KSMU

Department of clinical
pharmacology

Main principles of clinical pharmacology and

rational pharmacotherapy

Lecturer, associate Professor Yulia Luneva

 Clinical pharmacology

• Clinical pharmacology is a
science that studies the
principles and methods of
effective and safe
pharmacotherapy, methods
for determining the clinical
value and optimal use of
drugs.
• Clinical pharmacology
includes two main sections:
 pharmacokinetics and
 pharmacodynamics
 Pharmacokinetics is a science that studies the
movement of drugs in the human body:
• -absorption
• - distribution
• - biotransformation
• -excretion
Different routes of administration
• oral,
• transbucсal,
• sublingual,
• rectal,
• parenteral,
• local,
• inhalation.
 Oral route of administration
• The mucous membrane of the mouth
characterized by a thin epithelium and a rich
vascularity that should, at first glance, to
facilitate the absorption. At the same time,
the drug placed in the space between the
gums and the cheek (for transbucal
administration) or under the tongue (for
sublingual administration), remains in the oral
cavity longer, which contributes to increased
absorption.
 Oral route of administration
• The stomach has a relatively large epithelial surface area, but
the thickness of its mucous membrane and the short time
spent in it of the drug limit absorption.
• Since absorption mainly occurs in the small intestine, the rate
of gastric emptying is often also a factor limiting the rate of
absorption.
• Food, especially fat, slows down the emptying of the stomach
(and the rate of absorption of the drug); this explains why
taking the drug on an empty stomach accelerates absorption.
• Drugs that change the rate of gastric emptying (for example,
parasympatholytic agents) may also affect the rate of
absorption of other drugs.
• Food can increase the absorption of poorly soluble drugs,
reduce it for drugs that break down in the stomach (example,
benzylpenicillin), have a minimal effect on absorption or do
not have it at all.
 Oral route of administration
• The small intestine has the largest surface area for absorption
of the drug in the gastrointestinal tract, and its membranes are
more permeable than in the stomach.
• Therefore, most drugs are absorbed mainly in the small
intestine, and acids, despite their ability as non-ionized
substances to easily pass through the membranes, are absorbed
faster in the intestine than in the stomach.
• The pH value in the lumen of the duodenum is 4-5, but as you
move in the distal direction, it gradually increases, reaching 8 in
the lower ileum.
• Microflora of the gastrointestinal tract can also reduce the
suction.
• A drop in the intensity of blood supply (for example, in shock)
leads to a decrease in the concentration gradient of the drug on
both sides of the intestinal mucosa and consequently reduces
the absorption that occurs through passive diffusion.
 Parenteral route of administration
• Drugs administered intravenously enter the systemic
bloodstream directly.
• However, when administered intramuscularly or
subcutaneously, the drug must pass through one or
more membranes before entering the bloodstream.
• If protein preparations with a molecular weight of
more than 20,000 daltons are administered
intramuscularly or subcutaneously, their progress
through the capillary membranes is so slow that
absorption is mainly carried out through the lymphatic
system. In such cases, the drug reaches the systemic
blood flow slowly and often not completely due to
first-pass metabolism (i.e., metabolism before entering
the systemic blood flow) by proteolytic enzymes in the
lymphatic pathways.
• Regardless of the route of administration, the
drug must be in a dissolved state in order for
absorption to become possible. Therefore,
solid dosage forms (for example, tablets) must
have the ability to break down after oral
administration
• before entering the systemic bloodstream, the
drug passes through several semipermeable cell
membranes (the exception is the intravenous
route of administration).
• Cell membranes are biological barriers that
selectively inhibit the passage of drug molecules.
• The basic structure of biological membranes is a
lipid bilayer, which determines their semi –
permeability.
 Drugs can penetrate cell membranes
in the following ways:

• Passive diffusion
• Lightweight passive diffusion
• Active transport
• Pinocytosis
 Passive diffusion
• Drugs diffuse through the cell membrane from an area
with a high concentration (for example, the lumen of
the gastrointestinal tract) to an area with a low
concentration (for example, blood).
• The rate of diffusion is directly proportional to the
concentration gradient, but also depends on the
solubility of the molecule in lipids, its size, degree of
ionization and surface area of absorption.
• Since the cell membrane is made up of lipids, fat-
soluble substances diffuse more quickly. Small
molecules can penetrate membranes faster than large
ones.
 Lightweight passive diffusion
• Some molecules that are characterized by low fat solubility (such as
glucose) pass through the membranes faster than one might
expect.
• This is due to facilitated passive diffusion: the carrier molecule in
the membrane reversibly binds to the substrate molecule from the
outer surface of the cell membrane, after which the "substrate-
carrier" complex quickly diffuses through the membrane, releasing
the substrate at its inner surface.
• In such cases, only substrates with a relatively specific molecular
configuration are transported through the membrane, and the
carrier concentration is a factor limiting the speed of the process.
• Facilitated diffusion is not associated with transport against the
concentration gradient and therefore does not require energy
expenditure.
 Active transport
• Active transport is selective, requires energy,
and may involve the transfer of substances
against a concentration gradient.
• Active transport is typical for drugs that are
structurally similar to endogenous substances
(ions, vitamins, carbohydrates, amino acids).
These drugs are usually absorbed in certain
areas of the small intestine.
 Pinocytosis
• In pinocytosis, the liquid or particles are
absorbed by the cell. The cell membrane thus
invaginates, capturing liquid or particles, then
closes again, forming a bubble, which then
breaks off and moves inside the cell. This
process requires energy costs. Pinocytosis
probably plays a minor role in drug transport,
with the exception of protein drug transport
 The bioavailability
• The bioavailability of a drug is largely
determined by the properties of the dosage
form, which partly depend on its composition
and method of manufacture. Differences in
the bioavailability of dosage forms may be of
clinical significance; therefore, it is necessary
to know whether they are equivalent.
• Chemical equivalence means that the dosage forms
contain the same amount of the same active
ingredients and meet the current approved standards;
however, the excipients in the drug may differ.
• Bioequivalence indicates that if the compared dosage
forms are prescribed to the same patient in the same
dosage, equal concentrations of the drug in blood
plasma and tissues will be achieved.
• Therapeutic equivalence indicates that if ready-made
dosage forms are prescribed in the same dosage to the
same patient, they have a comparable therapeutic and
side effect.
• It is assumed that bioequivalence of the
dosage form are therapeutically equivalent.
Therapeutic inequivalence (for example, a
higher frequency of side effects, less
effectiveness) is usually detected during long-
term treatment, when patients whose
condition has stabilized as a result of taking a
single drug were prescribed an inequivalent
substitute.
 Reasons for low bioavailability
• Drugs administered internally must pass through the
intestinal wall, and then through the portal vein system
to the liver; in both cases, the drug is subject to the
effect of the first passage (metabolism before entering
the systemic bloodstream).
• Thus, many medicinal substances can be metabolized
before their adequate concentration in the blood
plasma is reached. Low bioavailability is most typical
for oral dosage forms of low-water-soluble and slow-
absorption drugs.
 Reasons for low bioavailability
• Insufficient time for absorption in the
gastrointestinal tract is a common cause of low
bioavailability.
• If the dissolution of the drug is difficult or it is not
able to pass through the epithelial membrane
(for example, due to a high degree of ionization
or polarity), the time of its stay at the site of
absorption may not be enough. In such cases, the
bioavailability may be either high or low.
 Reasons for low bioavailability

