Nomograms and Tabulations in designing dosage regimen


Presentation Description

Nomograms and Tabulations in designing dosage regimen Determination of dose and dosing intervals, Drug dosing in the elderly and pediatrics and obese patients. Dedicated to PharmD students in India and abroad


Presentation Transcript

Nomograms and Tabulations in designing dosage regimen :

Dr P R Deshpande Nomograms and Tabulations in designing dosage regimen

Overview :

Overview Synonym Definition General info Uses

What is nomogram?:

What is nomogram ? Syn = Nomograph , alignment chart Def= A line chart in toxicology that relates time since toxic ingestion with blood levels of the offending agent to estimate levels of toxicity and to guide therapy.


BASICS OF NOMOGRAMS In order to keep the dosage regimen calculation simple, complicated equations are often solved and the results displayed diagrammatically on special scaled axes to produce a simple dose recommendation based on patient information. Some nomograms make use of certain physiologic parameters, such as serum creatinine concentration, to help modify the dosage regimen according to renal function


USES OF NOMOGRAMS For ease of calculation of dosage regimens, many clinicians rely on nomograms to calculate the proper dosage regimen for their patients. The use of a nomogram may give a quick dosage regimen adjustment for patients with characteristics requiring adjustments, such as age, body weight, and physiologic state .

Slide 6:

For many marketed drugs, the manufacturer provides tabulated general guidelines for use in establishing a dosage regimen for patients, including loading and maintenance doses. For drugs with a narrow therapeutic range, such as theophylline , a guide for monitoring serum drug concentrations is given. Another example is the aminoglycoside antibiotic, tobramycin sulfate USP ( Nebcin , Eli Lilly), which is eliminated primarily by renal clearance. Thus, the dosage of tobramycin sulfate should be reduced in direct proportion to a reduction in creatinine clearance

Slide 7:

The manufacturer provides a nomogram for estimating the percent of the normal dose of tobramycin sulfate assuming the serum creatinine level (mg/100 mL ) has been obtained.



Overview :

Overview Important concepts PAH clearance GST Types of pediatric population Problems with pediatric population e.g. less research, PKPD changes Some examples of solutions e.g. calibrated dropper, gluteus medius injections, cherry flavor Infant vs adult (body weight, body water, insulin clearance, PAH clearance) Half lives of some drugs in infant and adult

Slide 12:

PK parameters and examples A: gastric pH, GET, intestinal CYP , transport, GST, percutaneous absorption D: Body water: Fat ratio, Protein binding, M: Phase I and II enzymes E: GFR, Reabsorption and secretion Phase 2 enzyme activities Mosteller’s equation Some more info Practice problem

PAH clearance:

PAH clearance Para- aminohippurate (PAH) clearance is a method used in renal physiology to measure renal plasma flow, which is a measure of renal function. The concentration of PAH is measured in one arterial blood sample (PPAH) and one urine sample(UPAH).


GST Glutathione S- transferases (GSTs), previously known as ligandins , comprise a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the purpose of detoxification.

Slide 15:

Infants and children have different dosing requirements than adults. Types of pediatric patients preterm newborn infant, newborn infant (birth to 28 days), infant (28 days to 23 months), young child (2 to 5 years), older child (6 to 11 years), adolescent (12 to 18 years) Unfortunately, the pharmacokinetics and pharmacodynamics of most drugs are not well known in children under 12 years of age.

Slide 16:

The variation in body composition and the maturity of liver and kidney function are potential sources of differences in pharmacokinetics with respect to age. For convenience, "infants'' are here arbitrarily defined as children 0 to 2 years of age. However, within this group, special consideration is necessary for infants less than 4 weeks (1 month) old, because their ability to handle drugs often differs from that of more mature infants.

Slide 17:

In addition to different dosing requirements for the pediatric population, there is a need to consider the use of pediatric dosage forms that permit more accurate dosing and patient compliance. For example, liquid pediatric drug products may come with a calibrated dropper or a premeasured teaspoon (5 mL ) for accurate dosing and have a cherry flavor for pediatric patient compliance. Pediatric drug formulations may also contain different drug concentrations compared to the adult drug formulation. Furthermore, alternative drug delivery such as an intramuscular antibiotic drug injection into the gluteus medius may be considered for a pediatric patient, as opposed to the deltoid muscle for an adult patient.

