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Samenvatting - Pharmacokinetics (WBFA018-05)

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Samenvatting colleges Pharmacokinetics met ondersteunende afbeeldingen en formules.

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  • 9 mei 2023
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  • 2020/2021
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PHARMACOKINETICS
LECTURE 1 - BELJAARS
Contents of the PK course: ADME, therapeutic window, various routes of
administration, 1- and 2-compartment kinetics, and plasma
concentration-time profiles.
The goal of pharmacokinetics is to give the right drug, in the right dose, on the
right time to the right patient. It is essential knowledge of pharmacists that
complements that of physicians to optimize the treatment of the patient.

Exam: 18 January 2021: 12:00 – 15:00. No MC-questions, only open questions.
Test questions available on SOWISO + examples in lectures.

SECTION I: BASIC CONSIDERATIONS
CHAPTER 1: THERAPEUTIC RELEVANCE AND CHAPTER 2: FUNDAMENTAL
CONCEPTS AND TERMINOLOGY
Pharmacology consists of pharmacokinetics (what is the body doing to the
drug) and pharmacodynamics (what is de drug doing to the body). Drug
development consists of a preclinical and various clinical phase. The ultimate
goal for pharmacokinetics is to give the right drug to the right patient on the right
time in the right dose.
Pharmacokinetics is the study of
fate of a drug in the body in time. It
is divided in various processes:
absorption (how will it get in?) –
distribution (where will it go?) –
elimination (how does it leave the
body?). Elimination is divided into
excretion and metabolism.
Difference between distribution and
disposition: distribution is the process how the drug divided over the body and
disposition is the term used for the combination for distribution and elimination.

Absorption is influenced by the variety of administration routes and dosage
forms.
Intravascular vs Extravascular
(directly into the blood) (needs absorption)
- Intravenous injection/infusion
- Intra-arterially
Parenteral vs Enteral
- Intravenous/intra-arterial - Oral
- Intramuscular - Rectal
- Sub/-intracutaneous - Sublingual
- Pulmonary - Buccal
- Intranasal
- Intra/-transdermal
- Inhalation
Local/Regional vs Systemic
- Skin - Via the gastrointestinal
- Mucosa route
- Cerebrospinal fluid - Into the bloodstream
- Pleural

, - Peritoneal cavity

Distribution is the term used for the way the drugs divided over the body. Some
drugs only distribute into the bloodstream, whereas other drugs distribute to
organs. How a drug is distributed is related to the effects of the drug, which may
be adverse and toxic. Moreover, some drugs tend to accumulate in the body,
which is also linked to the distribution of the drug. The enterohepatic cycle is part
of the distribution process, it means a cyclic of drugs between the entero in the
gut wall and lumen and the hepatics in the liver.




The enterohepatic cycle typically is part of distribution, whereas the first pass
effect is typically part of the elimination process and linked to the bioavailability.
The first pass effect is only in one direction, whereas the enterohepatic cycle is a
recirculation. Drug must pass through the gut wall and liver before reaching the
systemic circulation properly. Loss of the drug can sometimes be so high that a
non-oral administration of the drug is demanded.

Elimination and metabolism mainly occurs in the kidneys and liver. In these
organs metabolites are formed. These are compounds formed from the drug
usually by enzymatic reactions (cytochrome P450 enzymes). There are inactive
and active metabolites, these active metabolites have an effect on their own,
which can influence with the effect of the drug.

In pharmacokinetics the quantitation of the concentration of a drug and its
metabolites in the body in time is studied. This is usually done with a plasma-
concentration curve. From this drug typical pharmacokinetics terms can be
derived, like absorption, distribution, and elimination. Sampling sites for the
plasma concentrations are at the venous sites, feces and urine samples. Plasma-
concentration curves differ from one another depending on the route of
administration. When the graph first shows an increase in concentration, the drug
needed to be
absorbed in the
bloodstream. When
the graph has a
high initial
concentration it is
most probably

, directly injected into the bloodstream. Increasing concentration to a steady state
is typically for slow-device drug releasers and infuse drug administration.

The concentration of the drug is wanted
between the therapeutic window, in
which there is therapeutic success. Below
and above the therapeutic window the
patient will undergo therapeutic failure. A
lot of drug have a wide therapeutic window,
but some drugs have a narrow
therapeutic window and for these drugs
the plasma concentration should be at the
desired level, but also have to be measured.
The difference between blood, plasma, and serum:
- Blood: plasma (including plasma proteins) + cells (RBC, WBC, and blood
platelets)
- Plasma: water (90%) + ions + lipids + plasma proteins. No cells
- Serum: plasma (including plasma proteins) but without clotting factors
(fibrinogen/fibrin)

To calculate the optimum concentration appropriate models are created to
describe observations and predict outcomes in other situations. Models within
pharmacokinetics can be:
- Equations: C = C(o)e-kt
- Physiological models
- Compartment models

When pharmacokinetics and pharmacodynamics are combined, a correlation
between plasma concentration and effect is created. In these typical PK/PD-
curves, the effect is visualized versus the time. Sometimes there is not a direct
response of the body from the effect of the drug. There is a delay in the
pharmacodynamics graph, and the highest response is not at the highest
concentration.
The variability in the drug response can be caused by:
- Gender, race, body size - Type/degree/concomitant
- Renal/hepatic function diseases
- Gastric pH - Drug metabolism
- Drug-drug interaction polymorphisms
- Environmental factors - Medication compliance

The medical compliance, or adherence, is major factor in what kind of
concentrations are obtained in a patient. If a drug isn’t given at the right time
and dose, the concentration can be lower than expected. A digital medicine
system gives a signal when the drug concentration is too low, this will increase
the medical compliance.

DIGOXIN CASE
Patient: Woman, 55 years, 70 kg, 1dd 0.375 mg digoxin
Lately patient has complains about constant feeling of nausea and diarrhoea.
First of all, the plasma concentration of digoxin is determined via a blood sample.

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