Masaryk University
Faculty of Medicine
Selected chapters from general
pharmacology for students of general
medicine and dentistry at MF MU
doc. MVDr. Mgr. Leoš Landa, Ph.D.
doc. PharmDr. Jan Juřica, Ph.D.
Mgr. Kristýna Nosková, Ph.D.
doc. PharmDr. Ondřej Zendulka, Ph.D.
Brno 2020
Translated by doc. PharmDr. Jan Juřica, Ph.D., Mgr. Jana
Kubátová, Ph.D., doc. MVDr. Mgr. Leoš Landa, Ph.D., doc.
PharmDr. Ondřej Zendulka, Ph.D.
English language correction by Emily Shadbolt
Translation of this text was supported by grant
MUNI/FR/1234/2019
CONTENT
1. Introduction to Pharmacodynamics 1
1.1 Non-specific mechanisms of action 2
1.2 Specific mechanisms of action 5
1.2.1 Receptor mechanisms of action and receptor theory 5
1.2.1.1 Types of receptors 5
1.2.1.2 Most important ligand types 9
1.2.1.3 Interactions of receptor ligands 12
1.2.1.4 Regulation of the number of receptors and changes in their sensitivity over time 14
1.2.2 Non-receptor mechanisms of action 16
2. Basics of pharmacokinetics 21
2.2 General patterns of drug movement in the body 21
2.2.1 Physico-chemical properties of the drug 21
2.2.1.1 Molecular size and shape 21
2.2.1.2 Partition coefficient of the drug between the aqueous and lipid phases 22
2.2.1.3 Acid-base properties of the drug 22
2.2.2 Drug permeation through biological membranes 23
2.2.2.1 Simple diffusion 23
2.2.2.2 Membrane pores 23
2.2.2.3 Carrier-based transport 23
2.2.2.4 Vesicular transport 25
2.2.3 Drug binding 25
2.2.3.1 Plasma protein binding 26
2.2.3.2 Binding to blood cells 27
2.2.3.3 Binding in tissues 27
2.2.4 Tissue perfusion 27
2.3 Pharmacokinetic processes and parameters 27
2.3.1 Drug invasion 29
2.3.1.1 Drug absorption 29
2.3.1.2 Drug distribution 32
2.3.2 Drug elimination 34
2.3.2.1 Metabolism 36
2.3.2.2 Excretion 38
2.4 Plasma concentrations of a drug over time 39
2.4.1 Single dose of a drug 39
2.4.2 Repeated administration of the drug 41
2.4.3 Continuous drug delivery 42
2.5 Compartment models 43
3. Routes of drug administration and
drug dosage forms 48
3.1 A brief overview of drug dosage forms 48
3.1.1 Solid drug dosage forms 49
3.1.1.1 Powders 49
3.1.1.2 Granules 49
3.1.1.3 Tablets 50
3.1.1.4 Gelatine capsules 51
3.1.1.5 Suppositories and vaginal globules 51
3.1.1.6 Tea mixtures 51
3.1.1.7 Implants 52
3.1.2 Semi-solid drug dosage forms 52
3.1.2.1 Ointments 52
3.1.2.2 Creams 53
3.1.2.3 Gels 53
3.1.2.4 Pastes 53
3.1.2.5 Medicated patches 54
3.1.3 Liquid drug dosage forms 54
3.1.3.1 Liquid preparations for topical administration 54
3.1.3.2 Liquid preparations for peroral use 55
3.1.3.3 Drops 55
3.1.3.4 Injections and infusions 56
3.1.4 Gaseous drug dosage forms 56
3.1.4.1 Inhalants 57
3.1.4.2 Medicated foams 57
3.2 Routes of drug administration 57
3.2.1 Classification of routes of administration 57
3.2.1.1 Disruption of biological integrity (invasiveness) 58
3.2.1.2 Site of administration and type of evoked effect 58
3.2.2 Routes of administration to evoke only a local effect of a drug 61
3.2.2.1 Intraurethral and intravesical administration 61
3.2.2.2 Intracavernous administration 61
3.2.2.3 Dental and gingival administration 61
3.2.2.4 Endotracheopulmonal administration 62
3.2.2.5 Intraaural administration 62
3.2.2.6 Intraamniotic administration 62
3.2.2.7 Conjunctival administration 62
3.2.2.8 Intraocular (intravitreal) administration 63
3.2.2.9 Intrathecal administration 63
3.2.2.10 Intraarticular administration 64
3.2.2.11 Oral administration 64
3.2.3 Administration routes used for both local and systemic effect 65
3.2.3.1 Vaginal administration 65
3.2.3.2 Topical administration on skin and transdermal drug delivery 65
3.2.3.3 Intranasal administration 66
3.2.3.4 Inhalational administration 66
3.2.3.5 Transbuccal, sublingual administration 67
3.2.3.6 Rectal administration 68
3.2.3.7 Peroral (oral) administration 68
3.2.3.8 Injectional types of drug administration 72
3.3 Factors determining selection of administration routes 75
3.4 New trends in drug administration 77
4. Adverse drug reactions 79
4.1 Classification of adverse reactions by nature and
mechanism of origin 80
4.1.1 Type A adverse reactions 80
4.1.2 Type B adverse reactions 81
4.1.3 Type C adverse reactions 81
4.1.4 Type D adverse reactions 81
4.1.5 Type E adverse reactions 82
4.1.6 Type F adverse reactions 82
4.2 Classification of adverse reactions by causality evidence 82
4.3 Classification of ADR to serious / non-serious 84
4.4 Reporting of adverse reactions 84
5. Drug interactions 90
5.1 Biopharmaceutical drug interactions 93
5.2 Pharmacokinetic interactions 94
5.3 Pharmacodynamic interactions 100
5.4 Interactions of drugs and food, food supplements 103
5.4.1 Influence of pharmacokinetics of drugs 103
5.4.2 Pharmacodynamic interactions of drugs and food supplements 105
1
1. Introduction to Pharmacodynamics
Pharmacodynamics is a sub-branch of general pharmacology, which studies the
mechanisms of effects of drugs. It investigates how a drug affects an organism on
different levels and focuses not only on the therapeutic effects but the toxic effects
too. Essentially, pharmacodynamics describes “what the substance does to the body”
(in comparison, pharmacokinetics looks at “what the body does with the substance”).
The mechanism of a drug’s effect can be divided into specific and non-specific. The
basis of non-specific mechanisms of action are the physical and chemical properties
of the substance. Drugs with this mechanism affect all parts of the body into which
they were administered in the same way. With specific mechanisms of action, the
drug interacts with a particular structure in the body; frequently a receptor, enzyme,
carrier or ion channel (for example, components cell signalling).
To induce the effect of a drug, not only the pharmacological activity of the molecule
but also its concentration at the location of its action is important. This depends not
just on the amount of drug administered but also on its pharmacokinetics (see
Chapter 2. Introduction to Pharmacokinetics). Based on these factors the effect of the
drug can range from ineffective to therapeutic to toxic and at the extreme, lethal.
Sometimes even a change of concentration of the substance can lead to a change in
the character of the effect. For example, salicylic acid applied to the skin can have
effects ranging from keratoplastic (concentrations of around 1-5%) to keratolytic
(conc. 10%), but at higher concentrations induces necrosis.
To express the relationship between dose and effect, a graph known as the doseresponse
curve is used (see Fig. 1).
2
Figure 1. Relationship between dose and effect. The curve of dependence of the
dose of administered substance and its effect has (with semilogarithmic
representation) a typical sigmoid shape. (The X axis shows concentration in
logarithmic scale and the Y axis shows the effect on a linear scale). EC50 and ED50
depict the dose (concentration) required to reach 50 % of the maximum possible
effect.
1.1 Non-specific mechanisms of action
The effects induced by substances with a non-specific mechanism of action are not
limited to specific tissues or organs containing the corresponding target structure
(e.g. receptors). This is in contrast with substances with specific mechanisms of
action, which are. The effect of these substances is therefore non-selective, which
can lead to (especially with systemic administration) a host of undesirable effects and
because of this they are used primarily for local application.
Examples of non-specific mechanisms of action and their therapeutic uses:
Substances acting on the basis of their osmotic properties
These substances do not pass through the cell membrane, which nevertheless
allows the passage of water. Water moves along the concentration gradient from
areas of low concentration to areas of high concentration until the osmotic pressures
are balanced (Fick’s diffusion law). Saline laxatives such as magnesium sulfate (for
the emptying of the bowel before endoscopy) and osmotic diuretics such as mannitol
3
(for the decrease of intracranial pressure and oedema of the brain) both work in this
manner.
Substances which affect pH
Antacids: basic substances which balance protons, e.g. magnesium hydroxide,
aluminium hydroxide, sodium bicarbonate and calcium carbonate (for excessive
acidification of the stomach and mild forms of oesophageal reflux disease)
Substances which change the pH of urine-acidifying substances such as ammonium
chloride (for treatment of mmphetamine intoxication). Alkalizing substances such as
sodium bicarbonate (for treatment of intoxication by barbituates, salicylates or
tricyclic antidepressants).
Substances used to treat systemic disruption of acid-base balance - for example
sodium bicarbonate for metabolic acidosis; sodium citrate or potassium citrate for
metabolic alkalosis.
Substances acting via oxidation-reduction properties
Oxidating agents: hydrogen peroxide (3% solution for disinfection); reducing agents:
methylene blue (for treatment of methemoglobinemia). Note: methylene blue has,
apart from its oxidoreductive properties, a range of specific effects e.g. inhibition of
NO synthase and inhibition of guanylate cyclase.
Substances with a large adsorption area
Intestinal adsorbents such as Carbo adsorbens (activated charcoal) or diosmectite
(for treatment of diarrhoea) are able to bind other substances and toxins to
themselves.
Surfactants and detergents
Surfactants, or surface active agents such as carbethopendecinium bromide and
other quarternary ammonium salts are used primarily as antiseptics. By decreasing
the surface charge they disrupt the protective barrier of the microorganism’s
membrane, disturbing the internal environment leading to its death.
4
Some antibiotics (e.g. polymyxins - basic peptides) act as cationic detergents and
disrupt phospholipids in bacterial membranes.
Chelating Agents
These substances form complexes (chelates) with metals, preventing their bonding.
An example of these agents is EDTA (for the treatment of heavy metal poisoning) or
deferoxamine (for the treatment of iron overdose).
Mechanical covering of surfaces
One member of this group is sucralfate. This substance acts locally and forms a
protective layer of proteins of the necrotic tissue in an ulcerated area. The layer
formed protects the wound from the action of pepsin, stomach secretions and bile
salts (for the treatment of stomach and duodenal ulcers), but also prevents the
absorption of a range of different medications.
Ionizing radiation
For the therapy of some tumours or inflammatory diseases, it is possible to use
radionuclides (e.g. 131I or 90Y). Ionizing radiation also aids in diagnostic purposes
(18F, 11C).
Alkylating agents
Alkylating cytostatics (e.g. cisplatin, oxaliplatin, busulfan, thiotepa) are abundantly
used in the therapy of some tumour diseases. In essence, the action of these
substances is facilitated by their highly reactive alkylation properties, which change
the structure of DNA and cause a cytotoxic effect on rapidly-dividing tumour cells.
The fact that they behave non-specifically means that they will also affect
physiologically rapidly-dividing cells, manifesting as a host of typical undesirable
effects (anaemia, neutropenia, thrombocytopenia).
5
1.2 Specific Mechanisms of Action
Specific mechanisms of action are further divided according to the target structure
which they influence into
• receptor mechanisms
• non-receptor mechanisms
The word “receptor” in this instance is understood to mean a specific cell structure,
usually a protein, which participates in the transfer of the signal from outside of the
cell into the cell.
1.2.1 Receptor mechanisms of action and receptor theory
Receptors can be localised on the cell membrane (transmembrane) and in the
cytoplasm or nucleus of the cell (intracellular). Substances, which are able to bind to
receptors can be referred to as ligands. In most cases, ligands bind to a location
which endogenous (i.e. the body’s own) substances also bind to under physiological
conditions - known as orthosteric binding. In some situations, the ligand can bind to
other locations apart from those for normal ligation. In this case, we speak of
allosteric binding. This type of interaction is known as allosteric modulation, an
example of which is the binding of benzodiazepine to GABAA receptors.
Certain substances exist which can bind orthosterically and allosterically. For example, the antiemetic
palonosetron acts via the serotonin 5-HT3 receptor. Binding to a non-substrate location on the receptor
(allosteric binding) increases the ease of binding of a second molecule of palonosetron to the binding
site of serotonin (orthosteric binding). In this case we speak of an allosteric antagonist (see next
pages) with positive cooperation.
1.2.1.1 Types of receptors
Receptors are divided by their means of signal transfer into 4 basic types:
I. Ligand-gated ion channels (ionotropic receptors). Receptors of this type
facilitate in the nervous system the fastest form of synaptic transmission (in the order
of milliseconds). An example of these channels are nicotinic NM receptors of the
neuromuscular junction (for acetylcholine).
6
After the binding of the ligand, the ion channel is opened through which a stream of
ions flow from the extracellular environment to the intracellular environment. It is a
non-specific ion channel, across which Na+ and K+ ions are able to pass. After the
opening of the channel, the flow of Na+ ions into the cell is somewhat higher than the
K+ ion flow out of the cell. This is a result of the fact that the internal surface of the
membrane is, during a polarized state, negatively charged and this supports the entry
of particles with a positive charge into the cell. The influx of Na+ ions causes
depolarization of the neuromuscular junction and this causes an action potential in its
surroundings which further propagates.
II. G-protein coupled receptors (metabotropic receptors). This group includes a
large number of receptors which are well-influenced pharmacologically. The
response occurs in a matter of seconds. This group contains for example muscarinic
receptors, adrenergic receptors, serotonergic receptors, dopaminergic receptors,
opioid receptors, cannabinoid receptors, histamine receptors, prostaglandin receptors
and a whole host of others. The receptor protein is formed from a peptide chain,
which is in the shape of an α-helix and crosses the phospholipid membrane 7 times.
Transmission of the signal is facilitated by a protein, which binds guanylnucleotide
(from this point on, G-protein). This protein is found on the internal side of the cell
membrane and has 3 subunits: α, β, γ. On the α-subunit, guanosine diphosphate
(GDP) is bound during the resting state.
Upon binding of a ligand with the same character as the agonist (see following
pages) to the binding site of the receptor, the protein receptor undergoes a
conformational change which enables contact with the G-protein subunits.
Subsequently the α-subunit releases GDP and binds guanosine triphosphate (GTP).
The α-subunit with bound GTP splits from the remaining two subunits and induces a
functional change of the effector protein located in the cell membrane. The α-subunit
has GTPase activity; it removes one phosphate group from GTP, creating GDP.
Following this, the α-subunit dissociates from the effector protein and once again
binds to the subunits β and γ, by which it returns the system to the original resting
state.
7
Cell signalling facilitated by G-proteins makes use of intracellular signalling molecules
called “second messengers”. According to the type of second messenger molecule,
we are able to divide metabotropic receptors into subgroups, among which the most
important are:
• Gs: a system based on the activation of the enzyme adenylyl cyclase, which forms
the second messenger cAMP from ATP (e.g. beta-adrenergic receptors, histamine H2
receptors)
• Gq/1l: a system based on the activation of phospholipase C which breaks the
membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) into second
messengers inositol triphosphate (IP3) and diacylglycerol (DAG) (e.g. α1 adrenergic
receptors and histamine H1 receptors)
• Gi/o: a system which includes the inhibition of adenylyl cyclase resulting in the
decrease of cAMP levels in the cell (e.g. muscarinic M2 receptors or opioid μ
receptors).
Receptors with tyrosine kinase activity (receptors with enzymatic activity).
Note: In the last few years these receptors have become the target of a range of antitumor drugs
which work by the suppression of activation of proliferation in many haematological malignancies.
These drugs include imatinib, sunitinic, dabrafenic, trametinib, dasatinib, vemurafenib, ponatinib and
many more.
Endogenous ligands of these receptors are in most cases hormones, cytokines and
growth factors of protein nature. An example of these receptors is the insulin receptor
or the receptor for vascular endothelial growth factor VEGF. The speed of signal
transmission is in the order of minutes.
The insulin receptor is composed of two α and two β subunits, which are connected
by a disulphide bond. Α-subunits are located extracellularly and carry a binding site
for insulin. The phosphorylation of tyrosine on the intracellular part of the receptor
causes activation of the intracellular signalling cascade. Upon the binding of insulin, a
conformational change in the intracellular β-subunit is induced which initiates tyrosine
8
kinase activity. Tyrosine kinase transfers phosphate groups onto tyrosine in some
proteins, which change their functional state. Subsequently, the enzyme catalyses
the phosphorylation of the β-subunits and this increases the enzyme activity. In this
way, insulin stimulates the transport proteins in the membrane of the cell (e.g.
transport proteins for glucose).
Receptors which regulate the transcription of DNA (cytoplasmic and nuclear
receptors). These receptors, in contrast with the aforementioned types, are found
intracellularly. They bind to substances which have the ability to cross the cell
membrane (e.g. steroids or thyroid hormones). The biological response to the
stimulation of these receptors manifests with a latency of hours to days.
After binding of the ligand to the receptor a complex forms, which acts as a
transcription factor and can stimulate or inhibit the expression of genes, depending
on the corresponding gene. Changes in the expression of genes result in changes of
mRNA (transcription) for the synthesis of proteins by ribosomes (translation). For the
manifestation of an effect, two complexes of ligand and receptor (dimers) must form.
Receptors on the presynaptic terminal can be, from the point of view of sensitivity to mediators of
various origins, classified as heteroreceptors and autoreceptors. Heteroreceptors regulate the
synthesis and/or release of mediators of other ligands than their own. They are receptors which
correspond to synapses in the nervous tissue, neuromodulators or neurohormones released from
neighbouring neurons or cells. An example of such receptors are GABAergic inhibitory receptors or
5HT2A or 5HT2C receptors, which suppress the release of dopamine and noradrenaline in specific
regions of the CNS. In contrast to heteroreceptors are autoreceptors, which are sensitive only to
neurotransmitters or hormones released by cells attached to their cell membrane. Autoreceptors serve
to transmit the signal as part of a feedback mechanism (usually negative). For example, the
presynaptic neuron releases into the synaptic cleft noradrenaline. Noradrenaline acts on the
postsynaptic adrenergic receptors, and also the α2 autoreceptors localized presynaptically. Activation
of these autoreceptors causes, by negative feedback mechanisms, the inhibition of further
noradrenaline release. In a different example, the release of acetylcholine from presynaptic terminals
of the parasympathetic system. Acetylcholine binds to the presynaptic muscarinic M2 receptors and
inhibits, by negative feedback, its further release. 5HT1A presynaptic receptors behave similarly.
9
1.2.1.2 Most important ligand types
For the sake of repetition: ligands are characterized as substances which bind to
receptors. Every ligand has two basic properties - affinity and intrinsic activity
(efficacy - E). Affinity defines the ability of the substance to bind to a receptor.
Intrinsic activity describes the ability of the ligand to activate the receptor - i.e. induce
the transmission of a signal.
According to the differences in intrinsic activity we are able to define the following
types of ligands (Fig. 2 and 4):
Figure 2. Ligands separated by their intrinsic activity (E). This example shows a
ligand-gated ion channel.
Agonists (full agonist): have the maximal possible intrinsic activity and following
their binding to a receptor, induce the maximal possible transmission of a signal.
Intrinsic activity is of order 1 (100%). We can categorize most endogenous ligands as
full agonists. Examples of drugs in this group include fentanyl (full agonist of opioid μ
receptors) and adrenaline or noradrenaline (full agonists of β2-adrenergic receptors).
Partial agonists (dualists:) bind to receptors but do not cause the maximal
transmission of the signal. Intrinsic activity of these ligands lies in the range of 0-1
(0%-100%). When not in the presence of full agonists, dualists act as agonists - i.e.
activate the receptor. In the presence of full agonists however, they behave as
10
antagonists. This is because they do not allow the full agonist to exert its (100%)
intrinsic activity. An example of this type of ligand is the partial agonist of nicotinic
receptors (subunits α4β2) vareniklin, which is used to help quit smoking. The effect of
partial agonists is schematically depicted by curve B in Figure 3.
Antagonists: have an intrinsic activity of 0 (0%). When they bind to a receptor, they
prevent the binding of endogenous ligands, and therefore the transmission of a
signal. An example of an antagonist is the parasympatholytic atropine which blocks M
receptors, or the drug naloxone which blocks the effects of morphine on opioid
receptors.
Inverse agonists: Specific parts of a signal may be transmitted by a receptor, even
though an agonist is not bound to it (for example, a partially opened ion channel
through which a small number of ions are able to pass through). In such a case, we
speak of the resting activity of a receptor, which does not change after the binding of
an antagonist. Ligands do however exist which have a negative intrinsic activity. They
are known as inverse agonists and their binding to a receptor leads to decrease of
resting activity (i.e. the receptor goes from a resting state to an inactive state). In
recent times a large number of drugs which were known as antagonists have been
found to actually be inverse agonists (e.g. H1 and H2 antihistamines).
11
Figure 3. The difference in affinities of substances. Curves A and C depict the effects
of full agonists with different affinities to the same receptor, while curve B shows the
effect of a partial agonist on the same receptor. Differences in the affinity of these
substances can be determined by comparison of the concentrations which are able to
produce half the maximal effect (EC50). The lower EC50 is, the higher the affinity of
the substance to the given receptor. This means that the affinity of these substances
can be described in this order: C<B<A.
Figure 4. Comparison of ligands according to their abilities to activate a receptor and
induce a cell response. Full agonists in a sufficient concentration induce the maximal
possible response of the organism, which is not able to be increased by further
increases in concentration (the receptor is activated 100%). Partial agonists at certain
concentration are able to reach their maximum effect, this maximum is however less
than the maximum of full agonists. Antagonists induce zero effect, respectively
preventing agonists from inducing their effect (the receptor stays in a resting activity
state). Inverse agonists suppress even this resting (physiological) activity.
