PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Medicines By Design by Alisa Zapp Machalek, National Institute of General Medical Sciences The advances in drug development and delivery described in this article reflect scientists' growing knowledge about human biology. This knowledge has allowed them to develop medicines targeted to specific molecules or cells. In the future, doctors may be able to treat or prevent diseases with drugs that actually repair cells or protect them from attack. No one knows which of the techniques, such as SNPs, will help illuminate valuable future medicines, but it is clear that thanks to pharmacology research, tomorrow's doctors will have an unprecedented array of weapons to fight disease. ABCs of Pharmacology Know why some people's stomachs burn after they swallow an aspirin tablet? Or why a swig of grapefruit juice with breakfast can raise blood levels of some medicines in certain people? Understanding some of the basics of the science of pharmacology will help answer these questions, and many more, about your body and the medicines you take. So, then, what's pharmacology? Despite the field's long, rich history and importance to human health, few people know much about this biomedical science. One pharmacologist joked that when she was asked what she did for a living, her reply prompted an unexpected question: "Isn't 'farm ecology' the study of how livestock impact the environment?" Of course, this article isn't about livestock or agriculture. Rather, it's about pharmacology—the study of how the body reacts to medicines and how medicines affect the body. Pharmacology is often confused with pharmacy, a separate discipline in the health sciences that deals with preparing and dispensing medicines. For thousands of years, people have looked in nature to find chemicals to treat their symptoms. Ancient healers had little understanding of how various elixirs worked their magic, but we know much more today. Some pharmacologists study how our bodies work, while others study the chemical properties of medicines. Others investigate the physical and behavioral effects medicines have on the body. Pharmacology researchers study drugs used to treat diseases, as well as drugs of abuse. Since medicines work in so many different ways in so many different organs of the body, pharmacology research touches just about every area of biomedicine. Many scientists are drawn to pharmacology because of its direct application to the practice of medicine. Pharmacologists study the actions of drugs in the intestinal tract, the brain, the muscles, and the liver—just a few of the most common areas where drugs travel during their stay in the body. Of course, all of our organs are constructed from cells, and inside all of our cells are genes. Many pharmacologists study how medicines interact with cell parts and genes, which in turn influences how cells behave. Because pharmacology touches on such diverse areas, pharmacologists must be broadly trained in biology, chemistry, and more applied areas of medicine, such as anatomy and physiology. Body, Heal Thyself Scientists became interested in the workings of the human body during the "scientific revolution" of the 15th and 16th centuries. These early studies led to descriptions of the circulatory, digestive, respiratory, nervous, and excretory systems. In time, scientists came to think of the body as a kind of machine that uses a series of chemical reactions to convert food into energy. The Body Machine Scientists still think about the body as a well-oiled machine, or set of machines, powered by a control system called metabolism. The conversion of food into energy integrates chemical reactions taking place simultaneously throughout the body to assure that each organ has enough nutrients and is performing its job properly. An important principle central to metabolism is that the body's basic unit is the cell. Like a miniature body, each cell is surrounded by a skin, called a membrane. In turn, each cell contains tiny organs, called organelles, that perform specific metabolic tasks. The cell is directed by a "command center," the nucleus, where the genes you inherited from your parents reside. Your genes—your body's own personalized instruction manual—are kept safe in packages called chromosomes. Each of your cells has an identical set of 46 chromosomes, 23 inherited from your mother and 23 from your father. One important type of metabolism that occurs constantly in our bodies is the reading and interpreting of genes to make proteins. These proteins underlie the millions of chemical reactions that run our bodies. Proteins perform structural roles, keeping cells shaped properly. Proteins also work as enzymes that speed along chemical reactions—without an enzyme's assistance, many reactions would take years to happen. Before the first towns were built, before written language was invented, and even before plants were cultivated for food, the basic human desires to relieve pain and prolong life fueled the search for medicines. No one knows for sure what the earliest humans did to treat their ailments, but