Pharmacology and pharmacokinetics
15 minutes exam + 30 minutes preparation → 1 theory question and 2 think-questions (drug-drug interactions, side-effects)
Part 1: An introduction to pharmacology and concepts of pharmacokinetics
Chapter 1 = Absorption: transport of drugs across biological membranes
After oral intake and passage through the esophagus, the drug arrives in the stomach. With the exception of drugs that
have a delayed release or stomach resistant formulations, the drug (i.e. the active pharmaceutical ingredient, API) is
released into the stomach before being available for absorption: this is called the pharmaceutical phase. The
pharmaceutical phase includes disintegration of the tablet (or capsule, etc.) and dissolution of the compound into the
watery environment of the stomach, so that it becomes available for uptake. The pharmaceutical phase will be more
efficient if the drug is taken with a sufficient amount of water (i.e. 240 mL). After the pharmaceutical phase, there is
longitudinal gastrointestinal transport (i.e. from proximal to distal), as a result of the movement of the chime by
peristalsis, as well as axial transport, as a result of diffusion. The actual absorption into the vascular space occurs mainly
in the proximal small intestine, the duodenum and the jejunum. As a result, the stomach can be viewed as a ‘portal’ that
influences the speed with which the drug is presented to the small intestine, thus influencing the speed of uptake and,
indirectly, the speed with which the drug takes effect. The stomach has a low pH level of 1-2 due to HCl which could break
down the tablet and dissolve in order to get through the tissue’s.
1. Concerning the uptake of substances across biological membranes
1.1 Paracellular transport
= transport of substances through pores between cells. Only small, highly water-soluble compounds are absorbed in this
way.
1.2 Transcellular transport
= transport of substances across the cellular membrane and is quantitatively speaking the most important route for the
uptake of compounds across the intestinal mucosa. Different types of transcellular transport are:
A. Passive diffusion: transport which uses the concentration gradient (high to low) as its driving force. The rate of
diffusion (i.e. flux, v) or the number of particles which is transported across a membrane per time unit, is described
by Fick’s law of diffusion: V = D . P . (Ad) . (Co-Ci) → V = k . ΔC
- D=diffusion constant
- A= surface area (enterocytes make the area bigger)
- d= membrane thickness
- P=partition coefficient → preferably 1; if >>1 =
dissolves only in lipid (solution = take w/ food); if <<1
dissolves in water (stomach, lumen, intestines). P =
[D]fat / [D]water
Fick’s law describes a linear correlation between the rate of diffusion and the concentration gradient. Therefore,
the rate of absorption increases when:
1. the molecule is smaller (i.e. larger D); MW <500 and maximum 1000.
o Biologicals: large molecules = get straight into the tissue → subcutaneous, injection, …
2. the surface area A across which diffusion takes place is larger (i.e. small intestine > stomach)
3. the substance is more lipophilic (= larger P). When P becomes too extreme (i.e. P>5) diffusion
becomes problematic as drug can start to accumulate in the cell membrane preventing actual
absorption.
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4. the concentration gradient between the lumen of the intestine and the vascular space is larger (i.e.
a larger dose).
Hydrophilic drugs are easier dissolved in the aqueous environment of the gastro-intestinal tract. In contrast, the
absorption rate as a result of diffusion increases when a drug is lipophilic. Not only the physicochemical properties
(molecular size, lipid solubility) influence dissolution an uptake; the drug’s pKa and the environmental pH are also
very important factors. The relationship between these parameters determines the degree of ionization of the
compound and thus also the ratio between its lipophilic (i.e. non-ionized) and hydrophilic (i.e. ionized) forms.
The pH partition theory = a compound accumulates on that side of the membrane where it has the highest degree
of ionization (i.e. water-solubility). Since only uncharged (non-ionized) forms can diffuse across membranes, a
weak acid will be quickly absorbed in the acidic environment of the stomach (pH 1-2).
Acid HA A- + H+ (negative A = iron = more water soluble because it has a water-coat = goes into stomach easier)
Example = ASA = acetyl salicylic acid ➔ when the pH is lower than the pKa, [HA]
increases; i.e. the concentration of uncharged, more permeable salicylic acid increases (e.g. in the stomach).
pKa – pH = log[HA]/[A] → 3 – 1 = log2 → [A-]= 100
After absorption, the salicylic acid ends up in the plasma (pH 7.4) and [A-] becomes larger than [HA]; i.e. the
concentration of charged, non-permeable salicylic acid increases, ’trapping’ the drug in the plasma (’ion
trapping’). (Stomach acid =) HA A- + H+ → 3-7 = log 10-4 → 104 [HA] = [A-] ➔ equation shifts to the right or
more lipophilic.
When a patient is intoxicated w/ aspirin we can change the ionization by changing the pH in urine and this will
make the aspirin soluble.
