Module 6 Section 5 (Special Populations)

Question 1

Numerous factors can affect how a patient needs to be treated. What are those?

Answer 1

Numerous factors can affect how a patient needs to be treated, including disease, physiological conditions, and/or effects of concurrent drugs that can alter the pharmacokinetics of medications, thus influencing the appropriate dose for a patient.

Question 2

What is chronic liver disease?

Answer 2

Chronic liver disease is characterized by progressive destruction and regeneration of the liver, eventually leading to fibrosis and cirrhosis.

Question 3

What are some causes of chronic liver disease?

Answer 3

Many causes of chronic liver disease exist, including hepatitis B virus and alcoholic liver disease.

Question 4

The body’s ability to handle medications is also altered due to chronic liver disease. What are the effect of chronic liver disease on pharmacokinetics (ADME)

Answer 4

Absorption: chronic liver disease does not have a direct effect on the absorption of drugs into the body, although it can affect oral bioavailability of a drug.

Distribution: chronic liver disease is also associated with an increase in extracellular fluid (i.e. peripheral edema and ascites) affecting its distribution. As such, the apparent volume of distribution (Vd) of hydrophilic drugs is increased.

Metabolism: the decline in liver function that is associated with chronic hepatic disease is accompanied by a decline in the oxidative enzyme activity of the liver.

Excretion: drugs that depend primarily on the liver for systemic clearance and/or are excreted via the biliary system are likely to have reduced elimination in patients with chronic liver disease. This can lead to drug accumulation which may be associated with adverse effect.

Question 5

What is the consequence of increased Vd levels on circulating levels of a hydrophilic drug?

Answer 5

This would result in a decrease in circulating levels of hydrophilic drugs, which would result in less drug reaching the site of action, thus potentially having an impact on the effect of the drug, depending on its therapeutic window.

Question 6

What is the effect that this would have on the metabolizing activity of cytochrome P450 enzymes? What effect could this have on oral bioavailability? Why?

Answer 6

Decrease; Increase; For a drug that typically undergoes first pass metabolism, with chronic hepatic disease, the decrease in CYP activity (which contributes to first pass metabolism) results in an increased amount of active drug reaching systemic circulation.

Question 7

Whenever possible, individuals with chronic hepatic disease should be prescribed what three types of drugs?

Answer 7

• Drugs that are primarily eliminated by renal excretion,
• Drugs that are metabolized by Phase II conjugation, and/or
• Drugs that have high oral bioavailability (i.e. are not susceptible to first pass metabolism).

Clinical observation of these patients should guide dosage adjustments.

Question 8

Chronic renal disease, which decreases the functional ability of the kidney, can have a major impact on the pharmacokinetics of many drugs. What kind of impact may occur?

Answer 8

As kidney function declines, so too does the ability of many drugs to be eliminated from the body. Additionally, as kidney function is reduced, extracellular fluid increases, increasing the Vd of hydrophilic drugs.

Question 9

In general, patients with chronic kidney disease will need to be prescribed decreased dosages of drugs (since they are removed from the body slower). This is especially true for drugs that are primarily eliminated by glomerular filtration of the parent compound. Why is this the case?

Answer 9

This is particularly true for drugs primarily eliminated by glomerular filtration of the parent compound because these drugs do not have to undergo metabolism to be excreted. Remember, metabolism often inactivates a drug, decreasing the active drug that can reach the therapeutic target.

Question 10

What is cardiovascular disease (CVD)? What is the most common cause?

Answer 10

Cardiovascular disease refers to any disease that affects the heart or blood vessels.

Many different causes of cardiovascular disease exist, however atherosclerosis and hypertension are the most common.

Cardiovascular disease can progress to chronic heart failure, which refers to the progressive decline in the ability of the heart to adequately pump blood throughout the body.

Question 11

Chronic heart failure has many effects on the function of other organs in the body. What effects are these?

Answer 11

A direct result of chronic heart failure is a reduction in cardiac output.

• Reduced cardiac output results in impaired organ perfusion (e.g. liver, kidney, gastrointestinal tract), and compensatory changes lead to sodium and water retention, causing peripheral edema and visceral congestion.
• These changes in perfusion lead to a decreased volume of distribution for most drugs.
• For instance, the absorption of drugs from the gastrointestinal tract or intramuscular sites is delayed or reduced, hepatic metabolism is impaired, and renal elimination is impaired.

Question 12

For patients with CVD, recommended dosages will need to be reduced by 50%. Why does this occur?

