Routes of Administration and the Drug Cycle
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- Bartholomew Roberts
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1 CHAPTER 4 Routes of Administration and the Drug Cycle CHAPTER CONTENTS Routes of Administration The Drug Cycle Quiz Yourself Spelling Tips Clinical Applications Multimedia Extension Exercises Learning Objectives After you study this chapter, you should be able to 1. Name 11 routes of drug administration. 2. Describe the advantages and disadvantages of oral administration of a drug. 3. Describe the differences between an intradermal, subcutaneous, and intramuscular injection. 4. Recognize and define Latin abbreviations for topical administration. 5. Define the role of plasma proteins and the blood brain barrier in the distribution of a drug. 6. Describe how the liver metabolizes drugs. 7. Describe how the kidneys excrete drugs. 8. Describe how drug doses are adjusted for patients with liver or kidney disease, elderly patients, or premature infants. 9. Define the words and phrases buccal route, intracardiac route, intrathecal route, intravesical route, I.V. piggyback, parenteral, pharmacokinetics, receptor, and sublingual route.
2 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 47 Before a drug can receive final approval by the FDA, the drug company must clearly state what routes of administration have been found to be safe and effective for that drug. Different forms of a drug are appropriate for different routes of administration. Some drugs are ineffective when administered by a certain route; other drugs may seriously injure the patient if administered by the wrong route. Once a drug is administered, it goes through the steps of the drug cycle. These steps include absorption, distribution, metabolism, and excretion. Routes of Administration There are various routes by which drugs can be administered. Some drugs are approved for use via more than one route and are manufactured in different drug forms appropriate for those different routes. Each route of administration has distinct advantages and disadvantages. A drug given by the recommended route of administration will be therapeutic; if given by another route, it may be ineffective, harmful, or even fatal. 1. Topical. When a drug is applied directly to the skin or the eyes or ears, it is administered via the topical route (see FIGURE 4 1). The therapeutic effect of the drug only extends to the local area (e.g., antibiotic ointment for a skin injury, Timoptic eye drops for glaucoma, or antibiotic drops for an ear infection). The word topical contains the combining form topic/o- (a specific area) and the suffix -al (pertaining to); the word means pertaining to a specific area. Sites of topical administration are abbreviated as follows (see TABLE 4 1). FIGURE 4 1 Topical route of administration. The nurse is administering a topical ophthalmic antibiotic ointment to the patient s eye by pulling down the lower eyelid so that a ribbon of ointment can be laid in the sac between the eye and the lower eyelid. As the patient blinks, the ointment is distributed across the eye. Topical ophthalmic ointment is specially formulated to be nonirritating to the eye; it is not interchangeable with other topical ointments that are used on the skin.
3 48 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS TABLE 4 1 Abbreviations for topical administration Abbreviation Latin Meaning Medical Meaning A.D. auris dextra right ear A.S. auris sinistra left ear A.U. auris unitas both ears auris uterque each ear O.D. oculus dexter right eye O.S. oculus sinister left eye O.U. oculus unitas both eyes oculus uterque each eye Clinical Applications When you are administering a topical drug to a patient, remember that, as you face the patient, your right-hand side corresponds to the patient s left-hand side. If the physician s order is for ointment in the right eye, you have to consciously think about correctly identifying the patient s right side. 2. Transdermal. This route of administration differs from the topical route in that the drug is applied to the skin, but the therapeutic effect is felt systemically, not just at the site of administration. Drugs delivered by the transdermal route are manufactured in the form of a transdermal patch (see Chapter 3). A transdermal patch is worn on the skin and releases the drug slowly over one or more days, providing a sustained therapeutic blood level (e.g., Nicoderm CQ patch to stop smoking). The word transdermal contains the prefix trans- (across; through), the combining form derm/o- (skin), and the suffix -al (pertaining to); the word means pertaining to through the skin. 3. Oral. The oral route is the most convenient route of administration and the one most commonly used. The oral route involves placing the drug in the mouth and swallowing it (see FIGURE 4 2). Tablets, capsules, and liquids are all given orally. The drug is then absorbed from the stomach or small intestine into the blood. The oral route is routinely abbreviated as PO or p.o. (Latin for per os, meaning through the mouth). Disadvantages of the oral route include the following. It is difficult for some patients to swallow the largest tablets and capsules (see FIGURE 4 3). The oral route cannot be used for patients who are unconscious or vomiting. Some drugs (e.g., penicillin, an antibiotic drug) are inactivated by stomach acid and cannot be given orally. After oral administration, some drugs (e.g., lidocaine for cardiac arrhythmias) are metabolized so quickly by the liver as they pass through the portal circulation that a therapeutic blood level cannot be achieved. Some drugs (e.g., tetracycline, an antibiotic drug) cannot be taken with certain foods and beverages because they combine chemically to form an insoluble complex. Some drugs (e.g., MAO inhibitor drugs for depression) cannot be taken with certain foods because they produce severe adverse effects. 