• Age, gender, physical activity, genotype, stress, various

disorders (such as achlorhydria, malabsorption syndrome), or
previous gastrointestinal surgery may also affect
bioavailability.
• Chemical reactions that reduce absorption also reduce the
bioavailability of the drug. These reactions include the
formation of complexes (for example, tetracycline and
polyvalent metal ions), hydrolysis with the participation of
stomach hydrochloric acid or digestive enzymes (for
example, benzylpenicillin or chloramphenicol palmitate),
conjugation in the intestinal wall (for example,
sulfoconjugation of isoproterenol), adsorption by other drugs
(for example, digoxin colestyramine) and metabolism by the
intestinal microflora.
 Assessment of bioavailability
• Bioavailability is usually estimated by determining the area
under the graph of the dependence of the drug
concentration in blood plasma on time (AUC-the
Pharmacokinetic curve of a hypothetical drug after a single
oral administration).
• This parameter is the most reliable measure of
bioavailability.
• This value is directly proportional to the total amount of
unchanged drug that has entered the systemic circulation.
• Finished dosage forms can be considered as bioequivalent
in terms of the degree and rate of absorption, if their AGS
coincide.
Pharmacokinetic curve of a hypothetical drug
after a single oral administration
• The bioavailability of drugs that are excreted
unchanged in the urine can be assessed by
measuring the total amount of the drug that is
excreted after a single administration. Ideally,
urine is collected over 7-10 half-lives to assess
complete elimination of the drug.
• After repeated administration and reaching an
equilibrium state, bioavailability can be assessed
by measuring the amount of unchanged drug
detected in the urine over a 24-hour period.
 Distribution
• After the drug enters the systemic bloodstream, it is
distributed in the body's tissues. Distribution is usually
uneven due to differences in blood supply intensity, binding
to tissues (for example, with different fat content), local pH,
and cell membrane permeability.
• The degree of penetration of the drug into a tissue depends
on blood flow rate, mass of tissue and the nature of the
distribution of substances between the blood and tissue.
Equilibrium distribution (when the rates of penetration and
exit from the tissue coincide) is achieved faster in areas with
rich vascularization, if diffusion through the cell membrane is
not a speed-limiting factor. After reaching equilibrium, the
concentration of the drug in tissue and extracellular fluids is
proportional to the concentration in blood plasma.
Metabolism and elimination occur simultaneously with
distribution, making the process dynamic and complex.
Binding • The degree of distribution of drugs in the
tissue depends on its relative binding to
plasma proteins and tissues.
• In the bloodstream, drugs are transported
partly as a free (unbound) fraction, and
partly as a bound fraction (for example,
with plasma proteins or blood cells).
• Albumin, alpha-1-acid glycoprotein and
lipoproteins are the most important
proteins of plasma, that can interact with
drugs, alpha-1 acid glycoprotein, and
lipoproteins.
• Weak acids usually bind more intensively
to albumin; bases, on the contrary, – to
alpha-1-acid glycoprotein and/or
lipoproteins.
• Only an unbounded drug is
capable of passive diffusion
into extravascular spaces or
tissues where its
pharmacological action
occurs.
• Therefore, the concentration
of an unbounded drug in the
systemic bloodstream usually
determines its concentration
at the site of implementation
of the effect and, thus, the
severity of the latter.
• The accumulation of drugs in the tissues of the body
can be the reason for prolonging their effect, because
the tissues release the accumulated drug as its
concentration in the blood plasma decreases.
• Some drugs accumulate in cells due to binding to
proteins, phospholipids, or nucleic acids. For example,
the concentration of chloroquine in white blood cells
and hepatocytes can be a thousand times higher than
in blood plasma.
• The drug substance in the cells is in balance with its
concentration in the blood plasma and passes there as
the drug is eliminated from the body.
 Hematoencephalic barrier
• Drugs penetrate the Central nervous system through the
capillaries of the brain and through the cerebrospinal fluid.
• The blood-brain barrier consists of the endothelium of the
brain capillaries and astrocyte processes.
• Endothelial cells of the brain capillaries, which are more
closely connected to each other than the cells of other
capillaries, slow down the diffusion of water-soluble drugs.
• The astrocytes' membrane consists of a layer of glial cells of
connective tissue (astrocytes) adjacent to the basement
membrane of the capillary endothelium. With age, the
protective function of the blood-brain barrier becomes less
effective, which leads to increased penetration of various
substances into the brain.
• Brain penetration is slow for drugs that are largely protein-
bound, and virtually nonexistent for ionized forms of weak
acids and bases. Since the Central nervous system is well
supplied with blood, the speed of distribution of the drug is
