8. Paediatric drug therapy. Flashcards
aspects of perinatal drug therapy should be focussed on what ?
access of the drug to the fetus
pharmacodynamics aspect of drug action during breast feeding
clinical pharmacology in pediatrics
access of drug to the fetus depends on what ?
lipid solubility - lipid soluble drugs easily cross over the placenta
ionised drugs do not
molecular size
protein binding
placental and fetal metabolism
placenta excludes drugs of what molecular weight ?
MM250-500 = readily cross the placenta
500-1000 = difficult to cross the placenta
more than a 1000 - excluded
the more the molecular weight the harder the drug to cross the placenta EXCEPT for maternal antibodies
how does protein binding of a drug effect the drug given ?
if there is higher protein binding of the drug they will not readily diffuse through the placenta
plasma protein binding is also different in fetal blood there might be more free drugs in the fetal plasma than in the mother
such as sulfonimides , barbiturates , phenytoin
in the placenta what type of metabolism takes place ?
placenta goes through aromatic oxidation reaction such as hydroxylation , n dealkylation , demythylation
phenobarbital is oxidied by the place
and 40-50 percent of umbilical venous blood enters the fetal liver
what are the pharmacodynamic aspect of the drug action on the fetus ?
maternal drug action - mother may need to take drugs such as pregnancy induced diabetes or heart failure
therapeutic action on fetus - drugs given to stimulate the fetus and well being such as corticosteroids for lung development if preterm
phenobarbitural = induce fetal hepatic enzyme which glucorinide bilirubin
toxic action on fetus = opiates - cause withdraw syndrome
ACE INHIBITORS - renal toxicity
teratogenic action
acts predominantly in a defined stage of fetal life
dose dependancy
what are the teratogenic antibiotics ?
ahminoglycosides
tetracylines ,
quinolones
sulfonamides
what are the teratogenic effects of these antibiotics ?
ahminoglycosides :deafness , vestibular damage ,
tetracycline : anomalies of teeth and bone
sulphonamides - kernicterus
why is anticholinergics teratogenic
cause meconium ileus
why is anticoagulants such as warfarin teratogenic
skeletal and cns defects
what are the anticonvulsant drugs which are teratogenic ?
carbamazepine - neural tube defects
phenytoin - growth retardation and CNS defects
valproic acid - neural tube defects
trimethadione - CNS and facial defects
what are other teratogenic drugs ?
antidepressant - lithium - Epstein anomaly ( heart defect of the tricuspid valve)
hypotonia
ACE inhibitors - renal failure and decreased ossification
antithyroid - PTU - goiter , hypothyroidism
diuretics - furosemide - hyperbilirubinemia
thiazides - neonatal thrombocytopenia
what are the things to consider of drugs on lactating mother ?
drug affects lactation
drug concentration in breast milk
pharmacodynamics of the drug ingested in breastmilk
what dugs inhibit prolactin
bromocriptine , ergotamine , cabergoline , lisuride , metergoline
= estrogen anatgonises prolactin
which drugs inhibit milk ejection and prolactin
clonidine
which drugs suppress lactation ?
thiazides
drug concentration in breast milk is directly proportional to what ?
maternal plasma concentration
milk concentration does not usually exceed the maternal plasma concentration
what is the characteristic of drug which pass into the breast milk
through PASSIVE DIFFUSION - human milk is acidc , and drugs that pass into it are weak bases , water soluble , lipid soluble and poorly bound to proteins
what servers as a ratio for drug excretion in milk ?
milk plasma ratio
drug concentration in breast milk is difficult to predict and measured how ?
empirically -by observation or experience
rather than logistics
drug affects on breast feeding mother is greater on whom the infant or the mother ?
the mother
how can the amount of drug the baby ingest be reduced ?
