Pharmacokinetics Flashcards
What dosing strategies almost double when use?
What would these methods do for neonates overestimate/underestimate?
What would these methods do for infants and children under 5 overestimate/underestimate?
Clarks rule and BSA-based dosing
Neonates: Overestimate
Infants, children under 5: under/over or appropriately-estimate dose
What factors INCREASE drug absorption in children relative to adults (4)
- inc AMOUNT of Gastric emptying (kids eat more)
- inc GI pH (more basic) (eg. penicillin absorption increased)
- small intestinal length in proportion to body weight (quicker absorption)
- Higher absorption of topical drugs
What factors DECREASE drug absorption in children relative to adults (4)
- intestinal surface area
- biliary flow and acid secretion
- transporter expression and activity
- metabolic enzyme expression and activity
What factors are consistent between adults and children for drug absorption (2)
- Small intestinal transit TIME
- Gastric emptying TIME
Describe the drug distribution in child (1 year0 vs adults.
Water vs. fat
Child (1 year)
- more water
- less fat
**inc V for hydrophilic drugs
**dec V for hydrophobic drugs
Adult
- more fat
- less water
**inc V for hydroPHOBIC drug
**dec V for hydrophilic drug
What is the drug distribution in children regarding protein binding (higher unbound or bound drugs)
Higher unbound protein drugs
- less conc of proteins
- lower affinity for protein
In drug metabolism in children, what is AUC greatly dependent on for moderate extraction ratio drugs?
CLint
Is total absolute clearance higher/lower in children compared to adults
Always lower
- lower mg dose than adults
is total weight normalized clearance higher/lower in children than adults
Can be higher/lower than adults
eg. 3 weeks old at same mg/kg has way HIGHEST plasma conc
When dosing mg/kg, how will the AUC factors change in adult levels
at birth
early life
adult (at what age is the same)
AUC:
at birth: higher at birth (low CL)
early life: lower (high CL)
adult: same levels at 6+
When dosing mg how will the AUC factors change in children levels?
AUC will always be higher in adults (higher plasma conc, lower clearance)
- dose will never exceed in adults
Clearance per Kg (higher/lower)
1 year
Adult
1 year: higher Cl
Adult: lower Cl
Clearance overall (higher/lower)
1 year
Adult
1 year: lower Cl
Adult: higher Cl
Compare GFR/kg in children vs adults. Compare GFR to tubular secretion
inc GFR/kg in children than adults
Tubular secretion doesn’t have the same sharp rise that renal clearance does
What happens to INR when you give a low warfarin dose to children vs adults
INR increases with low dose in children
- thinner blood
In large molecules for pediatrics, what is changed (5)
- Inc capillary surface area
- Inc leaky tight capillary ratio
- Inc lymph flow rate
- Inc hematopoietic cells
- DEC FcRN (EcF) expression –> inc in drug clearance
mg/kg dosing for biologics children vs adults. Lower/higher exposure?
Lower exposure
- children are sub-therapeutic
What is the minimum are for Clark’s rule? Young’s rule
Clark: 2-12
Young: 1-12
Filtration
Passive/active
What gets filtered?
Passive
- unbound drug gets filtered
Tubular SECRETION
active/passive
What gets transported?
Active
- transport drug from blood to urine
Tubular reabsorption
passive/active
Both
Using CL, fu, GFR
What indicates more reabsorption is occurring
What indicates more secretion is occurring
Reabsorption
- CL < fu x GFR
Secretion
- CL > fu x GFR
What happens to the following factors with a renal impairment patient
Half-life
k
V of D
CL
Time to steady state
Concentration at steady state
Half-life: increased
k: decreased
CL: decreased
V of D: the same
Time to steady state: increased
Concentration at steady state: increased
Effect on peak and trough when you change:
Dosing interval
Change the dose
Dosing interval
- maintain same peak and trough
Change the dose
- decrease difference between peak & trough
What is the goal of therapeutic drug monitoring?
Optimize the time within the therapeutic window
When is a good time to take a sample for therapeutic drug monitoring.
- What type of conc do you get if you take a sample right before the next dose is administered (trough/peak)
- What type of conc do you get if you take a sample right after the maintenance dose is administered (trough/peak)
WHEN STEADY STATE IS REACHED
- after 3-5 half lives
- Trough conc
- Peak conc
Does using a loading dose make patient reach steady state faster?
No
Do you achieve steady state concentrations quicker?
Yes
- close to steady state almost immediately
(not actually at steady state)
What is the VofD across groups of patients
0.5L/kg
When would you perform therapeutic drug monitoring (3)
- If you’re using medications known to interact with the drug
- If there is is a therapeutic failure (eg. exacerbation of lung disease)
- Following the development of potential signs/symptoms of toxicity
What happens to half life with the following diseases
Smoking -> induces enzymes
Hepatic disease –> inhibits enzymes
Obesity –> larger V
Smoking -> induces enzymes
- dec half-life
Hepatic disease –> inhibits enzymes
- inc half-life
Obesity –> larger V
- inc half-life
