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MIT HST 151 - Lecture 1 - Principles of Pharmacology: Introduction

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Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Carl Rosow Carl Rosow, M.D., Ph.D. 1 HST-151 Lecture 1 - Principles of Pharmacology: Introduction A drug is a chemical agent which can affect living processes. For purposes of this course we will mainly be talking about small molecules which affect cellular processes. Most of these are Xenobiotics (Gr. xenos - stranger) chemicals that are not synthesized by the body, but introduced into it from outside. There is inevitably a certain amount of ambiguity in this definition: Is oxygen or water a drug? How about Vitamin C in a glass of orange juice? How about an injection of Vitamin C to treat scurvy? Pharmacology (Gr. pharmakon - a drug or poison, logos - word or discourse) is the science dealing with actions of drugs on the body (pharmacodynamics) and the fate of drugs in the body (pharmacokinetics). It overlaps with pharmacy, the science of preparation of drugs; much of it deals with therapeutics, the treatment of disease (by whatever means). Toxicology is the branch of pharmacology dealing with the "undesirable" effects of drugs on biological processes (in the case of a nerve gas the bad effect may be a desired one). In order for a drug to work, it must enter the body and somehow be distributed in such a way that it gets to its site of action. In most cases the site of action is a macromolecular "receptor" located in the target tissue. Most drug effects are temporary, because the body has systems for drug detoxification and elimination. We will consider these issues broadly for now and go into more depth in individual lectures. As you read, refer to the figure below: ic iGI iBound Drug Unbound Drug Metabolites BLOOD Biotransformation EnterohepatCycle Excret on Tract Muscle Lung Skin Bound Unbound Bound Unbound DRUG RECEPTORS TISSUE RESERVOIRS Excretion Effect? Effect Absorpt onCarl Rosow, M.D., Ph.D. 2 HST-151 Overview of Pharmacokinetics - "What the body does to the drug" 1. The drug may enter the body in a variety of ways: as an oral liquid, pill, or capsule; as an inhaled vapor or aerosol; absorbed through intact skin or a mucous membrane; injected into muscle, subcutaneous tissue, spinal fluid, or directly into the bloodstream. As we shall see, the physical properties of the drug and the specific way it is prepared greatly influence the speed of absorption. 2. If the drug is given orally and swallowed, it must be absorbed from the GI tract into the portal circulation. If it is absorbed from the skin, mouth, lungs or muscle it will go directly into the systemic circulation. If drug is injected directly into the bloodstream (e.g., intravenous injection), 100% of it is available for distribution to tissues. This is not usually the case for other modes of administration. For example, drug which is absorbed via the portal circulation must first pass through the liver which is the primary site of drug metabolism (biotransformation). Some of the drug may therefore be metabolized before it ever reaches the systemic blood. In this case, "first-pass" metabolism reduces the bioavailability to less than 100%. 3. Once the drug is in the bloodstream a portion of it may exist as free drug, dissolved in plasma water. Some drug will be reversibly taken up by red cells and some will be reversibly bound to plasma proteins. For many drugs, the bound forms can account for 95-98% of the total. This is important because it is the free drug which traverses cell membranes and produces the effect. It is also important because protein-bound drug can act as a reservoir which releases drug slowly and thus prolongs its action. 4. The unbound drug may then follow its concentration gradient and distribute into peripheral tissues. In some cases, the tissue contains the target site and in others the tissue is not affected by the drug. Sites of non-specific binding act as further reservoirs for the drug. This total volume of distribution determines the equilibrium concentration of drug after a specified dose. 5. Tissue-bound drug eventually reenters the bloodstream where it perfuses the liver and kidneys. The liver metabolizes most drugs into inactive or less active compounds which are more readily excreted. These metabolites and some of the parent compound may be excreted in the bile and eventually may pass out of the body in the feces. Alternatively, some of the drug may be reabsorbed again, farther down the GI tract (the so-called enterohepatic cycle). Any biotransformed drug which is not excreted in bile passes back into the systemic circulation. 6. Parent drug and metabolites in the bloodstream may then be excreted: most are filtered by the kidney, where a portion undergoes reabsorption, and the remainder is excreted in the urine. Some drugs are actively secreted into the renal tubule. Another route of excretion is the lung: Drugs like alcohol and the anesthetic gases are eliminated by this route. Smaller amounts of drug are eliminated in the sweat, tears and breast milk.Carl Rosow, M.D., Ph.D. 3 HST-151 7. Biotransformation may sometimes produce metabolites with a great deal of activity. Occasionally, we administer a parent drug which is inactive (a pro-drug) and only the metabolite has activity. [How might this be useful?] Overview of Pharmacodynamics - "What the drug does to the body" As stated above, the majority of drugs bind to specific receptors on the surface or interior of cells, but there are many other cellular components and non-specific sites which can serve as sites of drug action. 1. Water can be a target. Osmotic diuretics like mannitol are not reabsorbed by the kidney, and the osmotic load they create in the renal tubule obligates the loss of water. Laxatives like magnesium sulfate work in the intestine by the same principle. 2. Hydrogen ions can be targets. Ammonium chloride is sometimes used to acidify the urine. When it is taken orally, the liver metabolizes ammonium ion to urea, while the chloride is excreted in the urine. The loss of Cl-obligates the loss of H+ in the urine, thus the pH is lowered. 3. Metal ions can be targets. Chelating agents like EDTA may be used to bind divalent cations like Pb++. Metal ions are most frequently drug targets in cases of poisoning. 4. Enzymes are targets of many therapeutically useful drugs. Drugs may inhibit enzymes by competitive, non-competitive, or


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MIT HST 151 - Lecture 1 - Principles of Pharmacology: Introduction

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