Example = Azoles (itraconazole and posaconazole; used in suspension) only dissolve in the stomach fluid if it
is strongly acidic (pH 1-2). However, patients with cystic fibrosis or hematologic patients, who are often treated
with these azoles, are also frequently treated with proton pump inhibitors which increase gastric acidity to 5-
6. These azoles dissolve much more difficult in this less acidic environment, resulting in a reduced absorption.
➔ solution = drink with acid drink like cola.
B. Carrier-mediated active transport = polarized transport against
a concentration gradient, requiring energy. This type of
transport is important for hydrophilic substances that would
otherwise be unable to cross the cell membrane, e.g.
monosaccharides such as glucose, amino acids, bile salts. Among
others, L-dopa, penicillins, cefalosporins, ACE-inhibitors and
methotrexate. This transport system is found in the small
intestine, the biliary ducts, renal tubules and blood-brain
barrier. The rate of uptake through this mechanism follows the
𝑑𝑆 𝑉𝑚𝑎𝑥 . 𝐶
Michaëlis-Menten kinetics: 𝑑𝑡 = 𝑉 = 𝐾𝑚+𝐶
Example = More frequently giving small doses will result in more effect and will not lead to saturation that will
lead into, when giving a higher dose, most of the drug will exit through the faeces. If you give the drug like L-
dopa w/ food the AA of the food will compete with the drug for the transporter and so a decrease in the
amount of L-dopa. There is a substrate selectivity = only if there is a sufficient affinity between the substrate
and enzyme it will be taken by the transporter.
C. Pinocytosis = through the formation of vacuoles or vesicles (apical endocytosis followed by basolateral
exocytosis), high molecular compounds can be absorbed.
D. Transcytosis = carrier-mediated transport where the compound-carrier complex is absorbed through endocytosis
(e.g. vitamin B12 and iron).
E. Facilitated diffusion = diffusion (i.e. in the direction of the concentration gradient) dependent on a carrier protein.
Pinocytosis, transcytosis and facilitated diffusion are qualitatively unimportant for the uptake of drugs.
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2. Mechanisms influencing the uptake of substances across membranes
2.1. Efflux mechanisms and transport molecules
Efflux mechanisms actively remove xenobiotics from cells. A membrane protein that is ubiquitously present in the body
and is called P-glycoprotein (P-gp). P-gp is the gene product of a multiple drug resistance gene (MDR gene) and is of great
importance in the development of resistance to cytostatics. They are found in several organs (e.g. small intestine, liver,
blood-brain barrier, kidneys, etc.). These transport proteins are ATP-Binding Cassette (ABC) transport molecules and use
ATP as a driving force to transport endogenous and exogenous substances across cell membranes. The development of P-
gp inhibitors (e.g. cyclosporine, valspodar, tariquidar) might make the oral intake of P-gp substrates possible, otherwise it
should be admitted intravenously into the body.
2.2. Metabolic enzymes
Metabolic enzymes in the intestinal wall, especially CYP3A4, limit the systemic availability of a number of drugs by
degrading them before they reach the portal circulation. Both mechanisms (efflux ‘pumps’ and small intestine enzymes)
decrease the uptake of drugs and lower their biological availability to the systemic circulation; they contribute to the ‘first
pass effect’.
2.3. Uptake from the gastro-intestinal system: interfering factors
Results in an altered gastrointestinal uptake in terms of rate (slower/faster) and/or amount (more/less).
A. Acidity or pH
An increase in stomach pH (by drugs, achlorhydria, food, etc.) can lead to premature release of compounds meant
for delayed release: this is called ‘dose dumping’. The acidic pH of the stomach for some drugs is a prerequisite
for dissolution, and therefore for successful absorption. This is especially the case with weak bases such as azoles.
By taking the drug under acidic conditions, the gastric fluid may be temporarily acidified and the solubility
improves again. Also, compounds that are degraded by an acidic environment can be broken down in the stomach
(e.g. erythromycin, penicillin, didanosine). This can be avoided by ‘wrapping’ the drug in an acid-resistant or gastric
juice-resistant tablet.
B. Gastric emptying and transit time
Under fasting conditions, a drug will pass the stomach after 30
to 60 minutes. Delaying factors (e.g. food, antidiarreica, narcotic
analgesics, gastroparesis, etc.) can make the transit time
increase up to 3-4 hours, which in turn causes a delayed uptake
of the drug. For some poorly soluble (lipophilic) drugs, a longer
transit time in the stomach combined with a high-fat meal can
improve the solubility (e.g. azole antimycotics). An increase in
motility (gastro-prokinetics, hyperthyroidism, diarrhea, etc.) can
result in an incomplete uptake, while decreased motility can
improve the uptake for poorly lipid-soluble drugs.
