Drug Action and Drug Interactions

"Just give me the magic pill to make me normal again." You probably said something like that the last time you felt under the weather and your home remedies didn't make you feel better. You might have even reached the point when you'd welcome an injection of a miracle drug if it would get you back on your feet quickly.

Drugs aren't miracles and have nothing to do with magic although you might think differently when your nose is running, eyes watering, and you feel rotten all over. A drug is a chemical compound specifically designed to combat disease.

In this chapter, you'll be introduced to the scientific principles that describe how drugs interact with cells in your body to bring about a pharmaceutical response that either directly attacks the pathogen that is causing your sniffles or stimulates your body's own defense mechanism to stamp them out.

Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of use.

Drug Actions

Drug action is the physiochemical interaction between the drug molecule and molecules in the body that alters a physiological process of the body in one of three ways.

• Replacement: The drug replaces an existing physiological process such as estrogen replacement.

• Interruption: The drug interferes with a physiological process. This occurs when an antihypertensive (high blood pressure) drug interferes with the process that constricts blood vessels and may cause blood pressure to rise. The blood vessels remain dilated and pressures remain normal or drop.

• Potentiation: The drug stimulates a physiological process as in the case of furo-semide (Lasix) which is a diuretic and stimulates the kidneys to excrete urine.

A drug action begins when the drug enters the body and is absorbed into the bloodstream where the drug is transported to receptor sites throughout the body (see Pharmacokinetics, in this chapter). Once the drug hooks onto a receptor site, the drug's pharmacological response initiates. The pharmacological response is the therapeutic effect that makes the patient well.

Drugs have multiple actions. These are the desired effect and effects other than the desirable effect. The desirable effect is what makes the patient well or prevents the disease or disorder. An effect other than the desirable effect is known as a side effect. Some side effects are desirable and others are undesirable (see Side Effects, in this chapter).

The strength of a drug action is determined by how much of the drug is given, (the dose) and how often the drug is given (the frequency). For example, a patient who has a sore throat can be given a large dose of an antibiotic—a loading dose— on the first day of treatment and a normal or maintenance dose for the next five days.

Drug activity is divided into three phases. These are:

• Pharmaceutic Phase: This phase occurs after the drug is given and involves disintegration and dissolution of the dosage form.

• Pharmacokinetic Phase: This is the way the drug is absorbed, distributed, and eliminated.

• Pharmacodynamic Phase: This is the effect the drug has on the body.

PHARMACEUTIC

The pharmaceutic phase is the form of the drug such as a tablet, capsule, liquid, elixirs, or syrups. The drug in solid form must disintegrate before dissolution, which is the process by which a drug goes into solution before it becomes avail able for absorption. Drugs contain an active ingredient and inactive ingredients. The active ingredient is the substance that causes the pharmaceutical response. The inactive ingredient, called excipient, is the substance that has no pharmaceutical response but helps in the delivery of the drug. These are fillers and inert substances that give the drug its shape and size. The coating around tiny particles of a capsule that causes a timed-release action of the drug is an inactive ingredient.

Nearly 80% of all drugs are administered orally (P.O.) and are carried to the small intestine by the gastrointestinal tract where the drug is absorbed into the bloodstream. The time necessary for the drug to disintegrate and dissolve so it can be absorbed is called the rate limiting time.

A drug has a higher rate limiting time (Table 2-1) if it is absorbed in acidic fluids rather than alkaline fluids. Children and the elderly have a lower pH in their GI tract and therefore drugs are absorbed more slowly than in a healthy adult.

Some drugs are more effective if absorbed in the small intestine rather than the stomach. However, the stomach is more acidic than the small intestine. Therefore, pharmaceutical manufacturers place an enteric coating around the drug that resists disintegration in the stomach. The coating disintegrates in the alkaline environment of the small intestine. Enteric coating is also used to delay the onset of the pharmaceutical response and to prevent food in the stomach from interfering with the dissolution and absorption of the drug.