Answer 12

In acute therapy, this reduction in dosage is to compensate for the reduced volume of distribution, while in chronic therapy, this reduction in dosage is to compensate for impaired metabolic and renal clearance.
- Additionally, intravenous administration may be preferred where oral or intramuscular absorption is severely impaired.

Question 13

What is obesity? What is it characterized by?

Answer 13

Obesity is defined as an individual having a body mass index (BMI) greater than 30, while morbid obesity is defined as having a BMI greater than 33.

Obesity is characterized by increases in body fat, lean body mass (20-40%), cardiac output, and glomerular filtration rate in the kidney.

Question 14

How is the pharmacokinetics impacted in those with obesity?

Answer 14

Absorption: obesity is accompanied by increased gastric emptying as well as increased gut perfusion, both of which are associated with an increase in the rate and extent of a drug’s oral absorption.

Distribution: an increase in body fat is associated with an increased Vd for lipophilic drugs.

• Fat can store lipophilic drugs, thus decreasing the amount of an acute (one-time) drug dose that is available at the site of action.
• For lipophilic drugs that are dosed repeatedly, drug metabolism must be considered.

Metabolism: fat is not metabolically active, nor is it involved in the elimination of drugs.

• Therefore, metabolism of drugs is dependent on the lean body mass of an individual.
• So, while Vd is increased with lipophilic drugs which requires an increase in dose of these drugs for an acute dose, for a drug requiring chronic dosing, because only lean body mass is metabolically active, lean body mass is used to calculate the dose. Otherwise, this could lead to drug accumulation within the body.

Excretion: the effect of obesity on drug excretion remains controversial. It appears that glomerular filtration rate may be increased in obese patients, which would increase the rate of renal clearance of drugs. Obesity is also associated with numerous diseases that may have an impact on drug excretion, including kidney disease and hepatic disease.

Question 15

Older adults are often prescribed multiple medications, which can further complicate drug pharmacokinetics. What effects does old age have on the pharmacokinetics of drugs?

Answer 15

Absorption: there is little evidence that age has any major effect on drug absorption, although some conditions associated with age may alter absorption of certain drugs (i.e. greater consumption of non-prescription drugs such as laxatives or antacids).

Distribution: increasing age is associated with a decrease in total body water, as well as an increase in fat which is not accompanied by an increase in body weight.
- Both of these physiological changes have an impact on the distribution of a drug.

Metabolism: metabolic reactions are impaired with age due to reduced activities of cytochrome P450 enzymes, however, there is little change in phase 2 reactions with age (i.e. conjugation reactions).

• Additionally, cardiac output generally declines by 50% from age 20 to age 80, resulting in decreased blood flow to the liver.
• Together, these can lead to increased half life of numerous drugs as well as reduced hepatic clearance.

Excretion: renal elimination is also reduced, in part due to decreased glomerular filtration rates, which are reduced to 50-60% of middle-aged adult values in older adults.
- Renal tubular function also declines with age, leading to reduced active tubular secretion and reduced reabsorptive capacity.

Question 16

Pharmacodynamics are also associated with an increased age. How does this occur?

Answer 16

Generally speaking, geriatric patients have reduced compensatory reserves, meaning they are unable to compensate for compromised function, as well as diminished homeostatic response.
- Ex: memory has a cholinergic basis, and the elderly have reduced cholinergic function. As a result, anticholinergic medications can readily cause confusion and disorientation in the elderly. Therefore caution is used with agents that have significant anticholinergic activity such as antihistamines and over-the-counter sedatives.

Benzodiazepines often produce increased sedation and confusion in the elderly.

Blood pressure medication is typically met with compensatory effects that in essence ‘work against’ the blood pressure medication. In older adults, these mechanisms are not as prevalent, and so often a lower dose is required to achieve the same effect.

Question 17

Neonates have a number of changes to pharmacokinetics that can have a significant effect on how their bodies handle drugs. What are these?

Answer 17

Absorption: newborns have slower gastric emptying time, which can result in more complete absorption of some orally administered drugs that are primarily absorbed in the stomach.
- This may also result in delayed therapeutic effect of drugs that are absorbed primarily from the intestine.

Distribution: approximately 70% to 75% of a newborn’s weight is water, whereas approximately 50% to 60% of an adult’s weight is water. This means that hydrophilic drugs will have a greater volume of distribution in newborns compared to adults.

• Plasma-binding proteins are also found at lower levels in the neonate, resulting in reduced bound-to-free ration of the drug.
• The young also have a poorly developed blood brain barrier, increasing the exposure of the brain to certain drugs.