12
1.2.1.3 Interactions of receptor ligands
If, nearby to the receptor, ligands are present which differ in their intrinsic activity, this
will affect the transmission of the signal to the receptor. In the body there are
practically always natural (endogenous) full agonists in the vicinity of the receptor.
Administered drugs may also have agonist behaviour and in such cases their effect
and the effect of the endogenous agonists is combined - known as additive effect.
In cases where the administered drug behaves as a partial agonist or antagonist, an
antagonistic reaction will result. The reason for this is that the intrinsic activity of
these ligands is, in comparison with the full agonist, lower and therefore the
stimulation of the receptor will also be lower than if only the full agonist was to bind to
the receptors in question (e.g. endogenous ligands).
Speaking generally about the possible effects of drugs (medicaments) and not just with a view to the
receptor mechanism of the effect, we could define their combined effect as synergy and antagonism.
Synergy can be further subdivided into summation and potentiation. In an example of summation, if
the effect of drug A is for example 50 % and the effect of drug B is also 50 % then their combined
administration would result in effect C of 100 % (C = A + B). In the example of potentiation where drug
A would have an effect of 20 % and drug B would have an effect of 40 %, the resulting effect C when
they are administered together would be 100 % (C > A + B). Antagonism in this example would mean
a reverse effect (the effect is weakened or suppressed).
The character of antagonistic interactions is dependent on many factors in the case
of receptor mechanisms of action of two substances. If both ligands bind to the same
binding site on the receptor, it is known as competitive antagonism (see Fig. 5).
Substances compete for this binding site and are able to mutually displace each
other. The resulting effect is then given by the affinity and the concentration of the
ligands in proximity to the receptor. This can be described by the following
relationship, in which the higher the affinity to the receptor and the higher the
concentration of the substance in the vicinity of the receptor, the higher the likelihood
that the ligand will occupy the receptor binding site. This means that if we increase
the concentration of the agonist we can decrease or even eliminate the effect of the
antagonist, because the antagonist will be displaced from the receptor (or vice
versa).
13
Figure 5. Competitive antagonism. This figure shows the interaction between full
agonists and competitive antagonists. Curve A describes the effect of the full agonist
without the presence of the antagonist. Curve B and C then show the interactions
between agonist and competitive antagonist where the competitive antagonist is at a
lower (B) or higher (C) concentration. With increasing concentration of competitive
antagonist, increase in concentration of agonist is also required to produce the same
effect (curve moves to the right).
If the antagonist binds to the receptor allosterically (at a different location than that of
the normal ligand) or irreversibly, this would be known as non-competitive
antagonism. It is not possible to displace such a substance from the place of its
binding and even increased concentration of agonist will not result in stimulation of
the receptor (Fig. 6).
In the case of two ligands, one of which is a partial agonist, the result would depend
on the character of the other ligand. In the interaction of a partial agonist and a full
agonist, the partial agonist in this instance would behave as an antagonist. If the
second ligand is however an antagonist, then the partial agonist will behave as an
agonist. This is the reason why partial antagonists are also called “dualists”.
14
Figure 6. Non-competitive antagonism. This figure depicts the interaction between
full agonists and non-competitive antagonists. With increasing concentration of
antagonist, the effect of the agonist decreases regardless of concentration
(downward shift of the curve of the agonist).
Competitive and non-competitive antagonism represent so called pharmacological types of
antagonism. Apart from the type of antagonism at the level of the receptor, in pharmacology we can
also describe more general forms such as chemical antagonism, pharmacokinetic antagonism and
physiological antagonism. An example of chemical antagonism can be a situation where a solution
contains two substances, one of which weakens the effect of the other (chelator dimercaprol binds to
heavy metals and decreases their toxicity, infliximab has an anti-inflammatory effect due to its abilities
to inhibit inflammatory cytokine TNF). In pharmacokinetic antagonism, the “antagonist” decreases the
concentration of active substance in the location of its action (e.g. decreasing the anticoagulative
effect of warfarin by the administration of phenytoin, which speeds up its metabolism in the liver). In
physiological antagonism, two differing ligands work simultaneously on differing target structures, and
their converse effects manifest in the organ (e.g. histamine causes bronchoconstriction in the lungs via
H1 receptors, while salbutamol causes bronchodilation via adrenergic β2 receptors in the lungs.
Histamine acts on the H2 receptors of the parietal cells in the mucosa of the stomach and stimulates
the secretion of acid, whilst omeprazol blocks this effect by inhibition of the proton pumps).
1.2.1.4 Regulation of the number of receptors and changes in their sensitivity
over time
The number of receptors and their sensitivity to ligands is not constant, but changes
over time depending on the current state of the effector cells, which serve as one of
the mechanisms for maintaining homeostasis. The organism is able to react to
activation or inhibition of receptors in two ways with differing time courses. The acute
effect is comprised of desensitisation of receptors and the long-term effect of
15
agonistic or antagonistic stimulation is a change in the number of receptors. If an
excessive stimulation of receptors occurs it attempts to protect the effector cells by
decreasing the number of receptors or their sensitivity to ligands (and vice versa).
Regulation of the number of receptors
If receptors are excessively stimulated a decrease in their number results, known as
down-regulation. The process of decreasing the number of receptors is facilitated
by their internalization into the cell, where they are not accessible to their ligands or
by the decrease in their genetic expression and therefore de novo production; these
processes are also able to combine. In clinical practice this manifests after long-term
administration of medications which behave as agonists. An example of this is
sanorinism, which occurs after the administration of decongestive substances from
the α1 sympathomimetic group, or alternatively chronic administration of opioid
analgesics. The clinical expression of down-regulation is a decrease in the effects of
the administered medications.
The opposite situation is an increase in the number of receptors presented on
membranes which occurs after the administration of antagonists, known as upregulation.
In up-regulation the cell reacts to insufficient stimulation by physiological
ligands by increasing the number of receptors. Similarly to down-regulation this may
also run the risk of changing the efficacy of the medication. A different problem can
occur with the sudden cessation of intake of a drug. In this case there is now an
abnormally increased number of receptors to which the physiological ligands of the
body may bind producing an excessive response by cells or tissues to these
endogenous stimuli. This is known as rebound phenomenon. A typical example of
rebound phenomenon is tachycardia and hypertension after a sudden withdrawal of
β1 receptor antagonists (beta-blockers) without internal sympathomimetic activity.
Desensitization of receptors
If, after administering the same dose of a drug, we do not induce the same level of
response from receptors as with the previous dose, we classify this as
desensitization of receptors. Mechanisms of desensitization are different in
dependence on its type. With long-term administration of agonists, resulting chronic
stimulation leads to dissociation of the G-proteins from metabotropic receptors, which
16
causes an inability of the activated receptor to transmit the signal. Similarly to downregulation,
this mechanism occurs during the development of tolerance to the effects
of opioid analgesics. This phenomenon has also been described in nicotinic or
(glutamatergic) NMDA receptors. If desensitization occurs within minutes to hours
after the administration of the substance, this is known as tachyphylaxis. In this
situation the cause may be the depletion of the substrates of the signalling cascade
which, under physiological conditions, is not stimulated continuous way. For example,
after the administration of amphetamine an increased release of catecholamines from
the presynaptic terminals takes place which is so quick and intensive that it outpaces
the neuron’s ability to synthesize new catecholamines and create new vesicles. In
this way the stores of neurotransmitters are depleted. If we therefore administer
amphetamines a short time after the previous dose, no psychostimulatory effect will
usually occur. The most common cause of development of desensitization in clinical
practice is the long-term and regular administration of agonists of a given receptor
(e.g. β2 sympathomimetics in therapy of asthma or α1 sympathomimetics in
decongestant nasal drops). It is possible to overcome this (if the state of the patient
allows it) by administration of the drug in an interrupted manner, e.g. administration of
β2 mimetics only during an asthma attack. Note: Some authors class desensitization
and tachyphylaxis as synonyms, however desensitization occurs after a long-term
administration of the ligands, whereas tachyphylaxis occurs quickly and after each
individual administration, within several hours.
1.2.2 Non-receptor mechanisms of action
I. Influencing of ion channels
Ion channels are gates in the cell membrane which selectively allow the passage of
individual ions, and in which it is possible to induce opening and closing by a whole
host of mechanisms. Two important types are ligand-gated ion channels and voltagegated
ion channels. Ligand-gated ion channels are opened only by the binding of one
or more molecules of an agonist, and are more correctly classified as receptors (see
above) for the reason that for their activation the binding of an agonist is required.
Voltage-gated ion channels are controlled by changes in the transmembrane
potential.
17
The functions of both can generally be affected by medications via several
mechanisms:
• Binding onto the protein structure of the channel, either to the binding site of the
physiological ligand (orthosteric) or to a different (allosteric) site, or in a simpler case
(e.g. the mechanism of local anesthetics on voltage-gated sodium channels) the
molecule physically blocks the channel and prevents the passage of ions.
• Altering the level of expression of the ion channel on the surface of the cell. For
example, the antiepileptic gabapentin decreases the embedding of neuronal calcium
channels into the plasma membrane.
• Activating the opening of the ion channel - levosimendan (apart from its binding to
troponin causing increased sensitivity to calcium) opens ATP-sensitive K+ channels in
blood vessels (vasodilatory effect).
Other examples include calcium channel blockers (nifedipin, isradipin - treatment of
hypertension) or potassium channel blockers (fampridine - treatment of multiple
sclerosis, flupirtin - treatment of pain, oral antidiabetics - treatment of type 2
diabetes).
II. Control of enzymes
Many medications act via the control of enzymes. Often, the medication is a
substrate analogue, which behaves as a competitive inhibitor of the enzyme (e.g.
antihypertensive kaptopril, affecting angiotensin converting enzyme); but in other
cases, the binding is irreversible and non-competitive (e.g. acetylsalicylic acid which
blocks cyclooxygenase 1). Medications can also behave as false substrates, where
the molecule of substance undergoes a chemical transformation and forms an
abnormal product, which disrupts the normal metabolic pathway. An example of this
effect is the cytostatic fluorouracil, which replaces uracil as an intermediate product in
the synthesis of purine, therefore inhibiting thymidylate synthetase by which it blocks
the synthesis of DNA and prevents cell division.
It is also necessary to mention that some medicaments use enzymatic degradation
as a means of changing themselves from an inactive form (prodrug) to an active form
18
(e.g. enalapril is transformed via esterases to enalaprilat, which is an inhibitor of
angiotensin converting enzyme).
The result of this transformation by enzymatic activity can also affect the toxicity of
the medication (changing molecules of medication into a reactive metabolite).
Paracetamol, respectively its metabolite NAPQI (N-acetyl p-benzoquinoneimine)
causes in this way damage to the liver in this way. If this affects the effect of the drug
it is classed as an unwanted side-effect with great clinical significance.
Further examples of therapeutic uses of enzyme inhibition: reversible inhibition of
acetylcholinesterase (pyridostigmine - treatment of myasthenia gravis), reversible
inhibition of phosphodiesterase (methylxanthine - treatment of asthma, sildenafil PDE
V - treatment of erectile dysfunction, amrinone, milrinone iPDEIII - cardiotonicity),
reversible inhibition of monoaminoxidase A (moclobemide - antidepressant),
irreversible inhibition of monoamine oxidase B (selegiline – antiparkinson drug),
irreversible inhibition of aldehyde dehydrogenase (disulfiram - treatment of alcohol
addiction).
III. Control of transport systems
Transport of ions and small organic molecules across cell membranes is generally
facilitated either via channels (see above) or with the help of transport proteins,
because transported molecules are often too polar (i.e. insufficiently liposoluble) to be
able to cross the lipid membrane independently. There are many such transporters
known, but examples with special pharmacological importance are, for instance, the
transporters for the transport of ions and many organic molecules across the kidney
tubules, intestinal epithelium and the blood brain barrier, transport of Na+ and Ca+ out
of the cell, uptake of transmitter precursors (such as choline) or transmitters of such
molecules (such as amines and amino acids) at nerve endings and transport
molecules of medications and their metabolites across membranes and epithelial
barriers.
In many cases the energy required for the transport of substances against their
electrochemical gradient is obtained by the hydrolysis of ATP. Such transport
proteins have a separate binding site for ATP known as the ABC (ATP-binding
19
cassette) proteins. Important examples include sodium pumps (Na+/K+ ATPase) and
transporters of multiple drug resistance (MDR), which pump out cytostatic drugs from
tumour and microbial cells, which causes resistance to these medications.
Na+/K+ ATPase is the target structure for digoxin (treatment for heart failure). It is
located in the cell membrane of cardiomyocytes and its blockade has positive
inotropic effects.
If the transport of the molecule connected to the transport of the ion (often Na+)
occurs in the same direction we designate this as a symport, and if the transport
occurs in the opposite direction then we call this an antiport.
Transport proteins contain a recognition site, which marks them as specific for a
transported agent/molecule, and these recognition sites can also be the target for
medications whose effect is to block this transport system.
As an example, the control of a transport mechanism can be achieved by fluoxetine antidepressant
of the SSRI class (Selective serotonin reuptake inhibitors), which
blocks serotonin transporters and in doing so prevents the reuptake of serotonin to
the cell from which it was released. Tricyclic antidepressants behave similarly,
although nonspecific for more transporter systems (5-HT, NA, DA).
Another example of inhibition of transport systems, in this case of lipids, is lomitapide,
inhibitor of microsomal transfer proteins (MTP, of intracellular proteins, transporter of
lipids between membranes in the lumen of the endoplasmic reticulum) or ezetimibe,
which is the inhibitor of intestinal transporter Niemann-Pick C1-Like 1, which
transports sterols.
IV. Other mechanisms
• Inhibition of the formation of tubulin chains of colchicine prevents the formation and
repair of the cytoskeleton, which prevents cell division.
• Alkylating or intercalating cytostatics affect DNA transcription.
20
• Control of the immune response, specifically of certain pathways (filgrastim,
erythropoietin, IFN, glatiramer acetate - RS).
• α-dornase cleaves extracellular DNA (used in patients with cystic fibrosis).
Literature
Informační systém léčivých přípravků (AISLP), stav k 1. 4. 2018.
Hakl, M., Ševčík, P. Transdermální fentanyly na českém trhu. Remedia 2007, 17,
390-393.
Katritch, V., Reynolds, K.A., Cherezov, V., Hanson, M.A., Roth, C.B., Yeager, M.,
Abagyan, R. Analysis of Full and partial agonists binding to β2-adrenergic receptor
suggests a role of transmembrane helix V in agonist-specific conformational
changes. Journal of Molecular Recognition 22, 2009, 307-318.
Lüllmann, H., Mohr, K., Wehling, M. Farmakologie a toxikologie. Překlad 15. zcela
přepracovaného vydání, Grada, Praha, 2004.
Máchalová, A., Babinská, Z., Juřica, J., Dovrtělová, G., Kostková, H., Landa, L.,
Merhautová, J., Nosková, K., Štark, T., Tabiová, K., Pistovčáková, J., Zendulka, O.
Farmakologie pro studenty bakalářských oborů na LF MU. 2016.
Martínková, J., Chládek, J., Mičuda, S., Cermanová, J., Grim, J. Obecná
farmakologie jako základ studia farmakologie experimentální a klinické. Lékařská
fakulta v Hradci Králové, 2001.
Martínková, J. a kol. Farmakologie: pro studenty zdravotnických oborů. Grada,
Praha, 2007.
Slíva J., Votava M. Farmakologie. Triton, Praha, Kroměříž, 2010.
Tomíška, M. Antiemetická profylaxe chemoterapií indukované nevolnosti a zvracení.
Remedia 21, 2011, 441-447.
21
2. Basics of pharmacokinetics
Pharmacokinetics is part of general pharmacology which describes the fate of a drug
in an organism from its administration to its excretion. It describes four basic
pharmacokinetic processes that the drug undergoes from its administration to the
patient – absorption, distribution, metabolism, and excretion – both qualitatively, and
quantitatively. Knowledge of the pharmacokinetics of an individual drug is as
essential for the clinical practice as its mechanism of action. Based on the
pharmacokinetic parameters of the drug, we can set a patient's dosing regimen
properly. If we know what is happening to the drug after its administration, we can
predict how the effect of the substance changes due to comorbidities or concomitant
drugs, and by adjusting the dosing regimen, we can prevent complications such as
ineffectiveness or risk of toxicity.
2.2 General patterns of drug movement in the body
How the drug overcomes the biomembranes that form natural barriers between parts
of the body is essential for all pharmacokinetic processes. To a large extent, it is
possible to estimate the pharmacokinetic properties of a substance on the grounds of
generally applicable principles of the movement of molecules in the body. These
principles are dependent mainly on the following factors:
2.2.1. Physico-chemical properties of the drug
The fate of the drug in the body is mostly dependent on its physico-chemical
properties, particularly the size and shape of the molecule, the partition coefficient
between the aqueous (polar) and lipid (non-polar) phases, and the acid-base
properties.
2.2.1.1 Molecular size and shape
Generally, smaller molecules pass through the biomembranes easier. Most of the
therapeutically used drugs have a molecular weight 100−1000 Da. Clinically used
drugs with the lowest molecular weight include, for example, lithium (7 Da). In
contrast, high molecular weight drugs, such as monoclonal antibodies (up to 150 000
Da), penetrate the biomembranes slowly or not at all. The influence of molecular
22
weight must be considered by choosing a proper route of administration or
formulation of an advanced dosage form (see Chapter 3 - Routes of drug
administration and drug dosage forms).
2.2.1.2 Partition coefficient of the drug between the aqueous and lipid phases
The partition coefficient value indicates the ratio at which the drug is distributed
between the lipid membrane bilayer and the aqueous phase. Drugs that are more
soluble in fats diffuse better through biomembranes. The partition ratio is determined
experimentally in the octanol−water system.
2.2.1.3 Acid-base properties of the drug
Most drugs are electrolytes, i.e., they dissociate in the aqueous environment of the
organism, and act as weak acids or weak bases depending on the pH of the
environment and the dissociation constant of the molecule (pKa). The HendersonHasselbach
equation expresses the relationship between pH, pKa and the ratio of
dissociated and undissociated fractions:
AH
ka
↔ A−
+ H+
pka = pH + log (
[AH]
[A−]
)
B + H+
ka
↔ BH+
pka = pH + log (
[BH+]
[B]
)
The dissociated (charged) form of the molecule is hydrophilic and does not cross
non-polar membranes. In contrast, the non-dissociated (non-charged) form is more
lipid-soluble, and therefore can readily permeate through a phospholipid bilayer.
From the equations mentioned above, it is possible to infer that in the acidic
environment drugs acting as weak acids penetrate the biomembranes easier and in
the basic environment, substances of basic character penetrate easier.
Example: Ibuprofen is a weak acid (pKa = 4.9), and its dissociation is suppressed in
the acidic environment of the stomach. As most of its molecules in the stomach are
non-dissociated (not charged), the absorption of ibuprofen by passive diffusion
begins there. On the contrary, phenytoin is a weak base (pKa = 8.3). In the stomach,
a larger percentage of the drug is dissociated and charged. Thus, phenytoin
23
molecules cannot pass through the stomach wall by simple diffusion. The situation
changes after the drug passes into a more alkaline environment of the intestine. A
higher percentage of drug molecules are not dissociated there and can be absorbed.
2.2.2 Drug permeation through biological membranes
2.2.2.1 Simple diffusion
Simple diffusion is quantitatively the most important transport mechanism for drugs. It
is a non-saturable process for which Fick's laws apply. The rate of transfer is directly
proportional to the concentration difference of the drug on both sides of the
membrane (the higher the concentration difference, the faster the diffusion). Other
factors that affect diffusion rates are the thickness of the membrane and the surface
through which the molecule diffuses. The drug must be lipophilic (to some extent) to
cross the phospholipid barrier. Simple diffusion of substances with a larger molecule
or charge is quite difficult.
2.2.2.2 Membrane pores
The passage through membrane pores is determined by the size of a drug molecule
and its water-solubility. Molecules larger than the pore diameter cannot penetrate, as
well as water-insoluble drugs (pores are filled with the aqueous environment). Drugs
pass through the pores in two ways. Firstly, by simple diffusion of the substance
through the pore downstream the concentration gradient. Secondly, by filtration,
which means the solute passes through the pore with the solvent based on
differences in hydrostatic and osmotic pressure on both sides of the membrane.
Filtration is not a typical process in pharmacology. Example of this transport is the
excretion of a drug by renal glomeruli. Under physiological conditions, the limit for
permeation through glomerular filtration is a molecular weight up to 60−70 kDa.
2.2.2.3 Carrier-based transport
Facilitated diffusion
In contrast to simple diffusion, a membrane protein which mediates substance
transfer is involved in facilitated diffusion. A common feature with simple diffusion is
no energy consumption and the alignment with the direction of the concentration
gradient. Organic cation transporters (OCTs) belonging to the solute carrier family
24
(SLC transporters) are an example. They are involved in drug transport in the renal
tubules, hepatocytes, and blood-brain barrier, and their substrates include, for
example, some antiviral drugs (lamivudine, acyclovir), cytostatics (paclitaxel,
oxaliplatin), and antidiabetics (metformin). Since the carrier protein has a specific
capacity, this transfer method is, in contrast to simple diffusion, saturable and its
capacity is determined by the concentration of carrier molecules in the membrane.
After reaching a maximum, the speed of transport can no longer be increased.
Furthermore, substrate specificity and the possibility of competition or inhibition (e.g.,
omeprazole inhibits OCT) are typical for this transport.
Active transport
This mode of transport usually takes place against a concentration gradient, and
therefore, it requires the supply of energy in the form of ATP. The carrier membrane
protein, substrate specificity, saturation, and the possibility of its inhibition are
features shared with the facilitated diffusion. Examples of active transport from
human physiology are tubular glucose reabsorption or a sodium pump.