Tip: Never crush a capsule that contains enteric release beads or is coated for timed-release.

The form of a drug influences the drug's pharmacokinetics and pharmacodynamics.

Table 2-1. Rate limiting time rating for drug forms.

Preparation

Absorption Rate (fastest to slowest)

Lipid soluble non-ionized liquids, elixirs, syrups

1

Water soluble ionized liquids, elixirs, syrups

2

Suspension solutions

3

Powders

4

Capsules

5

Tablets

6

Coated tablets

7

Enteric-coated tablets

Pharmacokinetics is the study of the drug concentration during absorption, distribution, and elimination of a drug in the patient. About 80% of all drugs are administered orally and flow through the gastrointestinal tract (GI) into the small intestine where the membrane of the intestine absorbs drug particles passing them into the bloodstream, where plasma circulates the particles, throughout the body. Drug molecules move to the intended site of action in the plasma but sometimes this journey can be limited because they have to get into the interior of a cell or body compartment through cell membranes. These membranes could be in the skin, the intestinal tract, or the intended site of action. Drug particles then attach themselves to receptor sites resulting in its therapeutic effect.

There are three ways in which drug particles are absorbed. These are:

Passive Diffusion

Passive diffusion is the flow of drug particles from a high concentration to a low concentration—similar to how water flows downstream. There is a higher concentration of water upstream than there is downstream. There is no energy expended in passive diffusion because drug particles are moving along the natural flow.

Active Diffusion

Active diffusion is how drug particles swim upstream against the natural flow when there is a higher concentration of plasma than there is of drug particles. Drug particles don't have enough energy to go against the natural flow without help. Help comes from an enzyme or protein carrier that transports drug particles upstream across the membrane and into the plasma. The enzyme or protein carrier expends energy to move drug particles.

Pinocytosis

Pinocytosis is the process of engulfing the drug particle and pulling it across the membrane. This is similar to how you eat an ice pop by engulfing a piece of it in with your mouth and swallowing it.

ABSORPTION RATE

Absorption begins where the drug is administered. This can be by mouth, injection, through the skin, and many other sites. How quickly the drug becomes ther apeutic will depend on how fast the drug is absorbed. How long the drug will be effective and how much drug is needed depends on the route of administration, the dose of the drug, and the dosage form (tablet, capsule, or liquid).

The absorption rate of a drug is influenced by a number of factors that might increase or decrease the rate, This is similar to how more gasoline is used to drive at faster speeds. Absorption is affected by many factors that include pain, stress, hunger, fasting, food, and pH. Hot, solid, fatty foods can slow absorption such as eating a Big Mac before taking medication. Even exercise—which is usually good for the body—affects absorption of a drug. During exercise, circulation to the stomach is diverted to other areas of the body and drug absorption is decreased.

Circulation

Blood flow to the site of administration of the drug will help increase the rate of absorption. An area that has a lot of blood vessels and good circulation will help absorb the drug quickly and circulate it to the intended site. When a patient is in shock and has a low blood pressure due to decreased circulation (blood flow) drugs may not be absorbed very quickly.

Route of Administration

The rate at which drug particles are absorbed is determined by the amount of blood vessels there are in the area where the drug is administered. Drug particles are nearly instantaneously absorbed if the drug is injected intravenously (IV). A slower absorption rate occurs if the drug is administered intramuscularly (IM). The IM rate is dependent on the amount of blood vessels there are at the site of the injection. For example, a drug is absorbed faster in the deltoid (arm) muscle than in the gluteal (butt) muscle because there are more blood vessels in the deltoid muscle. Drugs injected in subcutaneous (SC) tissue are absorbed slower than those injected via IM injections because there are fewer blood vessels in subcutaneous tissues than in muscles.

