Throughout history, pharmacologists have tread a fine line in determining dosage: too much of a medication can have negative consequences, but too little might fail to cause the desired response. The goal is to give a drug in such a way as to keep the blood concentration above the minimum therapeutic dose, but below a toxic level for as long as needed to treat the disorder or disease. Sometimes a single dose of a drug will do the trick; other times, lifelong therapy is required.
Because most modern drugs travel through the bloodstream, only a portion of the medication makes it to the part of the body where it is needed. Some drugs stay in the bloodstream only; others enter the cells or the spaces between them. The more the drug needs to be diluted before it makes it into the body, the higher the dosage required to achieve a desirable concentration. Some drugs are metabolized by the liver and other organs, while others are eliminated in the bile or urine. Each drug has an expected duration of action after which subsequent doses must be administered.
If a drug must attain a certain concentration in the body, and has a short duration of action, multiple daily doses will be needed. For example, morphine sulfate is dosed at 10 milligrams every 4 hours for continuous control of severe cancer pain. If a follow-up dose is missed or delayed, the pain will come back.
Tablets and Capsules
One challenge to such treatment is that short intervals interfere with a patient's sleep. Advanced-tablet technology has solved this problem. In the morphine sulfate example, an MS Contin timed-release tablet continuously dissolves over a 12-hour period, meaning that it only needs to be taken twice per day. The tablet is designed to allow only a certain amount of the drug to enter the body per a given unit of time.
There are many examples of such sustained-release products. Some capsules are made of plastic so that water cannot penetrate the tablet except through a tiny, laser-drilled hole. Since only a specific amount of liquid (and the drug dissolved therein) can escape, the drug is released over a long period of time. In a capsule core coat system, capsules are filled with drug pellets. Each one contains a top layer of the drug that is immediately absorbed into the bloodstream, a second layer of coating that dissolves slowly, and a third layer of medication. Enteric coatings are another gradual-release option. These dissolve in the small intestine, releasing the drug lying underneath so that it can be absorbed by the body.
Injections and Inhalers
In some cases, it is preferable to deliver a drug directly to the part of the body where it is needed, or to give a drug in a form that will travel to the site of action before becoming activated.
Local delivery of medication has been used for decades. For example, dentists administer lidocaine injections into the mouth nerves to numb the area, but include some adrenaline as well. The adrenaline does not deaden the pain, but it causes blood-vessel constriction in the mouth so that the anesthetics are not taken up by the bloodstream and rushed away. Asthma sufferers take inhaled beta-2 agonists, salmeterol, or corticosteroids through an inhaler. This allows high drug concentrations in the lungs—where the medicine is needed the most—and lower total body concentrations. The result is better asthma control with fewer side effects. In 2006, pharmaceutical giant Pfizer Incorporated unveiled an insulin inhaler called "Exubera," designed specifically for people with diabetes.
Transdermal Skin Patches
As an alternative to tablets and capsules, some medications are available in patches worn on the skin. The medication in the patches passes through the skin and is slowly taken into the bloodstream at a constant rate. The size of the patch determines the amount of medication the body receives, with larger patches dispensing more medication than smaller ones. The shape of the patches varies with the manufacturer.
The patches resemble the plastic bandages used on cuts, except that their adhesive is around all four edges. The basic design of the patch, called a transdermal skin patch, is simple. The side away from the body is a waterproof covering. Below this is a reservoir that contains the medication in a dispersal medium (such as mineral oil) in which the medication is evenly distributed. Below the reservoir is a porous synthetic membrane that controls the rate at which materials leave the reservoir. The patches are fairly small. The surface across which medications pass ranges from about 0.5 square inch (3.2 square centimeters) to 4.6 square inches (30 square centimeters).
Nitroglycerin patches have been available since the mid-1980s. A steady supply of this medication helps relieve the symptoms of angina, a heart condition that causes suffocating chest pains. Clonidine, a medication for high blood pressure, also comes in skin patches. Another medication available in skin patches is scopolamine, which is used to treat motion sickness. The nitroglycerin and clonidine patches are usually worn on the chest or inner thigh, while the scopolamine patches are placed behind the ear. As body temperature slowly melts the dispersal medium, the correct dosage is absorbed into the body.
Other skin patches include nicotine patches to wean people from smoking; estrogen patches for women in need of estrogen supplements; and fentanyl (Duragesic) patches for chronic cancer pain.
The transdermal skin patch does not upset the stomach like certain orally administered medications, and it is not messy like topical ointments. On the negative side, the patch is usually more expensive than conventional treatments, it may fall off, and it can cause skin irritations.
Some people require regular doses of natural body products, such as hormones and other chemicals, which their bodies do not produce in sufficient quantities. Some body products, often proteins, break down in the digestive system if taken orally. The molecules of such proteins are too large to diffuse through the skin. Until recently, the only method of getting these products into the bloodstream has been by injection.
