Drugs used at extremes of age Dr. Padmaja Marathe

Extremes of ageEmbryo: FetusNeonateInfantToddlerChildAdolescentAdultSenior citizen

Drugs at extremes of age are not different

Difference is in PK-PD at the extremes of age

Pediatric medicineNeed for a special approach

Differences in physiology & rapid changes of growth - PK,PD features, ADRsInability of child to expressDrugs given to lactating women

Individualized therapy for the child

"Pediatric does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but . . . has its own independent range and horizon = Dr. Abraham Jacobi

Remember

Geriatric medicineNeed for a special approach

Low physiological reserveSeveral comorbid conditions and concomitant medicationEasy toxicity of drugs Decreased dosing compliance General problems in elderly nutritional, financial, behavioural,

Pediatric Pharmacology

Classifying Pediatric populationPaediatric patients: 0-18 yrs. of ageClassifying them-Preterm:

Oral AbsorptionGastric acid secretionPremature infants- Gastric Acid reaches to highest level on 4th day of life

Applicationweak bases are less ionized and have greater bio availability e.g. ampicillin, erythromycin, penicillins

weakly acidic drugs-decreased bio availability e.g. phenobarbitone

Gastric emptyingGastric emptying- prolonged and does not reach adult value till 6-8 months

Application: Drugs absorbed in stomach: increased e.g. salicylates, barbituratesdrugs absorbed in small intestine: effect delayed e.g. morphine, quinine

PeristalsisIrregular & slow, hence absorption unpredictable

GI enzyme activityGI enzyme activities are lower in new born

Applicationlow concentration of bile acids, lipase may decrease absorption of lipid soluble drugs e.g. vitamins A, D, E (so water soluble forms need to be administered)Intestinal micro flora is not developed, so entero hepatic cycling of some drugs does not occur e.g. diazepam

Rectal absorptionIt is quite erraticBut rapid and efficient absorption with proper drug & dosage forms e.g. rectal administration of diazepam solution is important in neonates with seizures in whom rapid i.v. access is not available, acetaminophen

Intra muscular absorptionIn neonates, premature and term babies - both rate & amount is reduced due to- a. decreased muscle mass and blood flow b. higher water content in muscles c. diminished muscular contractionsAminoglycosides, anticonvulsants Infants and children perfusion improves

Percutaneous absorptionIncreased in neonates (up to 3 times than adults) due to- a. decreased thickness of stratum corneum b. increased skin hydration c. increased surface area per kg of body wt.Application: neonates prone to toxicity of topical drugs such as bacitracin, neomycin, polymyxin B, salicylic acid, glucocorticoids etc.

DistributionIncreased Vd70-75% is water contentIncreased ECF 40%

Application: Gentamicin is water soluble and gets distributed to ECF hence, higher doses are needed

Plasma protein bindingReduced in infantsIncrease free drug conc - toxicity increasesDrugs compete with serum bilirubin for binding to albumin, can cause displacement of bilirubin kernicterus. Eg:- sulfonamides, cephalosporinsConversely bilirubin can displace some drugs causing their toxicity. Eg:- phenytoin.

Drug Metabolism

enzymes are deficient in the new born especially premature.deficit is made up in first few monthsdecreased metabolism: t1/2 of drugs in increased Drugs accumulate and predispose to adverse effects. Application chloramphenicol- in premature new born -- grey baby syndrome.

Excretion--GFR - adult value by 6- 12 monthsTubular transport mechanisms are also immature in new born so t is prolonged to 3-5 times.Tubular secretion reaches adult rates by 7 months.Eg:- dose of Ampicillin in neonates 7 days old- 100-200mg/kg/day in 3 doses at 8 hrs interval Toddlerhood - high dose / kg BW for digoxin, theophylline

Pediatric drug dosageApproximation of dosage can be made by several methods based on age, weight, surface area.Age: Youngs formula: child dose = age x adult dose. (age+12)

Dillings formula: child dose= age x adult dose. 20

Body weight: individual dose = BW ( kg ) x avg. . 70 adult dose

BSA: individual dose = BSA (sq.m ) x avg. adult dose. 1.7

PEDIATRIC drug dosage

Pharmacodynamics consideration.ExamplesLack of efficacy of some antidepressants in children.Paradoxical seizures after exposure to benzodiazepinesIncreased expression of opioid receptors increased sensitivity in neonatesPatent Ductus Arteriosus - Indomethacin & PGE1.

