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FUN2: 10:00-11:00
Scribe: Marjorie Hannon
Tuesday, December 02, 2008
Proof: Brittney Fain
Dr. Prasain
Pharmacology- General Principles
Page 1 of 3
I. General Principle 1: Pharmacokinetics-Elimination [S1]
II. Drug distribution [S2]
a. Where the drug goes after it has been absorbed.
III. What is volume of distribution? [S3]
a. Following absorption, the drug distributes to a different compartment. The drug may distribute into any or all of
the following compartments: plasma (the main compartment), interstitial fluid (tissue fluid), and intracellular fluid.
b. There is a pharmalogical term which quantifies the amount of drug distributed between plasma and the rest of
the body. That term is “Volume of distribution” (denoted by VD)
c. Volume of distribution (VD):
i. It is not a real physiological volume (in other words, it is not an identifiable physiological volume), rather it is
a volume that is necessary to contain the amount of drug observed in the blood concentration. (VD takes
into account how the drug distributes in the body, including tissues, organs, cells and other non-fluid
compartments).
d. In mathematical terms, VD = Amount in Body/Plasma Conc.
e. What happens when a person has renal failure? Or what happens in a situation of dehydration?
i. The distribution varies.
ii. For a person with renal failure, will the VD increase or decrease? Increase.
iii. For a person who is in dehydration (less fluid), will the VD increase or decrease? Decrease.
f. [SQ] When does VD increase? [A] When you have a lot of volume. In a renal failure situation, the fluid
contained is high (so the volume of fluid increases).
g. VD is an important parameter that indicates how a drug is distributed. The volume is expressed in liters. VD
depends on the physical and chemical parameters of the compound:
i. When a drug is lipophilic, the drug distributes outside of the plasma.
ii. When a drug is hydrophilic (or more water soluble), then the plasma concentration of the drug would be
high (that means it is less distributed in the rest of the body).
h. If drug binds to a plasma protein (mostly lipophillic drugs), then the less likely a drug will distribute to the rest of
the body.
IV. [S4] We can calculate VD in a problem:
a. A 50 mg iv bolus dose of a drug is administered to a patient. A sample of blood drawn for analysis immediately
after dosing shows a plasma concentration of 25 μg/L. What is the volume of distribution of this drug?
i. VD = Dose / plasma concentration
1. VD=50, 000 ug/25 ugL-1
2. VD=2,000L (This drug has a very high VD)
ii. This means this drug distributes outside the blood stream
iii. Must distribute to tissues/membranes
iv. Must be a lipophillic drug/compound
b. More about VD [S5]
i. Mr. X has been admitted to the hospital with acute heart failure. A doctor decided to put him on digoxin. He
wanted to achieve a serum concentration of 1 ng/mL. How much does he administer?
ii. If you know the Vd of the drug and the blood concentration, you can calculate dose.
1. Dose = ? C= 1 ng/mL
Vd= 500 L
2. Remember: Vd = Dose/concentration.
a. Therefore, Dose = Vd x concentration and you can now calculate the dose.
V. Elimination, or “how quickly will this go away”? [S6]
a. Elimination is the final part of pharmacokinetics.
b. Elimination means how quickly the drug eliminates from our body.
c. Elimination of a drug – Why is elimination necessary? [S7]
i. Drugs have a finite duration of action in the body. That is very important. Because drugs are ?? (inaudible:
audio 10:45) and ?? should be eliminated from our body. (We listened to this probably 20 times and cant
figure out what he said here. Sorry.)
ii. Elimination actually involves two processes: metabolism (biotransformation) and excretion. These
processes are the major determinants of this duration.
d. Some drugs are eliminated or excreted after metabolism, and some are in un-metabolized form. This depends
on chemistry of the compound (the physio-chemical components of the drug).
e. Is it possible to eliminate a lipophillic drug without biotransformation/metabolism? No.
i. Some drugs (those that are polar or water soluble) can be eliminated without any metabolism- the
compound is found unchanged in urine.
