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Kinetics > Introduction > Flashcards

Introduction Flashcards

1
Q

absorption:
- first pass effect?
- which drugs are most affected by the first - pass effect?
- examples

A
  • 1st pass:
    1. 50% of the rectal blood supply bypasses the liver
    2. the blood that perfuses all the GI tract passes through the liver via the hepatic portal vein.
    3. Drugs absorbed in the buccal cavity bypass the liver
  • drugs with high hepatic extraction ratio
  • morpine, isosorbide dinitrate, verapamil, diltiazem, propranolol, metoprolol, amitiptyline, lidocaine, nifedipine
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2
Q

enterohepatic circulation:
- what happens
- occurs with which drugs
- examples

A
  • Drugs excreted through the bile into the duodenum, metabolized by normal flora in the GI tract, and reabsorbed into the portal circulation
  • drugs that have a good biliary (hepatic elimination) and good oral absorption
  • digoxin, imipraine, indomethacin, estrogen, testosterone, valproic acid, vitamin A, rifampin
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3
Q

p glycoprotein:
- what is it
- more important in?
- CYPs role?
- examples

A
  • efflux pump that pumps drugs back into the GI lumen.
  • drug absorption drug interactions that intesinal CYP3A4
  • many CYP3AA4 inhibitors / inducers can inhibit / induce PGP
  • dabigatrin and protease inhibitors are afffected by rifampin and st john’s wort
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4
Q

what is bioavailability (F)?
what is it affected by?

A
  • % or fraction of the administered dose that reaches the systemic circulation
  • dissolution, absorption of the chemical form, route of administration, dosage form, stability in the GI tract, metabolism
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5
Q

chemical form:
- represented by which letter?
- what is it?
- affects what?

A
  • S
  • fraction of the total MW that reaches the systemic circulation
  • the amt of drug absorbed and reaching the systemic circulation
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6
Q

distribution:
- what is the apparent Vd?
- can be affected by?
- ex?

A
  • proportionality constant which relates the total amount of drug in the body with the concentration
  • lipid solubility of the drug, blood flow to distributing organs, disease state, extent of protein binding, regional differences in the physiological pH
  • protein binding by albumin, alpha 1 acid glycoprotein, lipoprotein
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7
Q

clearance:
- after how many half lives do we reach the steady state?
- what is drug elimination?
- includes what?

A
  • 3 - 5 half lives
  • Drug elimination: irreversible removal of the drug from the body by all routes of
    elimination
  • Includes: metabolism & excretion
  • Metabolism: drug is chemically converted in
    the body to a metabolite
  • Excretion: removal of parent drug pre
    dominantly via kidneys (but also bile, saliva,
    lungs,…)
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8
Q
  • what is the half life?
  • table:
    2 half lives:
    3 “ “:
    4:
    5:
  • steady state can be assumed after?
A
  • time required for a drug concentration to decline to half its original concentration
  • 75%
  • 87.5%
  • 93,75%
  • 97%
  • 3 - 5 half lives
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9
Q

basic pharmaceutic equations:
- F?
- K?
- T1/2?
- clearance?
- Vd?
- C1?

A
  • F = (dose iv x auc ev) / (dose ev x auc iv)
  • (ln C1 - ln C2) / t2 - t1
  • 0.693 / k
  • clearance = dose / auc or k x vd
  • vd = f x dose / C0
  • C1 = Co e^(-kt)
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10
Q

drug collection sampling and interpretation

timing of collection?

A
  • After completion of absorption and distribution phases (esp. for digoxin, aminoglycosides)
  • After completion of redistribution postdialysis (esp. for aminoglycosides)
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11
Q

specimen requirements:

whole blood
plasma
serum

A

Specimen requirements
- Whole blood: use anticoagulated tubes (ex.
cyclosporin, amiodarone)
- Plasma: use anticoagulated tube and centrifuge, clotting proteins and some blood cells are maintained
- Serum: use red top tube, allow to clot, and
centrifuge (ex. most analyzed drugs including
aminoglycosides, vancomycin, phenytoin, and digoxin)

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12
Q

assays should be?
sensitivity
specificity

A
  • precise (reproducible) and accurate (measurement reflects the true value)
  • Sensitivity: ability of an assay to quantitate
    low drug concentrations accurately
  • Specificity: ability of an assay to differentiate
    the drug in question from like substances
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13
Q
  • where is creatine produced?
  • what is creatinine?
  • filtered where?
  • useful how?
A
  • in the liver
  • the product of creatine metabolism in skeletal muscle
  • at the glomerulus (creatinine)
  • CrCl is useful in approximating GFR
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14
Q
  • how is CrCl calculated?
  • what is the equation
  • after age 30,
A
  • from 24 hour urine collection
  • (volume of urine / 1440 minutes) x urine creatinine concentration / SCr
  • 1% of GFR is lost per year
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15
Q

factors affecting SCr concentrations

A
  • gender
  • age
  • weight / muscle mass
  • renal function
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16
Q

what is the Jeliffe equation?
limitations?
controversy?

A
  • CrCl = 98 - 0.8 (age - 20) / SCr
  • multiply above equation by 0.9 for females
  • SCr must be stable, adults 20 - 80
  • rounding up SCr in elderly wth low concentrations (< 0.7 - 1 mg/dl)
17
Q

cockcroft - gault equation?
when to use the actual body weight? when to use the IBW?

