Principle of Pediatic Care 2014

8/12/2019 Principle of Pediatic Care 2014

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Best medical judgment

Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ 2000;320:79

2262 drug prescriptions were administered to 624 children in the five hospitals.Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label.


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75% prescription drugs in children off-label

Consequences of off-label usage-Benefit, No effect, Harm

Drug Off label use

BeclometasoneUsed in infants under 12 months. Licensed for 2 years and over in Italy

Fluticasone 250 g twice daily in 4 year old. Maximum dose 100 g twice daily

Trimeprazine Used as sedative in child with pneumonia.

Licensed for urticaria, pruritus,

and pre-anaesthetic medication.

Rifampicin Used for enzyme induction in infant with biliary atresia

Salbutamol Used two hourly (12 times daily). Licensed for 4 times daily.

Tobramycin Used once daily in neonate. Licensed for twice daily.

Examples of

off label drug use


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Best medical judgment Folli et al.(1987): 0.45 to 0.49 ordering errors per 100 medication orders (2 ped.

hospitals X 6 mos). Most common type were dosing errors (PICU)/ Antibiotics.

Kaushal RB (1999): 6 ordering errors per 100 medication orders (2 ped. hospitals

X 6 wks). Most errors involved incorrect dosing (NICU).

Few drugs are preprepared in doses appropriate for children. This necessitatesthe frequent dilution of stock medicationserror calculating /dilution.

Folli HLPoole en's hospitals. Pediatrics. 1987;797 18- 722 / Kaushal RBates DWLandrigan C et al. Medication errors and adverse drug events in pediatric inpatients.JAMA. 2001;2852114-2120


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Preterm / Premies 37 Full term infant - 37-41

Post term infant - 41 Neonate/ new born 0-28 Infant/ baby 1 - 1 Child 1 - 12 Adolescent 13 - 18


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... ...

Nelson Textbook ofPediatrics

The Pediatric DruginformationHandbook

Harriet LaneHandbook

Guidelines forAdministration of IV

Pediatric Journals-Pediatrics,Journal of Pediatrics, etc.


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http://www.medscape.com/viewpublication/

87

2 2


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Causes of medication errors in children

2 mg/kg/day divided q..hr mg/kg q..hr

mkd

Young children have less developed communication skills than adults, limiting

feedback about potential adverse effects or mistakes in medication administration.


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Weight-based dosing is needed for virtually all pediatric drugs.

10%

3-6 20-30 4-5 2

1 3

2 4

1-6 : = () x 2 + 87-12 : = ( ) x 2 5

2

...


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10

...

... 6

5 ........

Domperidone 5 mg/5mL

DOSAGE AND DIRECTIONS FOR USEAcute conditions (mainly nausea, vomiting, hiccup)Adults: 20 mg (20 mL of suspension or 4 medicine measures) 3 - 4 times per day,15 to 30 minutes before meals and, if necessary, before retiring.

Children: 5 mg (5 mL of suspension or 1 medicine measure) per 10 kg bodymass, 3 - 4 times per day, 15 to 30 minutes before meals and, if necessary before

retiring.

Chronic conditions (mainly dyspepsia)Adults: 10 mg (10 mL of suspension or 2 medicine measures) taken 3 times perday, 15 to 30 minutes before meals and, if necessary, before retiring. The dosage

may be doubled.

Children: 2.5 mg (2.5 mL suspension or a medicine measure) per 10 kg bodymass taken 3 times per day, 15 to 30 minutes before meals and, if necessary before

bedtime.


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Solu-Medrol 50 mg, IV then Prednisolone (equivalent dose) 6 5 ....???

Overall potency (equivalent dosages)High potency

Betamethasone 0.6 to 0.75 mg

Dexamethasone 0.75 mg

Medium potencyMethylprednisolone 4 mgTriamcinolone 4 mg

Prednisolone 5 mg

Prednisone 5 mg

Low potencyHydrocortisone 20 mg

Cortisone 25 mg Methylprednisolone 500 mg in 4 mL


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... (BSA)


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... (BSA)

= x 1.73 () = 0.024265 x H0.3964 x W0.5378

(Salisbury rule): 30 = ( x 2)% 30 = ( + 30)% child = x (/) ( = 70 )


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6 5 60 chronic myeloid leukemia (CML)

Imatinib Mesylate 340 mg/m2 1 2 600 mg

???