FUN2: 10:00-11:00
Scribe: Marjorie Hannon
Tuesday, December 02, 2008
Proof: Brittney Fain
Dr. Prasain
Pharmacology- General Principles
Page 2 of 3
ii. Lipophilic compounds usually undergo extensive metabolism (like gluconation and sulfonation). This
makes the compound more water soluble and is a process of inactivation: basically, it makes it easier for
elimination of the lipophilic drug.
f. Therefore whether a compound is eliminated in the metabolized or unchanged (un-metabolized) form is
dependent on the chemistry of a drug.
g. [S8] How a drug is eliminated from a kidney
i. The most important route of drug elimination is via the kidney.
ii. Elimination involves glomerular filtration.
iii. The three processes of excretion in the kidney are: filtration, tubular secretion, and reabsorption.
1. Not all drugs are eliminated, so there is a reabsorption mechanism in the kidney.
h. Try to understand that absorption and elimination of a compound are opposite. When we are talking about
absorption from the GI tract, unionized compounds absorb better than ionized compounds. That means that
ionized forms are more likely to be eliminated.
i. Acidification of urine increases the excretion of basic drugs. When the pH is lower, then a basic drug exists in
an ionized form.
j. Alkalinization of urine increases the excretion of acidic drugs.
k. [S9] Table- Influence of pH on drug excretion:
i. High renal clearance when urine is acidic. Drugs like amphetamines are basic drugs. If you look at its
structure, it has NH2, it is a weak base. When tubular urine has an acidic pH, then it is easily excreted.
ii. High renal clearance when urine is basic. Drugs like Asprin and Nalidixic acid are acid drugs.
iii. Ionized form helps eliminate compounds and unionized forms help reabsorption.
l. What is the clinical significance of this (acidification or alkalinization)?
i. For example: drug poisoning: if you want to eliminate or excrete some of the metabolites (some of the
compounds) quickly
VI. Clearance [S10]- This is very important in drug elimination
a. When a drug is eliminated, what happens? The plasma concentration will decrease, so there is a relation
between plasma concentration and rate of elimination.
b. The sodium drug has high clearance.
c. Clearance: ability of organs of eliminating a drug from the bloodstream. (Indicates how efficiently a drug is
eliminated)
d. Clearance: volume of fluid which is completely cleared of drug per unit of time.
i. It is not an amount, rather a volume
e. Clearance (Cl) = rate of elimination / plasma concentration
f. Clearance could be Cl liver, Cl renal or others.
g. Rate of elimination = Cl x C (clearance x concentration)
VII. Plasma half-life (T ½) [S11]
a. The time required for a drug to be reduced in concentration by half.
b. This graph is showing the accumulation and elimination (happening at the same time).
i. When you inject a drug, what happens? There is a certain time when you have saturation. At the same
time you have elimination.
ii. Elimination can be expressed with half-life. In this particular case, we look at the 50% plasma
concentration (% of steady state) to find half life. (half of 100% is 50%).
iii. The time needed from 0 to 1 is the point where the accumulation and elimination intersect. And then from
50 to 25 is a half (at 2).
iv. In first order kinetics, the t ½ is the same (half life is constant).
c. [S12] Graph: first order kinetics
i. Can be expressed in two ways
1. First one is the amount plotted in regular scale.
a. Say you inject a compound and there is a decrease, there is elimination. The concentration
decreases exponentially.
2. Using a logarithmic scale, a straight line is observed.
a. That is a characteristic of first order kinetics.
ii. T ½ is constant.
d. [S13] You can calculate half-life with this equation: t ½ = 0.693/ rate of elimination
i. T ½ and rate of elimination are inversely proportional.
ii. If your t ½ is high, the rate of elimination is small.
iii. The first order elimination rate constant for acetaminophen (Tylenol) is 0.23 per hour. What is its half-life?