The most common condition in which a body product is lacking is diabetes, a disorder in which the body does not metabolize sugar properly because it produces too little insulin, or fails to use its insulin effectively. Many diabetics must inject themselves with insulin daily. The amount of insulin must be balanced with activity and diet to prevent side effects.
An alternative to daily injections, the implantable infusion pump has progressed to the production of miniaturized pumps about the size of a deck of cards. The pump is surgically placed in the abdomen or wall of the chest, much like a heart pacemaker. The cylinder in the pump that holds insulin is refilled through the skin every week. Once in place, the pump delivers programmed doses of insulin to the body.
An infusion pump is also being used to relieve severe pain in cancer patients. The tiny device, which contains concentrated amounts of a painkiller and programmed to dispense a predefined dose, is implanted under the skin, usually in the abdomen.
The body's natural defense system produces proteins called antibodies as one response to an invasion by foreign materials (such as pollen), called antigens. Antibodies are specific: a given antibody recognizes and attaches itself to a specific antigen. The antibodies circulate in the blood. When they come in contact with the specific antigen, they bind together, forming an antibody-antigen complex. Other blood cells, in turn, recognize an antibody-antigen complex and destroy it.
The disease-fighting chemicals produced by vaccination are antibodies. Blood plasma that contains antibodies to a given disease can be administered to a person to provide temporary immunity to that disease. Antibodies can also be used diagnostically. The antibodies for a specific pathogen are added to a blood sample; if antibody-antigen complexes form, doctors know that the organism is present.
But there are problems with using the antibodies that are present in normal blood plasma. There is a mixture of many different kinds of antibodies in any blood sample. The amount of antibodies produced in response to a particular antigen varies from individual to individual, whether the suppliers are humans or animals. In addition, the level of antibodies in the living body is simply too small for many clinical applications.
In 1975, scientists found a way to obtain a pure supply of antibodies from mice. First the mice were injected with a desired antigen; then they were given time to produce antibodies to that antigen. Next, scientists removed antibody-producing cells from the spleens of the mice. Unfortunately, the amount was not enough to grow these cells outside the animals' bodies. Mouse spleen cells live only a few days in culture. While they continue to produce antibodies during this time, the total amounts are small. The scientists used a technique called cell fusion to unite each mouse spleen cell with a mouse skin cancer cell. Because cancer cells divide eternally, the fused cells, or hybridomas, not only live, they increase in number while still producing their antibodies.
Each spleen cell produces only one kind of antibody, so each hybridoma produces only one antibody. The next step in this process is to separate the hybridomas from one another and grow each one individually. As individual hybridomas grow, they divide again and again to form a colony of identical cells. Finally, the antibody produced by each hybridoma is identified. Hybridomas producing the desired antibodies are kept and the rest are discarded. Since each colony, or clone, produces one kind of antibody, the products are called monoclonal antibodies. Using this technique, scientists can now get pure antibodies for many different antigens in almost unlimited quantities. This breakthrough was so significant that its discoverers, Georges Köhler of Germany and César Milstein of Argentina, received a Nobel Prize in Physiology or Medicine in 1984 for their work.
One major problem with this technique was that the human immune system had the tendency to fight and destroy mouse-derived monoclonals, viewing them as alien invaders. Newly developed monoclonals are more similar to human antibodies, so they are more likely to be accepted by the human immune system. These compounds are viewed as potential treatments for a wide range of maladies, from bacterial infections to arthritis and cancer.
Monoclonals are currently being used in a variety of diagnostic situations. A tool to help physicians diagnose patients at risk for heart attack and stroke uses monoclonal antibodies to identify fibrinogen, a blood protein that plays a key role in blood-clot formation. Since high levels of fibrinogen can cause coronary-artery disease, early detection of high fibrinogen levels may help physicians prevent or predict heart failure.
Certain disease-causing microorganisms as well as certain antigens that cause allergies can be detected using monoclonal antibodies. The sexually transmitted diseases herpes, gonorrhea, and chlamydia can be identified at very early stages. This is especially important with gonorrhea and chlamydia because, in women, these diseases may not cause any symptoms until they have done a great deal of damage. Rabies, too, can be diagnosed more quickly and accurately with monoclonal antibodies. In addition, monoclonal antibodies are helping scientists learn more about the basic structure of cells, an approach that may give more insight into cancer.
A few applications have been introduced, particularly drugs that help prevent the rejection of organ transplants. Also, it is possible to inhibit the clumping of platelets, which helps prevent the reclogging of arteries in patients recovering from angioplasty. New drugs show promise in treating rheumatoid arthritis and in shrinking tumors.
