Obesity Flashcards
Pediatric absorption
-gastic acid secretion reaches adult production around 2-3 years of age
-higher serum concentrations of acid-labile drugs
-lower concentrations of weak acids
Newborn tummy
-gas pH ranges from 6-8 at birth and drops to 1-3 within 24-48 hours
-delayed emptying = slower absorption
-even slower
GI tract peds
-gastric eemptying slower
-slower absorption
-delayed Tmax
-decreased capacity to absorb sustained-release formulations compared to adults
-reliable uptake of rectally admin drugs
pediatrics IM
-rare
-dec muscle mass
-poor perfusion
Skin absorption
-inc due to underdeveloped stratum corneum and inc skin hydration
-ratio of BSA to total body weight is highest in newborns and young children = inc exposure of topically applied drugs compared to adults
Pediatrics Distribution
-high total body water
-high ECF volume
-higher volume of distribution of hydrophilic drugs in younger age groups
-body fat
-Protein binding decreased
-need larger doses
Protein binding in newborns
-dec plasma protein
-lower binding capacity of protein
-dec affinity of proteins for drug binding
-competition for certain binding sites by endogenous compounds
-inc volume of distribution, need larger doses
Peds metabolism
- CYP
- Glucuronosyltransferase
Glucuronosyltransferase (UGT)
-reduced activity in neonates and young children; adult levels by adolescents
-metabolism enzyme
-uncojugated bilirubin and acetaminophen
High concentrations unconjugated bilirubin in newborns
-can enter the brain and cause brain damage
Acetaminophen metabolism
Peds CrCl
-dec in neonates
-inc rapidly to reach max value at 6 months
-remains above adult values thru childhood
Geriatric Population
-65 year and older is fastest growing segment
-drug therapy important in older pts
-underrepresentation of older pts in clinical studies (PK studies)
Older adults absorption
-oral not altered in advancing age for drugs with passive diffusion-mediated absorption
-dec absorption for drugs req acidic enviroment (azoles)
older pt GI
-inc pH
-delayed emptying
-dec splanchnic blood flow
-dec absorption surface
-dec GI motility
Transdermal absorption old people
-good potential for application in older pt
-age-related changes in composition (thinning and dec structural integrity of dermis
-inc sensitivity to transdermal fentanyl in older pt, no dif for buprenorphine
-more research needed
SC absorption older adults
-capillaries and lymph channels
-skin blood supply and lymphatic drainage chanfe w age
-insulin has faster onset and shorter duration of action in elderly
IM absorption in old pt
-not really altered
-reduced muscle mass
Pulmonary absorption in old pt
-lung anatomy and physiology change w age
-dec surface, elasticity, cap volume, ratio, CO capacity
-inc residual volume
-lower concentrations of isoflurane and sevoflurane (inhaled anesthetics)
Drug distribution older adults
-changes in body comp
-changes in plasma protein concentrations
-more a1-acid gcp
-less albumin
-changes may not effect exposure
-dec lean body mass, dec water, inc fat
-dec Vd of hydrophilic drugs (digoxin/aminoglycosides)
-inc Vd of lipophilic drugs (benzos)
Phase II metabolism older adults
-does not change w age
-glucuronidation, sulfation, acetylation
-liver does change w aging
-may reduce hepatic Cl of high extraction ratio drugs
Older adults elimination
-dec blood flow, GFR, secretion and reabsorption
-dec cl of drugs eliminated by GFR and active secretion
sex differences in PK
-differences in exposure between men and women following admin
women are 1.5-1.7 likely to develop and ADR compared to men
Absorption in women
-GI pH higher in women
-transit time longer
-bioavailability of alc is greater
-(diff in Vd and gastric alcohol dehydrogenase activity)
-no difference in BAC
Distribution dif in women
-women higher body fat
-greater Vd for lipophilic drugs (inc half-life, accumulation, exposure)
-smaller Vd for hydrophilic drugs and smaller plasma volume
Sex differences in PK
-CYP1A2, CYP2D6 higher in men
-CYP3A higher activity in women
Elimination differences in sex
-CrCl higher and faster in men
Sex differences in PK
-diff not that relevant
Obesity
-excess mortality due to obesity-related co-morbidities
-adipokines, cytokines, chemokines –> pro-inflammatory state
-inc risk of infection
-inc prevalence of nosocomial, surgical site, and RTI
Effect of obesity on absorption
-absorption not that effected, delayed SQ
Distribution in obesity
-physiochem properties of the drug
-obesity as a disease: change in plasma protein, dec tissue, inc adipose tissue mass, cardiac output, blood flow
Hydrophilic abx
-B-lactams
-glycopeptides
-aminoglycosides
-polymyxins
-fosfomycin
Lipophilic Abx
-fluoroquinolones
-macrolides
-lincosamides
-tetracyclines
-Tigecycline
-TMP/SMZ
-Rifampin
-chloramphenicol
Hydrophilic drugs in obese pt
-inc Vd unadjusted for body weight, due to inc body water
-adipose 30% water
-obese pt tend to hace inc LBW
-plasma volume positively correlated w body weight
-Regional differences in blood flow between adipose/lean tissues
-usually require dosing based on IBW, LBW, AdjBW
Lipophilic drugs
-inc Vd, adjusted for body weight in obesity
-usually require dosing based on TBW
Effect of obesity on metabolism
-obese pt have fatty infiltration in the liver resulting in non-alcoholic fatty liver disease, w w/o liver
-consistent and significant inc in cl of CYP2E1 substrates in obesity
-dec CYP3A4
Renal elimination in obesity
-inc GFR = inc renal cl
-co-morbidities could dec it tho
-inc secretion
Loading Dose (LD)
-primarily based on Vd
-weight used to calc LD depends on how the drug distributed
If primarily distributed into lean mass
-use IBW
If primarily distributed into fat tissue
-use TBW
if distributed into both lean and fat tissues
ABW
Maintenance Dose
-primarily based on drug Cl
-maybe estimated from CrCl
Aminoglycoside Dosing in obesity
-correction factor for weight to estimate Vd ranges from 0.37-0.58
-Cl inc due to faster GFP but elimination rate dim
Clearance inc in obesity
-correlated w TBW
Pharmacodynamics of B-lactam
-time-dependent bactericidal
-little to no PAE for gram neg pathogens
-target fT>MIC as percentage of dosing
Linezolid
-conflicting data in morbid obesity
-600mg q12h
-q8h id over 40
-1200mg over 60
Daptomycin
-dosing based on TBW
-inc AUC and Cmax compared to non-obesee pt
-use DBW
Dosing in obesity
-acyclovir, ganciclovir, foscarnet, liposomal
Obesity Dosing for oral antibiotics
-limited data on oral abx for obesity
-considerations: max dose, clinical knowledge
