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Pharmacology for lawyers: to take on a pharmaceutical claim, you don't have to be a scientist - but you do have to know science. A grounding in the basics of pharmacology will give your case a shot in the arm.

'I don't do math and science; that's why I became a lawyer." How many times have you heard or said that? But in pharmaceutical cases, not knowing science can get you into trouble. An understanding of scientific processes is vital to establishing causation, liability, and damages, and it is necessary for successful discovery, expert witness preparation, and Daubert (1) (or Frye (2)) motions.

Rest assured, the other side will know the science--cold. Pharmaceutical manufacturers spend hundreds of millions of dollars developing a single product and seeing it through the approval process. If a drug is challenged in court, the company's lawyers will be completely comfortable with the scientific issues involved. You should be, too.

Pharmacology--the study of pharmaceuticals and their effects--is the fundamental science of drug development? Have you ever wondered how aspirin makes your headaches go away? How does it know where the ache is located? How does it stop the pain when it gets there? These are the questions pharmacology asks and answers.

The field of pharmacology has two branches: pharmacokinetics and pharmacodynamics. Pharmacokinetics examines what your body does to a drug, including how a drug gets where it needs to go and how your body gets rid of it. Pharmacodynamics studies the drug's effect on your body: for example, how a pill works its therapeutic effect. Pharmacokinetics can explain adverse events when drugs interact, while pharmacodynamics can describe adverse events resulting from the body's response to a drug.

How drugs get where they're going

First, a drug has to get into the body. This can happen several ways, although the most common route is orally, in pills, tablets, capsules, and the like. Once a drug reaches your stomach, it must cross the stomach or intestinal wall, then blood vessel walls, and enter the bloodstream to reach the treatment target. Pharmacokinetics considers four areas: absorption, distribution, metabolism, and excretion or elimination, usually identified by the acronym ADME.

Absorption. The size and chemical properties of a drug molecule determine how easily the body can absorb it. Drugs can pass through a membrane several ways. Some do so by diffusion--typically drugs are fat-soluble because cellular membranes are mostly lipids, that is, fat. Other drugs use transport proteins, present in membranes, to help them across. How readily a drug is absorbed affects how much of it gets into the bloodstream and how much is available to exert a therapeutic (or toxic) effect.

Other factors can affect absorption. One is stomach acidity: Some drugs are not absorbed as well if you have recently taken an antacid, because they are highly sensitive to the stomach's pH level. Another factor is food in the stomach, which may decrease the absorption rate. Alcohol is an example of this effect: Two or three cocktails will probably result in a lower blood alcohol content if you have a meal before you drink them.

Absorption affects the percentage of a dose the body will take up and how quickly. This information is key to determining the amount of drug needed, the timing of the doses, and the way they are administered.

Some drugs move more easily than others from the stomach and intestinal tract into the bloodstream. Drugs that are not readily absorbed are often given intravenously. Morphine, for example, is usually injected because it is not very well absorbed through the stomach or intestinal wall and if taken orally requires much larger doses to produce a beneficial effect. However, as doses increase, so may unwanted side effects. Therefore, researchers developing a new drug must consider its absorption rate and corresponding dosage in assessing the risk of side effects.

Distribution. Some drugs travel widely throughout the body; others aim at one specific organ. When a drug enters the bloodstream, the first organ it reaches is the liver. Some drugs' chemical properties make them remain there. This can be advantageous but can also cause adverse reactions.

For example, some drugs to treat high cholesterol remain primarily in the liver. Since almost all of the body's cholesterol production occurs in that organ, this is where they confer the most benefit. On the other hand, many different drugs, including cholesterol-lowering drugs, can cause liver damage because they concentrate there and become toxic. Because of this well-known risk, people who take these drugs require periodic checks of liver function. If a drug is causing liver damage, distribution may explain how the damage occurred.

Another factor that affects drug distribution is its protein-binding. Most drugs bind to proteins, such as albumin. These proteins in the blood serve a variety of purposes. When drugs become bound to these proteins, the drugs are no longer floating around free, so they may not be able to cross membranes and exert their intended effect.

Protein-binding in the bloodstream is not permanent: Drug molecules are continually being bound to and released from proteins. In situations with substantial protein-binding, only a small amount of the drug is available in the bloodstream to yield its intended effect.

Typically, drugs that are highly protein-bound are not widely distributed--that is, they do not reach many organs but stay in the bloodstream because they are unable to cross biological membranes. The small amount of the drug moving freely in the bloodstream may not be enough to reach target organs and produce a significant effect. On the other hand, patients with severe liver disease may have less albumin in their blood; less protein-binding occurs, leaving more active drug free in the bloodstream to cross membranes. Patients with liver disease may therefore require a smaller dose.

