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Summary Pharmacology (De Hoon) (E03N9A)
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Pharmacology and Pharmacokinetics 28/9/21Exam: oral, 1 prof but questions about all parts. 3 questions, 30 min to prepare, 15 to defend. Make schemes,
graphs, …
Bcfi = digital version en summary van klein boekje met alle drugs
Part 1: introduction
Pharmacokinetics (PK)
Has to do with the change of a drug in the body.
Increase in concentration → peak → decrease: most
typical profile of PK of a drug. A = absorbed. D =
distributed in the body. E = eliminated
Pharmacodynamics (PD)
The consequence of the drug in the body. Drug
usually interacts with a target (often receptor) →
drug-receptor complex. Might be a desired or non desired effect.
By increasing the dose you get increasing effect and at some time you get plateau (maximum
effect).
Log (C). E = effect of response
H1: Absorption of drugs across biological membranes
ABSORPTION
Paracetamol: in para position an amino. Is also called acetaminophen.
Paracetamol = active pharmaceutical ingredient (API)
Chemical name (para aceto aminophenol)
Substance name (paracetamol)
Specialty name (brand name, invented)
Patient takes paracetamol (500mg) in a fasting state and with water (240mL) = international
agreement of how ppl should take drugs if you study PK (bc you must standardise).
No chewing. 2 things can go wrong
Active substance in tablet might be very susceptible to enzymes and changes in pH.
Substance should not be exposed too quickly.
Sometimes active substance might have toxic effects itself. If you chew you might get lesions.
(unless it’s a chewing tablet ofc)
→ tablet goes into stomach: H2O environment; tablet will disintegrate into small pieces. Once API is
liberated, it will go into dissolution. The disintegration and dissolution = part of the pharmaceutical
phase (happens in the stomach). API in solution very important! If not, it cannot get absorbed. Acidic
,pH stomach = 1-2. pH = negative log of the concentration of protons (-log[H+]). The acid: HCl,
produced by parietal cells, located on the upper part of the stomach. How do they produce HCl: H+
get in the stomach through a K-H-ATP-ase. Intracell conc K is higher and requires energy to get out so
uses ATP.
Duration of the pharmaceutical phase: 30 min – 1h in fasting state. Liquid formulations result in a
quicker availability of the API in the small intestines.
→ quicker uptake in the patient.
→ difference between oral tablets and solutions!
→ into the upper intestines: actual absorption of the drug. Zie afb:
closer look mbr. When you enlarge that part you see enterocytes.
API in the lumen of the intestines. Drug should get from the luminal
side, across the mucosal part into the vascular compartment. From
there it can be distributed in the body and can go in the tissues
where it’s needed.
To clarify: in stomach: tablet, in intestine: molecule!
In intestine molecule can get across membranes in 2 ways:
1) In between cells = paracell transport. Not through the cells but along the side of the cells.
Most mol cannot get absorbed in between cells and only very fine and smalls molecules can
get through (ex: lithium)
2) Across the mbr = transmembrane transport.
o Passive diffusion: zie afb (enlargement). Cell mbr exists of
lipophilic bits pointing to the inside of the mbr and hydrophobic
to the outside → bilayer lipid structure. API needs to get across
the mbr in between the cells. Efficiency (v = velocity) with which
the mol can get across, what will it depend on, what will be the
driving force? Co = outside cell = high C. Ci = inside the cell = 0.
So concentration gradient (delta c), is actually the driving force
for the mol to move along the mbr. Lipid bilayer is very hydrophobic and mol has to
get through that. The extent to which the mol can do that will depend on P =
partition coeff, has to do with the lipophilicity of the API.
Tube: H20 and a lipophilic layer (N-octanol = 8 carbon atoms and OH at the end, very
hydrophobic). Take an amount of drug → in tube → measure C of the drug in the
lipid layer vs in hydrophilic layer. This ratio = partition coeff (P = [D]L/[D]H2O)
If mol is lipophilic → P is higher. If mol is hydrophilic → P is smaller. If P very small,
drug will not get through the mbr. That’s why this kind of tests very early on in
development. If P too small, they will never take it orally.
Absorbance area: the larger, the more mol get across. The thickness/distance (d) of
mbr might limit the diffusion.
D = diffusion constant. Has to do with the size of the API.
, D is larger for small mol. D is smaller for large mol.
D ± 500 – 700 Da = small mol, ideally.
P ~ 1 ideally
If P too high mol will get stuck in the mbr, accumulate, and cause that way toxicity
(disintegration of the mbr).
P with lipophilic mol, not very soluble. Solution: take it with a meal. With a fatty meal
it will dissolve in the stomach and can get soluble afterwards. For some drugs, the
profile completely changes with food.
v = P x D x (A/d) x (C0 – Ci) = Fick’s equation, describes the efficiency of diffusion
across a mbr.
Linear relationship where the independent variable = C. and the slope of the line
is determined by the combo of the Ctes and the C
Fick’s law is linear 29/9/21
The slope of this line can differ depending on the K value. If you have a lower slope it
probably means that P is small and that the drug is more hydrophilic, results in a
poorer absorption across the mbr. If P>5 → API gets stuck.
o Carrier mediated transport:
Again, move mol from the apical to basolateral side into the vascular compartment,
into the circulation.
ATP dependent transporter,
→ API binds,
→ moves into the cell, is released, gets into the cytosol
→ across cell mbr
Efficiency (v): Michaelis-Menten equation: the uptake is depending on the C of the
drug but also limited/depending on the Michaelis menten cte (Km says smth abt
affinity between substrate and transporter) and C but it is also depending on vmax.
, If the C of the API is small compared to Km, you
can ignore the C in the nominator. vmax and Km
are cte so you get a linear relationship again
(comparable to Fick’s law).
If C becomes extremely large, you can ignore
Km, C can be deleted bc noemer en teller. And
you get v = vmax.
Differences with Fick’s law, 3 typical characteristics of this kind of transport:
▪ Element of saturation: if patient gets dose D and you double this dose:
(black) you’re still ok. But if you double the red, there will be almost no
increase of efficiency even though you’ve doubled the dose. Better thing to
do is to give multiple small doses.
▪ This kind of transport is subject to competition: depending on which mol has
the highest affinity with the transporter, that one will bind and the other mol
have to wait.
Glucose and other essential AA are very hydrophilic. In order to get them
into our body we need help: transporter systems.
L-DOPA: benzyl group, typical AA group (amino, H, COOH) and 2 OH groups.
Competes for its uptake across mbr with transporter that transports AA.
Once transported it becomes dopamine.
L_dopa in fasting state bc in food
you have proteins that get
degraded into AA. U get all the AA
in presence of L-DOPA and you get
competition → decrease in
efficiency of uptake. L-DOPA
always with decarboxylase
inhibitor. Bc when L-DOPA in
circulation, you get immediately
decarboxylation en you get dopamine (highly hydrophilic) and will not get
into the brain anymore.
→ decarboxylase inhibitor so that L-DOPA can get transported across the
mbr to get into brain and once in the brain you get decarboxylation bc
decarboxylase inhibitor does not get into the brain.
▪ Affinity of transporter with the substrate. Km.
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