1. Drugs used in special age
groups like Children, Elderly
and Pregnant Women
DR.ROOPALI SOMANI
PG RESIDENT
MRMC GULBARGA

2. Contents
 Introduction
 Drug therapy in Pediatrics
 Drug therapy in Pregnancy
 Drug therapy in Elderly

3. Introduction
 Clinical responses achieved following drug administration
are influenced by
o Age of the patient
o Relative maturity of particular organ system that is
targetted
 Age dependent changes in body functions are known to
alter pharmacokinetic parameters which determine each
compound’s duration of action, extent of drug-receptor
interaction, and the drug’s rate of absorption, metabolism
and excretion. These differences are important from the
therapeutic point of view.

4. Drug therapy in Paediatrics
 Pharmacokinetic process in Paediatric patients
Absorption
2. Distribution
3. Biotransformation
4. Elimination
 Pharmacodynamic process in pediatric patients
 Paediatric dosage forms and compliance
1.

5. Pharmacokinetic process in pediatric
patients
I.
II.
III.
IV.
V.
Absorption:
GI factors altering drug absorption:
Prolonged gastric emptying time and irregular gut motility
interfere with achievement of peak plasma conc of drug
Reduced transit time in upper intestine
Presence of food decreases absorption of paracetamol,
penicillin and ampicillin.
High protein diet and low carbohydrate diet increases
clearance of theophylline
Absorption of lipid soluble drugs reduced in infants as
they have low conc of lipase and bile acid .

6. Oral drug absorption of various drugs in
neonate compared with older children and
adults
Drug
Oral absorption
Acetaminophen
Ampicillin
Diazepam
Digoxin
Penicillin G
Sulfonamides
Phenobarbital
Phenytoin
Decreased
Increased
Normal
Normal
Increased
Normal
Decreased
Decreased

7. PARENTERAL ROUTE
 Absorption from IM and SC routes is erratic due
to low proportion of skeletal mass and fat
respectively. Perfusion is diminished to muscles
in premature infants eg- digoxin, gentamicin &
kanamycin.
 IV route should be prefered in serious condition.
 Absorption from rectum is adequate eg:
diazepam and theophylline

8. PERCUTANEOUS ROUTE
 Drugs are readily absorbed from intact skin as the stratum
corneum is thin and skin is well hydrated.
Therefore lower dose of drug is required when
administered through this route.
 Excessive percutaneous absorption has resulted in
significant toxicities eg: absorption of hexachlorophene
used in soaps has resulted in brain damage and death.
 Absorption of napthalene has produced hemolytic
anaemia and jaundice esp in infants with G6P deficiency

9. DISTRIBUTION
 Factors determinig distribution of drugs are:
a.
b.
c.
d.
e.
Size of body water compartments
Plasma protein binding
Degree of development of blood brain barrier
Ph and composition of body fluids and tissues
Blood flow and tissue specificity for tissue receptor site

10. Size of body water compartments
 Total body water content is high in children ranging from
65% in older children to 80% in neonates, resulting in
higher dose of drug in neonates, if calculated on the basis
of body weight eg:- aminophylline, digoxin,
aminoglycosides, frusemide.
 A or in extracellular fluid space such as in diarrhoea
and nephrotic syndrome result in higher or reduced
plasma conc of drugs. Hence dose needs to be adjusted
accordingly.
 Dose of drugs calculated on the basis of body surface area
Eg: anticancer, immunomodulators, ibuprofen ( hepatic
disorders), aminoglycosides ( renal disorders)

11. Plasma protein binding
 Albumin α-glycoprotein and lipoproteins are important plasma
proteins.
 Higher fraction of unbound (free) drug due to:
1. Reduced concentration of plasma proteins in infancy
2. Decreased affinity for drug binding eg:
digoxin, theophylline,
3. High conc of endogenous compounds such as
bilirubin, hormones transferred through placenta, free fatty
acids which compete with drugs for binding . Eg;
phenytoin
4. Disease states leading to reduced plasma proteins eg:
PEM, nephrotic syndrome.
5. Decreased binding in disease states.

