Question

Distribution, Metabolism, Drug Interactions, and the Effects of Aging, Obesity, and Disease

Problem #4

Please describe 3 different processes through which a drug can exert pharmacokinetic non-linearity and give an example of a drug (different drug for each type) that exerts this type of non-linearity for each example (e.g., saturablemetabolism and phenytoin)

Absorption-related non-linearity – mechanism and example of a drug

Distribution-related non-linearity – mechanism and example of a drug

Metabolism-related non-linearity – mechanism and example of a drug

Problem #5

Please describe the influence of extremes of age, obesity, and a disease state of your choice on the following processes and give an example of a drug that may be affected by each. If none – state “no effect.”

5a. Influence of extremes of age (neonate vs. elderly)

Absorption –

Example of drug:

Distribution –

Example of drug:

Metabolism –

Example of drug:

Excretion –

Example of drug:

5b. Influence of obesity

Absorption –

Example of drug:

Distribution –

Example of drug:

Metabolism –

Example of drug:

Excretion –

Example of drug:

5c. Disease state of your choice (write in disease state) _________________________

Absorption –

Example of drug:

Distribution –

Example of drug:

Metabolism –

Example of drug:

Excretion –

Example of drug:

Problem #6

Explain the influence of aging on each of the following:

Drug metabolism through CYP3A4 (consider both gut and liver)

Glucuronidation

Sulfation

Acetylation

Answer 1

Problem #4

Please describe 3 different processes through which a drug can exert pharmacokinetic non-linearity and give an example of a drug (different drug for each type) that exerts this type of non-linearity for each example (e.g., saturablemetabolism and phenytoin)

Absorption-related non-linearity – This non-linearity is dependent on the absorption of drugs in the body and varies considerably with any change in dose and the saturation of drugs. The metabolism of the body also plays a part in this as the quicker the metabolism, the faster the drug would be absorbed in the body. Example: Verapamil and Propranolol. These drugs are sensitive not only to the systemic circulating drug concentrations but also on the rate of absorption.

Distribution-related non-linearity – Drug distribution is dependent on the saturation of binding sites on plasma proteins for some drugs (example: Phenyl Butazone) and on the saturation of binding sites on tissues (Example: Thiopental).

Metabolism-related non-linearity – This can basically be due to three factors:

1. Limited metabolism due to enzyme or co-factor saturation (Example: Phenytoin)
2. Enzyme induced (example: Carbamazepine)
3. Saturation of binding sites, inhibitory effect of the metabolite on the enzyme, different pathological conditions and also changes in hepatic blood flow. Example: Acetaminophen

Problem #5

Please describe the influence of extremes of age, obesity, and a disease state of your choice on the following processes and give an example of a drug that may be affected by each. If none – state “no effect.”

5a. Influence of extremes of age (neonate vs. elderly)

Absorption –The effects of drugs can be different for some drugs in a neonate and an elderly. Since the metabolism rate in neonates are higher than that in an elderly, the drug would be absorbed faster in neonates than in elderly thus the difference in dosages given in neonates and elderly.

Example of drug: Amoxicillin

Distribution – Depending on the saturable plasma proteinin blood and the tissue binding properties of a drug, the drugs that bind quicker get distributed slower. As the cell membrane permeability is higher in neonates, and the barriers between blood and tissues and the total tissue surface area is lower in neonates, the distribution of drug is quicker than that in elderly.

Example of drug: Naproxen

Metabolism –Overall hepatic metabolism of many drugs significantly decreases with age. First pass metabolism is also affected by age and decreases by about 1% after age of 40. Thus, for a given dose, the elderly may have a higher circulating drug level and the chances of toxicity thus increases.

Example of drug: Propranolol

Excretion –The renal elimination of drugs significantly decreases in elderly. Although the age related decrease may vary substantially from person to person, there is a decrease in GFR as elderly are less physically active and which also goes parallel to the decrease in tubular function even when the creatinine levels may be normal. Since, renal function is dynamic, dosages of drugs affecting excretion of these drugs need to be adjusted when patients become ill or are dehydrated.

Example of drug: Meperidine, Theophylline

5b. Influence of obesity

Absorption –Gastric emptying may be increased or decreased or may be unpredictable in obese patients thus altering the gastric absorption of drugs. Absorption through subcutaneous compartment will be slowed due to poor blood flow to the subcutaneous fat. Injectable method may become difficult due to poor access thus affecting drug absorption.

Example of drug: Paracetamol. The drug should be administered based on total body weight rather than on ideal body weight.

Distribution –There is an increased volume of distribution for lipid soluble drugs and decreased volume of distribution for systemic drugs due to decreased blood flow. There are also increased volume of distribution for water soluble drugs as the body fluid volume increases.

Example of drug: Warfarin

Metabolism –Hepatic clearance is slowed not only due to decreased cardiac output but also due to fatty infiltration. The lean tissue mass (Liver enzyme)may be increased which makes it difficult to say if metabolic activity is going to be more or less thus effecting metabolism of drug.

Example of drug: Propranolol, Isoniazid

Excretion –In patients who are obese and have diabetes, the kidneys may be damaged leading to slower renal clearance. In healthy Obese patients the GFR may be increased thus affecting drug excretion. Biliary clearance may also be slowed by bile stasis due to obesity affecting the excretion of the drug.

Example of drug: Sodium Salicylate

5c. Disease state of your choice (write in disease state) _____________Diabetes Mellitus____________

Absorption –Oral absorption is unlikely to be affected by diabetes but subcutaneous absorption is more rapid whereas intramuscular absorption is slower.

Example of drug: Insulin

Distribution –The distribution of drugs with little or no binding to blood plasma are generally not altered as the disease does not affect the plasma concentration of albumin. The absorption of drugs that bind to blood is reduced due to glycosylation of plasma proteins.

Example of drug: Furosemide

Metabolism –The metabolic clearance of drugs is unaffected or slightly reduced by diabetes. If the patient is suffering from a fatty liver and Non-insulin dependent DM, the absorption may be reduced whereas decreased binding in the blood may increase metabolism and clearance of the drug from the body.

Example of drug: Glipizide

Excretion –In diabetes, the GFR is elevated in patients within 10 years of their onset of diabetes post which the GFR declines impairing the renal function. Thus the renal clearance of drugs in newly diagnosed patients is similar to non diabetic individuals or reduced.

Example of drug: Amoxicillin