Clayton's Basic Pharmacology for Nurses 18th Edition: Chapter 3 Drug Action Across the Life Span

Placebo

- A drug dosage form (e.g., tablet, capsule) that has no pharmacologic activity because the dosage form has no active ingredients. - Frequently used in studies of new medicines to measure the pharmacologic effects of a new medicine compared with the inert placebo.

Factors That Affect Drug Therapy: Cumulative Effect

- A drug may accumulate in the body if the next dose is administered before the previously administered dose has been metabolized or excreted. - Excessive drug accumulation may result in drug toxicity.

Factors That Influence Absorption: Age (Topical Administration Infants)

- Absorption is usually effective for infants because their outer layer of skin (the stratum corneum) is not fully developed. - Because the skin is more fully hydrated at this age, water-soluble drugs are absorbed more readily. - Infants who wear plastic-coated diapers are also more susceptible to skin absorption because the plastic acts as an occlusive dressing that increases the hydration of the skin. - Inflammation (e.g., diaper rash) also increases the amount of drug that is absorbed.

Factors That Affect Drug Therapy

- Age - Body weight - Gender - Metabolic rate - Illness - Psychology - Tolerance - Dependence - Cumulative effect

Selected Medications That Require Dosage Adjustment for Renal Failure

- Antibiotics - Antifungal agents - Antiviral agents - Cardiovascular agents - Gastrointestinal agents - Others (lithium, allopurinol, meperidine, methotrexate)

Factors That Affect Drug Therapy: Body Weight

- Considerably overweight patients may require an increase in drug dosage to attain the same therapeutic response. - Patients who are underweight, compared with the general population, tend to require lower dosages for the same therapeutic response. - Most pediatric dosages are calculated by milligrams of drug per kilogram of body weight (mg/kg) to adjust for growth rate. - For accurate measurements, the patient's weight should be taken at the same time of day and while the patient is wearing similar-weight clothing.

Factors That Affect Drug Therapy: Dependence

- Drug dependence, which is also known as addiction or habituation, occurs when a person is unable to control his or her desire for ingestion of drugs. - The dependence may be physiologic, in which the person develops withdrawal symptoms if the drug is withdrawn for a certain period, or psychological, in which the patient is emotionally attached to the drug. - Drug dependence occurs most commonly with the use of the scheduled or controlled medications (e.g., opiates, benzodiazepines). - Less than 1% of patients using opioids for acute pain relief become addicted

Factors That Influence Absorption: Gender

- Generally, a woman's stomach empties solids more slowly than a man's does, and it may have greater gastric acidity, thus slowing the absorption of certain types of medicines (e.g., aspirin). - A slower gastric emptying time may allow the drug to stay in contact with the absorptive tissue longer, thereby allowing for more absorption and a higher serum concentration. - Women also have lower gastric levels of the enzyme alcohol dehydrogenase, which is needed to metabolize ingested alcohol. Thus larger amounts of ingested alcohol may be absorbed instead of metabolized in the stomach, thereby leading to a higher blood alcohol level in a woman than in a man for equal amounts of ingested alcohol. - Other factors, such as body weight and drug distribution (see the next section of this chapter), may aggravate the higher blood alcohol level and state of intoxication in women compared with men.

Factors That Influence Absorption: Age (Gastric pH (Geriatric))

- Geriatric patients often have a higher gastric pH because of the loss of acid-secreting cells. - Drugs that are destroyed by gastric acid (e.g., ampicillin, penicillin) are more readily absorbed in older adults because of the decrease in acid production, which results in higher serum concentrations. - By contrast, drugs that depend on an acidic environment for absorption (e.g., phenobarbital, acetaminophen, phenytoin, aspirin) are more poorly absorbed, thereby resulting in lower serum concentrations in older adults.

Factors That Influence Distribution: Age & Gender III

- Highly fat-soluble medicines (e.g., diazepam) must be given in smaller milligram-per-kilogram dosages to low-birth-weight infants, because there is less fat tissue to bind the drug, thereby leaving more drug to be active at receptor sites. - Drugs that are relatively insoluble are transported in the circulation by being bound to plasma proteins (albumin and globulins), especially albumin.