12. Blood brain barrier
 Blood brain barrier is not well developed, so
drug penetration is more in CNS eg:
unconjugated bilirubin, lipid soluble drugs,
morphine.
 Acidosis, hypoxia, hypothermia and
hypoglycaemia often associated in disease states
in newborn and infants confound the problem
leading to enhanced penetration.

13. Biotransformation of drugs
 Drug metabolizing enzymes are immature in neonates, so drug




metabolizing capacity limited.
Phase 1 oxidation reaction and glucoronidation are immature
at birth hence increased toxicity eg: chloramphenicol produces
gray baby syndrome.
Plasma esterases are reduced in infants leading to prolonged
apnoea due to succinylcholine.
Sulfation reaction more active in infants and children leading
to more toxic metabolite of paracetamol.
Drug metabolism is faster for certain drugs after 1st year of life
leading to reduced t ½. Eg; theophylline, phenytoin,
carbamazapine, phenobarbitone.

14.  Enzyme induction: clinically used to treat
neonatal jaundice by using phenobarbitone
 Therapeutic effect of drug decreases due to
reduced plasma conc of drugs in neonate born to
mother who is receiving enzyme inducer like
phenobarbitone.

15. Elimination
 GFR is low and tubular transport not fully developed at
term, gradually increases in about 5-7 months and by 1
year function reaches to adult level .
 Hence dose of drugs eliminated by kidney should be
reduced in infants eg: aminoglycosides, diuretics.
 t1/2 of theophylline and prednisolone are reduced due to
high plasma clearance. t1/2 of ampicllin, digoxin and
certain drugs increased due to reduced renal clearance
 In patients with renal insufficiency dosage guides are
based on serum creatinine levels.

16. Drug
Plasma half life ( hours)
Neonate
Adult
Diazepam
Plasma t1/2
of some of
the drugs in
neonate
and adult
25-100
40-50
Phenobarbital
0-5 days
5-15 days
1-30 months
200
100
50
64-140
Digoxin
60-70
30-60
Paracetamol
2.25
0.9-2.2
Salicylate
4.5-11
10-15
Theophylline
13-26
10-15

17. Age related maturation of selected
systems
System
Age adult level attained
1.
Gastric acid production
3 months
2.
Gastric emptying
6-8 months
3.
Hepatic metabolism
•
5 months-5 yr
•
4.
Phase I enzyme reactive
Phase II enzyme reactive
3-6 months
Excretion
Glomerular filtration
3-5 months
Tubular secretion
6-9 months
Renal blood flow
5-12 months

18. Pharmacodynamic alterations
 Response of drug may be different in pediatric age group and




adults though mechanism of action is same. Possibly due to
immature receptors or neurotransmitters system.
Antihistaminics and barbiturates cause paradoxical excitement
while amphetamine decreases abnormal hyperactivity in
children
Sensitivity to succinyl choline reduced while response to dtubocurarine enhanced.
Premature infants are less sensitive to vasoconstrictive action
of adrenaline and mydriatic action of phenylephrine.
Indomethacin is used for closure of patent ductus arteriosus,
while alprostadil is used to keep it open.

19. Adverse drug
reactions
Glucocorticoids
affect the growth
and development
due to premature
fusion of epiphysis
Delayed
development of
bone and teeth occur
due to tetracycline
beacuse of their
affinity to calcium
containing tissues.
Drug
Reaction
furosemide
nephrocalcinosis
Indomethacin
Renal failure, bowel perforation
Adrenocorticoids
Increased intracranial pressure, growth
suppression
Tetracyclins
Discoloured teeth
Phenobarbital
Hyperactivity, impaired intellectual
development
Phenytoin
Thickened skull coarse features
Chloramphenicol
Grey baby syndrome
Aspirin
Reye syndrome in viral fever
Valproic acid
Fetal hepatotoxicity
Hyperosmolar drugs
Intraventricular haemorrhage
Fluroroquinolones
Juvenile arthropathy
Pediatric specific adverse drug
Sulphonamides
Kernicterus in neonates
reactions