determined primarily by the permeability of cell membranes.
 Metabolism
• The liver is the main organ in which the metabolism of
drugs occurs.
• Although metabolism usually results in drug
inactivation, some metabolites are pharmacologically
active, sometimes even more active than the original
compound.
• A prodrug is a medication or compound that, after
administration, is metabolized (i.e., converted within
the body) into a pharmacologically active drug,
especially if it was specifically created to provide more
effective delivery of the active substance.
• The goal of metabolism is to facilitate the elimination
of drugs.
• Drugs can be metabolized by oxidation, reduction,
hydrolysis, hydration, conjugation, or isomerization.
• The metabolism of many drugs takes place in 2 phases.
These reactions are non-synthetic. Phase I reactions include
the formation of new or modification of existing functional
groups, or the cleavage of a molecule (by oxidation,
reduction, or hydrolysis). Phase II reactions involve
conjugation with endogenous substances (for example,
glucuronic acid, sulfate, glycine) and are synthetic.
Metabolites formed as a result of synthetic reactions are
more polar and are more easily excreted by the kidneys
(with urine) and liver (with bile) than metabolites formed
by non-synthetic reactions. Thus, the phase designation
reflects functional rather than sequential classification.
Some medications only undergo phase I or phase II
reactions.
 Cytochrome P450
• Cytochrome P-450 is the most important enzyme system of
phase I metabolism. It is a family of microsomal enzymes
that catalyze the oxidation of many drugs.
• Enzymes of the cytochrome P450 family can be induced
and inhibited by many drugs and substances, which
explains the mechanism of many drug interactions, when
one of the drugs increases the toxicity or reduces the
therapeutic effect of the other.
• The functional activity of the liver in the process of
metabolism through the CYP450 enzyme system decreases
by ≥ 30% with age, due to a decrease in liver volume and
blood flow. Therefore, medicinal substances metabolized by
this enzyme system in elderly patients reach a higher
concentration and have a long half-life/
 Conjugation
• Glucuronidation is the most frequent phase II reaction
and the only reaction occurring in the liver microsomal
enzyme system.\
• Glucuronides are secreted in the bile, and are also
excreted in the urine. Conjugation makes most drugs
more soluble, which facilitates their excretion by the
kidneys. As a result of conjugation with glutamine or
glycine, products are formed that are easily excreted in
the urine and only slightly secreted into the bile. The
intensity of glucuronidation does not change with age.
However, in newborns, the process of formation of
glucuronide is slower, which can cause the
development of serious undesirable effects
 Excretion
• The kidneys excrete water-soluble substances
and are the main organs of excretion.
• The biliary system is also involved in the excretion
of drugs, provided that they are not subsequently
reabsorbed in the gastrointestinal tract.
• The role of the intestine, saliva, sweat, breast
milk and lungs in excretion is small, except for the
removal of volatile drugs for anesthesia.
• Excretion with breast milk, without affecting the
mother, may cause harm to the baby who is
breastfed.
 Renal excretion
• Renal filtration is the main route of
excretion of most drugs.
• About 20% of the blood plasma
entering the glomerular apparatus is
filtered by its endothelium; water and
most electrolytes are passively or
actively reabsorbed from the renal
tubules back into the bloodstream.
• Polar compounds, which include most
drug metabolites, cannot diffuse back
into the bloodstream and are
eliminated from the body.
 Excretion with bile
• Some drugs and their metabolites are actively excreted
with bile. Since the transfer of drugs through the
epithelium of the biliary tract occurs against the
concentration gradient, the presence of active transport
mechanisms is required.
• Drugs with a molar mass > 300 g/mol and simultaneously
having polar and lipophilic groups are most likely to be
excreted with bile; smaller molecules are usually excreted
this way only in small quantities. Conjugation with
glucuronic acid facilitates excretion with bile.
• The medicinal substance secreted with bile is absorbed
from the intestine back into the bloodstream. Excretion
with bile removes substances from the body only to the
extent that enterohepatic circulation is incomplete—when
a certain amount of secreted medicinal substance is not
reabsorbed from the intestine.
 Pharmacodynamics (PD) is the study of the
biochemical and physiologic effects of drugs
 The pharmacodynamics of a drug may change under the influence of
physiological changes caused by:
• disorder
• Aging
• other medications.
 Conditions that can affect the pharmacodynamic response include
genetic mutations, thyrotoxicosis, malnutrition, myasthenia gravis,
Parkinson's disease, and some forms of insulin-resistant diabetes.
These pathological conditions can change the degree of binding of
drugs to receptors, affect the concentration of binding proteins, or
reduce the sensitivity of the receptors.