... (BSA)


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...


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Schwartz equation: CrCl (ml/min/1.73m2)= [length (cm) x k] / Scr (mg/dL)

(Patient population: infants over 1 week old through adolescence (18 years old))

Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A: A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259-263, 1976.

K = Constant of proportionality that is age specific

Age K_

Preterm infants up to 1year 0.33

Full-term infants up to 1 year 0.45

2-12 years 0.55

13-21 years female 0.55

13-21 years male 0.70

To convert serum creatinine in mol/L to mg/dL, the value in mol/L is multiplied by 0.0113


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Shull et al: Crcl (ml/min/1.73m2

) = ((0.035 x age) + 0.236) x 100)/ Scr

Shull BC, Haughey D, Koup JR, Baliah T, Li PK. A useful method for predicting creatinine clearance in children. Clin Chem. 1978 Jul;24(7):1167-9.

Counahan-Barratt: GFR (ml/min/1.73m2) = ( 0.43 x length )/ Scr

Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of glomerular filtration rate from plasma creatinine concentration in children.

Arch Dis Child. 1976 Nov;51(11):875-8.

- 6 5 60 SCr 0.6 mg/dL Crcl

(Schwartz equation)


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(Pharmacokinetics)- What the body does to the medication

Absorption

Distribution

Metabolism

Elimination

(Pharmacodynamics)- What the medication does to the body

Therapeutic

Toxic

Drug disposition in children

is variable - 3

Risks and Benefits of Generic Antiepileptic Drugs

The Neurologist Volume 14, Number 6S, November 2008 (A grant from GlaxoSmith-Kline-Spain)


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Gastric pH - F neonate infant Ampicillin

F neonate infant Phenobarbital


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Variable Age Group Result ExamplesGastric and intestinalmotility /

Neonates,infants,Olderinfants, children

Unpredictable bioavailability Digoxin

Biliary function/Bileacid production

Neonates infant child neonate

Vit E, Vit K

Pancreatic function

Neonates ester clindamycin F hydrolysis neonate

Clindamycin

Digoxin F neonate neonate

digoxin


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Intramuscular absorption

Neonate -- >

Infant -- > Child -- >

Benzathine penicillin G

Child

Total body fat

Neonate -- Infant -- > Child -- > ( 5-10 )

diazepam

(1.4-1.8 L/kg in neonate 2.2-2.6 L/kg in adults)

Vd


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Total water andextracellular water Neonate -- Infant --> Child -- >

Usual Pediatric Dose Gentamicin for Bacterial InfectionAGE Birthweight Dose (IV or IM)

0-4 weeks < 1200 2.5 mg/kg q 18-24 hrs

0-1 weeks > 1200 2.5 mg/kg q 24 hrs

1-4 weeks 1200 2000 2.5 mg/kg q 8-12 hrs

1-4 weeks > 2000 2.5 mg/kg q 8 hrs

> 1 month 1-2.5 mg/kg q 8 hr

Adult 1.5 to 2 mg/kg loading dose, followed by 1 to 1.7

mg/kg IV or IM every 8 hours or 5 to 7 mg/kg

IV every 24 hours.

aminoglycosides, caffeine, theophylline Vd neonate infant

total body water & extracellular water > Vd


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Total plasma protein Neonate -- > Infant -- > Child -- >

phenytoin sulfonamide Vd phenytoin

neonate infant albumin concentration; protein binding free

fraction (active); Competetion with endogenous bilirubin (displacement)


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Excretion

Metabolism

0 10 20 30 2 3 4 5 6

Age Days Months

Glomerularfiltration

Tubularsecretion

Sulfation

Acetylation Glucuronidation

Conjugation

Source: Massanari M, McLockin A, Sayles R, et al. J Pediatr Pharm Pract 1997;2:139-57.