20. Pediatric drug dosage
 Dose calculation on the basis of age, surface area and
weight
Based on age (young’s rule)
 Dose Adult dose x Age ( years)
Age +12
Based on weight
 Dose = Adult dose x weight(kg)
150

22. DRUGS USED IN ELDERLY
 Pharmacokinetic changes
Absorption
2. Distribution
3. Metabolism
4. Elimination
 Pharmacodynamic changes
 Major drug groups
 Adverse drug reactions in elderly
1.

23. PHARMACOKINETIC CHANGES
 Absorption: factors affecting GI absorption
1.
altered nutritional habits
2.
Greater consumption of non prescription drugs
3.
Slower gastric emptying time
DISTRIBUTION:
Reduced lean body mass
2.
Reduced body water
3.
Increased fat
4.
Decreased serum albumin
5.
Increased α- acid glycoprotein
These changes alter the loading dose of drug.
1.

24. Changes related to aging that affect
pharmacokinetics of drugs
Variable
Young adult
(20-30 years)
Older adult
(60-80 years)
Body water (% of body weight)
61
53
Lean body mass
19
12
Body fat
26-33 (women)
18-20 (men)
38-45
36-38
Serum albumin(g/dl)
4.7
3.8
Kidney weight(%of young adult)
100
80
Hepatic blood flow(%of young
adult)
100
55-60

25. Metabolism
o Metabolizing capacity of liver is decreased only for certain
drugs.
o Greatest changes are seen in phase I reactions
o Conjugation reactions are not significantly affected
o Decreased hepatic blood flow causes
i.
ii.
slower metabolic inactivation of drug
Decreased first pass metabolism of drugs Eg: neuroleptics,TCA.
o Decreased induction of hepatic enzymes with drugs eg-
rifampicin
o Decline with age of the liver’s ability to recover from injury
o Malnutrition and diseases that affect hepatic function are more
common in elderly

26. Effect of age on hepatic clearance of
some drugs
Age related decrease in hepatic clearance
found
No age-related difference found
Alprazolam
Ethanol
Barbiturates
Isoniazid
Clobazam
Lidocaine
Diazepam
Lorazepam
Flurazepam
Nitrazepam
Imipramine
Oxazepam
Nortriptyline
Prazocin
Propanolol
Salicylate
Theophylline
Warfarin
Tolbutamide

27. Elimination
•
1)
2)
3)




Renal parameters reduced are:
Renal blood flow
Glomerular filtration
Tubular secretion
Serum creatinine level may be in normal range
Toxicity may result with drugs mainly eliminated through
kidney and having narrow therapeutic index eg: lithium,
digoxin.
Lungs are important for excretion of volatile drugs. As a
result of reduced respiratory capacity and increased incidence
of active pulmonary disease in elderly, parenteral anaesthetic
agents are preferred over inhalational.
In patients with renal insufficiency dosing schedule based on
serum creatinine level and creatinine clearance level

28. Formula for dose calculation in renal
insufficiency
Normal
therapeutic dose
Dose for a case of
renal insufficiency
Serum
creatinine
level (mg/dl)
CORRECTED DOSE = NORMAL DOSE X PATIENT’S CREATININE CL
NORMAL CREATININE CL

29. Cockcroft- Gault formula
If only the adult dose is known for drug that requires renal clearance ,
correction can be made using this formula
Creatinine
clearance
(ml/min)
(140-age) x
weight(kg)
72 x serum creatinine
(mg/dl)

30. Pharmacodynamics
Pharmacodynamic changes with age include receptor
alterations(change in number and sensitivity), impaired signal
transduction and decreased homeostatic regulation.
Response decreased
Response increased
•Reduced sensitivity of
Response to β agonists and β
baroreceptors ,more chances of
blockers is reduced due to
reduced number of β receptors orthostatic/postural hypotension
•Enhanced response to sedativehypnotics and more respiratory
depression .
•Intolerance to digitalis
•Greater response to coumarin