Factors That Influence Distribution: Age & Gender (Protein Binding) Adults Over 40

- In adults who are more than 40 years old, the composition of body proteins begins to change. - Although the total body protein concentration is unaffected, albumin concentrations gradually decrease and other protein levels (e.g., globulins) increase. - As albumin levels diminish, the level of unbound active drug increases. Increased levels of naproxen and valproate have been found in older adults, presumably as a result of decreased albumin levels. - Disease states such as cirrhosis, renal failure, and malnutrition can lower albumin levels. - Initial doses of highly protein-bound drugs (e.g., warfarin, phenytoin, propranolol, diazepam) should be reduced and then increased slowly if there is evidence of decreased serum albumin. - Lower protein binding may also lead to a greater immediate pharmacologic effect because more active drug is available; however, the duration of action may be reduced because more of the unbound drug is available for metabolism and excretion.

Factors That Affect Drug Therapy: Gender

- In almost every body system, men and women function differently, as well as perceive and experience disease differently. - In 1993, the US Food and Drug Administration (FDA) issued guidelines stating that drug development must evaluate the effects on both genders. - Testing is also needed to assess differences in pharmacokinetic parameters between men and women. In the women's studies, the research must distinguish between premenopausal and postmenopausal women and among women in different phases of the menstrual cycle.

Factors That Affect Drug Therapy: Age

- Infants and the very old tend to be the most sensitive to the effects of drugs. - There are important differences with regard to the absorption, distribution, metabolism, and excretion of drugs in premature neonates, full-term newborns, and children. - The aging process brings about changes in body composition and organ function that can affect the older patient's response to drug therapy.

Factors That Influence Absorption: Age (Hydrolysis (Newborn))

- Infants cannot metabolize palmitic acid from chloramphenicol palmitate (an antibiotic), thereby preventing the absorption of the chloramphenicol. - Oral phenytoin dosages are also greater in infants who are less than 6 months old because of poor absorption (i.e., in neonates, the dosage is 15 to 20 mg/kg/24 hr compared with infants and children, in whom the dosage is 4 to 7 mg/kg/24 hr).

Factors That Influence Distribution: Age & Gender (Protein Binding) Men vs Women

- Little difference exists between albumin protein in men and women, although there are some differences between the globulin proteins (i.e., corticosteroid-binding and sex-hormone-binding globulins).

Factors That Influence Metabolism: Age

- Liver weight, the number of functioning hepatic cells, and hepatic blood flow decrease with age; this results in the slower metabolism of drugs in older adults. - Reduced metabolism can be seriously aggravated by the presence of liver disease or heart failure. - Drug metabolism can also be affected in all age groups by genetics, smoking, diet, gender, other medicines, and diseases (e.g., hepatitis, cirrhosis). - No specific laboratory tests are available for measuring liver function that can be used to adjust drug dosages. Renal function must be assessed and dosages adjusted based on creatinine clearance.

Factors That Influence Metabolism: Gender

- Males and females differ with regard to the concentrations of enzyme systems throughout life. - The CYP3A4 component of the cytochrome P450 (CYP) system of enzymes metabolizes more than 50% of all drugs, and it is 40% more active in women. - Drugs such as erythromycin, prednisolone, verapamil, and diazepam are metabolized faster in women than in men.

Factors That Influence Absorption: Age

- Medicines given intramuscularly are usually erratically absorbed in neonates and older adults. - Differences in muscle mass, blood flow to muscles, and muscle inactivity in patients who are bedridden make absorption unpredictable.

Excretion

- Metabolites of drugs, which are the products of metabolism—and, in some cases, the active drug itself—are eventually excreted from the body. - The primary routes are through the renal tubules into the urine and through the GI tract into the feces. - Other generally minor routes of excretion include evaporation through the skin, exhalation from the lungs, and secretion into the saliva and breast milk.

Factors That Influence Distribution: Age & Gender

- Most medicines are transported either dissolved in the circulating water (i.e., in blood) of the body or bound to plasma proteins within the blood. - Total body water content of a preterm infant is 83%, whereas that of an adult man is 60%; this drops to 50% in older persons. - The significance of this is that infants have a larger volume of distribution for water-soluble drugs and thus require a higher dose on a milligram-per-kilogram basis than an older child or an adult.