Slide 18:

In general, complete hepatic function is not attained until the third week of life. Oxidative processes are fairly well developed in infants, but there is a deficiency of conjugative enzymes. In addition, many drugs exhibit reduced binding to plasma albumin in infants. Newborns show only 30-50% of the renal activity of adults on the basis of activity per unit of body weight. Drugs that are heavily dependent on renal excretion will have a sharply decreased elimination half-life. For example, the penicillins are excreted for the most part through the kidney.

Mosteller’s equation:

Mosteller’s equation Surface area= (height X weight) ½ / 60

Some more info:

Some more info Infants and children require larger mg/kg doses than adults because: Their body surface area per kg body weight is larger hence Larger Vd Child’s maintenance dose can be calculated from adult dose by following equation: Child dose= SA of child in sq. m./1.73 X adult dose SA (in sq. m)= Body weight (in kg) 0.7

Slide 25:

As TBW in neonates is 30% more than the adult Vd for most of the water soluble drugs is larger in infants Vd for most lipid soluble drug is smaller

Practice Problem:

Practice Problem The elimination half-life of penicillin G is 0.5 hour in adults and 3.2 hours in neonates (0 to 7 days old). Assuming that the normal adult dose of penicillin G is 4 mg/kg every 4 hours, calculate the dose of penicillin G for an 11-pound infant.




OVERVIEW Basic concepts LBW Baroreceptor MDRD equation CrCl Cockroft gault formula Introduction Types of elderly Changes in elderly

Slide 31:

Pharmacokinetic aspects Absorption Distribution Metabolism Elimination Response Drug examples Practice problem

Basic concepts:

Basic concepts

Lean body weight:

Lean body weight Your lean body mass is the amount of weight you carry on your body that isn't fat.

Baroreceptor :

Baroreceptor Baroreceptors (or archaically, pressoreceptors ) are sensors located in the blood vessels of all vertebrate animals. They sense the blood pressure and relay the information to the brain, so that a proper blood pressure can be maintained.

MDRD equation:

MDRD equation Modification of Diet in Renal Disease

Cockroft Gault formula:

Cockroft Gault formula For calculating CrCl

Slide 38:

Defining "elderly'' is difficult. The geriatric population is often arbitrarily defined as patients who are older than 65 years, and many of these people live active and healthy lives. In addition, there is an increasing number of people who are living more than 85 years, who are often considered as the "older elderly'' population. The aging process is more often associated with physiologic changes during aging rather than purely chronological age. Chronologically, the elderly have been classified as the young old (ages 65-75 years), the old (ages 75-85 years), and the old old (age > 85 years).

Slide 39:

Performance capacity and the loss of homeostatic reserve decreases with advanced age but occurs to a different degree in each organ and in each patient. Physiologic and cognitive functions tend to change with the aging process and can affect compliance and the therapeutic safety and efficacy of a prescribed drug. The elderly also tend to be on multiple drug therapy due to concomitant illness. Decreased cognitive function in some geriatric patients, complicated drug dosage schedules , and/or the high cost of drug therapy may result in poor drug compliance, resulting in lack of drug efficacy, possible drug interactions , and/or drug intoxication.

Slide 40:

Several vital physiologic functions related to age as measured by markers show that renal plasma flow, glomerular filtration, cardiac output, and breathing capacity can drop from 10% to 30% in elderly subjects compared to those at age 30. The physiologic changes due to aging may necessitate special considerations in administering drugs in the elderly. For some drugs, an age-dependent increase in adverse drug reactions or toxicity may be observed. This apparent increased drug sensitivity in the elderly may be due to pharmacodynamic and/or pharmacokinetic changes

Slide 41:

The pharmacodynamic hypothesis assumes that age causes alterations in the quantity and quality of target drug receptors, leading to enhanced drug response. Quantitatively, the number of drug receptors may decline with age, whereas qualitatively, a change in the affinity for the drug may occur. Alternatively, the pharmacokinetic hypothesis assumes that age-dependent increases in adverse drug reactions are due to physiologic changes in drug absorption, distribution, and elimination, including renal excretion and hepatic clearance.