Functional drug biotransformation patterns

Onset in Days: CYPs 2C9, 2D6, 2E1;

UGTs 1A and 2B7? Onset in Weeks: CYP3A4

Onset in Months: CYP1A2

Onset in Years: FMO3Chloramphenicol-->impaired glucoronizationin neonates--> Gray Baby Syndromeabdominal distension, diarrhea, vomiting, dusky gray color, circulatory collapse & death


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UDP-Glucuronyl TransferaseNeonate -- > (10%-20% )Infant -- > ( 3-4 )

Child -- > Breastmilk contains beta-glucuronidase; enterohepatic circulation is increased

Sulfonamides : Kernicterus(neonatal encephalopathy due to

bilirubin displacement)

CYP3A4

Neonate -- > (30%-40% ) Infant -- > ( 6 ) Child --> ( 1-4 )

Carbamazepine

10, 11-epoxide infant child

CYP3A4


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CYP2C9 Neonate -- > Infant -- > ( 3-4 ) Child -- > ( 3-10 )

Phenytoin

0-2 : T = 80

3-14 : T = 15 14-150 : T = 6

CYP2C19 Neonate -- > Infant -- > ( 6 ) Child -- > ( 3-4 )

Diazepam

T : neonate infant = 25-100 T Diazepam: child = 7-37

T Diazepam: = 20-50


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Renal- Glomerular filtration-Tubular secretion

- GFR is more developed thantubular function

Metabolism :- Hepatic > 90%

-Others < 10% Primary component of Half-life Primary determinant of dosing frequency

Excretion

Metabolism

0 10 20 30 2 3 4 5 6

Age Days Months

Glomerular

filtration

Tubular

secretion

Sulfation

Acetylation Glucuronidation

Conjugation

Source: Massanari M, McLockin A, Sayles R, et al. J Pediatr Pharm Pract 1997;2:139-57.

Pre-term neonates (< 36 weeks) GFR markedly reduced from term infants

Neonates, infants Glomerular filtration (GFR) t clearance Aminoglycoside


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Solvents Propylene glycol :

cardiac arrhythmias, seizures, respiratory depression, severe hyperosmolality,lactic acidosis, severe thrombophlebitis

phenobarbital, phenytoin, diazepam must be administered slowly when givenintravenously

Polyethylene glycol : nephrotoxicity (large doses lorazepam)

Ethanol : alcohol intoxication- 6-12 < 5% alcohol- > 12 < 10% alcohol


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Preservative Preservative: Chlorbutol, Benzyl alcohol

(induced gasping baby syndrome), Sodium

benzoate, Sorbic acid, Phenol, Thimerosal,

Parabens, Benzalkonium chloride (induced

bronchoconstriction)

Antioxidants: Butylated hydroxytoluene andhydroxyanisole, Propyl gallate and sulfites

The FDA and the American Academy of Pediatricsnow recommend that benzyl alcohol containingproducts should be avoided whenever possible ininfants

Conjugation

X

immaturity of

glycine conjugation

Metabolic acidosis, seizures, gasping,

intraventricular hemorrhage, death

Benzyl Alcohol MetabolismPreservative in many multiple dose IV and PO formulations (pentobarbital, heparin flush, etc.)


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Sweeteners and flavorings Conc. of sweeteners in oral solutions and susp. ~ 30-50% w/v Saccharin, Sucrose, Sorbitol, Aspartame, Fructose, Xylitol (~ 10 g/day*) Sorbitol (< 0.5 g/kg*) and Lactose (esp. lactose-intolerant patient) may

be associated with diarrhea and abdominal pain Sucrose (> 25 g/day*) decrease in dental plaque pH, dissolving tooth

enamel and promoting dental cariogenesis Aspartame containdicated in phenylketonuria

* clinical tolerance


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Dyes and colorants > 100 dyes and coloring agents approved by FDA for use in pharmaceutical

preparations (oral liquid formulations contain 1-3 dyes) FD&C Yellow 6, Tartrazine (FD&C Yellow 5) = cross-reactivity with aspirin

and indomethacin FD&C Red 36, FD&C Red 17, xanthene dyes (FD&C Red 3 and Red 22)

= photosensitizers

Triphenylmethane dyes (FD&C Blue 1 and 2 and Green 3) = hypersensitivityreactions,anaphylaxis, bronchoconstriction, angioedema, urticaria,abdominal pain, vomiting, contact dermatitis


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... Ranitidine HCl syrup (15 mg/mL)

Alcohol (7.5%) Butylparaben Sodium phosphate HPMCPeppermint flavor Potassium phosphate Propyl paraben WaterSaccharin sodium Sodium chloride Sorbitol FD&C Yellow 5

...?