There are several important drug carrier proteins. Two major groups are ABC
proteins (ATP-binding cassette protein) and SLC transporters. Of the ABC group, Pglycoprotein
(permeability glycoprotein) is the most important. It is a transmembrane
pump that is coded by the MDR1 gene (multidrug resistance). It can be found in
many tissues and organs where it physiologically performs a barrier and excretion
function. From the pharmacological point of view, its ability to interfere with the
pharmacokinetics of some drugs and to significantly influence their effects is
particularly important. In enterocytes, P-glycoprotein can reduce the bioavailability of
drugs. In proximal renal tubule cells or hepatic canaliculi, it can increase drug
elimination. P-glycoprotein can also be found in tumours, and its overexpression is
the cause of resistance to cytostatics. Many drugs inhibit P-glycoprotein, which can
lead to clinically severe drug interactions. An example is an increase in digoxin
plasma concentrations when combined with clarithromycin. Digoxin is a substrate of
P-glycoprotein and clarithromycin is its inhibitor. This drug interaction results in
increased digoxin bioavailability and reduced excretion.
Beside OCTs, which utilise facilitated diffusion, the SLC protein family also includes
organic anion transporters (OAT), which use ATP for transport. OATs are part of the
25
secretory system in the kidneys and play an essential role in the excretion of drugs
with weak acid properties. Competition for these proteins may slow the excretion. An
example of this effect is the concomitant administration of penicillins or some of the
antiviral drugs and probenecid, OAT inhibitor, which prolongs the half-life of these
antimicrobial agents. Other examples of carrier proteins are MATE - 1 and MATE -
2K transporters (multidrug and toxin extrusion protein) responsible for the secretion
of organic cations and zwitterions into bile and urine. These transporters are also an
example of the so-called secondary active transport, where the transfer through the
membrane uses the energy of the primary membrane gradient of other ions.
2.2.2.4 Vesicular transport
From the pharmacological point of view, there are two most important types of
vesicular transport:
1. Fluid endocytosis – drug-containing fluid is taken up by a cell;
2. Receptor-mediated endocytosis – active endocytosis mediated by the
megalin (LRP2 protein) system is an example. Megalin is a receptor present
on the apical membrane of epithelial cells of renal tubules or in the placental
and small intestine epithelium. It mediates the entry of many endogenous and
exogenous proteins, larger peptides, and some drugs into cells. For instance,
nephrotoxicity of aminoglycosides is caused by the reabsorption and
accumulation of these antibiotics in the proximal tubular cells by megalin.
Generally, large molecules such as monoclonal antibodies are transported by
vesicular transport, as well.
2.2.3 Drug binding
Drugs in the body are present not only in a free form but to some extent also as
bound. The nature of the binding may be either depot, where the bound substance
does not produce any effect on the structure, or it may be a pharmacodynamically
active binding, where the substance induces a change in the state of the target
structure, and consequently a pharmacological effect. The level of drug binding is
determined in vitro and knowledge of this parameter is very important because it
affects the pharmacokinetics (depot binding) and pharmacodynamics (active binding)
of the drug. Drug binding can be characterised by the ratio of the bound and free
fraction, the strength of the binding, and the number of binding sites. The affinity of
26
depot binding sites for substances is generally lower than that of active sites. On the
other hand, depot binding sites are present in a higher number, and thus can bind a
large amount of the drug.
We distinguish the following types of binding:
2.2.3.1. Plasma protein binding
According to the affinity for specific ligands, we distinguish specific and non-specific
plasma proteins. Specific include, e. g., binding proteins for thyroxine, cortisol, and
sex hormones, with high affinity for these substances. Three types of proteins are
non-specific and essential for drug binding: albumin, glycoproteins, and globulins.
Albumin is the most abundant plasma protein of 68 000 Da. It has an exceptional
binding capacity and binds a wide range of different drugs. It can bind weak acids (e.
g., warfarin, non-steroidal anti-inflammatory drugs, sulphonamides, penicillins),
lipophilic drugs (e. g., cyclosporin A, acitretin), basic drugs (benzodiazepines), neutral
drugs, as well as anions.
The most important of the glycoproteins is the α1-acid glycoprotein (orosomucoid)
with a molecular weight of 41 100 Da. Although it has a much lower concentration in
plasma than albumin, it is an important binding protein for some drugs. It is also an
acute-phase protein that increases in some pathological conditions. It is mainly
associated with binding of weak bases and cations (e. g., verapamil, dipyridamole,
vincristine, imatinib, beta-blockers, digoxin).
Globulins are a wide group of proteins with molecular weight about 150 000 Da.
Lipoproteins that bind lipophilic drugs (e. g., nystatin, amphotericin B, glucocorticoids)
also belong to this group.
Plasma protein binding is rapid and reversible. If the free drug concentration in the
plasma decreases due to metabolism or excretion, the appropriate proportion of the
substance is released from the plasma protein binding, and equilibrium is restored.
When two different drugs have an affinity for the same binding site, competition
occurs, and one drug may force out the other. This pharmacokinetic interaction
increases the plasma free fraction of the drug that has been forced out. The drug is
then available for further distribution in the body or binding to receptors. This
27
interaction can lead to an increase of pharmacological effect or even trigger
intoxication.
2.2.3.2. Binding to blood cells
Binding of the drug to blood cells is not as crucial as plasma protein binding.
Examples of drugs that bind to blood cells are methotrexate (erythrocytes) or heparin
(platelets). Binding of heparin together with cytokine PF4 (platelet factor 4) to
platelets can lead to antibody production. Antibodies against the complex of heparin
and PF4 induce peripheral platelet thrombus formation (heparin-induced
thrombocytopenia type II).
2.2.3.3 Binding in tissues
This type of binding is drug-specific. An example is the binding of tetracyclines to
hydroxyapatite in teeth and bones. Intensive binding of a drug in tissues results in a
decrease of drug plasma level, although the substance is not yet eliminated.
2.2.4 Tissue perfusion
One of the factors determining how quickly a drug is distributed to a given tissue or
organ is the rate of blood flow. Drugs reach the tissues with abundant blood supply
(brain, kidney, liver, heart) faster and in higher concentrations. On the other hand, the
drug is eliminated more rapidly from these tissues. In the case of poorly perfused
tissues, the situation is inverse. The drug reaches them more slowly, and the
elimination is slow (e. g., adipose tissue). In some cases, especially with lipophilic
drugs (e. g., general anaesthetics), drug accumulation can occur.
2.3 Pharmacokinetic processes and parameters
We distinguish four basic pharmacokinetic processes: absorption, distribution,
metabolism, and excretion. The processes of absorption and distribution together
are called the phase of drug invasion into the organism. The processes of
metabolism and excretion are called the phase of drug elimination.
The individual processes are described by pharmacokinetic parameters which divide
into primary and secondary. The primary parameters change when changes in the
28
physiological variables (blood flow, plasma protein content, glomerular filtration)
occur. They include:
clearance (Cl)
distribution volume (Vd)
Secondary parameters depend on the primary parameters and include:
maximum plasma concentration (cmax)
time at which cmax (tmax) is reached
biological elimination half-life (t1/2),
area under the curve (AUC)
drug bioavailability (F)
absorption constant (ka)
elimination constant (ke)
Diagram of plasma concentrations (y-axis) versus time (x-axis) is usually used to
represent pharmacokinetic events and parameters (Fig. 7).
Figure 7. Diagram of plasma concentrations of a drug versus time after extravascular
drug administration
29
2.3.1 Drug invasion
2.3.1.1 Drug absorption
Absorption is required to achieve a systemic effect of the drug. It does not apply only
in case of the intravascular route of administration, as the entire dose of a drug is
administered directly to the systemic circulation. Conversely, for drugs with a local
effect absorption is undesirable because it reduces the concentration of the drug at
the site of administration, and thus its efficacy and duration of action. Besides,
systemic absorption of drugs with local effect possess a risk of systemic adverse
effects.
It is important to know at what rate absorption is occurring and how much of the
administered drug is absorbed at all. Pharmacokinetic parameters tmax and cmax
describe the rate of absorption. The tmax value expresses the time required to reach
the maximum plasma concentration (cmax) of the drug after a single administration.
The lower the tmax value, the faster the absorption is. In the case of i.v. administration,
the tmax value is 0 because the maximum plasma concentration is reached at the time
of administration.
The extent of absorption is described by a parameter called drug bioavailability (F).
Bioavailability is the ratio between the amount of drug that enters the systemic
circulation (and is available to induce a systemic effect) and the total dose
administered. It reaches 0 to 100% (or 0-1). After the intravascular administration, F
is always 100%. For other types of administration, F depends on several different
factors and reaches 0-100%, as was already mentioned. Bioavailability of a drug is
frequently expressed by the area under the curve of its plasma concentration
(AUC) (Fig. 8).
30
Figure 8. AUC – Area under the curve of plasma drug concentration
We distinguish absolute and relative drug bioavailability. Absolute bioavailability
meets the general definition of bioavailability and indicates the actual amount of drug
available in the body to induce an effect. For intravascular administration, it always
equals 100%. For other routes of administration, it is calculated as the ratio of AUC
after extravascular administration to AUC after intravascular administration. In
addition to the route of administration, it also depends on the dosage form.
𝐅 =
𝐀𝐔𝐂 𝐩.𝐨.,𝐢.𝐦.,𝐬.𝐜.…
𝐀𝐔𝐂𝐢.𝐯.
Relative bioavailability is used to compare two extravascular routes of
administration or two different dosage forms administered by the same way. Unlike
absolute bioavailability, it does not inform us about the real amount of a substance
that reaches the systemic circulation. Relative bioavailability describes the difference
in bioavailability (in %) between the compared routes of administration or dosage
forms. This parameter is essential especially in the bioequivalence studies used in
the marketing authorisation process of generic drugs. Unlike the original medicinal
product, generic drugs are tested only for so-called bioequivalence. Bioequivalence
means that after administration of the same dose of the same drug by two different
medicinal products, the course of plasma concentrations is similar (it may not be
identical). The compared parameters (cmax, tmax, AUC) of the generic medicinal
31
product must not be outside the range of 80-125% of the values of the original
product1.
𝐅 =
𝐀𝐔𝐂 𝐩𝐨
𝐀𝐔𝐂 𝐩𝐨
or
𝐅 =
𝐀𝐔𝐂 𝐩𝐨
𝐀𝐔𝐂𝐢.𝐦.
Presystemic drug elimination
Factors that reduce the bioavailability of a drug can be covered by the term
"presystemic drug elimination". There are many reasons why not all the amount of
drug reaches systemic circulation.
The most common route of administration is oral use, and many influences are
reducing the bioavailability of orally administered drugs. The drug can interact with
co-administered food to form non-absorbable complexes (e.g. tetracyclines +
polyvalent cations). It can be a substrate of efflux pumps present in enterocytes (Pglycoprotein),
which actively excrete the drug back into the intestinal lumen. Due to
GIT motility, the drug can then enter parts of the GIT unsuitable for its absorption
(outside its absorption window). Part of the drug can also be metabolised in
enterocytes, which are especially rich in enzymes of the cytochrome P450 family.
The so-called "first-pass effect" is also very significant. All substances absorbed
from the intestine first enter the portal circulation, which brings the blood to the liver.
After that, the blood goes to other tissues and organs where drugs usually act. In the
liver, which is the primary metabolic organ, the biotransformation of a drug to inactive
metabolites can occur before the drug enters the target organ. Cytochrome P450
enzymes are involved in this process. This first-pass effect significantly reduces drug
bioavailability. It influences drugs administered orally and partly also rectally.
1 The range of 80-125% does not apply to all products. For substances with a low therapeutic index,
the acceptance interval is 90-111.11%, and bioequivalence studies are also more stringent for
substances with non-linear pharmacokinetics (see below).
32
Examples of factors that can affect drug absorption:
- age (changes in liver enzyme activities, GIT motility)
- weight (adipocyte layer strength for transdermal or subcutaneous drug
administration)
- pathophysiological condition (GIT atony, liver disease, circulatory disorders)
- perfusion at the site of administration (i.m. administration to subcooled vs
heated muscle, ischemic tissue)
- area of absorption (GIT resection)
- concomitant administration of drugs (prokinetics, antibiotics)
- drug solubility
- concentration gradient
2.3.1.2 Drug distribution
After the absorption of a drug, the substance penetrates from the blood into various
body tissues and organs. Distribution is a dynamic process in which a balance is
continuously established between the amount of drug in the blood and other tissues.
We are usually interested in the rate of the equilibrium establishment and the ratio of
the concentration in the blood to the concentration in the monitored tissue.
The parameter describing the distribution phase is the volume of distribution (Vd).
Mathematically, the volume of distribution is the ratio of the total amount of drug in
the body to its concentration in blood or plasma. The amount of drug in the body is
calculated as the dose administered multiplied by the bioavailability. Combing these
two equations we get:
𝐕𝐝 =
𝐚𝐦𝐨𝐮𝐧𝐭 𝐨𝐟 𝐝𝐫𝐮𝐠 𝐢𝐧 𝐭𝐡𝐞 𝐛𝐨𝐝𝐲
𝐜
=
𝐃. 𝐅
𝐜
[𝐥]
where c is the plasma concentration of the drug reached after absorption with no
metabolism, D is the dose of drug administered, and F is the bioavailability.
The unit of volume of distribution is either a litre [L] or if we relate the volume to body
weight, a litre per kilogram [L/kg].
33
The volume of distribution is a hypothetical volume in which the drug is dispersed to
reach the same concentration as is its plasma concentration. Vd can reach low
values for substances that are practically non-distributed and remain mainly in the
blood (5 - 7L). However, it can also be very high (hundreds to thousands L), mostly
for lipophilic substances that accumulate in adipose tissue or skeletal muscle and
whose plasma concentration is very low compared to the dose administered.
The value of Vd informs us not only about the extent of drug distribution, but it can
also be interesting from a practical point of view:
1. Based on the knowledge of the volume of distribution, we can calculate the
loading dose according to the relation:
𝐃 = 𝐕𝐝. 𝐜 𝐓
where D is a loading dose, and cT is the target plasma concentration.
2. Based on the knowledge of the volume of distribution, we can estimate the
amount of drug in the body according to the relationship:
𝐌 = 𝐕𝐝. 𝐜
where M is the amount of drug in the body, and c is the measured concentration of
drug in the blood.
3. We can assess the success of hemodialysis or hemoperfusion for drug
elimination in the case of intoxication caused by a substance known to us.
Hemodialysis or hemoperfusion will be effective for substances with low Vd,
and conversely, substances with high Vd cannot be effectively removed from
the body by these techniques.
Factors influencing the distribution of drugs include, for example:
- physico-chemical properties of a drug
- comorbidities (cardiovascular disease – decreased perfusion and impaired
distribution; liver disease – hypoalbuminemia; nephropathy, limb amputation,
ascites etc.)
- binding of the drug to plasma proteins (it may be crucial for the efficacy of the
drug, as the protein-bound drug is not able to exert an effect or cross
biological barriers)
34
- age - the proportion of body fluid decreases, and the proportion of body fat
increases with age, serum albumin decreases and α1-glycoprotein increases
with age2
2.3.2 Drug elimination
The term "elimination" includes all processes removing the active form of the drug
from the body. The drug can be eliminated by metabolism (biotransformation) to the
inactive metabolite, excretion in an unchanged form, or a combination of both.
According to the dependence of the elimination rate on the plasma concentration, we
distinguish zero-order and first-order elimination. Most drugs are eliminated by
first-order kinetics, meaning their rate of elimination and the drug plasma
concentration is in direct proportion. The higher the plasma level is, the faster the
drug is eliminated. The course of plasma concentrations as a function of time then
has the shape of an exponential curve (Fig. 9A). In a semi-logarithmic representation,
the curve gets linear shape, and thus the term "linear kinetics" (Fig. 10).
For elimination kinetics according to the zero order, the elimination rate is constant
mostly due to a saturable enzymatic or transport elimination system. The same
amount of drug is eliminated per unit time (Fig. 9B). The elimination pathway
becomes saturated at a specific plasma concentration of the drug, and the organism
cannot respond to further increases in plasma levels by faster elimination. Such
drugs have a higher risk of intoxication and adverse effects. Ethanol or phenytoin are
examples of substances eliminated by zero-order kinetics. Theoretically, zero-order
elimination kinetics can be achieved for almost all drugs. However, we would have to
use extremely high doses above the standard therapeutic range.
2 Small children have a higher proportion of total body fluid, so hydrophilic drugs have to penetrate
relatively larger extracellular space. Therefore, it is necessary to increase the relative dose
administered to children in some cases.
35
Figure 9. Drug elimination rate according to first (A) and zero order kinetics (B)
Figure 10. Drug elimination rate according to first-order kinetics in semi-logarithmic
representation
The fundamental parameter describing elimination is clearance (Cl). It is defined as
the ability of the body to get rid of the drug. Specifically, it gives the volume of plasma
that is completely purified from the drug per unit time, and the unit of Cl is the unit
volume per unit time [L/min].
𝐂𝐥 =
𝐞𝐥𝐢𝐦𝐢𝐧𝐚𝐭𝐢𝐨𝐧 𝐫𝐚𝐭𝐞
𝐜
36
The total clearance of the organism consists of individual organ clearances according
to the ways by which the drug is eliminated from the organism:
The elimination constant (ke) characterises the rate of elimination:
𝐤 𝐞 =
𝐥𝐧 𝐜𝟏 − 𝐥𝐧 𝐜𝟐
𝐭𝟐 − 𝐭𝟏
From the practical point of view, biological half-life (t1/2) is a more comprehensible
constant. It also characterises the rate of elimination, and ke is used for its
calculation. t1/2 is the time required for the plasma concentration of a drug to fall to
half its value.
𝐭 𝟏/𝟐 =
𝐥𝐧 𝟐
𝐤 𝐞
=
𝟎, 𝟕
𝐤 𝐞
2.3.2.1 Metabolism
Metabolism of most drugs is performed enzymatically. Based on the nature of the
metabolites produced, metabolic reactions can be divided into bioactivation and
biodegradation. Bioactivation reactions are essential for prodrugs. These are
pharmacologically ineffective or less effective molecules that are converted in the
organism to the active form. Prodrugs can be used to increase oral bioavailability
(e.g. penamecillin). Biodegradation is a more common type of metabolism, and it
leads to the production of less active or inactive metabolites.
Biodegradation processes usually have two phases. Their primary goal is to reduce
the biological activity of substances and subsequently increase their hydrophilicity,
improve their solubility in body fluids, and thus facilitate their elimination from the
body. The first phase involves the oxidoreductase system of cytochrome P450
(CYP), but also other enzymes (deaminases, hydrolases, reductases, etc.). Change
in the structure of the drug is usually associated with a decrease in biological activity
because the interaction of the drug with the target structure is dependent on the
characteristic structure of the drug molecule. If the drug is sufficiently polar, it can be
𝐂𝐥 𝐓𝐎𝐓 = 𝐂𝐥 𝐑𝐄𝐍 + 𝐂𝐥 𝐇𝐄𝐏 + 𝐂𝐥 𝐏𝐔𝐋 …
37
excreted by the excretory organs. If not, it enters the second phase of metabolism,
in which enzymes catalyse conjugation reactions. The resulting conjugates have a
higher molecular weight and are more hydrophilic than the maternal drug. Examples
of conjugation reaction are conjugation with glutathione, glycine, methionine, sulfuric
acid, glucuronic acid, acetic acid, bile acids etc.
Drugs may undergo one or both of these phases. Some hydrophilic drugs are not
metabolised at all are excreted in an unchanged form (e.g. aminoglycosides,
gabapentin, penicillins). The most important biotransformation organs are liver and
kidneys. Less important are lungs and intestines (intestinal enzymes).
Interindividual differences in the metabolic activity of biotransformation enzymes and
drug interactions at the CYP level are essential for clinical practice. Metabolic activity
is influenced by several exogenous and endogenous factors. Some medicines, as
well as some food components, can affect the activity of CYP enzymes. CYP
inducers increase its activity (rifampicin, carbamazepine, St. John's wort), leading to
faster elimination of drugs and the need to increase their doses or shorten dosing
intervals. In contrast, CYP inhibitors (fluoxetine, clarithromycin, grapefruit
constituents) reduce enzyme activity and increase the risk of intoxication with
standard doses of drugs. For example, tobacco smoking (exogenous factor) induces
CYP1A2 activity, while genetic polymorphisms (endogenous factor) can influence
plasma levels of CYP2D6, CYP2C9 and CYP2C19 substrates. Based on the
observed change in the metabolic activity of a particular enzyme, we divide
individuals into four categories (this does not apply to all biotransformation enzymes):
- poor metabolisers – low or no metabolic activity of the enzyme
- intermediate metabolisers – enzyme activity is between slow and fast
metabolisers, with no change observed clinically
- extensive metabolisers – most of the population, normal enzyme function
- ultra-rapid metabolisers – duplication or multiplication of the gene for a given
enzyme, metabolic activity is higher than in extensive metabolisers
Examples of other factors influencing drug metabolism:
- age – newborns do not have fully mature enzymes (CYP, UDPglucuronosyltransferase),
while elderly have reduced enzyme activity due to
impaired blood flow to biotransformation organs
38
- gender – sex hormones affect biotransformation enzymes; adult men
metabolise drugs faster than adult women by some CYP enzymes
- diseases of biotransformation organs – liver or kidney diseases can slow
biotransformation processes and prolong the elimination half-life
- nutritional status of the organism, diet
2.3.2.2 Excretion
The journey through the body ends with excretion of the drug by a suitable excretory
organ. The main excretory organs are kidneys, bile/stool and lungs, but other
pathways exist, such as sweat, saliva, tears, breast milk, etc. From a quantitative
point of view, these excretion pathways remove a negligible amount of drug.