Factors That Affect Drug Therapy: Tolerance

- Occurs when a person begins to require a higher dosage of a medication to produce the same effects that a lower dosage once provided. - Tolerance can be caused by psychological dependence, or the body may metabolize a particular drug more rapidly than before, thereby causing the effects of the drug to diminish more rapidly.

Factors That Influence Absorption: Age (Oral Administration Infants)

- Often lack a sufficient number of teeth for chewable medicines. - Chewable tablets should not be given to children with loose teeth. - Capsule forms are often too large for pediatric patients to swallow safely. - It is often necessary to crush a tablet for administration with food or to use a liquid formulation for easier and safer administration.

Factors That Influence Absorption: Age (Oral Administration Geriatric)

- Often lack a sufficient number of teeth for chewable medicines. - Chewable tablets should not be given to patients with loose teeth. - Capsule forms are often too large for elderly patients to swallow safely. - Geriatric patients often have reduced salivary flow, which makes chewing and swallowing more difficult. - It is often necessary to crush a tablet for administration with food or to use a liquid formulation for easier and safer administration.

Factors That Affect Drug Therapy: Illness

- Pathologic conditions may alter the rate of absorption, distribution, metabolism, and excretion of a drug. - Patients who are in shock have reduced peripheral vascular circulation and will absorb intramuscularly or subcutaneously injected drugs more slowly. - Patients who are vomiting may not be able to retain a medication in the stomach long enough for dissolution and absorption. - Patients with conditions such as nephrotic syndrome or malnutrition may have reduced amounts of serum proteins in the blood that are necessary for adequate distribution of drugs. - Patients with kidney failure generally will excrete drugs at a slower rate and must have significant reductions in dosages of medications that are excreted by the kidneys.

Factors That Affect Drug Therapy: Metabolic Rate

- Patients with a higher-than-average metabolic rate (e.g., patients with hyperthyroidism) tend to metabolize drugs more rapidly, thus requiring larger doses or more frequent administration. - The converse is true for those patients with lower-than-average metabolic rates (e.g., patients with hypothyroidism). - Chronic smoking enhances the metabolism of some drugs (e.g., clozapine, olanzapine), thereby requiring larger doses to be administered more frequently for a therapeutic effect.

Factors That Influence Absorption: Age (Intestinal Transit) Premature and Full-Term Newborns

- Premature and full-term newborns have a slower transit time. - As the healthy newborn matures into infancy, the GI transit rate increases to a relatively standard rate by about 4 months of age.

Factors That Influence Absorption: Age (Gastric Emptying Time (Premature Infants and Geriatric))

- Premature infants and geriatric patients also have a slower gastric emptying time, partly because of their reduced acid secretion. - A slower gastric emptying time may allow the drug to stay in contact with the absorptive tissue longer, thereby allowing for increased absorption with a higher serum concentration. - There is also the potential for toxicity caused by extended contact time in the stomach for drugs that have the potential to cause gastric ulcers (e.g., nonsteroidal antiinflammatory drugs).

Factors That Influence Distribution: Age & Gender (Protein Binding)

- Protein binding is reduced in preterm infants because of decreased plasma protein concentrations, lower binding capacity of protein, and decreased affinity of proteins for drug binding. - Drugs that are known to have lower protein binding in neonates than in adults include phenobarbital, phenytoin, theophylline, propranolol, lidocaine, and penicillin. - Because serum protein binding is diminished, the drugs are distributed over a wider area of the neonate's body, and a larger loading dose is required than is needed in older children to achieve therapeutic serum concentrations. - Several drugs that are used to treat neonatal conditions may compete for binding sites.

Distribution

- Refers to the ways in which drugs are transported by the circulating body fluids to the sites of action (receptors), metabolism, and excretion. - Distribution is dependent on pH, body water concentrations (i.e., intracellular, extracellular, and total body water), the presence and quantity of fat tissue, protein binding, cardiac output, and regional blood flow.

