Intro to Pharm Sciences Therapeutic Variability Flashcards
Intensity of drug response
Varies among patients due to individual differences in pharmacokinetics, pharmacodynamics, or immune responses
Pharmacokinetic variability
Caused by differences in ADME of the drug in patients, differing concentrations of drug at the target site, and alterations in efficacy and/or toxicity
Sources of pharmacokinetic variability
Body weight and composition
Age
Gender
Health status
Typical dose
ED50 for an effect in 70 kg male, 18-65 years
Adjustment based on body weight
(Typical dose / 70 kg) * Weight of individual (kg)
Does body weight formula for dosing work for everyone?
Not reliable for extremely lean or obese individuals because dramatically altered body composition
Normal body water and fat percentages
~60% and 19-25%
Obese body water and fat percentages
~50% and 33%+
Lipophilic drugs
More fat available for drug distribution in obese patients
Increase in Vd
Lower plasma drug concentration
Differences in body composition
Large differences in drug distribution and PK variability
Therapeutic variability with age
Variability in very old and young cannot be explained by body size or composition alone
People at age extremes are generally more sensitive to drugs, due to differences in ADME
These people fall on extreme left on a quantal dose-response curve
Infants and children variability statistics
Absorption: Increased due to higher permeability of tissues, skin, and blood-brain barrier
Metabolism: Decreased due to metabolic enzymes being under-developed
Excretion: Decreased due to lower rate of blood flow to kidneys
Elderly variability statistics
Absorption: Slightly decreased due to reduced absorption efficiency
Metabolism: Decreased due to decreased hepatic mass, blood flow, and enzyme activity
Excretion: Decreased due to reduced number of nephrons, functioning glomeruli, and renal blood flow
Pregnancy variations
Small molecular weight drugs can cross the placenta by passive diffusion
Drug concentration in fetus can be equal to mother, can be deadly and cause birth defects
Gender differences
Higher body fat %
Lower metabolic rates
Health status variability
Impaired liver or renal function can cause drug toxicity
Edema vs. dehydration
Acidosis vs. alkalosis
Pharmacodynamic variability
Variability in drug effects caused by differences in the structure or function of target receptors
Two major factors of PD variability
Drug resistance
Drug tolerance
Drug resistance
Lack of or decreased responsiveness to a drug that normally inhibits cell growth or causes cell death
Intrinsic resistance
A cell or organism is inherently insensitive
Acquired resistance
Cells or organisms initially respond to the drug but eventually fail to respond because of acquired property
Drug resistant microbes and cancer cells
Transfer genes to other microbes and cancer cells, spreading resistance
Drug resistance mechanisms
Production of drug-inactivating enzymes
Alteration of the drug target or binding site
Decreased permeability of drug
Increased efflux of the drug
Production of inactivation enzymes
Some bacteria make them naturally, making them inherently resistant
Some bacteria express them only in the presence of the inducer, making them acquired resistant
Decreased permeability of drug
Decreased rate of passive diffusion
Decreased carrier-mediated transport
Increased efflux of drug
More drug leaving the cells
Resistance to a broad range of drugs that are often structurally and functionally distinct
Drug Tolerance Overall
Condition of decreased responsiveness acquired after repeated exposure to a drug
Need increased dose to get the same effect
Develops slowly
Pharmacodynamic and pharmacokinetic
Pharmacodynamic drug tolerance
Due to alteration of target site
Decreased receptor number, receptor affinity, and receptor sensitivity
Pharmacokinetic drug tolerance
Due to reduction in drug concentration at the site of action
Example: Ethanol and barbiturates increase own metabolism and need higher dose to get same effect
Drug tolerance special cases
Cross tolerance: Tolerance to different drugs of the same pharmacological class
Tachyphylaxis: Acute tolerance following rapid, repeated drug administration (few hours to few days) Rapid pharmacodynamic tolerance
Immunologic variability
Drug allergy: Adverse drug response to previous exposure to the drug
Different from drug toxicity and unrelated to usual effects of drug
Not dose dependent
Antagonists do not inhibit allergic reaction
Drug allergy mechanism
Caused by false recognition of drugs as antigens by the immune system
Can be very onset symptoms or delayed
