Upload
louise-lawrence
View
241
Download
3
Embed Size (px)
Citation preview
.... و خدایی که در این نزدیکیست ....
Altered Pharmacokinetics In Pediatrics & Geriatrics
By: Yalda.H.Ardakani
Introduction
• Pediatrics :
Branch of medicine dealing with the development of
disease and disorders in children.
• Children are not “miniature adults”
Subdivisions in children
• Subdivision in children:
Preterm newborn infant
Newborn infant (Birth-28 days)
Infant (28 Days-23 months)
Young Child (2-5 years)
Old Child (6-11 years)
Adolescent (12-18 years)
General considerations
• Pediatric patients were always considered in the past for treatment as MINI ADULTS.
• In 1998, FDA required drug manufacturers to determine
whether existing were sufficient to support information on
pediatric use for drug labeling purpose .
• Only 20-30% of approved drugs have pediatric labeling.
General considerations
• Infancy and childhood is a period of rapid growth
and development of organ systems and so …..
Scaling adult doses to infants based on body
weight or surface area does not account for
developmental changes that affect drug
disposition.
Dose adjustment in pediatrics
Dosage is adjusted based on
pharmacokinetic data of a given age
group for the desired response.
Pediatric dosage forms
• Pediatric dosage forms should permit more accurate
dosing and patient compliance.
• Pediatric drug formulations may also contain different drug concentrations compared to the adult drug formulation.
• Alternative drug delivery may be required.
potential sources of differences in pharmacokinetics
Differences in pharmacokinetics
body composition
Kidney function
maturity of liver
Receptor response
Absorption
Absorption in the Pediatric Patient
• Absorption in the Pediatric Patient Gastrointestinal absorption
Percutaneous absorption
Intra muscular absorption
Absorption - GI
• Gastrointestinal pH changes
• Gastric enzymes
• Gastrointestinal flora
• Gastric emptying & GI motility
• Bile acids & biliary function
Absorption - GI
• Gastrointestinal pH changes
• Gastric pH is neutral at birth, and approaches adult values
approximately in 3 month in full-term infants, so….
– Bioavailability increased for acid-labile drugs
(penicillin derivatives)
– Bioavailability decreased for drugs requiring
acid to be absorbed.
(Phenobarbital)
Absorption - GI
• Gastric emptying
– Delayed and unpredictable in newborns .
– Reaches adult values at ~ 6 month.• GI motility
– Slow in newborns; may be increased in
children.
– Usually affects the rate but not the fraction
of drug absorbed.
– The impact on absorption is usually
minimal but is unpredictable.
Absorption - Skin
• Percutaneous absorption
– Directly related to the degree of skin
hydration.
– Directly related to the perfusion of
subcutaneous layer
– Inversely related to the thickness of the
stratum corneum.
• Thinnest in premature neonate
• Premature infant has a significantly less
effective skin barrier to absorption of
drugs and toxins
– Hexachlorophene toxic to immature infants
– hydrocortisone over dosage
Absorption - Intramuscular
• Intramuscular
– Highly susceptible to variance in absorption due to...
- reduced blood flow to skeletal muscles,
-weak muscle contractions .
- Because of pain associated with injection and the
risk of nerve damage….
Infants 0.5ml
Older children 1ml
Pediatric Distribution
• Body Composition
– total body water & extracellular fluid
– adipose tissue & skeletal muscle
• Protein Binding
– albumin, bilirubin, 1-acid glycoprotein
• Tissue Binding
– compositional changes
Pediatric Distribution-Body Composition
total body water & extracellular fluid
adipose tissue & skeletal muscle
0 20 40 60 80 100
Premature
Newborn
4 mo
12 mo
24 mo
36 mo
Adult
0 20 40 60 80 100
Premature
Newborn
4 mo
12 mo
24 mo
36 mo
Adult
Extra Cellular water
Intra Cellular water
Protein
Fat
Others
Pediatric Distribution
Volume of Distribution of sulfisoxazole
Newborn
Infant
Children
Adults
Elderly
Pediatric Distribution-Protein Binding
Protein Binding (%)
Cord Adult
Acetaminophen 36.8 47.5
Chloramphenicol 31 42
Mophine 46 66
Phenobarbital 32.8 50.7
Phenytoin 74.4 85.8
Promethazine 69.8 82.7
30.2 17.3
• Glomerular filtration rate
– Low at birth
– GFR doubles by 1 week of age
– Adult values by 6-12 months of age
• Tubular function
– Secretory function impaired at birth
– Glomerulo-tubular imbalance
– Adult values by 1 year of age
Pediatric Renal Function
0.04 0.06 0.08 0.1 0.12
0-2 days
3-7 days
8 days
0.04 0.06 0.08 0.1 0.12
0-2 days
3-7 days
8 days
Gentamicin Clearance
Postnatal Age
Gentamicin Clearance [L/kg•hr]
Premature (<37 weeks)
Full term
Pediatric Renal Function
• Therapeutic implications
– Estimation of renal function necessary for
determining dose regimen for drugs with
extensive renal clearance
• Ex. Ceftazidime, famotidine, aminoglycosides.
