Key Terms

absorption: what happens to a drug from the time it enters the body until it enters the circulating fluid; intravenous administration causes the drug to directly enter the circulating blood, bypassing the many complications of absorption from other routes

active transport: the movement of substances across a cell membrane against the concentration gradient; this process requires the use of energy

chemotherapeutic agents: synthetic chemicals used to interfere with the functioning of foreign cell populations, causing cell death; this term is frequently used to refer to the drug therapy of neoplasms, but it also refers to drug therapy affecting any foreign cell

critical concentration: the concentration a drug must reach in the tissues that respond to the particular drug to cause the desired therapeutic effect

distribution: movement of a drug to body tissues; the places where a drug may be distributed depend on the drug’s solubility, perfusion of the area, cardiac output, and binding of the drug to plasma proteins

enzyme induction: process by which the presence of a chemical that is biotransformed by a particular enzyme system in the liver causes increased activity of that enzyme system

excretion: removal of a drug from the body; primarily occurs in the kidneys, but can also occur through the skin, lungs, bile, or feces

first-pass effect: a phenomenon in which drugs given orally are carried directly to the liver after absorption, where they may be largely inactivated by liver enzymes before they can enter the general circulation; oral drugs frequently are given in higher doses than drugs given by other routes because of this early breakdown

glomerular filtration: the passage of water and water-soluble components from the plasma into the renal tubule

half-life: the time it takes for the amount of drug in the body to decrease to one half of the peak level it previously achieved

hepatic microsomal system: liver enzymes tightly packed together in the hepatic intracellular structure, responsible for the biotransformation of chemicals, including drugs

loading dose: use of a higher dose than what is usually used for treatment to allow the drug to reach the critical concentration sooner

passive diffusion: movement of substances across a semipermeable membrane with the concentration gradient; this process does not require energy

pharmacodynamics: the study of the interactions between the chemical components of living systems and the foreign chemicals, including drugs, that enter living organisms; the way a drug affects a body

pharmacogenomics: the study of genetically determined variations in the response to drugs

pharmacokinetics: the way the body deals with a drug, including absorption, distribution, biotransformation, and excretion

placebo effect: documented effect of the mind on drug therapy; if a person perceives that a drug will be effective, the drug is much more likely to actually be effective

receptor sites: specific areas on cell membranes that react with certain chemicals to cause an effect within the cell

selective toxicity: property of a chemotherapeutic agent that affects only systems found in foreign cells without affecting healthy human cells (e.g., specific antibiotics can affect certain proteins or enzyme systems used by bacteria but not by human cells)

Pharmacodynamics

Study of the interactions between the chemcials components of living systems and the foreign chemicals including that enter theose systems.

Drugs usually work in one of four ways:

1. To replace or act as substitutes for missing chemicals

2. To increase or stimulate certain cellular activities

3. To depress or slow cellular activities

4. To interfere with the functioning of foreign cells, such as invading microorganisms or neoplasms leading to cell death (drugs that act in this way are called chemotherapeutic agents)

Receptor Sites

Drugs act at receptor sites on cell membranes. They react with chemicals, causing an effect. Enzymes may break down the chemicals and open the receptor site again.

• Think of how a key works in a lock. The specific chemical (the key) approaches a cell membrane and finds a perfect fit (the lock) at a receptor site

Agonist interaction w/ receptor site on the cell

Drugs called agonists interact with receptor sites and cause the same activity as natural chemicals. For example, insulin interacts with insulin-receptor sites to change cell membrane permeability, allowing glucose to enter the cell.

Competitive Antagonism:

Curare (used on tips of spears in Amazon) blocks acetylcholine receptor sites, preventing muscle stimulation & causing paralysis. It is a competitive antagonist of acetylcholine.

Non-competitive Antagonism:

Drugs can be noncompetitive antagonists, preventing the reaction of another chemical with a cell receptor site. The exact mechanisms of many drugs are unknown, but it's speculated they act through receptor sites.

Drug–Enzyme Interactions

Drugs can interfere with enzyme systems that catalyze chemical reactions. Enzymes activate in a cascade, and if one is blocked, normal cell function is disrupted.

• Example: Acetazolamide (Diamox) blocks the enzyme carbonic anhydrase, which alters hydrogen ion and water exchange in the kidney and eye.

Selective Toxicity

The ability of a drug to attack only those systems found in foreign cells is known as selective toxicity.

• Example: Penicillin, an antibiotic used to treat bacterial infections, has selective toxicity. It affects an enzyme system unique to bacteria, causing bacterial cell death without disrupting normal human cell functioning.

Other chemotherapeutic agents also damage normal human cells, causing adverse effects. Rapidly-reproducing/replacing cells (e.g. bone marrow, GI, hair follicles) are more easily affected. Thus, chemotherapeutic regimens aim to deliver a dose toxic to invading cells while causing least amount of host toxicity.

