Determination of a safe and effective drug dose for the paedi- atric patient is essential for the treating physician. Doses and dosing intervals in children differ from that of an adult because of age-related variations in drug absorption, distribution, metabolism and elimination. Oral drug absorption matures by four to five months of age. Drugs like phenytoin and chloramphenicol are absorbed slowly and erratically whereas penicillin and ampicillin are absorbed more efficiently than in the adults because of a higher gastric pH in the neonates. Most drug metabolizing enzymes are expressed at low levels at birth followed by postnatal induction of specific isoenzymes. For most drugs including phenytoin, barbiturates, digoxin and analgesics the plasma half-lives are 2 to 3 times longer in neonates as compared to adults. Renal elimination of drugs is also reduced in the neonates. As a result, neonatal dosing regimens for a number of drugs must be reduced to avoid toxicity. Drug pharmacodynamics may also be different in children, e.g., antihistamines and barbiturates that are generally sedatives in adults may be excitatory in pediatric age group. Similarly, specific drug toxicities may be unique to this age group as evident in case of tetracyclines affecting teeth and glucocorticoids reducing linear growth of bones.
Because of these maturational differences in infants and children, simple proportionate reduction in the adult dose may not be adequate to determine an optimal paediatric dose. The most reliable dose information is usually the one provided by the drug manufacturer in the package insert or paediatric doses listed in the formulary. However, such information is not available for the majority of drugs since proper dose optimization studies are often not performed in the paediatric age range. Consequently, initial doses are derived by scaling down the dosages used in adults and then titrating according to clinical response.
In the absence of specific paediatric dose recommendations, an estimate can be made by any of several methods based on age, weight or surface area.
Various rules of dosage in which the paediatric dose is a fraction of adult dose based on relative age havebeen used. Two of these are mentioned below:
Young’s rule (for children 2 years and older)
Child’s dose (approx.) = Age (years) + 12/ Age (years) +12 x Adult Dose
Fried’s rule (for children up to 2 years old)
Child's dose (approx.) = Age (months) / 150 x Adult dose
Because of large variability in weight among children of same age group, estimation of drug dosage for children on the basis of body weight is considered more reliable than that based solely on age. A rule proposed by Professor A. J. Clark ( known as the Clark’s rule) introduced weight proportional regimen for drug therapy.
Child's dose (approx.) = Weight (kg) / 70 x Adult dose
The most dependable methods for calculation of paediatric drug doses are those based on body surface area (BSA). Rate of metabolism and redistribution of drug, organ size, blood volume, extracellular fluid volume, renal blood flow and assays of blood concentration of drugs correlate closely with the BSA
Child’s dose (approx.) =BSA (m2) / 1.73 m2 x Adult dose
For calculation of doses based on BSA, standard nomogram which includes both body weight and height as factors determining BSA should be used. To calculate a child’s BSA, draw a straight line from the height column to the weight column. The point at which the line intersects the surface area (SA) column is the BSA (m2). If the child is of roughly normal proportion, BSA can be calculated from the weight alone (in the enclosed area)
Note: This nomogram was published in Nelson Textbook of Pediatrics, 18th Edition, Richard E. Behrman, Robert M. Kliegman, MD, Hal B, Jenson, MD and Bonita F. Stanton, MD, Nomogram for the estimation of surface area, page no. 2951, fig no. 715-1, W. B. Saunders Company, 2007 and has been reproduced with permission.
The above mentioned rules are helpful in situations requiring the use of a drug that is unlicensed in children and for which no paediatric prescribing information is available. However, these rules are not precise and doses should not be calculated if it is possible to obtain the actual paediatric dose. Whatever be the method chosen to calculate the child’s dose, it should never exceed that of an adult.
Aging is a natural process of human development and is characterised by a progressive loss of physiologic and reproductive functions. Altered response to drugs with aging occurs at both pharmacokinetic and pharmacodynamic levels.
Pharmacokinetic changes occur with the age as a result of the inevitable anatomical and physiological changes which occur with time, such as loss of an organ’s functional units (nephrons, neurons) and distruption of some regulatory processes between cells and organs, resulting in decrease in function of body systems. For example, first pass metabolism decreases due to decrease in liver mass and blood flow, resulting in an increase in bioavailability of drugs which undergo extensive first pass metabolism, such as, propranolol. Another example of a pharmacokinetic change is the reduced clearance of renally-cleared drugs due to reduced renal plasma flow and glomerular filtration. This increases the potential for toxic effects particularly with those drugs where even marginal accumulation can have toxic effects, e.g., digoxin and lithium. Changes in body composition such as increase in body fat proportion and decrease in total body water result in a decreased volume of distribution for water soluble drugs such as digoxin, which increases their serum concentrations and potential for adverse effects.
Geriatric patients are much more “sensitive” to the action of many drugs, implying a change in the pharmacodynamic interactions of the drugs with their receptors. Elderly are more sensitive to some sedative-hypnotics and analgesics. Certain homeostatic control mechanisms appear to be blunted in elderly. Since homeostatic responses are often important components of the total response to a drug, these physiological alterations may change the pattern or intensity of drug response.
The age-related changes in the functions and composition of the human body require adjustments of drug selection and dosage for old individuals. Drug excretion via the kidneys declines with age, the elderly should therefore be treated as renally insufficient patients. A rough estimate of creatinine clearance can be obtained from the Cockcroft-Gault formula:
Creatinine clearance (ml/min) = (140 - Age) x (Weight in kg) / 72 x serum creatinine in mg/dL (for males)
For females, the result is multiplied by 0.85. The formula is applicable to patients between the age of 40 and 80.
The metabolic clearance is primarily reduced with drugs that display high hepatic extraction (‘blood flow-limited metabolism’), whereas the metabolism of drugs with low hepatic extraction (‘capacity-limited metabolism’) usually is not diminished. Reduction of metabolic drug elimination is more pronounced in malnourished or frail subjects. The water content of the aging body decreases, the fat content rises, hence the distribution volume of hydrophilic compounds is reduced in the elderly, whereas that of lipophilic drugs is increased. Intestinal absorption of most drugs is not altered in the elderly. Aside of these pharmacokinetic changes, one of the characteristics of old age is a progressive decline in counter-regulatory (homeostatic) mechanisms. Therefore drug effects are mitigated less, the reactions are usually stronger than in younger subjects, the rate and intensity of adverse effects are higher. Examples of drug effects augmented in this manner are, postural hypotension with agents that lower blood pressure, dehydration, hypovolemia and electrolyte disturbances in response to diuretics, bleeding complications with oral anticoagulants, hypoglycemia with antidiabetics, and gastrointestinal irritation with non-steroidal anti-inflammatory drugs. The brain is an especially sensitive drug target in old age. Psychotropic drugs, but also anticonvulsants and centrally acting antihypertensives, may impede intellectual functions and motor coordination. The antimuscarinic effects of some antidepressants and neuroleptic drugs may be responsible for agitation, confusion and delirium in the elderly. Hence, drugs should be used very restrictively in geriatric patients. If drug therapy is absolutely necessary, the dosage should be titrated to a clearly defined clinical or biochemical therapeutic goal starting from a low initial dose.