Pharmacokinetics Part 2 Flashcards
Altered absorption
Gastric motility, metoclopramide
pH
Flora
Surface area, food
Lithium
2 compartmental PK
Distribution alpha
and elimination phase beta
Linear PK adjustment
No protein binding
Renal elimination
NSAIDs decrease clearance
Acute mania increases clearance
AE: induced diabetes insipidus
Decrease GFR, hypothyroid
Digoxin traits
Prototype pgp substrate
TDM sample prior to daily dose, no sooner than 6 hours after
Hypothyroid more sensitive to digoxin activity
Give loading doses divided
Non Renal clearance = 40 unless CHF
Rifampin
Induces pgp efflux and CYP 3A4 metabolism
Fruit juice
Inhibit OATP uptake
Altered drug protein binding
High Vd more in tissue longer t1/2
Low Vd more protein binding and possible displacement DDI
Albumin binds acidic drugs
1-gp binds basic drugs
Lipoproteins binds neutral
Ka binding coefficient
Pharmacological effect correlates with unbound concentration
High clearance drug displacement increases Fu and risk of excessive effects. Clearance is the same
Don’t make dose changes on low clearance drugs. Unbound is same
Caution phenytoin, warfarin
Altered metabolism
Phase I CYP mainly 3A4
Phase II UGT mainly 2B7
Smoking increases 1A2 clearance
Metabolic drug interactions are most important altering factor
St John wort
3a4, 2E1, 2C19 warfarin
Garlic
Avoid protease inhibitors
Saquinavir
Ginkgo
Increases GABA
Possible warfarin interaction
Licorice
Pseudoaldosteronism
Placenta
Gatekeeper for fetus
Fetal pH < maternal blood
CYP 3A7 fetal liver
Breast feeding
Feed baby then take drug
Inhaled rather than systemic administration
Neonates
Oral absorption: Reduced gastric secretion
Can use suppository
Caution transdermal surface area
More total body water than adults greater Vd and half life
Lower albumin
Underdeveloped renal excretion
3A4 increases then drops @ puberty
Sulfate conjugation well developed
Phenytoin
NTI, warfarin 2C9 interaction Non-linear PK, k changes with Cp Low Vd, high protein binding Saturable metabolism Rapid distribution to brain Less albumin more AE Dose rate<Vmax Half life is meaningless do T90% Target 10-20mg/L
Nonlinear PK
K changed with dose
Saturate absorption transport
Saturate protein binding
Saturate metabolism
Vmax Max rate of function
Km=Cp of 1/2 Vmax
Smaller Km, faster metabolism
Altered protein binding
Decrease albumin: burns, cirrhosis, CrCl < 10, pregnancy, CF, elderly
Valproic acid
Low Vd
Saturable metabolism like phenytoin and protein binding displacement by phenytoin
Low extraction, dependent on Fu
Phenytoin calculation
Population parameters
Vmax 7 mg/kg
Km 4mg/L always
Calculate patient specific Vmax with Css level
Use new Vmax to calculate dose with desired Css level
Digoxin
Inotrope for CHF
AE: see yellow
Caution hypomag, hypoK,spironolactone, verapamil
A: decreased with metoclopramide, antacids, cholestyramine MAC
D: large Vd, decreased by quinidine and renal failure!
