1: Introduction to Pharmacology
- Define pharmacokinetics and pharmacodynamics.
- Distinguish among a drug's chemical, generic, and trade name.
- Describe the paths a drug may take when it is free in circulation.
- Recognize and interpret a dose-response curve.
- Memorize the meaning of basic pharmacologic terminology such as agonist, antagonist and other bolded terms.
1.0 Introduction to Pharmacology
Pharmacology is the study of the effects of drugs on the function of living systems. Drugs may be chemical agents synthetically manufactured from plants or animals or genetically engineered products such as biopharmaceuticals. Pharmacokinetics is the term for what happens to the drug within the body or the body’s actions on the drug, while the action of drugs on the body is called pharmacodynamics .
The preparation of drugs is called pharmacy practice, with much of the practice focusing on pharmacotherapeutics and the treatment of disease. Most drugs are xenobiotics, a chemical that originates outside the body (also referred to as exogenous) and is introduced into the body by various routes of administration. For a drug to be effective, it must enter the body and be distributed to its site of action. This site of action is often a macromolecule receptor in the target tissue, but drugs may also be designed to interrupt a signaling pathway.
A common challenge in studying pharmacology is recognizing the thousands of drug names. Drugs have three different names: chemical, generic, and trade. Each drug's chemical structure and name are unique. For example, the chemical name for aspirin is 2-acetoxybenzoic acid, and its structure is
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There is only one generic name for a drug. Most organizations, including the World Health Organization (WHO) and Food and Drug Administration (FDA), usually refer to drugs by their generic name (note generic names are not capitalized). The drug's trade name is assigned by the pharmaceutical company marketing the drug. The trade name is sometimes called the brand or proprietary name, such as Bayer's Aspirin.
1.1 Overview of Pharmacokinetics
A drug can enter the body by several different routes. Pharmacokinetics is what happens to the drug after it’s in the body. Pharmacokinetics focuses on the absorption, distribution, metabolism (also referred to as biotransformation), and elimination of the concentration of a drug in the body over time. Principles of chemistry are applied while studying pharmacokinetics because the interactions between drug and body molecules are simply a series of chemical reactions. Understanding the chemical encounters between drugs and biological environments is necessary to predict how much of a drug will be metabolized by the body. Most drug effects are temporary because the body has systems for drug detoxification and elimination. Toxicology is the branch of pharmacology that focuses on drugs that produce adverse or unwanted effects.
In Chapter 1, we will consider these issues broadly and go into more depth in the following chapters. As you read, refer to Figure 1.1 below.
Drugs Routes of Administration
- A drug may enter the body in a variety of ways: as an oral liquid, tablet, or capsule; as an inhaled vapor or aerosol; topically absorbed through intact skin or a mucous membrane; or injected into muscle, subcutaneous tissue, spinal fluid, or intravenously (directly into the bloodstream). The physical properties of the drug and the specific way the drug is prepared greatly influence the speed or rate of its absorption. Drugs given intravenously have the quickest absorption.
- If the drug is given orally and swallowed, it must be absorbed from the GI tract into the portal circulation (stomach → gut → portal vein → liver). If the drug is absorbed through the skin, mouth, lungs, or muscle, it will go directly into systemic circulation. If the drug is injected intravenously, 100% of the drug is “bioavailable” for distribution to tissues. This is not usually the case for other modes of administration. For example, an oral drug that is absorbed via portal circulation will first pass through the liver, which is the primary site of drug metabolism. Once a drug is metabolized, it is more likely to be excreted, causing less drug to reach the systemic circulation. This phenomenon is known as " first-pass " metabolism. First-pass metabolism reduces an oral drug’s bioavailability to less than 100%. Examples of drugs with a significant first-pass effect include alcohol, insulin, and morphine.