Solubility

Drug particles dissolve in either lipid (fat) or water. Lipid-soluble drugs are absorbed more quickly than water-soluble drugs because membranes in the GI tract are composed of lipids making those membranes a perfect highway for lipid soluble drugs to move from the GI tract and into the bloodstream. However, membranes of the GI tract do not directly absorb large water-soluble molecules and a carrier must be used to transport the water-soluble drugs across the GI membrane and into the bloodstream. This additional step causes water-soluble drugs to be absorbed more slowly than fat-soluble drugs.

pH Level

The pH level of a drug determines how easily drug particles will be absorbed in the GI tract. Those drugs that are a weak acid—such as aspirin— can pass rapidly across the GI tract membrane while weak base drugs—such as an antacid— are absorbed more slowly than a weak acidic drug. Strong acids and bases destroy cells and are not absorbed.

The concentration of the drug will also affect the rate of absorption. If a high concentration of the drug is given, it will tend to be absorbed more rapidly. Sometimes larger (loading or priming) doses of a drug may be given that will be more than the body can excrete. When this is done, the drug becomes therapeutic much faster. After the first large dose, small maintenance doses will help keep the therapeutic effect.

The form (solid, liquid) the drug is given can affect the absorption rate. Drugs can be processed when they are manufactured to add other ingredients that will help or hinder absorption.

BIOAVAILABILITY

Not all drug particles reach the circulatory system. Some particles are misdirected or destroyed during the absorption process. For example, hydrochloric acid in the stomach destroys some drug particles before it can pass through the membrane and into the bloodstream.

The percentage of a dose that reaches the blood stream is called the bioavailability of a drug. Typically, between 20% and 40% of drugs that are administered orally reach the blood stream. This is called the first pass effect and is the beginning of the metabolism of a drug that is given orally. After a drug is absorbed in the GI tract it is carried to the liver and metabolism occurs. Sometimes very little of the drug remains available for a therapeutic effect after the first pass. Only drugs administered intravenously have a 100% bioavailability because they are directly injected into the vein.

Pharmaceutical manufacturers must consider bioavailability when determining the dose for a drug. For example, the dose for a drug administered PO (orally) might be 4 times higher than if the same drug is administered intravenously.

There are a number of factors that alter bioavailability. These are:

• Form: tablet, capsule, slow-release, liquid, transdermal patch, suppository, and inhalation.

• Route: PO (mouth), topical, parenteral, and rectal.

• GI: The ability of the mucosa (lining) in the GI tract impacts the ability to absorb drug particles and the ability to move food through the digestive tract.

• Food: Drug particles for some drugs are better absorbed if they are taken with certain foods, while other foods slow down or block absorption.

• Drugs: Some drugs increase or decrease another drug's absorption when both drugs are taken together.

• Liver metabolism: Liver dysfunction can prevent or delay the metabolism of a drug.

• Concentration: A higher portion of active ingredient in a dose increases the amount of drug particles that are absorbed.

• Cell membrane: Single layer cell membrane, such as those found in the intestine, increase absorption, while some drugs are absorbed more slowly in multiple-layers, such as skin.

• Surface area: A larger surface area, such as in the small intestine, absorbs drugs faster than a smaller area such as in the stomach.

DRUG CONCENTRATION

A drug contains an active ingredient, which produces the therapeutic effect, and other materials that give the drug form and protection. The percent of active ingredient in a dose is referred to as the drug concentration.

There are generally two levels of concentrations. These are primary loading— a large concentration that is used to achieve a fast therapeutic effect such as the first dose of an antibiotic, and maintenance dose—a typical concentration of the drug that is used to provide an ongoing therapeutic effect such as subsequent doses of an antibiotic.

DISTRIBUTION

Once absorbed, drug particles are transported in blood plasma. These are referred to as "free" drugs because they are not bound to any receptor sites. Only free drugs can cause a pharmacological response. Drugs bind to proteins in plasma, usually albumin or globulins. These drug-protein complexes decrease the concentration of free drug in the circulation. This protein-drug molecule is too large to pass through the membrane of a blood vessel and is not available for therapeutic use. This process can be reversed when free drug is excreted from the body. The drug molecule is released from the protein and it becomes free drug and can be absorbed for use. Drugs affect areas of the body with good blood supply first, such as the heart, liver, kidney, and brain and then flow to areas with less blood supply, such as muscles and fat.

