Medical Pharmacology Topics
Urine is the main drug excretion route. Biliary excretion is also important, especially for metabolites. Other minor routes include breath (volatile substances only), sweat, tears, saliva, feces and breast milk.
Renal excretion refers to the rate at which the kidneys put drug into urine. In the kidneys, excretion occurs by glomerular filtration and/or tubular secretion. Hepatic excretion refers to the rate at which a drug is biotransformed. The rate of diffusion at glomeruli or hepatocytes (r) is proportional to the amount of drug in blood (n):
r = k n
The proportionality constant k reflects the characteristics of the eliminating organ: blood flow, capillary permeability and number of capillaries, as well as difussivity of the drug.
Acid/Base Equilibra
Urine pH may be changed to increase the rate of excretion. The equilibria of weak acids can be pushed towards ionization by bicarbonate infusion, making blood and urine more alkaline:
HA + OH
H2O + A
excretion
pH = pKa
+ log [A]/[HA]
A week base can be pushed towards ionization by infusion of diluted hydrochloric acid, making blood and urine more acid:
B + H
BH
excretion
pH = pKa
+ log [BH]/[B]
These treatments are successful only if the pKa of the drug is close to the urine pH, within two pH units. Other ways to increase excretion of a drug are diuresis (increased water intake), increasing the glomerular filtration rate or the renal blood flow (aren't these last two the same?).
Example Problems - Excretion of Weak Acids/Bases
Clearance
Excretion may be measured in terms of excretion rate (UxV) or clearance (Cl):
excretion = (excretion
rate)(volume)
= UxV =
(mg/mL
min)(mL)
= mg/min or
(mL/min)(mg/mL)
= Cl Px
Excretion is directly proportional to plasma concentration (Px), with clearance (Cl) as the proportionality constant. Clearance is defined as the volume of fluid from which drug is completely removed per unit time.
Cl = excretion / Px = UxV / Px = (mg/min) / (mg/mL) = mL/min
Hepatic and renal blood flows exist within a narrow range of normal, therefore clearance of specific drugs tend to be similar from person to person. Clearance of a specific drug remains the same in an individual, and is reduced in patients with impaired renal or hepatic function. Since clearance is constant, the higher the plasma concentration, the more drug is excreted, or removed from the same volume of fluid.
Excretion Kinetics
Excretion may occur by either zero-order kinetics (constant rate) or first-order kinetics (decreasing rate).
First-order
elimination occurs at a decreasing rate and is proportional to concentration.
Therefore the fractional elimination is constant. This means that the body will
always eliminate the same fraction of the total amount of drug in the body at
a given time. For example, if a drug has a t1/2 = 1 hr,
0.5 mg will be eliminated one hour after a dose of 1 mg, while 0.25 mg will
be eliminated one hour after a dose of 0.5 mg.
If P0 is the initial drug concentration, Pt is the concentration after time t and ke is the elimination rate:
ln (Pt/P0) = -ke t
which describes a decreasing hyperbola. Looking at the time when half the drug has been eliminated, or half-time (t1/2):
ln (1/2) = -ke t1/2
Þ
t1/2 = 0.693
ke
Since
the fractional elimination is constant under fisrt-order elimination, the t1/2
is independent of the dose. Drugs are mostly eliminated in four half-times (4t1/2).
A logaritmic plot of a first-order reaction yields a straight line with slope equal to -ke.
The first-order elimination rate ke relates to clearance:
Cl = ke
Vd = 0.693 dose
t1/2 Pss
Þ
t1/2 = 0.693 Vd
Cl
With first-order kinetics, the relationship between drug dosage and duration of action is not directly proportional. Doubling the dosage will double the duration of action, but quadrupling the dose will only triplicate the duration of action. This is a reflection of the exponential relationship between concentration and duration of action.
Most processes involve first-order elimination before reaching a saturation point. Glomerular filtration is always first-order, never saturated. Zero-order elimination occurs at a constant rate, independent of concentration, due to the saturation of the elimination process. Biotransformation and tubular secretion are processes that may occur at zero-order kinetics if saturated. Both processes will revert to first-order when substrate concentration drops below saturation.
With zero-order elimination, the rate of elimination is constant but the fractional elimination will vary. For example, it takes longer to eliminate 50% of the drug if we start at 700 and go down to 350 than it will take to eliminate 50% starting at 350 and going down to 175. More drug is eliminated in the first interval and the time interval to eliminate a is longer. Therefore, the elimination half-time is dose dependent.
Continue
to "Dosing" or take a quiz: [Q1].
