DR.ROOPALI SOMANIPG RESIDENT

MRMC GULBARGA

Drugs used in special age groups like Children, Elderly

and Pregnant Women

Contents

IntroductionDrug therapy in PediatricsDrug therapy in PregnancyDrug therapy in Elderly

Introduction

Clinical responses achieved following drug administration are influenced byo Age of the patiento Relative maturity of particular organ system

that is targettedAge 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.

Drug therapy in Paediatrics

Pharmacokinetic process in Paediatric patients1. Absorption2. Distribution3. Biotransformation4. Elimination Pharmacodynamic process in pediatric

patients Paediatric dosage forms and compliance

Pharmacokinetic process in pediatric patients

Absorption:GI factors altering drug absorption:

I. Prolonged gastric emptying time and irregular gut motility interfere with achievement of peak plasma conc of drug

II. Reduced transit time in upper intestineIII. Presence of food decreases absorption of

paracetamol, penicillin and ampicillin.IV. High protein diet and low carbohydrate diet

increases clearance of theophyllineV. Absorption of lipid soluble drugs reduced in

infants as they have low conc of lipase and bile acid .

Oral drug absorption of various drugs in neonate compared with older children and adults

Drug Oral absorption

Acetaminophen Decreased

Ampicillin Increased

Diazepam Normal

Digoxin Normal

Penicillin G Increased

Sulfonamides Normal

Phenobarbital Decreased

Phenytoin Decreased

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

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

DISTRIBUTION

Factors determinig distribution of drugs are:a. Size of body water compartmentsb. Plasma protein bindingc. Degree of development of blood brain

barrierd. Ph and composition of body fluids and

tissues e. Blood flow and tissue specificity for tissue

receptor site

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)

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 infancy2. 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.

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.

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.

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.

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.

Plasma t1/2 of some of the drugs in neonate and adult

Drug Plasma half life ( hours)

Neonate Adult

Diazepam 25-100 40-50

Phenobarbital0-5 days5-15 days

1-30 months

20010050

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

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• Phase I enzyme reactive 5 months-5 yr

• Phase II enzyme reactive 3-6 months

4. ExcretionGlomerular filtration 3-5 months

Tubular secretion 6-9 months

Renal blood flow 5-12 months

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 d-tubocurarine 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.

Pediatric specific adverse drug reactions

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

Sulphonamides Kernicterus in neonates

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.

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 +12Based on weight Dose = Adult dose x weight(kg)

150

DRUGS USED IN ELDERLY

Pharmacokinetic changes1. Absorption2. Distribution3. Metabolism 4. Elimination

Pharmacodynamic changesMajor drug groupsAdverse drug reactions in elderly

PHARMACOKINETIC CHANGES

Absorption: factors affecting GI absorption 1. altered nutritional habits2. Greater consumption of non prescription drugs3. Slower gastric emptying time

DISTRIBUTION:4. Reduced lean body mass5. Reduced body water6. Increased fat7. Decreased serum albumin8. Increased α- acid glycoproteinThese changes alter the loading dose of drug.

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)

38-4536-38

Serum albumin(g/dl) 4.7 3.8

Kidney weight(%of young adult)

100 80

Hepatic blood flow(%of young adult)

100 55-60

Metabolism

o Metabolizing capacity of liver is decreased only for certain drugs.

o Greatest changes are seen in phase I reactionso Conjugation reactions are not significantly affectedo Decreased hepatic blood flow causes

i. slower metabolic inactivation of drugii. 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

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

Elimination

• Renal parameters reduced are:1) Renal blood flow2) Glomerular filtration3) 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

Formula for dose calculation in renal insufficiency

Normal therapeutic dose

Serum creatinine level (mg/dl)

Dose for a case of renal insufficiency

CORRECTED DOSE = NORMAL DOSE X PATIENT’S CREATININE CL NORMAL CREATININE CL

(140-age) x weight in kg

72 x serum creatinine (mg/dl)

Creatinine clearance (ml/min)

Cockcroft- Gault formula

If only the adult dose is known for drug that requires renal clearance , correction can be made using this formula

Pharmacodynamics

Response decreased Response to β agonists and β blockers is reduced due to reduced number of β receptors

Response increased•Reduced sensitivity of baroreceptors ,more chances of orthostatic/postural hypotension•Enhanced response to sedative-hypnotics and more respiratory depression .•Intolerance to digitalis•Greater response to coumarin

Pharmacodynamic changes with age include receptor alterations(change in number and sensitivity), impaired signal transduction and decreased homeostatic regulation.

Factors affecting the occurence of ADR in elderly patients

Impaired organ function Altered end organ response

Adverse drug reaction Prior disease

Multiple drug administration

Altered drug concentratio

n

Decreased homeostatic regulation

Multiple disease states

Altered compliance

Ageing

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. Postural hypotension-TCA, levodopa, bromocriptine2. Constipation-anticholinergics, antidepressants, nifedipine3. Urinary incontinence- β blockers, diuretics, labetolol,

antipsychotics.4. Depression-antipsychotics, anxiolytics,methydopa5. Confusional state- anticholinergics, antihistaminics,

theophylline, β blockers, anti-convulsants.6. Loss of postural reflexes (fall)- benzodiazepines,

neuroleptics, antihistaminics, antidepressants.

