*Clinical Pharmacology in Special Populations

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Learning ObjectivesDefine pharmacokinetics and pharmacodynamicsDefine older adultDescribe physiologic changes associated with aging and their potential impact on PK and PD of drugs in older adults.Define the stages of early human development important for determining doses in pediatric patients.Describe physiologic changes associated with growth and development and their potential impact on the PK/PD of drugs in children

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The Clinical Pharmacology Paradigm: Pharmacokinetics, Pharmacodyamics and Therapeutics*Drug

Concentrationin theCirculationPKAbsorptionDistributionMetabolismExcretion

Drug EffectPDDrug-receptor interactionsConcentration at receptorHomeostatic mechanisms

DesirableTherapeuticOutcomeEfficacycompliancedisease characteristics

Clinical Pharmacology in Special Populations: Pediatrics

Definitions

Premature infantGestational age less than 36 weeksFull-term infantGestational age 36 weeks to birthNeonateFirst month of postnatal lifeInfant1to 12 months of ageChild1to 12 years of ageAdolescent12 to 18 years of ageAdultGreater than 18 years of age

IntroductionBy their first 5 years of life, 95% of children have been prescribed medications.The greatest number of prescriptions is given to children between 7 and 12 months of age.Only recently have pediatric clinical pharmacology studies been expected by the FDA to support new drug approvals.PK studies are difficult to perform in children due to ethical concerns and limited volume and number of blood samples that can be obtained.

Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents.Kearns GL et al. N Engl J Med 2003;349:1157-1167.

*Figure 1. Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents.Physiologic changes in multiple organs and organ systems during development are responsible for age-related differences in drug disposition. As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first two months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific. Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution for drugs. Infants in the first six months of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. Panel C shows the age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (Panel A), the activity of cytochrome P-450 1A1 (CYP1A1) in the intestine is low during early life. Panel D summarizes the effect of postnatal development on the processes of active tubular secretion represented by the clearance of para-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 months of age. Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body-surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood. Data were adapted from Agunod et al.,4 Rodbro et al.,5 Poley et al.,9 Gibbs et al.,21 Okah et al.,24 West et al.,27 Friis-Hansen,38 Young and Lietman,39 Hines and McCarver,40 Treluyer et al.,41 Kinirons et al.,42 Pynnnen et al.,43 Aranda et al.,44 Miller et al.,45 Barrett et al.,46 Murry et al.,47 and Robillard et al.48

Drug Absorption

Population

Physiologic Change

Effect on PK

Neonates, infants, young children

(gastic pH

Change in rate of dissolution and absorption

Neonates, infants

(gastric emptying and GI transit times, (peristalsis

Variable effects on rate and extent of absorption

Older infants, children

( GI transit time and

( motility

Unpredictable effects on rate and extent of absorption

Drug Absorption

Population

Physiologic Change

Effect on PK

Premature infants

(GI enzyme activity

Variable effects on rate and extent of absorption

Neonates

(bile salts

(absorption of some drugs

Infants

Changes in intestinal microflora

( absorption of some drugs

Drug Absorption

Population

Physiologic Change

Effect on PK

Neonates, infants, young children

Blood flow ((in newborns and ( in infants and children), vasomotor instability, insufficient muscle tone, (muscle oxygenation

Unpredictable intramuscular absorption

Neonates, infants

(skin permeability

Increased absorption through the skin

ExamplesHydrocortisoneSystemic absorption and toxicityPovidone-IodineIodine toxicity in neonates

Absorption:Take home messageMost drugs are well absorbed in pediatric patients. The rate of absorption may be delayed, but the extent is not significantly changed for most drugs. Physiologic changes as well as concurrent diseases (Ex: inflammatory bowel disease, prolonged diarrhea, gastroenteritis, malabsorption syndrome, congenital heart disease) are responsible for the increased variability in drug absorption observed in pediatric patients.

Drug Distribution

Population

Physiologic Change

Effect on PK

Neonates, infants

(total body water

(extracellular water

(body fat

(volume of distribution for water soluble drugs

( volume of distribution for lipid-soluble drugs

Kearns GL, et al., NEJM 2003;349:1157-1167.

Drug Distribution

Population

Physiologic Change

Effect on PK

Neonates, infants

( albumin levels (80% of adult value for neonates), (binding capacity, (binding affinity, competition for binding with endogenous compounds such as bilirubin and free fatty acids

(fraction bound for drugs highly bound to albumin

Neonates

( (1-acid glycoprotein binding

(fraction bound for drugs highly bound to (1-acid glycoprotein

Examples:

Trimethoprim/SulfamethoxazoleSulfamethoxazole displaces bilirubin from protein binding sitesDigoxinMyocardial-to-plasma digoxin concentration: 2-3 times adult valuesIncreased distribution to heart tissue has to be accounted for in dosingGentamicinLarger weight-based doses needed because gentamicin distributes in body water

Drug Distribution:Take home message Distribution of drugs may be altered in pediatric patients not only due to age-related physiologic changes, but due to concurrent diseases as well. The clinical significance of these changes depends on the drug under consideration.