4. Sublingual and buccal. Sublingual administration involves placing the drug (usually in a tablet form) under the tongue and allowing it slowly to disintegrate. Buccal administration involves placing the drug (usually in a tablet form) in the pocket between the cheek and the lower teeth on one side of the mouth and allowing it slowly to disintegrate. The tablet is not swallowed (as this would be oral administration). The dissolved drug is absorbed quickly through the oral mucous membranes and absorbed into the large blood vessels under the tongue and oral mucosa. Drugs
4 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 49 FIGURE 4 2 Oral route of administration. This is the most common route of drug administration. Drugs can be given as tablets, capsules, or liquids. Many pediatric drugs are in a liquid form. For oral administration of a drug to an infant, the liquid drug is mixed with a small amount of formula and given orally through the nipple which has been removed from the bottle of formula. FIGURE 4 3 Oral route of administration. Some patients have difficulty swallowing very large tablets or capsules. Their physicians can prescribe an alternate drug form, such as a liquid. given by the sublingual route provide a faster therapeutic effect than those given by the oral route (e.g., nitroglycerin tablets and spray for treating angina attacks). At the present time, few drugs are administered by the buccal route. The word sublingual contains the prefix sub- (below; underneath), the combining form lingu/o- (tongue), and the suffix -al (pertaining to); the word means pertaining to underneath the tongue. The word buccal contains the combining form bucc/o- (cheek) and the suffix -al (pertaining to); the word means pertaining to the cheek.
5 50 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS 5. Nasal. Nasal administration involves spraying a drug into the nasal cavity. This is usually done topically to treat allergy symptoms of nasal stuffiness (e.g., Nasonex, a topical corticosteroid drug for inflammation), but some nasal spray drugs act systemically throughout the body (e.g., Miacalcin nasal spray for Paget s disease of the bones). 6. Inhalation. This route of administration involves the inhaling of a drug that is in a gas, liquid, or powder form (see FIGURE 4 4). The drug is absorbed through the alveoli of the lungs (e.g., an anesthetic gas). The word inhalation contains the prefix in- (in; within), the combining form hal/o- (breathe), and the suffix -ation (a process); the word means a process of breathing in. FIGURE 4 4 Inhalation route of administration. This patient is receiving a drug in the form of an anesthetic gas to produce unconsciousness prior to having surgery. 7. Nasogastric. This route is used to administer drugs to patients who cannot take oral drugs. Nasogastric administration is accomplished with a nasogastric tube that is passed from the nose through the esophagus and into the stomach. Any liquid drug that can be given by the oral route can be given by this route. Nasogastric is abbreviated as NG. The word nasogastric contains the combining form nas/o- (nose), the combining form gastr/o- (stomach), and the suffix -ic (pertaining to); the word means pertaining to the nose and stomach. Did You Know? The first nasogastric tube, developed in the late 1700s, was constructed from eel skin. It was used for several weeks to feed a patient who could not eat. 8. Gastrostomy and jejunostomy. These routes are used to administer drugs to patients who cannot take oral drugs. These routes use a surgically implanted feeding tube to deliver liquid drugs directly into the stomach (gastrostomy) or jejunum (jejunostomy). Any liquid drug that