31. Factors affecting the occurence of ADR
in elderly patients
Prior
disease
Ageing
Impaired organ function
Altered drug
concentration
Altered end organ response
Decreased
homeostatic
regulation
Adverse drug reaction
Multiple disease
states
Multiple drug
administration
Altered
compliance

32. Adverse drug reactions in elderly
 Overall incidence of ADR is 2-3 times found in young adults
 Commonly used drugs causing unwanted adverse effect:
1.
2.
3.
4.
5.
6.
Postural hypotension-TCA, levodopa, bromocriptine
Constipation-anticholinergics, antidepressants, nifedipine
Urinary incontinence- β
blockers, diuretics, labetolol, antipsychotics.
Depression-antipsychotics, anxiolytics,methydopa
Confusional stateanticholinergics, antihistaminics, theophylline, β blockers, anticonvulsants.
Loss of postural reflexes (fall)benzodiazepines, neuroleptics, antihistaminics, antidepressants.

33. Major drug groups
DRUGS TO BE
AVOIDED
Reasons
SAFER ALTERNATIVES
Diazepam, barbiturates,
Prolonged half life due to
decreased hepatic and renal
clearance
Oxazepam. Lorazepam,
alprazolam
Indomethacin, piroxam
CNS side effects
Ibuprofen, Cox-2 inhibitors
Phenothiazine analogues
Haloperidol analogues
Greater risk of extrapyrmidal
side effects and postural
hypotension
Thioridazine, olanzapine,
risperidone, aripiprazole
Tricyclic antidepressants
Anticholinergic side effects
SSRI
Tacrine for alzheimer’s
CNS toxicity because of
anticholinergic activity
Donepezil, rivastigmine,
galantamine
Propanolol, methyldopa,
for hypertension
Postural hypotension,
propanolol should not be given
in asthamatics
Thiazides in low doses,
selective β1 blocker , CCB,
ACE inhibitor
Platelet inhibitorsdipyridamole
Coronary steal phenomenon
Clopidogrel or aspirin

34. Drugs used in pregnancy
 Physiological changes during pregnancy
 Pharmacodynamics
 Teratogenic actions
 Common problems in pregnancy and safe drugs

35. Physiological changes during pregnancy
 Pharmacokinetic changes
 Absorption
 Distribution
 Metabolism
 Elimination
 Factors affecting placental drug transfer and drug effects

36. Pharmacokinetic changes
 Absorption:
Gut motility is reduced but no significant effect on
absorption, onset may be delayed
2. Vasodilatation leads to increased tissue perfusion, absorption
on IM administration is highly effective
 Distribution:
1. Total body water due to haemodilution, so large volume of
distribution for water soluble drugs
2. Plasma albumin concentration
3. Increased body fat acts as a reservior of lipid soluble drugs
1.

37.  Metabolism
Hepatic metabolism is increased though blood flow to liver
2. Drugs metabolized by liver have increased clearance
1.
 Elimination
1.
Renal blood flow is doubled hence rapid elimination of
drugs excreted by kidney eg: amoxycillin, and if it is
used to treat systemic infection its dose should be
doubled but for the treatment of UTI, as amoxycillin
gets concentrated in urine there is no need to change the
dose

38. Factors affecting placental transfer
of drugs
 Critical factors affecting placental drug transfer and drug
affects on the fetus include
1. The physiochemical properties of drug
2. Rate at which drug crosses placenta and amount of drug
reaching fetus
3. Duration of exposure to the drug
4. Distribution characteristics in different fetal tissues
5. Stage of placental and fetal development at the time of
exposure
6. Effect of drug used in combination

39.  Lipid solubility
1.
2.
Drug passage across placenta depends on lipid solubility and
degree of drug ionisation eg: thiopental, being lipid soluble
diffuses readily across placenta
Impermeability of placenta to polar compounds is relative
rather than absolute . If high enough maternal-fetal
concentration gradients are achieved, polar compounds croses
the placenta in measurable amounts.eg: salicylate