Slide 42:

In the elderly, age-dependent alterations in drug absorption may include a decline in the splanchnic blood flow, altered gastrointestinal motility, increase in gastric pH, and alteration in the gastrointestinal absorptive surface. The incidence of achlorhydria in the elderly may have an effect on the dissolution of certain drugs such as weak bases and certain dosage forms that require an acid environment for disintegration and release.

Slide 43:

From a distribution consideration, drug protein binding in the plasma may decrease as a result of decrease in the albumin concentration, and the apparent volume of distribution may change due to a decrease in muscle mass and an increase in body fat. Renal drug excretion generally declines with age as a result of decrease in the glomerular filtration rate and/or active tubular secretion. Moreover, the activity of the enzymes responsible for drug biotransformation may decrease with age, leading to a decline in hepatic drug clearance.

Slide 44:

Elderly patients may have several different pathophysiologic conditions that require multiple drug therapy that increases the likelihood for a drug interaction. Moreover, increased adverse drug reactions and toxicity may result from poor patient compliance. Both penicillin and kanamycin show prolonged t 1/2 in the aged patient, as a consequence of an age-related gradual reduction in the kidney size and function.

Slide 45:

The Gaultâ €“ Cockroft rule for calculating creatinine clearance clearly quantitates a reduction in clearance with increased age. Age-related changes in plasma albumin and 1-acid glycoprotein may also be a factor in the binding of drugs in the body.

Pharmacokinetic Changes of Aging Absorption :

Pharmacokinetic Changes of Aging Absorption Though numerous structural and physiological age-related changes in the GI tract exist, they are of minimal clinical significance in the absence of gastrointestinal pathology Decreased first-pass after oral administration – morphine, isosorbide dinitrate Heart failure can affect the absorption of some medications including furosemide Effects of aging on percutaneous , subcutaneous and intramuscular absorption is largely unknown but in states of poor perfusion expect delayed or incomplete absorption

Distribution (volume of distribution) :

Distribution (volume of distribution) Body Composition Changes Lean-to-fat ratio altered – digoxin Decreased total body water - lithium Protein concentration changes – warfarin

Pharmacokinetic Changes of Aging Metabolism (clearance) :

Pharmacokinetic Changes of Aging Metabolism (clearance) Liver size, blood flow decline with age altering the metabolism of drugs with high-flow dependent metabolism such as propranolol and verapamil Some but not all Phase I metabolic pathways performed by the CYP system (oxidation, reduction, hydrolysis) diminish with age Diazepam , chlordiazepoxide , alprazolam , flurazepam Phase II (conjugation) metabolic pathways do not appear to diminish with age Lorazepam , oxazepam , triazolam , temazepam

Pharmacokinetic Changes of Aging Elimination (clearance) :

Pharmacokinetic Changes of Aging Elimination (clearance) Majority of people over the age of 50 lose 10% of renal function per decade Digoxin , aminoglycosides , vancomycin , pencillins , cephalosporins , salicylate metabolites, quinolones , etc. Reliability of the Cockroft-Gault equation for estimating CrCl Underestimates true CrCl in older people of normal weight Overestimates true CrCl in older people who are under weight MDRD equation (Modification of Diet in Renal Disease) – not validated in older people


PRACTICE POINTS Drug dose should be reduced in elderly patients because of general decline in body functions Lean body mass decreases and body fat increases by 100% in geriatric patients Because of smaller volume of body water, higher peak alcohol levels are observed in elderly Vd of a water soluble drug may decrease

Equation :

Equation Maintenance dose of a patient of any age (except neonates and infants) = (pt weight in kg) (140-age in years) 0.7 /1660 X Adult dose

Practice problem:

Practice problem The clearance of lithium was determined to be 41.5 mL /min in a group of patients with an average age of 25 years. In a group of elderly patients with an average age of 63 years, the clearance of lithium was 7.7 mL /min. What percentage of the normal dose of lithium should be given to a 65-year-old patient?