Hydrophilic drugs are usually excreted by the kidneys, in which three mechanisms
are involved: glomerular filtration, tubular secretion, and reabsorption. Only free
substances not bound to plasma proteins with a molecule smaller than the size of
albumin can enter the primary urine by filtration. Other drugs enter urine by the
mechanism of tubular secretion using specific transporters. Competition of two
substances for the same transporter can slow the elimination and prolong the
biological half-life (e.g. penicillins + probenecid). The increase of drug reabsorption in
the renal tubules can have the same effect.
Alkalinisation (NaHCO3) or acidification of urine (NH4Cl) affects reabsorption or
increase solubility and reduce the risk of urinary tract precipitates of poorly soluble
substances. Increasing the pH of the urine leads to ionisation of weak acid molecules
present in the urine, which limits their reabsorption and thus increases their excretion.
Weak bases, on the other hand, will be excreted less, because at higher pH they will
have a non-ionized form and will more easily transfer from the filtrate back to the
blood. The reverse situation occurs for acidified urine.
Bile plays a vital role in digestion and fat absorption. Substances excreted in bile can
undergo enterohepatic circulation, as bile acids do. This prolongs their biological
half-life. In some cases, substances are excreted to the bile in the form of conjugates
and can only be reabsorbed after cleavage of the conjugates by the colonic
microbiota. Colonic microbiota can significantly affect the pharmacokinetics of drugs.
For example, the use of broad-spectrum antibiotics can disrupt the enterohepatic
circulation of drugs and thus accelerate their excretion.
39
In breastfeeding women, drugs and other xenobiotics can be excreted to breast milk.
Because the milk is slightly more acidic than plasma, weak bases (e.g. nicotine,
caffeine, and theophylline) reach higher concentrations in milk than in maternal
plasma.
2.4 Plasma concentrations of a drug over time
2.4.1 Single dose of a drug
Plasma concentrations of a drug differ significantly after extra- and intravascular
administration of a single dose (Fig. 11 and 12). After intravascular administration,
the absorption phase does not apply, and only the elimination part of the curve is
present. In other words, cmax is reached immediately after administration, and drug
levels continue to decrease after that. After extravascular administration, plasma
concentrations are increasing (i.e. the drug is absorbed) until tmax and cmax are
reached, and then the elimination phase similar to intravascular administration
follows. Such a description of the course of plasma drug concentrations is only
theoretical and very simplified compared to the real situation. Actually, the drug is
eliminated from the body as soon as it appears in the plasma, while the elimination
rate is very low due to the first-order kinetics (i.e. due to the low plasma
concentration). On the other hand, high concentration of drug at the site of
administration sets a significant concentration gradient for the movement of the drug
into the blood, and the rate of absorption is therefore very high. With the decreasing
concentration of the substance at the site of administration and increasing
concentration of the substance in the plasma, the absorption and elimination rates
start to balance, and right at tmax, both are equal. Subsequently, elimination
predominates, and although the drug is still being absorbed into the body, the
amount of drug absorbed decreases over time. The curve shape of the plasma levels
at elimination phase after intravascular administration is not the very same as after
the extravascular administration. After reaching cmax at time tmax, the curve of
extravascular administration is deformed due to the ongoing absorption. This period
is sometimes called the post-absorption phase.
40
Figure 11. Time course of plasma drug concentrations after single intravascular (red)
and extravascular (green) administration
Figure 12. Schematic representation of the time course of plasma drug
concentrations after a single administration by various routes of administration
41
2.4.2 Repeated administration of the drug
Repeated administration of a drug means that the next dose of a drug is
administered to the patient before the previous dose is completely eliminated from
the patient's body. Assuming that the drug is administered at the same dosing
intervals, a gradual increase in the mean plasma concentrations of the drug occurs
within the dosing intervals. This phenomenon is called drug accumulation. However,
the increase in mean plasma drug concentrations gradually slows down due to the
same phenomenon described for single drug administration, i.e. with increasing
plasma concentration, the elimination rate increases. After a specific time, equal to
approx. 4-5 t1/2, so-called steady state is reached. It is a state where the average
plasma concentrations no longer change during the individual dosing intervals, as
well as the minimum and maximum plasma concentrations. The mean plasma
concentration during a single dosing interval is referred to as the steady-state
concentration (Css) (Fig. 13) and depends mainly on the body's ability to eliminate
the drug (Cl) and also on the dose or bioavailable portion of the dose (D x F) and
dosing interval (τ). The following relation applies:
𝐂𝐬𝐬 =
𝐃. 𝐅
𝛕. 𝐂𝐥
Dose and dosing interval determine the rate of fluctuation of plasma drug
concentrations. With the lower dose and shorter dosing interval, the minima and
maxima of plasma concentrations are closer to Css, and the fluctuation is lower.
Dose size and frequency of drug administration are practical tools for changing
plasma concentrations of drugs. Together with TDM, changing the dose or dosing
interval is a useful tool for individualising therapy with drugs of a narrow therapeutic
range.
42
Figure 13. Time course of plasma drug concentrations after repeated extravascular
administration
2.4.3 Continuous drug delivery
When the drug is delivered at a constant rate, plasma concentrations increase,
similarly to repeated administration, until the rate of delivery equals the elimination
rate. At this point, the so-called steady state is reached, and the plasma
concentration (CSS) does not change any further. The time required to reach CSS is
again dependent on the elimination rate and is approx. 4-5 times t1/2. The specific
value of CSS is also dependent on the elimination rate, so the same drug
administered at the same rate to different patients leads to different CSS. The
following relationship applies:
𝐝𝐫𝐮𝐠 𝐝𝐞𝐥𝐢𝐯𝐞𝐫𝐲 𝐫𝐚𝐭𝐞 [
𝐦𝐠
𝐦𝐢𝐧
] = 𝐂𝐥 . 𝐂𝐬𝐬
If the patient has problems with drug elimination (hepatic or renal impairment), the
drug delivery rate should be reduced to achieve the same CSS as in the patient with
intact elimination mechanisms. The crucial advantage of continuous drug delivery is
the zero fluctuation of plasma concentrations. There is no risk that part of the dosing
interval includes plasma concentrations outside the therapeutic range. Therefore,
continuous drug delivery is the most preferred for drugs with a narrow therapeutic
range. On the other hand, not all drugs have non-invasive methods of continuous
43
drug delivery in the form of patches. The administration of substances in the form of
infusions or implants has several disadvantages, especially in terms of patient
comfort and economic costs.
At the end of the continuous drug delivery, the shape of the curve corresponds to a
single intravascular dose, and the substance is completely eliminated after approx. 4-
5 biological half-lives (Fig. 14).
Figure 14. Course of plasma drug concentrations after continuous drug delivery and
after withdrawal
2.5 Compartment models
Abstract compartment models are used to simplify the movement of the drug in the
body (Figures 15 and 16). A compartment is a part of the body (e.g., plasma, tissue,
organ, or organ system) of a specific volume or composition that exhibits the same
properties. The drug is homogeneously dispersed in such compartment. For
modelling using compartmental models, the human organism is simplified to various
interconnected compartments. The rate constants define the movement of the drug
between these compartments. As the number of compartments increases, so does
the number of possible interconnections. Thus, the mathematical complexity of such
system increases, as well. Therefore, only a one-compartment model is usually
applied to calculate pharmacokinetic parameters of drugs, but there are also two and
multi-compartment models.
44
Figure 15. One-compartment models
Figure 16. Two-compartment models
Dose
i.v. administration
Vd1
ke
Vd2
k1-2
k2-1
Central compartment Peripheral compartment
Dose
p.o. administration
Vd
ke
GIT
ka
Dose
i.v. administration
Vd
ke
45
Dose
p.o. administration
Vd1
ke
Vd2
k1-2
k2-1
Central compartment Peripheral compartment
GIT
ka
Dose
i.v. administration
Vd1
ke1
Vd2
k1-2
k2-1
Central compartment Peripheral compartment
ke2
Dose
i.v. administration
Vd1
ke
Vd2
k1-2
k2-1
Central compartment Peripheral compartment
46
Dose
p.o. administration
Vd1
ke1
Vd2
k1-2
k2-1
Central compartment Peripheral compartment
GIT
ka
ke2
47
Literature
Fasano, M., Curry, S., Terreno, E., Galliano, M., Fanali, G., Narciso, P. et al. The
extraordinary ligand binding properties of human serum albumin. IUBMB Life. 57,
2005, 12, 787–96.
Ficková, D., Vlček, J., Topinková, E. Role P-glykoproteinového transportu v klinicky
významných lékových interakcích. Remedia, 3, 2002, 207-213.
Huang Z., Ung T., Effect of alpha-1-acid glycoprotein binding on pharmacokinetics
and pharmacodynamics. Current Drug Metabolism, 14, 2013, 2, 226–38.
Lüllmann, H., Mohr, K., Wehling, M. Farmakologie a toxikologie. Překlad 15. zcela
přepracovaného vydání, Grada, Praha, 2004.
Máchalová, A., Babinská, Z., Juřica, J., Dovrtělová, G., Kostková, H., Landa, L.,
Merhautová, J., Nosková, K., Štark, T., Tabiová, K., Pistovčáková, J., Zendulka, O.
Farmakologie pro studenty bakalářských oborů na LF MU. 2016.
Martínková, J., Chládek, J., Mičuda, S., Cermanová, J., Grim, J. Obecná
farmakologie jako základ studia farmakologie experimentální a klinické. Lékařská
fakulta v Hradci Králové, 2001.
Olson, R.E., Christ, D.D., Chapter 33. Plasma Protein Binding of Drugs. Annual
Reports in Medicinal Chemistry. 1996, 327–36.
Pechandová, K., Buzková, H., Slanař, O., Perlík, F. et al. Efluxní transmembránový
transportér–P-glykoprotein. Klinická biochemie a metabolismus, 4, 2006, 196-201.
Trejtnar, F. Základní mechanismy transportu léčiv v organismu. Remedia, 26, 2016,
460–463.
48
3. Routes of drug administration and drug dosage
forms
The knowledge of a drug’s mode of action and its pharmacokinetics are not the only
determinants of safe and efficacious use of drugs. The route of drug administration
and in some cases also drug dosage form (pharmaceutical form) could be essential
for the final effect of a drug. Suitable selection of administration route and the
pharmaceutical form of the drug can significantly influence the onset of the drug’s
action or its duration of effect. Moreover, it can diminish the risk of unwanted effects
or increase the patient’s adherence to therapy. In some situations, different means of
drug administration can result in different effects of the same drug. For example,
osmotically active mannitol administered orally is a laxative agent, whereas the same
drug administered intravenously has diuretic effect. Both effects are based on the
same mode of action. Another example of medications where the effect is dependent
on the administration route are iodine-containing drugs. These, when applied on skin
or mucosa, have only a local antiseptic effect at the site of administration based on
the oxidative properties of iodine. On the other hand, when administered orally the
iodine is trapped in the thyroid and influences the release of thyroid hormones. This
effect can be used both at lower doses in the treatment of goitre or at higher doses
for its thyreostatic effect.
Drug dosage forms and routes of drug administration along with their characteristic
benefits and risks will be described in the following text.
3.1 A brief overview of drug dosage forms
Most drugs are in their pure form crystalline substances and must be dissolved or
„diluted” with other substances, usually lacking their own pharmacological activity,
called vehicles. Such mixtures of active drugs and vehicles are supplemented with
other substances (pharmaceutical additives) to improve the stability or organoleptic
characteristics of mixtures. The final physical form of the mixture of active
substances, vehicles and additives in which they are given to the patient is called the
pharmaceutical form or drug dosage form.
49
Pharmaceutical forms can be classified with respect to various characteristics, for
example with respect to their shape. We recognize shape specific forms, which
possess their own shape regardless of the external packaging (tablet, suppository).
By contrast, shape non-specific forms adopt the final shape of the external packing
(ointments, solutions, gases). Another classification criterion closely related to the
previous is whether the form is divided into single doses with accurate content of the
active substance or not (dose divided vs dose undivided). In the latter case, the dose
of a drug is measured by the patient before each administration. An example of the
divided form which is usually shape specific is again tablet or suppository, while
ointments or solutions can be given as examples of non-divided forms.
The most common type of pharmaceutical form classification, which can also be
found in the Czech pharmacopoeia, is organized with respect to the physical
character of the dosage form. There are four basic groups: solid, semi-solid, liquid,
and gaseous forms.
3.1.1 Solid drug dosage forms
Solid drug dosage forms represent a variable group of pharmaceutical forms, for
which it is common that they are all formed or at least their external coating is formed
by solid particles.
3.1.1.1 Powders
Powders are one of the simplest solid pharmaceutical forms. They can be composed
of crystals of the drug alone or in combination with additives, both pulverized to
particles of specified size. Typical representatives of undivided powders, in which the
patient measures the dose of a drug before administration, are dusting powders or
powder of potassium manganate used for the preparation of antiseptic solutions.
Some ready-made preparations can be in the form of divided powders with single
doses divided into paper sacks. The advantage of this drug dosage form is the
simplicity of its production.
3.1.1.2 Granules
Other example of a relatively simple pharmaceutical form is granules. Granules are
intermediate products in the production of tablets, but can be used as a unique drug
form. Granules are produced by moistening the aforementioned powders with liquid
50
additives, the mixture is then pushed through a granulating sieve and dried.
Granules, as well as powders, can be undivided or divided and their advantage is
again the simplicity of their production and speed of onset of the drug effect in
comparison with other solid drug dosage forms. The fact, that granules must be
dissolved prior their administration can be both advantageous and disadvantageous
under specific circumstances.
3.1.1.3 Tablets
Tablets are shape-specific, divided drug dosage forms that are prepared from
granules by pressing them into tablet moulds. There are several administration
routes for tablets used in clinical practice. Nevertheless, oral use is the most common
way of administering tablets to patients. This pharmaceutical form is highly variable in
its shape and size. Basic types of tablets are non-coated and can be manufactured
with a scoring line. This enables the patient to split the pill into halves or quarters with
corresponding decrease in the amount of active substance. Non-coated tablets
disintegrate quickly in the stomach after oral use with quick release of the active
substance. The process of dissolution can be significantly influenced by tablet
coating. External coating can control the speed of drug release or the site where the
drug is released. Coating with materials soluble under specific pH is used to guide
the tablet to a specific part of the GIT to release the drug (e.g. enterosolvent coating).
The control of the speed of drug release influences the speed of drug absorption and
its plasma levels, and enables us to prolong the dosing interval with preserved drug
efficacy. Splitting of the tablet disrupts the coating and its function. Therefore, tablets
coated with functional film are never equipped with the scoring line. The tablet can
be coated with a pigmented film-forming coating. Such a coating can improve the
stability of active substances and mechanical integrity of the tablet during its
manufacturing. It has no effect on drug release and often it is used together with the
specific shape of the tablet for marketing purposes (to differentiate it from other pills
on the market). Less common types of tablets are effervescent, vaginal or orally
disintegrating tablets.
In some cases, lozenges are incorrectly called tablets, too. Their appearance can be
tablet-like with a sugar coating. The difference is that lozenges don’t have a core
produced from granules by pressing. Their whole body is formed by sequential drying
of sugar solutions.
51
3.1.1.4 Gelatine capsules
Gelatine capsules are another common pharmaceutical form. Contrary to tablets,
capsules are not produced by pressing of granules. The gelatine outer coating is
filled with powders or the drug dissolved in a lipophilic vehicle. Capsules are
classified into “soft” and “hard” with respect to their production and characteristics.
The “hard” capsule coating consists always of two pieces (body and cap) and are
filled mostly with a mixture of powders or other solid particles with different sizes.
“Soft” capsules have a one-piece body containing the drug dissolved in oil. The
gelatine coating dissolves in the aqueous environment of the GIT and the drug is
released. Similarly to tablets, the gelatine coating can be supplied with a functional
coating controlling release of the drug. Even non-coated capsules cannot be divided,
because of their structure. Gelatine capsules are probably the most common
pharmaceutical form for dose-divided solid individually prepared preparations
because of the simplicity of their manufacture and low cost. Together with tablets,
capsules represent another of the commonest forms of orally taken solid ready-made
preparations.
3.1.1.5 Suppositories and vaginal globules
Suppositories are shape and size suitable forms for rectal/vaginal delivery of drug
and are prepared by pressing (ready-made) or pouring (individually prepared)
suppository mixture into the moulds. Suppositories are classified into lipophilic and
hydrophilic types with respect to the additives and vehicles used. Because of a small
amount of liquid present in the rectum, lipophilic suppositories are preferred for
hydrophilic drugs. The lipophilic vehicles melt at body temperature and release the
drug, which can be dissolved in an aqueous environment and become ready for
absorption. Vaginal globules have similar characteristics, but differ from suppositories
namely in shape, size, and additives. Lactic acid is used in globules as an additive for
the restoring of pH of the vaginal environment making it suitable for vaginal
microflora.
3.1.1.6 Tea mixtures
Today, tea mixtures are less frequently encountered pharmaceutical forms for the
preparation of herbal infusions (mixture has hot water poured over) or decoctions
52
(mixture is boiled for app. 10 minutes). Tea mixtures consist of dried herbs shredded
to a specified size of particles.
3.1.1.7 Implants
Implants are sterile solid drug dosage forms inserted into body cavities or
subcutaneously. Drug is released from the implant continuously and the speed of its
release is again controlled by a functional coating (membrane) or by the matrix
structure of the body of implant. Some implants are degradable and under the
physiological conditions of the human body are continuously broken down while
releasing the drug. The great advantage of implants is constant and continuous drug
release. On the other hand, implantation of the device is invasive, and the implant
cannot be easily removed if needed. Sometimes local immune reaction to the implant
resulting in its encapsulation is reported. The most common use of implants is for
continuous hormone delivery.
3.1.2 Semi-solid drug dosage forms
By their consistency, semi-solid preparations are in between solid and liquid
formulations. They are applied to skin or mucosa and their advantage is that they
easily attach to these body parts and prolong the time for drug absorption in
comparison to dusting powders or liquids administered in the same way. Semi-solids
are frequently dispersions (emulsions or suspensions), and therefore must be stable
and homogenous at least for the time necessary for administration of the preparation.
Additives to increase the stability of suspensions (preventing sedimentation of
particles) or emulsions (emulsifiers, that prevent separation of oil and water phase)
are used, because the active principle is usually found only in one of the phases of
the dispersion system. Additives can also significantly influence penetration of the
drug through the skin.
3.1.2.1 Ointments
Ointments are formed either by lipophilic or hydrophilic bases in which the drug is
dispersed. Chronic dermatologic defects are the main indication for these
formulations because it enables the molecules of drug to penetrate deeply into the
lower layers of the skin. Typical lipophilic bases include paraffin, vaselines, waxes, or
silicones whereas typical hydrophilic bases include macrogols or gel-forming
53
substances (gelatine, methylcellulose). Ointments are characteristic for their one
phase basis, that can adopt a limited amount of immiscible liquid to form an emulsion
ointment. Ointments are simple drug dosage forms suitable also for individually
prepared preparations.
3.1.2.2 Creams
Creams are different to ointments because their base consists of two phases (oil and
water) and they are therefore emulsions. Creams are produced from ointment bases
by adding bigger amount of immiscible liquids and emulsifiers what makes them
more liquid in comparison to ointments. With respect to the character of the emulsion,
creams can be classified into hydrophilic creams (oil in water emulsion type) and
lipophilic creams (water in oil emulsion type). Creams have a cooling effect on the
skin thanks to the higher water content and its evaporation from skin surface. The
clinical use of creams lies namely in subchronic and acute phases of skin diseases.
Because of the emulsion character of creams and the possible instability of these
preparations their individual preparation is rare.
3.1.2.3 Gels
Gels are formed by liquids and gel-forming substances, which, under suitable
conditions, create a three-dimensional structure in which the molecules of liquid are
trapped. Similarly to previous semi-solid forms, gels can also be classified with
respect to the characteristics of the continuous (external) phase to hydro- and
oleogels. Because the preparation of gels is time consuming and technologically
demanding, similarly to creams, gels are only a marginal pharmaceutical form for
individually prepared formulations.
3.1.2.4 Pastes
Pastes are prepared by the addition of solid substances into an ointment or cream
base. With regard to the type of base which is used, hydropastes, oleopastes,
hydrocream pastes, and oleocream pastes can be prepared. The content of solid
particles represents at least 25 % of the total weight of the preparation. One of the
most common pastes used in dermatology is indifferent zinc paste containing zinc
oxide.
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3.1.2.5 Medicated patches
In contrast to previous semi-solid formulations patches are shape specific. They can
contain a drug with local effect at the site of administration or a drug which penetrates
into the hypodermis and passes into the capillaries where it can be absorbed and
evoke a systemic effect. The body of the patch always consists of an adhesive and
cover layer. Nevertheless, other parts of the patch can be different. The simplest
patches contain drug dissolved directly in the adhesive layer. This construction is not
suitable for controlled drug release. Therefore, some patches are equipped with a
drug reservoir which is separated from the adhesive layer by a membrane regulating
the release of the medicine. Similarly to implants, another possibility of controlledrelease
is a matrix structure of the drug reservoir. Patches combine the advantages
of implants (controlled drug release) without the need to implant the device or
complicated discontinuation of medication. Patches are pharmaceutical forms used
only for ready-made preparations.
3.1.3 Liquid drug dosage forms
True solutions, liquid emulsions and suspensions, or different kinds of drops are
examples of liquid pharmaceutical forms. Administration routes for these
preparations vary from topical use to intravenous injections. Therefore, their
composition and requirements for their quality vary too.
3.1.3.1 Liquid preparations for topical administration
All types of liquids can be administered on skin. Nevertheless, the requirement for
homogeneity of the pharmaceutical form at least for the time of drug administration
persists. There is a warning note on the external package of suspensions and
emulsions to shake the preparation well before use. Except for the common vehicles
for hydro- and lipophilic liquids, formulations often contain additives as emulsifiers,
stabilizers or antimicrobials. Separation of phases in case of emulsions and
suspensions is not disqualifying if a homogenous mixture can be easily reconstituted
by shaking the preparation. Liquid formulations administered onto the skin contain
almost exclusively locally active drugs and their effect is primarily determined by the
concentration of drug in the medicine. Examples of such preparations are salicylic
spirit or Iodine tincture. There are also preparations with sophisticated compositions.
