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Summary of all the lectures of pharmacokinetics
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PharmacokineticsLecture 1 Beljaars Chapter 1 + 2
Pharmacokinetics: What is the body doing to the drug? The fate of a drug in the body in time. Doses
are different at different times of administration.
Pharmacodynamics: What is the drug doing to the body?
Pharmacology is pharmacokinetics and pharmacodynamics combined.
First testing in cell tissue, then animals (preclinical) and then on human (clinical). Kinetics is an
essential part of testing the drug.
Goal of pharmacokinetics: to have the right patient, with the right drug at the right time and the right
dose.
ADME:
Absorption how will it get in?
Distribution where will it go?
Elimination How does it leave the body?
- Excretion
- Metabolism (get rid of your original structure)
Absorption to get the drug into the blood. From there it can distribute and via elimination it goes out
of your body.
Distribution means where does it go.
Disposition means how is the drug handled; combined distribution and elimination processes.
Elimination vs excretion. Can be the same but also can be something else. Not all elimination is
excretion. It can also be metabolism. If there is excretion you can exclude metabolism, but if there is
elimination there can be excretion and metabolism.
Intravascular: directly into the blood.
Extravascular: absorption is needed. Drug has to be transferred to the bloodstream.
Parenteral: everything that is not administered via the intestines. (I.v., i.m., pulmonary, intranasal,
inhalation, dermal)
Enteral: everything that goes in via the digestive tract. (oral, rectal, sublingual, buccal)
Local/regional: administration only local. Just a part of the body/body surfaces is reached by the
drug.
Systemic: administration into your bloodstream.
, Sites of administration (absorption):
A = intra-arterial
B = intravenous
C = intramuscular, subcutaneously
D = inhalation
E = rectal, oral
Enterohepatic cycle (between liver and gut) is cycle between the
intestinal system and liver system. Part of distribution. Drug is
already in the bloodstream, it is taken up by the liver and excreted
ends up in the intestinal system carrier proteins takes up the
drug via the portal system to the liver and then giving it back to the
bloodstream. The drug is not eliminated.
First pass effect: bioavailability. One way route. Drug gets into the
gut lumen and here it is taken up into the blood. On the way from
gut to the bloodstream there can be loss of the amount of drug
because there are elimination processes playing a role. Most of the
time not all that is in the drug will also end up in the bloodstream. It
refers to absorption.
Distribution: some drugs distribute everywhere. If a drug has access to your tissues it can have an
effect there which can be a wanted effect of an adverse effect. If the concentration in off-targeted
tissues is high you get toxic effects. This can also happen in the targeted tissues, but then you can
reduce the dose in order to get rid of the adverse effect. You also need to know where the drug
accumulates.
Elimination routes: metabolism or excretion. The red arrows are routes of elimination. There are
more ways of elimination than the main routes that are showed here. Also via other tissues and the
lungs. The main organs for elimination processes are the kidneys and the liver.
Metabolites are compounds formed from the drug usually by enzymatic reactions (c-p450 enzymes).
Metabolites can be active or inactive. When the metabolite is active, it can have the same effects as
the original drug or it can induce another effect.
Sampling sites: in the veins/blood, and urine/fecus (indication if the liver plays a role in the
elimination). To get more information of elimination and absorption.
Plasma concentration-time curve:
Before Cmax = absorption
After Cmax = elimination
In case of i.v everything is dosed into the bloodstream,
there is no absorption there so the first part of the curve
(before Cmax) is not there. Only elimination processes take
place.
,The left curve is i.v. only elimination. The right curve is dermal/subcutaneous gradually in time
the drug will be released. A certain time is needed to reach steady state concentrations, once it is at
the steady concentration, the drug will be released at a constant rate.
PK: quantification of the time course of a drug and its metabolites in the body. This is done in order
to assess a proper doze regimen to achieve adequate therapeutic responses. You want the best
effect, without side effects.
You relate the dose, the plasma concentration and the concentration in biophase to the effects. With
these factors you can predict your effect.
How do we know when plasma concentrations are right therapeutic window. You aim for the
plasma concentration to be between the therapeutic window. Above the line there are toxic
effects/side effects, and if you go below the line there is not enough drug to exert the effects.
When you have a therapeutic effect, we know the plasma concentration and we know the dose. But
you also want to measure if the plasma concentration is what we think it is. For some drugs this
needs to be measured because the therapeutic window is small. The plasma concentration can differ
when the liver/intestines/… function a little bit different which can cause difference in elimination or
absorption. This can lead to a concentration outside of the therapeutic window when the window is
very small.
Blood, plasma and serum all include plasma proteins. Some drugs bind highly and tightly to plasma
proteins. Drug bound to plasma protein is not effective. Most used is plasma full blood and add an
anti-coagulant to separate the plasma from the blood cells. You can then more clearly analyse the
drugs.
Models to describe observations and predict outcomes in other situations. Equations, physiologic
models and compartment models. You can have a one-compartment or two-compartment model.
Majority will be one compartment in the
beginning.
Depending on the characteristics of your drug,
there is a certain number of compartments.
, Pharmacodynamics is described with a concentration-effect curve. Pharmacokinetics is described
with a concentration-time curve. These can be combined to an effect-time curve.
There is a direct relation between the plasma concentration and the effect. If you increase the
concentration the effect will increase. Not always a direct response can take some time before
you see the change in effect.
Variability: not everybody is the same. We assume everybody is the same but there might be
individual differences. The effect of a drug may differ in the kind of people.
Sources of variability for pharmacokinetics (how the body affects the drug):
- Gender, race, body size
- Renal/hepatic function
- Gastric pH
- Drug-drug interactions
- Environmental factors
- Type/degree/concomitant diseases
- Drug metabolism polymorphisms
- Medication compliance (how faithful is you patient in taking the drug)
Sources of variability for pharmacodynamics (how the drug affects the body):
- Gender, race
- Drug-drug interactions
- Environmental factors
- Type/degree/concomitant diseases
- Placebo effect
- Drug receptor or enzyme polymorphisms
- Tolerance, tachyphylaxis
The cause of a different response can be because of the difference in kinetics or a difference in
dynamics. When a person gets a certain dose, people do not necessarily end up with the same
plasma concentration after a set time. The variability is more tricky when a drug has a very narrow
therapeutic window, because the plasma concentration in some patients may become too high or
too low.
Non-adherence to prescribed medication is a major source of variability in drug therapy in time
more and more patients get less precise (adherence drops). They do not take the drugs as they
expect.
Health care professionals can check on computer based system that the patient really took the drug.
In the drug there is a kind of chip which gives a signal when it is properly taken. When the chip gets
contact with the stomach, it will be activated and you can then see if the patient took the drug.
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