Drug Absorption and Distribution PDF

Lesson 2: DRUG ABSORPTION and DISTRIBUTION ========================================== **Absorption --** refers to the movement of drug from the site of administration into the blood circulation. It is the transfer of a drug from its site of administration to the blood stream. The rate and efficienc...

Lesson 2: DRUG ABSORPTION and DISTRIBUTION ========================================== **Absorption --** refers to the movement of drug from the site of administration into the blood circulation. It is the transfer of a drug from its site of administration to the blood stream. The rate and efficiency of absorption depends on the route of administration and the drug dosage form. Drug administration by other routes may result in only partial absorption. For example, oral administration requires that a drug dissolve in the gastrointestinal fluid and then penetrate the epithelial cells of intestinal mucosa. The duodenum is the major site of drug absorption. Knowing the rate of absorption of the drug is important because in part, it allows inferences to be made about the onset of its action. The extent of absorption is also important, because it determines the magnitude of the response to the drug. **Factors influencing Drug Absorption** A. ***Bioavailability*** -- It is the amount of drug that that reaches the systemic circulation following administration by any route. It is expressed as the fraction of the administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug is administered orally and 70 mg of this drug is absorbed, the bioavailability is 70%. 1. ***First pass hepatic metabolism/first pass elimination*** -- when a drug is absorbed across the GI tract, it must transverse the portal system before entering the systemic circulation. The drug may be partially metabolized by the liver and may be inactivated. The amount of unchanged drug that gain access to the systemic circulation is decreased. Drugs administered via the intraperitoneal route are also subject to first pass metabolism as the also cross through the portal circulation. 2. ***Solubility of the drug*** - drugs that are very hydrophilic are poorly absorbed because of their inability to cross the lipid- rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in the aqueous body fluids and, therefore, cannot gain access to the surface of the cells. For a drug to be readily absorbed it must be largely hydrophobic yet have some solubility in aqueous solutions. 3. ***Chemical Instability ­***- some drugs, such as Penicillin G, are unstable to the pH of gastric juice contents. 4. ***Nature of Drug Formulation*** -- may be altered by several factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, and the presence of excipients. These can influence the ease of dissolution and therefore, alter the rate of absorption and the bioavailability. B. ***The ability of drugs to cross membranes/Drug passage across membranes*** -- drugs normally need to cross membrane barriers to reach their receptor sites. Such barriers are present at various levels in the animal, restricting passage of water and other solutes. For example, a drug needs to cross the blood-brain barrier to gain access to the brain. Body barriers from the external environment include the ff: skin and cornea, gastrointestinal epithelium, and lung epithelium. Examples of internal barriers include the ff: capillaries, blood-brain barrier, renal tubular epithelium, peritoneum, and placenta. 1. ***Passive diffusion or Simple Diffusion*** -- Cell membranes have biomolecular lipoprotein layer that act as barriers to drug transfer across the membrane. Cell membranes also contain pores. Thus, drugs cross membranes based on their ability to dissolve in the lipid portion of the membranes based on their molecular size, which regulates their filtration through pores. The movement of the drug is due to and is directly related to its concentration gradient across the membrane. 2. ***Filtration*** -- Membranes contain pores and channels. Some low molecular weight chemicals can cross these channels readily. The glomerular filtration process of the kidney provides evidence for the existence of pores large enough to permit the passage of large molecular weight substances but small enough to retain albumin (MW = 60,000). 3. ***Facilitated Diffusion*** - Facilitated diffusion is not a major mechanism for drug transport. Examples of this type of process include reabsorption of glucose by the kidney and intestinal absorption of vitamin B~12~ along with intrinsic factor. In some cases, relatively selective carrier molecules have been found to facilitate diffusion across membranes. The carrier molecules combine with the drug to produce a readily absorbable complex which then dissociates. Some amino acids are absorbed into the brain in this way. 4. ***Active Transport*** - The chemical structure of the drug is important in attaching to the carrier molecule. For example, the anticancer drug 5-fluorouracil is absorbed from the intestine by the same system used to absorbed uracil. In some tissues or cells, specialized transport proteins are present. These processes can usually be blocked and are saturated. Drugs which are substrates of these carriers may be actively transported. For example, Iodine is transported into the thyroid tissue, catecholamines are transported into neuronal cells, and weak acids (e.g. penicillin) are actively transported into the renal tubule. 5. ***Pinocytosis*** - Is a minor method for drug absorption, but it may be important in the absorption of some polypeptides, bacterial toxins, antigens and food proteins by the gut. Cells have the ability to engulf either particles (phagocytosis) or droplets (pinocytosis). If the engulfed material is not susceptible to enzyme degradation, it will persist (e.g. particles of talc or droplets of liquid paraffin). The absorption of immunoglobins through the gut mucosa of young calves depends on pinocytosis. C. ***Route of Drug Administration --*** Many routes of administration involve an absorption process in which the drug must cross one or more tissue membranes before entering the blood stream. The IV route is an exception because the drug is placed directly into the systemic circulation. When administered SC or IM, most of the drug may enter the systemic circulation through openings or fenestrations in the capillary wall and not penetrate any membrane. 