When initiating therapy with a geriatric patient, remember the following:

- Start at one-third to one-half of the normal adult recommended dosage, and then gradually increase the dosage at appropriate intervals to assess for the therapeutic effect and the development of adverse effects. - Keep multidrug regimens simple; use aids such as a calendar or a pillbox with time slots to prevent confusion. - Use therapeutic drug monitoring when serum drug level data are available for a particular medicine. - Offer assistance with destroying expired prescriptions to minimize confusion with the current medication regimen. - Periodically review the regimen to see whether any medications can be discontinued (e.g., allergy medicines outside of allergy season). Ask whether new prescriptions from other healthcare providers or nonprescription or herbal medicines have been started. - Geriatric patients may have difficulty with swallowing large tablets or capsules. Tablets may need to be broken in half or crushed if there is a score mark on the tablet. Remember that timed-release tablets, enteric-coated tablets, and sublingual tablets should never be crushed because of the effect on the absorption rate and the potential for toxicity. Applesauce, ice cream, pudding, and jelly are good foods to use to administer crushed medications. - It is extremely important that patients understand the purposes of the medications that they are taking and any complications that could occur if they discontinue their drugs. - When handing a patient a new prescription to be filled, inquire about his or her ability to pay for the new medicine. Do not let an inability to pay be a barrier to therapy; refer the patient to social services, as needed.

Therapeutic Drug Monitoring

- The measurement of a drug's concentration in biologic fluids to correlate the dosage administered and the level of medicine in the body with the pharmacologic response. - Assays of blood (serum) samples for drug concentrations are most commonly used, but assays that involve the use of saliva are being perfected for some medicines. - Therapeutic drug monitoring is essential for neonates, infants, and children to ensure that drugs are within an appropriate therapeutic range, given the major physiologic changes that affect drug absorption, distribution, metabolism, and excretion.

Gender-Specific Medicine

A developing science that studies differences in the normal function of men and women and addresses how people of each gender perceive and experience disease.

Factors That Influence Absorption: Age (Intestinal Transit) Older Adults

Older adults develop decreased GI motility and intestinal blood flow. This has the potential for altering the absorption of medicines and for causing constipation or diarrhea, depending on the medicine.

Factors That Influence Absorption: Age (Gastric Acidity: Premature Infants)

Premature infants have a high gastric pH (6 to 8) as a result of the immature acid-secreting cells in their stomachs.

Factors That Influence Absorption: Age (Intestinal Transit)

Refers to the speed at which the intestine moves foods, secretions, and other ingested matter along, and this rate varies with age.

Age: 13-18 Years

Stage: Adolescent

Age: 19-54 Years

Stage: Adult

Age: 65-74 Years

Stage: Elderly

Age: 1-24 Months

Stage: Infant, toddler

Age: 0-1 Month

Stage: Newborn, neonate

Age: 55-64 Years

Stage: Older adult

Age: 6-12 Years

Stage: Older child

Age: <38 Week Gestation

Stage: Premature

Age: 75-84 Years

Stage: The aged

Age: 85 Years or Older

Stage: The very old

Age: 3-5 Years

Stage: Young child

Carcinogenicity

The ability of a drug to induce living cells to mutate and become cancerous

Nocebo Effect

The belief that negative expectations about therapy and the care received can result in less-than-optimal outcomes of therapy.

Therapeutic Drug Monitoring (Dosage and the Frequency of Administration)

The dosage and the frequency of administration must often be adjusted to help maintain therapeutic serum concentrations. Therapeutic drug monitoring is routine for conditions such as epilepsy (e.g., phenytoin, carbamazepine, valproic acid, phenobarbital), stroke (e.g., warfarin), heart failure (e.g., digoxin), and antimicrobial therapy (e.g., gentamicin, tobramycin, vancomycin) to prevent toxicities and to ensure that dosages are adequate to provide appropriate therapeutic levels.

Placebo Effect

The phenomenon in which a patient's positive expectations about treatment and the care received can positively affect the outcome of therapy.

Drug Metabolism

The process whereby the body inactivates medicines. It is controlled by factors such as genetics, diet, age, health, and the maturity of enzyme systems. Enzyme systems, primarily in the liver, are the major pathways of drug metabolism.