Drugs accumulate in an area of the body and form a reservoir by binding to tissues. This is referred to as pooling. There are two types of pooling. These are protein binding—when a drug binds to plasma proteins, and tissue binding—fat soluble drugs are stored in adipose (fat) tissue. Inderal (propranolol) is a heart medication that is highly bound to and only about 7% of free drug is available for use at a time. Thiopental (pentothal) is an anesthetic agent that is stored in fat tissue. In addition, some drugs, such as the antibiotic Tetracycline like to be stored in bones which can interfere with growth of fetal skeletal tissues and can discolor teeth if given to children under eight years of age.

Distribution of drugs is affected by three factors.

Level of Plasma Protein

A low level of plasma protein and albumin might not provide enough binding sites for drug particles. This results in a buildup of drugs which can reach a toxic level. This happens when there is liver or kidney disease or if the patient is malnourished resulting in low albumin levels (hypoalbuminemia). The elderly are prone to hypoalbuminemia. Healthcare professionals should monitor a patient's plasma protein and albumin levels and the protein-binding percentage of all drugs before administering drugs to the patient.

Bloodflow

There must be adequate bloodflow to target areas of the body; otherwise, insufficient drug particles will reach affected parts of the body. Drugs can also be stored in fat, bones, muscle, and the eyes. Drugs that accumulate in fat are called lipid soluble and remain for about three hours because there is low blood flow in fat tissue.

The body also has a blood-brain barrier that enables only lipid soluble drugs—such as general anesthetics and barbiturates—into the brain and cerebral spinal fluid (CSF). The only way for nonlipid soluble drugs to enter the brain is if they are instilled intrathecally, that is, injected directly into the CSF, bypassing the blood-brain barrier.

Competing Drugs

Two drugs administered simultaneously might compete for the same binding sites making some drug particles unable to find a binding site. The result is an accumulation of free drug that could reach toxic levels. Two drugs that are highly protein bound—such as Coumadin (warfarin) and Inderal (propranolol)—will compete for the protein sites. This can cause serious problems and can result in toxic levels of one or both of the drugs when increased amounts of free drug become available.

Abscesses, exudates, body glands, and tumors hinder the distribution of drugs in the body. In addition, antibodies do not distribute well at abscess and exudates sites. The placenta metabolizes some drugs making then inactive and thereby protecting the fetus from drugs given to the mother. However, steroids, narcotics, anesthetics, and some antibiotics can penetrate the placental barrier and cause adverse effects to the fetus.

ELIMINATION

Drugs accumulate in a reservoir and are gradually absorbed and eventually eliminated by the body. This metabolism—called biotransformation—occurs in the liver where enzymes inactivate a drug by changing it into more water-soluble compounds that can be excreted from the body. Elimination occurs mainly through the kidneys, although some drugs are also eliminated in bile, feces, lungs, sweat, and breast milk.

Patients suffering from liver diseases are prone to drug toxicity because the diseased liver no longer metabolizes the drug sufficiently to allow elimination through the kidneys. The result is a buildup of the drug, which can eventually lead to a toxic effect on the body.

The amount of time for half of the drug concentration to be eliminated from the body is called the drug's half-life and is a crucial measurement used to determine how often to administer a drug. Some drugs have a short half-life (less than 8 hours) while other drugs have a longer half-life (24 hours).

For example, Digoxin has a half-life of 36 hours. This means it takes 5 to 7 days before there is a steady state of Digoxin in the serum. This is referred to as the steady state serum concentration and is the time it takes for the drug to have a therapeutic effect.

