AGE AND DRUG

DISPOSITION

•Dr Emmanuel Ndosi

•Facilitator Dr Muasya
Factors affecting drug
metabolism
• AGE
• DISEASE
• SPECIES DIFFERENCES
• GENDER
• PREGNANCY
• ENVIRONMENTAL
• DRUG DOSE
• ENZYME INDUCTION/INHIBITION
• DIET
• HEREDITARY/GENETICS
 Definitions of terms
• Bioavailability:
• fraction of unchanged drug reaching the
systemic circulation i.e AUC,for i.v dose
bioav. = unity
• Oral administered bioav. Maybe less than
100%,two reasons:incomplete extent of
absorption and first-pass elimination.
 First-Pass Elimination
• Portal blood delivers drug to the liver prior
entry into the sytemic circ.Drugs can be
metabolised in the gut wall(CYP3A4
enzyme system) or the portal blood BUT
mostly the LIVER,liver can excrete drug
into bile,overall process= first-pass
elimination…can contribute to reduction in
bioav.
 Perinatal & Pediatric Aspects
• In pregnancy most drugs can cross the placenta exposing the
fetus to pharmacological & teratogenic effects,factors
affecting transfer:
• physiochemical drug properties.
• Rate at which drug crosses the placenta & amount reaching
the fetus.
• Duration of exposure to the drug.
• Distribution characteristics in diff. Fetal tissues.
• Stage of placental & fetal developmt.
• Effects of drugs used in combinstion.
 Lipid Solubility
• Lipophilic drugs readily diffuse across the
placenta,highly ionised drugs cross slowly
& achieve very low conc. in fetus e.g
thiopental in c/sec cross the placenta almost
immediately,can lead to sedation/apnea in
the newborn,c.f succinylcholine &
tubocurarine(highly ionized)
 Other Factors
• Protein binding.
• Placental & fetal metabolism e.g 1)
phenobarbital oxidaion by the placenta.
2)may augment
toxicity(ethanol,benzpyrenes)
• Molecular Size/wt of drug.i.e Mwt 250-500
cross placenta easily.
DRUG THERAPY IN INFANTS
& CHILDREN
• Physiologic processes influencing
pharmacokinetic variables change
significantly esp. in first few
months.Pharmacological differences btn
paeds & other groups not been explored in
great detail.
 Drug Absorption
• Will be influenced by:
• A.blood flow at the SITE of
ADMINISTATION: Cardiovascular
shock,vasoconstriction & heartfailure might
reduce blood flow to these areas,sick
premature infants have little mass &
diminished peripheral perfusion,drug
absorption is irregular and difficult to predict.
 Gastrointestinal Function
• Significant biochemical and physiological
changes occur in the GI shortly after birth:
• in full-term gastric acid secretion begins soon
after birth,increases gradually over several hrs.
• in preterm infants GA secretion slower,peaks
on the 4th day of life,so drugs partially or
totally inactivated by low pH shd not be adm
orally.
 Cont’d
• Gastric emptying time prolonged(6-8hrs)in
the 1st day.
• Peristalsis in neonates is irregular,may be
slow,absorption unpredictable,could result in
potential toxicity from an otherwise standard
dose.
• Diarrheal d’ses(increase in peristalsis)
decreases absortion.
 Cont’d
• GI enzyme activity tends to be lower in
newborn,alfa-amylase & other pancreatic
enzymes in the duodenum are low in infants
upto 4 months,also have low conc. Of bile
acids + lipase:may decrease absorption of
lipid- soluble drugs.
 Drug Distribution
• As body composition changes with
development,distributiion vol. Of drugs
change.
• Neonates have higher % of its Bwt in the
form of water(70-75%)cf to adults(50-60%)
& preterm neonate(85% of Bwt).
• Extracellular water is 40% and 20% in
neonates and adults respectively.
 Cont’d
• Preterm infants have much less fat(1% of
TBwt) cf 15% in full-term neonates,lipid-
soluble drugs will accumulate less in the
former.
• Some drugs compete with serum bilirubin
for binding to albumin,neonate with
jaundice, could cause kernicterus e.g
sulfonamides.
 Cont’d
• As serum bilirubin rises for physiologic
reasons or in blood grp
incompatibility,bilirubin can displace a drug
frm albumin and substantially raise the free
drug,hence potential toxicity,e.g phenytoin.
 Drug Metabolism