- Once in the bloodstream, a portion of the drug may exist as free drug, having been dissolved in plasma water and able to bind to other molecules. Some drug will be reversibly taken up by red cells, and other drugs will be reversibly bound to plasma proteins. Reversible means the chemical bond can be broken. For many drugs, the bound form of the drug accounts for 95-98% of the total concentration of the drug in the body. This is important because the free drug is active , traversing cell membranes and producing the clinically desired effect. It is also significant because protein-bound drug can act as a reservoir. When the chemical bonds are broken, the drug is released. Once the drug is unbound or in a free state, it can become active. The action of drugs that are protein-bound or those that bind to other reservoir sites in the body (adipose, bone) are prolonged and somewhat unpredictable.
- Unbound drug may then follow its concentration gradient and distribute into peripheral tissues. In some cases, the tissue contains the target site in others, the tissue is unaffected by the drug.
- The total amount of the drug within the body (in circulation and reservoir sites) reflects the volume of distribution. The volume of distribution determines the drug's equilibrium concentration after a specified dose. How long the drug is expected to remain in the body can be calculated using volume of distribution.
- 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 (non-metabolized drug) 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 (enterohepatic cycle). Any biotransformed drug that is not excreted in bile passes back into the systemic circulation.
- The parent drug and metabolites in the bloodstream may be excreted through kidney filtration, where a portion undergoes reabsorption and returns to plasma, and the remainder is excreted in the urine. Some drugs are actively secreted into the renal tubule. Another route of excretion is the lung; alcohol and anesthetic gases are eliminated by this route. Smaller amounts of drug are eliminated in sweat, tears, and breast milk.
- Biotransformation of a drug may sometimes produce very biologically active metabolites, which may be intended or unintended. A parent drug manufactured to be inactive until it is biotransformed after administration is referred to as a prodrug. Enalapril, clopidogrel, and codeine are examples of prodrugs.
1.2 Overview of Pharmacodynamics
Pharmacodynamics is the study of a drug's biochemical and physiologic effects on the body. The specific site of action of a drug is called the mechanism of action (MOA). The MOA for most drugs is binding to specific receptors on the surface or interior of cells. However, there are many other cellular components and non-specific sites that can serve as sites of drug action or drug targets.
- Water can be a target. The kidney does not reabsorb osmotic diuretics such as mannitol, and the osmotic load they create in the renal tubule forces the loss of water. Laxatives like magnesium sulfate work in the intestine by the same principle.
- Hydrogen ions can be targets. Ammonium chloride is sometimes used to acidify urine. When it is taken orally, the liver metabolizes the ammonium ion to urea, while the chloride is excreted in the urine. The loss of Cl- forces the loss of H+ in the urine, thus lowering the pH.
- Metal ions can be targets. Chelating agents like EDTA (ethylene diamine tetra-acetic acid) may be used to bind divalent cations like Pb++. Metal ions are most frequently drug targets in cases of poisoning.
- Enzymes are targets of many therapeutically useful drugs. Drugs may inhibit enzymes by competitive, non-competitive, or irreversible blockade at a substrate or cofactor binding site. Digitalis glycosides increase myocardial contractility by inhibiting the membrane enzyme, Na+-K+ - ATPase. Antimicrobial and antineoplastic drugs commonly work by inhibiting enzymes that are critical to the functioning of the cell. To be effective, these drugs must have at least some selective toxicities toward bacterial or tumor cells. This usually means that there is a unique metabolic pathway in these cells or some difference in enzyme selectivity for a common metabolic pathway the drug disrupts. An example of this is the inhibition of folate synthesis by sulfonamides. Sulfonamides are effective antibacterial agents because the bacteria depend on folate synthesis, whereas the host does not. This example will be covered in detail in one of our case discussions.
- Nucleic acids are targets for antimetabolites and some antibiotics. In the case of fluorouracil (5FU), the compound acts as a substitute for uracil and becomes incorporated into a faulty mRNA.
- Biologics are drugs designed to interrupt the immune system's signaling (e.g., interleukins, TNF-α) involved in the pathogenesis of chronic inflammatory disorders. Biologics are extracted or isolated from human, animal, or microorganism sources. They may also be produced by biotechnology.