Children and the elderly might be unable to absorb and/or eliminate drugs. This can result in toxicity should additional doses be given before the previous does is eliminated from the body. Free drugs, water-soluble drugs, and unchanged drugs are filtered by the kidneys and eliminated through urine. Protein-bound drugs do not filter through the kidneys until the drug is released from the protein.

The quantity of drugs that can be excreted by the kidneys is influenced by the pH of the urine, which normally is between 4.5 and 8.0. Acidic urine (4.5) elimi nates weak base drugs; alkaline urine (8.0) eliminates weak acid drugs. The pH of urine can be altered to increase the elimination of certain drugs. For example, urine can be made more alkaline by giving the patient sodium bicarbonate or made more acidic by giving the patient high doses of vitamin C or ammonium chloride.

Kidney disease decreases the glomerular filtration rate (GFR) and thereby reduces the quantity of drugs that can be eliminated by the kidneys. This can result in drug toxicity. A similar effect can be caused by a decrease in bloodflow to the kidneys.

Kidney function is tested by the creatinine clearance test. A decrease in GFR causes an increase in creatinine in serum and a decrease in creatinine in urine. The results of the creatinine clearance test vary with age and whenever there is decreased muscle mass.

In some situations, it is important to reduce the excretion of a drug to prolong the drug's therapeutic effect, such as with penicillin. Giving the patient another drug, such as Probenecid, blocks excretion of penicillin.

Drugs can be excreted artificially through the use of dialysis, which is a common treatment in certain drug overdoses. Drugs that are excreted by the kidneys can be eliminated using hemodialysis. These drugs include stimulants, depressants, and some non-narcotic analgesics.

Drugs that are metabolized by the liver are secreted into bile and then passed through the intestines and eliminated in feces. During this process, the bloodstream might reabsorb fat-soluble drugs and return them to the liver where they are metabolized and eliminated by the kidneys. This is called the enterohepatic cycle.

The lungs eliminate drugs that are intact and not metabolites such as gases and anesthetic drugs. The rate at which these drugs are eliminated corresponds to the respiratory rate. Some drugs, such as ethyl alcohol and paraldehyde, are excreted at multiple sites. A small amount is excreted by the lungs and the rest by the liver and the kidneys. Volatile drugs such as anesthetics and drugs that are metabolized to CO2 and H20, are excreted through the lungs.

Sweat and salivary glands are not a major route of drug elimination because elimination depends on the diffusion of lipid-soluble drugs through the epithelial cells of the glands. However, side effects of drugs, such as rashes and skin reactions, can be seen at these sites. Some intravenously administered drugs are excreted into saliva and cause the patient to taste the drug. Eventually, drugs that are excreted into saliva are swallowed, reabsorbed, and eliminated in urine.

Many drugs or their metabolites are excreted in mammary glands. These include narcotics such as morphine and codeine. Diuretics and barbiturates, which are weak acids, are less concentrated in breast milk. However, even small amounts of drugs can accumulate causing an undesirable effect on an infant receiving breast milk.

The First Pass Effect

The most common way drugs are administered is orally, by swallowing a pill. The drug is then absorbed into the GI tract and enters the portal circulation system where drug particles are transported through the portal vein into the liver where the drug is metabolized. This is referred to as the first pass effect.

Not all drugs are metabolized in the liver. Some drugs bypass the first pass effect by sublingual administration (under the tongue) or buccal administration (between the gums and the cheek) where they are absorbed directly into the bloodstream from the mouth. These drugs do not enter the stomach where the hydrochloric acid might destroy drug particles. Other drugs go directly to the liver through the portal vein and also bypass the stomach. The drug is then metabolized in the liver and much of the drug may be eliminated and not available for a therapeutic effect. Sometimes this effect is so great that none of the drug is available for use if given by mouth. The drug must then be given in very high doses or parenterally (intramuscularly or intravenously) to bypass the liver.