Metabolism: metabolism (both phase 1 and phase 2) is generally reduced in the neonate, resulting in prolonged elimination half lives of drugs in early months of life.

Excretion: renal excretion and glomerular filtration is reduced to 30% to 40%, reaching adult values by 6 to 12 months of age. Interestingly, the half life of some drugs in toddlers is actually shorter than in adults, which is thought to be associated with increased renal elimination.

Question 18

Pregnancy results in multiple physiological changes for the mother. What is increased during pregnancy?

Answer 18

• Metabolism
• Blood volume
• Cardiac output
• Renal clearance
• Fat (increasing volume of distribution of lipophilic drugs)

As a result of these changes to the mother’s body, drug dosages may need to be adjusted to achieve the same pharmacological effects achieved prior to pregnancy.

Question 19

Given the physiological increases in metabolism, blood volume, and renal clearance, in general, how do you think you would need to adjust the dose of a drug to achieve the same therapeutic effect as before pregnancy?

Answer 19

In general, you would need to increase the dose of a drug to achieve the same therapeutic effect as in the same person pre-pregnancy.
- Increased metabolism, cardiac output, and renal clearance are all associated with faster elimination of a drug.

While the placenta was once thought of as a ‘placental barrier’, most drugs that a pregnant woman is exposed to will reach the developing embryo/fetus at some concentration.

• Certain drugs, however, are more readily able to cross the placenta.
• Lipophilic drugs and small drugs, for example, readily diffuse across the placenta and into fetal circulation.

The risks and benefits for both the mother and the baby must be considered. If a drug therapy is being initiated once a woman is already pregnant, care can often be taken to prescribe a pharmaceutical with the least amount of known harm.

However, if a woman in continuing a drug therapy that was initiated pre-pregnancy, it may be unwise to change her prescription during pregnancy (i.e. if a seizure medication or antidepressant is effective in a particular patient, the risk of switching the prescription to a drug with less known risk may be outweighed by the benefit of controlled symptoms in the patient).

Question 20

The effect of a drug on a fetus can be organized into two broad categories. What are they?

Answer 20

1) Unpredictable teratogenic effects: these are the unexpected effects that can occur following exposure to a drug.
- Teratogenic effects can happen with as little as a single exposure to a drug during a critical window of development.
- Ex: thalidomide exposure during the 4th to 7th week of gestation, when limbs are developing, can result in phocomelia in exposed offspring.

2) Predictable toxic effects: these are the effects that we can anticipate will occur in the fetus or neonate upon exposure to certain drugs.
- Ex: withdrawal syndrome in neonates following in utero exposure to an opioid.

Question 21

True or false: While most drugs taken by a lactating woman are detectable in breastmilk, the concentrations achieved in breastmilk are typically at levels too low to cause an adverse effect in the infant.

Answer 21

True

Unfortunately, due to misconception of this fact, mothers taking medication often end up not breastfeeding or stopping breastfeeding when prescribed a drug.

Question 22

Some drugs, however, do reach levels in the breastmilk to cause a pharmacological effect in the infant. What are the classes of drugs?

Answer 22

Such classes of drugs include (but are not limited to):

• Sedative/hypnotics
• Some antibiotics
• Opioid

Question 23

What should a nursing mother who requires medication do?

Answer 23

Generally speaking, if a nursing mother must take medications and the drug is considered to be relatively safe, it is best to take said medication 30-60 minutes after nursing and 3-4 hours before the next feeding, whenever possible.
- In some cases this may allow time for drugs to be partially cleared from the mother’s blood, and the concentrations in breast milk to be relatively.

Question 24

Which one of the statements regarding therapeutics in the elderly is correct?

a) Aging is associated with a decrease in the development of disease
b) The average elderly patient is taking approximately two different medications
c) In general, the elderly have a decreased risk of experiencing drug interaction
d) Cardiac output declines as we age, affecting metabolism and clearance of drugs

Answer 24

d) Cardiac output declines as we age, affecting metabolism and clearance of drugs

Question 25

Which one of the statements listed is correct?

a) Pregnancy decreases metabolism, renal clearance, and cardiac output
b) All prescription medications are safe to use during pregnancy
c) Drugs are not excreted into breast milk, and are therefore not a concern
d) A risk-benefit analysis has to be conducted regarding therapy during pregnancy and breastfeeding

Answer 25

d) A risk-benefit analysis has to be conducted regarding therapy during pregnancy and breastfeeding