Chapter 8

1. Chapter 8 Individual Variation in Drug Responses

2. Individual Variation in Drug Responses • Key factors that cause one patient to respond to drugs differently than another patient • Important for nurses to know to be better prepared to reduce individual variation in drug responses

3. Individual Variation in Drug Responses • Body weight and composition • Body surface area (BSA) versus weight • Age • Significant variability with age • Infants and elderly patients especially sensitive to drugs • Infants: organ immaturity • Elderly patients: organ degeneration • Due to increased severity of illness, multiple pathologies, treatment with multiple drugs

4. Individual Variation in Drug Responses • Pathophysiology • Kidney disease • Reduced excretion and increased toxicity • Liver disease • Reduced metabolism and increased toxicity • Acid-base imbalance • pH changes that alter absorption, distribution, metabolism, and excretion of drugs • Altered electrolyte status • Rare for electrolyte changes to have a significant impact on drug responses

5. Fig.8-1. Effect of renal failure on kanamycin half-life. Kanamycin was administered at time “0” to two patients: one with healthy kidneys and one with renal failure. Note that drug levels declined very rapidly in the patient with healthy kidneys and extremely slowly in the patient with renal failure, indicating that renal failure greatly reduced the capacity to remove this drug from the body. (T1/2 = half-life.)

6. Fig. 8-2. Altered drug distribution in response to altered plasma pH. Lower curve, Plasma (extracellular) pH. Note the decline in pH in response to inhalation of CO2. Upper curve, Plasma levels of phenobarbital. Note the decline in plasma drug levels during the period of extracellular acidosis. This decline results from the redistribution of phenobarbital into cells. (See text for details.)

7. Individual Variation in Drug Responses • Tolerance • Decreased responsiveness to a drug as a result of repeated drug administration • Higher doses required • Three categories of drug tolerance • Pharmacodynamic tolerance • Metabolic tolerance • Tachyphylaxis

8. Three Types of Drug Tolerance • Pharmacodynamic tolerance • Associated with long-term administration of drugs such as morphine or heroin • Metabolic tolerance • Resulting from accelerated drug metabolism • Tachyphylaxis • Reduction in drug responsiveness brought on by repeated dosing over a short time

9. Placebo Effect • Any response a patient has to a placebo is based solely on his or her psychologic reaction to the idea of taking a medication, and not to any direct physiologic or biochemical action of the placebo itself. • Nurses need to present a positive but realistic assessment of the effects of therapy. • Primary use is control group for clinical trials.

10. Variability in Absorption • Bioavailability • Ability of the drug to reach the systemic circulation from its site of administration • Occurs primarily with oral preparations, not with parenteral administration • Tablet disintegration time, enteric coatings, sustained-release formulations • Other causes of variable absorption • Changes in gastric pH, diarrhea, constipation, food in the stomach

11. Genetics and Pharmacogenomics • Pharmacogenomics: study of how genes affect individual drug responses • Altered drug metabolism • May accelerate or retard the metabolism • Warfarin, succinylcholine, isoniazid, cytochrome P450

12. Variations • Altered drug targets • Genetic variations alter the structure of drug receptors. • Other ways genetics can influence drug responses • Some genetically determined drug responses are based on factors other than changes in drug metabolism or drug targets.

13. Variations • Gender • Alcohol is metabolized more slowly by women than by men. • Certain opioid analgesics are much more effective in women than in men. • Quinidine causes greater QT interval prolongation in women than in men. • Race • Genetic variations • Psychosocial factors

14. Variations • Failure to take medicine as prescribed • Issues include manual dexterity, visual acuity, intellectual capacity, psychologic state, attitude toward drugs, and ability to pay for medication. • Drug interactions • One drug alters the effects of another. • Diet • Starvation reduces protein binding of drugs, which increases levels of free drugs.