 The effect of age related changes on the pharmacodynamic response is

due to a violation of receptor binding or sensitivity of postreceptor
reactions.
 Drug–Receptor Interactions
• Receptors are macromolecules involved in chemical
signaling between and within cells; they may be located
on the cell surface membrane or within the cytoplasm.
Activated receptors directly or indirectly regulate cellular
biochemical processes (eg, ion conductance, protein
phosphorylation, DNA transcription, enzymatic activity).
• Molecules (eg, drugs, hormones, neurotransmitters) that
bind to a receptor are called ligands. The binding can be
specific and reversible. A ligand may activate or
inactivate a receptor; activation may increase or
decrease a particular cell function. Each ligand may
interact with multiple receptor subtypes.
• A drug’s ability to affect a given receptor is
related to the drug’s affinity (probability of the
drug occupying a receptor at any given instant)
and intrinsic efficacy (intrinsic activity—degree to
which a ligand activates receptors and leads to
cellular response). A drug’s affinity and activity
are determined by its chemical structure.
• The pharmacologic effect is also determined by
the duration of time that the drug-receptor
complex persists (residence time).
 Agonists and antagonists
• Agonists activate receptors to produce the desired response. Conventional
agonists increase the proportion of activated receptors. Inverse agonists
stabilize the receptor in its inactive conformation and act similarly to
competitive antagonists. Many hormones, neurotransmitters (eg,
acetylcholine, histamine, norepinephrine), and drugs
(eg, morphine, phenylephrine, isoproterenol, benzodiazepines,
barbiturates) act as agonists.
• Antagonists prevent receptor activation. Preventing activation has many
effects. Antagonists increase cellular function if they block the action of a
substance that normally decreases cellular function. Antagonists decrease
cellular function if they block the action of a substance that normally
increases cellular function.
• Receptor antagonists can be classified as reversible or irreversible.
Reversible antagonists readily dissociate from their receptor; irreversible
antagonists form a stable, permanent or nearly permanent chemical bond
with their receptor (eg, by alkylation). Pseudo-irreversible antagonists
slowly dissociate from their receptor.
 Chemical Interactions

• Some drugs produce effects without altering

cellular function and without binding to a
receptor. For example, most antacids decrease
gastric acidity through simple chemical
reactions; antacids are bases that chemically
interact with acids to produce neutral salts.
The primary action of cholestyramine, a bile
acid sequestrant, is to bind bile acids in the
gastrointestinal tract.
 Dose-Response Relationships
• Regardless of how a drug effect occurs—
through binding or chemical interaction—the
concentration of the drug at the site of action
controls the effect. However, response to
concentration may be complex and is often
nonlinear. The relationship between the drug
dose, regardless of route used, and the drug
concentration at the cellular level is even
more complex
• Dose-response data are typically graphed with the
dose or dose function (eg, log10 dose) on the x-axis and
the measured effect (response) on the y-axis. Because
a drug effect is a function of dose and time, such a
graph depicts the dose-response relationship
independent of time.
• Measured effects are frequently recorded as maxima at
time of peak effect or under steady-state conditions
(eg, during continuous IV infusion). Drug effects may
be quantified at the level of molecule, cell, tissue,
organ, organ system, or organism.
 A hypothetical dose-response curve
has features that vary:
• Potency (location of
curve along the dose
axis)
• Maximal efficacy or
ceiling effect (greatest
attainable response)
• Slope (change in
response per unit dose)
• Dose-response, which involves the principles of
pharmacokinetics and pharmacodynamics, determines
the required dose and frequency as well as the
therapeutic index for a drug in a population.
• The therapeutic index (ratio of the minimum toxic
concentration to the median effective concentration)
helps determine the efficacy and safety of a drug.
Increasing the dose of a drug with a small therapeutic
index increases the probability of toxicity or
ineffectiveness of the drug.
 PHARMACOECONOMICS

