by AE Routes · Cited by 4 — These two characteristics, rate and completeness of absorption, comprise bioavailability. Generally, the bioavailability of oral drugs follows the order:

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19DRUG ABSORPTION, DISTRIBUTION AND ELIMINATION; PHARMACOKINETICS I. DRUG ADMINISTRATION Often the goal is to attain a therapeutic drug concentration in plasma from which drug enters the tissue (therapeutic window between toxic concentration and minimal effective concentration). A. Enteral Routes 1. Sublingual (buccal) Certain drugs are best given beneath the tongue or retained in the cheek pouch and are absorbed from these re gions into the local circulation. These vascular areas are ideal for lipid-soluble drugs that would be metabolized in the gut or liver, sin ce the blood vessels in the mouth bypass the liver (do not undergo first pass liv er metabolism), and drain directly into the systemic circulation. This r oute is usually reserved for nitrates and certain hormones. 2. Oral By far the most common route. The passage of drug from the gut into the blood is influenced by biologic and phys icochemical factors (discussed in detail below), and by the dosage form. For most drugs, two- to five-fold differences in the rate or extent of gastrointestinal ab sorption can occur, depending on the dosage form. These two characteristics, rate and completeness of absorption, comprise bioavailability . Generally, the bioavailability of oral drugs follows the order: solution > suspension > capsule > tablet > coated tablet. 3. Rectal The administration of suppositories is usually reserved for situations in which oral administration is difficult. This route is more frequently used in small children. The rectum is devoid of villi, thus absorption is often slow. B. Parenteral Routes 1. Intravenous injection Used when a rapid clinical response is necessary, e.g., an acute asthmatic episode. This route allows one to achieve relatively precise drug concentrations in the plasma, since bi oavailability is not a concern. Most drugs should be injected over 1-2 minutes in order to prevent the occurrence of very high drug concentra tions in the injected vein, possibly causing adverse effects. Some drugs , particularly those with narrow therapeutic indices or short half-lives, are best administered as a slow IV infusion or drip. 2. Intra-arterial injection Used in certain special situations, notably with anticancer drugs, in an effort to deliver a high concentrati on of drug to a particular tissue. Typically, the injected artery lead s directly to the target organ.

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203. Intrathecal injection The blood-brain barrier limits the entry of many drugs into cerebrospinal fluid. Under some circumstances, usually life-threatening, antibiotics, antifungals and anticancer drugs ar e given via lumbar puncture and injection into the subarachnoid space. 4. Intramuscular injection Drugs may be injected into the arm (deltoid), thigh (vastus lateralis) or buttocks (gluteus maximus). Because of differences in vascularity, the rates of absorption differ, with arm > thigh > buttocks. Drug absorption may be slow and erratic. The volume of injection, osmolality of the solution, lipid solubility and degree of ionization influence absorption. It should not be assumed that the IM route is as reliable as the IV route. 5. Subcutaneous injection Some drugs, notably insulin, are r outinely administered SC. Drug absorption is generally sl ower SC than IM, due to poorer vascularity. Absorption can be facilitated by heat, ma ssage or vasodilators. It can be slowed by coadministration of vasoc onstrictors, a practice commonly used to prolong the local action of local anesthetics. As above, arm > thigh. 6. Inhalation Volatile anesthetics, as well as many drugs which affect pulmonary function, are administered as aeroso ls. Other obvious examples include nicotine and tetrahydroc annabinol (THC), which are absorbed following inhalation of tobacco or marijuana sm oke. The large alveolar area and blood supply lead to rapid absorption into the blood. Drugs administered via this route are not subject to first-pass liver metabolism. 7. Topical application a. Eye For desired local effects. b. Intravaginal For infections or contraceptives. c. Intranasal For alleviation of local symptoms. d. Skin Topical drug administration for skin disorders minimizes systemic exposure. However, systemic absorption does occur and varies with the area, site, drug, and state of the skin. Dimethyl sulfoxide (DMSO) enhances the percutaneous absorption of many drugs, but its use is controversial because of concerns about its toxicity. e. Drug patches (drug enters syst emic circulation by zero order kinetics Πa constant amount of dr ug enters the circulation per unit time).