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 analoguesHaloperidol 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 inhibitors- dipyridamole

Coronary steal phenomenon

Clopidogrel or aspirin

Drugs used in pregnancy

Physiological changes during pregnancy

PharmacodynamicsTeratogenic actionsCommon problems in pregnancy and

safe drugs

Physiological changes during pregnancy

Pharmacokinetic changes Absorption Distribution Metabolism Elimination

Factors affecting placental drug transfer and drug effects

Pharmacokinetic changes

Absorption:1. Gut motility is reduced but no significant effect

on absorption, onset may be delayed2. Vasodilatation leads to increased tissue perfusion,

absorption on IM administration is highly effectiveDistribution:1. Total body water due to haemodilution, so large

volume of distribution for water soluble drugs2. Plasma albumin concentration 3. Increased body fat acts as a reservior of lipid

soluble drugs

Metabolism1. Hepatic metabolism is increased though blood flow

to liver2. Drugs metabolized by liver have increased

clearance Elimination1. 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

Factors affecting placental transfer of drugs

Critical factors affecting placental drug transfer and drug affects on the fetus include

1. The physiochemical properties of drug2. Rate at which drug crosses placenta and amount

of drug reaching fetus3. Duration of exposure to the drug4. Distribution characteristics in different fetal

tissues5. Stage of placental and fetal development at the

time of exposure6. Effect of drug used in combination

Lipid solubility1. Drug passage across placenta depends on lipid

solubility and degree of drug ionisation eg: thiopental, being lipid soluble diffuses readily across placenta

2. 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

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 poorlyEg: 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

Placental transporters: 1. 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 MRP3Protein bindingA. Degree of protein binding affects the rate of transfer across

placentaB. Lipid soluble drugs are not much affected by plasma protein

binding and is more dependent on placental blood flowC. Differential protein binding- eg sulfonamides, barbiturates,

phenytoin

Placental and fetal drug metabolism

Mechanism of placental metabolism1. Placenta is semipermeable2. It is a site of metabolism, several types of oxidation

reaction are known to occur( hydroxylation, N-dealkylation, demethylation). Eg: Phenobarbitol is oxidised by this way.

3. Metabolic capacity of placenta may lead to productin of more toxic metabolite eg: ethanol.

Fetal metabolism4. 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

5. Drug present in umblical artery may be shunted through the placenta to the umblical vein and into the liver again

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 effect2. Abortion3. A sublethal gross anatomic defect4. A permanent subtle metabolic or functional defect

Effect of drugs in late preganancy

Effect of drugs during labour

Effect Likely drug

Masculinization Sex hormones

Foetal goiter Antithyroid drugs

Tooth and bone development

Tetracyclins

Growth retardation

Corticosteriods

Onset of labour is delayed, impaired cns development

NSAIDS eg aspirin, indomethacin

Effect Drug

Respiratory depression

Opoid analgesics

Foetal distress ( due to reduced uterine blood flow)

Sedatives and GA

Prolongation of labour

Sedatives and GA

Hypotonia bezodiazepines

Floppy baby syndrome

Lithium

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 SecondThird

Hypolastic nasal bridge,CNS malformationRisk of bleeding

Pharmacodynamics

Maternal drug actions 1. 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

Effect of drug on foetus

Therapeutic effect: drugs are administered to pregnant women targeting foetus

1. Corticosteroids: used for lung maturation2. Phenobarbitone: prevents neonatal jaundice3. Zidovudine or nevirapine: inhibits transmission of

AIDS to foetus from motherPredictable toxic effect:1. Opoids : respiratory depression2. ACE inhibitors: congenital anomalies3. Diethylstilboesterol: vaginal carcinoma in female

offspring

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 development3. Shows a dose dependent incidenceTeratogenic mechanism: poorly understood 4. Indirect action: vasoconstriction leads to reduced uterine

blood supply and thus fetal anoxia. Eg: prostagladin analogues, ergot alkaloids

5. Direct action on process of differentiation eg: vitamin A analogues produce significant teratogenic effect by altering the normal process of differentiation.

6. Deficiency of a critical substance may cause abnormality eg: spina bifida due to folic acid deficiency

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

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 (teratogenic or embryocidal ). Drugs should be given only if the potential benefits justifies the potential risk to the fetus

Most of the drugs

D Fetal risk shown in human studies, but the benefits from 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)

Phenytoin

X Proved teratogen, contraindicated in pregnancy

Thalidomide

Common problems in pregnancy and safe drugs

Nausea and vomiting: pyridoxine, meclizine diphendyramine Constipation: mild purgative like sennaPeptic ulcer: sucralfate, H2 blockersHaematopoitic: iron and folic acid usedUrinary tract infections: ampicillin ,amoxycillin,cefurixime

axetilOther infections: βlactam antibiotics, cephalosporins,Malaria: chloroquine, quinine, proguanil Amoebiasis: metronidazole and diloxanide furoateWorm infestation: piperazine citrate, pyrantel pamoate Fungal infection: miconazole, clotrimazole, nystatinHIV 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

Diabetes mellitus: insulin Hypothyroidism : thyroxineThyrotoxicosis : propylthiouracilHypertension :α methydopa , emergency- hydralzine ,

β blockers – labetolol, atenololThromboembolic disease: heparinHeadache & inflammatory condition: paracetamol,

avoid other NsaidsEpilepsy: sodium valproate and phenytoin must be

avoided, carbamazepine used in lower doseMigraine: paracetamol, propanolol, amitriptylineAntidepressants: amitriptyline amd imipramine

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.

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