feeding the infant just before or at the time of administration
this is because even if the M:P ratio was 1:0 the amount of drug ingested is not sufficient to attain therapeutic concentration
even when M:P ratio is 1:0 why is not concerting
the amount of drug ingested is not sufficient to attain therapeutic concentration
what concentration of drug in the childs system should be concerning
drugs in systemic circulation of over 10 percent
what are some examples of breast milk drug ingested drugs adverse effects
tetracycline - permanent tooth staining in infants
diazepam - sedation in infants
cancer chemotherapy - immunosuprssion and neutropenia
lithium - same conc of great milk as in plasma - tremor and involuntary movements
amiodarone - thyroid disturbance because of high iodine content
ASA - reye syndrome
NSAID - premature closure of ductus arteriosusu
chloramphenicol - grey baby syndrome = circulatory collapse
sulphonamides - jaundice - competition of bilirubin binding to albumin
quinines - cartilage development defect
tinidazole - carcinogen and mutagen
phenolphthalein contains laxatives - carcinogen
cemtidine h2 antagonist - gastric acidity and inhibition of cp450
what is the difference between pharmacokinetics and pharmacodynamics ?
kinetics drug dosage absorption distribution plasma conc metabolism excretion
dynamics
sites of action
clinical effects
what are the things to consider in drug absorption in IM injection
blood supply and flow - exercise enhances absorption
muscle mass - obese , malnourished
muscle is more acidic than blood
phenytoin is converted into acid in IM injection
the sodium also precipitates at site of injection = flower absorption
what are the things to consider with drug absorption from the GIT
gastric acidity slowly rises in premature infants
gastric emptying is prolonged = increase absorption
peristalsis is slower in neonates = increase absorption
diarrhea = effects is exaggerated in neonates and drug action interference
bacterial flora slowly rises
what drugs with oral drug absorption in neonates is greater than that of a child
ampicillin
penicillin
what are the drugs when oral drug absorption has lower in neonates that of a child
acetaminophen
phenobarbitural
phenytoin
when is rectal administration of drugs used ? and which drugs does rectal Administration is most successful ?
in nausea , vomitting , status epileptics , induction of anaesthesia and for administration of drug that has large first pass metabolism
diazepam well absorbed rectally barbiturates midazolam lorazepam atropine - anticholinergic
drugs given orally and nasogastrically may have altered absorption due to ?
altered PH
edema of gastrointestinal mucosa
alterations blood flow
presence of ileum
coadminisration of formulas
what does drug distribution in children depend on ?
membrane permeability
plasma protein binding
bound drugs do not cross membrane
malnourishes - decrease albumin and increased drug in plasma
lipophilic profile
lipophilic drugs readily cross the membrane nmore than unionised
lipophilic drugs accumulate in adipose tissue
volume distribution
24wks preterm infant - TBW = 86 percent
(ecf= 60 percent , icf=35 percent)
term = 75 percent (ecf= 40 recent , icf = 35 percent)
neonates have larger plasma volume
at around 3 months the switch comes
1 year = 60 percent
(ecf=25 and icf 35)
adult = 50-60 percent
(icf=40, ecf= 20)
ECF determines drug conc
body fat has higher body weight percentage that extracellular fluid in 9months to 1 year old and stay equal till 10 years old until ECF takes over and body fat drops
birth = 12 percent
6 months = 25 percent
1 year = 30 percent
5-6 years = 12 percent
adult = 10 percent
affecting distribution of lipid soluble drugs
neonates undergo diuresis when
beginning 48 hours
what affects protein binding in infants
conc of free ffatty acids and indirect bilirubin and albumin levels
FFa and havs a high affinity for albumin result in competition and displacemnt of drugs = exp sufonamides and phenytoin
change of affinity for albumin at different stages of maturation - acidic drugs high affinity to serum albumin over the frst few weeks of life
where do drugs undergo metabolism
lungs
blood
liver
why do the body undergo drug metabolism ?
to make the more water soluble so they can be excreted out
however it can also transform drugs into an active compound a prodrug into an active drug
drugs undergo two phases of metabolism what is part of PHASE1 ?
phase 1 - CYP450
located in the endoplasmic reticulum of hepatocytes
goes through oxidation and reduction
through hydrolysis
demythlation
methylation
alcohol dehydrogenase
drugs undergo two phases of metabolism what is part of PHASE 2 ?
a polar group conjugated to drug so increase in water solubility
glycine (amminoacidi) , glucoroniditaion , acetylation , sulfation , acetyle group , glutathione
slower drug metabolism in infants and neonates
yes
when does Phase 1 reactionsreach maximal maturity?