When many drugs are in the bloodstream at once, they may compete to bind with proteins, and this may cause a drug interaction. For example, many patients with heart disease take warfarin. Warfarin has a very narrow window where it is beneficial--that is, there is a very small range between the dose that is helpful and the dose that can cause serious problems, including bleeding. If another drug is present in the bloodstream, that drug may bind with more of the proteins and send more warfarin into the bloodstream, putting the patient at risk for bleeding or hemorrhage. To assess this risk, pharmaceutical companies test their products' protein-binding properties as one of the first experiments done on any drug.

Metabolism. To our bodies, drugs are foreign substances. Our systems do not recognize them and attempt to expel them, not discriminating between a chemical that is helpful and one that is harmful. Many drugs must be changed or transformed--metabolized before they can be removed.

If your body didn't eliminate a drug, it would remain in your system and you would never need to take it again--but this could lead to serious consequences. If you kept taking the drug, it would accumulate to toxic levels in your bloodstream. Generally, your body metabolizes the drug to make it inactive or turn it into a molecule that the body can easily eliminate.

However, in some cases, metabolism actually makes a drug more active. Pharmaceutical companies have taken advantage of this fact to design drugs that are inactive as administered and become active only after a certain change takes place in the body. One example is the cholesterol drug Zocor (simvastatin), which is inactive until the body changes its molecular structure to activate it. For certain drugs, there is an advantage to taking them in an inactive form because their chemical properties make them more easily absorbed into the body than active drugs, so they are more effective. This is not true for all drugs.

The most common way the body metabolizes drugs is by using a family of proteins known as the cytochrome P450 pathway. The enzymes of the P450 family are proteins that help our bodies remove drugs. These individual proteins are also called isozymes. There are dozens of them, each identified by a combination of letters and numbers-for example, the 3A4 enzyme, the 2D6 enzyme, and so on. These labels designate different subfamilies, but all the enzymes perform similar functions. About half of all drugs are thought to be metabolized by the 3A4 enzyme. (4)

This is very important to understand, because if one enzyme is metabolizing two drugs being taken together, the enzyme may not metabolize them as quickly as it would if only one were present. This can affect dosing.

For example, you may have seen or heard warnings to avoid grapefruit juice while taking certain medications. Grapefruit juice interferes with the 3A4 metabolic pathway. There is a limited number of 3A4 molecules in the liver, so if they are already being used to metabolize grapefruit juice, they are not available to metabolize the drug.

The 3A4 enzyme also metabolizes erythromycin, a common antibiotic. So if you take erythromycin and another drug metabolized by 3A4 at the same time, the amount of one or both drugs in the bloodstream can increase to potentially toxic levels.

Drug interactions are the reason some drugs are withdrawn from the market. It is critical for drug companies to study how a compound is metabolized, along with other pharmacokinetic effects, in order to identify potential harmful interactions with other commonly used drugs.

For instance, Posicor--a calcium channel blocker used to treat high blood pressure and chronic angina--was withdrawn after it was shown that certain drugs rose to dangerous levels when administered with Posicor. In fact, at the time it was withdrawn, researchers had identified more than 25 drugs that had these interactions. (5)

Baycol--a medication used to treat high cholesterol--was also withdrawn from the market, after it showed increased risks of inducing a severe muscle adverse reaction. One risk factor for this reaction was mixing Baycol with gemfibrozil, another cholesterol-lowering medication. These examples show how important it is to understand pharmacokinetic drug interactions. (6)

Elimination or excretion. The body typically expels drugs through the urine or feces. Some leave the body unchanged, while others are eliminated after they are metabolized. The process usually occurs in the kidneys, which filter the drug or drug metabolites into the urine.

Toxins, other drugs, and diseases that cause renal impairment can affect this mechanism. Because drugs filter through the kidneys and ultimately concentrate there, these organs are susceptible to drug-induced toxicity. When a patient with kidney disease experiences symptoms, they may be due to an adverse drug effect rather than the disease itself. For this reason, physicians must carefully monitor patients with renal failure and other kidney diseases when these patients are using medications. Many drugs contain warning labels aimed at this special patient population.

How drugs do what they do

Most people do not care how a drug works, as long as it does. But knowledge of pharmacodynamics is important if you are to understand the basic science behind a pharmaceutical product in litigation.

Typically, drugs bind to a cellular receptor or enzyme where they initiate a series of biochemical reactions. This is separate and distinct from the protein-binding discussed earlier. If a drug binds to a protein in the blood, it does not initiate any biological response. It is only when a drug binds to its intended target, a receptor or enzyme, that a pharmacologic effect can occur.