Back to Basics: Glomerular Filtration (Physiology)
Advance Topics: Kinetics
(Intro to Pharm and Tox)
Absorption
and Elimination (Intro to Pharm and Tox)
Clearance and Excretion Ratio
(Intro to Pharm and Tox)
Need more practice? Answer the review questions below.
Need more practice? Answer the review questions below (after sponsor).
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Continue scrolling to answers below (after sponsor).
Hey! DON'T PEEK!!! Finish the questions fist!
1- What is the main drug elimination
route?
urine
2- What is the main elimination route
for drug metabolites?
bile
3- What is the main elimination route
for volatile substances?
breath
4- List 2 major elimination routes.
urine and bile
5- List 6 minor elimination
route.
breath, sweat, tears, saliva, feces and milk
6- What is renal excretion?
rate at which the kidneys put drug into urine
7- List 2 components of
renal excretion.
glomerular filtration and tubular secretion
8- What is hepatic excretion?
rate at which a drug is biotransformed
9- What is the relationship
between rate of diffusion at glomeruli or hepatocytes and amount of drug in
blood?
The rate of diffusion at glomeruli or hepatocytes (r) is proportional to the
amount of drug in blood (n): r
= k n
10- In the equation r =
k n, were r = rate of diffusion at glomeruli or hepatocyte and n is the amount
of drug, what is k?
a proportionalilty constant that reflects the characteristics of the eliminating
organ.
11- List 4 components of
k (as in r = k n, were r = rate of diffusion at glomeruli or hepatocyte and
n is the amount of drug).
blood flow, capillary permeability, number of capillaries and difussivity of
the drug
12- What is the effect of
raising the pH of urine in the excretion of weak acids?
The equilibria of weak acids will be pushed towards ionization, increasing their
rate of excretion.
13- What is the effect of
lowering the pH of urine in the excretion of weak bases?
The equilibria of the weak base will be pushed towards ionization, increasing
their rate of excretion.
14- In a clinical setting,
how can the pH of urine be safely increased or decreased?
pH can be increased by bicarbonate infusion or decreased by diluted hydrochloric
acid infusion.
15- How is the pKa
of a drug important to achieve increased excretion by change the pH of urine?
Changes in urine pH are effective in increasing drug excretion only if the pKa
of the drug is close to the urine pH, within two pH units.
16- List 3 other ways (in
addition to changing urine pH) to increase drug excretion.
diuresis, increasing glomerular filtration rate, increasing blood flow
17- What is clearance?
Volume of fluid from which drug is completely removed per unit time. Proportionality
constant between excretion and plasma concentration: excretion = plasma concentration
x clearance = Px Cl .
18- How variable is clearance
from one individual to another and why?
Hepatic and renal blood flows exist within a narrow range of normal, therefore
clearance of specific drugs tend to be similar from person to person.
19- How variable is clearance
in the same individual?
Clearance of a specific drug remains the same in an individual, and is reduced
in patients with impaired renal or hepatic function.
20- What is the impact of
the variability (or lack of) of clearance in drug excretion?
SInce clearance is virtually constant, the higher the plasma concentration,
the more drug is excreted, or removed from the same volume of fluid.
21- List 4 main features
of first-order elimination.
occurs at a decreasing rate
is proportional to concentration
fractional elimination is constant
independent of dose
22- What equation defines
fist-order elimination in terms of plasma concentration and time?
ln (Pt/P0) = -ke
t ; were P0 is the initial drug concentration, Pt
is the concentration after time t and ke is the elimination
rate
23- In the context of drug
elimination, what is half-time (t1/2)? Give an equation.
The time when half the drug has been eliminated; t1/2
= 0.693/ke
24- How can the first-order
ke be derived from experimental data?
A logaritmic plot of a first-order reaction yields a straight line with slope
equal to -ke.
25- In general, how many
hal-times it takes to eliminate most of a drug?
four (4t1/2)
26- What equation relates
the elimination half-time to clearance?
Cl = ke Vd
= 0.693/t1/2 x dose/Pss
Þ
t1/2 = 0.693Vd/Cl
27- In first-order elimination,
what is the effect of doubling and quadrupling the dose? Why?
With first-order kinetics, the relationship between drug dosage and duration
of action is not directly proportional. Doubling the dosage will double the
duration of action, but quadrupling the dose will only triplicate the duration
of action. This is a reflection of the exponential relationship between concentration
and duration of action.
28- What happens when a
first-order elimination process reaches saturation?
Become zero-order elimination processes.
29- List 3fisrt-order elimination
processes and indicate if they are saturable.
glomerular filtration - not saturable
tubular secretion - saturable
biotransformation - saturable
30- List 4 main features
of zero-order elimination.
occurs at a constant rate
independent of concentration
fractional elimination varies
dose-dependent