mod 15 pdti

age range definitions:

newborn infants

infants and toddlers

children

adolescents

0-27 days

28-23 months

2-11 years

12 to 16-18 years

most dramatic changes during the

first 1-2 years

developmental changes in physiologic factors that influence drug ADME in children (5)

metabolic capacity, developmental changes in distribution sites, gi function, integumentary development, renal function

At birth, gastric pH ranges --, falls within 3 to 5 hours to adult values (i.e., ph 1-5)

6-8

volume of gastric juice and the acid concentration are ---dependent factors

age

gastric acid secretions generally approach adult values by -- years of age

2 years of age

factors (e.g., nutrition) most likely responsible for initiating -- production

acid

-- also affects stomach acidity in the newborn

milk intake

neonates, infants, young children increase gastric pH (neonates >5, infants 4-2, children 2-3 (normal) which increases bioavailability of -- and acid labile drugs (penicillin, ampicillin) and decrease bioavailability of -- drugs (phenobarbital)

basic, acidic

Neonatal period: gastric emptying rate is variable and characterized by irregular and unpredictable peristaltic activity. gastric emptying time for neonates and infants under 6-8 months is --

6-8 hours

Marked increase in gastric emptying during the --

first week of life

Factors affecting the rate of gastric emptying:

gestational and postnatal age -- of feeding composition of the meal

type

neonates, infants have variable gastric and intestinal motility (usually decreased) which leads to -- absorption (Digoxin)

unpredictable

neonates, infants decrease bile acid and lipase production which leads to decrease -- lipid soluble drugs (vit DEK)

bioavailability

neonates decrease microbial flora which increase bioavailability of drugs metabolized by the --

*differences in formula vs breast fed (limited data)

microbial flora

peds: intramuscular absorption

- highly --

- erratic absorption for poorly -- drugs asphenytoin or diazepam

- rate of absorption depends on -- and --

variable

soluble

blood flow

muscle tone

Neonates and infants:

Reduced skeletal-muscle -- flow

Inefficient -- contractions

Relatively higher -- of skeletal-muscle capillaries in infants than in older children -> more efficient -- (ex: amikacin)

blood

muscular

density

absorption

percutaneous absorption in peds

- -- stratum corneum

- High skin --

- Relatively -- surface area

- Leads to increased/decreased absorption

Thin

permeability

large

increased

rectal absorption in peds

Drugs absorbed in lower rectum bypass the --

-- diffusion

-- rectal wall and enhanced mucosal translocation

Example: Diazepam, Barbiturates -> absorbed and attain systemic drug concentrations sooner

liver

Passive

Thin

-- drugs less space for distribution per kg of body weight in small children than in adults

Lipophilic

-- soluble drugs more space for distribution per kg of body weight in small children than in adults

Water

t/f from premature to elderly, in the body,m amount of water decreases and amount of fat increases

true

Drug mainly distributed in water like --

Water soluble drugs and distribution is mainly restricted to extracellular fluids

Adults 0.2 - 0.3 L/kg

Infants and children 0.5 - 1.2 L/kg

-- loading dose

-- dosing interval

Aminoglycosides

Higher

Longer

Drug distributed in --

Diazepam (highly lipophilic drug)

Adults 1.6 - 3.2 L/kg

Neonates and infant 1.3 - 2.6 L/kg

fat

in neonates and infants decrease albumin levels, binding capacity and binding affinity and increase levels of --drugs and acidic drugs

active free

in neonates decrease -- glycoprotein and increase levels of active free drugs and basic drugs

alpha1-acid

protein binding in neonates/infants

Possible net result: increased -- concentrations, greater drug -- at receptor sites, and both higher frequency of adverse effects at -- drug concentrations

free drug

availability

lower

phenytoin (protein binding example)

-- protein-bound drug

-- binding in neonates (lower plasma protein levels and binding capacity)

Higher free -- levels in neonates higher effect and possible toxicity

Therapeutic range for neonates = 6-15 mg/kg

Therapeutic range for adults and children = 10-20 mg/kg

High

Lower

phenytoin

Protein Binding Displacement

Some drugs can displace bilirubin from albumin as for example sulfisoxazole and ceftriaxone

Hyperbilirubinemia increases the risk of -- (encephalopathy due to increased bilirubin in the CNS) in at risk neonates

kernicterus

phase i (oxidation, hydrolysis, reduction, demethylation)