Drug Metabolism

Population

Physiologic Change

Effect on PK

Premature, neonates, infants

(oxidative enzyme activity (neonates have 20-70% of adult values for cytochrome p450 activity)

(drug metabolism or use of alternate routes of metabolism

Neonates, infants

(glucuronide conjugation, but well-developed sulfate conjugation

(drug metabolism or use of alternate routes of metabolism

Young children

(enzyme capacity for methylation

(drug metabolism

Kearns GL, et al., NEJM 2003;349:1157-1167.

Examples

CYP1A2 and caffeineApproximately 50% reduction in neonates Approximately 50% higher doses than adults for children 2-10 years of age Adolescents similar to adult dosesChloramphenicolGlucuronidation 10% of adult values until 2-4 years of ageGray baby syndrome

Drug Metabolism:Take home message In general, hepatic oxidative drug metabolism is decreased in neonates and infants. There is generally an increase in drug clearance in children under 10 years of age compared to adults. The effects of development may be compounded by diseases such as heart failure which can reduce liver blood flow.

Renal Elimination

Population

Physiologic Change

Effect on PK

Neonates, infants

(filtration, reabsorption, secretion by the kidney

(clearance of renally-excreted drugs and metabolites

Kearns GL, et al., NEJM 2003;349:1157-1167.

ExampleDigoxin

Renal Elimination:Take home message Decreased renal clearance of drugs in pediatric patients is an important age-related change in PK, and may be due to changes in filtration, reabsorption, or secretion.

PharmacodynamicsMuch less is known about PD changes in pediatric patients. Receptor binding or the function of homeostatic mechanisms may be altered.

*Clinical Pharmacology in Special Populations: Geriatrics

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INTRODUCTIONDefinition of elderlyAging versus diseaseUsual versus Successful Aging

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*http://lydia.bradley.edu/hilltopics/11winter/feature/

Drug Absorption * gastric pH GI fluid volume GI surface area GI transit time intestinal/hepatic blood flow gut wall enzymes

ExamplesAlendronate, NSAIDS: Should ensure that immobile patients are sitting up for at least 30 minutes after dosingVitamin D, folate and B12 absorption may be decreased in elderlyLevodopa bioavailability increased by three-fold due to reduction in gastric wall content of dopa decarboxylase in older adults

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Drug absorption muscle blood flow muscle mass skin hydration keratinized cells thinning of dermis abraded areas use of occlusive dressings

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ExamplesThere may be reduced absorption rate of some antibiotics from the site of an intramuscular injection in the elderlyWith topical steroids such as fluocinonide, systemic absorption is more likely to occur when used on large surfaces, with occlusive dressings, or with age-related changes in the skin.

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Drug Absorption:Take home message*Most drugs are well-absorbed in the elderly. The rate of absorption may be delayed for some drugs in some patients, but the extent is not significantly changed. Age-related changes as well as concurrent diseases result in increased variability in drug absorption in the elderly.

Distribution lean body mass total body water total body fat serum albumin levels (15-20%)

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ExamplesEthanol distributes in body water. Volume of distribution decreases by about 20% in the elderly.Diazepam distributes in body fat. Its volume of distribution increases and is correlated with age.

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Distribution:Take home messageDistribution may be altered in the elderly due to age-related physiologic changes and concurrent diseases. Lipid-soluble drugs may show an increased volume of distribution and water-soluble drugs may show a decreased volume of distribution in older patients related to these changes in body composition. Age-related changes in protein binding do not generally result in clinically significant changes in drug therapy for elderly patients.

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Renal Excretion renal blood flow, glomerular filtration rate, altered tubular function Glomerular filtration rate declines about 10% per decade after age 20

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ExamplesAllopurinol (dose based on CrCl: 140 ml/min = 400 mg qd; 20 ml/min = 100 mg qd)Amantidine (half-life = 2-7 hr for normal renal function, 24-29 hr in the elderly) Digoxin (half-life = 38-48 h in normal renal function, 69 h on average in the elderly)Ceftazidime (dose based on renal function and not more frequently than every 12 h in the elderly)Nitrofurantoin (less effective when CrCl < 60 ml/min)

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Renal Excretion:Take home message*Decreased renal elimination of drugs in the elderly is the most significant age-related change in PK. It accounts for the majority of necessary dosage adjustments.

Metabolism liver mass/volume and membrane permeability liver blood flow (about 40%) Phase I metabolism (oxidation)No change in Phase II (conjugation)

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ExamplesFor drugs which undergo oxidative metabolism, decrease dose by 30%.

(Ex: phenytoin, midazolam)For drugs which are eliminated following conjugation, no change in dose is needed based on PKLorazepam and oxazepam are preferred over diazepam and flurazepam in the elderly (Beers criteria)

*http://www.americangeriatrics.org/health_care_professionals/clinical_practice/clinical_guidelines_recommendations/2012

Metabolism:Take home message*Drugs metabolized exclusively by Phase II mechanisms are preferred in the elderly. For oxidatively metabolized drugs, dosages should generally be reduced. After initial dosing, doses can be adjusted based on patient response and tolerability. The potential for significant drug interactions, particularly resulting from hepatic enzyme inhibition in elderly patients on multiple medications, must be carefully considered.