40. Molecular size and ph
 Molecular weight influences the rate of transfer and amount of
transfer
 Drugs having molecular weight 250-500 cross easily, those
with mol weight 500-1000 cross with more difficulty
 Drugs with mol wt >1000 cross very poorly
Eg: choice of heparin as an anticougulant is based on this property,
because it is very large and polar ,heprin is unable to cross placenta
 Placenta contains drug transporters which can carry large
molecules to the fetus eg: maternal antibodies
 Ion trapping of weakly basic drugs having pKa >7.4

41.  Placental transporters:
p-glycoprotein encoded by MDR1 gene pumps back into the
maternal circulation a variety of drugs eg: vinblastine,
doxirubicin.
2. Viral protease inhibitors are substrates of P- glycoprotein.
3. Glyburide is effluxed by BCRP transporter as well as by MRP3
 Protein binding
A. Degree of protein binding affects the rate of transfer across
placenta
B. Lipid soluble drugs are not much affected by plasma protein
binding and is more dependent on placental blood flow
C. Differential protein binding- eg sulfonamides, barbiturates,
phenytoin
1.

42. Placental and fetal drug metabolism
 Mechanism of placental metabolism
1. Placenta is semipermeable
2. It is a site of metabolism, several types of oxidation reaction are
3.
known to occur( hydroxylation, N-dealkylation, demethylation).
Eg: Phenobarbitol is oxidised by this way.
Metabolic capacity of placenta may lead to productin of more
toxic metabolite eg: ethanol.
Fetal metabolism
1. Drugs enter fetal circulation via umblical veins. 40-60% of
umblical venous blood passes through the fetal liver, hence a drug
maybe partially metabolized before reaching general fetal
circulation
2. Drug present in umblical artery may be shunted through the
placenta to the umblical vein and into the liver again

43. Effect of drug on stage of foetal
development
 The foetal age, drug dosage and potency determine the
magnitude and seriousness of a drug on foetal development .
 Drugs given during embryonic or zygotic stage(before the 20th
day of gestation) may have an all or none effect, either killing
the embryo or not affecting it all.
 Drugs given during organogenesis (4-10 weeks)may produce
1. No measurable effect
2. Abortion
3. A sublethal gross anatomic defect
4. A permanent subtle metabolic or functional defect

44. Effect of drugs in late
preganancy
Effect
Likely drug
Masculinization
Sex hormones
Foetal goiter
Effect of drugs
during labour
Effect
Drug
Respiratory
depression
Opoid analgesics
Sedatives and GA
Antithyroid drugs
Tooth and bone
development
Tetracyclins
Foetal distress ( due
to reduced uterine
blood flow)
Growth retardation
Corticosteriods
Prolongation of
labour
Sedatives and GA
Onset of labour is
delayed, impaired
cns development
NSAIDS eg aspirin,
indomethacin
Hypotonia
bezodiazepines
Floppy baby
syndrome
Lithium

46. Drugs with significant teratogenic
effects
Drug
Trimester
Effect
ACE Inhibitors
All
Renal damage
Carbamazepine
First
Neural tube defects
Clomipramine
Third
Neonatal lethargy, hypotonia, cyanosis
Lithium
First, third
Ebstein’s anamoly
Methotrexate
First
Multiple congenital malformation
Methythiouracil
All
Hypothyroidism
Phenytoin
All
Fetal hydantoin syndrome
Valproic acid
All
Neural tube defects
Warfarin
First
Second
Third
Hypolastic nasal bridge,
CNS malformation
Risk of bleeding

47. Pharmacodynamics
 Maternal drug actions
Endocrine environment appropriate for pregnancy alters the
effect of drugs on reproductive tissues such as breast and uterus
2. Cardiac glycosides and diuretics may be required for heart
failure precipitated by increased cardiac work loaad during
pregnancy
3. Insulin may be required to control blood sugar level in
pregnancy induced diabetes mellitus
1.