Their single components increase the stability of the formulation and a great example
55
of this is the liquid dusting powder. Its advantage over the classical dusting powders
is its better adhesion to skin and therefore longer duration of the effect without a
need of frequent administration.
3.1.3.2 Liquid preparations for peroral use
Liquids for oral use are usually available as undivided preparations. On one hand,
this brings a great variability in their dosing on the other hand it also increases the
risk of improper or inaccurate dosing. Patients measure the dose of the medicine
themselves, usually with measuring cups in ready-made preparations and with tea or
tablespoons in individually prepared medicines. The risk of improper dosing is high,
and those forms are suitable mainly for drugs with high therapeutic index. For drugs
requiring more accurate dosing the form of oral drops is used. Liquids for oral use
are suitable for paediatric and geriatric patients. Children and elders can have a
problem with oral intake of solid preparations. With respect to the bitter taste of most
of drugs, namely if they are not administered in small volumes like drops, these
preparations contain sweeteners and other taste and smell corrigents. Suitability of
adjuvants and vehicles should be considered when selecting formulations for specific
patients (syrups for diabetics or ethanol solutions for children).
Exceptional cases of peroral liquids are syrups (aqueous solutions of saccharose),
tinctures (spirituous herbal extracts), and aromatic waters (aqueous saturated
solutions of essential oils). Their clinical use is minimal today.
Liquids administered into oral cavity for use without swallowing are also available.
This group of preparations contain gargles, oral and sublingual sprays, or solutions
for irrigation.
3.1.3.3 Drops
Except for solutions for oral use with accurate dosing, drops are also used for drug
delivery into the eye, nose, or ear. These preparations differ in requirements for their
quality and in the types of active components. Eye drops must fulfil the highest
quality requirements. They contain drugs for the local treatment of the eye.
Therefore, these formulations should not irritate the eye to prevent lacrimation and
removal of the preparation from the eye bulb. Because of that, eye drops should be
isotonic and isoacid, if possible. Eye drops are the only drops for which Czech
56
pharmacopoeia requires sterility. The expiration of eye drops is four weeks from the
first use with respect to sterility, if the preparation is not equipped by antibacterial
membrane filter. Typical drugs administered in the eye drops are antiglaucomatics,
mydriatics, H1 antihistamines, antibiotics, or decongestants.
Nasal drops should also cause minimal irritation after their administration to prevent
drug removal from the nasal cavities. Therefore, the requirement for isotonicity
remains. Contrary to eye drops, nasal drops don’t have to be sterile and can also be
used for drugs with systemic effect, for instance for hormones (oxytocin, calcitonin).
Among drugs with local action in the nasal cavity decongestants or H1 antihistamines
are used.
Ear drops are used for the treatment of the external ear duct. Drugs in ear drops do
not get into contact with mucosa and neither osmotic pressure nor pH have to be
adjusted. Most common active components of ear drops are antiphlogistics, local
anaesthetics, or cerumenolytics (earwax softeners).
3.1.3.4 Injections and infusions
Solutions for parenteral use in the form of intravascular injections or infusions must
be always sterile and apyrogenic. If it is also possible and it is not the therapeutic
goal to change the plasma pH or oncotic pressure, they should also be isoacid and
isotonic. True hydrophilic solutions and special microemulsions (oil in water type) with
specified sizes of particles can be administered intravascularly due to possible risk of
thromboembolism. For other types of injections lipophilic solutions, emulsion and
suspensions can be used. These types of formulations can release the drug slowly
and can extend the duration of their effect.
3.1.4 Gaseous drug dosage forms
With respect to state, gaseous formulations are available in pressurized cans
(gaseous form at room temperature) or in containers that enable the release of an
aerodispersion containing the drug which is in a liquid or solid state at room
temperature (inhalers, mechanic sprays). An essential difference, except for the
phase of drug, is the size of the particles of drug. Macroscopic dispersions are used
for topical drug administration for instance for air disinfection, whereas
microdispersions (aerosols) with size of particles up to 5 µm are used for inhalations.
57
Pressurized cans are used for formulation of aerodispersions from substances that
are dissolved or suspended in a solution of propellant gas. Propellant quickly
evaporates after its release from can. Hydrofluoroalkanes, a substitute for ozone
layer destroying chlorofluorocarbons (CFC), are used today.
3.1.4.1 Inhalants
Preparations for inhalation contain a drug in solid or liquid form. Inhalation is possible
thanks to a special device, usually a part of the external container (dry powder
inhaler, metered dose inhaler etc.). Another possibility is electronic devices producing
aerosols (nebulisers). The bigger the particles of inhaled drug are, the more proximal
the place of their sedimentation in the airways. This can be used to target the effect
of drug into specific parts of the airways. Inhaled drugs include various types of
antiasthmatics.
3.1.4.2 Medicated foams
Medicated foams are formed by huge volumes of gas trapped in a liquid where a
drug is also dissolved. It is a pharmaceutical form used in dermatology. In contrast to
semi-solid preparations the foam is readily spreadable, and its administration doesn’t
irritate the skin at the site of its administration. A liquid in the foam can have a cooling
effect itself. This effect is present in dexpanthenol-containing foams used in skin
burns after sunbathing.
3.2 Routes of drug administration
Selection of the appropriate route of drug administration is as important as selection
of the drug itself for successful pharmacotherapy. The means of administration of a
drug given to a patient can influence the character of its effect as well as the speed of
onset of its effect, duration of its effect, side effects and therefore the patient’s
willingness to continue with the pharmacotherapy.
3.2.1 Classification of routes of administration
Three basic aspects can be used for this classification: disruption of biological
integrity, site of drug administration, and type of evoked effect.
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3.2.1.1 Disruption of biological integrity (invasiveness)
In some types of drug administration, the natural barriers protecting human body from
the negative effects of environment have to be overcome. Therefore, invasive routes
of drug administration are risky because they break those natural barriers and the
benefit to risk ratio of such types of drug administration should always be evaluated.
Disruption of skin by the puncture of injection needle or parenteral administration of
contaminated preparations increases the risk of infections of various aetiology. There
is also a risk of organ damage by injection needle in some types of injections
(conductional anaesthesia) and in case of implantation an immune reaction to the
implanted device/material can develop. Because of that, invasive routes of drug
administration are namely used in acute situations to achieve faster onset of the
effects in comparison to other means of drug administration or in severe conditions
when there is no alternative way to reach the desired therapeutic effect
(aminoglycosides in the treatment of severe systemic bacterial infections).
Disadvantages of invasive routes of administration are, except the abovementioned,
the inability for self-administration of drugs by patients. Invasive drug administrations
are performed by health care professionals (apart from s.c. delivery of hormones or
heparin) which brings additional costs to the therapy. The review of invasive and noninvasive
routes of drug administration is presented in Table 1.
Table 1. Review of invasive and non-invasive routes of administration.
Non- invasive Invasive
peroral intravascular
sublingual intraosseous
rectal intramuscular
inhalational subcutaneous
intranasal intracerebral/cerebroventricular
transdermal intrathecal
vaginal implantation
3.2.1.2 Site of administration and type of evoked effect
Sometimes “local” and “systemic” types of drug administration are used within
pharmacology. An example is topical administration of glucocorticoids on skin (local)
and peroral use (systemic). These words better represent not the type of
59
administration but the type of drug effect that can be either localized to the site of
administration (local) or present in the whole body after drug absorption and
distribution to various organs and tissues (systemic). Type of effect depends more on
the specific drug and drug dosage form than on the means of administration. In
general, both types of effects can be evoked by any method of drug administration.
Intravenously administered heparin acts locally inside of the vessels whereas
intravenously given morphine will evoke systemic analgesia.
Drugs have to have limited possibilities of absorption from the site of administration to
evoke a local effect only. In some cases, we actively prevent or slow down drug
absorption from the site of its administration to prolong its effect or prevent its
adverse effects (combination of local anaesthetics with vasoconstringents). An
advantage of local use of drugs is the ability to target its effect only to the site where
it is required together with minimization of possible adverse effects in other parts of
the human body. An example of such drug use is the inhalational use of
glucocorticoids with minimal risk of their systemic metabolic side effects. The final
concentration of a drug at the site of administration and the time for which the drug is
present at the site of administration are the major determinants of its effect.
Absorption, the process of penetration of a drug from the site of administration to
systemic circulation, is followed by the distribution of a drug to its target structures in
drugs with systemic effect. Theoretically, such a drug can influence any tissue or
organ of human body, which can also evoke unwanted effects. The toxicity of a drug
with systemic effects always depends on the pharmacodynamic and pharmacokinetic
characteristics of each drug. The advantages of local administration are therefore
applied also to the systemic use of drugs. A selection of drugs with the most selective
mode of action or at least with limited/specific distribution in the body are used to
minimize its effect on structures other than target ones. The latter drug characteristic
can be supported with the use of 3rd generation drug dosage forms or with specific
types of drug administration as can be shown in the case of intraarterial
administration of chemotherapeutics into arteria hepatica in the treatment of liver
metastases. The size of the effect and the time of its duration are determined by total
dose together with the pharmacokinetics of the drug which determines the final
concentration of agent at the site of its effect.
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As was already mentioned, any type of drug administration can evoke a local effect of
a drug. Nevertheless, not all ways of drug administration can evoke a systemic effect.
The pharmacokinetic properties of each drug are essential, because in systemic
effect a drug enters a body in a site different to the tissue or organ where the effect is
required. Therefore, the drug has to pass from the site of administration to the target
site and this process takes some time and includes factors that can significantly
influence the portion of the drug that actually reaches the target site. It is necessary
to realize that essential differences between administration routes leading to systemic
effect are found in the pharmacokinetic processes of absorption and distribution. The
size of effect and speed of its onset can therefore be different for the same drug
administered via different routes.
Fundamental differences between routes of administration for systemic effect are the
sites where the drug enters the body. With respect to that, routes of administration
are classified as enteral and parenteral (see Scheme 1). Drug enters the organism
via the gastrointestinal tract in enteral routes. This represents a natural and noninvasive
way of drug administration, but on the other hand there are some
disadvantages and risks that thwart this possibility for some types of drugs. Firstly,
some kinds of drugs can be inactivated by gastric acid or degraded by digestive
enzymes or gut microflora. Because of that, it is practically impossible to administer
proteins e.g. insulin orally. Another problem is that drug absorbed from the GIT first
enters through enterocytes to the portal system and arrives at the liver which is the
main organ of drug metabolism. There is a high chance that a significant portion of a
drug will be metabolized to inactive products prior to its arrival at the site of action.
This phenomenon is called the first-pass effect and is further described in Chapter 2.
Liver metabolism of an oral drug after its absorption can be so intensive, that it is
practically impossible to use this route of administration in some cases. Delayed
onset of effect should be also considered in orally given drugs in comparison to, for
instance, i.v. injections, because the drug has to pass through the GIT to a part
suitable for its absorption, then it has to pass the liver and accumulate at the site of
action in a level sufficient to evoke the effect.
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Scheme 1. Classification of systemic routes of administration with respect to the site
of administration.
3.2.2 Routes of administration to evoke only a local effect of a drug
3.2.2.1 Intraurethral and intravesical administration
Intraurethral drug use is not very common. Sometimes it is used prior the
catheterization of urinary bladder, when a local anaesthetic is applied to decrease the
pain during the catheter insertion. Intravesical administration is used for both
diagnostic purposes in the case of florescent cystoscopy and also to decrease the
systemic toxicity of drugs. An example of this would be in the case of
chemotherapeutic agent doxorubicin that is used in the therapy of urinary bladder
tumours or the BCG vaccine that is administered intravesicaly in the prevention of the
same tumours.
3.2.2.2 Intracavernous administration
Erectile dysfunction is the main indication for drug injection into the corpora
cavernosa. To be more specific, the synthetic analogue of prostaglandin E1
alprostadil is used. With the same structure as the endogenous molecule, it is
metabolized at the site of administration with minimal absorption to systemic
circulation.
3.2.2.3 Dental and gingival administration
These routes of administration are characteristic for dentistry. Toothpastes applied
directly to teeth with a high content of fluorides are used to prevent or treat tooth
decay. A mixture of paraformaldehyde with lidocaine for devitalization of tooth pulp or
62
framycetin for antiseptic treatment of root canals prior to their filling are other
examples of dentally administered drugs. Antiseptic and local anaesthetic solutions
or semi-solid preparations are administered onto gingiva in cases of inflammatory
disease like gingivitis or parodonditis.
3.2.2.4 Endotracheopulmonal administration
The only indication in which endotracheopulmonal drug administration is used is
respiratory distress syndrome in preterm newborns when a suspension of
phospholipids is given to substitute missing surfactant in the airways.
3.2.2.5 Intraaural administration
Various formulations can be administered into the external ear duct including drops,
ointments and medicated tampons. The most common pharmacotherapeutic groups
are antiphlogistics, antibiotics, and anaesthetics. Oil and water solutions for the
softening and removal of ear wax are also available.
3.2.2.6 Intraamniotic administration
Intraamniotic injections are highly risky during physiological pregnancy. The only
situation in which drug is delivered by this route is for the induction of abortion with
dinoprostone (prostaglandin E2) in conditions of pathological development of the
foetus.
3.2.2.7 Conjunctival administration
Administration of drugs to the conjunctiva is the most common method of drug
delivery in ophthalmology. Nevertheless, only a portion of drugs administered via this
route influence the conjunctiva itself, most drugs also influence other parts of the eye
like m. ciliaris and m. dilatator pupilae or regulate the production of intraocular fluid.
Conjunctival drug administration delivers the drug to the whole surface of the eye
bulb in general. There is a multilayer barrier protecting the epithelium of cornea on
the surface of eye ball. Individual layers of this barrier each have different characters
to the lipid outer layer, with the aqueous phase representing the thickest part to the
mucin tightly attached to corneal epithelium. Drugs like mydriatics, miotics or
cycloplegics must have amphiphilic structure to penetrate through this complicated
structure to the sites of their action. The eye bulb is permanently hydrated and
washed with produced tears. Therefore, one of the essential requirements of
63
ophthalmologics is to be non-irritant. That can be achieved with isotonic and isoacidic
preparations. In the opposite case, excessive lacrimation leads to fast drug removal
and discontinuation or shortening of the drug’s effect. Ointments can be used to
prolong the time for which drugs stay on the eye surface. The ointment base slowly
melts or dissolves which can cause blurred vision. Eye ointments are therefore
suitable for administration before going to bed, while eye drops with the same active
substance can be used during daytime. It should be stressed that eye drops are often
administered improperly. The correct way to use these formulations is the following:
1. Wash your hands. 2. Heat the bottle with eye drops to body temperature to
decrease its irritant effect. A few minutes in the clenched palm or in the pocket of
clothes worn should be enough. 3. Give one drop to the eye, close it and gently press
the tear duct for approximately 1 minute. Compression of the tear duct is important
namely in preparations containing drugs capable of absorption via nasal mucosa.
Because of high concentrations of drugs in ophthalmologics, even a small volume of
preparation that gets to the nasal cavity via the tear duct can lead to significant
systemic adverse effects. It is not rational to administer more than one drop to an eye
because the volume of preparation in one drop is even higher than the volume that
can be spread over the eye bulb. Typical drugs administered to eye are previously
mentioned miotics and mydriatics, or antiglaucomatics, antihistamines,
decongestants, antiinfectives, H1 antihistamines, or artificial tears.
3.2.2.8 Intraocular (intravitreal) administration
Intraocular administration is an invasive type of drug administration when a solution
of drug or implant is injected or inserted directly to the chamber of the eyeball. Such a
measure is used to deliver monoclonal antibodies in the therapy of macular
degeneration. These antibodies target the VEGF that plays an important role in the
pathophysiology of this disease. This is also the only route of administration with the
possibility of achieving a local effect of drug on the retina. Mydriatics and
antiphlogistics are also injected intraocularly to induce post-operative mydriasis and
to decrease pain after eye lens transplantation.
3.2.2.9 Intrathecal administration
Drug solutions infused or injected into the spinal cavity represent the intrathecal drug
delivery route. This route of administration presents an opportunity for drugs
64
incapable of passing the hematoencephalic barrier to cross this structure. Except for
drugs that do not cross the hematoencephalic barrier, this administration route can
also be used to minimize the systemic side effects of drugs that target the spine and
brain. The spinal cavity is usually accessed in the lumbal area (L3/L4 or L4/L5). It is
appropriate to aspire the same volume of liquor as volume of administered drug prior
to its intrathecal injection to maintain intracerebral pressure. Different solutions with
respect to their oncotic pressure can be delivered. Apart from isotonic solutions,
hypo- and hypertonic solutions can be also given. Suitable positioning of the patient
then moves the solution to the specified part of the spine and also enables us to
influence segments of the spine other than lumbal. This measure is used in spinal
anesthesia. In some cases, namely when there is a need for repeated intrathecal
administration of a drug, a subcutaneously implanted pump with a catheter inserted
into the spinal canal can be used. This type of device is used for instance in
chemotherapeutics or the central muscle relaxant baclofen.
3.2.2.10 Intraarticular administration
Drugs injected directly into the joints are used in degenerative disorders such as
rheumatoid arthritis. Glucocorticoids with strong antiphlogistic effects, radionuclides
or hyaluronic acid can be delivered in this way. This route of administration is also
suitable for autologous transplantation of expanded chondrocytes. Drugs can be
injected into big joints (shoulder, knee), but also to smaller ones (wrist,
temporomandibular joint) if needed. Administration itself often requires appropriate
positioning of the patient to facilitate the insertion of the injection needle into the joint
cavity.
3.2.2.11 Oral administration
Oral administration in this section describes the administration of a drug into the oral
cavity to obtain a local effect. Different formulations are used for this method of
administration including solutions for gargling and irrigation, lozenges, mucoadhesive
tablets, or oral sprays. It is suitable to use drugs that are not absorbable from the oral
cavity and are safe enough even when accidentally swallowed. Typical groups of
drugs fulfilling these requirements are local anaesthetics, antiseptics, and some anti-
infectives.
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3.2.3 Administration routes used for both local and systemic effect
3.2.3.1 Vaginal administration
The vaginal environment is characteristic in its microflora and mucosa, which can be
used for the systemic delivery of drugs. Anti-infectives in the form of vaginal globules,
suppositories or fluids for irrigation are the most common types of preparations for
local use in the therapy of microflora disbalance. Uterotonic prostaglandins are used
in local preparations in obstetrics. They are administered in the form of vaginal
tablets to the external orifice with specialized applicators. Prostaglandins promote
contractions of myometrium and enhance cervical ripening.
Systemic effects of vaginally delivered drugs are achieved with combined hormonal
contraceptives. These are administered in the form of vaginal rings with controlled
release of drug usually for 21 days. It is a type of continuous drug release and its
advantage over classical oral contraceptives is a lower dose of oestrogen thanks to
elimination of the first pass effect and increased adherence to therapy thanks to a
simpler dosing schedule. On the other hand, some adverse effects including local
irritation can develop.
A similar principle of continuous drug release is used in intrauterine devices.
Monocomponent gestogen preparations containing levonorgestrel are used as
hormonal contraception. Intrauterine devices are introduced with specialized
applicators supplied with the preparations. The drug is released for a long time (3-5
years). Its disadvantage is complicated discontinuation of therapy and requirement of
device removal after the end of its lifetime.
3.2.3.2 Topical administration on skin and transdermal drug delivery
Local administration of drugs to skin is used mainly in dermatology. The character of
drugs administered in various semi-solid or liquid formulations is wide and contains
drugs from antiseptics, anti-infectives, antiphlogistics, or drugs typical for
dermatology like emollients, granulating and epithelizing agents. Adjuvants play an
important role in topically administered drugs on skin where they can enhance the
penetration of a drug to deeper layers of skin or can have therapeutic effects
themselves (substitution of epidermal lipids, mechanical protection). Local irritation of
the administration site is the most common complication of drugs administered
66
topically. Nevertheless, topical drugs administered chronically or on large areas of
the body surface (glucocorticoids, boric acid) can evoke even systemic adverse
effects.
Transdermal drug administration is a route of non-invasive drug delivery. The
molecules of a drug must have suitable characteristics (small and lipophilic) to be
able to penetrate the skin into blood capillaries and then be absorbed to evoke a
systemic effect. Drugs can be administered continuously transdermally, patients
adhere to this type of therapy well, and the drug can be simply discontinued. First
pass effect is also eliminated in contrast to oral drug administration. Transdermal
therapeutic systems (TTS) with controlled release of the drug are mostly represented
by transdermal patches. A disadvantage of this method of drug administration is the
slow onset of drug action and the higher cost of this type of pharmacotherapy.
Nicotine for substitution therapy in the smoking cessation, combined oral
contraceptives, or opioid analgesics are available in TTS. Less often liquids, gels, or
creams with a dose dispenser for accurate dose measurement are used for
transdermal delivery. These are not used for continuous, but for intermittent drug
administration and they are used for example, in hormonal substitution therapy with
estrogens.
3.2.3.3 Intranasal administration
Nasal formulations with local effect mostly contain (similarly to ophthalmologics),
decongestants, H1 antihistamines, various antiphlogistics or anti-infectives. These are
administered in the same pharmaceutical forms as intranasal drugs with systemic
effects like nasal sprays, drops or ointments. Opioids (fentanyl, pentazocine),
antivirals (acyclovir in liposomes), or hormones (oxytocin, ADH) are administered
intranasally to produce a systemic effect. This type of drug application is noninvasive,
with a fast onset of drug effect and with elimination of first pass effect.
