BIO PHARM: drug excretion

drug excretion

removal of intact drug from body; irreversible transfer of drug from blood to urine

kidney

major site of excretion

less common sites of excretion

1. skin

2. saliva

3. bile

4. lungs / alveolar air

5. tears

6. milk

7. liver/stool/feces

8. urine

9. sweat

nephron

basic and functional unit of renal function

basic components of nephron

1. glomerulus

2. proximal tubule

3. loop of Henle

4. distal tubule

5. collecting tubule

three major processes

1. glomerular filtration

2. tubular secretion

3. tubular reabsorption

120

glomerulus receives blood and filters ____ mL of plasma water

1-2 mL

_____ mL/min leaves kidneys

drug in urine

net result of filtration, secretion, reabsoprtion

filtration and secretion

adds drug to proximal part of lumen of nephron

reabsorption

movement of drug from lumen back to bloodstream

Fr

fraction reabsorbed from lumen

100-300 mL/min

normal GFR

low

all ___ MW are filtered out of blood

inulin

GFR is measured by renal clearance of ____

inulin

is readily filtered in glomerular and not subject to tubular secretion and reabsorption

proximal tubule (tubular secretion)

where reabsorption of water and active secretion of weak electrolytes (weak acids) occur

tubular secretion

requires carrier and supply energy; competitive

drugs actively secreted

1. penicillins

2. cephalosporins

3. salicylic acid

4. probenecid

5. ethacrynic acid

probenecid

decreases the active secretion of penicillin, increases duration of penicillin

uric acid

probenecid competes with ____ for reabsoprtion in renal tubule

acidic drugs

more ionized and not reabsorbed in alkaline urine

basic drugs

more ionized and not reabsorbed in acidic urine

acidification and alkalinization

facilitates renal excretion basic and acidic drugs

basic

urine pH in barbiturate and aspirin poisoning

acidic

urine pH in morphine, amphetamine poisoning

distal tubule (tubular reabsoprtion)

where passive excretion and reabsorption of lipid soluble drugs occur

0.25-1.0

liver secretes ___ L bile daily

• antithyroid

• lithium

• chloramphenicol

• anticancer

do not nurse if taking these drugs

extremely narrow TI drugs

1. gentamicin

2. kanamycin

non-ionized compounds (sweat)

1. alcohol

2. antipyrine

3. urea

weak acids (sweat)

1. sulfonamides

2. salicylic acid

thiamine

a weak base (sweat)

metals (sweat)

1. I

2. Br

3. Hg

4. Pb

volatile compounds (expired air)

1. alcohol

2. ethereal oils

lungs

major organ for excretion of gaseous and volatile substances (breath analyzer test)

anticancer drugs

causes malformations in seminal fluid

intestinal excretion

verified by presence of drugs in gut lumen after IV

1-2 mL/min

normal flow of urine

drug elimination

excretion of unchanged drug into urine, gut, air, sweat to metabolic conversion (liver)

acidification of urine

1. ammonium chloride

2. vit. C

3. cranberry juice

alkalinization of urine

1. sodium bicarbonate

2. acetazolamide

probenecid

used in gout, promotes excretion of uric acid

1. maintenance dose

2. loading dose

3. peak onsent

4. duration

clearance determines:

clearance (CL)

ability of organs to clear drug from bloodstream; volume of fluid cleared of drug per unit of time

clearance

intrinsic ability of body to remove drug from body or plasma; efficiency of irreversible elimination

k

fraction of drug in body removed per hour

10%

____ of volume cleared drug per hour

decrease

if V increases then k must ____ as CL is constant

plasma

low (unbound clearance) extraction ratio depends on

perfusion rate-limited

insensitive

high (unbound clearance) elimination becomes ______ and clearance becomes ____ to changes in binding

<0.3

low extraction ratio

0.3-0.7

intermediate extraction ratio

>0.7

high extraction ratio

elimination rate

amount of drug eliminated per unit time

elimination rate constant

factor that determines rate of drug elimination

clearance

PK parameter that determines maintenance dose rate required to achieve target plasma concentration

steady state (Css)

rate of drug administration equal to rate of drug elimination so amount of drug in body remains constant

total body clearance (Clt)

sum of all different clearance processes occurring for given drug

extraction ratio

decline of drug concentration in plasma from arterial to venous side of kidney; rate of plasma drug removal by organ of elimination, divided by rate presented

extraction ratio close to 0

indicates most drug escapes elimination during single pass

extraction ratio close to 1

indicates most drug is eliminated during single pass

decreased

decrease

in uremic patients, rate of renal drug clearance has ____, leading to ____ in total body clearance

renal drug clearance

hypothetical volume of plasma from which substance is removed per minute of one pass in kidney; method of quantitatively describing renal excretion; used to investigate mechanism of drug excretion

renal drug clearance

net result of three process: filtration, secretion, reabsoprtion; measure of how efficient kidneys remove drug from blood

creatinine clearance (CLcr)

volume of blood plasma cleared of creatinine per unit time; useful measure for approximating GFR; common clinical test for renal function

creatinine

breakdown product of creatinine phosphate which is an important part of muscle

creatinine or inulin

GFR is evaluated using

PAH (p-aminohippurate)

effective renal blood flow is evaluated with

hepatic clearance

clearance of drug by liver metabolism

intrinsic clearance

expresses activity of drug metabolizing enzyme with drug substrate

Michaelis Menten constant (Km)

expresses how tightly enzyme binds drug substrate

clinical pharmacokinetics

application of pharmacokinetic principles for rational design of individualized dosage regimen; optimizing drug therapy by balancing effects

pharmacodynamics

looks at how drug conc. at receptor site and how mechanism translates into therapeutic response; controlled by receptor proteins

optimal drug therapy

to determine appropriate drug choice for clinical diagnosis of patient

therapeutic drug monitoring (TDM)

individualization of dosage by maintaining plasma or blood drug conc within target range