University of Jordan

Faculty of dentistry

Third year

2015/2016

Sheet
Slide
Handout

LejanAsnan

dentalcommittee2014@gmail.com

DENTAL CORRECTION

dentalcorrection@gmail.com
Pharmacology sheet #6

In our last lecture we talked about drug pharmacokinetics "what the

body does to the drug" and we said that it includes 4 main processes
(ADME): Absorption, Distribution, Metabolism and Elimination.
To understand these parameters we have to determine the safe and
effective drug concentration at the site of action.
When we studied metabolism we have to mention that drug metabolism
has two phases (stages):
1 . First order metabolism
2 . Zero order metabolism

- First order metabolism:

In short terminology Most drugs are eliminated from the body
by "first order kinetics" one of them is by metabolism. This means
that there is a relationship between the amount of drug inside the
body and the rate of its metabolism, when you plot it in a curve
there is a straight line relationship, in other words as you increase
the amount of drug in the body you increase the metabolism of
the drug , e.g as you increase the concentration of the drug in the
plasma of the blood you increase in a proportional manner the
drug metabolism .
( at the way you administrate a drug between the therapeutic
dosage region).
So the elimination is independent on the drug concentration or
the amount of the drug, this represents that the ability of the
metabolizing drug in a way that is independent on the dose or the
drug concentration .
Again, as we increase the dose or as we increase the blood
concentration there is a proportional increase in the metabolism
or elimination, we call this process "first order elimination or first
order kinetics".

- In comparison with the zero order kinetics, as you increase the

dose of the drug, after short period of time you will reach a
saturable level of the enzymes through kinetics, you increase the

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metabolism of the drug in a proportion to the concentration of

the dose. So when you plot the curve we start from the beginning
of the straight line then curve. So as you increase the amount of
the drug the drug accumulates in the body no more metabolism,
no more increasing in the elimination of the drug, so the drug will
accumulates and here you will reach a toxic level very rapidly,
even if you increase the dose in a small amount, a huge
accumulation of the drug will reach rapidly a toxic level and cause
that consequences in your patient.

*Most of the drugs are eliminated under the rules of first order
kinetics, few drugs are eliminated by zero order kinetics such as
Phenytoin, Sanicilates, Alcohol.. etc.

Let's talk about the most common drugs that follows first order
kinetics.
The rules of this process (first order kinetics) are determined by
few parameters :
1 . drug elimination half-life (which is constant).
2 . drug clearance (constant).
3 . drug accumulation.

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If you understand these rules you can design the therapeutic

region according to the need of your patient and you can predict
blood level and you can calculate any change in the dosage region
according to the patients need and so on .

The first parameter is the elimination half-life (which is constant

as long as any other factors that effects on the kinetics, don't
change e.g Drug-drug interactions )
The unit of the elimination half-life is time, so it's the time needed
for the drug in the plasma to drop to the half of its starting point.
For example a 100mg dose of drug X , after 1 half-life the
remained amount of drug is 50mg, after 2 half-lives the remained
drug amount is 25mg and 75mg are eliminated, after 3 half-lives
remained 12.5mg and 87.5mg were eliminated and after 4 half-
lives 6.25mg of drug remained, and so on..
The dr. asked how much time we needed to reach a zero value?
The answer is infinity.

The second parameter is drug clearance: a pharmacokinetic

measurement of the volume of plasma from which a
substance is completely removed per unit of the time.
(by liver "hepatic clearance", kidney renal clearance ..)
When the drug which is cleared by liver was summated with drugs
cleared by other organs, this is called total clearance or systemic
clearance.
The unit of clearance is volume/time.

The third parameter is drug accumulation in the body,

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due to repeated drug administration or over-dosage .

the rules of accumulation are the same rules of elimination.
If we give a 100mg dose of drug at zero time, there will be 100mg
of drug in the body, after 1 half-life 50mg of drug will remain in
the body, and if we administered one more dose of drug (100mg)
after the first half-life, there will be 150mg of drug accumulated in
the body, after the second half-life 75mg of drug is remained, and
if we applied one more dose there will be 175mg accumulated in
the body, and so on .

Elimination half-lives and accumulation half-lives are mirror

image to each other

When do we reach the steady state level in first order kinetics?

In about five times the elimination half-life
(Steady state: is when the amount of drug entering the body is
equal to the amount of drug being eliminated in a given in
dynamic equilibrium)

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If we doubled the dose of drug the concentration is also doubled,

and if we decreased the dose the concentration decreases,
whereas the time needed for the drug to accumulate is constant.

If we had a drug with a half-life of 1 day, such as Digoxin, this drug

has very narrow therapeutic range (the range between the
effective and toxic dose), and you have a patient in a very
dangerous case like heart failure , we have to duplicate the
Loading dose which is within the therapeutic range and
higher than maintenance dose, we use it to achieve
therapeutic level on the first dose to reach the steady
state, It is used for drugs which would take a long time for
the amount of them in the body to reach that level, such as :
Digoxin, Teicoplanin, Voriconazole and Procainamide.
The concept in these drugs, If we increase the drug
concentration, velocity of the diffusion will increase , but the
parameters are constant half-lives, clearance ,
If we increase the dose, the concentration and the amount of
drug in the blood will incease, and the time to reach this level is
constant.

Maintenance dose : is one that continues to keep the drugs in

the desired therapeutic range, Its used after loading dose and for

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many drugs, patients receive the maintenance dose both at start

therapy and throughout it.

The equations are not required.

The advantages and disadvantages of intravenous

administration:
Disadvantages:
1- It has to be sterilized.. Drug injection process in the blood needed to
be sterilized either method of injection or the drug.
2- It needs aqueous media.. If the media is lipid, it will kill the patient.
3- Upon entering the drug into the blood it is lost control of it and
cannot be retrieved.
Advantages:
1- Gives rapid effects
2- We can make sure that the entire dose is reached

Done by : Yara Younes

Corrected by : Alaa Dawahdeh

Good Luck

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