It is also possible to attach drugs or poisons to monoclonal antibodies. Drugs specific for certain types of cells, such as disease-causing microorganisms or cancer cells, can be released when the antibodies bind to the cells. The antibodies take the drugs or poisons directly to the target cell, reducing any effects on other healthy cells.
Liposomes are tiny bubbles of various sizes. Their outer boundary is a double phospholipid membrane like that of a cell. Inside is a watery medium. Liposomes are not new cell organelles; they are human-made vehicles. Temperature-sensitive liposomes, which may release the drugs they contain by breaking apart at sites exposed to heat generated by radio frequency energy, are being evaluated as a means of attacking specific targets, such as tumor-afflicted liver tissue, while sparing other tissues.
Liposomes are made by mixing precise proportions of phospholipids and water. Phospholipid molecules are characterized by having one end that is hydrophilic (attracted to water) and one end that is hydrophobic (repelled by water). When phospholipids are mixed with water in the right way, the phospholipids form hollow spheres with the hydrophilic ends all inside the spheres and the hydrophobic ends facing out. The spheres are the liposomes; they enclose the water with which they were mixed. If drugs or other water-soluble materials are present, they become enclosed within the liposomes as they form. If fat-soluble drugs are added, they become part of the surrounding membrane.
Depending on the exact procedure being used, different forms of liposomes are produced. Some have a single outer membrane, while others are like spheres within spheres—with a watery solution in between each pair of spheres.
By carefully selecting the phospholipids used in making the liposomes and adding cell surface proteins, scientists can create liposomes with an affinity for a specific type of cell. Once the liposomes reach the desired cell, directed heat may break them down or they may interact in one of several ways. They may attach to the cell surface; the materials within them then diffuse into the target cell. They may be taken into the cell, where they break down and release the material they carry. Or they may fuse with the cell membrane and empty their contents into the target cell.
Research on liposomes began in the 1960s, but was slowed by an unexpected difficulty. Scientists had thought that the similarity between liposomes and normal cells would be sufficient for the human body to accept the carriers, but the immune system destroyed the liposomes. The problem began to be solved in the late 1980s, when scientists incorporated glycolipids into the liposomes. Coupled with other developments, this has led to encouraging results with the anticancer drug doxirubicin.
Liposomes containing amphotericin B have been used to treat fungal infections. Liposomes are also used in the treatment of pulmonary illnesses.
Another drug-delivery technique is the use of nasal spray as an alternative to injections. One such product, a nasal-spray influenza vaccine carrying the brand name FluMist, became available by prescription for the 2003–2004 flu season. Nasal sprays and inhalers can also be used to administer nicotine to help wean smokers off tobacco.
Even foods may someday deliver drugs. Scientists may modify a plant's genes to include proteins from disease-causing organisms. Eating such a plant could stimulate a person's immune system to produce antibodies. Maintaining the food chain's integrity may become a concern—researchers are testing crops that have been genetically engineered with vaccines against several other illnesses as well.
Improved drug-delivery methods mean very little if an insufficient quantity of drug is available for delivery. Many people have medical problems caused by the body's inability to produce certain hormones, enzymes, or other compounds. The problems can be combated by delivering the compounds; but these compounds often exist in limited quantities, making them costly or necessitating the use of substitutes. For instance, people with diabetes are unable to produce adequate amounts of insulin. Until recently, insulin was extracted from animals, mostly pigs. Although similar to human insulin, pig insulin is not identical, and some diabetics are sensitive to it. Thanks to a technique called recombinant DNA, diabetics can take human insulin, and thus avoid adverse reactions.
In recombinant DNA, the human gene responsible for directing production of the desired chemical is inserted into the genetic material (DNA) of another organism, usually a bacterium or yeast. The host organism then is able to produce the chemical—and passes this ability on to its descendants. It is the human insulin produced in this manner that is now used in the treatment of diabetes.
Other medications and drugs produced using recombinant DNA techniques include interferon, used to treat hepatitis, muscular sclerosis, and certain types of cancer; and somatostatin, a hormone that inhibits the synthesis and secretion of growth hormone.
Some chemicals are too complex to be mass-produced in bacteria or yeast. One of these is Protein C, a compound present in trace amounts in human blood, where it plays a role in clotting. Researchers inserted the gene for Protein C into pig embryos, attached to regulators that cause the protein to be produced only in milk. They were thus able to induce production of it in amounts large enough to be easily purified. Researchers also have been able to produce other proteins in farm animals, including human hemoglobin.
Recombinant DNA technology has also been applied in the development of vaccines. The first such human vaccine to win U.S. government approval was created to protect against hepatitis B, a highly infectious viral disease of the liver transmitted through blood and body fluids. Other vaccines currently under development will take aim against such conditions as AIDS, Lyme disease, acellular perussis, and hepatitis A.
The information provided should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies.
Copyright Information: Public domain information with acknowledgement given to the U.S. National Library of Medicine.