A Short Question break.1. Complete the statementTetracyclines are contraindicated in pregnant women and ____________________ and Justify._____ is contraindicated for control of seizures in children below 2 years of age.2. State T / F Aspirin can be prescribed to a 10 year old child for fever and headache due to viral infection.-------- is not used for dewarming in children below 2 years of age. Instead ______ is preferred.

Drugs in breast milkIf medication in nursing mother is required

30-60 min after nursing.

3-4 hours before next feeding.

AntimicrobialsChloramphenicol:- grey baby syndrome, diarrhoea, BM depression.Tetracycline:- permanent staining of teeth. Decreased bone growthSulphonamides:- kernicterus.Metronidazole:-may make milk taste bitter.FQ- Possible risk of arthropathyChloroquine- Retinal damage in newborn infants

Analgesics Aspirin: - Reyes syndrome CNS effects, convulsions

OpioidsInfants are more susceptible to respiratory depressant action of morphine.

AMIODARONEPossible effects of released iodine on neonatal thyroid. Risk of hypothyroidism.radio- iodine thyroid suppression in infants.DiazepamSedative effect on nursing infants long half life drug accumulation BarbituratesLethargy, sedation, poor suck reflexes.

Problems with pediatric drug therapyPostnatal periodAdministration: oral route may cause aspirationIM route : sciatic nerve damage preferred site will be lateral aspect of thigh Regimen : renal and hepatic considerationsDrugs given to mother during labour and lactation period

Problems.

GeneralTaste of the medicine complianceAccidental overdose - ToddlersProne to get recurrent infections----OTC medications

Principles of pediatric drug prescribingParents role : clear instructionsMeasuring errorsSpillingSpittingDisappearance of symptomsWarning / worsening signs

Use of calibrated measurement spoon/syringe pill containersrandom pill count and measurement of serum conc.

Principles of pediatric drug prescribingReview the need of drug therapyReassure parentsSelection of Practical and convenient dosage forms and dosing schedules Prefer palatable syrups, use of chasersliquid formulations SUSPENSIONS thorough shaking. Eg. PhenytoinEmphasis on completion of the course of antimicrobialsAvoid OTC / previously used medicines

AgingProgressive, universal decline first in functional reserve and then in function that occurs in organisms over time.

The biochemical composition of tissues changes Physiologic capacityHomeostasis Vulnerability to disease processes

Geriatric Age groupAccording to the WHO, generally accepted age is >65 years.TheNational Policy of Older Personsrecognizes a person who is 60 years of age and above as a Senior Citizen.

http://www.who.int/healthinfo/survey/ageingdefnolder/en/index.html,http://india.gov.in/citizen/senior_citizen/general.php#q2 accessed on 8/05/12

Ageing Population Figures -India

Drug Consumption amongst the elderly> 65 yrs constitute about 8 % of the population and consume 31% of prescribed drugs.

40% of all OTC drugs.

Average of 4 - 6 medications at any one time.

Average of 13 to 15 prescriptions per year.

Absorption

Condition associated with age altering rate of absorption Altered nutritional habitsIncreased consumption of non prescription drugs(laxatives, antacids)Slow gastric emptying esp. diabetics

DistributionDecrease total body waterDecrease lean body mass and increase in fat content Decrease Blood flowAlteration in Size & composition of compartments of the body.Decrease in albumin causes altered bound: free drug ratio - alter loading dose, Decrease loading and maintenance dose Eg:- digoxin- early CHF decrease apparent Vd & clearance - decrease loading dose & maintenance dose

Metabolism decrease in hepatic blood flow- thickening & defenestration of sinusoidal endothelium.Decrease capacity of the enzymesDecrease ability to recoverDecrease clearance of drugs with high hepatic extraction ratioEffect of liver / comorbid conditions

Hepatic metabolism can be of two types :

1. Flow-limited metabolism: Highly extracted substratesDecreases for: Pethidine, Morphine, Propranolol, Amitriptyline, Verapamil, Imipramine, Lignocaine.