6 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 51 can be given orally can be given by these routes. The word gastrostomy contains the combining form gastr/o- (stomach) and the suffix -stomy (surgically created opening); the word means a surgically created opening in the stomach. The word jejunostomy contains the combining form jejun/o- (jejunum) and the suffix -stomy (surgically created opening); the word means a surgically created opening in the jejunum. 9. Vaginal. The vaginal route is used to treat vaginal infections by means of creams, ointments, and suppositories (e.g., Monistat vaginal cream or suppositories for a yeast infection). Contraceptive foams are inserted vaginally as well. 10. Rectal. This route is reserved for certain situations, such as when the patient is vomiting, is unconscious, or the drug cannot be given by injection (e.g., Tylenol suppository for a fever). Systemic absorption of a drug via the rectal route of administration is slow and often unpredictable, so this route is not used often. However, the rectal route is the preferred route when drugs are administered topically to relieve constipation (e.g., Fleet enema) or to treat hemorrhoids (e.g., Anusol cream or suppositories) or ulcerative colitis (e.g., Proctofoam- HC aerosol foam). 11. Parenteral. Parenteral administration theoretically includes all routes of administration other than the oral route; but in clinical usage, parenteral administration commonly includes these routes: intradermal, subcutaneous, intramuscular, and intravenous. The word parenteral contains the prefix par- (beside; apart from), the combining form enter/o- (intestine), and the suffix -al (pertaining to); the word means pertaining to apart from the intestine, i.e., a route other than through the mouth. Intradermal administration involves using a syringe to inject a liquid drug into the dermis, the layer of skin just below the epidermis or skin surface (see FIGURE 4 5 and FIGURE 4 6). Intradermal administration is used for allergy scratch tests and for the Mantoux test that screens for tuberculosis. The word intradermal contains the prefix intra- (within), the combining form derm/o- (skin), and the suffix -al (pertaining to); the word means pertaining to within the skin º Epidermis Dermis Subcutaneous tissue Muscle FIGURE 4 5 Intradermal route of administration. The needle is inserted at a 10- to 15-degree angle so that it does not penetrate too deeply. The epidermis itself is less than 1/20 inch thick; therefore, when an intradermal injection is positioned correctly, the tip of the needle is still visible through the epidermis.
7 52 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS FIGURE 4 6 Syringe. A syringe is used to withdraw a liquid drug from an ampule or vial. This tuberculin syringe is calibrated to measure liquid drug doses to the hundredth of a milliliter (ml). The needle on the syringe is used to penetrate the skin to the correct depth to administer the liquid drug. This type of syringe is used to give either intradermal or subcutaneous injections. A longer needle and a larger syringe are used to administer liquid drug doses via the intramuscular route. Subcutaneous administration involves using a syringe to inject a liquid drug into the subcutaneous tissue (the fatty layer of tissue just beneath the dermis of the skin but above the muscle layer) (see FIGURE 4 7). There are only a few blood vessels in this fatty layer, so drugs are absorbed more slowly than by the intramuscular route. Examples of drugs given via the subcutaneous route include insulin for diabetes mellitus, allergy shots, and heparin. This route is abbreviated as subq, SQ, or subcu; there is no one official abbreviation. The word subcutaneous contains the prefix sub- (below; underneath), the combining form cutane/o- (skin), and the suffix -al (pertaining to); the word means pertaining to below the skin. 45º Epidermis Dermis Subcutaneous tissue Muscle FIGURE 4 7 Subcutaneous route of administration. The needle is inserted at a 45-degree angle to reach the fatty subcutaneous tissue, but not penetrate into the muscle layer. Diabetic patients who inject insulin daily use the subcutaneous route. A subcutaneous injection can also be classified as a hypodermic injection (hypo- means below and derm/o- means skin). Intramuscular administration involves the injection of a liquid drug into the belly (area of greatest mass) of a muscle (see FIGURE 4 8 and FIGURE 4 9). The muscles of the body are well supplied with blood vessels, and drugs injected intramuscularly are absorbed more quickly than with subcutaneous administration. Also, a muscle is able to absorb a larger amount of a liquid drug (up to 5 ml). An intramuscular injection must be given into
8 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 53 a muscle that is large enough that the needle will not accidentally injure a nearby nerve. Examples of drugs given intramuscularly include meperidine (Demerol) for severe pain and penicillin for bacterial infection. Some liquid drugs, such as Valium (an antianxiety drug), can never be given by intramuscular injection because they are not water soluble and, if injected, would form precipitate particles in the muscle tissue. The word intramuscular is abbreviated as either IM or I.M. The word intramuscular contains the prefix intra- (within), the combining form muscul/o- (muscle), and the suffix -ar (pertaining to); this word means pertaining to within the muscle. 90º Epidermis Dermis Subcutaneous tissue Muscle FIGURE 4 8 Intramuscular route of administration. The needle is inserted at a 90-degree angle to reach the muscle layer. An intramuscular injection can also be classified as a hypodermic injection. FIGURE 4 9 Newborn intramuscular injection. The vastus lateralis muscle is the preferred site for giving injections such as infant immunizations, as this is the muscle that has the greatest bulk.