Key Points

• Pharmacodynamics is the process by which a drug works or affects the body.

• Drugs may work by replacing a missing body chemical, by stimulating or depressing cellular activity, or by interfering with the functioning of foreign cells.

• Drugs are thought to work by reacting with specific receptor sites or by interfering with enzyme systems in the body.

Pharmacokinetics

Pharmacokinetics studies drug absorption, distribution, metabolism, excretion. In clinical practice, this includes onset of action, half-life, peak effect, duration of effects, metabolism, excretion site.

Critical Concentration

Once a drug is taken, its molecules need to be absorbed by the body and reach the reactive tissues. To work effectively and have a therapeutic effect, the drug must reach its critical concentration in the body.

Drug evaluation studies assess the necessary concentration for a desired therapeutic effect. The recommended dose is based on the amount that must reach the critical concentration. Too much of the drug is toxic and too little won't produce the desired results.

Loading Dose

• Some drugs may take a prolonged period to reach a critical concentration. If their effects are needed quickly, a loading dose is recommended.

• Example:

Digoxin (Lanoxin) and many xanthine bronchodilators (e.g., theophylline) used for asthma require a loading dose to reach critical concentration quickly. The regular dosing schedule then maintains the concentration.

Dynamic Equilibrium

The actual concentration that a drug reaches in the body results from a dynamic equilibrium involving the rate of several processes:

• Absorption from the site of entry

• Distribution to the active site

• Biotransformation (metabolism) in the liver

• Excretion from the body

Administering a drug requires consideration of pharmacokinetics phases for determining dose and scheduling repetition to achieve desired concentration for length of time. Nurse needs to make drug regimen as effective as possible.

Absorption

Drug absorption is the process of a drug entering the body's fluids and tissues, which can happen through the GI tract, mucous membranes, skin, lung, muscle, or subcutaneous tissues.

Routes of Administration

Drug absorption varies by administration route; oral typically slower than parenteral. IM injections tend to be faster than subcutaneous due to more capillaries. Direct injection into the bloodstream skips the absorption step. Oral is most common, non-invasive, and cost-effective, with patients able to easily continue regimens at home.

Oral drugs are subject to a number of barriers in the body, such as the acidic environment of the stomach. Pharmaceutical companies factor in this acidity when preparing drugs in capsule or tablet form. Certain foods may increase acidity, speed breakdown, chemically bind drugs, or block absorption. To reduce these effects, drugs should be given 1 hour before or 2 hours after a meal.

Some drugs that can't be taken orally are given via injection into the body. These drugs enter the bloodstream immediately, leading to an immediate onset with a narrow margin for error, thus making them more likely to cause toxic effects. Drugs injected IM are absorbed slowly into capillaries in the muscle and circulated in the veins. Men have more vascular muscles than women, causing drugs to reach peak levels faster.

Subcutaneous injections deposit the drug just under the skin, where it is absorbed into circulation at varying speeds based on fat content of injection site and local circulation.

Absorption Processes

Passive diffusion is the major process through which drugs are absorbed into the body.

• Passive diffusion occurs across a concentration gradient. When there is a greater concentration of drug on one side of a cell membrane the drug will move through the membrane to the area of lower concentration.

• DOES NOT REQUIRE ANY CELLULAR ENERGY.

Active transport: is a process that USES ENERGY to actively move a molecule across a cell membrane. The molecule may be large, or it may be moving against a concentration gradient. This process is not very important in the absorption of most drugs, but it is often a very important process in drug excretion in the kidney.

Filtration: involves movement through pores in the cell membrane, either down a concentration gradient or as a result of the pull of plasma proteins (when pushed by hydrostatic, blood, or osmotic pressure).

• Filtration is another process the body commonly uses in drug excretion

Distribution

• Distribution involves the movement of a drug to the body’s tissues

Factors affecting drug distribution include its lipid solubility and ionization, as well as tissue perfusion.

• (Diabetes) Poor blood flow to a certain area, such as a patient's lower limb infection, can reduce drug effectiveness.

• Similarly, vasoconstriction in a cold environment can prevent drug circulation to extremities. Many drugs are bound to proteins and cannot pass into the CNS due to the blood-brain barrier.

Protein Binding

Most drugs bind to proteins in the blood, making it difficult for them to be released. This affects how quickly the drug acts and how long it lasts. Some drugs are tightly bound, while others are loosely bound, causing them to act quickly and be excreted quickly. Some drugs compete for protein-binding sites, affecting the effectiveness or causing toxicity when taken together.

