Pharmacokinetic Variability PDF

Differences in drug levels at site of action (as inferred by drug concentration in the plasma. Differences in the effect produced by a given drug concentration. Two sources of variability Called pharmacokinetic variability. Drug concentration resulting from given dose. Principal variation Both...

Differences in drug levels at site of action (as inferred by drug concentration in the plasma. Differences in the effect produced by a given drug concentration. Two sources of variability Called pharmacokinetic variability. Drug concentration resulting from given dose. Principal variation Both sources contribute to variability in response to Both pharmacokinetic and pharmacodynamic, midazolam, (intravenous benzodiazepine) Wide range of blood levels also seen in same subject taking drug on different occasions. Intersubject variability much greater than Intrasubject variability. Contributing factor to intrasubject variability Renal clearance of digoxin significantly higher during a period of normal physical activity than during a period of immobilization. Physical activity Bioavailability of drug from the dosage form Factors contributing to variability Those that may affect the completeness of absorption. Those that affect drug disposition. Age-related phenomena Genetic and environmental factors ADME subject to individual variation Consequences of disease Concomitant administration of other drugs Important source of variability Patients fail to follow directions about taking medicine. Anatomic space into which it distributes Relative degree of vascular and extravascular binding. Volume of both total body water (TBW) and extracellular fluid (ECF) in adults with normal lean-to-fat ratios directly proportional to body weight. Apparent volume of distribution determined by Relationship particularly evident for drugs poorly bound in body. Initial blood levels following single dose or loading dose of a drug that is rapidly absorbed largely dependent on apparent volume of distribution Larger volume of distribution lower is blood level. If peak blood levels are of concern Body weight should be considered in determining the appropriate dose Organ size, function, and blood flow also related to body weight Relationship between drug clearance and body weight not clear. BODY WEIGHT AND SIZE Correlation between drug clearance and body weight in normal young adults is poor Infants, children, and the elderly confounded by age effects on drug clearance. No general guidelines to relate maintenance doses of drugs to body weight. When are weight adjustments thought necessary ? In practice, adjustments for weight made only for children and for unusually small, or obese adult patients Weight of an individual differs by more than 50% from the average adult weight (70 kg). 50kg±1kg/2.5cmabove or below 150 cm in height IBW(men) Obesity Ideal body weight (IBW)is usually defined as follows Condition when patient’s total body weight is more than 25% above desirable weight 45 kg ± 1 kg/2.5 cm above or below 150 cm in height IBW (women) Drug distribution changes due to changes in body composition in the obese patient. Height (in inches) Weight (in kilograms) Percentage of fat and lean body mass in an individual estimated by measuring using the umbilical level at exhalation Girth (in inches) = 90 — 2 (Height — Girth) Percent fat how to calculate IBW in men and women? & to learn calculations for Percent fat and Lean body mass Data used in equations Lean body mass = (100 — Percent fat) x Weight Check the slide no.17 to find the examples sometimes conflated with fat-free mass, is a component of body composition. Fat free mass (FFM) is calculated by subtracting body fat weight from total body weight: total body weight is lean plus fat. LBM = BW − BF Lean body mass equals body weight minus body fat. LBM + BF = BW Lean body mass plus body fat equals body weight. it would typically be 60–90%. Instead, the body fat percentage, which is the complement, is computed, and is typically 10–40%. Lean body mass (LBM) for prescribing proper levels of medications. The lean body mass (LBM) has been described as an index superior to total body weight For men LBM=(0.407×W)+(0.267×H)− 19.2 For women The Boer formula for calculating LBM is for assessing metabolic disorders, as body fat is less relevant for metabolism. LBM = (0.252 × W) + (0.473 × H) − 48.3 where W is body weight in kilograms and H is body height in centimeters. Smaller ratio of body water and muscle mass to total body weight. Fat contains less extracellular fluid than other tissues. More fat + less water in their body = so low dose will be given. Distribution space for polar drugs, like antibiotics, is relatively less in obese. Drug binding, metabolism, and excretion affected by obesity. If drug largely excreted unchanged or eliminated through formation of sulfate or glucuronide conjugates. Greater proportion of body fat in obese Creatinine clearance increased in obese patients. What could lead to changes in drug partitioning into various body compartments? Renal clearance may be increased to a similar or greater extent. formidable challenge Selection of appropriate dosing regimens for severely obese patient Renal excretion greater in obese patients. Changes in dosing regimen for obese patients anticipated Changes in renal blood flow and glomerular filtration rate secondary to increased blood volume and cardiac output. Metabolic clearance reflecting conjugation with sulfate or glucuronic acid also increases as function of body weight Dosing guidelines for children more complicated than those for adults. Children require and tolerate larger mg/kg doses of many drugs than do adults. These doses result in average digoxin concentrations in plasma of about 1 to 1.5 ng/ml when given to patients of appropriate age. Neonates, Infants, and Children On basis of surface area of young patient relative to surface area of an adult. Pharmacokinetic Variability Body surface area (SA) calculated using the following