C. Adsorption and chelation
Dietary fibers can adsorb drugs, which strongly decreases their uptake (e.g. statins). Other drugs form
insoluble complexes or chelates with di- or trivalent cations such as calcium, iron and magnesium,
which causes them to precipitate and makes absorption impossible. This is frequently described for
tetracyclines (such as doxycycline) and the fluoroquinolones (such as ciprofloxacin and levofloxacin),
reducing consequently the therapeutic effect of these antibiotics. One should also be aware of this
interaction when these antibiotics are taken with milk or are administered -after crushing- through the
nasogastric tube. Consequently, these medicines are best taken in a fasting state.
Example = AB (quinolones and tetracyclines) → cations can result in complications by binding on the drug and
precipitate again, it will not be uptaken. So do not take with calcium, magnesium, aluminum, or iron.
Also for thyroid hormone (levothyroxine) chelation with divalent cations is described.
Bisphosphonates or strontium ranelate used in the treatment of osteoporosis and is taken simultaneously with
calcium and vitamin D3. However, bisphosphonates and strontium ranelate precipitate in the presence of
calcium, hence the intake of these drugs must be at least 2 hours before or after the intake of calcium.
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D. Metabolic enzymes and efflux mechanisms (elimination)
Both the metabolic enzymes in the intestinal wall and the P-gp efflux pump can be inhibited or
stimulated by drugs (e.g. inhibition by valspodar and elacridar) and/or nutrients, possibly altering the
bio-availability of a drug (e.g. inhibition of CYP3A4 by grapefruit juice, induction of P-gp by rifampicin).
Sometimes this is a deliberate strategy (e.g. pharmacokinetic boosting with ritonavir or cobicistat), but this
usually leads to unwanted interactions. Interactions based on inhibition or induction with drugs (e.g., azole
antimycotics, macrolide antibiotics and calcium channel blockers). Regular intake of grapefruit juice will
result in clinically relevant inhibition of CYP3A4 in the enterocyte with increased absorption of drugs.
Conversely, the intake of rifampicin or St. John's Wort will lead to induction and increased CYP3A4 and / or
P-gp expression in the intestine, resulting in a decreased absorption and bioavailability.
- To prevent the uptake of drug, e.g. Rifampicin (used for tuberculosis) =
o Enzymes can convert the drug into a metabolyt (inactive molecule). → CYP3A4 = oxidazes the drug
o Efflux pumps that can pump the drug out of the cells and back in to the lumen
E. Diseases and bariatric surgery
Achlorhydria and gastroparesis (cfr. supra), inflammatory bowel diseases (e.g. Morbus Crohn and Colitis Ulcerosa)
can severely disturb the normal absorption. Absorption of orally administered drugs, of course, is also greatly
modified and reduced in patients undergoing bariatric surgery. → The solubility in the stomach decreases because
the pH changes and the stomach lumen is greatly reduced (which greatly reduces the transit time). In addition,
the surface available for absorption in the proximal small intestine is also greatly reduced in case of bypass surgery.
Summary
The absorption of drugs at the level of the gastro-intestinal tract is determined by their solubility and permeability. Passive
transcellular diffusion is quantitatively speaking the most important mechanism for the absorption of drugs from the
gastro-intestinal tract. Since the available surface area is a crucial parameter for the uptake of drugs, the small intestine is
the most important organ in this process. For an increasing number of drugs, a modulating effect of enzymes and
transporters is demonstrated. This contributes to significant inter-individual variability in absorption and, thus, varying
exposure to orally administered drugs. The stomach may then again play an essential role in the dissolution of the drug
(role of pH). Food delays the emptying of the stomach and thus the rate of uptake, but usually food does not influence the
total amount of drug that is absorbed. Only strongly lipophilic substances can benefit from being ingested with food, since
solubility improves. For those reasons, drugs are normally taken under fasting conditions and with a sufficient
amount of water, unless indicated differently in the leaflet.
Chapter 2 = Distribution (mostly reversable)
1. Distribution volume
After absorption into the body, drugs are transported and distributed from the vascular compartment to the different
tissues (i.e. distribution) and subsequently removed from the body (i.e. elimination) = disposition. Since only the unbound
drug molecules are able to diffuse into the tissues and interact with receptors or other target molecules, only the unbound
concentration is pharmacologically active. A steady state is reached when the unbound concentrations of the drug in the
tissues and the plasma are equal, so that per time unit, an equal amount of molecules moves from the plasma to the
tissues and vice versa. Vd = Ab / Cp (dimension: liter or liter/kg) = total amount of drug in body/ in the plasma conc. Vd is
a parameter indicating how much of the drug leaves the vascular space, without indicating to which tissue or organ it
moves primarily.
The speed with which a steady state is established depends on the perfusion of the tissues and the ease with which the
drug can pass tissue barriers. If the physicochemical properties of a drug are advantageous for crossing membranes, the
distribution is limited by perfusion. If, on the other hand, permeability is the limiting factor for uptake into the tissues, the
distribution is limited by diffusion. The drug will initially spread to the best perfused organs (i.e. brain, kidneys, liver); only
afterwards will it spread to the less perfused organs (i.e. fat, bone).
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