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21II. DRUG ABSORPTION A. Biologic Factors 1. Membrane structure and function The cell membrane is a semipermeable lipoid sieve containing numerous aqueous channels, as well as a variety of specialized carrier molecules. a. For most tissues, passive aqueous diffusion through channels occurs only for molecules le ss than 150-200 MW. A notable exception is the endothelial capilla ry lining, whose relatively large pores allow molecules of 20-30,000 to pass. However, the capillaries of most of the br ain lack these large pores. b. Passive lipid diffusion is probably the most important absorptive mechanism. Lipid-soluble drugs dissolve in the membrane, and are driven through by a concen tration gradient across the membrane. c. Carrier-mediated facilitated transport occurs for some drugs, particularly those which are an alogs of endogenous compounds for which there already exist specific membrane carrier systems. For example, methotrexate, an anticancer drug which is structurally similar to folic acid, is actively transported by the folate membrane transport system. 2. Local blood flow is a strong determinant of th e rate of absorption because it continuously maintains the concentration gradient necessary for passive diffusion to occur. For orally administered drugs, remember that the blood supply draining the gut passes thr ough the liver before reaching the systemic circulation. Since the liver is a major site of drug metabolism, this first-pass effect may reduce the amount of drug reaching the target tissue. In some cases, the first-pass effect results in metabolic activation of an inert pro-drug. 3. Gastric emptying times vary among patients and c ontribute significantly to intersubject variability in drug absorption. 4. Drug binding Many drugs will bind strongly to proteins in the blood or to food substances in the gut. Binding to plas ma proteins will increase the rate of passive absorption by main taining the concentration gradient of free drug. For many drugs, the gastrointestinal ab sorption rate, but not the extent of absorption, is reduced by the presence of food in the gut. Some drugs are not affected by food, while the absorp tion of a third group of drugs is enhanced by food (bile secretion by liv er in response to food in GI tract increases drug absorption). Some drugs are irritating and should be administered with meals to reduce adverse effects.

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22B. Physicochemical Factors: pH Partition Theory 1. Background review The simplest definition of an acid is that it is a substance, charged or uncharged, that liberates hydrogen ions (H +) in solution. A base is a substance that can bind H + and remove them from solution. Strong acids, strong bases, as well as strong electrolytes are essentially completely ionized in aqueous solution. Weak ac ids and weak bases are only partially ionized in aqueous solution and yi eld a mixture of the undissociated compound and ions. Thus a weak acid (HA) dissociates reversibly in water to produce hydrogen ion H+ and A-. HA <-----> H+ + A- (1) Applying the mass law equation, which de mands that concentrations are in moles per liter, we obtain the following equation: [H+] [A -] = Ka (2) [HA] where Ka is the ionization or dissocia tion constant of the acid. Since the ion concentrations are in the numerat or, the stronger the acid, the higher the value of Ka. Similarly, one coul d derive Kb for a weak base BOH. Rearranging equation (2) yields the following: [H +] = Ka [HA] (3) [A -] Taking the log of both sides of the equation: log [H +] = log Ka + log [HA] Рlog [A-] (4) And multiplying by -1, we obtain: -log [H +] = -log Ka Рlog [HA] + log [A-] (5) By definition, -log [H +] = pH, and -log Ka = pKa. Thus, we obtain the important relationships for acids: pH = pKa + log [A -] (6) [HA] for bases: pH = pKa + log [B] (7) [BH +] From the pKa, one can calculate th e proportions of drug in the charged and uncharged forms at any pH: log [A -] = (pH РpKa) (8) [HA] [A -] = 10(pH ΠpKa) (9) [HA] [B] = 10(pH-pKb) (10) [BH +] pKb = (1-pKa)

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232. Ion trapping The influence of pH on transfer of drugs across membranes. What does this background review have to do with pharmacology. Plenty! Most drugs are too larg e to pass through membrane channels and must diffuse through the lipid portion of the cell membrane. Nonionized drug molecules are readily lipid-soluble, while ionized molecules are lipophobic and are insoluble. The distribution of a drug across the cell membrane is usually determined by its pKa and the pHs on both sides of a membrane. The difference of pH across a membrane influences the total concentration of drug on either side, since, by diffusion, at equilibri um the concentration of nonionized drug will be the same on either side. For example, let’s consider the infl uence of pH on the distribution of a drug which is a weak acid (pKa = 4.4) between plasma (pH = 7.4) and gastric juice (pH = 1.4). The mucosa can be considered to be a simple lipid barrier. Figure 1