Blood–Brain Barrier

The blood–brain barrier is a protective system to keep foreign invaders and poisons away from the CNS. Drugs that are lipid-soluble can pass through the barrier, while those that are not cannot. This is clinically significant for treating infections with antibiotics, as almost all antibiotics are not lipid-soluble, and the infection must be severe enough to alter the barrier to allow them to cross. In some cases, adverse CNS effects can be caused by indirect drug effects, such as alterations in glucose and electrolyte levels.can interfere with nerve functioning and produce CNS effects such as dizziness, confusion, or changes in thinking ability.

Biotransformation (Metabolism)

The body is capable of metabolizing foreign chemicals. Enzymes in the liver, GI tract, and body work to detoxify these chemicals and maintain homeostasis. Most of these reactions involve making chemicals less active and more easily excreted. The liver is the main site of biotransformation, or drug metabolism, which changes drugs into inactive chemicals. The liver can be thought of as a sewage treatment plant, as it detoxifies chemicals and produces needed enzymes and structures.

First-Pass Effect

Drugs taken orally are usually absorbed from the small intestine into the portal venous system, with aspirin and alcohol absorbed from the lower end of the stomach. The liver transforms most of the chemicals into metabolites, some of which are active and cause effects in the body, and some of which are deactivated and excreted. This is known as the first-pass effect. The portion that gets through is then delivered to the circulatory system. Injected drugs and drugs absorbed from sites other than the GI tract undergo a similar biotransformation in the liver, hence a lower dose of parenteral drugs is often more effective than the oral equivalent.

Hepatic Enzyme System

Intracellular hepatic cells contain enzymes of the hepatic microsomal system, which biotransform orally administered drugs. This effect, known as the first-pass effect, neutralizes most drugs.

• Phase I biotransformation is an oxidation, reduction, or hydrolysis of the drug via the cytochrome P450 system, abundant in the liver.

  • Examples of drugs that induce or inhibit the cytochrome P450 system are given in Table 2.2.

• Phase II biotransformation involves a conjugation reaction that makes the drug more polar and easier to excrete.

The presence of a chemical that is metabolized by a particular enzyme system often increases the activity of that enzyme system. This process is referred to as enzyme induction. Increased enzyme activity speeds the metabolism of drugs, resulting in lower therapeutic levels when taken together. Some drugs inhibit enzyme systems, reducing their effectiveness. Drugs can speed metabolism of other drugs, inhibiting enzyme systems and preventing breakdown for excretion. This buildup can lead to toxic levels, so liver function is a contraindication when administering certain drugs. If the liver isn't working properly, toxic levels can develop quickly.

Excretion

Removal of a drug from the body.

• Skin, saliva, lungs, bile, and feces are routes of used to excrete.

• The kidneys, however, play the most important role in drug excretion.

Drugs often excreted from kidney by glomerular filtration. Other drugs are secreted/reabsorbed through renal tubule by active transport systems. Urine acidity can influence drug excretion. Consider kidney function & urine acidity before administering drug; kidney dysfunction can lead to toxic levels of drug in body due to excretion difficulty.

Focus on Safe Medication Administration

The liver and kidneys are key in metabolizing and excreting drugs from the body. Checking a patient's liver and renal function should be done before starting a drug regimen. If either function is impaired, dose adjustment should be considered.

Half-Life

The half-life of a drug is the time it takes for the amount of drug in the body to halve. For example, if a patient takes 20 mg with a 2-hour half-life, 10 mg will remain 2 hours later, 5 mg after 4 hours, and 2.5 mg after 6 hours. This is essential for determining dose timing and drug effects duration.

Drug half-life is determined by absorption rate, tissue distribution, biotransformation speed, & excretion rate. The half-life indicated in drug monographs is for healthy people. It may be prolonged in those with kidney/liver dysfunction, requiring changes in dosing schedules. Nurses can use half-life knowledge to explain drug administration importance.

Factors Influencing Drug Effects

No two people react the same to drugs, so the nurse must consider a number of factors before administering any drug. These are detailed in the following sections and summarized.

Weight

Recommended drug doses are based on studies of 150-lb persons. Heavier people may require larger doses due to more tissue and receptors. Smaller persons may need less drug and can be at risk of toxic effects at the recommended dose.

Age

Children and older adults are more likely to have different responses to drugs due to their age. Children can have different metabolization, and older adults can have lower plasma proteins and reduced kidney efficiency. Many drugs have recommended pediatric and older doses reported to the FDA, and for other drugs, doses can be converted using formulas. Close monitoring of patients at either end of the age spectrum is recommended to be sure the desired effects are reached.

Gender

Men and women can respond differently to drugs. Men have more vascular muscles and effects of drugs are seen sooner, while women have more fat cells and drugs can remain in body for longer. Women should always be asked about possible pregnancy before taking any drug, as using drugs during pregnancy may carry risks to the fetus.

Physiological Factors

Physiological factors such as diurnal rhythm, acid-base balance, hydration, and electrolyte balance can affect drug efficacy. If no desired effect is seen, review patient's acid-base & electrolyte profiles and drug timing.

