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Unit I, Principles of Drug Therapy part II Cheat Sheet by

lippincott pharmacology book

DRUG CLEARANCE THROUGH METABOLISM

Once a drug enters the body, the process of elimin­ation begins. The three major routes of elimin­ation are hepatic metabo­lism, biliary elimin­ation, and urinary elimin­ation. Together, these elimin­ation processes decrease the plasma concen­tration expone­nti­ally. That is, a constant fraction of the drug present is eliminated in a given unit of time.
Most drugs are eliminated according to first-­order kinetics, although some, such as aspirin in high doses, are eliminated according to zero-order or nonlinear kinetics. Metabolism leads to production of products with increased polarity, which allows the drug to be elimin­ated. Clearance (CL) estimates the amount of drug cleared from the body per unit of time.
A. Kinetics of metabo­lism 1. First-­order kinetics: The metabolic transf­orm­ation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis- Menten kinetics.
2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large.
The enzyme is saturated by a high free drug concen­tra­tion, and the rate of metabolism remains constant over time. This is called zero-order kinetics (also called nonlinear kinetics). A constant amount of drug is metabo­lized per unit of time. The rate of elimin­ation is constant and does not depend on the drug concen­tra­tion.
B. Reac­tions of drug metabo­lism: The kidney cannot effici­ently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-­soluble agents are first metabo­lized into more polar (hydro­philic) substances in the liver via two general sets of reactions, called phase I and phase II.
1. Phase I: Phase I reactions convert lipophilic drugs into more polar molecules by introd­ucing or unmasking a polar functional group, such as –OH or –NH2. Phase I reactions usually involve reduction, oxidation, or hydrol­ysis. Phase I metabolism may increase, decrease, or have no effect on pharma­cologic activity.
a. Phase I reactions utilizing the P450 system: The phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed-­fun­ction oxidases). The P450 system is important for the metabolism of many endogenous compounds (such as steroids, lipids) and for the biotra­nsf­orm­ation of exogenous substances (xenob­iot­ics). Cytochrome P450, designated as CYP, is a superf­amily of heme-c­ont­aining isozymes that are located in most cells, but primarily in the liver and GI tract.
Inducers: The CYP450­-de­pendent enzymes are an important target for pharma­cok­inetic drug intera­ctions. One such intera­ction is the induction of selected CYP isozymes. Xenobi­otics (chemicals not normally produced or expected to be present in the body, for example, drugs or enviro­nmental pollut­ants) may induce the activity of these enzymes. Certain drugs (for example, phenob­arb­ital, rifampin, and carbam­aze­pine) are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotra­nsf­orm­ation of drugs and can lead to signif­icant decreases in plasma concen­tra­tions of drugs metabo­lized by these CYP isozymes, with concurrent loss of pharma­cologic effect. For example, rifampin, an antitu­ber­culosis drug (see Chapter 41), signif­icantly decreases the plasma concen­tra­tions of human immuno­def­iciency virus (HIV) protease inhibi­tors, thereby dimini­shing their ability to suppress HIV replic­ation. St. John’s wort is a widely used herbal product and is a potent CYP3A4 inducer. Many drug intera­ctions have been reported with concom­itant use of St. John’s wort. Figure 1.18 lists some of the more important inducers for repres­ent­ative CYP isozymes. Conseq­uences of increased drug metabolism include 1) decreased plasma drug concen­tra­tions, 2) decreased drug activity if the metabolite is inactive, 3) increased drug activity if the metabolite is active, and 4) decreased therap­eutic drug effect.
Inhibi­tors: Inhibition of CYP isozyme activity is an important source of drug intera­ctions that lead to serious adverse events. The most common form of inhibition is through compet­ition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not substrates (for example, ketoco­naz­ole), leading to drug intera­ctions. Numerous drugs have been shown to inhibit one or more of the CYP-de­pendent biotra­nsf­orm­ation pathways of warfarin. For example, omeprazole is a potent inhibitor of three of the CYP isozymes respon­sible for warfarin metabo­lism. If the two drugs are taken together, plasma concen­tra­tions of warfarin increase, which leads to greater antico­agulant effect and increased risk of bleeding. [Note: The more important CYP inhibitors are erythr­omycin, ketoco­nazole, and ritonavir, because they each inhibit several CYP isozymes.] Natural substances may also inhibit drug metabo­lism. For instance, grapefruit juice inhibits CYP3A4 and leads to higher levels and/or greater potential for toxic effects with drugs, such as nifedi­pine, clarit­hro­mycin, and simvas­tatin, that are metabo­lized by this system.
b. Phase I reactions not involving the P450 system: These include amine oxidation (for example, oxidation of catech­ola­mines or histam­ine), alcohol dehydr­oge­nation (for example, ethanol oxidat­ion), esterases (for example, metabolism of aspirin in the liver), and hydrolysis (for example, of procaine).
2. Phase II: This phase consists of conjug­ation reactions. If the metabolite from phase I metabolism is suffic­iently polar, it can be excreted by the kidneys. However, many phase I metabo­lites are still too lipophilic to be excreted. A subsequent conjug­ation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-­soluble compounds that are often therap­eut­ically inactive. A notable exception is morphi­ne-­6-g­luc­uro­nide, which is more potent than morphine. Glucur­oni­dation is the most common and the most important conjug­ation reaction. [Note: Drugs already possessing an –OH, –NH2, or –COOH group may enter phase II directly and become conjugated without prior phase I metabo­lism.] The highly polar drug conjugates are then excreted by the kidney or in bile.
 

DRUG CLEARANCE BY THE KIDNEY

Drugs must be suffic­iently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being elimin­ation through the kidney into the urine. Patients with renal dysfun­ction may be unable to excrete drugs and are at risk for drug accumu­lation and adverse effects.
A. Renal elimin­ation of a drug Elimin­ation of drugs via the kidneys into urine involves the processes of glomerular filtra­tion, active tubular secretion, and passive tubular reabso­rption.
1. Glomerular filtra­tion: Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate (Figure 1.19). The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish signif­icantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in GFR and protein binding of drugs do affect this process.
2. Proximal tubular secretion: Drugs that were not transf­erred into the glomerular filtrate leave the glomeruli through efferent arteri­oles, which divide to form a capillary plexus surrou­nding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy­-re­quiring active transport systems: one for anions (for example, deprot­onated forms of weak acids) and one for cations (for example, protonated forms of weak bases).
Each of these transport systems shows low specif­icity and can transport many compounds. Thus, compet­ition between drugs for these carriers can occur within each transport system. [Note: Premature infants and neonates have an incomp­letely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate.]
3. Distal tubular reabso­rption: As a drug moves toward the distal convoluted tubule, its concen­tration increases and exceeds that of the periva­scular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circul­ation. Manipu­lating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesi­rable drug. As a general rule, weak acids can be eliminated by alkali­niz­ation of the urine, whereas elimin­ation of weak bases may be increased by acidif­ication of the urine. This process is called “ion trapping.” For example, a patient presenting with phenob­arbital (weak acid) overdose can be given bicarb­onate, which alkali­nizes the urine and keeps the drug ionized, thereby decreasing its reabso­rption.
4. Role of drug metabo­lism: Most drugs are lipid soluble and, without chemical modifi­cation, would diffuse out of the tubular lumen when the drug concen­tration in the filtrate becomes greater than that in the periva­scular space. To minimize this reabso­rption, drugs are modified primarily in the liver into more polar substances via phase I and phase II reactions (described above). The polar or ionized conjugates are unable to back diffuse out of the kidney lumen

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