Final Exam Flashcards
What happens to the PK parameters with the administration of a competitive inhibitor of renal secretion?
-clearence decrease
-V=no change
-increase half life
-decrease Fe
-no change in oral bioavailibility`
What problem do antacids propose?
-increase gastric pH
-decrease bioavailibility(rate and extent of absorption)
How to fix antacid problem?
-seperate medication and antacid by at lease 2 hours
medications that interact with antacids
-atenolol
-ciprofloxacin
-enoxacin
-isoniazid
-ketoconazole
-norflloxacin
-ofloxacin
-tetracycline
Which enzyme are in higher concentration in upper GI?
-CYP3A4
-do most of drug metabolism
Transporters in DDI
-control the concentration of drugs accross membrances
-drugs can induce or inhibit them
OATP
-polymorphs in this transportes
-variability in the HMG-CoA reductase inhibitors(AKA statins)
OAT transporters
-anion transporter in the kidneys
-remove foreign chemicals from the body
OCT transporters
-organic cation transporters
-passivly remove chemicals from the body
ABCB Family
-AKA multidrug resistance/transporters associated with atigen processing(MDR/TAP)
-P-gp(MDR1/ACBC)
P-gp(MDR1/ACBC)
-efflux transporter expressed in most cancer cells
-limits drugs that cross the BBB
what does it mean to be multidrug resistant?
they are cancer cells that pump medications out of affected cells
P-gp inducers
-decrease drug concentration
-Carbamzepine
-Phenytoin
-Rifampin
-St Johns Wort
-Ritonavir
-Tipanavir
-Avasimbe
P-gp inhibitors
-increase drug concentration
-Cyclosporin
-Quinidine
-Verapamil
-Amiodarone
-Erthromycin
-Claritromycin
-Azithromycin
Factors that affect drug distribution
-protein binding
-transporters
Factors that affect metabolism
-enzyme induction depends on activation of transcription factors
-PXR
-CAR
-AhR
-Estrogen
-Glucocorticoid
Broad spectrum enzyme inducers
-carbamzepine
-phenytoin
-phenobarbital
-rifampin
Selective 3A4 inducers
-Felbamate
-topiramate
-oxcarbazepine
-Griseofulvin
-Nevirapine
-St Johns wort
Selective 1A2 inducers
smoking
Selective 2E1 inducers
alcohol
Selective UGT inducers
-lamotrigine
-oxcarbazepine
-oral contraceptives
Strong enzyme inducers
> 80% decrease in AUC
moderate inducers
50-80% decrease in AUC
weak inducers
<50% decrease in AUC
UGT1
conjugate variety of drugs
UGT2
glucornidation of steriods and bile acids as well as some other drugs
substrates of UGT2
morphine, valproate, zidovudine, lorazepam, oxazepam, lamotrigrine
Oxidation
-NADPH dependent
-CYP450 reductase: seven enzymes responsible for most metabolism
Name the 7 enzymes responsible for most drug metabolism via oxidation
-1A2
-2C8
-2C9: has polymorphisms
-2D6: has polymorphisms
-2E1: has polymorphisms
-3A4
polymorphisms
genetic variability
Inhibitors of 3A4
-ketokonazole
-erthromycin
-verapamil
-grapefruit juice
Inducers of 3A4
-phenytoin
-carbanazepine
-rifampin
-St Johns wort
3 types of inhibition
-competitive at hepatic enzyme sites
-non-competitive
-mechanism based inhibition
strong inhibitor
> 5 fold increase in AUC
moderate inducer
2-<5 fold increase in AUC
weak inhibitor
1.25-<2 increase in AUC
UGT Inhibitors
-VPA
-Lamotrigrine
-Lorazepam
OAT inhibitors
-Probenecid
-NSAIDs
-indomethacin
-didanosine
-salicylate
OCT inhibitors
-cimetidine
-cisplatin
-famotidine
-ranitidine
-certirizine
Dihydropyridine(calcium channel blockers) DDI
-interact with CYP3A4 sybstrates
-deceased drug level
warfarin DDI
-antizeziure medications that affect 3A4 and 2C9 alter warfain levels
Characteristics of non-linear PK
1)one or more ADME process are saturable
2) dose and concentration are not proportional
3) PK parameters change with dose
How do you accomadate saturable kinetics?
-divide daily dose
-slow release formulations: crystal size, osmotic pump, staggered-dissolution granules
Protien binding
-doesn’t typically affect unbound Css
-highly bound drugs with low V(<0.2 L/Kg) DO AFFECt Css
What is the effect of a larger dose in saturable kinetics?
-increase time to steady state
-increase Css disproportionally
What factors alter absorption in Peds?
-gastric pH: increase ionization at higher pH for weak acids
-gastric emptying
-intestinal transit
-larger small intestine area
-reduced bile production
How is percutaneous absorption different in kids?