• Measurement of drug levels often necessary
• Some drugs also alter renal maturation
or renal blood flow .
– Ex betamethsone, indomethacin
Elimination Half-Lives of Drugs in Infants and Adults
Drug Neonates (hr) Adults (hr)
Penicillin G 3.2 0.5
Ampicillin 4 1-1.5
Methicillin 3.3/1.3 0.5
Carbenicillin 5–6 1–1.5
Kanamycin 5–5.7 3–5
Gentamicin 5 2–3
• Phase 1 (oxidation, hydrolysis, reduction,
demethylation)
– Activity low at birth
– Mature at variable rates
• Oxidative metabolism increases rapidly after
birth
• Alcohol dehydrogenase reaches adult levels at
5 yrs
• Phase I enzyme activity in young children
can actually exceed adult levels.
Pediatric Hepatic Function
• Phase 2 (conjugation, acetylation, methylation)
– Conjugation:
• Glucuronidation: - at birth
• Sulfatation: at birth
– Acetylation: - at birth
Pediatric Hepatic Function
0.3
0.75
1.6
1.8
G:S
Acetaminophen Metabolism
0 20 40 60 80 100
Newborn
3-9 years
12 years
Adults
AcetaminophenGlucuronideSulfate
0 20 40 60 80 100
Newborn
3-9 years
12 years
Adults
AcetaminophenGlucuronideSulfate
0.15
0.17
0.19
0.18
kel
% of Dose
Cytochrome P450 (CYP) Enzymes
• Half of all drugs metabolized by CYP3A subfamily.
• CYP3A4 is most abundant hepatic P450 enzyme and
metabolizes at least 50 drugs.
>30w0
0.5
1
1.5
0
0.05
0.1
0.15
0
0.5
1
1.5
0
0.05
0.1
0.15
<30w
<24h1-7d
8-28d
1-3mo
3-12mo
>1yrAdult
FetusPostnatal Age
CYP3A7
CYP3A4
Relative Half-lives of CYP3A Substrates
Relative Half-lives of CYP1A2 Substrates
Dosing of Drugs in Infants and Children
Dosing of Drugs in Infants and Children
Dosing of Drugs in Infants and Children
Practice Problem
• The elimination half-life of penicillin G is 0.5 hr in adults and 3.2 hr 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 5 Kg infant.
hr
Practice Problem (cont.)
Dose=4 mg/kg
Weight= 5 kg
Alternatively, 10 mg every 12 hr would achieve the
same .
Dose=4*5=20 mg every 24 hr
? خداوند برکتی عظیم به تو بخشیده است. تو چه چیزی به ”او“ تقدیم می کنی
.هر روز، چیزی، هر چند کوچک به ”او“ تقدیم کن. از روی عشق و به نیازمندان
The Aging Imperative
• Persons aged 65y and older constitute
13% of the population and purchase
33% of all prescription medications
• By 2040, 25% of the population will
purchase 50% of all prescription drugs
Definition
• Chronologically, the elderly have been classified as the…
young old (ages 65–75 years),
old (ages 75– 85 years),
old old (age > 85 years).
Specific Therapeutic Challenge of Prescribing for the Elder Patient
• Principle factors:
– Altered Pharmacokinetics
– Multiple and severe illness
– Multiple drug therapy
– Poor adherence
Aging
• Most body organs in size with age fewer cells to
carry out organ functions
• Pharmacological changes:
• Drug absorption
• Drug distribution
• Drug metabolism
• Drug excretion
Pharmacokinetic changes (Absorption)
• Changes to intestinal tract:• decreased blood flow• reduced absorptive surface area• decreased gastric secretions• decreased motility
• Result:– SLOWED rate of drug absorption– Delayed time to peak concentration
• Peak drug level:– tends to decrease with age– same amount of drug will be absorbed but over a longer
period of time
Pharmacokinetic changes (Absorption)
Pharmacokinetic changes (Distribution)
• Distribution of Drugs:
– Increased body fat
– Decreased lean muscle mass
– Decreased serum albumin
– Decreased cardiac output
– Decreased total body water
Effects of Aging on Volume of Distribution
Aging Effect Vd Effect Examples
body water Vd for hydrophilic drugs ethanol, lithium
lean body mass Vd for drugs that bind to muscle digoxin
fat stores Vd for lipophilic drugs diazepam, trazodone
plasma protein (albumin) % of free drug diazepam, valproic acid,
phenytoin, warfarin
plasma protein (1-acid glycoprotein) % of free drug quinidine, propranolol,
erythromycin,
Pharmacokinetic changes (Metabolism)
• For drugs with extensive first-pass metabolism, BA may
increase because less drug is extracted by the liver
– Decreased liver mass
– Decreased liver blood flow
– Decreased activity of hepatic enzymes
– morphine, meperidine, metoprolol, propranolol,
verapamil, amitryptyline, nortriptyline
Metabolic Pathways
Pathway Effect Examples
Phase I:
oxidation,
hydroxylation,
reduction
Conversion to
metabolites of
lesser, equal, or
greater
diazepam,
quinidine,
piroxicam,
theophylline