6 months
CP450 and conjugating enzymes are reduced in activity in neonates ?
yes
Glucorunidation reach adult levels in?
3rd-4rth year of life
Sulfation pathway-reach adult levels ?
days after birth
Decreased ability of neonates to metabolize drugs result in
in prolonged elimination half lives leading to ADR or toxicity from overdose
Infants more susceptible to drug toxicity vs adults when
drug must undergo hepatic elimination
what are the different routes of elimination ?
pulmonary expired in air
bile = excreted in feces be aware of enterohepatic circulation
renal =
be aware of GFR
tubular reabsorption
tubular secretion
how does GFR increase after birth and when does it reach adult values ?
Week 1 GFR -30%-40% of adult values (even
lower in prematures)
Week 3 - 50-60% of adult values
By 6-12 months -reaches adult values
tubular secretion in neonates is how much lower compared to adults and when does it reach maturity ?
25-50% lower in newborn reaching adult levels at age 1- 3 years
what is steady state ?
he amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level
which drugs reach steady state quicker ?
Drugs with short half-life
drugs with long half-life take days to weeks to reach steady state
when a CHILD has renal disease what can be done different to drug administration ?
hepatic metabolism unchanged
same/ increased volume distribution
prolonged elimination
DOSING INTERVALS HAVE TO BE INCEASED
when a CHILD has hepatic disease what can be done different to drug administration ?
elimination is constant
same or increased volume distribution
slow rate of enzyme metabolism
DECREASE DOSE AND INCREASE THE DOSING INTERVALS
when a child has cystic fibrosis what can be done to drug administration
increased metabolism and elimination
larger volume distribution
increase dosage decrease dosage intervals
what entails pharmacodynamics ?
mechanism of drug action
efficacy = degree drug can produce desired response
potency = amount of drug needed to produce 50 percent of its maximal effect
safety profile
what does the drug do in a cellular level and general
what does effective concentration mean
ED 50 = con of drug that induces a specific therapeutic response in 50 percent of the subjects
what does lethal dose means ?
LD50 = conc of drug which bring death to 50 percent of subjects
what is a therapeutic index ?
LD50/ED50
measure the safety of a drug
what is margin of safety
margin between therapeutic and lethal effect doses of a drug
what is pharmacogenetics ?
science of assessing genetical y determined variation in population and its effect on pharmacodynamics and pharmacokinetics
in clinical practice how will you do a prescription
select drug
select the dose
select the formulation
the route of administration
the anticipated length of therapy
what are other factors that needs to be looked at when prescribing drugs
drug to drug interaction - that can alter absorption , metabolism , protein binding competition and excretion
drug food interactions - if given nasogastrially
what are the special dosage form for infants and children ?
elixir = alcoholic solution where drug is dissolved no shaking is needed
suspension - undissolved particles - MUST shake
first dose will contain less drug than last dose
chewable tablets
when working with children and drugs what should we look out for
patient compliance
how can we improve patient compliance ?
take time to explain the nature of the illness
provide precise instruction for treatments
give specific instructions about osage
how can we calculate paediatric dosages ?
young’s rule
clarks rule - more precise
BSA
what is young’s rule ?
adult dose x { (age in yrs)/ (age +12) } = child’s dose
what’s clark’s rule ?
child’s dose = adult’s dose x { weight kg / 70 }
what is BSA ?
(neonate BSA / adult BSA ) x 100 = % adult dose needed
labelling info of manufacturers do not contain dose information for people less than ?
12