height-weight formula. How do you estimate dose required for infants and children ? SA = (height X weight)1/2/60 Age-related changes in drug distribution Water- soluble drugs Decreased volume of distribution in adults compared with neonates. Lipid soluble drugs Lower volume of distribution in neonates More water content in neonates. Less lipid content in neonates. Why? Age-related differences in adipose tissue. also affects drug distribution. Age-related changes in body composition at other end of life Lean body mass decreases. Elderly Patients Body fat increases in relation to total body weight in aging individual. Water-soluble drug such as Apparent volume of distribution antipyrine Lipid-soluble drugs such as may remain the same or decrease slightly with age. Diazepam may be much larger in elderly patients than in younger ones. Drug binding, metabolism, and excretion change with age. AGE Not fully kidney functioning, even if size is perfect. Drug elimination impaired in newborns, particularly premature newborns. Pharmacokinetics in the Elderly Patients This will be improved with age and tends to be more efficient in older infants and children. Thereafter drug elimination declines with age. Their titers usually lower than adult levels. Most of the enzymatic microsomal systems required for drug metabolism present at birth Drugs subject to biotransformation are eliminated more slowly in newborns than in adults. Binding to plasma proteins less in the newborns than in the adults. An increase in apparent volume of distribution in the newborn. Plasma Protein Binding in Newborns Diazepam Drug Metabolism in Newborns despite the fact that the fraction unbound to plasma proteins is 4 times larger in neonates than in adults. Ratio of kidney weight to total body weight in the newborn is twice that in the adult. Organ is anatomically and functionally immature. All aspects of renal function are reduced. Renal Excretion in Newborns Risk of adverse drug effects in newborns is high. Aminoglycosides Indomethacin Digoxin Immature renal function affects elimination of : Penicillins Sulfonamides and many other drugs Drug metabolism impaired in neonates compared to adults. Older infants and children actually metabolize certain drugs more rapidly than adults. Rates of drug metabolism for many drugs reach a maximum somewhere between 6 months and 12 years of age and Declines with age. Accordingly children often require higher mg/kg doses than do adults. antipyrine clindamycin Drug Metabolism in Children diazoxide phenobarbital Drugs showing faster elimination in children than in adults carbamazepine valproic acid ethosuximide theophylline Body surface area better correlate dosing requirements in children than body weight. Child’s maintenance dose : Child’s dose =SA of child (m2)/1.73 m2 x Adult dose (mg/day) Probability of experiencing adverse effects increase with age. Decline in organ function with advancing age. Cardiac output decreases by 30 to 40% between ages of 25 and 65 years. Glomerular filtration rate (GFR) declines progressively with age after age of 20 yr. Diminished urinary excretion of digoxin in the elderly. Differences in the pharmacokinetics of certain drugs between young and old adults Drug Elimination in the Aged Same amount (0.5 mg) of digoxin administered intravenously to elderly men (73 to 81 years) and young men (20 to 33 years) Partly because of reduced cardiac output Changes in drug metabolism with age are not as predictable as changes in renal excretion of drug. Hepatic blood flow declines with age Smaller central compartment Elderly develop high serum levels of thiopental quickly Require less drug to show an effect Dose of thiopental required to reach a surgical level of anesthesia significantly decreased with increasing age. Kinetics of large number of benzodiazepines studied with respect to sex-related difference. Clearance or apparent clearance of temazepam, oxazepam and lorazepam significantly less in human female subjects than in males. Clearance 40% greater in males than in females Studies in human subjects with acetaminophen Increased activity of glucuronidation pathway in males 252 mI/min in males Formation clearance of acetaminophen glucuronide Salicylic acid clearance 60% higher in male than in female subjects Why? 173 mI/min in females Enhanced activity of glycine conjugation pathway in males. Delayed gastric emptying Decreased motility of gastrointestinal tract Changes may reduce rate of drug absorption Growth of uterus Pregnancy Volume available for drug distribution increases during pregnancy Why? placenta fetus Maternal plasma volume and ECF volume also increase. Concentration of plasma proteins tend to fall gradually during pregnancy Protein binding of many (but not all) drugs decreased during pregnancy Glomerular filtration increases For drugs largely eliminated by renal excretion Drug binding may be reduced. particularly during last trimester. May result in unusually rapid elimination Major cause of intersubject variability in drug metabolism. Individuals who metabolize a drug much more slowly or much more rapidly than average person. GENETIC FACTORS Genetic factors contribute substantially to large differences among people in metabolic clearance of drugs. The study of these differences is called pharmacogenetics Studies in Twins Reason Increasing age associated with reduced renal function. Decreasing renal function might contribute to alteration in drug disposition. ‘Increased sensitivity’ of the elderly to thiopental. Gender Higher blood concentrations and longer half-lives in the elderly. Genetic component can be estimated by comparing pharmacokinetics of a drug in identical and fraternal twins. Variability in rates of drug metabolism will be much smaller in monozygotic (identical) twin pairs than in dizygotic (fraternal) twin pairs. Why? Clearance of drugs with liver blood flow- dependent elimination may decrease in the elderly. Important age-related changes reported for drugs showing marked first-pass metabolism.