugs actually reach the systemic circulation. Because of this extensive first-pass metabolism, the oral dose of most drugs must be significantly higher than the IV dose to generate a therapeutic plasma concentration. In addition, time until peak concentration is prolonged and variable, making the oral route impractical to utilize in the perioperative setting. 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 tract. Sublingual administration of drug has the additional advantage that absorbed drug directly enters the systemic venous circulation and therefore is able to bypass the metabolically active intestinal mucosa and hepatic first-pass metabolism. Therefore, small doses of drug can rapidly achieve high plasma concentration and therapeutic effect.14 However, because of formulation limitations and the small surface area available for absorption, there are only a limited number of drugs that are available for sublingual administration (e.g., nitroglycerin, fentanyl). Transcutaneous Administration A few lipophilic drugs have been manufactured in formulations that are sufficient to allow penetration of intact skin. Although scopolamine, nitroglycerin, opioids, and clonidine all produce therapeutic systemic plasma concentrations when administered as “drug patches,” the extended amount of time that it takes to achieve an effective therapeutic concentration limits practical application except in the context of maintenance therapy. The use of electric current to increase the speed of passive drug diffusion has been described for fentanyl but is still limited in practicality.15 Intramuscular and Subcutaneous Administration Absorption of drugs from depots in subcutaneous or muscle tissue is directly dependent on the drug formulation and the blood flow to the depot. Blood flow to muscles is high in most physiologic states. Therefore, intramuscular drug absorption is relatively rapid and complete. As a result, some aqueous drugs can be administered as intramuscular injection with rapid and predictable effects (e.g., neuromuscular junction blocking agents). Drug absorption following subcutaneous administration is more unpredictable because of the variability of subcutaneous blood flow, especially in the context of certain disease pathologies; this is the primary reason that subcutaneous heparin and regular insulin administered perioperatively have variable times of onset and maximum effect. Intrathecal, Epidural, and Perineural Injection Because the spinal cord is the primary site of action of many anesthetic agents, direct injection of local anesthetics and opioids into the intrathecal space bypasses the limitations of drug absorption and drug distribution by any other route of administration. This is not the case for epidural and perineural administration of local anesthetics, because such administration still requires that drug be absorbed through the dura or nerve sheath in order to reach its site of action. The major downside to these routes of administration is the relative expertise required to perform them. P.228 Inhalational Administration Owing to the large surface area afforded by pulmonary alveoli and high volume of blood flow in the pulmonary capillaries, administration of drugs by inhalation is extremely desirable.16 New technologies have been developed which can rapidly and predictably aerosolize a wide range of drugs and thus achieve pharmacokinetic effects comparable to IV administration.17,18 These devices are currently in Phase II Food and Drug Administration (FDA) trials.