Solution The dose should be proportional to clearance; therefore, The dose of lithium may be reduced to about 20% of the regular dose in the 65-year-old patient without affecting the steady-state blood level.

Changes in Renal Function with Age:

Changes in Renal Function with Age Many studies have shown a general decline in glomerular filtration rate (GFR) with age. reported that the GFR as measured by creatinine clearance decreases at a mean rate of 1% per year after 40 years of age. However, there is considerable variation in this rate of decline in normal healthy aging adults. In a previous study by , approximately two-thirds of the subjects (162 of 254) had declining creatinine clearances, whereas about one-third of the subjects (92 of 254) had no decrease in creatinine clearance.

Slide 56:

Since muscle mass and urinary creatinine excretion decrease at nearly the same rate in the elderly, mean serum concentrations may stay relatively constant. Creatinine clearance measured by serum creatinine concentrations only (see ) may yield inaccurate GFR function if urinary creatinine excretion is not measured.


CASE STUDY An elderly 85-year-old adult patient with congestive heart failure has a serum creatinine of 1.0 mg/ dL . The 24-hour urinary creatinine excretion was 0.7 g. Based on the serum creatinine only, this patient has normal renal function, whereas based on both serum creatinine concentration and total 24-hour urinary creatinine excretion, the patient has a GFR of less than 50 mL /min. In practice, serum creatinine clearance is often estimated from serum creatinine concentration alone for dose adjustment. In elderly subjects, the clinician should carefully assess the patient, since substantial deviation from the true clearance may occur in some elderly subjects.



Overview :

Overview IBW BMI Obesity: Epidemiology, problems Important considerations



Slide 61:

Obesity is a major problem in the United States and is also becoming a problem in other countries. Obesity has been associated with increased mortality resulting from increases in the incidence of hypertension, atherosclerosis, coronary artery disease, diabetes, and other conditions compared to nonobese patients . A patient is considered obese if actual body weight exceeds ideal or desirable body weight by 20%.

Slide 62:

Ideal or desirable body weights are based on average body weights and heights for males and for females considering age. Athletes who have a greater body weight due to greater muscle mass are not considered obese. Obesity often is defined by body mass index (BMI), a value that normalizes body weight based on height. BMI is expressed as body weight (kg) divided by the square of the person's height (meters) or kg/m2.

Slide 63:

BMI is calculated according to the following two equations:

Slide 65:

The obese patient (BMI > 30) has a greater accumulation of fat tissue than is necessary for normal body functions. Adipose (fat) tissue has a smaller proportion of water compared to muscle tissue. Thus, the obese patient has a smaller proportion of total body water to total body weight compared to the patient of ideal body weight, which could affect the apparent volume of distribution of the drug. For example, showed a significant difference in the apparent volume of distribution of antipyrine in obese patients (0.46 L/kg) compared to ideal-body-weight patients (0.62 L/kg) based on actual total body weight.

Important general considerations:

Important general considerations Apparent Vd is affected by weight. For drugs such as digoxin that don’t significantly distribute in the excess body space the Vd don’t change hence dose to be administered to be calculated on IBW basis. For polar drugs such as antibiotics ( gemntamicin ) which distribute in excess body space of obese patients to an extent less than that in lean tissues, the dose should be lesser on per kg total body weight basis but more than that on IBW basis

Slide 67:

In case of drugs such as caffeine, theophylline , lidocaine , and lorazepam which distribute to the same extent in both lean and adipose tissues, the Vd is larger in obese patients but same on per kg total body weigh basis For drugs such as phenytoin , diazepam and thiopental which are lipid soluble and distribute more in adipose tissues; the Vd is larger per kg body weight in obese patients and hence they require larger doses, more than that on TBW basis

References :

References http:// Applied Biopharmaceutics and pharmacokinetics by Shargel , Wu Pong and Yu A. Fifth edition .

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