1. ***Absorption of drugs through the oral route/alimentary route*** -- This is the safest route of drug administration. This route however, generally has lower bioavailability than other routes due to the first pass metabolism. a. Greater absorptive area means greater rate of absorption b. The presence of food in the stomach. This may retard the absorption of some drugs and it may enhance others. The type of food present should also be considered. For example, the presence of dairy products may retard the absorption of tetracycline. c. Blood flow may also affect GI absorption, but not as rate limiting as that in IM or SC routes. d. Digestive differences between animals. This refers to monogastric animals and animals with compound stomachs. Large volumes of GI contents in ruminant stomachs make oral administration of drugs impractical due to drug inactivation. Oral administration may also ruin the normal gut microflora of the ruminant stomach. e. A hyperactive gut may shorten transit time and thus, lessen the drug-gut contact time leading to reduced absorption. f. Enteric coated tablets may protect the drug from destruction. In some cases, this may enhance absorption. 2. ***Absorption of drugs through the parenteral route*** -- Parenteral refers to drug absorption that circumvent the gastrointestinal tract. These include; IV, IM, SC, IP etc. Blood flow is an important consideration (except in IV routes). Procedures that can cause vasoconstriction may impair absorption. a. Asepsis is necessary b. Parenteral administration may cause pain. c. Adverse responses to the drug are more readily and frequently encountered (e.g. allergic reactions). d. In food animals, discoloration of the meat or abscess formation may occur with intramuscular injections and these may devalue the carcass. 3. ***Absorption of drugs from the skin/Intradermal route*** -- Highly lipid soluble drugs are almost completely absorbed from the skin. Disruptions on the skin like burns may impair its absorptive capabilities. 4. ***Absorption from the respiratory tract*** -- Used in veterinary medicine to administer gas and volatile anesthetics. Some drugs such as bronchodilators, mucolytics, and decongestants may be administered as aerosols. The size of particles is important for absorption. A. ***Dose and route of administration*** B. ***Blood flow**­* -- the rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of the cardiac output to various organs. For example, blood flow to the brain, liver, and the kidney is greater than that of the skeletal muscles. C. ***Physicochemical properties of drugs*** -- Lipid solubility, pH, and molecular size influence the rate of distribution of a drug to various fluid compartments. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge readily move across biological membranes. These drugs can dissolve in the lipid membranes and are therefore permeable to the entire cell's surface. By contrast, hydrophilic drugs, which either have a non-uniform distribution of electrons or a positive or a negative charge, do not readily penetrate cell membranes. D. ***Binding to Plasma Proteins*** -- only unbound drug is able to cross cell membranes. Plasma protein binding is a reversible process. a. Acidic drugs are bound primarily to albumin, and basic drugs are bound primarily to a~1~ --acid glycoprotein b. Binding does not prevent a drug from reaching its site of action, but it slows the rate at which a drug reaches a concentration sufficient to produce a pharmacologic effect c. Effects on drug elimination 1. Drug --protein binding limits glomerular filtration as an elimination process, because bound drug cannot be filtered. 2. Binding does not typically limit the elimination of drugs that are actively secreted by the kidney or metabolized by the liver, because the fraction of the drug that is free is transported and metabolized. As the free drug concentration is lowered, there is rapid dissociation of the drug-protein complex to maintain the amount of drug in the free state. 3. Sulfa drugs with a high affinity for binding to protein are eliminated more slowly in urine than those sulfa drugs with lower binding affinity for plasma proteins E. ***Drug Interactions*** - may occur when two drugs are used that bind at the same site on the plasma proteins. Competition for the same site increases the percent of drug in the free form, thereby increasing the pharmacologic-toxicologic response to the displaced drug. F. ***Interspecies Differences*** - In veterinary pharmacology, the differences in the relative mass of the gastrointestinal tracts of ruminant species account for some inter-species differences in drug distribution. G. ***Drug Redistributi*on --** sequestration of the drug to tissues with low blood flow may terminate the action of the drug. The biologic response to a drug is usually terminated by metabolism (biotransformation) and excretion; however, redistribution of a drug from its site of action to other tissues lowers its concentration at its site of action, thereby terminating the drug response. Drugs exhibiting the redistribution phenomenon are highly lipd-soluble such as thiopental. A. ***CNS Distribution*** - **D**istribution of drugs into the central nervous system (CNS) and cerebrospinal fluid is **restricted. T**here are three processes that contribute to keeping drug concentration in the CNS slow. 1. ***Blood Brain Barrier*** -- generally believed to be the continuous layer of tight junctions between the capillary endothelial cells in the CNS (except in the area postrema, pineal body, and the posterior lobe of the hypothalamus. A drug should be highly lipid soluble to cross the BBB. The process of incorporating a lipophilic group to a drug to allow passage to the BBB is called Latentiation. Inflammation of the brain may allow passage of certain drugs. 2. ***Active transport mechanisms*** exist for organic acids and bases in the choroid plexus, allowing transport of drugs from the cerebrospinal fluid into the blood. For example, CNS concentrations of penicillin, a weak acid, are kept low by this active transport system. 3. ***Cerebrospinal fluid*** produced within the ventricles circulates through the ventricles circulates through the ventricles and over the surface of the brain and spinal cord to flow directly into the venous drainage system of the brain. This process continuously dilutes the drug's concentration in the cerebrospinal fluid. B. ***Transplacental Distribution*** -- Drugs can cross the placenta by simple diffusion (primary mode of transfer). The rate of diffusion however, varies with the physicochemical properties of the drug. All drugs can cross the placenta to a certain extent and reach the fetus. As a general rule, drugs that affect the maternal CNS (e.g. analgesics, anesthetics, sedatives, tranquilizers) have physicochemical characteristics to freely cross the placenta and affect the fetus. C. ***Others*** -- The prostate, the testicles, and globe of the eye contain barriers that prevent drug penetration, thus limiting drug concentration in these tissues.