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Flashcards in Pharmacokinetics Part 2 Deck (53):
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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

1

Altered absorption

Gastric motility, metoclopramide
pH
Flora

Surface area, food

2

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

3

Rifampin

Induces pgp efflux and CYP 3A4 metabolism

4

Fruit juice

Inhibit OATP uptake

5

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

6

Altered metabolism

Phase I CYP mainly 3A4
Phase II UGT mainly 2B7

Smoking increases 1A2 clearance

Metabolic drug interactions are most important altering factor

7

St John wort

3a4, 2E1, 2C19 warfarin

8

Garlic

Avoid protease inhibitors
Saquinavir

9

Ginkgo

Increases GABA

Possible warfarin interaction

10

Licorice

Pseudoaldosteronism

11

Placenta

Gatekeeper for fetus

Fetal pH < maternal blood

CYP 3A7 fetal liver

12

Breast feeding

Feed baby then take drug

Inhaled rather than systemic administration

13

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

14

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 rateHalf life is meaningless do T90%
Target 10-20mg/L

15

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

16

Altered protein binding

Decrease albumin: burns, cirrhosis, CrCl < 10, pregnancy, CF, elderly

17

Valproic acid

Low Vd
Saturable metabolism like phenytoin and protein binding displacement by phenytoin
Low extraction, dependent on Fu

18

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

19

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

20

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

21

Pharmacogenetics

Basis of genetic differences in drug metabolism

22

Pharmacogenomics

Genome approach to understand the basis of differences between persons in response to drugs

23

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

24

MDR1

Efflux transporter

25

Myopathy SNP

Chromosome 12

CC genotype susceptible to myopathy

26

Pharmacogenomic tests

Abacavir- HLA-B*5701

Irenotecan- UGT1A1*28

Azathioprine, 6-mercaptopurine- TPMT

Warfarin 2C9/VKORC1

27

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

28

Drugs causing most AE in geriatric patients

Steroids
Digoxin
NSAIDs

29

Diazepam low extraction drug

No net change in Cl in old age

30

Syndrome X

Insulin resistance
Hypertension
Lipids disturbance
Obesity

31

Hydrophilic drugs

Vd Correlate with lean body mass

32

Lipophilic drugs

Vd Correlate with total body mass

33

Obesity PK

Fatty liver decrease metabolism
2E1increase, 3A4 decrease

No generalizations can be made

34

Hepatic clearance

Correlates with LBM

35

Metabolic syndrome

Waist circumference
Triglycerides
HDL
Blood pressure
Fasting glucose

36

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

37

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

38

Digoxin monitoring

Weekly serum Cp
BUN creatinine
Weight
Urine output

TDM no sooner than 6 hours after dose

39

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

40

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

41

Pharmaceutical equivalent

Same dosage form, active ingredient, route, strength or concentration

42

Not pharm equivalent

Pharm alternative

Different salt forms
Esters

Different strength and dosage forms

Extended and standard release

43

Therapeutic equivalent

Pharm equivalents with same effect and safety profile

AB coded

44

Bioavailability

Fraction absorbed x fraction escaping first pass clearance Fh

Absolute: oral, rectal compare to IV

45

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

46

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

47

Multiple short infusions

Cmax2 = cmax1+cmin1
Cmax3 = cmax1+cmin2

Cmax1 plus min before it

Cminss is important in clinical practice

48

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

49

IBW
AjBW

50+2.3 inches>5ft
45.5+2.3 inches >5ft

AjBW=IBW+0.4(TBW-IBW)

50

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

51

Vancomycin

MRSA, oral C. diff
2 compartment distribution and elimination
Renal excretion

Loading dose severe infections

52

Vancomycin dosing Lake and Peterson

8mg/kg AjBW

Tau based on CrCl