-Higher BSA
-thinner stratum corneum
-greater skin perfusion and hydration
Why is percutaneus absorption in kids important to know?
higher systemic exposure to topical medications
-Can be DANGEROUS
IM ingections in kids considerations
-reduced muscle mass
-feeble muscle contractions
-prefer thigh inj. because of increased movement
-volume limit
(0.5 mL for neonates, 1 mL for infants)
Drug distribution in peds
-water bags
-distribution of hydrophillic and lipophillic drugs is affected
Gentamycin dosing in peds
-hydrophillic
-need a higher dose(4-5 mg/kg) in neonates than in adults
-need a longer dosing interval because of reduced renal function
Albumin in peds
-reduced amount in neonates and infants
-bilirubin elevated in neon.
-compete for drug binding: increase unbound drug concentrations
What drugs pose a risk of causing kinicterus in peds?
-ceftriaxone: < 6 weeks
-Bactrim: <2 months
-because they displace bilirubin into the bloodstream: can cause jaundice and kinicterus
Which phase I enzymes are high at birth, then rapidly decline?
-CYP3A7
4A1
Which phase I enzymes are expressed in early neonates?
2D6
2E1
Which phase I enzymes are expressed in late neonates?
3A4
2C family
1A2
Caffiene metabolism in children
-neonates/infants: 2E1, 3A, renal excretion
->4 months: CYP1A2\
-increased half life in neonates so you need a loading dose to reach therapeutic concentration quickly
Phenobarbital metabolism in peds
-CYP2C9
-half life is decrease in kids 1-12 so a higher dose is needed
UDT glucornidation/Phase II metabolism in kids
-limited at birth
-adult level 2-6 months
Chloramphenicol in peds
-metabolized in liver by UGT: slower in peds
0can accumulate to toxic levels and penetrate BBB
-Gray baby syndrome
-do NOT use in preterm and neonates
GFR in peds
-renal system beveloped by 36 weeks gestation
-blood frow improve after birst
-GFR: rises rapidly first 2 weeks, adult level 8-12 months
Inplications of reduced renal function in peds
-may need longer dosing intervals because of reduced CL
Simple Dirrect Effect(rapid)
plasma drug concentrations are in rapid equillibrium with the effect site
Hysteresis
-response and concentration do not match with time
-detect time delay or other mechanism
Counter clockwise hysteris
-time delay: active metabolite, biophase distribution, turnover process
-Dose-response curve shifts left: lower concentrations needed to achieve the same effect after a time delay
Clockwise hystersis
-tolerance effect: curve shifts right
-need higher concentrations to reach same effect
Direct delayed model
-biological effect lag behind plasma concentration: bc of delayed distribution
-effect corrlates with the concentration in the biophase rather than plasma concentration
Indirect, reversible basic turnover model
-Kin: drug input, zero order
-Kout: first order elimination, proportional to drug conc., exponential decay
Warfarin inhibition
-inhibits VKORC1
-reduces vitamin K dependent proteins
delayed response of drug effect
Omeprazole inhibition
-irreversible inactivation of proton pump receptor
-slow restoration of gastric acd secretion(3 days)
-slow synthesis of new receptor
How does CL relate to organ blood flow?
CLb approached organ blood flow as E approaches 1
components of the nephron
-GLOMERULUS
-tubule
-bowman’s space/capsule
glomerular filtration barrier
-driving force for filtration is the large hydrostatic pressure created by kidney blood flow
renal flow and filtration
-firtration increases moderatly with increased plasma flow
-filtration decreases GREATLY with decreaing plasma flow
What passes through the filtration barrier?
-MW<5.5 kDA
-NOT albumin
-macromolecules: positive charge>neutral>negative, flexible molecules, small molecules
Active tubular
-secretion requires energy
-need transport systems to work againist concentration gradient
Reabsorption in the kidneys
-passive process
-prefers lipophillic, low MW, unionized drugs
Why is inulin a good glomerular marker?
-Only filtered, not secreted or reabsorbed
-it is not synthesized or metabolized by the kidney
PAH
-filtered and secreted
drug used to increase pH
sodium bicarbonate
drug used to decreae pH
Ammonium chloride
Very polar: reabsorption
-minimal reabsorption
-urine pH dependent
Nonpolar weak base(pKa less than 7): reabsorption
-extensive reabsorption
Non polar strong base: reabsorption
minimal reabsorption
Non-polar weak base(pka 7-12)
-reabsorption ranges from extensive to minimal
-pH sensitive
Diuresis
increased urine flow
-increase fluid intake or diuretic
When is forced diuresis useful?
-increase urine flow
-dilute urine
-decrease drug concentration in the tubule
-DECREASE REABSORPTION
What drugs can be cleared with forced diuresis?
-Drugs primarily eliminated by renal excretion AND
-drugs where reabsorption is extensive
Crockroft-Gault
-not used for CKD
-estimates CrCL
CKD-EPI
-calculate eGFR using normalized body surface area
-preferred in >18yrs old, diabetes, organ transplant, alcoholics
MDRD
-valid in patients 18-70 with lowere GFR, non-diabetic, without kidney transplant
-ONLY use if eEFR< 60mL/min/1.73m2
24 hour urine collection
-measure in lab
-useful when Scr change is due to change in muscle mass