3.2.3.4 Inhalational administration
Sizes of particles of the inhaled drugs are important in this route of application. The
bigger the size of the particles the shorter the journey of the drug in the airways and
the more proximal the site of its deposition. On the other hand, molecular dispersions
can reach the alveoli and can penetrate into the bloodstream. Local drug
67
administration in the airway is used mainly in diseases of the respiratory system such
as bronchial asthma. Inhalations themselves do not guarantee a local effect,
therefore manifestations of systemic adverse effects should be expected after huge
doses of drugs such as glucocorticoids or β2 sympathomimetics. Inhalations are also
the only possible method of administration of gaseous drugs under normal
conditions. They are used namely in anaesthesiology for the administration of
inhalational anaesthetics. A great advantage of these inhalations is easy regulation of
the level of anaesthesia and its fast discontinuation in case of need. On the other
hand, this administration route requires specific instrumentation in the case of volatile
liquids (sevoflurane, isoflurane) that ensures accurate concentration of the drug in
inhaled air. A gas container equipped with a reduction valve is necessary for the
administration of gaseous anaesthetics such as nitrous oxide or xenon.
There is a possibility to use insulin in inhalations for the treatment of diabetes in
outpatients. Only short-acting insulins for the control of postprandial glycaemia are
available in this type of formulation today.
Correct technique of inhalation is essential to obtain the required effect of a drug.
Problems with this route of administration can be seen in the elderly and children. It is
necessary to carefully synchronize the release of drug with its inhalation, what can be
complicated in these subcategories of the population. Various additional devices for
inhalations like spacers or containers that are activated (releasing a measured dose
of drug) by suction during aspiration can help in these patients. The most common
complications of inhalations include: local irritation with cough and risk of bronchial
spasms. Cold vapours of propellant released from pressurized containers can also
increase the risk of bronchial spasms. Advantages of inhalations are similar to other
parenteral types of drug delivery and include elimination of the first pass effect. Fast
onset of the effect can be also of importance for instance in the case of quick-relief
antiasthmatics.
3.2.3.5 Transbuccal, sublingual administration
Similarly to nasal mucosa, the oral cavity is richly perfused and is suitable for
absorption of drugs with small lipophilic molecules. Fast onset of effect suitable for
acute situations is obtained and first pass metabolism is eliminated after transbuccal
or sublingual drug delivery. Drugs are applied in the form of sprays, mucoadhesive or
68
dispersible tablets. Nitro-glycerine for the treatment of myocardial ischemic pain,
analgesic fentanyl for breakthrough pain in oncology, hypnotics (zolpidem), or
antiemetics (ondansetron) are absorbed from the oral cavity. Sublingual
administration is also used for the administration of sublingual tablets. These types of
administration evoke only systemic effects. For a local effect of a drug in the oral
cavity, oral formulations as described above can be used.
3.2.3.6 Rectal administration
Rectal drug administration can be a suitable alternative if oral drug administration is
impossible (nausea, unconsciousness, or children). Only a part of the drug absorbed
from the rectum enters portal circulation as most of the perfusing blood goes directly
to systemic circulation via the vena cava inferior. The first pass effect decreases the
dose by approximately 30 % in contrast to oral delivery. Rectally administered drugs
with systemic effect are, for instance, antiemetics, antimigrenics, or diazepam. The
speed of onset of effect after rectal administration is determined by pharmaceutical
form. The absorption is fast from aqueous and spirituous solutions whereas delayed
absorption caused by adjuvants can be seen in some types of suppositories.
Examples of drugs administered for their local effect in the rectum are laxatives
(glycerol), antiphlogistics (mesalazine), or local anaesthetics.
3.2.3.7 Peroral (oral) administration
Administration by mouth represents a natural method for the intake of various
substances and it should be preferred every time it is possible. A variety of drugs and
pharmaceutical forms for oral intake give us many possibilities for the selection of
suitable pharmacotherapeutic strategies. On the other hand, the oral route of
administration is highly variable with respect to interindividual differences in the
conditions and functions of the gastrointestinal tract (GIT). That can be a reason for
dose optimization, change in the drug dosage form or in exceptional cases for the
change of the administration route. The first pass effect should be also stressed as
an important factor influencing the bioavailability of orally administered drugs.
Some drugs, like antacids, laxatives, or antibiotics (rifaximin), are not absorbed after
oral intake and evoke only local effects within the GIT. An advantage of these drugs
is minimal adverse effects. Nevertheless, possible drug-drug interactions with coadministered
drugs should always be evaluated. A typical example is concomitant
69
use of adsorbents in the treatment of diarrhoea (diosmectite or activated charcoal)
together with other drugs.
Absorption of drugs from the GIT is not only determined by physico-chemical
properties of the drug itself, but can also be significantly influenced by its localization
within the GIT. Drugs can be ionized in specific parts of the GIT with respect to
changes of pH in various segments of this system. Ionization also determines a
drug’s lipophilicity and therefore influences the process of absorption. Weak acids are
absorbed from the stomach, if released readily from the formulation after use.
Contrary, weak bases have to reach the duodenum and jejunum with a more alkaline
pH to be absorbed. Therefore, a longer time delay until effect can be seen in drugs
with a weak base character in comparison to acids.
An essential factor influencing absorption of a drug from the GIT is also diet and
intestinal content. Decrease of intestinal passage should be expected after a drug is
co-administered with food, whereas an increase is probable when a drug is
administered on an empty stomach. This effect again influences the time delay which
describes the delay from drug administration to the start of its absorption. Diet can
even interfere with the absorption of some drugs. Tetracyclines and calcium ions,
common in milk products or mineral waters, can form un-absorbable complexes. In
these cases, patients should avoid specific types or food, or should be instructed to
use the drug on an empty stomach, which means at least 30 minutes prior to or 120
minutes after the meal. Generally, it is better to use drugs together with a meal if the
interaction of drug and food is not known, because of lower GIT irritation.
Drug dosage form is another substantial factor determining drug absorption from GIT.
Two different groups of pharmaceutical forms can be described with respect to their
influence on the time course of a drug’s plasma level. The first group are “classical”
forms that do not influence the release of the drug from the formulation. The drug is
released at once and the process of absorption depends only on the properties of the
drug itself (Fig. 17a). Examples of these forms are solutions, suspensions, noncoated
capsules and tablets. The second type of these drug dosage forms are
preparations with controlled release of the drug. Various reasons, why controlled
release of active substance is advantageous, as well as various mechanisms by
which drug release can be controlled, exist. One of the possibilities is the release of
drug in pulses (Fig. 17b), where drug is released either in one or more pulses
70
separated by a defined time interval. Contrary to “classical” forms, a latency from the
administration of the preparation to the release of the first pulse is precisely defined.
Antiasthmatics with delayed release can prevent nocturnal attacks that are most
common in the early morning. The drug is used in the evening and is subsequently
released in the required period. This principle allows us to decrease the total amount
of the drug administered and therefore the risks of adverse effects. A similar principle
can be used to prevent development of tachyphylaxis (nitrates).
Another type of drug dosage form with controlled release of active substance is drugs
with prolonged, extended, or slow release. Contrary to the previous types of
preparations, the drug is not released at once. Gradual release of the drug for a
longer time ensures prolonged duration of its effect and dosing interval can be also
prolonged. Finally, the patient’s adherence and compliance to the therapy increases.
Mechanisms that can control extended release of a drug from the formulation involve
semi-permeable membranes, matrix systems, osmotic, or microparticle systems. The
time course of drug plasma levels in extended release preparations show less
fluctuations than “classical” formulations and are more similar to preparations with
continuous drug release (Fig. 17c). Diuretics in the treatment of hypertension
(indapamide) or calcium channel blockers (verapamil) are examples of drugs used in
these types of preparations.
Drug dosage forms combining the abovementioned systems of drug release exist. A
part of a drug can be released immediately after administration to insure fast onset of
effect, whereas the rest of the drug is released slowly to prolong its efficacy (Fig.
17d).
71
Figure 17. Time course of plasma levels of drug in peroral drug dosage forms with a)
classical; b) pulse; c) prolonged; d) combined drug release
a)
b)
72
c)
d)
3.2.3.8 Injectional types of drug administration
Individual types of injections differ namely in the speed of drug absorption, in the
volume of preparation that can be administered and in the character of the liquid that
can be used. With respect to invasivity of administration, injections are administered
mostly by healthcare professionals and are used namely for inpatients. Exceptions
are subcutaneous injections with minimal risk of improper drug administration and
73
related complications. They are used for the administration of insulins or lowmolecular
weight heparins.
True aqueous solutions are used for intravascular administration because of the risk
of thromboembolism. In case of systemic toxicity of local anaesthetics
microemulsions can also be used. Drugs injected directly to the bloodstream have
an almost immediate onset of effect because of lack of absorption and fast
distribution of active substance to its target sites. Superficial veins that are visible to
the naked eye are easily accessible for injections in comparison to arteries hidden
deeper in the tissues. Therefore, intravenous (i.v.) is preferred to intraarterial (i.a.)
drug administration. Venepunction into the forearm of the non-dominant hand is the
most common site of intravenous injections. In newborns, venepunction of the head
veins is an alternative. Surgical preparation of a vein (vena saphena magna, vena
basilica, or vena mediana cubiti) is an option in case venepunction is not possible.
Intraarterial drug administration is rare and it is used in case we need to aim the
effect of a drug towards an organ perfused by distinct artery. An example of such a
measure can be intraarterial application of chemotherapeutics into arteria hepatica in
the treatment of hepatocellular carcinoma or liver metastases. There are almost no
limitations of administered volume in intravascular drug administration. Nevertheless,
intravenous infusions should be used in case of big volumes or in case of continuous
drug administration. Peripheral or central catheters are used in case of repeated
intravascular administration to prevent traumatisation of the patient by repeated
venepunctions. A subcutaneous venous port with catheterisation of jugular vein can
be also used.
Typical drugs for intravenous administration are antibiotics (aminoglycosides,
glycopeptides), chemotherapeutics (methotrexate, anthracyclines), or general
anaesthetics (propofol). Examples of intravenous drugs with minimal distribution and
practically only local effects within the bloodstream are unfractioned heparin or
various blood derivates.
Disadvantages of intravascular drug administration are the risk of infection and in
some cases difficulty in to finding suitable veins for venepunction (children, elderly,
shock or polytrauma). In these cases, intraosseous (i.o.) drug delivery can be used
as an alternative to intravenous administration in prehospital emergency care. Drug is
delivered directly to the marrow of long bones (tibia, humerus, femur, sternum).
74
Intraosseous needles or catheters are firstly introduced with manual, semi-automatic,
or automatic devices. The site of implantation can be pre-treated with local
anaesthetic to prevent pain. The introduction of a needle is described as pain free
contrary to the aspiration of marrow for the verification of correct position of needle.
Drugs that are insoluble in aqueous vehicles can be administered in oily injections
(progesterone), or emulsions intramuscularly (i.m.). Similarly drugs soluble in water
can be administered in suspensions to prolong their release, absorption, and effect
(procaine penicillin). Intramuscular injections are administered mostly to m. gluteus
medius or maximus, less often to m. quadriceps femoris. Risk of vein or nerve
impairment is minimal at these sites. Nevertheless, aspiration to prevent
venepunction prior to the drug being administered is required. The volume of a
preparation injected intramuscularly is determined by the injection site and patient’s
status and it should not exceed 5 ml. Multiple injections to different target sites should
be used in case bigger volumes have to be injected. The effect of intramuscularly
injected drugs occurs usually 10-20 minutes after the injection. Venepunction, nerve
injury, development of abscess, or infection at the injection site are the most common
complications. Injection sites should vary in case of repeated i.m. injections.
Injections of true solutions, emulsions, or suspensions are administered
subcutaneously (s.c.). A 25-35 mm needle is usually inserted into the skin fold under
a 90°or 45° angle. The volume of injected drug is usually around 1 ml (2 ml is the
maximum for one injection site). This type of injection is mostly used for chronic
administration of drugs that cannot be delivered with non-invasive methods
(proteins). Subcutaneous injections are safe and can be safely administered by
outpatients themselves, in comparison to the previous types of injections.
Subcutaneous implants or catheters (insulin pumps) can be used for continuous drug
delivery. The most suitable site for s.c. injections is the later aspect of the upper arm
and abdomen in the umbilical region. Alternatively, drugs can be subcutaneously
injected in the area of the thighs. Absorption of a drug after s.c. delivery is influenced
by physical activity. With respect to that, the absorption is the fastest and with the
lowest variability after injection to the abdominal area. Similarly to i.m. injections,
aspiration prior to drug administration is required to exclude accidental i.v. injection.
75
Intradermal injections are only of diagnostic importance. Solutions of allergens
administered in tenths of millilitres are used in allergology to test sensitivity in the
prick test.
3.3 Factors determining selection of administration routes
Selection of suitable administration routes can play an important role in the
pharmacotherapy itself. Suitable route of drug delivery can lead not only to the
desired therapeutic effect, but also to decreased risk of adverse effects or to
simplification of the dosing schedule. These effects also increase the patient’s
adherence to prescribed therapy. Not all drugs are suitable to be delivered by all
administration routes. Essential factors that determine the possibilities of drug
administration involve its chemical-physical properties. There can be a limited
number of pharmaceutical forms suitable for a drug. For instance, it is impossible to
prepare tablet or ointment from a drug that is gaseous under room temperature. Each
drug dosage form is also suitable for the specific route of administration and the
effect of a drug can be totally different when the preparation is used incorrectly. For
instance, it is hard to imagine that a TTS patch with hormonal contraceptives would
be taken orally. It would be almost impossible to swallow the device and the amount
of drug released and absorbed from the device would hardly be predictable. Another
problem is that even if there is a possibility to prepare the required drug dosage form
with the drug, the drug must also be suitable for the required route of administration.
It is purposeless to deliver peptides orally or in TTS, although it is not a problem to
prepare tablets, capsules, or patches with peptides. More about the influence of
physico-chemical properties on the drug’s pharmacokinetics can be found in Chapter
2.
Another factor significantly influencing the administration route is the drug indication.
Local drug administration should be always preferred to systemic use to prevent
possible toxicity. Therefore, the administration route of glucocorticoids will differ in the
treatment of asthma (inhalational route preferred) and in the management of
autoimmune diseases like sclerosis multiplex, when glucocorticoids are administered
systemically. An important criterion for the selection of administration routes is the
severity of the patient's condition. Administration with the fastest onset of drug effect
76
and a minimal delay in drug absorption (ideally i.v. administration) after application
should be selected in acute or emergency situations. Intravenous administration
doesn’t always guarantee fast onset of the effect. In some cases, the drug's mode of
action delays its effect (warfarin) or the body must first deplete physiologic stores of
the substances involved in pathophysiologic conditions. The latter case applies in
thyrostatics (propylthiouracyl, metimazol). These drugs interfere with the synthesis of
thyroid hormones, which are stored in the human body in amounts sufficient to cover
its needs for approximately one month. It is always necessary to evaluate benefits
and risks of individual administration routes. Based on this principle, it is logical to
use “more risky” and namely invasive routes of administration that can harm the
patient in serious and life-threatening situations.
The administration route can be significantly influenced by a patient’s comorbidities.
Inflammation at the administration site plays an important role in locally acting drugs.
The speed or extent of absorption can be modified due to a change in pH of the
inflamed area. Orally administered drugs can be rapidly removed in cases of vomiting
or diarrhoea. Another complication of peroral therapy is suppression of the first pass
effect and increase of drug bioavailability due to the hepatopathy. Comorbidities with
an impact on drug absorption include impaired peripheral perfusion in transdermal
administration.
Co-administration of drugs can cause formation of un-absorbable complexes
(activated charcoal + with other orally administered drugs). A simple solution to
prevent these interactions is possible. Sufficient delay between administrations of
individual drugs is advisable. Besides that, another mechanism of drug-drug
interactions is described. One of the drugs may change the function of an organ
important for the absorption of the other drugs. Simple time separation of these drugs
would not be effective. An example of such an interaction is the use of laxatives or
prokinetics together with other oral formulations or the use of vasoconstringents that
decrease or slow down the absorption from TTS.
77
3.4 New trends in drug administration
Recent medicine has probably discovered all possibilities for drug delivery to the
human body. Most of the innovations in the area of drug delivery are therefore
targeted at drug dosage forms. Formulations of second (with controlled release) and
third (with controlled distribution) generations are the results of such innovations. The
goal of these inventions is to increase the safety and efficacy of administered drugs.
Decreased fluctuations of a drug’s plasma levels during repeated administration
minimizes the risk of inefficacy or toxicity of the drug in the part of the dosing interval
when the drug gets out of the therapeutic window. Targeted biodistribution with
specific drug “carriers” enables us to target the effect of a drug towards specific
tissues and again makes the pharmacotherapy safer. Limited toxicity and
simplification of dosing regimens increases the adherence of the patient to prescribed
pharmacotherapy. In some cases, the modification lies in drug release. Some of the
formulations release the medicine “on demand” (triptans in treatment of migraine or
opioids in the treatment of breakthrough pain). Last but not least, some modifications
are aimed at the possibilities for non-invasive routes of administration and also how
they can be extended for drugs that are available only as injections today.
The transdermal route of administration is an interesting prospect for innovative
formulations. There are transdermal patches, that release the drug when needed,
available for clinical use today. Those are suitable for the treatment of breakthrough
pain in oncology. A patch is equipped with control mechanisms that allow the release
of a specified amount of a drug in a time period to prevent the risk of drug
overdosing. Another interesting possibility is to use transdermal administration of
drugs that do not penetrate through skin under physiologic circumstances. It is
necessary to disrupt the epidermis and create pores with microneedles or other
suitable devices. The drug then diffuses through these micropores to the dermis with
blood capillaries and is absorbed. An advantage of this “semi-invasive” method is the
possibility to deliver drugs with a high molecular weight. It seems that this type of
drug application could be an alternative to some types of injections (e.g. vaccination).
An interesting alternative to injectional administration is represented by intestinal
patches that could be used to deliver macromolecules including peptides.
Micropatches are millimetres or micrometres in size and are delivered in gelatine
78
capsules. The micropatch consists of a protective layer that protects the drug from
destruction by intestinal juices, enzymes, and an adhesive layer that attaches it to the
mucosa of the GIT and through which the drug is released.
Some research in this field is also concerned with the prospects of various particle
and nanoparticle systems. They can be used to decrease the toxicity or enable
targeted biodistribution of drugs. Biocompatible liposomes with a membrane formed
from a phospholipid bilayer can be used as a carrier for both polar and nonpolar
drugs. Liposomes are highly variable with respect to their size and membrane
characteristics. Their surface can be pegylated – substituted with polyethylenglycol.
This modification increases their hydrophilicity and the duration of their circulation in
plasma. Nanoparticles are also highly variable with respect to material, size, and
surface modifications. More about the problems of innovative drug dosage forms can
be found elsewhere (Current Opinion in Pharmacology, 36, 2017).
Literature
Máchalová, A., Babinská, Z., Juřica, J., Dovrtělová, G., Kostková, H., Landa, L., Merhautová,
J., Nosková, K., Štark, T., Tabiová, K., Pistovčáková, J., Zendulka, O. Farmakologie pro
studenty bakalářských oborů na LF MU. 2016.
79
4. Adverse drug reactions
The adverse drug reaction (ADR) is an unintended adverse reaction to the
administration of any dose of the drug. In developed countries, it is estimated that
adverse drug reactions are the cause of up to 6-8 % of hospitalizations, and ADRs
even occur in 10-20 % of hospitalized patients. According to some resources,
adverse drug reactions are considered the 4th leading cause of death. Approximately
0.32% of hospitalized patients die due to an adverse effect in hospitals. Resolving
the consequences of adverse drug reactions also significantly increases the overall
cost of treatment. These costs could be utilized in more meaningful way, if at least
some of these adverse reactions could be avoided by rational pharmacotherapy.
Attention should be drawn to distinguishing Adverse Drug Event (ADE) from Adverse
Drug Reaction. The WHO and EMA distinguishes ADE as any unfavourable and
unintended sign (including an abnormal laboratory finding, for example), symptom, or
disease temporally associated with the use of a medicinal product, whether or not
considered related to the medicinal product. In contrast, ADR describes in response
to a drug that is harmful and unintentional and which occurs at doses normally used
in humans for the prophylaxis, diagnosis, or therapy of diseases or for the
modification of physiological functions and a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility, i.e., the relationship
cannot be ruled out. Schematically, the relationship between ADE and ADR is shown
in Figure 18.
Figure 18. The relationship between ADE and ADR
80
The old term "side effect" has been used in various ways in the past, usually to
describe negative (unfavourable) effects, but also positive (favourable) effects. It is
recommended that this term no longer be used and particularly should not be
regarded as synonymous with adverse event or adverse reaction.
Adverse drug reactions are closely monitored by national drug authorities. From the
perspective of regulatory authorities, adverse reactions can be categorized according
to their frequency of occurrence as defined by the SmPC. The most common side
effects are reported as very common (with a frequency of ≥ 10%), followed by
common (1% - 10%), uncommon (0.1% - 1%) rare (0.01% - 0 1%) or very rare
(<0.01%). The SPC summarizes the ADRs into categories according to their
occurrence on different organ systems (e.g. cardiovascular diseases, psychiatric
disorders, eye disorders, etc.). Pharmacovigilance is the science and activities
relating to the detection, assessment, understanding and prevention of adverse
effects or any other medicine-related problem. The European Medicines Agency
(EMA) coordinates the European Union (EU) pharmacovigilance system and
operates services and processes to support pharmacovigilance in the EU. Within the
framework of individual national or supranational regulatory authorities (SÚKL, EMA),
specialized committees and departments are established to ensure safety and to
monitor adverse effects. The Pharmacovigilance Department thus operates within the
State Institute for Drug Control (SÚKL, Czech), and the European Medicines Agency
has established a PRAC (Pharmacovigilance Risk Assessment Committee).