Activity -- or inexistent at birth

Maturation at -- rates

Oxidative and reduction metabolism -- rapidly after birth

Alcohol dehydrogenase reaches adult level at --

-- in children exceeds adult level

low

variable

increases

5 yrs

Activity

phase ii at birth:

which ones increase

which ones decrease

sulfatation

glucuronidation, glycine, gluthatione, cysteine conjugation, acetylation

t/f Half of all drugs metabolized by the CYP3A subfamily

true

major isoform in the human embryonic, fetal, and newborn liver

CYP3A7

Late fetal to early neonatal life, there is a peak in -- activity

CYP3A7

Within 1-4 weeks of birth: transition in isozymes: CYP3A7 disappears and -- predominates

CYP3A4

pediatrics: CYP3A4 expression and activity then reaches 30% to 50% of adult levels from --

3 to 12 months of age

Glucuronyl transferase is depressed at birth and reaches adult levels in children by -- years of age

Chloramphenicol is eliminated exclusively through glucuronidation by glucuronyl transferase

three

When chloramphenicol is linearly scaled according to body weight, the resulting exposure in newborns is five fold higher than that reached in adults, causing the well known --

Neonates and infants: concentrations should be maintained between 15 to 25 mg/L

Dose adjustment: neonates and infants up to 1 month are given half of the dose recommended to other groups (25 mg/kg/day)

grey baby syndrome

Drug excretion in the kidney mainly dependent on the --

Pre-terms: ~ 15% (or less of the renal capacity of adults

Term-babies: ~ 30%

4-5 weeks: ~ 50%

1-2 years: renal capacity equal to that of adults

GFR and active tubule secretion

neonates, infants have decreased GFR which means theres reduced -- (aminoglycosides)

clearance

neonates, infants have decreased tubular secretion which means theres reduced -- (beta lactam antibiotics)

clearance

half life for theophyllin and gentamicin are much higher in neonates and infants than adults. adjust dosing interval accordingly to avoid --

toxicity

newborns

have higher ph and decrease bile which decreases absorption

more body water so higher half life in hydrophilic drugs

decrease fat which means higher peak in liipophilic drugs

lower protein binding so more free active drug

decrease metabolism so decrease clearance and increase half life

decrease renal excretion so decrease clerance and increase half life

child

more body water, so higher half life in hydrophilic

decrease fat which means higher peak lipophilic

decrease protein binding which means more free active drug

increase metabolism increase clearance

increase renal excretion increase clearance

elderly pharmacological challenges

- -- changes

- -- co-morbidities

- --pharmacy

- more -- effects

- adherence

- -- well-design trials

pk/pd

multiple

poly

adverse

few

three types of age

chronological, biological, physiological

number of years lived

chronological age

age by body function

biological age

age how individuals feels it

physiological age

young old are ages

middle old are ages

oldest old are ages

65-74

75-84

> 85

t/f elderly exhibit more diseases

true

*especially arthritis, hypertension, heart disease, cerebrovascular disease

physiological changes on pk processes in the elderly

absorption, metabolism, distribution, elimination

for high extraction drugs, clearance =

blood flow (Q)

for low extractoiin drugs, clearance =

fu x Clint

high extraction: if protein binding changes, the total plasma concentration remains -- but the pharmacologically relevant unbound plasma concentration--

unchanged, will change

low extraction: if protein binding changes, the total plasma conc will --, but the pharmacologically relevant unbound plasma concentration --

change, remains unchanged

For drugs that distribute primarily into lean tissue (many hydrophilic drugs): age-related increase/decrease in volume of distribution (ex:ethanol)

decrease

For drugs that distribute primarily into fatty tissue (many lipophilic drugs): age-related increase/decrease in volume distribution (example: thiopental)

increase

antiyprine, caffeine, acetaminophen, and acebutolol increase/decrease Vd with age

decrease

vancomycin, midazolam, diazepam, chlormethiazole, amitriptyline increase/decrease Vd with age

increase

excretion in elderly: decreased in -- and --

glomerular filtration rate (GFR)

renal plasma flow (decreased creatinine formation)

PK changes in the Elderly

Absorption

- Remains relatively --

- Decrease -- metabolism

unchanged

first pass

PK changes in the Elderly

Distribution:

- Lower Vd of -- drugs

- Higher Vd of -- drugs

- Reduced plasma -- -> higher active drug

hydrophilic

lipophilic

albumin

PK changes in the Elderly

• Metabolism and Excretion

- Lower renal --

- Lower -- clearance

- Usually -- half-lives

clearance

metabolic

longer

t/f In general, effects of drugs are increased in older adult

true

older adults are "more sensitive" to drugs than younger people

- changes in -- affinity

- changes in receptor --

- post-receptor --

- age-related impairment of homeostatic mechanisms (decrease baro-receptor reflexes)

receptor

number

alteration

enhance effects in elderly

--

reason: possible increase in the number of receptors, affinity or both

warfarin and some CNS depressants

drugs less effective in the elderly

- -- are less effective in older adults

reason: possible reduction in the number of [answer 1], the affinity of [answer 1] for the blocking agents

beta blockers

Aging may influence the various processes of --

drug disposition (ADME)

Aging may have impact on drug PD response, usually increase -- to drug effects

sensitivity

More PK/PD studies are needed to find out if and when dosing adjustments are needed in the --

elderly

Understanding of the physiological changes in aging and the mechanism of drug action will allow a -- approach to questions

rational

t/f chronic kidney disease affects more than 1 in 7 us adults (15% of us adults)

true

functional unit of the kidney

nephron

4 functions of kidney

filtration, reabsorption, secretion, excretion

excretion =

filtration - reabsorption + secretion

Each nephron functions as an independent unit, so that when there is a kidney damage, the -- of the function of all remaining nephrons determines the whole kidney's GFR.

sum

The renal clearance of drugs is -- to the same degree regardless of the location of the disease

reduced

overall measure of renal function

GFR

In renal diseases, there appears to be a corresponding decrease in --

filtration, secretion and reabsorption

ideal markers for GFR

- freely -- at the glomerulus

- neither secreted nor reabsorbed by the tubules

- -- concentrations in blood

- no -- route of excretion

- -- and accurately measured

filterable

steady state

extra-renal

easily

two markers for GFR

exogenous = inulin

endogenous = creatinine

exogenous inulin marker for GFR

- -- standard

- not bound to plasma proteins, filtered freely in glomeruli, and neither reabsorbed nor secreted by the renal tubules

- limited use: -- and -- to measure and very time consuming

- limited to --

gold

expensive

difficult

investigational

endogenous creatinine marker for GFR

- closest to ideal -- marker

- generation determined by -- and -- -> elderly

- daily variability ~ 8%

- no -- binding; -- filtered by the glomerulus

- undergoes active tubular -- (~15%)

- severe impairment -> excretion in GI

- need 24-hour urine collection and blood sampling

endogenous

muscle mass, dietary intake

protein, freely

secretion

glomerular filtration rate is -- ml/min (GFR) protein,

125

(only free fraction is filtered)

tubular secretion occurs if clearance is

greater than fu*GFR

tubular reabsorption if clearance is

less than fu*GFR

-- = urinary excretion rate/serum concentration

creatinine clearance

Creatinine clearance measurement using only a -- creatinine conc is routine, quick and reliable

serum

Multiple methods (Cockcroft and Gault method, Wagnermethod, etc) have been developed to estimate -- clearance using the serum creatinine along with other routine clinical data such as patient age, gender, height, and weight

creatinine

method to evaluate renal function from serum creatinine in adults

cockcroft and gault method

modification of diet in renal disease method (MDRD)

chronic kidney disease epidemiology collaboration method (CKD-EPI)

method to evaluate renal function from serum creatinine in children

schwartz method

GFR < 90/ml/min/1.73m^2 abnormal in

young adult

GFR < -- ml/min/1.73 m^2 for 3 months classified as having chronic kidney disease irrespective of the presence of absence of kidney damage

60

GFR of -- ml/min/1.73 m^2 could be normal from approximately 8 weeks to 1 years of age and in older individuals

60-80

How can we readjust the patient's dosing regimens in renal disease?

reduce dose and increase dosing interval

Css,av = F(1/ClT)(Dose/tau)

The Impact of Renal Dysfunction

If the drug has a long half-life and there is a need to -- achieve steady state concentrations

Moreover, if the Vd is highly -- in this patients we may also need a loading dose to reach adequate plasma concentrations

rapidly

increased

drug mainly through urinary excretion

cefepime

The Impact of Renal Dysfunction on Drug Disposition

Absorption

- increased -- for certain drugs in severe renal dysfunction

- changes presystemic --

tmax

elimination

The Impact of Renal Dysfunction on Drug Disposition

Distribution

- Plasma protein binding of many acidic drugs -- in renal impairment

- -- glycoprotein levels may show an increase

- changes in --

decrease

alpha1-acid

volume of distribution