2. Capacity-limited metabolism: Poorly extracted medications & in some cases, protein bound drugs.Decreases for: Theophylline, Antipyrine.

ExcretionDecrease in renal plasma flow, GFR, tubular secretionDose on basis of creatinine clearance Cockcroft Gault formula creatinine clearance(ml/min)= (140-age) x wt (in kg) 72 x serum creatinine(mg/dl).For women the result should be multiplied by 0.85

Reduced lung volumes & comorbid disorders Elimination, eg. , Inhalational anaesthetics not used

Increase in pharmacological responseSeen with benzodiazepines, barbiturates, opioid analgesics, halothane; anticoagulants, thrombolytic therapy.

Drugs acting on -adrenergic receptors : asthma, HTN.

Pharmacodynamics Postural hypotension Occurs in-20% of ambulatory patients >65years of age & 30% in patients>75 years of ageMechanismImpaired baro receptor functionFailure of cerebral blood flow autoregulation E.g. Drugs with sympatholytic activity Alpha blockers , Phenothiazines, TCAVolume depleting-DiureticsVasodilator-Nitrates & Alcohol

Receptor sensitivitySelective decline in cholinergic system in neocortex & hippocampus.Increase in MAODecrease in sensitivity of adrenergic receptors particularly beta receptors.

Pharmacodynamics

Which of the following drug classes is most often associated with cognitive decline in elderly patients?A. Diuretics C. AntidepressantsB. Benzodiazepines D. Antiarrhythmics

Which of the following drugs can lower the seizure threshold?A. Ciprofloxacin C. ClozapineB. Bupropion D. All of the above

ADRsIncidences of ADR is high in

PolypharmacyComorbid conditionsPersonal errors decrease in cognitive functionsUse of OTC drugsPD & PK

Factors predisposing ADRs in elderlyPatient related: Non- adherence: cognitive impairment, restricted movements, economical problems, suicidal tendenciesOTC Drugs: analgesics, sleep-pills, hidden drugs e.g. AntihistaminicsDoctor shopping

Doctor-related:Unawareness of other drugs , PK & PD peculiarities in elderlyDrug interactionsComplicated regimensPolypharmacy

Common ADRsPostural HypotensionConstipationIncontinenceParkinsonismDepressionConfusional stateLoss of postural reflexes

Drugs common ADR Atropine: Urinary retention Aspirin: G I irritation and bleeding NSAIDS: Irreversible renal damage Cumulation of NSAIDS->More renal damageCorticosteroids: OsteoporosisBZD & Barbiturates: pshycomotor effectsOpioids: respiratory depression & urinary retentionHaloperidol - causes EPR

Precautions to avoid ADRDrug selection and administration.Start low go slowFinal dosage schedule with min. no of pillsHistory of OTCRegular follow up

Non-adherence to medication

Non-adherence to medication

Multiple drugsMultiple daily dosagesFrequently changing drug regimensExpensive drugsADRsDependence on othersProgressively diminishing cognition, vision, dexterity, mobility.Social factors: loneliness, economical stress, loss of spouse, social and familial neglectIntentional/ intelligent non-adherence.

Improving Drug ComplianceHealth BuddyPill Organizer

BLISTER PACK!!!