M: prototypical pgp substrate
E: renal clearance, affected by CHF
Linear PK dose adjustment at SS
Digoxin calculation
Calculate CrCl, Vd equation or 7L/kg if good renal function
Calculate LD with Vd and Cp
Calculate maintenance dose with total clearance equation(or CHF Cl equation)
Afib goal: 1-2
CHF goal: 0.5-0.8
Pharmacogenetics
Basis of genetic differences in drug metabolism
Pharmacogenomics
Genome approach to understand the basis of differences between persons in response to drugs
Human genome
99.9% of nucleotide based are exactly the same in all people
Genotype assortment and gene coding
Phenotype outward characteristic
Wild: most common phenotype
Mutant
MDR1
Efflux transporter
Myopathy SNP
Chromosome 12
CC genotype susceptible to myopathy
Pharmacogenomic tests
Abacavir- HLA-B*5701
Irenotecan- UGT1A1*28
Azathioprine, 6-mercaptopurine- TPMT
Warfarin 2C9/VKORC1
Geriatric changes
Old Depends on body function not age
Gastric pH more basic (ketoconazole requires acid environment)
Less microvilli, surface area
More body fat, increase Vd and half life of lipophilic drugs
Liver blood flow is reduced (less first pass, more bioavailability)
Decline GFR
PD: impaired receptor sensitivity and homeostasis
Drugs causing most AE in geriatric patients
Steroids
Digoxin
NSAIDs
Diazepam low extraction drug
No net change in Cl in old age
Syndrome X
Insulin resistance
Hypertension
Lipids disturbance
Obesity
Hydrophilic drugs
Vd Correlate with lean body mass
Lipophilic drugs
Vd Correlate with total body mass
Obesity PK
Fatty liver decrease metabolism
2E1increase, 3A4 decrease
No generalizations can be made
Hepatic clearance
Correlates with LBM
Metabolic syndrome
Waist circumference Triglycerides HDL Blood pressure Fasting glucose
Diabetes
Delayed gastric emptying
Protein glycation may increase Fu
Reduced hepatic blood flow
3A4 down-regulation statin myopathy
But not 3A5
Higher expression of 2E1
Questions arise from NAFLD and obesity on diabetes
Methotrexate
Prevent synthesis of normal metabolites in cancer cells
Probenecid, salicylate, NSAID may increase Fu from protein displacement
2 compartment model 0.5E-6
Delayed clearance due to 3rd space of distribution, Ascites effusions
Need polyglutamated metabolite to be active
80% renal clearance, aspirin penicillin probenecid affect excretion
Bone marrow does not form polyglutamated rescued by leucovorin
Toxic>1micromole/L treat w/voraxaze
Digoxin monitoring
Weekly serum Cp
BUN creatinine
Weight
Urine output
TDM no sooner than 6 hours after dose
Amiodarone
Delays repolarization for next heartbeat
Poor oral onset months
IV emergency
Slow GI absorption
High Vd, long half life 55 days
Biliary excretion
Routine TDM not recommended
N-dethyl active metabolite AE effects
Bioavailability
Rate and extent of absorbed active ingredient
Tmax - rate of absorption
AUC - extent
Vmax to keep in therapeutic range
Gold standard IV
Measured by parent, metabolite, pharmacodynamic marker
Pharmaceutical equivalent
Same dosage form, active ingredient, route, strength or concentration
Not pharm equivalent
Pharm alternative
Different salt forms
Esters
Different strength and dosage forms
Extended and standard release
Therapeutic equivalent
Pharm equivalents with same effect and safety profile
AB coded
Bioavailability
Fraction absorbed x fraction escaping first pass clearance Fh
Absolute: oral, rectal compare to IV
Bioequivalence
Relative bioavailability of new formulation
Plasma level profiles are superimposable 80-125%
Confirms therapeutic equivalence
Test formulation to a reference formulation
Concern with generic NTI drugs
Non compartmental analysis
Not useful for prediction/simulation
Fewer assumptions
Body has many compartments
Describe non-accessible pool as instantly homogenous
AUMC CpT vs time
MEan residence time in body
Multiple short infusions
Cmax2 = cmax1+cmin1 Cmax3 = cmax1+cmin2
Cmax1 plus min before it
Cminss is important in clinical practice
Aminoglycosides
Nephrotoxicity, ototoxicity Poor GI absorption, IV most common Rapid distribution to ECF CHF , edema, Ascites increase Vd E: kidney, renal dosing Burn, stress increases clearance
AjBW to estimate Vd if overweight
Linear PK
2 compartments
Furosemide, amphB, vanco, cyclosporine FAVC increase nephrotox
Once daily not for Renally impaired, pregnant, severe burn
IBW
AjBW
50+2.3 inches>5ft
45.5+2.3 inches >5ft
AjBW=IBW+0.4(TBW-IBW)
Aminoglycoside calculation
Empiric q 8 hours
Tau=3 t1/2
Calculate k from Cp=Cpoe-kt or population k, Vd
Calculate Vd at Cmaxtrue ( infusion tau)
Calculate new true Cmax from desired
Plug new true Cmax as Cmaxss and solve for k0 using new Vd and T
Vancomycin
MRSA, oral C. diff
2 compartment distribution and elimination
Renal excretion
Loading dose severe infections
Vancomycin dosing Lake and Peterson
8mg/kg AjBW
Tau based on CrCl