they probably sought cures in the plants, animals, and minerals around them. Nature's Medicine Cabinet Times have changed, but approximately 60 percent of the world's population still relies entirely on plants for medicines, and plants supply the active ingredients of most traditional medical products. Plants have also served as the starting point for countless drugs on the market today. Researchers generally agree that natural products from plants and other organisms have been the most consistently successful source for ideas for new drugs, since nature is a master chemist. Drug discovery scientists often refer to these ideas as "leads," and chemicals that have desirable properties in lab tests are called lead compounds. Relatively speaking, very few species of living things on Earth have actually been seen and named by scientists. Many of these unidentified organisms aren't necessarily lurking in uninhabited places. Just recently, for instance, scientists identified a brand-new species of millipede in a rotting leaf pile in New York City's Central Park, an area visited by thousands of people every day. Scientists estimate that Earth is home to at least 250,000 different species of plants and that up to 30 million species of insects crawl or fly somewhere around the globe. Equal numbers of species of fungi, algae, and bacteria probably also exist. Despite these vast numbers, chemists have tested only a few of these organisms to see whether they harbor some sort of medically useful substance. Pharmaceutical chemists seek ideas for new drugs not only in plants, but in any part of nature where they may find valuable clues. This includes searching for organisms from what has been called the last unexplored frontier: the seawater that blankets nearly three-quarters of Earth. Molecules to Medicines As you've read so far, the most important goals of modern pharmacology are also the most obvious. Pharmacologists want to design, and be able to produce in sufficient quantity, drugs that will act in a specific way without too many side effects. They also want to deliver the correct amount of a drug to the proper place in the body. But turning molecules into medicines is more easily said than done. Scientists struggle to fulfill the twin challenges of drug design and drug delivery. Medicine Hunting While sometimes the discovery of potential medicines falls to researchers' good luck, most often pharmacologists, chemists, and other scientists looking for new drugs plod along methodically for years, taking suggestions from nature or clues from knowledge about how the body works. Finding chemicals' cellular targets can educate scientists about how drugs work. Aspirin's molecular target, the enzyme cyclooxygenase, or COX (see "No Pain, Your Gain"), was discovered this way in the early 1970s in Nobel Prize-winning work by pharmacologist John Vane, then at the Royal College of Surgeons in London, England. Another example is colchicine, a relatively old drug that is still widely used to treat gout, an excruciatingly painful type of arthritis in which needle-like crystals of uric acid clog joints, leading to swelling, heat, pain, and stiffness. Lab experiments with colchicine led scientists to this drug's molecular target, a cell-scaffolding protein called tubulin. Colchicine works by attaching itself to tubulin, causing certain parts of a cell's architecture to crumble, and this action can interfere with a cell's ability to move around. Researchers suspect that in the case of gout, colchicine works by halting the migration of immune cells called granulocytes that are responsible for the inflammation characteristic of gout. Current estimates indicate that scientists have identified roughly 500 to 600 molecular targets where medicines may have effects in the body. Medicine hunters can strategically "discover" drugs by designing molecules to "hit" these targets. That has already happened in some cases. Researchers knew just what they were looking for when they designed the successful AIDS drugs called HIV protease inhibitors. Previous knowledge of the three-dimensional structure of certain HIV proteins (the target) guided researchers to develop drugs shaped to block their action. Protease inhibitors have extended the lives of many people with AIDS. However, sometimes even the most targeted approaches can end up in big surprises. The New York City pharmaceutical firm Pfizer had a blood pressure-lowering drug in mind, when instead its scientists discovered Viagra®, a best-selling drug approved to treat erectile dysfunction. Initially, researchers had planned to create a heart drug, using knowledge they had about molecules that make blood clot and molecular signals that instruct blood vessels to relax. What the scientists did not know was how their candidate drug would fare in clinical trials. Sildenafil (Viagra's chemical name) did not work very well as a heart medicine, but many men who participated in the clinical testing phase of the drug noted one side effect in particular: erections. Viagra works by boosting levels of a natural molecule called cyclic GMP that plays a