4.1 Classification of adverse reactions by nature and
mechanism of origin
Depending on the nature and mechanism of the adverse reaction, adverse reactions
can be divided into several groups:
4.1.1 Type A adverse reactions
Type A (augmented) side effects result from the enhanced 'normal' effects of drugs
that are seen at the usual therapeutic doses. These side effects are dose-dependent
and predictable. By appropriate use of drugs, in particular by an appropriately
selected indication and dose, these adverse reactions are usually avoided. Examples
81
include opioid-induced respiratory depression, warfarin-induced bleeding,
hypoglycaemia following insulin and sulphonylureas, or anticholinergic syndrome
following tricyclic antidepressants or antipsychotics.
4.1.2 Type B adverse reactions
Type B ADR (B-bizarre) is an unexpected response to drug. It is not originated from
the mechanism of action and is rare; these ADRs may therefore only appear for the
first time after the medicinal product has been placed on the market. Type B NRCs
include allergic reactions or idiosyncrasia - an abnormal drug response due to
genetic variation in a particular patient (e.g. receptor, enzyme, transporter
polymorphism, resulting in a qualitatively completely different response to drug
administration).
An allergic reaction is an abnormal immune system response mediated by antibodies
or T lymphocytes occurring after previous contact with an allergic substance
(allergen). Thus, unlike idiosyncrasia, they appear at full intensity only after repeated
drug administration.
4.1.3 Type C adverse reactions
Type C (continuing, continous, chronic) is a consequence of long-term administration
of the substance and may have an additive character (cumulative effect, even at low
therapeutic doses).
Examples of long-term ADRs include nephrotoxicity of some non-steroidal antiinflammatory
drugs or analgesics-antipyretics (mainly phenacetine) or osteonecrosis
of the jaw bone following bisphosphonate administration.
4.1.4 Type D adverse reactions
Type D (delayed) adverse effects are also referred to as “late ADR”. These ADRs
appear longer after drug administration (even several years) and are therefore
sometimes difficult to be identified as adverse reactions; causality is difficult to be
proved.
Examples of type D ADRs are leucopaenia following the administration of the
cytostatic lomustine or the late procancerogenic and teratogenic effects of some
82
cytostatics or hormones. Another example is tardive dyskinesia after administration of
neuroleptics.
4.1.5 Type E adverse reactions
This type of ADR occurs only after discontinuation of the drug (hence E-end-of-use).
Examples include insomnia and anxiety after discontinuation of benzodiazepines or
hypertension upon abrupt withdrawal of beta-blockers. In the latter case, we refer to
the so-called "rebound phenomenon" - the cause is the adaptation mechanisms on
the receptors after long-term administration of receptor antagonists, which leads to
up-regulation (i.e. increase in the number of receptors). Consequently, if this
increased number of receptors is no longer occupied by the antagonist (drug) but by
their natural ligand (noradrenaline = natural agonist), it may result in increased blood
pressure and tachyarrhythmia.
4.1.6 Type F adverse reactions
Sometimes, a special type F is also classified, indicating therapeutic failure. A Type F
side effect is an unexpected therapy failure. The cause may be unknown (e.g.
primary resistance of microorganisms that should theoretically be susceptible to
antibiotics), but it is also in unrecognized drug interaction where, for example, due to
the induction of enzymatic biotransformation, effective drug concentrations decrease
more rapidly and therapy fails.
Drugs that most often (considered as % ADR per number of uses) cause
hospitalization due to an adverse effect include antitumor drugs (classical cytostatics
and biological therapy), as well as vaccines, antibiotics, anticoagulants or drugs of
the cardiovascular system.
4.2 Classification of adverse reactions by causality
evidence
The causality of an adverse event is always studied very carefully, however, it is not
always clear. According to causality evidence, the strength of evidence can be
classified in several stages of causality (according to WHO). The highest degree of
83
causality is “certain” - when a clinical event (including an abnormality of one of the
laboratory parameters) occurs with plausible time relationship to drug intake and
cannot be explained by other circumstances (other disease, other drug or chemical
substances) and, at the same time, response to withdrawal of the suspected drug is
plausible (pharmacologically, pathologically). The adverse reaction is well described
pharmacologically and phenomenologically and is verified by drug re-challenge.
The category is "probable": A clinical event (including an abnormality of any of the
laboratory parameters) occurs sequentially with drug administration and is unlikely to
be attributed to disease or to other circumstances (other disease, other drug, or
chemicals). The response to withdrawal of suspected drug is clinically reasonable.
The rechallenge is not required. „Possible": A clinical event (including an
abnormality of one of the laboratory parameters) sequentially with drug
administration, but may be explained by the disease or by the administration of
another drug (chemical). Information on the follow-up after withdrawal is lacking or
unclear.
“Unlikely”: A clinical event (including an abnormality of one of the laboratory
parameters) occurs with a time to drug intake that makes a relationship improbable
(but not impossible) and the event may be explained by disease or administration of
another drug (chemical).
“Conditional/Unclassified”: A clinical event (including an abnormality in any of the
laboratory parameters) that has been reported as an adverse reaction but more data
for proper assessment is needed or additional data is under examination
“Unassessable/Unclassifiable”: Report suggesting the ADR that cannot be judged
because information is insufficient or contradictory and data cannot be supplemented
or verified.
There are more algorithms for assessing causality of adverse reactions, some of
them are internationally recognized and used in pharmacovigilance studies, e.g. the
so-called 10-item classification (scale, nomogram) Naranjo (according to the first
author of published work from 1981), resp. a newer and more sophisticated Liverpool
Adverse Drug Reaction Causality Assessment Tool.
84
4.3 Classification of ADR to serious / non-serious
Accordingly with the valid legislation (EMA Note for guidance on clinical safety data
management: definitions and standards for expedited reporting (CPMP/ICH/377/95)
or in the Czech Rep. Act on Pharmaceuticals No. 378/2007 Coll.), we have to
distinguish between serious and non-serious ADRs and expected and unexpected
ADRs.
A serious ADR is one that causes
• death or is life-threatening
• requires inpatient hospitalisation or prolongation of existing
hospitalisation
• results in persistent or significant disability/incapacity
• cause a congenital anomaly/birth defect.
All other ADR are therefore non-serious
Unexpected side effects are those where the nature or severity of which is not
consistent with the applicable product information (e.g., Investigator's Brochure for an
unapproved investigational medicinal product).
4.4 Reporting of adverse reactions
In the Czech Rep. (but also other European countries), pursuant to the
Pharmaceuticals Act, (or pursuant to the EMA Note for guidance on clinical safety
data management: definitions and standards for expedited reporting
(CPMP/ICH/377/95), MAH is obliged to report serious adverse reactions within a
period of 15 days, while healthcare professionals are obliged to report
immediately unexpected or serious adverse reactions to the State Institute for
Drug Control or distinct national regulatory authority (e.g. MHRA).
In addition, MAHs are required to report, at regular 3-year intervals, newly identified
adverse reactions - all, including non-serious or expected, to specify their Periodic
Safety Update Report (PSUR), which will then be reflected in the updated Summary
of Information. (SPC).
85
Patients can report any suspicion of ADR to all mentioned subjects - MAH (a
pharmaceutical company that authorized the product in the Czech Republic), who is
legally obliged to process this information and report to SÚKL/national authority
within a period of 15 days. Other option (for patients) is to report directly to the State
Institute for Drug Control, also via the online form on its website. However, the
marketing authorization holder must also report suspected non-serious
adverse reactions occurring in the European Union within 90 days of the day on
which he became aware of the suspicion.
National regulatory authority (MHRA/SÚKL) then passes information on ADR to the
European Eudravigilance database. This database is managed by the
Pharmacovigilance Risk Assessment Committee at the European Medicines Agency
(EMA). The Committee then makes recommendations on the safety of medicinal
products. A schematic representation of the reporting and transmission of information
between subjects is shown in Figure 19. An example of the CIOMS form (for
proffesionals) shown in Figure 20 and the Yellow card form (UK, MHRA) is shown is
in the Figure 21. The regulatory authorities (EMA, MHRA etc.) can then decide on
measures to ensure the safe use of medicines. These measures may result in
reduced indications, reduced duration of administration, definition of a new
contraindication, notification of a new interaction and, as a last possibility, suspension
or withdrawal of a marketing authorization (i.e. withdrawal of the product from the
market). The special adverse event reporting regime applies to the clinical trials (CT)
on medicinal products. In case of suspicion of a serious unexpected ADR
(Suspended Unexpected Serious Adverse Reaction; SUSAR) within the CT, the
Sponsor of CT is obliged to report this ADR even within 7 days to National
authority/SÚKL and to the relevant ethics committee, which approved the given CT.
86
Figure 19. Scheme of obligatory and voluntary reports of adverse drug reactions to
national authority (SUKL)
87
Figure 20. Sample form for reporting ADR (CIOMS)
88
Figure 21. Sample form for reporting ADR (MHRA)
89
Literature
Adverse drug reactions: definitions, diagnosis, and management EMA: PRAC
(Pharmacovigilance Risk Assessment Committee).
Bates D.W., Cullen D.J., Laird N. a kol. Incidence of adverse drug events and
potential adverse drug events-implications for prevention. Journal of the American
Medical Association 274, 1995, 29-34.
Bates, D.W., Spell, N., Cullen, D.J., Burdick, E., Laird, N., Petersen, L.A., Small,
S.D., Sweitzer, B.J., Leape, L.L. The costs of adverse drug events in hospitalized
patients. Adverse Drug Events Prevention Study Group. JAMA, 277, 1997, 307-311.
Lazarou J., Pomeranz B., Corey P. Incidence of adverse drug reaction in hospitalized
patients. Journal of the American Medical Association 279, 1998, 1200-1205.
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of
adverse drug reactions. Clinical Pharmacology & Therapeutics 30, 1981, 239–45.
World Health Organization Collaborating Centre for International Drug
Monitoring, the Uppsala Monitoring Centre (WHO–UMC).
Zaki S. A. Adverse drug reaction and causality assessment scales. Lung
India. 2011, 28(2): 152–153.
Act No. 378/2007 Sb.
90
5. Drug interactions
Drug interactions are one of the factors influencing the overall efficacy and safety of
pharmacotherapy. Concomitant administration of two or more drugs may affect the
other’s efficacy or frequency/severity of adverse effects. In a broader context, this
also means interactions of drugs with food supplements or food ingredients.
A drug can increase the effect of another (or two drugs each other) and cause a so
called synergistic interaction or, on the other hand, reduce the effect of another
drug (or each other) and cause an antagonistic interaction.
Interactions do not always have to be percieved as negative - there are
advantageous interactions between drugs which lead to an increase in efficacy or
decrease of required dose of each drug and thus decreased risk and severity of
adverse effects, respectively. Thanks to some beneficial combinations of antibiotics,
the antimicrobial spectrum may be significantly broadened.
Another example of a beneficial interaction between 2 drugs is the use of specific
antidotes (e.g. administration of naloxone in an overdose with opioids, flumazenil in
an overdose with benzodiazepines, atropine in organophosphate poisoning, calcium
chloride in overdose with calcium channel blockers or fomepizole or ethanol use in
methanol poisoning). We call such interactions “beneficial” or “desirable”; on the
contrary, a combination of drugs is described as an adverse (or undesirable) drugdrug
interaction when the effect of one or both of the combined drugs is reduced or
toxicity increased. Thus, interactions can be understood as synergistic or antagonistic
and beneficial/desirable or adverse/undesirable.
Synergistic interactions may result from so-called summation, which is an
increase in effect due to a combination of 2 or more drugs. Thus we preferably
combine, for example, analgesics, antihypertensives or some cytostatics (e.g.
bleomycin + etoposide + cisplatin, irinotecan + calcium folinate + 5-fluorouracil). In
some combinations of antibiotics the effect is also increased, but the effect increase
is not only a sum, but rather a multiplication of the effects of the individual drugs. We
call this interaction potentiation. Examples include a combination of
aminoglycosides with penicillin-type antibiotics, a combination of clarithromycin and
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warfarin, when clarithromycin inhibits cytochrome P450 metabolic activity and
potentiates its effect, or a combination of several sedative agents with different
mechanisms of action (H1 antihistamines, benzodiazepines and opioids).
Antagonistic interactions can be of the “pharmacological” type, where both
administered substances compete for the same receptor/enzyme/protein (e.g.
acetylcholine + atropine, noradrenaline and metoprolol). Physiological antagonism
occurs when both substances do not have the same mechanism of action but interact
with each other. For example, the vasoconstrictor effect of adrenaline or
noradrenaline antagonizes the vasodilatory effect of histamine in the treatment of
hypovolemic shock following an allergic reaction. Another type of antagonism used in
the therapy of intoxication is chemical antagonism - in this situation there is a
chemical reaction between two substances, which reaction can take place directly in
the body. An example is the binding of heparin to protamine sulphate, free iron by
deferoxamine or other chelating agents, or even the reaction of a specific antibody
with a drug (idarucizumab + dabigatran, an anti-digoxin antibody).
The risk of interactions logically increases with the number of drugs used. The risk of
interaction with a combination of 6 drugs is reported to be about 7%, but with a
combination of 11 drugs it is almost 15%.
Interactions are also more dangerous for certain groups of patients - these are
primarily the age groups of the elderly who are more likely to take more than one
medication at the same time and are at risk of drug misuse (forgotten medication,
incorrectly measured dose, failure to comply with recommendations to avoid certain
combinations with food, time delay from food, etc.).
Elderly patients have logically lower compensatory capacities in terms of metabolism
and excretion. While elimination may accelerate in younger patients when the drug
levels are elevated (thanks to first-order kinetics), in elderly patients, due to the
impaired renal or hepatic function a threshold may be reached where functional
acceleration of elimination is not possible and first-order kinetics then change to 0.
order kinetics. This may lead to drug accumulation and manifestations of drug
toxicity.
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Premature babies are also at high risk for interactions, factors which increase the
overall risk include lower albumin levels, lower activity of biotransformation enzymes
and significant changes in drug distribution due to higher body water content.
Another group of patients at risk are cancer patients who also have disturbed
homeostatic mechanisms and their physiological reserves are often exhausted by
cancer or relatively aggressive treatment with cytostatics (nephrotoxicity,
hepatotoxicity, anaemia, hypoalbuminaemia, impaired renal function – elevated
creatinine and cystatin C levels, liver insufficiency, frequent ionic dysbalance).
Interactions in these conditions are easier to manifest and can have more serious
consequences. However, other specific groups are similar - for example, patients
with GIT diorders (inflammatory bowel disease, irritable bowel syndrome, reflux
disease), who are more likely to experience interactions at the level of absorption, or
patients with cardiovascular disease or diabetics.
There are several mechanisms by which drug interactions occur; accordingly, the
interactions can be classified as (bio)pharmaceutical (galenic), pharmacokinetic
and pharmacodynamic. Any of these interactions can be dangerous; this is more
often the case when a physician is unaware of these interactions. In some cases,
however, there may be an interaction that can be used in a therapeutically
advantageous way to increase bioavailability (e.g. ascorbic acid helps to reduce
ferrous iron to the more soluble ferric iron), increasing drug efficacy (cytostatics:
combination of calcium folinare + fluorouracil: 5-fluorouracil (5-FU) inhibits
thymidylate synthetase (TS), a key enzyme involved in pyrimidine biosynthesis;
calcium folinate promotes TS inhibition by increasing the intracellular folate reserve,
thus stabilizing the 5-FU-TS complex and thus enhancing fluorouracil activity) .
Another example of a preferred antagonistic interaction is the reduction of drug
toxicity (e.g., the mesna metabolite is excreted by the kidneys, where it is further
metabolized to a product that binds to ifosfamide or cyclophosphamide metabolites
and thus prevents their toxic effect on the bladder mucosa). The clinical
consequences of adverse drug reactions may occur as adverse reactions (type
A,C,D,E) or treatment failure - type F (failure) (see Chapter 4 - Adverse drug
reactions).
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5.1 Biopharmaceutical drug interactions
Biopharmaceutical drug interactions occur in the patient’s body – i.e. before the drug
is administered to the body or just at the moment of administration.
Biopharmaceutical (sometimes also referred as Pharmaceutical or “galenic”)
interactions occur on the basis of chemical reactions between 2 or more components
of medicinal products or administration aids or materials. Due to incompatible
physicochemical properties, one drug’s effect may abolished by reaction with another
or an excipient, exceptionally both drugs may abolish each others effect. These
interactions are almost all well identified, and do not occur in ready made drugs these
preparations are manufactured according to pre-approved and tested technological
procedures. Similarly, the pharmacist should solve potential problems by changing
excipients or modifying IPP preparation technologies.
Thus, probably the greatest risk for pharmaceutical drug interactions is when
medicines are mixed just before being administered to a patient by a nurse or nursing
staff who may not be sufficiently experienced to identify and prevent such interactions
properly. These risky procedures involve the mixing of more liquid drugs (injections
with infusions to reduce the number of punctures) of crushing and mixing of some
drugs with each other during swallowing or in gastric probes and so on.
An example of a pharmaceutical interaction, sometimes also referred to as
incompatibility, is a combination of tannins (astringent, weakly antiseptic chemical
compounds – active ingredients of some plants or black tea) with any alkaloid
(morphine, codeine, galantamine, ergometrine, etc.) When combined together, the
alkaloid is precipitated and rendered ineffective.
There are many incompatibilities known (aminoglycoside antibiotics are inactivated
by penicillins and cephalosporins, tannin and zinc oxide in semi-solid dosage forms
create very hard non-spreadable mixtures, etc.). Incompatibilities, however, are also
called drug interactions between the drug (active ingredient) and the solution as a
vehicle, and the active ingredient and the container, respectively. An example of a
drug that interacts with a vehicle is furosemide, which may precipitate when the pH
drops below 7 and according to the SPC it may not mix with substances that lower
94
the pH of the solution (noradrenaline, adrenaline, group B vitamins, ascorbate, local
anesthetics, antihistamines) however, precipitation may also occur when combined
with other drugs (amiodarone, ciprofloxacin, digoxin, morphine, proton pump
inhibitors).
This type of interaction often occurs with drugs that are in the form of chloride salts
and due to the common ion, the solubility may be reduced when diluted with saline
(e.g. methylene blue must only be mixed with a 5% glucose solution, similarly
oxaliplatin must be diluted to glucose solution and not saline). An example of drugcontainer
(syringe, tubes) interaction is PVC-diazepam or insulin interaction, where
adsorption leads to a decrease in concentration of the active ingredient.
5.2 Pharmacokinetic interactions
Pharmacokinetic interactions occur at the level of drug absorption, distribution,
biotransformation or elimination. These interactions can be very harmful as in some
cases the plasma concentrations may increase by several orders (or decrease,
depending on the particular type of interaction) and thus lead to adverse effects, an
increase in their severity or frequency, or treatment failure. There are many examples
of pharmacokinetic interactions; in the following sections, examples of interactions at
the level of individual pharmacokinetic processes are presented.
Absorbtion - The simultaneous administration of tetracyclines or some types of
quinolone antibiotics and divalent ions (Ca2+, Mg2+ in antacids, food supplements or
milk, supplements containing Fe2+), results in the formation of non-absorbable
complexes thus causing the antibiotic to become ineffective.
Another example is influence of the efflux transporters (usually inhibition) in the
intestinal wall (e.g., P-glycoprotein, P-gp or MRP1) which thereby increases the
bioavailability of the drug. P-glycoprotein is the most important efflux transmembrane
transport protein, expressed in the epithelial cells of organs involved in absorption
and distribution such as enterocytes, the blood-brain and testicular barrier, as well as
95
at sites with a purely excretory function - in the canalicular membrane of hepatocytes,
on the apical side bile duct cells and renal proximal tubule.
Another way in which drug-drug interactions occur at the level of absorption is by
change of the motility of GIT by prokinetics (metoclopramide, itopride, cisapride).
These substances accelerate the passage through the proximal part of the GIT and
can thus speed up the absorption (shorten Tmax) and increase the bioavailability of
some drugs, such as cyclosporine, levodopa, morphine, diazepam.
Conversely, anti-diarrheals, opioids, anticholinergic spasmolytics, or medical
cannabis and its ingredients may slow down a drug's passage through the entire GIT
and increase contact time with the intestinal wall. However, this may also increase
the availability of some other drugs. Bioavailability may also be reduced by creating a
mechanical barrier on the surface of the GIT mucosa by concurrent administration of
sucralfate or by a direct drug interaction - thereby reducing the bioavailability of
resins (hypolipidaemics), calcium ions, magnesium ions, iron or intestinal adsorbents
(carbo medicinalis, diosmectite).
Another kind of interaction at the site of absorbtion occurs via altering of the pH in the
stomach - weak acids are better absorbed from an acidic environment and their
biovailability is significantly decreased when combined with proton pump inhibitors,
antacids, or H2 antihistamines. Such drugs include acetylsalicylic acid, atazanavir,
itraconazole or ketoconazole.
Distribution - At the level of distribution, interactions occur when drugs bind to
plasma proteins, especially albumin. A clinically relevant example includes the
combination of warfarin with other drugs extensively bound to plasma proteins (e.g.
diclofenac, some oral antidiabetics). In this case warfarin is displaced from its bond,
thereby increasing the free warfarin fraction several times and causing bleeding.
Although these interactions do not usually have clinically significant consequences,
the warfarin example demonstrates that they may occur in drugs with a low
therapeutic index.
96
In a broader context, interactions at the level of distribution can also be understood
as those that affect the expression of efflux transporters, which affect the penetration
of some drugs through the barriers of the hepatobiliary system, blood-brain barrier or
renal tubules. The spectrum of P-glycoprotein substrates largely overlaps with
CYP3A4 substrates. An example of the influencing of distribution equilibria is the
interaction of statins with cyclosporine or HIV protease inhibitors – when (in addition
to inhibition of CYP enzymes by statins) the effect of statins is reduced due to
inhibition of the OATP1B1 transporter by cyclosporine or protease inhibitors.
This transporter (OATP1B1) is responsible for the transport of statins to the liver and
thus, although their plasma concentrations are elevated, they cannot reach their site
of action. Examples of P-gp substrates and other transport proteins are presented in
Tables 2 and 3. Influencing P-gp is not only important for distribution but also for
elimination as P-gp is found in the intestine, the blood-brain barrier, the placenta, and
the hepatobiliary system. This is particularly important for drugs that are not
metabolised but excreted unchanged into the bile.