PharmacodynamicsChanges in receptor responsiveness

receptor numberreceptor affinitysignal transduction mechanismscellular responsesChanges in homeostatic regulation

Decreased physiologic reserve*

Pharmacodynamics:Take home message*Age-related changes in receptors and homeostatic control may alter an elderly patients response to drug therapy.

Case Study*

Episode 1: Before Hospital Admission*You are a member of the Geriatric Management Team asked to provide consultation on OM, a resident of a LTC facility.OM is an 86 yo male referred to LTC from a local hospital. OM was admitted to the hospital after falling on the steps of the hospital on the way to an outpatient clinic visit.After his fall, he was taken to the ER, where he was found to have an extensive bruise on the right elbow and could not give a clear account of how he fell. He was confused and restless, so he was admitted to the hospital.

Before his admission, he had been seen in his home by a visiting nurse: He lived with his wife in an apartment for at least the previous 8 years. She had severe arthritis, and required assistance with ADLs (provided by OM). A visiting homemaker came twice a week to help in maintaining the apartment. Medical history included: prostatic hypertrophy and transurethral resection hospitalization 5 years age for abdominal pain bouts of constipation/diarrhea for years difficulty falling asleep for several years

For many years, OM enjoyed social contacts with friends. In recent months he noticed that his walking was becoming less steady. Six months before the nurses visit he had fallen in the bathroom and broken his wrist. His medications were: digoxin furosemide flurazepam a variety of OTCs

Episode 2: Hospital Course*On admission to the hospital, OM was described as confused, agitated, and demanding to be released. The admitting physician wrote that he was in incipient heart failure based on 1 to 2+ pitting edema and possible rales.In the days following admission he became more restless, confused, and agitated; restraints had to be used. He seemed unable to walk independently, had a shuffling gait and looked as though he would fall. His sight was impaired, in part due to a cataract.

Over the next 4 weeks, the patients condition remained unchanged, and it was judged that he could not return to his apartment, especially because his wife required considerable care.Medications: Theragran-M qd Slow K 2 tabs QID Digoxin 0.125 mg daily Flurazepam 30 mg hs Imodium 1 cap q6h prn Kaopectate 6 TBSP after each loose bm, prn Haldol 2 mg tid Furosemide 40 mg daily in the am

Episode 3: Placement in LTC*After the 4-week hospital stay, a conference was held with the patients son, and he stated that he could not accommodate his parents in his home. The family arranged for his wife to live with a married daughter in another city and institutional care was arranged for OM.Approximately 2 weeks after entering the nursing home, OM was referred for Geriatric Team evaluation. The team prepared a problem list and a plan of action. One primary objective was to determine the degree to which each of his medications were useful or indicated. A referral for cardiac evaluation was carried out.

*Cardiac evaluation indicated that the digoxin level was 1.5 ng/mL. The patient showed no overt signs of cardiac decompensation. The digoxin was d/cd.Shortly after admission to LTC, the flurazepam was reduced by half and then tapered down gradually over the next 4 weeks. OM was involved in social and recreational activities as much as possible, and daytime napping was discouraged.

*In the following weeks, OM became increasingly coherent and had less difficulty walking. One month later he was alert and oriented and had no difficulty with ambulation. He had mild short-term memory impairment, but his mental status exam was essentially normal. Although he was actively involved with the other patients, he longed to resume his former life with his wife and friends.

Epilogue*And now, what for OM? He no longer justified nursing home placement or skilled care. He received limited assistance from his children and obtained the assistance of social workers in obtaining housing for the well aged. His personal resources had been exhausted and the profound changes in his life, most of which were directly related to the medically prescribed drugs, had become essentially irreversible.

ReferencesBowie MW, Slattum PW. Pharmacodynamics in the elderly: A review. Am J Geriatr Pharmacother 2007;5: 263-303.Cusack BJ. Pharmacokinetics in older persons. Am J Geriatr Pharmacother 2004;2:274-302.Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical Pharmacology in the geriatric patient. Fund Clin Pharmacol 2007;21:217-30.

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Questions?

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*Figure 1. Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents.Physiologic changes in multiple organs and organ systems during development are responsible for age-related differences in drug disposition. As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first two months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific. Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution for drugs. Infants in the first six months of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. Panel C shows the age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (Panel A), the activity of cytochrome P-450 1A1 (CYP1A1) in the intestine is low during early life. Panel D summarizes the effect of postnatal development on the processes of active tubular secretion represented by the clearance of para-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 months of age. Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body-surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood. Data were adapted from Agunod et al.,4 Rodbro et al.,5 Poley et al.,9 Gibbs et al.,21 Okah et al.,24 West et al.,27 Friis-Hansen,38 Young and Lietman,39 Hines and McCarver,40 Treluyer et al.,41 Kinirons et al.,42 Pynnnen et al.,43 Aranda et al.,44 Miller et al.,45 Barrett et al.,46 Murry et al.,47 and Robillard et al.48 *