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24At equilibrium, the concentration of the unionized drug [HA] on either side of lipid barrier will be the same. Usi ng equation (9), we can calculate the molar ratios of ionized drug [A-] to [HA] on each side of the membrane. in plasma: [A -] [HA] = 10 (7.4 – 4.4) = 10 3 = 1000 in gastric juice: [A -] [HA] = 10 (1.4 – 4.4) = 10 -3 = .001 Figure 2 The pKa values of certain acidic and basic drugs. Those drugs denoted with an * are amphoteric. (From Rowland, M., and Tozer, T.N.)

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262. Effects on drug elimination The effects of plasma protein bindi ng on drug elimination are complex. For drugs excreted only by renal glom erular filtration, protein binding decreases the rate of elimination since only the free drug is filtered. For example, the rates of renal excretion of several tetracyclines are inversely related to their extent of plasma pr otein binding. Conversely, however, if drug is eliminated by hepatic metabol ism or renal tubular secretion, plasma protein binding may promot e drug elimination by increasing the rate that that drug is presented for elimination. 3. Tissue binding Binding to tissue proteins may cause local concentration of drug. For example, if a drug is bound more exte nsively at intracellular than at extracellular sites, the intracellular a nd extracellular concentrations of free drug may be equal or nearly so, but the total intracellular drug concentration may be much greater than the total extracellular concentration. C. Apparent volume of distribution (AVD or Vd). The volume of distribution, or more properl y the apparent volume of distribution, is calculated from measurements of the total concentration of drug in the blood compartment after a single IV injection. Suppose that we injected someone IV with 100 mg of a drug, and measured the blood concentration of the drug repeatedly during the next several hours. We then plot the blood concentrations (on a log scale) against time, and obtain the following graph:

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27Figure 3 If the drug is assumed to follow two-compartm ent kinetics, the initia l curvilinear portion of the data reflects the drug distribution phase, with drug moving from the blood into tissues. The linear portion of the curve reflects drug elimination. By extrapolation of the linear portion, we can find the blood concen tration at time 0, had mixing between both compartments been instantaneous; it is 10 mg/ml. We can also calculate V d, which is defined as: Vd = amount of drug injected = 100 mg = 10L blood concentration at time 0 10 mg/L Vd does not represent a real volume , but rather indicates th e size of the pool of body fluids that would be require d if the drug were distributed equally throughout the body. Drug concentrations in body compartments w ill vary according to the physicochemical properties of the drug. Thus, V d is a characteristic property of the drug rather than the patient, although disease states may influence V d. If binding to plasma proteins is marked, most of the drug will be maintained within the intravascular compartment and Vd will be small. If there is extravascular binding, or storage in fat or other tissues, V d will be large. For example, digoxin, a hydrophobic drug which distributes into fat and muscle, has a Vd of 640 liters (in a 70 kg man), approximately nine times the total volume of the man! Th e usefulness of the V d concept will become more apparent when we discuss pharmacokinetics and perform calculations of blood levels of drugs. In general, acidic drugs bind to pl asma proteins and have small V ds, while basic drugs tend to bind more extensively to extravascular sites and have larger V ds. V d may be influenced by disease states. For example, patients with chronic liver disease have lower serum albumin concentrations. Plasma protei n binding will be reduced, leading to lower plasma drug concentrations and higher V ds.

