Developmental Pharmacology Flashcards
Its okay to simply scale the adult dose based on the child’s body weight or surface area (T/F)
F.
Pediatric dosage regimens should take into account _____and _____.
- age or developmental stage
2. disease state of the child
Give the diseases caused by these drugs:
- THALIDOMIDE used to treat morning sickness of pregnant women
- Administration of IV CHLORAMPHENICOL in babies
- Exposure of DIETHYLSTILBESTROL in utero
- Phocomelia = loss/malformation of limbs
- Gray Baby Syndrome = immature liver enzyme cant metabolize chloramphenicol
- Adenovaginal Carcinoma
Marked the modern era of pharmaceutical regulation
Kefauver-Harris Drug Amendments of 1962
Children are not small adults.
Dosing should be based on a rule and scaling of body weight or surface area. What are those 2 rules?
Young’s Rule
Clark’s Rule
What is Clark’s Rule?
Clark’s Rule uses Weight in Lbs, NEVER in Kg.
Adult Dose X (Weight ÷ 150) = Childs Dose
What is Young’s Rule?
Young’s Rule uses age.
Adult Dose X (Age ÷ (Age+12)) = Child’s Dose
Developmental Continuum:
Weight doubles when? triples when?
Surface area doubles when?
Caloric expenditure increases how many fold by 1 year?
5 mos., 1 year;
1 year;
3-4x;
Developmental Changes that influence drug disposition
Clue: M-GRID
M-GRID:
Metabolism, GI fxn Renal fxn, Integumentary Dev’t, Distribution sites
PK - ABSORPTION:
2 main factors affecting Absorption in Pedia?
Give examples for each factor.
- Drug characteristics (solubility, size, ionization, conc, inactive components)
- Host Factors (Surface Area, Blood flow, GI Peristalsis)
Changes in GI Fxn:
Clue: P-BAGS
- Perfusion - in intestinal smooth muscles, it is decreased
- Biliary Fxn - not fully developed in neonates
- Acidity - Alakline at start (pH 6-8), becomes acidic later on (pH 1-3)
- GET - delayed (6-8hrs), during 6th-8th month of life
- Sterility
Changes in GI Fxn:
When is CYP1A1 produced?
When is glutathione conjugation possible?
@ 3mos;
1-3 y.o.;
Changes in GI Fxn:
Drugs that are absorbed in the stomach?
Drugs that are poorly absorbed?
- Weakly acidic, non ionized drugs
2. Chloramphenicol, Tetracycline, Erythro, Phenytoin, Phenobarbital, Paracetamol
Changes in GI Fxn:
2 drugs that cant be processed due to the sterile intestinal tract of neonates
Sterile GI = cannot hydrolyze prodrug into active drug:
- Chloramphenicol
- Pro-ampicilline
Integumentary Devt in Neonates:
4 routes of absorption
Percutaneous: (higher absorption in neonates than in children)
Parenteral: (erratic absopriton of IM and SQ morphine)
Rectal: (route of admin for paracetamol and diazepam)
Inhalational: (for asthma)
Integumentary Devt in Neonates:
Skin testing in Neonates to detect allergy is not informative. Why?
Due to absence of histamine in neonatal skin until 3rd week of life
PK - DISTRIBUTION:
4 factors affecting drug distribution
- Size of body compartments
- Protein binding
- Blood flow
- Development of Blood-organ barrier (blood brain, blood ocular)
Lipophilic drugs have higher Vd in neonates/infants. (T/F)
F. Neonates have more Body Water than Adults. High ECF volume leads to greater Vd of water soluble drugs (ex. Sulfa antibiotic).
Ontogeny of Body Composition:
What are the changes in body composition?
- Dec. in H2O content (85% in premature –> 75% in full term)
- Dec in ECF volume (due to shift of H2O from EC to Intracellular; 60% in premature –> 20% by puberty)
- Inc in Body fat (5% in premature –> 15% in fullterm; decreases when infant start walking)
In order to achieve comparable plasma and tissue concentration of drugs, higher doses per kg of body weight must be given to infants compared to adults. (T/F)
T
Tissue and Organ Weight:
What organs are enlarged in infants?