9 54 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS In adults, there are only four large muscle sites that are recommended for intramuscular injection of drugs: ventrogluteal, deltoid, dorsogluteal, and vastus lateralis. Did You Know? Fans of the Star Trek television series and movies have long been familiar with this futuristic drug delivery system: the imaginary hypospray! The injection requires no needle and causes no pain. Intravenous administration involves the injection of a liquid drug into a vein. A bag of intravenous fluid is hung from an I.V. pole that is elevated above the patient. The effect of gravity moves the fluid through the I.V. tubing, and into the patient s vein, with the drug flowing in drip by drip through the needle. Alternatively, an I.V. pump can be used to precisely regulate the amount of I.V. fluid given. The therapeutic effect of a drug given intravenously is often seen immediately. The intravenous route entirely bypassses the step of absorption because the drug is not absorbed from the tissues or stomach. Examples of drugs given intravenously include thiopental (Pentothal) for induction of general anesthesia, diazepam (Valium) to control continuous epileptic seizures, and most chemotherapy drugs. The word intravenous is abbreviated as either IV or I.V. The word intravenous contains the prefix intra- (within), the combining form ven/o- (vein), and the suffix -ous (pertaining to); the word means pertaining to within the vein. Intravenous administration can be done in one of three ways. Bolus. The whole amount of a drug can be injected in a short period of time through a port (rubber stopper) in the I.V. tubing by gently pushing on the plunger of the syringe. This is often referred to as I.V. push. I.V. infusion. The drug can be injected into the fluid of a large I.V. bag and administered continuously over several hours. This is known as I.V. drip. I.V. piggyback. The drug can be injected into a small I.V. bag of fluid that is then attached (or piggybacked) onto an existing primary I.V. line. For some drugs, the small I.V. bag already comes premixed (see FIGURE 4 10). 12. Other routes of administration. The following routes of administration are used less frequently and only in special situations. They include the central venous line, endotracheal tube, implantable port, intra-arterial route, intra-articular route, intracardiac route, intrathecal route, intraperitoneal route, intravesical route, and the umbilical artery or vein. Central venous line. This route is used to continuously administer intravenous fluids or drugs to critically ill patients or to administer chemotherapy drugs to patients with cancer. A special catheter (Broviac, Hickman, or Groshong) is tunneled through the subcutaneous tissue of the upper chest, inserted into a large vein, and advanced until its tip is positioned in the superior vena cava. For administration of chemotherapy drugs, the external end of the catheter is sealed, and is only uncapped when the chemotherapy drug is administered. This allows the patient to be ambulatory because there is no attached I.V. line. Endotracheal tube. This route is used to administer drugs through an endotracheal tube inserted through the mouth into the trachea (see FIGURE 4 11). This route is especially useful if there is no established intravenous access. With endotracheal administration, the drug dose is absorbed through the lung tissue and into the blood. Emergency drugs administered through the endotracheal route are identified by the memory aid NAVEL (naloxone, atropine, Valium, epinephrine, or lidocaine). The endotracheal route is also used to administer synthetic lung surfactant drug to treat respiratory distress syndrome in premature
10 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 55 FIGURE 4 10 I.V. piggyback route of administration. Because I.V. antibiotic drugs are frequently ordered in the hospital, small I.V. bags often come premixed with the antibiotic drug already in them; they can be attached quickly to the patient s existing I.V. line. This I.V. bag contains the trade name antibiotic drug Zosyn, a combination drug that contains the generic antibiotic drugs piperacillin and tazobactam; it is used to treat severe infections. FIGURE 4 11 Endotracheal tube route of administration. The paramedic is injecting a liquid drug in a syringe into the open end of the clear plastic endotracheal tube. After the drug is injected, it will be absorbed by the lungs and go into the blood. The patient also will receive oxygen and manual ventilation to assist her breathing until she can be evaluated in the emergency room. infants. The word endotracheal contains the prefix endo- (within), the combining form trache/o- (trachea), and the suffix -al (pertaining to); the word means pertaining to within the trachea. Implantable port. This is a special intravenous access device that is used to administer a chemotherapy drug to treat cancer. The port is a thin metal or plastic reservoir that is placed in a subcutaneous pocket of tissue. The reservoir is attached to a catheter that is threaded into the patient s superior vena cava. The chemotherapy drug is administered by