- Finally, some drugs act by binding to specific receptors . These drugs have both structural specificity and selectivity. By interacting with a drug, receptors may be turned on (agonist) or turned off (antagonist). When a specific drug binds to a receptor, the physiologic activity regulated by that receptor increases or decreases An example of this is using a beta-1 adrenergic receptor blocker or antagonist to decrease heart rate.
Unfortunately, no matter how effectively a drug works in a laboratory simulation, its performance in the human body will not always produce the same results, and individualized responses to drugs must be considered. Although many responses to medications may be anticipated, one’s unique genetic makeup may also significantly impact one’s response to a drug. Pharmacogenetics is the study of how people’s genes affect their response to drugs.
Below are important concepts that we will return to repeatedly throughout the course.
- An agonist is a drug that binds to its "receptor" and produces its characteristic effect. Depending on the maximal effect a drug produces, that drug may be a full agonist or a partial agonist .
- An antagonist binds to the receptor without causing an effect, thereby preventing an active substance from gaining access. Antagonists, like enzyme inhibitors, may be competitive, non-competitive, or irreversible .
- Dose-response . It is expected that as the dose of the drug increases, the response should increase. The curve generated is usually sigmoidal when the effect is plotted against the log dose. The effect may be measured as a graded variable (change in blood pressure, force of contraction) or as a quantal variable (number dead/alive). The slope of the curve is characteristic of the particular drug-receptor interaction. When two drugs act by the same receptor mechanism, we expect to see two parallel log-dose response curves. Figure 1.2 shows a dose-response curve for Drugs A (red) and Drug B (blue). The characteristic sigmoidal shape shows that as the dose increases the response to the drug is greater until a plateau or maximal effect is reached. The curve for Drug A is to the left of the curve for Drug B, indicating that less (a lower dose) of Drug A is needed to elicit a response.
Dose Response Curve Comparing the Efficacy of Two Drugs
- ED 50 . The median effective dose, or the dose which produces a response in 50% of the sample. If the response is death (known as lethality), we call it the LD 50 . Importantly, the EC 50 refers to concentration rather than dose.
- Potency . Potency is often misused to mean “effectiveness.” Rather, a drug's potency refers to the dose (the molar concentration) required to produce a specific intensity of effect. If the ED50 of drugs A and B are 5 and 10 mg, respectively, the relative potency of A is twice that of B. Relative potency specifically applies to comparing drugs that act by the same mechanism and, therefore, have parallel dose–response curves.
- Efficacy . Also called maximal efficacy or intrinsic activity , this is the maximum effect the drug can produce. A potent drug may have a low efficacy, and a highly efficacious drug may have a low potency. For the clinician, efficacy is more important than potency (within limits).
- Affinity . The stickiness or affinity refers to the strength of the binding between drug and receptor. It is quantified by the dissociation constant Kd and takes into account the off-rate (unbound) divided by the on-rate (bound).
- Selectivity . Selectivity refers to the separation between a drug's desired (targeted) effects and its undesired effects. Ideally, a drug is completely specific , and an effective dose does not elicit any undesired effect. However, that is usually not the case. Most drugs are selective, not exclusive. As a drug concentration increases, the drug can lose its selectivity to one receptor and may bind to other receptors.
- Therapeutic window . For every drug, there exists some concentration that is just barely effective (the effective concentration ) and some dose that is just barely toxic (the Toxic Concentration ). Between the two is the therapeutic window where the safest and most effective treatment occurs.
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Index
. The therapeutic index is the ratio of toxic to effective doses at the level of 0% response: TD50/ED50. In animal toxicology studies, it is usually the LD50/ED50.
This chapter titled Introduction to Pharmacology is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Karen Vuckovic from Introduction to Pharmacology by Carl Rosow, David Standaert, & Gary Strichartz ( MIT OpenCourseWare ) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request. Figures by Riley Cutler.