- Liver
- Kidney
- Brain (5x bigger than in adults by proportion)
Plasma Protein Binding:
Degree of drug binding to plasma proteins is proportional to the Vd (T/F)
F. It is inversely related to Vd.
Plasma Protein Binding:
Protein binding of drugs will affect 2 things. What are these?
Binding to plasma protein will affect
(1) renal clearance [only free drug filtered]
(2) amt of drug reaching target site [based on free drug conc]
Plasma Protein Levels:
What is the pattern?
LOW AT BIRTH compared to adults —> reaches adult level during:
(1) 3rd yr of life for Albumin (binds to Acidic drugs)
(2) 5-7th yr of life for a-glycoprotein (binds Basic drugs)
Plasma Protein Levels:
Higher levels of ____ and ____ can lower the fraction of drug that is bound.
Free fatty acid and Bilirubin.
Kasi nagbbind yung dalawa sa albumin so konti na lang yung drug na nagbbind sa albumin.
A slight difference in the fraction of drug bound to proteins matters. (T/F)
T. Especially for highly bound drugs.
In the case of highly protein bound drugs, they can displace bilirubin from albumin binding sites. This results in _______.
KERNICTERUS!!! or yellowing of skin.
Ex. sulfonamides, sodium benzoate, salicylates, etc (check trans, page 4, madami kasi)
CNS Growth and Dev’t:
Rate of growth of CNS volume?
Which is faster in terms of growth: Body Surface Area (BSA) or Weight?
Growth rate of CNS volume decreases as time passes.
Weight. BSA takes longer.
Implication: Use Weight as basis for drug dose administered in the CSF.
Blood-Organ Barrier:
2 reasons for the inc. in permeability of membrane allowing some drugs to penetrate Blood-brain barrier
(1) incomplete anatomic development of barrier
(2) incomplete myelination in the brain.
WEIGHT VS BSA Dosing guide:
Which leads to a more uniform serum drug concentration across a broad age range?
Body surface area (BSA), based on clinical experience sabi ng trans
PK - METABOLISM:
Phase I vs Phase II of liver metab
Phase I: non synthetic, reduces drug activity, mature at variable rates, Oxidation as the main process, adding/unmasking of fxnal groups
Phase II: synthetic, inactivates drug, Conjugation as the most important pathway; conjugation with glucoronide, sulfate, acetate, amino acid
Hepatic Ontogeny:
Major fetal hepatic CYP?
Most abundant hepatic CYP?
CYP3A7
CYP3A4
Hepatic Ontogeny:
How to measure CYP3A7 activity?
How to measure CYP3A4 activity?
16a hydroxylation of dehydroepiendrosterone
conversion of testosterone to its 6b derivative
Phase II processes: Inc/Dec at birth? a. Glucoronidation? b. Sulfation? c. Acetylation?
low at birth
high at birth
low at birth
Phase II processes:
Acetylation capacity can be divided into 2 phenotypes - fast and slow. What is the difference between the two?
A fast acetylator person can metabolize and excrete an acetylated drug faster than a slow acetylator. Little drug accumulation results from a fast acetylaor [more favored]
Hepatic Ontogeny:
Acetaminophen Metab in adults yields _____ conjugate while newborns yield _____ conjugate.
Glucuronide Conjugate
Sulfate Conjugate
More sulfation enzyme at birth (decreases as one gets older) while at same time glucuronization enzyme inc (as one gets older). Sulfation formation compensated for the deficiency in glucuronide conjugation.
Hepatic Ontogeny:
Theophylline Metab in children has age-dependent routes. Its metabolism __(inc/dec)___ as one gets older resulting in __(inc/dec)___ in its excreted unchanged form.