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28IV. DRUG BIOTRANSFORMATION The body is exposed to a wide variety of foreign compounds, called xenobiotics. Exposure to some such compounds is uni ntentional (e.g., environmental or food substances), while others are deliberately us ed as drugs. The following discussion of drug biotransformation is applicable to all xenobiotics, a nd to some endogenous compounds (e.g., steroids) as well. The kidneys are capable of eliminating drugs which are low in molecular weight, or which are polar and fully ionized at physiologi c pH. Most drugs do not fit these criteria, but rather are fairly large, unionized or partially ionized, lipophilic molecules. The general goal of drug metabolism is to transf orm such compounds into more polar (i.e., more readily excretable) water soluble pr oducts. For example, were it not for biotransformation to more water-soluble pro ducts, thiopental, a short-acting, lipophilic anesthetic, would have a ha lf-life of more than 100 y ears! Imagine, without biotransformation reactions, anesthesiologist s might grow old wait ing for patients to wake up. Most products of drug metabolism are less active than the parent compound. In some cases, however, metabolites may be responsible for toxic, mutagenic, teratogenic or carcinogenic effects. For example, overdoses of acetaminophen owe their hepatotoxicity to a minor metabolite which reacts with liver proteins. In some cases, with metabolism of so-called prodrugs , metabolites are actually the ac tive therapeutic compounds. The best example of a prodrug is cyclophosphami de, an inert compound which is metabolized by the liver into a highly active anticancer drug. A. Sites of drug metabolism 1. At the organ level The liver is the primary organ of drug me tabolism. The gastrointestinal tract is the most important extrahepatic site. Some orally administered drugs (e.g., isoproterenol) are conjuga ted extensively in the intestinal epithelium, resulting in decrea sed bioavailability. The lung , kidney, intestine , skin and placenta can also carry out drug metabolizing reactions. Because of its enormous perfusion rate and its anatomic location with regard to the circulatory system, the lungs may exert a first-pass effect for drugs administered IV. 2. At the cellular level Most enzymes involved in drug me tabolism are loca ted within the lipophilic membranes of the smooth endoplasmic reticulum (SER). When the SER is isolated in the laboratory by tissue homogenation and centrifugation, the SER membranes re-form into vesicles called microsomes . Since most of the enzymes ca rry out oxidation reactions, this SER complex is referred to as the microsomal mixed function oxidase (MFO) system . 3. At the biochemical level Phase I reactions refer to those which convert a drug to a more polar compound by introducing or unmasking polar functional groups such as – OH, -NH 2, or -SH. Some Phase I products are still not eliminated rapidly, and hence undergo Phase II reactions involving conjugation of the newly established polar group with endog enous compounds such as glucuronic acid, sulfuric acid, ace tic acid, or amino acids (typically glycine). Glucuronide formation is the most common phase II reaction. Sometimes,

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29the parent drug may undergo phase II c onjugation directly. In some cases, a drug may undergo a series of consecutive reactions resulting in the formation of dozens of metabolites. Most phase I MFO biotransformation re actions are oxidative in nature and require a reducing agent (NADPH), molecular oxygen, and a complex of microsomal enzymes; the terminal oxidizing enzyme is called cytochrome P450 , a hemoprotein so named because its carbon monoxide derivative absorbs light at 450 nm. We now know that cytochrome P 450 is actually a family of enzymes which differ primar ily with regard to their substrate specificities. Advances in molecular biology have led to the identification of more than 70 distinct P 450 genes in various species. The nomenclature of the P 450 reductase gene products has become complex. Based upon their amino acid homologies, the P 450 reductases have been grouped into families such that a cytochrome P 450 from one family exhibits < 40% amino acid sequence identity to a cytochrome P 450 in another gene family. Several of the gene families are further divided into subfamilies, denoted by letters A, B, C, etc. Eight major mammalian gene families have been defined (see Table 1). Table 1: Major Cytochrome P450 Gene Families P450 Gene Family/Subfamily Characteristic Substrates Characteristic Inducers Characteristic Inhibitor CYP 1A2 Acetominophen Estradiol Caffeine Tobacco Char-Grilled Meats Insulin Cimetidine Amiodarone Ticlopidine CYP 2C19 Diazepam, Omeprazole Progesterone Prednisone Rifampin Cimetidine Ketoconazole Omeprazole CYP 2C9 Tamoxifen Ibuprofen Fluoxetine Rifampin Secobarbital Fluvastatin Lovastatin Isoniazid CYP 2D6 Debrisoquine Ondansetron Amphetamine Dexamethasone? Rifampin? Cimetidine Fluoxetine Methadone CYP 2E1 Ethanol Benzene Halothane Ethanol Isoniazid Disulfiram Water Cress CYP 3A4, 5, 7 Cyclosporin Clarithromycin Hydrocortisone Vincristine Many, many others Barbiturates Glucocorticoids Carbamazepine St. John™s Wort Cimetidine Clarithromycin Ketoconazole Grapefruit Juice Many others 103 KB – 38 Pages