11 56 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS inserting a needle through the skin overlying the reservoir and injecting the drug into the reservoir. The reservoir then releases the drug slowly into the blood. Another type is an Ommaya reservoir that is placed beneath the scalp with the catheter placed in the ventricle of the brain. In the same way, this reservoir is filled with a chemotherapy drug that then circulates throughout the brain via the cerebrospinal fluid. Intra-arterial route. This route is used for administration of a chemotherapy drug directly into the area of a cancerous tumor. A catheter is inserted into the main artery that brings blood to the organ where the cancerous tumor is located. The catheter is connected to an infusion pump that is implanted under the skin or worn externally. This pump administers doses of chemotherapy drug through the intra-arterial catheter at preprogrammed intervals. The word intra-arterial contains the prefix intra- (within), the combining form arteri/o- (artery), and the suffix -al (pertaining to); the word means pertaining to within the artery. Intra-articular route. This route is used to administer a drug into a joint (e.g., corticosteroid drugs to decrease pain and inflammation). These drugs are injected once every few weeks or months. The word intra-articular contains the prefix intra- (within), the combining form articul/o- (joint), and the suffix -ar (pertaining to); the word means pertaining to within the joint. Intracardiac route. This route is only used during emergency resuscitation associated with cardiac arrest. If external compressions do not cause the heart to begin to beat again, then the intracardiac route is used with a needle inserted through the chest wall, between the ribs, and into one of the heart chambers. Then the drug epinephrine (Adrenalin) is injected to stimulate the heart muscle to begin to contract. The word intracardiac contains the prefix intra- (within), the combining form cardi/o- (heart), and the suffix -ac (pertaining to); the word means pertaining to within the heart. Intrathecal route. This route is used to administer drugs within the meninges around the spinal cord and into the cerebrospinal fluid (e.g., spinal anesthesia). The word intrathecal contains the prefix intra- (within), the combining form thec/o- (layers of membranes), and the suffix -al (pertaining to); the word means pertaining to within the layers of membranes (meninges). Intraperitoneal route. This route is used to administer drugs or fluids into the peritoneal cavity. A catheter is surgically implanted through the abdominal wall into the peritoneal cavity. Sometimes the intraperitoneal route is used to administer chemotherapy drugs. As the chemotherapy drug is dispersed throughout the peritoneal fluid, it comes in contact with the surfaces of all of the organs in the abdominopelvic cavity where there might be cancerous tumors present. In other cases, the intraperitoneal route is used to administer dialysis fluids for peritoneal dialysis in patients with kidney failure. The fluid draws waste products out of the blood of the abdominal organs and, after a period of time, the dialysis fluid is removed and discarded. The word intraperitoneal contains the prefix intra- (within), the combining form peritone/o- (peritoneum), and the suffix -al (pertaining to); the word means pertaining to within the peritoneum. Intravesical route. This route is used for the administration of chemotherapy drugs into the bladder to treat bladder cancer. A catheter inserted into the urethra carries the chemotherapy drug into the bladder, where it remains for a predetermined period of time. The word intravesical contains the prefix intra- (within), the combining form vesic/o- (bladder), and the suffix -al (pertaining to); the word means pertaining to within the bladder. Umbilical artery or vein. This route is accessible only in newborn infants before the umbilical cord has dried. It is used to administer intravenous fluids and draw blood. It is generally not used to give drugs. Instead, an I.V. line is inserted peripherally in the hand, foot, or scalp for drug administration.