Increases
Decrease
Theophylline is N-methylated to caffeine. Now, there is a delay in the elimination of caffeine in newborns (100hrs vs 4hrs in adults)
Hepatic Ontogeny:
Drug Metab in neonates differ from adults. Deficiency of U-glucuronosyltransferase (UGT) in neonates results in ________.
Salicylate, chlorampehnicol, PABA toxicity + bilirubin half-life is prolonged.
PK - EXCRETION:
Kidney is anatomically and functionally immature at birth. This mainly affects ______.
Renal Blood Flow (RBF)
this consequently affects GFR.
Renal Ontogeny:
GFR function is related to post-conception age. (T/F)
T.
GFR significantly lower in preterm (5-10mL/min/m2) than in term (10-15mL/min/m2).
Renal Ontogeny:
What mechanism is responsible for the increased RBF, and eventually GFR, as one gets older?
There is a dramatic decrease in renal vasculature resistance: RBF inc and also GFR.
Renal Ontogeny:
When can renal excretion be comparable with that observed in older individuals?
8 months to 1 year of age.
Renal Elimination:
When does GFR reach adult levels?
When does Tubular secretion reach adult levels?
Is tubular reabsorption high/low in neonates?
after 3 months of age;
after 5-6 months of life;
it is high in neonates
Renal Elimination:
Drugs that need to be monitored due to altered clearance capacity in neonates.
C-FAG:
Ceftazidime, Famotidine, Aminoglycosides, Gentamycin
Renal Elimination:
2 drugs that alter renal maturation of renal blood flow?
Betamethasone (glucocorticoid accelerates renal fxn maturation)
Indomethacin (induces vasoconstriction of renal vascular bed, delays renal maturation)
EFFECTS OF DISEASE STATES IN DRUG KINETIC:
High temp? Obesity? Edema? Malnutriton? Renal/Hepatic Failure?
- High Temp = High Metab Rate;
- Obesity = large Vd or lipophilic drugs
- Edema = decreased albumin and protein binding
- Malnutrition = excretion and Vd of highly protein bout drugs are affected
- Renal/Hepatic Failure = need dose adjustment (Antibiotics, CV drugs, GI drugs, Salicylates)
Pediatric-Specific ADRs (Memorize daw)
Furosemide?
Indomethacine?
Tetracycline?
- Nephrocalcinosis (high Ca in blood/urine)
- Renal Failure and Bowel Perforation
- Discolored Teeth
Pediatric-Specific ADRs (Memorize daw)
Adrenocorticoids?
Valproic Acid?
Chloramphenicol?
- Delayed dev’t, gowth suppression
- Hepatotoxicity
- Gray baby syndrome
Pediatric-Specific ADRs (Memorize daw)
Aspirin (acetyl salicylic acid ASA)?
Phenytoin?
Phenobarbital?
- Reye’s Syndrome (live and brain swelling)
- Thickened skull + coarse features
- Hyperactivity, impared intellligance
Pediatric-Specific ADRs (Memorize daw)
Phenothiazines?
Extrapyramidal reaction
Special Pharmacodynamic Features:
Indomethacin causes?
Prostaglandin E1 causes?
- rapid closure of patent ductus arteriosus
- opening of ductus, to save patient w/ tetralogy of Fallot or Transposition of Great Vessels
Chloramphenicol Story:
It was the 1st broad spectrum antibiotic.
Is it bacteriostatic/bacteriotoxic? How?
It is bacteriostatic.
It inhibits protein synthesis by binding to bacterial 50S ribosomal unit and blocking peptide bond formation
Chloramphenicol Story:
How is it detoxified in the liver?
Through conjugation with glucuronide (Glucuronidation).
Lack of UGT to metabolize chloramphenicol caused Gray Baby Syndrome.
Chloramphenicol Story:
Pathognomonic sign of Gray baby syndrome.
Gray color, cold and moist skin.
Chloramphenicol Story:
Symptom development?
Vomiting + refusal to feed —> Respiratory distress —> abdominal distention, periods of cyanosis, passage of loose green stools —> falccidity, ashen color, hypothermia, vascular collapse —> DEATH IN 5th day.