Pharmacodynamics

Pharmacodynamics is a drug's effect on the physiology of the cell and the mechanism that causes the pharmaceutical response. There are two types of effects that a drug delivers. These are the primary effect and the secondary effect. The primary effect is the reason for which the drug is administered. The secondary effect is a side effect that may or may not be desirable.

For example, diphenhydramine (Benadryl) is an antihistamine. Its primary effect is to treat symptoms of allergies. Its secondary effect is to depress the central nervous system causing drowsiness. The secondary effect is desirable if the patient needs bedrest, but undesirable if the patient is driving a car.

A period of time passes after a drug is administered until the pharmaceutical response is realized. This is referred to as the drug's time response. There are three types of time responses: onset, peak, and duration.

The onset time response is the time for the minimum concentration of drug to cause the initial pharmaceutical response. Some drugs reach the onset time in minutes while other drugs take days. The peak time response is when the drug reaches its highest blood or plasma concentration. Duration is the length of time that the drug maintains the pharmaceutical response.

The response time is plotted on a time-response curve that shows the onset time response, the peak time response, and the duration. All three parameters are used when administering the drug in order to determine the therapeutic range— when the drug will become effective, when it will be most effective, and when the drug is no longer effective. It is also used to determine when a drug is expected to reach a toxic level.

For example, the time-response curve of an analgesic is used for pain management. Once the peak response time is reached, the effectiveness of the drug to block pain diminishes. The time-response curve indicates when the pharmaceutical response is no longer present requiring that an additional dose be administered to the patient.

RECEPTOR THEORY

The pharmaceutical response is realized when a drug binds to a receptor on the cell membrane. These are referred to as reactive cellular sites. The activity of the drug is determined by the drug's ability to bind to a specific receptor. The better the fit, the more biologically active the drug. Receptors are proteins, glycoproteins, proteolipids, or enzymes. Depending on the drug, binding either initiates a physiological response by the cell or blocks a cell's physiological response.

Receptors are classified into four families.

1. Rapid-Cell Membrane-Embedded Enzymes: A drug binds to the surface of the cell causing an enzyme inside the cell to initiate a physiological response.

2. Rapid-Ligand-Gated Ion Channels: The drug spans the cell membrane causing ion channels within the membrane to open resulting in the flow of primarily sodium and calcium ions into and out of the cell.

3. Rapid-G Protein-Couple Receptor Systems: The drug binds with the receptor causing the G protein to bind with guanosine triphosphate (GTP). This in turn causes an enzyme inside the cell to initiate a physiological response or causes the opening of the ion channel.

4. Prolonged-Transcription Factors: The drug binds to the transcription factors on the DNA within the nucleus of the cell and causes the transcript factor to undergo a physiological change.

A drug that causes a physiological response is called an agonist and a drug that blocks a physiological response is referred to as an antagonist. The effect of an antagonist is determined by the inhibitory (I) action of the drug concentration on the receptor site. An inhibitory action of 50 (I50) indicates that the drug effectively inhibits the receptor response in 50% of the population.

Agonists and antagonists lack specific and selective effects. They are called nonspecific and have nonspecificity properties. Each receptor can produce a variety of physiologic responses. Cholinergic receptors are located in the bladder, heart, blood vessels, lungs, and eyes. A cholinergic stimulator or blocker will affect all of these sites. These drugs are called nonspecific or are said to have nonspecificity properties. A drug that is given to stimulate the cholinergic receptors will decrease the heart rate and blood pressure, increase gastric acid secretion, constrict bronchioles, increase urinary bladder contraction, and constrict the pupils. The effects may be beneficial or harmful.

Categories of Drug Action

Drugs are categorized by the type of action it causes on the body. There are four types of responses:

• Stimulation or Depression. These are drugs that either increase or depress cellular activity.

• Replacement. These are drugs that replace an essential body compound such as insulin or estrogen.

• Inhibition. These drugs interfere with bacterial cell and limit bacterial growth or eliminate the bacteria, such as penicillin.