12 The Drug Cycle CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 57 Following administration, most drugs go through a well-defined sequence of four steps before being excreted from the body. These steps are known as the drug cycle. 1. Absorption from the site of administration 2. Distribution via the circulatory system 3. Metabolism 4. Excretion from the body Pharmacokinetics is the study of how drugs move through the body in the processes of absorption, distribution, metabolism, and excretion. Absorption Absorption involves the movement of a drug from the site of administration through tissues and into the blood. For most drug forms, absorption involves three steps. Disintegrate. Tablets, capsules, suppositories, and so on, are drug forms that must first disintegrate before they can be absorbed; this step is omitted for drugs that are already in a liquid form or those that are effervescent tablets that disintegrate outside the body in a glass of water before being swallowed (see FIGURE 4 12). FIGURE 4 12 Disintegration. These two tablets are disintegrating in a glass of water before they can be taken by the oral route. Dissolve. Once the drug is in a liquid form, it dissolves in the surrounding body fluids (saliva, gastric juice, or tissue fluid). Absorb. From the body fluids, the drug passes through the walls of nearby capillaries and is absorbed into the blood. Absorption after topical administration. Following topical administration of a drug, the drug form does not need to undergo disintegration; it quickly dissolves in the tissue fluids of the skin. However, topical drugs do not complete the final step of absorption and do not go into the blood. Their therapeutic effect is only exerted locally at the site of administration.
13 58 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS Absorption after transdermal administration. Following application of a transdermal patch, the drug in the patch reservoir begins to be released. Because the drug is in a liquid form, it does not need to undergo disintegration; it quickly dissolves in the tissue fluids of the skin, passes through the walls of nearby capillaries, and is absorbed into the blood. Absorption after oral administration. Following oral administration of a drug, the drug form disintegrates, if necessary. It then dissolves in stomach or intestinal fluids, passes through the mucous membrane lining of the stomach or intestine into nearby capillaries, and then is absorbed into the blood. The presence or absence of food (particularly a large or fatty meal) can influence the rate of drug absorption. The presence of food in the GI tract can reduce absorption of a drug from 30 percent to as much as 80 percent. Some drugs are not absorbed at all following oral administration (e.g., neomycin, an antibiotic drug). This drawback can be overcome by administering the drug via a different route. However, nonabsorption of a drug via the oral route can also be turned into a therapeutic advantage. For example, neomycin can be given orally to exert its antibiotic effect solely in the intestinal tract to kill intestinal bacteria prior to abdominal surgery. Carafate, an antiulcer drug, is not absorbed following oral administration, but that is acceptable because its therapeutic effect is to bind directly to a stomach ulcer and form a protective coating so that the ulcer can heal. Another drug, Metamucil, also is not absorbed, but passes through the intestine, where it binds with water to increase stool bulk and exert its therapeutic effect to relieve constipation. Absorption after inhalation administration. Following administration of a drug by inhalation, the vaporized liquid or gas does not need to undergo disintegration. The drug immediately dissolves in the tissue fluids of the mucous membranes lining the lungs, passes through the walls of nearby capillaries, and is absorbed into the blood. Some drugs given by inhalation exert a topical effect (e.g., Maxair, an inhaled bronchodilator drug for asthma), while other drugs produce a systemic effect throughout the whole body (e.g., general anesthetic gas administered prior to surgery). Absorption after vaginal or rectal administration. Following vaginal administration, the drug form disintegrates and releases the drug topically into the vagina. Drugs administered vaginally are always intended to have only a topical therapeutic effect, and there is minimal absorption into the blood. The rate of absorption following rectal administration is rather slow and variable; therefore, the rectal route is not often used for drugs that act systemically. The rectal route is usually reserved for drugs that act topically within the rectum (e.g., Anusol to treat hemorrhoids). However, in a situation in which the patient is vomiting and the drug (e.g., Tylenol for fever) cannot be given orally and is not manufactured for I.M. or I.V. administration, it can be given rectally as a suppository. Absorption after parenteral administration. Following intradermal, subcutaneous, and intramuscular injections, the drug is already in a liquid form and so it quickly dissolves in the tissue fluids of the skin, passes through the walls of nearby capillaries, and is absorbed into the blood. Only intravenous injections entirely bypass the step of absorption because the drug is administered directly into a vein and immediately enters the blood. Distribution Once a drug has been absorbed into the blood, it is distributed throughout the body via the circulatory system (see FIGURE 4 13).