key role in cell signaling in many body tissues. This molecule does a good job of opening blood vessels in the penis, leading to an erection. Rush Delivery Finding new medicines and cost-effective ways to manufacture them is only half the battle. An enormous challenge for pharmacologists is figuring out how to get drugs to the right place, a task known as drug delivery. Ideally, a drug should enter the body, go directly to the diseased site while bypassing healthy tissue, do its job, and then disappear. Unfortunately, this rarely happens with the typical methods of delivering drugs: swallowing and injection. When swallowed, many medicines made of protein are never absorbed into the bloodstream because they are quickly chewed up by enzymes as they pass through the digestive system. If the drug does get to the blood from the intestines, it falls prey to liver enzymes. For doctors prescribing such drugs, this " first-pass effect" (see page "A Drug's Life") means that several doses of an oral drug are needed before enough makes it to the blood. Drug injections also cause problems, because they are expensive, difficult for patients to self-administer, and are unwieldy if the drug must be taken daily. Both methods of administration also result in fluctuating levels of the drug in the blood, which is inefficient and can be dangerous. What to do? Pharmacologists can work around the first-pass effect by delivering medicines via the skin, nose, and lungs. Each of these methods bypasses the intestinal tract and can increase the amount of drug getting to the desired site of action in the body. Slow, steady drug delivery directly to the bloodstream—without stopping at the liver first—is the primary benefit of skin patches, which makes this form of drug delivery particularly useful when a chemical must be administered over a long period. Hormones such as testosterone, progesterone, and estrogen are available as skin patches. These forms of medicines enter the blood via a meshwork of small arteries, veins, and capillaries in the skin. Researchers also have developed skin patches for a wide variety of other drugs. Some of these include Duragesic® (a prescription-only pain medicine), Transderm Scop® (a motion-sickness drug), and Transderm Nitro® (a blood vessel-widening drug used to treat chest pain associated with heart disease). Despite their advantages, however, skin patches have a significant drawback. Only very small drug molecules can get into the body through the skin. Inhaling drugs through the nose or mouth is another way to rapidly deliver drugs and bypass the liver. Inhalers have been a mainstay of asthma therapy for years, and doctors prescribe nasal steroid drugs for allergy and sinus problems. Researchers are investigating insulin powders that can be inhaled by people with diabetes who rely on insulin to control their blood sugar daily. This still-experimental technology stems from novel uses of chemistry and engineering to manufacture insulin particles of just the right size. Too large, and the insulin particles could lodge in the lungs; too small, and the particles will be exhaled. If clinical trials with inhaled insulin prove that it is safe and effective, then this therapy could make life much easier for people with diabetes. Bench to Bedside: Clinical Pharmacology Prescribing drugs is a tricky science, requiring physicians to carefully consider many factors. Your doctor can measure or otherwise determine many of these factors, such as weight and diet. But another key factor is drug interactions. You already know that every time you go to the doctor, he or she will ask whether you are taking any other drugs and whether you have any drug allergies or unusual reactions to any medicines. Interactions between different drugs in the body, and between drugs and foods or dietary supplements, can have a significant influence, sometimes "fooling" your body into thinking you have taken more or less of a drug than you actually have taken. By measuring the amounts of a drug in blood or urine, clinical pharmacologists can calculate how a person is processing a drug. Usually, this important analysis involves mathematical equations, which take into account many different variables. Some of the variables include the physical and chemical properties of the drug, the total amount of blood in a person's body, the individual's age and body mass, the health of the person's liver and kidneys, and what other medicines the person is taking. Clinical pharmacologists also measure drug metabolites to gauge how much drug is in a person's body. Sometimes, doctors give patients a "loading dose" (a large amount) first, followed by smaller doses at later times. This approach works by getting enough drug into the body before it is metabolized (broken down) into inactive parts, giving the drug the best chance to do its job. ### This article has been excerpted and reposted with permission of the National Institute of General Medical Sciences (NIGMS), National Institutes of Heath. ### << Previous Next >> [ View All Perspectives ] |
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