• Irritation. These drugs irritate cells to cause a natural response that has a therapeutic effect such as a laxative that irritates the colon wall to increase movement of the colon resulting in defecation.

Therapeutic Index and Therapeutic Range

Drugs have a pharmaceutical response as long as the dose remains within the drug's margin of safety. Some drugs have a broad margin of safety. This means that a patient can be given a wide range of dose levels without experiencing a toxic effect. Other drugs have a narrow margin of safety where a slightest change in the dose can result in an undesirable adverse side effect.

The drug's Therapeutic Index (TI) identifies the margin of safety of the drug and is a ratio between the therapeutic dose in 50% of persons/animals and the lethal dose in 50% of animals. The therapeutic dose is notated as ED50 and the lethal dose in animals is noted as LD50. The closer that the ratio is to 1, the greater the danger of toxicity.

TI = LD50/ED50

Drugs that have a low TI are said to have a narrow margin of safety. These drugs require that levels in the plasma be monitored and adjustments are made to the dosage in order to prevent a toxic effect from occurring.

The plasma drug levels must be within the therapeutic range, which is also known as the therapeutic window. The therapeutic range is between the minimum effective concentration (MEC) for obtaining the desired pharmaceutical response and the minimum toxic concentration (MTC). MEC is achieved by administering a loading dose, which is a large initial dose given to achieve a rapid plasma MEC.

PEAK AND TROUGH LEVELS

The plasma concentration of a drug must be monitored for drugs that have a narrow margin of safety or low therapeutic index. The concentration is measured at two points. These are the peak drug level and the trough level.

The peak drug level is the highest plasma concentration at a specific time. Peak levels indicate the rate a drug is absorbed in the body and is affected by the route used to administer the drug. Drugs administered intravenously have a fast peak drug level while a drug taken orally has a slow peak drug level because the drugs needs time to be absorbed and distributed. Blood samples are drawn at peak times based on the route used to administer the drug. This is usually M to 1 hr after drug administration.

The trough level is the lowest plasma concentration of the drug and measures the rate at which the drug is eliminated. Blood should be drawn immediately before the next dose is given regardless of the route used to administer the drug.

Side Effects

A drug can have a side effect in addition to its pharmaceutical response. A side effect is a physiologic effect other than the desired effect. Sometimes side effects are predictable and other times they are not and may be unrelated to the dosage. Some side effects are desirable and others are undesirable.

A severe undesirable side effect is referred to as an adverse reaction that occurs unintentionally when a normal dose of the drug is given to a patient. For example, an adverse reaction might be anaphylaxis (cardiovascular collapse)

Some adverse reactions are predictable by age and weight of the patient. Young children and the elderly are highly responsive to medications because of an immature or decline in hepatic and renal function. Body mass also influences the distribution and concentration of a drug. The dosage must be adjusted in proportion to body weight or body surface area.

Drug effects can also be related to other factors. These include:

Gender. Women typically are smaller than men and have a different proportion of fat and water which affects absorption and distribution of the drug.

Environment. Cold, heat, sensory deprivation or overload, and oxygen deprivation in high altitude create environmental factors that might interact with a drug.

Time of administration. A drug might be influenced by the presence or absence of food in the patient's gastrointestinal tract or by the patient's corticosteroid secretion rhythm. In addition, circadian cycle, urinary excretion pattern, fluid intake, and drug metabolizing enzyme rhythms all might influence a drug's effect.

Pathologic state. A drug can react differently if the patient is experiencing pain, anxiety, circulatory distress, or hepatic and/or renal dysfunction.

Idiosyncracy. This is an abnormal response that is unpredictable and unex-plainable that could result from the patient overresponding or underresponding to the drug or the drug having an effect that is different from what is expected.

Tolerance. The patient has a decreased physiologic response after repeated administration of the drug. This is common with tobacco, opium alkaloids, nitrites, and ethyl alcohol. The dosage must be increased to achieve the pharmaceutical response.