1. Can calculate when you know the rate of elimination (k).
2. t½ = 0.693/k = 0.693/0.23 hr-1 = 3 hours
FUN2: 10:00-11:00
Scribe: Marjorie Hannon
Tuesday, December 02, 2008
Proof: Brittney Fain
Dr. Prasain
Pharmacology- General Principles
Page 3 of 3
e. [S14] Another problem to help you see half-life more clearly.
i. Drug X has a half life of 4 hours and is administered as an intravenous bolus dose to produce a
concentration of 100 ug/ml. How long after administration of the dose of Drug X will the concentration drop
to 25 ug/ml? 8 hours.
ii. T ½ = 4 hours
Starting concentration = 100 ug/ml
1. After 4 hr, the concentration reduces to 50, so how much time is needed to reduce to 25? 8 hours.
VIII. Elimination kinetics: zero order elimination [S15]
a. Zero order is a constant amount of drug is eliminated per unit time and independent of plasma concentration
b. The graph is plotted concentration vs time. A constant amount of drug is eliminated and it decreases linearly
with time. R=k because the rate is independent of the concentration.
c. The difference from first order:
i. The decrease here is linear. On a first order, it decreases exponentially.
ii. Think about the half life: in first order, it is constant. Here, t ½ varies with concentration.
d. There are several drugs that follow zero order kinetics when given in high dose. Ethanol is an example.
Ethanol is rapidly and completely absorbed, the drug is distributed throughout the body, the elimination
mechanism is saturated, and the t ½ varies with concentration.
e. [SQ] Could you say it is independent of the drug concentration and plasma concentration? [A] Yes,
when it is given in very high concentrations.
IX. First order kinetics [S16]
a. Most drugs follow first order kinetics.
b. The rate of elimination is directly proportional to drug concentration
c. Not exceeding the ability of the liver to metabolize the drug
d. The decrease in concentration with respect to time is exponential.
e. T ½ is independent of concentration.
X. We can talk about metabolism since we have a few extra minutes.
a. Metabolism is important in elimination of a drug.
b. As I mentioned, some drugs are eliminated in unmetabolized form and some in metabolized form (so, phase
one and phase two reactions)
c. Phase one and phase two reactions convert a drug (especially phase two) to a more hydrophilic compound
which helps in its elimination. Water soluble drugs can be eliminated without any metabolism.
d. How do we determine the concentration of drug in plasma?
i. You could draw blood at different time points. Or examine the tissue.
ii. The blood sample will have a lot of proteins and a lot of endogenous compounds and the concentration of
your target drug would maybe be a submicro-molar concentration. So, it is not easy to determine the
precise concentration of a drug in plasma.
iii. There are several analogical techniques which can be used to determine the precise drug concentration.
The most widely used technique is mass spectrometry:
1. This is the method of choice to determine the concentration of drug in plasma or any biological
sample. Biological sample means it could be any fluid (urine, plasma, or saliva) or tissue sample.
2. Mass spectrometry can detect an ion of a certain molecular weight. It is a very specific, precise way
to detect the drug. Also, you can quantify the amount of drug in plasma and tissue using mass
spectrometry.
3. Compared to other techniques, mass spectrometry is very sensitive and specific. Therefore this
method is widely used in pharmacokinetics.
4. How it is done: If you have a blood sample and you want to measure the amount of compound of
interest in the sample. It is practically impossible to measure this directly (plasma has a lot of protein
and salt), so you have to process the sample in order to analyze a particular compound.
a. If your compound is not water soluble, then you have to extract from the plasma using
organic solvent or ether.
b. If your compound is water soluble, you can just precipitate the protein and take out the
supernatant and inject into mass spectrometry.
c. There are several ways to prepare a sample and once it is prepared, you can inject it into the
mass spectrometer. Then you can detect a compound.
iv. Analogical techniques are important when trying to approve a new drug (example: for FDA approval). How
we validate and externalize the method is a huge topic right now. There are strict regulations. Example: if a
certain concentration of drug X is given to a person, then that should be reproducible and so the analogical
technique is important when trying to approve a drug.
e. [end 40:27 min]