14 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 59 Drugs Drugs Stomach Absorption Distribution Kidney Bloodstream Small intestine Excretion Absorption Urine Large intestine Liver Metabolism Feces Excretion FIGURE 4 13 Steps in the drug cycle. Drugs pass through the four steps in the drug cycle: absorption, distribution, metabolism, and excretion. As a drug enters the blood, some of the drug binds to circulating plasma proteins, such as albumin. These large molecules have indentations in their molecular surfaces that permit drug molecules to bind to them. Drug molecules that are bound to plasma proteins are essentially pharmacologically inactive as they are carried through the blood. The other portion of the drug that did not bind to plasma proteins moves through the circulatory system, passing through the walls of capillaries, and into body tissues. As this portion of the drug leaves the blood, some of the bound drug is released by the plasma proteins so as to maintain an equilibrium of unbound drug in the blood. When a drug moves into body tissues, it comes in contact with a cell membrane and exerts an effect by interacting with one or more receptors. This process will be discussed in the next chapter.
15 60 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS There is one area of the body where some drugs are not readily distributed. The brain is protected by the blood brain barrier that exists between the capillary walls of blood vessels in the brain and the surrounding brain tissues. Some drugs are able to pass through the blood brain barrier and exert a therapeutic effect (e.g., Ritalin for attention deficit hyperactivity disorder; a general anesthetic drug given prior to surgery to produce unconsciousness). Other drugs are able to pass through the blood brain barrier and cause side effects such as drowsiness (e.g., antihistamine drugs) or euphoria (e.g., drugs for pain or addictive drugs). However, some classes of drugs are, for the most part, unable to cross the blood brain barrier. Unfortunately, sometimes the blood brain barrier actually blocks drugs that are needed to treat diseases of the brain. Some chemotherapy drugs for brain cancer cannot penetrate the blood brain barrier. Instead, a wafer form of the drug must be implanted directly in the brain (e.g., Gliadel wafer for brain tumors). Another example is Parkinson s disease, which is due to a deficiency of the neurotransmitter dopamine in the brain. Dopamine as a drug cannot cross the blood brain barrier. Fortunately, levodopa, which has a slightly different molecular structure, can cross the blood brain barrier; once in the brain, it is converted to dopamine to correct the deficiency and treat Parkinson s disease. Researchers have found a way to use genetic engineering to link a drug that cannot penetrate the blood brain barrier to an antibody that can, and so the drug-antibody combination easily passes through to the brain. At one time, it was thought that the placenta formed a barrier to protect the developing fetus from harmful substances. It is now known that the placenta allows nearly all drugs to pass from the maternal circulation to the fetus. Each year, many infants are born addicted to drugs that their mothers took, or they are born with birth defects due to the effect of drugs taken by their mothers. Therefore, pregnant women are advised not to take any drugs, even over-the-counter drugs, except those prescribed by a healthcare provider who knows that the woman is pregnant. Metabolism The process of metabolism is also known as biotransformation because the drug is gradually transformed or metabolized from its original active form to a less active, or even inactive, form. This process is accomplished in the liver, the principal organ of metabolism, by the action of liver enzymes. Drugs given orally are absorbed through the mucous membranes of the stomach or intestines and enter the blood of the portal vein. Before this vein empties into the inferior vena cava, it passes through the liver. Therefore, all drugs given by the oral route are absorbed into the blood of the portal vein and are immediately subjected to metabolism by liver enzymes. This initial metabolism by the liver is referred to as the first-pass effect, because the drug must first pass through the liver before it can enter the general circulation to exert a systemic effect. For some drugs, the first-pass effect is so extensive that most of the drug dose is immediately metabolized, and the drug must be given by a different route of administration in order to be therapeutic. Lidocaine (Xylocaine) cannot be given orally because no active drug remains after the firstpass effect. Therefore, lidocaine is given intravenously to treat cardiac arrhythmias or via the topical or transdermal routes to produce local anesthesia. If nitroglycerin is administered orally, 90 percent of the dose is metabolized by the liver in the first-pass effect. Therefore, the standard dose of nitroglycerin is set to take this into account and to make certain that sufficient amounts of the drug remain in the blood to be therapeutic in treating the symptoms of angina. Some drugs are actually administered in an inactive form and remain inactive until they are metabolized by the liver. So it is the metabolite form of the drug that is active and actually exerts a therapeutic effect. This type of drug is classified as a prodrug. The prefix pro- means before. A prodrug is a form of the drug that comes before the active drug is produced. Some classes of drugs such as ACE inhibitor drugs used to treat hypertension are examples of prodrugs (e.g., Mavik, Vasotec).