• This is a science that aims to evaluate the

economic efficiency of the use of health
resources aimed at pharmacotherapy, other
medical and pharmaceutical services.
 Cost-Benefit Analysis
• Simple analysis of the economic consequences
of outcomes (cost-benefit analysis) depends
on assumptions about the perceived dollar
value of prolonged life and improved health.
Such assumptions are often arguable and
rarely straightforward. Furthermore, although
such analyses determine whether a given
strategy saves costs or requires the net
expenditure of resources, they do not indicate
whether the expenditures are worthwhile.
 Cost-effectiveness analysis
• tracks medical costs and health outcomes separately. Both
outcome measures can be strongly affected by the perspective and
duration of the analysis and by the underlying assumptions.
Comparison of the costs and health outcomes of 2 management
strategies results in 1 of 9 pairings .
• When health outcomes are equivalent (center column), the choice
should be based on cost; when costs are equivalent (center row),
the choice should be based on outcome. When one strategy has
better outcomes and lower costs (upper right and lower left cells),
the choice is clear. The decision is difficult only when the strategy
that is more expensive also produces better outcomes (upper left
and lower right cells); in such cases, the marginal cost-effectiveness
ratio should be determined.
 Marginal cost-effectiveness ratio

• The marginal cost-effectiveness ratio is the

additional cost of a strategy divided by the
additional health outcome it achieves and
thus pertains to the situation in which there is
a choice between ≥ 2 effective management
strategies. Greater health improvement for a
given resource expenditure is derived when
the ratio is lower.
• For policy analysis, the most common measure of
effectiveness is the QALY, making the units of the
corresponding marginal cost-effectiveness ratio
“additional dollars spent per QALY gained.”
However, the marginal cost-effectiveness ratio
has been criticized because elderly patients or
patients with life-limiting comorbidities have a
smaller potential gain in survival from a
treatment and therefore have a higher (less
advantageous) cost-effectiveness ratio.
• For example (see table Calculating a Marginal Cost-
Effectiveness Ratio, Analysis 1), consider no antiarrhythmic
therapy vs prophylactic use of an implantable cardioverter-
defibrillator (ICD) for patients who have survived several
months after an acute anterior MI and who have a mildly
depressed ejection fraction (between 0.3 and 0.4). (All figures
and costs in this example are hypothetical.) Both strategies
assume similar baseline costs for routine care ($78,300), but
the ICD has an additional (marginal) cost of $53,100, based on
the cost of the device and professional fees, initial
hospitalization, and ongoing therapy (including extra physician
visits, laboratory tests, drugs, rehospitalizations for ICD-related
complications, and replacement of ICD generator or leads). If
patients with an ICD have a slightly increased life expectancy
(7.87 vs 7.42 QALY), the marginal effectiveness of ICD therapy
is 7.87 − 7.42 = 0.45 QALY. Thus, prophylactic ICD enhances
survival compared to no antiarrhythmic therapy at a cost of
$53,100/0.45 QALY, or $118,000/QALY.
• Now assume that a third strategy,
prophylactic amiodarone therapy, is available. This therapy is
less expensive but also less effective than ICD. The effect of
adding this third intermediate strategy is noteworthy because
marginal cost-effectiveness ratios are calculated sequentially
when there are multiple strategies (see table Calculating a
Marginal Cost-Effectiveness Ratio, Analysis 2). The marginal
cost-effectiveness ratio of amiodarone is lower ($68,519/QALY
gained) than that for an ICD calculated in the previous example,
and furthermore, because the effectiveness of an ICD is now
compared to amiodarone rather than to no therapy, the
addition of this intermediate cost strategy with partial
effectiveness increases the ICD’s marginal cost-effectiveness
ratio from $118,000 to $192,222/QALY gained. This analysis
suggests that for an expensive therapy such as an ICD, an
attempt should be made to identify subpopulations expected
to reap the greatest benefit.
 Pharmacoepidemiology
• Pharmacoepidemiology studies the use of
drugs and their effects at the level of
populations or large groups of people for the
rational use of the most effective and safe
drugs.
 Main tasks of
pharmacoepidemiological research:
• clarification of information about the
effectiveness of drugs obtained in the course of
randomized clinical trials;
• identification of new, previously unknown effects
of drugs (both favorable and undesirable) and
determining the relationship of these effects with
the use of drugs;
• assessment of the frequency and risk of the
identified effects in the population;
• study of existing models of drug use in order to
develop measures to improve pharmacotherapy.