Tablets Potential for Toxicity

Timed-release tablets, enteric-coated tablets, and sublingual tablets should not be crushed because this will increase their absorption rate and thus the potential for toxicity.

Factors That Influence Absorption: Age (The GI Absorption of Medicines is Influenced By...)

Various factors, including gastric pH, gastric emptying time, the motility of the GI tract, enzymatic activity, the blood flow of the mucous lining of the stomach and intestines, the permeability and maturation of the mucosal membrane, and concurrent disease processes.

Factors That Influence Absorption: Age (Gastric Acidity: Full-Term Newborns)

In a full-term newborn, the gastric pH is also 6 to 8, but within 24 hours the pH decreases to 2 to 4 in response to gastric acid secretion.

Factors That Influence Absorption: Age (Gastric Acidity: Newborns and Geriatric)

Newborns and geriatric patients have reduced gastric acidity and prolonged transit time compared with adults.

Therapeutic Drug Monitoring (Timing)

- The timing of the drug's administration and the collection of the specimen are crucial to the accurate interpretation of the data obtained after assay. _ Certain medicines (e.g., aminoglycosides, gentamicin, tobramycin) require that blood be drawn before and after the administration of the drug to assess subtherapeutic levels and the potential for toxicity. - One sample is drawn immediately before the next dose is to be administered to obtain the trough, or lowest, blood level of medicine, and another is drawn 20 minutes after the medicine has been administered intravenously or 60 minutes after the medicine has been administered orally to obtain the peak, or highest, blood level.

Polypharmacy

- The use of many different drugs concurrently in treating a patient, who often has several health problems. - Factors that place older adults at greater risk for drug interactions or drug toxicity include reduced renal and hepatic function, chronic illnesses that require multidrug therapy (polypharmacy), and a greater likelihood of malnourishment.

Factors That Influence Absorption: Age (Transdermal Administration Geriatric)

- Transdermal administration in geriatric patients is often difficult to predict. - Although dermal thickness decreases with aging and may enhance absorption, factors that may diminish absorption can be seen, including drying, wrinkling, and a decrease in the number of hair follicles. - With aging, decreased cardiac output and diminishing tissue perfusion may also affect transdermal drug absorption.

Factors That Influence Distribution: Age & Gender II

- With aging, lean body mass and total body water decrease and total fat content increases. - The body weight of a preterm infant may be composed of 1% to 2% fat, whereas a full-term newborn may have 15% fat. Adult total body fat ranges from 18% to 36% for men and 33% to 48% for women between the ages of 18 and 35 years. - Drugs that are highly fat soluble (e.g., antidepressants, phenothiazines, benzodiazepines, calcium channel blockers) require a longer onset of action and accumulate in fat tissues, thereby prolonging their action and increasing the potential for toxicity. - For water-soluble drugs (e.g., ethanol, aminoglycoside antibiotics), a woman's greater proportion of body fat produces a higher blood level compared with that of a man when the drug is given as an equal dose per kilogram of body weight.

Factors That Influence Excretion: Age

-Newborns, infants: 1st few months the kidneys are still developing (have limited capacity to excrete drugs) -Elderly: Kidneys start to fail (decreased renal excretion)

Factors That Influence Absorption: Age (Absorption by Passive Diffusion)

Across the membranes and gastric emptying time depend on the pH of the environment.

Factors That Influence Absorption: Age (Gastric Acidity: 1 Year Old)

At 1 year old, the child's stomach pH approximates that of an adult (i.e., pH of 1 to 2 when empty, up to 5 when full).

Factors That Affect Drug Therapy: Psychology

Attitudes and expectations play a major role in a patient's response to therapy and in his or her willingness to take the medication as prescribed.

Therapeutic Drug Monitoring (Suspected Toxicity)

Blood levels of drugs can be measured if toxicity is suspected. The extent to which a serum drug level is elevated may dictate how the toxicity should be treated (e.g., acetaminophen, digoxin). Blood and urine samples can also be obtained for legal purposes if it is suspected that drugs (e.g., ethanol, amphetamines, marijuana, benzodiazepines, cocaine) have been consumed illicitly.