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: Oseltamivir phosphate

... 6 5 60 39.6 Oseltamivir syrup

???


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oseltamivir 10 mg/mL

: Oseltamivir phosphate


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- 2 2

-

- - 1/2 2/3

-

-

- 7 2

-


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syringe syringe house hold measurement

syringe

syringe

syringe

(syringe)

...


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htt ://www.wto .com/267/3462181/Acetamino hen-What-are-the-health-risks-

About 150 Americans die a year

by accidentally taking too much

acetaminophen, the active

ingredient in Tylenol, federal data

from the CDC shows.

Taken over several days, as little as 25 percent above the maximum daily dose - or just two additional

extra strength pills a day - has been reported to cause liver damage.Taken all at once, a little less than

four times the maximum daily dose can cause death.


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1 month to 12 years: 10 - 15 mg/kg/dose every 4 to 6 hours as needed (Max:5 doses in 24 hours 4 months to 9 years:15 mg/kg /dose every 4 to 6 hours as needed

>=12 years: 325 to 650 mg every 4 to 6 hours or 1000 mg every 6 to 8 hours. : 4 g in adults and 90 mg/kg in children Toxicity: single acute ingestion of 150 mg/kg or ~ 7-10 g in adults

Increase risk: chronic ethanol use, malnourishment,diminished nutritional status, fasting, viral illness withdehydration, or if substances or medications that induce CYPoxidative enzymes CYP2E1, 1A2, 2A6, 3A4) to a reactivemetabolite, N -acetyl-p-benzoquinone-imine (NAPQI)


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Dose of drug was determined by the childs weight:paracetamol 15 mg/kg per dose and

ibuprofen 10 mg/kg per dose.

Ibuprofen toxicity 100 mg/kg -->

100-200 mg/kg --> 200-400 mg/kg --> 400 mg/kg --> severe metabolic acidosis

...

BMJ2008;337:a1302


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Hypothalamus maintain set point temp. = 37 c 98.6 F

- Rectal/Tympanic temp. > 38.3 c- Orally temp. > 37.8 c- Auxiliary temp. > 37.0 c

Set point : If temperature>40 c (104.0 F)-->Considering Bacteremia Tachypnea -- > Pneumonia

(10%-20% of visit)

FeverScan indicated over-diagnosed feverby 74%. The positive predictive value foraccurately detecting fever was only 57%.

Source: Colin Morley*, Matthew Murray and Katherine Whybrew. The relative accuracy of mercury, Tempa-DOT and FeverScant hermometers. Early Human Development Volume 53, Issue 2, 1 December 1998, Pages 171-178.Purssell E. Treating fever in children: paracetamol or ibuprofen ? Br J Community Nurs. 2002 Jun;7(6):316-20.

Meta-analysis : no clear benefit for one drug over another 1 hour after administration.By 6 hours, ibuprofen was clearly superior resulting in a mean temperature 0.58 degrees C lower .


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(Febrile convulsion)

http://www.youtube.com/watch?v=142_yvH0Eb0


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1

2 1 CNS disorder /Developmental delay Complex Seizure

2

: Phenytoin ineffective Phenobarbitone Poorly effective 4-5

mg/kg/day [Herranz et al 1984, Mamelle et al 198Wolf et al 1977] Sodium Valproate: Drug of choice (0.3mg/kg/dose)

: Diazepam oral / rectal (0.3 mg/kg/dose) Clobazam

...


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( )


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Antihistamines 12

paradoxic excitability, respiratory depression, and hallucinations

Chlorpheniramine 2


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Dextromethorphan 2 Dextromethorphan: 1 mg/kg/d divided into 3 to 4 doses No evidences of effectiveness

Codeine 2 - 1 mg/kg/d in four divided doses, not to exceed 60 mg/d

dosages of 3 to 5 mg/kg/d have produced somnolence, ataxia, miosis, vomiting, rash,facial swelling, and pruritis

No more effective than placebo Aspirin 1 Reyes syndrome


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Principle of Pediatic Care 2014