Drug dependence. This can be either a physical or psychological dependency. With a physical dependency, the patient experiences an intense physical disturbance when the drug is withdrawn. With psychological dependency, the patient develops an emotional reliance on the drug.

Drug interaction. The administration of one drug increases or decreases the pharmaceutical response of a previously administered drug.

Synergism. A more desirable pharmaceutical response is achieved through the interaction of two drugs that are administered.

Potentiation. Concurrent administration of two drugs increases the pharmaceutical response of one of those drugs.

Toxic effect. This occurs when the administered drug exceeds the therapeutic range through an overdose or by the drug accumulating in the patient.

Tachyphylaxis. The patient builds a tolerance to the drug due to the frequency in which the drug is administered. This occurs with narcotics, barbiturates, laxatives, and psychotropic agents. The patient may eventually need more of the drug to reach the desired effect.

Placebo effect. The patient receives a psychological benefit from receiving a compound that has no pharmaceutical response. A third of patients taking a placebo experience the placebo effect.

Pharmacogenetic effect. A drug varies from a predicted response because of the influence of a patient's genetic factors. Genetic factors can alter the metabolism of the drug and results in an enhanced or diminished pharmaceutical response.

Allergic reactions. If the patient was previously sensitized to the drug, a drug might trigger the patient's immunologic mechanism that results in allergic symptoms. Antibodies are produced the first time the drug is introduced to the patient creating a sensitivity to the drug. The next time the drug is given to the patient, the drug reacts with the antibodies and results in the production of histamine. Histamine causes allergic symptoms to occur. The patient should not take any drug that causes the patient to have an allergic reaction.

There are four types of allergic reactions. These are:

• Anaphylactic. This is an immediate allergic reaction that can be fatal.

• Cytotoxic reaction. This is an autoimmune response that results in hemolytic anemia, thrombocytopenia, or lupus erythematosus (blood disorders). In some cases, it takes months for the reaction to dissipate.

• Immune complex reaction. This is referred to as serum sickness and results in angioedema, arthralgia (sore joints), fever, swollen lymph nodes, and splenomegaly (large spleen). The immune complex reaction can appear up to three weeks after the drug is administered.

• Cell mediated. This is an inflammatory skin reaction that is also known as delayed hypersensitivity.

Summary

A drug has a physiochemical action with the physiological process of the body resulting in a pharmaceutical response. Drugs replace a missing element such as a hormone, interrupts a physiological process or stimulates a physiological process to occur. In addition to a therapeutic effect, drugs may have side effects that can be desirable or undesirable.

The strength of a drug action is determined by the dose administered to a patient and how frequently the dose is administered. The first dose is called a loading dose or priming dose and consists of a large concentration of the drug. Subsequent doses are called maintenance doses and consist of a normal concentration of the drug.

Drug activity is divided into the pharmaceutic phase, pharmacokinetic phase; and the pharmacodynamic phase. The pharmaceutic phase is the disintegration and dissolution of a drug taken orally. The pharmacokinetic phase is the mechanism used to absorb, distribute, and eliminate a drug. The pharmacodynamics is a drug's effect on the physiology of the cell and the mechanism that causes the pharmaceutical response.

Drugs bind to receptors on the cell membrane called reactive cellular sites. Receptors are proteins, glycoproteins, proteolipids, or enzymes. Depending on the drug, binding either initiates a physiological response by the cell or blocks a cell's physiological response. A drug that causes a physiological response is called an agonist. A drug that blocks a physiological response is called an antagonist.

The safety of a drug is identified by the drug's therapeutic index. A low therapeutic index means a drug has a narrow margin of safety requiring that that the drug's peak level and trough levels be closely monitored. A high therapeutic index means a drug has a broad margin of safety and does not require frequent monitoring of the patient and the serum drug level.

Now that you have a good understanding of the theory of how drugs work, in the next chapter we'll turn our attention to the practical aspect of pharmacology and see how pharmacology is used in the nursing process.

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