Table 2. Examples of P-gp substrates
P-gp, (product of the gene ABCB1)
Substrates amitriptyline, ciprofloxacin, cisplatin, dabigatran, digoxin,
fexofenadine, clarithromycin, cyclosporin, daunorubicin,
erythromycin, docetaxel, domperidone, etoposide, fentanyl,
fluorouracil, imatinib, lansoprazole, loperamide, losartan,
levofloxacin, methadone, methotrexate, morphine nelfinavir,
omeprazole, ondansetron, paclitaxel, pantoprazole, ritonavir,
saquinavir, tacrolimus, tamoxifen, trimethoprim, vincristine,
topotecan
Inhibitors amiodarone, carvedilol, clarithromycin, dronedarone,
itraconazole, lapatinib, lopinavir, ritonavir, propafenone,
quinidine, ritonavir, saquinavir, telaprevir, tipranavir, verapamil
Inducers amiodarone, bromocriptine, cisplatin, cyclosporine,
dexamethasone, dilthiazem, doxorubicin, etoposide,
fluorouracil, indinavir, clotrimazole, colchicine, methotrexate
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Table 3. Examples of substrates for other transport proteins
Transporter Gen Substrate Inhibitor
BCRP ABCG2 rosuvastatin, sulfasalazine curcumin, cyclosporin A
OATP1B1,
OATP1B3
SLCO1B1
SLCO1B3
asunaprevir, atorvastatin,
bosentan, cerivastatin,
danoprevir, docetaxel,
fexofenadine, nateglinide,
paclitaxel, pravastatin,
repaglinide, rosuvastatin,
simvastatin
atazanavir, ritonavir,
clarithromycin, cyclosporin,
erythromycin, gemfibrozil, lopinavir,
rifampicin, simeprevir
OAT1,
OAT3
SLC22A6,
SLC22A8
adefovir, cefaclor,
ceftizoxime, famotidine,
furosemide, ganciclovir,
methotrexate, oseltamivir,
penicillin G
p-aminohippuric acid, probenecid,
teriflunomide
MATE1,
MATE2-K
SLC47A1,
SLC47A2
metformin cimetidine, dolutegravir,
isavuconazole, ranolazine,
trimethoprim, vandetanib
P-gp: P-glycoprotein 1, syn. multidrug resistance protein 1 (MDR1)
BCRP: Breast Cancer Resistance Protein;
OATP1B1, OATP1B3: Organic-anion-transporting polypeptide 1 and 3 transporters expressed on the
basolateral (sinusoidal) membrane of hepatocytesOAT1, OAT3: organic anion transporter 1 a
3
MATE1, MATE2-K: multidrug and toxin extrusion-transport proteins expressed on the apical
membrane of the proximal tubule
Biotransformation - The most common interactions are interactions at the level of
cytochrome P450. This refers in particular to induction or inhibition. In the case of
induction due to repeated administration of one drug (e.g. carbamazepine,
rifampicin), there is a transient increase in the amount or activity of a cytochrome
P450 form and consequently, a higher biotransformation rate decreases the plasma
levels (and effect) of the drugs metabolized by the specific CYP enzyme more
quickly. In the case of inhibition, the interaction may occur immediately, even after a
single/simultaneous administration of the inhibitor. The consequences are the
opposite in case of induction - the inhibitor (e.g. fluoxetine, ketoconazole) slows down
biotransformation, increases plasma concentration and drug effects.
Conversely, a prodrug that is activated by biotransformation (clopidogrel, tamoxifen)
may thus be less effective. Inhibition of enzymatic biotransformation is most often
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reversible: the effect of the inhibitor does not persist after the inhibitor is cleared from
the body. Types of reversible inhibition include simple competitive (drugs compete for
enzyme binding), uncompetitive (inhibitor binds to enzyme-substrate complex) and
non-competitive inhibition where inhibition cannot be overcome by increasing
substrate concentration.
In contrast, irreversible or "quasi-irreversible" inhibition may persist even after the
inhibitor has been removed from the body. The inhibitor binds to the enzyme via a
covalent bond and complete de novo synthesis is required to restore its function.
Examples of irreversible inhibitors are clarithromycin, erythromycin or protease
inhibitors (HIV antivirals). In some databases, inhibitors are also classified according
to the degree of inhibition as potent, moderate and weak inhibitors, according to the
ability to increase the AUC of other drugs metabolised by the given CYP.
Strong inhibitors increase AUC by more than 5x, moderate by more than 2x and
weak by 1.25x - 2x. Examples of substrates, inducers and inhibitors of CYP forms are
given in Table 4. Information regarding ability to interact with P450 enzymes is very
valuable for clinical practice. Therefore, during drug discovery and development,
these interactions are monitored and considered clinically relevant when the ratio of
maximum plasma concentration of inhibitor to its Ki (in vitro inhibitory constant)
(Cmax/Ki) exceeds 1. It is also important to consider where the inhibition CYP occurs
- whether during absorption (intestinal CYP) or in the liver. Another set of interactions
concern the conjugation enzymes (NAT, UGT etc.), but these are quite rare and less
relevant compared to CYP-mediated interactions.
Table 4. Examples of substrates, inducers and inhibitors of CYP enzymes (next
page).
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Inducers Inhibitors Substrates
CYP1A2 omeprazole,
phenobarbital,
phenytoin, rifampicin,
polyaromatic
hydrocarbons
(cigarette smoke,
grilled meal)
cimetidine, ciprofloxacin,
isoniazid, fluvoxamine,
metronidazole, sertraline,
macrolide antibiotics,
paroxetine
amitriptyline, cyclobenzaprine,
desipramine, diazepam,
erythromycin, estradiol, naproxen,
paracetamol, theophylline,
warfarin
CYP2C9 rifampicin,
carbamazepine,
nevirapine,
secobarbital, St.
John's wort
amiodarone,
chloramphenicol,
cimetidine, fluvoxamine,
zafirlukast
celecoxib, diclofenac, losartan,
naproxen, phenobarbital,
phenytoin, paracetamol,
piroxicam, torsemide, S-warfarin
CYP2C19 rifampicin, St. John's
Wort, ritonavir,
carbamazepine
azole antifungals,
fluvoxamine, omeprazole,
topiramate
amitriptyline, citalopram,
diazepam, lansoprazole,
omeprazole, phenobarbital,
propranolol, topiramate, R-
warfarin
CYP2E1 alcohol (chronic),
isoniazid
acute alcohol, disulfiram alcohols, dapson, halogenated
alkanes, isoflurane, paracetamol,
theophylline
CYP2D6 dexamethasone,
rifampicin
bupropion fluoxetine,
paroxetine, quinidine,
amiodarone, citalopram,
methadone, midodrine,
moclobemide,
hydroxyzine,
metoclopramide,
ticlopidine, ritonavir
metoprolol, timolol, carvedilol,
propafenone, TCA, venlafaxine,
bufuralol, clonidine, donepezil
duloxetine, lidocaine,
dextromethorphan, codeine,
metoclopramide, risperidone,
tramadol
CYP3A4
carbamazepine,
dexamethasone,
etosuximide,
phenobarbital,
phenytoin, rifampicin /
rifabutin, St. John's
wort
amiodarone, aprepitant,
netupitant, azole
antifungals, cimetidine,
cyclosporin, fluoxetine,
macrolide antibiotics,
metronidazole,
nicardipine, propofol,
protease inhibitors,
quinine, sertraline,
verapamil, voriconazole,
boceprevir, delavirdine
alprazolam, amiodarone,
amitriptyline, amlodipine, azole
antifungals, budesonide,
calcineurin inhibitors,
carbamazepine, celecoxib,
cisapride, clarithromycin,
clindamycin, codeine, cortisol,
dapson, diazepam, digoxin,
diltiazem, donepezil,
ethinylestradiol, fentanyl,
fexofenadine, HMG-CoA
reductase inhibitors, lansoprazole,
loratadine,
losartan, macrolides, methadone,
omeprazole, propafenone,
sertraline, tamoxifen, theophylline,
verapamil, warfarin
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Excretion - Drug interactions may occur due to the effects of urine pH on drug
permeation across the microtubule membrane, on tubular secretion, on reabsorption
and finally by its influence on the P-glycoprotein transporter. Examples include
reduced digoxin excretion when amiodarone or clarithromycin are co-administered, or
slowed lithium excretion after thiazide diuretic administration (increased sodium
excretion causes increased reabsorption of lithium ions); or acceleration of
barbiturate excretion by urine alkalinisation (forced alkali diuresis) in case of
intoxication. Another example is uricosuric probenecid interactions, where tubular
secretion is decreased and plasma concentrations (and possible toxicity) of
methotrexate or penicillin are increased. This interaction was used therapeutically to
prolong the elimination half-life of penicillin.
Renal excretion is also affected by catecholamines (or generally vasopressor agents)
administered in hypovolemic postoperative circulatory failure, vasoplegia or septic
shock. Catecholamines increase the tone of the arteries while maintaining circulation
at the beginning, but may decrease splanchnic perfusion and through prolonged
vasopressor effect they may decrease renal flow and drug excretion.
Excretion of drugs may also be affected by the general nephrotoxic effect of some
drugs, which may subsequently result in delayed elimination of renally eliminated
drugs. Nephrotoxic drugs commonly include aminoglycoside antibiotics, vancomycin,
non-steroidal anti-inflammatory drugs, platinum derivatives (cytostatics), and
furosemide.
5.3 Pharmacodynamic interactions
Pharmacodynamic interactions occur at the target site of action, or on the effector
system (receptor, transporter, signaling pathway, enzyme). By this, an interaction
may be categorised as synergistic or antagonistic in nature. Interactions may also
occur at the same target site (e.g., the gamma aminobutyric acid receptor complex GABA
A) or may occur in two independent effector systems (e.g., opioid receptors
and GABA A receptor complex).
A pharmacodynamic interaction is for example the interaction of beta-blockers and
the antiarrhythmic drug and calcium channel blocker verapamil. Their concomitant
administration may result in severe cardiac arrest by supression of the cardiac
conduction system. Synergic (but undesirable) interactions also occur when
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benzodiazepines and alcohol are co-administered - both substances inherently
support the function of depressive endogenous systems (GABA-A and opioid) and
therefore can lead to severe, even life-threatening CNS depression. These
synergistic reactions are a common cause of the unexpected toxicity of a previously
problem-free drug. Interactions may involve one-sided or both-sided increases in
organ toxicity, such as combinations of multiple nephrotoxic drugs (e.g. vancomycin
+ gentamicin). Another example is the combination of several substances with
anticholinergic activity and the onset of the so-called anticholinergic syndrome (e.g. in
many psychoactive drugs and atropine), or the pro-arrhythmic effect of the whole
group of antipsychotics, a number of antidepressants, fluorinated quinolones,
prokinetics and antiemetics and some antihistamines. Their combination prolongs the
corrected QT interval and torsades de pointes arrhythmias. Additionally, the factor of
pharmacogenetics also affects this interaction, where patients with mutations in
genes for potassium, resp. sodium channels (KCNQ1, SCN5A) are predisposed to an
increased risk of long QT syndrome (LQTS). Another similar example is the
combination of several drugs causing hyperkalaemia and subsequently their
proarrhythmogenic effect (ACEi, potassium sparing diuretics).
In the case of a combination of diuretics and non-steroidal anti-inflammatory drugs,
the antihypertensive effect of diuretics is reduced, since non-steroidal antiinflammatory
drugs tend to cause sodium retention. Thus, due to the different
mechanisms of action, the variety of these interactions is wide.
Examples of pharmacodynamic-type drug interactions are presented in the Table 5.
Table 5. Examples of drug interactions
Drug 1 Drug 2 Mechanism of
interaction
Consequence/ type of
interaction
thiazide
diuretics
NSAIDs inhibition of
prostaglandin
synthesis, sodium
retention
reducing the antihypertensive effect
of thiazides
ASA ibuprofen,
metamizol,
NSAID
competition for the
COX1 binding site
competitive (reversible) COX1
inhibition, shorter, decreased antiaggregative
effects, antagonism
levodopa neuroleptics competition for
dopamine
receptors
reducing the effect of levodopa
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warfarin Vitamin K substitution,
competition
decreased anticoagulant effect of
warfarin
beta blockers clonidine adaptation
mechanisms on the
receptor-level
hypertensive crisis after clonidine
withdrawal
ACEi spironolactone synergistic effect at
level of absorbtion
hyperkalemia, arrhythmia
quinolones macrolide
antibiotics
cardiotoxic effect QTc interval prolongation,
arrhythmia
neuroleptics setrones cardiotoxic effect QTc interval prolongation,
arrhythmia
SSRIs prokinetics
(metoclopramide,
cisapride,
itopride)
cardiotoxic effect QTc interval prolongation,
arrhythmia
ASA SSRIs antiplatelet effect platelet
depletion in
serotonin +
inhibition of COX1
bleeding, petechiae
SSRIs triptans activation of
serotonin receptors
serotonin syndrome
tricyclic
antidepressants
(TCA)
neuroleptics (1st.
generation)
synergies of
anticholinergic
effects
anticholinergic crisis, constipation,
confusion, ileus, delirium
midazolam thiopental synergistic effect-
potentiating
depressant effects
through the GABA
A receptor
complex; 2 different
binding sites
severe sedation, respiratory center
depression
SSRIs tramadol increase in
serotonin
concentration
serotonin syndrome
SSRIs prokinetics
(metoclopramide,
cisapride,
itopride)
increase in
serotonin
concentration
serotonin syndrome
opioids Neurotropic
spasmolytics
reduced GIT
motility through
opioid receptors
and anticholinergic
effects
constipation
TCA antihypertensives TCAs increase the
availability of
catecholamines,
antagonizing the
antihypertensive
effect
hypertension
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5.4 Interactions of drugs and food, food supplements
5.4.1 Influence of pharmacokinetics of drugs
Absorbtion
Food and its components may affect the bioavailability of a drug as well as the rate of
absorption. Content of the GIT may present a simple mechanical barrier which
reduces contact of drug with the mucosa and hence absorption rate. Therefore, some
medicines (e.g. penicillins, levothyroxine, etc.) should be administered in the fasting
state, 30-60 minutes before a meal or 2-3 hours after the meal. On the other hand,
food can increase or facilitate the absorption of drugs, e.g. a fatty diet increases the
absorption of lipophilic drugs (lipophilic vitamins, griseofulvin, cyclosporine etc.).
Food ingredients and drugs can react chemically to form undesirable compounds.
Typically, for example, the chelation of bivalent and trivalent metal cations from food
with a drug and the subsequent formation of non-absorbable and thus systemically
inactive compounds. Thus, for example, fluoroquinolones or tetracyclines with Ca2+,
Mg2+, Al3+, Fe2+, Fe3+ cations from the diet, or Fe2+ and Fe3+ ions used as
supplements administered in anaemia may be chelated by polyphenols present in
coffee, tea, etc. By altering the pH, it is possible to influence the absorption of some
drugs and a typical example is iron supplementation, which requires the acidic
environment of the stomach for good absorption, preferably in the fasted state.
Among food ingredients there are also substances that specifically block
transporters located on the villous membrane. This may be, for example, an organic
anion-transporting polypeptide (OATP) transporter. By inhibiting this transporter, the
bioavailability of some drugs with organic anion nature may be reduced by preventing
their influx into the enterocyte. An OATP blocker is for example the flavonoid
narigenin, which citrus fruit species are rich in. The opposite example (from the
perspective of bioavailability) is another transporter - efflux P glycoprotein. Its
inhibition may increase the bioavailability of drugs by blocking the excretion of
xenobiotics (drugs) from the enterocyte back into the lumen of the intestine.
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Distribution
Naturally, dietary supplements can also affect the distribution of concomitantly
administered drugs. When the components of a dietary supplement bind to plasma
proteins, this may present a risk for drugs with a low therapeutic index, which are
also bound to albumin and other plasma proteins. In fact, their displacement leads to
an increase in their free fraction and thus an increase in their effect. This interaction
may result in an increased free concentration of warfarin in the plasma and thus an
increase in its effect. In addition, coumarins of natural origin alone have a slight
anticoagulant effect and thus the whole interaction becomes even stronger.
Biotransformation
Phase I biotransformation processes include reactions mediated by the cytochrome
P450 (CYP) enzyme system. Found on the membrane of the intestinal villi, some
CYP enzymes are responsible for presystemic elimination, i.e. biotransformation of a
drug which has not reached systemic circulation yet. Inhibition or induction of
intestinal CYP may affect the plasma level of the drug and its effect. Inhibition leads
to a decrease in presystemic elimination, a larger proportion of the drug is then
available for absorption and the plasma concentration of the drug increases (risk of
overdose, toxicity). Induction, on the other hand, leads to an increase in presystemic
elimination, a decrease in plasma drug concentrations and a risk of low efficacy or
treatment failure.
Some components of diet may also affect hepatic CYP metabolic activity. Induction of
hepatic CYP results in decreased plasma drug concentrations; whereas inhibition of
CYP leads to increased drug plasma levels. Clinically relevant inhibitors of intestinal
CYP3A4 are furanocoumarins (dihydroxybergamotin, bergamotin) contained in
grapefruit (Citrus × paradisi), pomelo (Citrus × maxima), Seville orange (Citrus ×
aurantium) and carambola (Averrhoa carambola). Some flavonoids, such as
quercetin contained in high concentrations in pomegranate (Punica granatum) also
have an inhibitory effect, but data on its interaction potential in humans are still
limited to case reports. Well-established evidence exists for the effects of grapefruit
juice however in the other fruit ingredients mentioned, reliable clinical studies are
missing or have methodological concerns, or are only individual case reports.
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Nevertheless, some flavonoids are considered to increase plasma concentrations
and the effect of benzodiazepines, calcium blockers, some H1 antihistamines, and
generally CYP3A4 and P-gp substrates. Inhibition of hepatic CYP is not usually
observed when furanocoumarin-containing foods are consumed.
Inducers of hepatic CYP1A include, for example, cruciferous vegetables and
polycyclic aromatic hydrocarbons (PAHs) which originate from, for example,
inappropriate cooking or tobacco smoking. Many medicinal plants that are consumed
most often in the form of infusion also affect biotransformation processes.
Phase 2 biotransformation takes place in enterocytes with the help of various
conjugation enzymes (e.g. glucuronyltransferases, sulphotransferases). Inducers of
these enzymes include, for example, cruciferous vegetables, ingredients of citrus
species and soybean products.
Excretion
Dietary composition affects urine pH. Vegetarians and vegans have alkaline urine,
and thus it is easier to reabsorb weak-alkaline medicines (e.g. morphine, pethidine,
amiloride, amphetamines etc.) back into the interstitium. Therefore these drugs
remain in the body for longer, while excretion of weak-acid medicines is accelerated
(methotrexate, sulphonamides, thiazide diuretics). Acidification of urine e.g. by
sipping fruit juices helps the elimination of drugs of the weak base nature. On the
contrary, acidic beverages may impair the solubility of some drugs and cause them to
crystallize in tubules and manifest nephrotoxicity (methotrexate, sulphonamides).
5.4.2 Pharmacodynamic interactions of drugs and food
supplements
Diet components and drugs may act synergistically (increase in effect) or
antagonistically (decrease in effect). An example of a synergistic effect is the
interaction of monoamine oxidase (MAO) inhibitors with a tyramine-rich diet.
Tyramine is a biogenic amine present in significant levels in bananas, cheese
(especially fermented), chocolate, coffee, fermented meat products, soybean sauce,
red wine, etc., which is normally decomposed by intestinal MAO. When drugs that
inhibit MAO are administered, tyramine from the diet is not metabolized and causes
hypertension (even hypertensive crisis), increased diuresis, headache and
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palpitations. Non-selective MAO inhibitors and MAO A inhibitors include
tranylcypromine, phenelzine or moclobemide.
Another example of synergism is the interaction of antithrombotic drugs and
anticoagulants with garlic extracts or simply garlic-rich meals. Antithrombotic agents
and anticoagulants are drugs that interfere with the coagulation cascade and are
used to prevent thrombotic events. Garlic contains the essential oils ajoene and
allicin, which affect platelet aggregation, the binding of fibrinogen to activated
platelets, and the production of prothrombotic thromboxane A2 for the reduction of
blood clotting. Excessive consumption of uncooked garlic or garlic supplements with
antithrombotic drugs or anticoagulants can cause bleeding disorders. A combination
of ginkgo supplements and antithrombotic or anticoagulants may also result in a
similar interaction.
An example of an antagonistic action is a combination of the oral anticoagulant
warfarin and a vitamin K-rich food. Warfarin is a vitamin K antagonist - competing
with its actions in the synthesis of new coagulation factors in the liver. By varying the
plasma vitamin K concentration, warfarin can be displaced or replaced by vitamin K
in biochemical processes, reversing its anticoagulant effect. Patients on
anticoagulant therapy with warfarin should be properly instructed about the
composition of their diet. Balanced intake of relatively lower amounts of vitamin K is
recommended and caution should be given to potentially risky foods (vegetables,
esp. cruciferous, rapeseed and olive oil, avocado, kiwi, parsley, spring onions, etc.).
Vitamin K is also produced by intestinal bacteria and there are clinical studies which
have evaluated the effect of diet as insignificant. However, routine clinical practice
suggests monitoring and informing of the patient.
Food supplements are available in pharmacies, but also frequently in online stores.
Any food supplements may cause some of the above-mentioned interactions. The
situation is perhaps even more complicated than with administration of the drug, for
the following reasons:
a) dietary supplements do not have a standardized and guaranteed content of
active substances and therefore sometimes the interaction occurs and
sometimes not
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b) the quality (content of ingredients) may vary a lot, depending on the
manufacturer
c) food supplements are not as extensively tested as drugs and their interactions
are often not mentioned in the literature
d) patients do not always tell their physicians what dietary supplements they use
and how frequently
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