Principles of drug prescribing Simplifying drug regimens

Cheaper alternative therapyUse drugs needing less frequent administration Link it with mealsUse of similar schedules, No frequent change in schedulesEasy handling: easy opening bottlesLarge label: large/ boldly written instructionElicit intelligent non-compliance and improve

Principles of drug prescribing

Patient education and counseling

Respectful communication with patientsDiscourage self-prescription, doctor shoppingensure complianceSocial & financial support

*Difficulty in recognising effects aswell as toxic effects*Because children are subject to many of the same diseases as adults, physicians often treat children, by necessity, with the same drugs and biological products used by adults, even if these products have not been tested on children. More than 100 year ago Dr. Abraham Jacobi, the father of American pediatrics, recognized the importance of and need for age-appropriate pharmacotherapy when he wrote, "Pediatric does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but . . . has its own independent range and horizon."*With age the fun capacity of most of the organ systems decline beginng at about 45 yrs of age*The paediatric population represents a spectrum of different physiologies,The spectrum extends from the very small pretermnewborn infant to the adolescent. Let us see how age- dependant changes in the physiologic and biochemical processes govern drug pk and pd.*Gastrointestinal function significant changes occur after birth. In full term infants gastric acid secretion begins soon after birth*Alpha amylase and other pancreatic enz are low till 4 months of age*Drugs given by rectal route: Preferred in newborns and young infants. especially when oral administration impossible. Efficient translocation across rectal mucosa.Reduced pre- systemic drug clearance.E.g. DiazepamAcetaminophen*Intramuscular:Anterolateral aspect of thigh v/s gluteal muscle.>5 yrs- Deltoid muscleIn neonates- premature and term:Less muscle massPeripheral vasomotor instabilityInsufficient muscular contractionsIncreased percentage of water per unit of muscle mass.Poor perfusion- also in sick infants

Net absorption- Erratic, unpredictable. Not a preferred route.

In infants and children:Relatively higher density of skeletal muscle capillaries. Perfusion improves. e.g. Amikacin, Cephalothin.

*Subcutaneous:Poor blood supply, site of administration- reservoir of drug.

*As compared to 50-60% in adults preterm neonate 85%, decresed conc at site of actionDetermined by- Physicochemical properties of the drug.PATIENT FACTORS- Extracellular and total body water Total body fatPlasma protein binding

*LA, ampicillin diazepam, phenytoin, phenobarbalthough higher free drug conc may result in faster elimination this conc may be quite toxic initially*CYP 450 MFOs and conjugating enzymes are substantially lower ( 50-70% ) of adult valuesGlucuronide conjugan rchs adult value by 3-4 the yr of life. If drug doses and dosing schedules are not altered properly - toxicity due to immature enz system. grey baby syndrome due to both impaired metabolisn and excretion. Deficiency of GT enz and inadequate renal excretion of unconjugated drug. If mother receiving phenobarb induction of eaarly maturation of fetal hepatic enz, faster metb, less therapeutic effect

*At birth 30 to 40% of adult value.Peculiarity Toddlers 36 months - increased renal elimination and metabolismDose per KG of digoxin is much higher in toddlers than in adultsIncrease metabolism of drugs- increase doses & frequency eg; phenobarbitone, phenytoin, theophylline

**How to calculate BSA if you know weight and height - Mosteller formulaBody size (incorporating both height and weight) correlates with-i) Body compositionii) Organ size and functionEstablished nomograms provide paediatric doses based on BSA, as percentage of adult dose.Newborn- 12% of adult dose 1 mg/kg would be 0.12 mg/kg, 1 yr 28%, 9 yr 60%, 12 yr 78% and 14- 90%. Pediatrician should always carry dosage book. BSA calculan is good . Mg/kg not advisable in obese and malnourished children. While prescribing always look at manufaturers recomendaed dose on package insert if not avalble, calculate from the above formuls

*The effect of normal growth and development on the pharmacodynamics of drugs has been less well studied. Age-dependent variation in receptor number, receptor afnity for drugs, or the responsiveness of the target organ or tissue to receptor occupancy could inuence drug effect. Drugs may also alter the growth and development process or express effects that are dependent on the stage of development.Appropriate use of drugs has made possible survival of neonates with sevre abnormalities whi would otherwise die after birth - Indomethacin & PGE1.

*Most drugs excreted but in too small amiounts. 3-4 hrs allow time for clearing from mothers blood and decrease in coc. In brest milk.Drugs with no safety data should be avoided or breast feeding discontinued while such drugs are given*Tetra conc almost 70 %of maternal conc.