A cellular receptor is a protein, usually on the surface of a cell, with a specific biological function that a drug can enhance or disrupt. When a drug turns a receptor "on" or "off," it starts or stops certain biochemical reactions that, in turn, alter the cell's physiology and yield a certain effect.

For example, proteins known as endorphins interact on a cell's surface with opioid receptors. When endorphins bind with the receptors, the biochemical reactions result in pain relief. Morphine mimics the action of endorphins, by turning "on" the opioid receptor and creating the same series of effects and the same result: pain relief.

Similarly, some drugs block or enhance the function of enzymes and proteins within cells. These include the class of cholesterol-lowering drugs called statins, which stop the enzymes they bind with from producing more cholesterol. By stopping production of cholesterol, they are able to lower the levels of cholesterol in the blood.

Because a cell contains only a limited number of receptors to which a drug can bind, the drug's effect is limited. This is why it isn't always better to take more of a drug. There may be a large increase in toxicity with a small increase in therapeutic benefit, an important consideration when raising doses. Pharmaceutical companies are aware of this principle and understand that larger doses may have larger risks of side effects.

A drug's effect depends on how well it fits into a specific receptor site. You can view this as a lock-and-key model. The receptor or enzyme is the lock. The molecule--either the natural compound (like endorphins) meant to activate the receptor or enzyme, or the unnatural one, the drug--is the key. The molecule must be the right shape: The better the fit, the better it can open the lock, activating the receptor to do its job.

Efficacy and potency

The lock-and-key concept is helpful in understanding two related, but not identical, characteristics of a drug: efficacy and potency. "Potency" refers to a drug's strength; "efficacy" refers to the degree to which it can produce a certain effect. Avery potent drug--which needs a very small dose--does not necessarily have as strong an effect as another drug given in larger doses. But it may "fit the lock" better so you need less to do the job. Efficacy means the degree to which a drug is able to induce an effect.

For example, one drug may reduce LDL cholesterol by 20 percent in a dose of 0.4 milligrams while another reduces it by 40 percent in a dose of 40 milligrams. The first is much more potent because the dose is one one-hundredth of the other. However, the second is much more effective.

Potency is typically used to compare drugs within a class or group that work by the same mechanism. Efficacy is used to compare drugs that have different mechanisms. Drugs that are more potent may also pose a higher risk of toxic side effects. Pharmaceutical companies that create potent new drugs need to be aware of these potential risks.

A related concept is that drugs can have more than one effect. Many locks can be opened by more than one key.

Similarly, many drugs treat the same conditions, forming a class of drugs. Conversely, just as many keys look alike and open more than one lock, a drug may work on more than one receptor. A drug created to fit one particular enzyme, or lock, may also act on another. This secondary activity can be helpful or harmful. It may lead to a new treatment or to unwanted side effects.

For example, researchers developed Rogaine to treat hypertension. During trials they noted that one side effect was hair growth. Today Rogaine is marketed as a remedy for thinning hair and rarely mentioned as a treatment for hypertension. Other drugs have unexpected side effects that are toxic.

A pharmaceutical company designs clinical trials according to the principles of pharmacokinetics and pharmacodynamics. During the discovery process, you must find out what the company was looking for and what it should have been looking for. Did the company ignore obvious signs of adverse effects? Were the trials thorough enough to detect potential problems? The answers to these and other questions rest in the pharmacology of the specific compound.

If you understand a drug's pharmacology, you will be in a better position to understand causation, liability, and damages--and to win your client's case.

Notes

(1.) Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579 (1993).

(2.) Frye v. United States, 293 F. 1013 (D.C. Cir. 1923).

(3.) Unfortunately, there are few books on pharmacology for nonscientists. One well-recognized text is ALFRED GOODMAN & LOUIS GILMAN, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (Joel Griffith Hardman et al. eds., 10th ed. 2001).

(4.) Grant W. Wilkinson, Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination, in GOODMAN & GILMAN, id. at 3.

(5.) FDA Talk Paper No. T98-33, Roche Laboratories Announces Withdrawal of Posicor from the Market (June 8, 1998), available at www.fda. gov, go to "Talk Papers" under "Information for Press" and select by date (last visited Jan. 25, 2005).

(6.) FDA Talk Paper No. T0-1-34, Bayer Voluntarily Withdraws Baycol (Aug. 8, 2001), available at www.fda.gov, go to "Talk Papers" under "Information for Press" and select by date (last visited Jan. 25, 2005).

STACY K. HAUER practices with Zimmerman Reed in Minneapolis.
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Date:Mar 1, 2005
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