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Clinical Pharmacology in Special Clinical Pharmacology in Special PopulationsPopulations

Patty Slattum, PharmD, PhDPatty Slattum, PharmD, PhDMarch 31, 2014March 31, 2014

Learning Objectives

Define pharmacokinetics and pharmacodynamics Define older adult Describe 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

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Drug

Concentrationin the

Circulation

PK

•Absorption•Distribution•Metabolism•Excretion

Drug

Effect

PD

•Drug-receptor interactions

•Concentration at receptor

•Homeostatic mechanisms

Desirable

Therapeutic

Outcome

Efficacy

•compliance

•disease characteristics

Clinical Pharmacology in Special Clinical Pharmacology in Special Populations: PediatricsPopulations: Pediatrics

Clinical Pharmacology in Special Clinical Pharmacology in Special Populations: PediatricsPopulations: Pediatrics

DefinitionsPremature infant

Gestational age less than 36 weeks

Full-term infant

Gestational age 36 weeks to birth

Neonate First month of postnatal life

Infant 1to 12 months of age

Child 1to 12 years of age

Adolescent 12 to 18 years of age

Adult Greater than 18 years of age

Introduction• By 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.

Drug AbsorptionPopulation 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 AbsorptionPopulation 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

Examples

• Hydrocortisone– Systemic absorption and toxicity

• Povidone-Iodine– Iodine toxicity in neonates

Absorption:Take home message

• Most 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 DistributionPopulation 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/Sulfamethoxazole

– Sulfamethoxazole displaces bilirubin from protein binding sites

• Digoxin– Myocardial-to-plasma digoxin concentration:

• 2-3 times adult values• Increased distribution to heart tissue has to be

accounted for in dosing

• Gentamicin– Larger 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 MetabolismPopulation 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 caffeine

– Approximately 50% reduction in neonates – Approximately 50% higher doses than adults

for children 2-10 years of age – Adolescents similar to adult doses

• Chloramphenicol– Glucuronidation 10% of adult values until 2-4

years of age– Gray 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 EliminationPopulation 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.

Example• Digoxin

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.

Pharmacodynamics

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

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Clinical Pharmacology in Special Clinical Pharmacology in Special Populations: GeriatricsPopulations: Geriatrics

INTRODUCTION

Definition of elderly Aging versus disease “Usual” versus “Successful” Aging

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

Drug Absorption

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gastric pH GI fluid volume

GI surface area

GI transit time

intestinal/hepatic blood flow

gut wall enzymes

Examples

Alendronate, NSAIDS: Should ensure that immobile patients are sitting up for at least 30 minutes after dosing

Vitamin D, folate and B12 absorption may be decreased in elderly

Levodopa 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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Examples

There may be reduced absorption rate of some antibiotics from the site of an intramuscular injection in the elderly

With 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

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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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Examples

Ethanol 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 message

Distribution 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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Examples

Allopurinol (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

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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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Examples

For 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 PK Lorazepam and oxazepam are preferred over

diazepam and flurazepam in the elderly (Beers criteria)

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

Metabolism:Take home message

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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.

Pharmacodynamics

Changes in receptor responsiveness– receptor number– receptor affinity– signal transduction mechanisms– cellular responses

Changes in homeostatic regulation– Decreased physiologic reserve

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Pharmacodynamics:Take home message

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Age-related changes in receptors and homeostatic control may alter an elderly patient’s response to drug therapy.

Case Study

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Episode 1: Before Hospital Admission

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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 nurse’s 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

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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 patient’s 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

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After the 4-week hospital stay, a conference was held with the patient’s 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.

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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.

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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

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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.

References

Bowie 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?Questions?Questions?Questions?