INH equilibrium high conc in milk pyridoxine defficiency in infant if no t supplied to mother**radio- iodine thyroid cancer risk increases tenfold*Administration of oral drugs: a challenge- Children should be encouraged and praised for their co- operation in taking medicine. Tablets crushed or capsule contents mixed with small amounts of food.Safety in storage - otherwise Accidental overdose *Spoon sizes from 2.5 to 7.8 ml. The form in which a drug is manufactured and the way in which the parent dispenses the drug to the child determine the actual dose administered. *should be chosen. Avoid drug therapy frpr cold , viral fever but treat with antibiotics - bulging red ear drum or pus on tonsils. However, doses should not be diluted into an entire scheduled feeding or prepared ahead in batches- Food drug interactions & drug instability.Improving the taste of liquid dosage forms- use of flavouring agents, use of chasers.. For a child over the age of one, you can give them a chaser of Hershey's Syrup on a spoon following the bad tasting medicine. Have it ready on the spoon so there is minimal lag time. The chocolate syrup/ honey is thick enough to coat the mouth and hide the bitterness of certain medicines. You can also use a softened Hershey's kiss.*Which age group would you call elderly ? 65 70 75 ??? health authorities in some countries consider the field of geriatrics to apply to 75 the gradual decline in functions of major organ system starts at ?? 45 years old age in many developing countries is seen to begin at the point when active contribution is no longer possible." (Gorman, 2000).Biological age and chronological age are NOT synonymous.

*In contrast to the chronological milestones which mark life stages in the developed world, *The elderly polpulation is increasing due to*Severe nutritional deficiency*Decreased liver blood flow heart failureLivers ability to recover from injury declines with age alcohol o viral hepatitisMalnutrtion hepatic met depends on Liver blood flowLiver massProtein bindingCo-morbid conditions

*Serum Creatinine levels are not a good indicator of the renal reserve

eGFR via creatinine clearance is better.

*Changes in response mainly due to altered PK and homeostatic mechanismsBlood sugar, GFR, Orthostatic hypotension * Polypharmacy is considered the most important. Comorbidity. Altered pharmacokinetics & dynamics

Homeostenosis9 drugs/day or 12 doses/day. Dietary supplements, vitamins, minerals.

Average of 3-4 med/day Average of 5 med in hospitalized pts.

Strongly associated with ADRs It may increase the risk of other geriatric syndromes like falls, cognitive impairment.

*Postural hypotension - ISDN, blockers, Diuretics, Antipsychotics, Tricyclics, Levodopa, Constipation Anticholinergics,Antidepressants,Antipsychotics,Opioids,Nifedipine,DisopyramideIncontinence Diuretics Parkinsonism- Methyldopa, Antipsychotics, Metoclopramide, Reserpine, Confusional state- Sedatives Anticonvulsants Antidepressants Anticholinergics Antihistaminics -blockersTheophylline

*New term for compliance. The extent to which the patients take medications as prescribed by their health care providersdec mobility & sensory ability. 2) cataract, macular degeneration.*The Health Buddy Appliance automatically dials a toll-free number to send the information to a secure data center, where it is viewed by a home care clinician. A wireless modem option is also available for patients without a phone line or home Ethernet connection.Improves self-care, treatment and medication compliance by educating, motivating and monitoring patients on a daily basisEnables clinicians to gather data during remote patient care.Frees clinicians to focus on their most critical patients, delivering care when appropriate instead of based on a fixed scheduleEnhances the productivity of provider organizations by allowing clinicians to

*Qulaity of life can be greatly improved and life span prolonged by intelligent use of drugs in elderlyFDCs, Modified release preparationsSimplify the regimen, integrated dosing regimen should be usedAvoid liquid preparations in patients with tremor and motor disability.

*Qulaity of life can be greatly improved and life span prolonged by intelligent use of drugs in elderlyFDCs, Modified release preparationsSimplify the regimenAvoid liquid preparations in patients with tremor and motor disability.Respectful communication with patients be patient hear them carefully

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