48. Effect of drug on foetus
 Therapeutic effect: drugs are administered to pregnant
women targeting foetus
Corticosteroids: used for lung maturation
2. Phenobarbitone: prevents neonatal jaundice
3. Zidovudine or nevirapine: inhibits transmission of AIDS to
foetus from mother
1.
 Predictable toxic effect:
1.
2.
3.
Opoids : respiratory depression
ACE inhibitors: congenital anomalies
Diethylstilboesterol: vaginal carcinoma in female offspring

49. Teratogenic effect
 Teratogen : any drug or substance is labelled teratogen if:
1. It produces characteristic sites of malformation with selectivity for
certain organs
2. Exerts its effect at a particular stage of fetal development
3. Shows a dose dependent incidence
Teratogenic mechanism: poorly understood
1. Indirect action: vasoconstriction leads to reduced uterine blood
supply and thus fetal anoxia. Eg: prostagladin analogues, ergot
alkaloids
2. Direct action on process of differentiation eg: vitamin A analogues
produce significant teratogenic effect by altering the normal process
of differentiation.
3. Deficiency of a critical substance may cause abnormality eg: spina
bifida due to folic acid deficiency

50.  Continuous exposure to a teratogen may produce
cumulative effect or may affect multiple organs which are
undergoing development eg: chronic alcohol consumption
leads to undergoing development, facial abnormalities
 Direct action: eg : thalidomide when administerd during
4-8 weeks causes phacomelia as arms and legs are
developed in this period

51. FDA category/rating of drugs in
pregnancy
Category
Risk
Example
A
No foetal risk shown in controlled human studies
Folic acid
B
Animal studies have not demonstrated a fetal risk , but
there are no controlled studies in pregnant women
Metronidazole
C
Studies in animals have revealed adverse effect on fetus Most of the drugs
(teratogenic or embryocidal ). Drugs should be given
only if the potential benefits justifies the potential risk
to the fetus
D
Fetal risk shown in human studies, but the benefits from Phenytoin
use in pregnant women may be acceptable despite the
risk( eg; if drug is needed in life threatening situation
or for a serious disease for which safer drugs cannot be
used or are ineffective)
X
Proved teratogen, contraindicated in pregnancy
Thalidomide

52. Common problems in pregnancy and safe
drugs











Nausea and vomiting: pyridoxine, meclizine diphendyramine
Constipation: mild purgative like senna
Peptic ulcer: sucralfate, H2 blockers
Haematopoitic: iron and folic acid used
Urinary tract infections: ampicillin ,amoxycillin,cefurixime axetil
Other infections: βlactam antibiotics, cephalosporins,
Malaria: chloroquine, quinine, proguanil
Amoebiasis: metronidazole and diloxanide furoate
Worm infestation: piperazine citrate, pyrantel pamoate
Fungal infection: miconazole, clotrimazole, nystatin
HIV infection: none of the anti HIV drugs are safe, but
zidovudine and nevirapine are considered safe
 Tuberculosis : INH and ethambutol are safe. If third drug is
needed then rifampicin

53. 








Diabetes mellitus: insulin
Hypothyroidism : thyroxine
Thyrotoxicosis : propylthiouracil
Hypertension :α methydopa , emergency- hydralzine , β
blockers – labetolol, atenolol
Thromboembolic disease: heparin
Headache & inflammatory condition: paracetamol, avoid other
Nsaids
Epilepsy: sodium valproate and phenytoin must be avoided,
carbamazepine used in lower dose
Migraine: paracetamol, propanolol, amitriptyline
Antidepressants: amitriptyline amd imipramine

54. References
 Bertram and katzung’s .Basic and clinical
Pharmacology 12th edition.
 S D seth , Vimlesh seth. Textbook of
Pharmacology 3rd edition.
 S K Srivatsava. A complete textbook of medical
Pharmacology
 H L Sharma, K K Sharma. Principles of
Pharmacology 2nd edition.