16 CHAPTER 4 ROUTES OF ADMINISTRATION AND THE DRUG CYCLE 61 Clinical Applications Because the liver is the principal organ for drug metabolism, a decreased rate of drug metabolism occurs in patients with chronic liver disease, such as hepatitis, or in elderly patients with decreased liver function due to degenerative changes associated with aging. In these patients, drug doses need to be reduced to compensate for the prolonged action of unmetabolized drug in the blood and to prevent toxicity from high levels of drug. Premature infants have very immature livers that are unable to metabolize drugs efficiently. The doses of their drugs must be carefully calculated to avoid toxicity. Chronotherapy is a method of drug therapy that attempts to coordinate the administration and metabolism of a drug to the body s own biological rhythms. Certain diseases, such as hypertension or asthma, tend to be worse at certain times of the day. If an antihypertensive drug is taken at bedtime, it is metabolized and reaches its highest therapeutic level in the early morning, just when the blood pressure rises dramatically and there is an increased incidence of heart attacks and strokes. Excretion The excretion of drugs is a necessary step in ridding the body of waste products (inactive drug metabolites) and removing active drugs that are not metabolized by the liver. The principal organ of drug excretion is the kidney, although other organs are involved to a limited degree. The lungs excrete certain inhaled drugs each time the patient exhales. Also, trace amounts of drugs are excreted in saliva, tears, sweat, and breast milk. A drug is not automatically excreted by the kidney just because it reaches the renal artery that leads to the kidney. A drug that remains bound to albumin does not pass through the glomerular membrane in the nephron of the kidney. Drug bound to albumin remains in the general circulation. However, unbound drug, which exists by itself as a small molecule, does pass through the glomerular membrane. Once through the glomerular membrane, a further distinction is made between watersoluble drugs and fat-soluble drugs. An unbound molecule of a water-soluble drug is excreted in the urine because of its affinity for the water content of urine. An unbound molecule of a fat-soluble drug is more attracted to the lipid (fat) structure of the renal tubule wall than to the urine. Its molecule passes through the wall of the renal tubule, into a nearby capillary, and returns to the blood. Eventually, molecules of the fat-soluble drug are metabolized by the liver into a more water-soluble form that can be excreted in the urine. Without the action of the liver, it would be difficult for any fat-soluble drug to be excreted by the kidneys. Indeed, it has been estimated that some fat-soluble barbiturate drugs could remain in the blood for years if the liver did not metabolize them to a water-soluble form. Poor renal function can significantly prolong the effects of some drugs. Patients with renal disease and elderly patients with decreased levels of kidney function due to aging are prescribed lower doses of drugs to prevent toxic symptoms due to decreased rates of drug excretion. Chapter Review Quiz Yourself 1. List two disadvantages encountered when administering some drugs by the oral route. 2. The sublingual route of administration provides more rapid absorption of a drug than the oral route. True or false?
17 62 UNIT ONE THE PAST HISTORY, PRESENT USES, AND FUTURE OF DRUGS 3. What is the meaning of the abbreviation A.S.? O.U.? 4. A diabetic patient would inject insulin via what route of administration? 5. Name three acceptable sites for an intramuscular injection in an adult. 6. Differentiate between the I.V. push, I.V. drip, and I.V. piggyback methods of administration. 7. A drug administered via the intravesical route would be administered into what organ? 8. Describe the steps of absorption, distribution, metabolism, and excretion of a drug that is administered orally. 9. What is meant by the phrase first-pass effect? 10. How do plasma proteins such as albumin regulate the amount of drug circulating in the blood? 11. What is the function of the blood brain barrier? 12. Give two reasons why standard drug doses may need to be decreased for elderly patients. 13. Give two reasons why drugs reaching the kidney may not be immediately excreted in the urine. 14. What is chronotherapy and how is it useful in determining when to administer drugs? 15. Define the words biotransformation, albumin, metabolite, and prodrug. Spelling Tips intravenous not intervenous. Also with intra-arterial, intracardiac, intradermal, intramuscular, and intrathecal. The prefix intra- means within. The prefix inter- means between. parenteral not parental. Clinical Applications 1. What route of administration is shown here? 90º Epidermis Dermis Subcutaneous tissue Muscle
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