Phase II:
glucuronidation,
conjugation, or
acetylation
Conversion to
inactive
metabolites
lorazepam,
oxazepam,
temazepam
Medications undergoing Phase II hepatic
metabolism are generally preferred in the
elderly due to inactive metabolites
(no accumulation)
Pharmacokinetic changes (Metabolism)
Pharmacokinetic changes (Excretion)
• Excretion of Drugs:
– Decreased renal blood flow
– Decreased glomerular filtration rate
– Decreased tubular secretion
– Decreased number of nephrons
– Decreased drug clearance:
atenolol, gabapentin, H2 blockers, digoxin,
allopurinol
Determining Creatinine Clearance
• Measurement of Creatinine Clearance – Time consuming– Requires 24 hr urine collection
• Estimate– Cockroft Gault equation
(IBW in kg) x (140-age)------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)
Estimating GFR in the Elderly
• Creatinine clearance (CrCl) is used to estimate
glomerular rate
• Serum creatinine alone not accurate in the
elderly
– lean body mass lower creatinine production
– glomerular filtration rate
• Serum creatinine stays in normal range,
masking change in creatinine clearance
Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman
301.190
411.170
531.150
651.130
CrClScrAge
Example:
Practice Problems
• 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?
Practice Problems
Practice Problems
Dose1= 100 %
Dose2 = ? %
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.
Practice Problems
• An aminoglycoside has a normal elimination half-life
of 107 min in young adults. In patients 70 to 90 years
old, the elimination half-life of the aminoglycoside is
282 min. The normal dose of the aminoglycoside is
15 mg/kg per day divided into two doses. What is the
dose for a 75-year-old patient, assuming that the
volume of distribution per body weight is not
changed by the patient's age?
Practice Problems
τ1= 12 hr
τ2= ? hr
Therefore, the same dose may be administered every 32 hr without affecting the average steady-state level of drug.
Clinical Example
• The pharmacokinetics of felodipine, was studied in young and elderly
subjects. After a dose of 5 mg oral felodipine, the AUC and C max in
the elderly patients were three times that of the young subjects.
• Side effects of felodipine in the elderly patients was reported in 3 of 11
subjects, whereas, only 1 of 12 of the young subjects reported side
effects. Systemic clearance in the elderly was 248 ± 108 L/hr compared
to 619 ± 214 L/hr in the young subjects. The bioavailability of
felodipine was reported to be about 15.5% in the elderly and 15.3% in
the young subjects.
Clinical Example
• What is the main cause for the difference in the
observed AUC between the elderly and young
subjects?
• The higher AUC in the elderly compared to young
adults is due to the decreased drug clearance in the
older subjects.
Clinical Example
• What would be the steady-state level of felodipine in the
elderly if dose and dosing interval are unchanged?
• If Dose, F, and τ are the same, the steady-state drug
concentration will be inversely proportional to clearance:
Pharmacodynamics
• Age-related changes:
– sensitivity to sedation and psychomotor
impairment with benzodiazepines
– level and duration of pain relief with narcotic
agents
– HR response to beta-blockers
– sensitivity to anti-cholinergic agents
– cardiac sensitivity to digoxin
PK and PD Summary
• PK and PD changes generally result in
decreased clearance and increased
sensitivity to medications in older adults.
• Use of lower doses, longer intervals,
slower titration are helpful in decreasing
the risk of drug intolerance and toxicity.
• Careful monitoring is necessary to ensure
successful outcomes.
وصیت نامه پاستور
در هر حرفه ای که هستید نه اجازه دهید که به بدبینی های
بی حاصل آلوده شوید و نه بگذارید که بعضی لحظات تاسف
بار که برای هر ملتی پیش می آید شما را به یاس و نا امیدی
بکشاند. در آرامش حاکم بر آزمایشگاهها و کتابخانه هایتان
زندگی کنید. نخست از خود بپرسید:“برای یادگیری و
?“ و این پرسش را آنقدر ادامه دهید خودآموزی چه کرده ام
تا به این احساس شادی بخش و هیجان انگیز برسید که شاید
سهم کوچکی در پیشرفت و اعتالی بشریت داشته اید. اما هر
پاداشی که زندگی به تالشهایمان بدهد یا ندهد، هنگامی که به
پایان تالشهایمان نزدیک می شویم هر کداممان باید حق آن را
داشته باشیم که با صدای بلند بگوییم:
” من آنچه در توان داشته ام، انجام داده ام.“