• Drug metabolising activities of the
cytochrome P450-dependent MFO &
conjugating enzymes are lower(50-70% of
adult values)in early neonatal life.
• Early maturation of fetal hepatic enzymes in
mothers who receives drugs e.g phenobarb
so tht some neonates can hv a greater than
expected ability to metabolize certain drugs.
 Drug excretion
• GFR calculated on basis of surface area is
30-40% of adult value,even lower in
preterm neonates at 34wks.
• At end of 1st wk,GFR & RPF increases by
50%,by end of 3rd wk GFR 50-60% of
adult value,reaches adult value by 6-
12mth(per unit SA).
 Drug use in Lactation
• Misperceptions of risks.
• If the nursing mother must take the
drug,and the drug is relatively safe one,she
shd optimally take it 30-60min after nursing
& 3-4hrs before next feeding.e.g of
drugs….
 GERIATRICS ASPECTS
• Who is an elderly?
• Society: >65years
• authorities:>75years
• general changes in the lives of older people hv
significant effects on the way drugs are
used:1)multiple diseases with advancing
age,2)nutritional problems,3)reduced financial
resources,4)decreased dosing requirements
 Drug Absorption
• Alterations in GI function:
• basal & peak gastric acid production
declines with age,resultant increase in
gastric pH alters lipid solubility or
dissolution of some drugs,may reduce
absorption
 Distribution
• Compared to young adults,elderly hv
reduced lean body mass,reduced total &
percentage body water,increase in fat as a
percentage of body mass(refer to table)
• decrease in serum albumin,which binds
many drugs,especially weak acids
 Cont’d
• There may be a concurrent increase in
serum orosomucoid(alfa-acid
glycoprotein),a protein that binds many
BASIC drugs.Thus the ratio of bound to
free drug may be significantly altered.May
alter loading dose of a drug.However,since
both the clearance and effects of drugs
 Cont’d
• are related to free concentration,the steady
state effects of a maintenance dosage
affected by other factors,e.g loading dose
digoxin in elderly pt with heart failure shd
be reduced(if used at all) because of the
decreased apparent vol. of distibution.The
maintenance dosage may hv to
 Cont’d
• be reduced bcz of reduced clearance of the
drug.
 Metabolism
• Aging results in a decrease in size of,blood
flow to liver & hepatic enzyme activity.
• Other factors are malnutrition,diseases etc
 Elimination
• The kidney:major organ
• decline in creatinine clearance in about 2/3 of
population
• this decline not reflected by equivalent rise in
serum creatinine as production of the latter is
reduced as muscle mass declines with age.
• Thus prolongation of half life of many
drugs;toxicity risks
 Genetically determined drug
disposition
• Clinically important genetic variants hv
been identified by DNA sequence
genotyping or phenotyping.
• Poor metabolizers(PM phenotype)..i.e with
2 alleles(variants) encoding for
nonfunctional protein)
 Cont’d
• Intermediate metabolizers(IM) with 1
functional allele & extensive
metabolizers(EMs)with 2 functional alleles.
 Cont’d
• Transferase Variants :
• TPMT gene,TPMT bioinactivates the
antileukemic drug 6-mecaptopurine(also an
active metabolite of immunosuppressive
azathioprine:homozygous for alleles
encoding inactive TPMT
 Cont’d
• (1 in 300) predictably exhibit sever &
potentially fatal pancytopenia on std. doses
of the two drugs,conversely homozygotes
for fully functional alleles may display less
antileukemic effect.
• Slow acetylators hv high incidence of
lupers synd. During therapy with e.g
hydralazine,procainamide.
 CYP Variants
• CYP3A4 most abundant
• CYP2D6 second to CYP3A4 in no. of
commonly used drugs,
• codein biotransformed by CYP2D6 to the
potent morphine,so its effects are blunted in
PMs.
• PMs display greater signs of beta-
blockade(bradycardia,brochospasms cf EMs
 Cont’d
• PMs phenotype for CYP2C19 is
common(20%) among asians:
• CYP2C19 metabolism demonstrated in PPi
omeprazole,ulcer cure rates lower in EM
pts(29%) than in PMs(100%).
Cont’d
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