Pathological Factors

Drugs used to treat disease can change body chemistry, altering the response to the drug. Other pathological conditions can affect drug absorption, distribution, biotransformation, and excretion, leading to toxic reactions with usual doses.

• For Example:

  • GI disorders can affect the absorption of many oral drugs.

  • Vascular diseases and low blood pressure alter the distribution of a drug, preventing it from being delivered to the reactive tissue, thus rendering the drug nontherapeutic.

  • Liver or kidney diseases affect the way that a drug is biotransformed and excreted and can lead to toxic reactions when the usual dose is given.

Genetic Factors

Genetic differences can explain varied responses to drugs. Pharmacogenomics studies how genetic makeup affects reactions to drugs. Mapping the human genome has boosted research in this area, and in the future, medical care and drug regimens could be tailored to each person's genetic makeup. An example is the drug trastuzumab (Herceptin), which only works if the tumor expresses human epidermal growth factor receptor 2—a genetic defect seen in some tumors. In 2007, the FDA approved a blood test to check for genetic markers that can change warfarin (Coumadin) dosing, but it hasn't proven effective in practice.

Immunological Factors

People may form antibodies to a drug after exposure, leading to allergic reactions ranging from mild (e.g., rash) to severe (e.g., anaphylaxis, shock, and death).

Psychological Factor

The patient's attitude & personality can affect drug effectiveness (placebo effect) & compliance with drug regimen. Health-seeking history & feelings about healthcare are important for planning educational programs & follow-up procedures. Nurses can influence patient's attitude & response to medication with positive attitude & comfort measures.

Environmental Factor

Environment can impact drug therapy. Quiet, cool, nonstimulating environments can help sedatives work better. Temperature may also affect drugs: antihypertensives may work better in cold weather and too effectively in warmer weather. If a drug's effect is unexpected, consider environmental changes.

Tolerance Factor

Tolerance may arise due to increased biotransformation/resistance to drug effects, causing the body to need larger doses to achieve a therapeutic effect. An example is morphine, where increasing doses are needed for pain relief. Clinically, this can be avoided by giving smaller doses or in combination with other drugs. Cross-tolerance to drugs within the same class may also occur.

Accumulation

Drug accumulation can lead to toxic levels & adverse effects. Strict compliance with a drug regimen can be difficult, but is key to avoiding this. Review drug regimen with patient to check how it's being taken & educate accordingly.

Drug–Drug or Drug–Alternative Therapy Interactions

Clinically significant drug–drug interactions occur with drugs that have small margins of safety. If there is very little difference between a therapeutic dose and a toxic dose of the drug, interference with the drug’s pharmacokinetics or pharmacodynamics can produce serious problems. For example, drug–drug interactions can occur in the following situations:

• At the site of absorption*:* One drug prevents or accelerates absorption of the other drug. For example, the antibiotic tetracycline is not absorbed from the GI tract if calcium or calcium products (milk) are present in the stomach. The calcium binds with the tetracycline.

• During distribution: One drug competes for the protein-binding site of another drug, so the second drug cannot be transported to the reactive tissue. For example, aspirin competes with the drug methotrexate (Rheumatrex) for protein-binding sites. Because aspirin is more competitive for the sites, the methotrexate is bumped off, resulting in increased release of methotrexate and increased toxicity to the tissues.

• During biotransformation*:* One drug stimulates or blocks the metabolism of the other drug. For example, warfarin (Coumadin), an oral anticoagulant, is biotransformed more quickly if it is taken at the same time as barbiturates, rifampin, or many other drugs. Because the warfarin is biotransformed to an inactive state more quickly, higher doses will be needed to achieve the desired effect. Patients who use St. John’s wort may experience altered effectiveness of several drugs that are affected by that herb’s effects on the liver. Digoxin, theophylline, oral contraceptives, anticancer drugs, drugs used to treat HIV, and antidepressants are all reported to have serious interactions with St. John’s wort.

• During excretion: One drug competes for excretion with the other drug, leading to accumulation and toxic effects of one of the drugs. For example, digoxin (Lanoxin) and quinidine are both excreted from the same sites in the kidney. If they are given together, the quinidine is more competitive for these sites and is excreted, resulting in increased serum levels of digoxin, which cannot be excreted.

• At the site of action*:* One drug may be an antagonist of the other drug or may cause effects that oppose those of the other drug, leading to no therapeutic effect. This is seen, for example, when an antihypertensive drug is taken with an antiallergy drug that also increases blood pressure. The effects on blood pressure are negated, and there is a loss of the antihypertensive effectiveness of the drug. If a patient is taking antidiabetic medication and also takes the herb ginseng, which lowers blood glucose levels, he or she may experience episodes of hypoglycemia and loss of blood glucose control.