A
  • (140 - age) x weight / 72 x SCr
  • multiply by 0.85 if female
  • Use actual body weight (ABW) in patients with body mass
    index (BMI) less than 18.5 kg/m 2 , ideal body weight (IBW) in patients with BMI 18.5 25 kg/m 2 , and IBW plus 40% of (ABW IBW) in patients with BMI greater than 25 kg/m 2
  • Ideal body weight (IBW) (men) = 50 kg + 2.3 kg for each inch over 5 feet
  • IBW (women) = 45.5 kg + 2.3 kg for each inch over 5 feet
  • SCr must be stable, for adults only
  • recommended when making dosage adjustments for patients with renal dysfunction
18
Q

what is the MDRD equation?

A

eGFR = 186 x (SrCr / 88.4)^-1.154 x age ^-0.203 x F x R
F = 0.742 if female
R = 1.2 if african american
mainly used for staging of CKD

19
Q

main categories of factors affecting CrCl estimates?

A
  • patient characteristics
  • disease states / clinical conditions
  • diet
  • PK interaction
20
Q

patient characteristics

A

-age + female: decreased creatinine production
race: inc creatinine in african americans

21
Q

disease states / clinical conditions

A

(all of these have dec muscle mass so dec creatinine)
- spinal cord injury
- amputation
- cushing syndrome
- muscular dystrophy
- guillan barre syndrome
- rheumatoid arthritis
- liver disease

22
Q

diet?

A
  • high meat high protein diets (inc creatinine ingestion)
  • vegetarians: dec creatinine ingestion
  • protein calorie malnutrition: dec creatinine ingestion
23
Q

in case of renal disease,
- loading dose?
- alteration in LD when?
- maintenance dose ?

A
  • in general, no alteration is required: it should be given to hasten the achievement of therapeutic drug concentration.
  • if the Vd is affected secondary to renal dysfunction
  • alteration in dose or dosing interval
24
Q

changing the dosing interval:

A
  • less costly
  • use when goal is to achieve similar SS conc
  • ideal for limited dosage forms
25
Q

changing the dose?

A
  • more costly
  • use when when goal is to achieve steady therapeutic conc
26
Q

changing the dose and dosing interval:

A

Often required for substantial dosage
adjustment with limited dosage forms
- Often required for narrow therapeutic index drugs with target concentrations

27
Q

what can decrease oral absorption in kidney disease?

A
  • N/V
  • inc binding of drugs to phosphate binders
  • increased gastric pH
  • edema
28
Q

PK in renal disease:
- changes in conc in highly water soluble drugs occurs?
-displaced?
other mechs?

A

Distribution
- Changes in concentrations in highly water soluble drugs occur as extracellular fluid status changes
- Acidic and neutral protein bound drugs are
displaced by toxin buildup
- Other mechanisms include conformational
changes of the plasma protein binding site (free fraction of the drug increases)

29
Q

rowland tozer estimate?

A

Q = 1 - (Fe (1-Kf) )
Q: correction factor
Fe: fraction of drug excreted unchaged in urine
Kf: pt’s clearance / 120

30
Q

why do we adjust the dose in dialysis??

A
  • drug accumulation due to kidney failure
  • drug removal from circulation during the procedure
    (and / or)
31
Q

drug related factors affecting removal during dialysis?

A

Molecular weight with high flux membranes, larger
molecules (e.g., vancomycin) can be removed
- Water soluble non soluble drugs not likely removed
- Protein binding because albumin cannot pass through
membranes, protein bound drugs cannot either
- Volume of distribution Drugs with a small Vd (less than 1 L/kg) available in central circulation for removal
- Large Vds cannot be removed (ex. digoxin and tricyclic antidepressants), even if the protein binding is very low

32
Q

procedure related factors affectinig drug removal during dialysis?

A
  • type of dialyzer (high flux widely used now)
  • blood flow rate –> inc rate = inc delivery and mainitain gradient across membrane
  • duration of session
  • dialysis flow rate = higer flow rate = inc removal by maintenance of gradient across membranes
33
Q

low hepatic extraction ratio drugs:
- when to adjust maintenance?
alteration in protein binding alone:
LD?

A

i. Adjustment of maintenance dose is
necessary only when hepatic disease alters
the intrinsic clearance (Cl int )
ii. Alterations in protein binding alone do not
require alteration of maintenance dose
iii. Loading doses may require reduction

33
Q

high hepatic extraction drugs:
IV?
oral?

A

High hepatic extraction ratio drugs
- Intravenous administration
i. Usually necessary to decrease maintenance
dose as hepatic blood flow rate changes
ii. Consider effect of hepatic disease on
protein binding as it alters free concentrations
- Oral administration: Similar to low hepatic extraction ratio drugs; necessary to decrease maintenance dose rate when hepatic disease alters Cl int

33
Q

rules for dosing in hepatic disease?
- high extraction ratio drugs
- exclusively conjugated

A
  • Hepatic elimination of high extraction ratio
    drugs is more consistently affected by liver
    disease than hepatic elimination of low
    extraction ratio drugs
  • The clearance of drugs that are exclusively
    conjugated is not substantially altered in liver
    disease
34
Q

PD: hysteresis loops

A

Hysteresis loops: concentrations late after a
dose produce an effect different from that
produced by the same concentration soon
after the dose

35
Q

causes of counterclockwise hysteresis

A
  • inc sensitivity
  • formation of active metabolite
  • delay in equilibrium between plasma concentrations and the conc at site of action
  • ex: digoxin
36
Q

causes of clockwise hysteresis

A
  • tolerance
  • formation of inhibitory metabolite
  • equilibrium reached faster between arterial blood and site of action vs venous blood and site of action
  • ex: pseudoephedrine, cocaine

Kinetics (3 decks)

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