Factors of the drug affecting drug

action – chemical structure, physical

and chemical properties, aggregate
condition, dose, dosage form. Types of
doses. Therapeutic window and
therapeutic index.

Assoc. prof. Delian Delev, MD, PhD

Dept. Pharmacology and Clinical Pharmacology

E-mail: delevg@gmail.com
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1. Physical properties of the drugs (physical

state, crystalline structure, the size of the
particles of solid dosage forms).
• These properties determine the speed of
absorption and bioavailability.
• Most rapidly are absorbed gaseous drugs and
evaporating liquids for inhalation, followed by
aqueous solutions for parenteral administration,
aqueous solutions for oral administration.
• The solid dosage forms have the slowest
absorption.
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2. Physical - chemical properties of the

drug - lipophilicity (hydrophobicity),

• pK-value, the Michaelis affinity constant (Km) -

the affinity of an enzyme to its substrate.
• These properties determine their absorption,
distribution, binding with plasma proteins,
metabolism and excretion.
• Lipophilicity (hydrophobicity) - the lipid soluble
unionized drug diffuse across the lipid
biomembrane.
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• A drug passes through membranes more readily

if it is uncharged (lipid-soluble). Most drugs are
either weak acids or weak bases.

• Acidic drugs (HA) release an H+ causing a

charged anion (A-) to form:
• HA ⇄ H+ + A -
• Weak bases (BH+) can also release an H+.
However, the protonated form of basic drugs is
usually charged, and loss of a proton produces
the uncharged base (B):
• BH+⇄B + H+
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• Thus, for a weak acid, the uncharged HA can

permeate through membranes, and A- cannot.
• For a weak base, the uncharged form, B,
penetrates through the cell membrane, but BH+
does not.
• Therefore, the effective concentration of the
permeable form of each drug at its absorption
site is determined by the relative concentrations
of the charged and uncharged forms.
• The ratio between the two forms is, in
turn,determined by the pH at the site of
absorption and by the strength of the weak acid
or base, which is represented by the pKa.
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• The pKa is a measure of the strength of the

interaction of a compound with a proton. The
lower the pKa of a drug, the more acidic it is.
Conversely, the higher the pKa, the more basic is
the drug.

• Km - the affinity of an enzyme to its substrate

(when the value of Km is high affinity of the
enzyme is low, and vice versa)
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3. Сhemical structure – determines

pharmacokinetics and pharmacodynamics.
• Example:
In the molecule of morphine there is a phenolic
group at 3rd position, an alcohol group at 6th
position, and a methyl group at 17th position. The
substitution of the hydroxyl group at the 3rd
position with a methyl group decreases first-pass
metabolism through the liver. The new substance
is called codeine and possesses antitussive activity
in addition to its analgesic properties.
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The substitution of the

hydroxyl group at the
3rd position with a
methyl group decreases
first-pass metabolism
through the liver.

Acetylation of
morphine converts
it into heroin
which is stronger
analgesic and
readily passes
through the blood-
brain barrier.
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4. Drug dosage form

• Determines the speed and rate of absorption and
bioavailability, e.g. effervescent tablets are
dissolved in water immediately prior to
ingestion and have faster absorption than coated
tablets;
• The coat thickness of coated tablets can be
designed such that release and absorption of
drug occur either in the proximal or distal bowel,
etc.
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5. Dose - the amount of drug

administered in the body
• A single dose of medication (dosis pro dosi) is:

• Minimum therapeutic dose - the smallest dose

that will produce a the typical effect of the drug;
• Optimal therapeutic dose – the dose that will
produce optimal therapeutic effect;
• Maximum therapeutic dose - the highest dose of
a drug or treatment that does not cause
unacceptable side effects.
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Dose (cont.)
• There are also daily dose, course dose, loading
dose, maintenance dose.
• ED50 ("median effective dose" ) - the dose that
produces an optimal therapeutic effect in 50% of
the population that takes it or in 50% of animals
tested.
• LD50 (“median lethal dose”) - this is the amount
of drug that causes death in 50% of treated
animals.
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Therapeutic window – the range of

doses between the minimum effective
dose and minimum toxic dose.
• It is a measure of drug's safety

• When the therapeutic window is broad the drug

is relatively non-toxic, e.g. penicillins.
• When the therapeutic window is narrow the
drug has the potential of serious ADRs at low
dose, e.g. cardiac glycosides.
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The therapeutic index of a drug is the ratio of the

dose that produces toxicity to the dose that
produces a clinically desired or effective response
in a population of individuals:
• TI = TD50/ED50
• where TD50 = the drug dose that produces a toxic
effect in half the population and ED50 = the drug dose
that produces a therapeutic or desired response in half
the population.
• The therapeutic index is a measure of a drug's safety:
• a large number = a wide margin of safety;
• a small number = a small margin of safety.
 Factors of the patient that affect
drug action – drugs in pregnancy,
breast-feeding, children, elderly, liver
and kidney diseases. Genetic
abnormalities and drug action

Assoc. prof. Delian Delev, MD, PhD

Dept. Pharmacology and Clinical Pharmacology

E-mail: delevg@gmail.com
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Drug Therapy During Pregnancy

Pregnancy is divided in three stages

• 1. Fertilization and implantation;

• 2. Organogenesis/embryonic stage;
• 3. Fetogenic stage.
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• 1. Fertilization and implantation

• Animal studies suggest that interference with the
fetus before 17 days gestation causes abortion, i.e. if
pregnancy continues the fetus is unharmed.
• 2. Organogenesis/embryonic stage
• At this stage, the fetus is differentiating to form
major organs, and this is the critical period for
teratogenesis. Teratogens cause deviations or
abnormalities in the development of the embryo
that are compatible with prenatal life and are
observable postnatal. Drugs that interfere with this
process can cause gross structural defects (e.g.
thalidomide - phocomelia). Some drugs are
confirmed teratogens, but for many the evidence is
inconclusive.
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• 3. Fetogenic stage

• In this stage, the fetus undergoes further

development and maturation.
• Even after organogenesis is almost complete,
drugs can still have significant adverse effects on
fetal growth and development, e.g. ACE
inhibitors and angiotensin receptor blockers
cause fetal and neonatal renal dysfunction,
tetracycline antibiotics inhibit growth of fetal
bones and stain teeth.
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Delivery

• Some drugs given late in pregnancy or during

delivery may cause particular problems, e. g.
pethidine, administered as an analgesic can
cause fetal apnea, warfarin given in late
pregnancy causes a hemostasis defect in the
baby, and predisposes to cerebral hemorrhage
during delivery.
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Pharmacokinetics in pregnancy
• Absorption
• Gastric emptying and small intestinal motility are
reduced.
• Distribution
• During pregnancy, the blood volume increases by
one-third, with expansion in plasma volume (from
2.5 to 4L at term) being disproportionate to
expansion in red cell mass, so that haematocrit
falls. There is also an increase in body water
due to a larger extravascular volume. For water-
soluble drugs (which usually have a relatively
small volume of distribution), this increases the
apparent volume of distribution.
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• Metabolism
• Metabolism of drugs by the pregnant liver is
increased, largely due to enzyme induction,
perhaps by raised hormone levels. This may lead
to an increased rate of elimination of some
drugs, e.g. theophylline.

• Renal excretion
• Excretion of drugs via the kidney increases
because renal plasma flow almost doubles and
the glomerular filtration rate increases. This has
been documented for cefalexin, gentamicin, etc.
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Breast-feeding
• Breast-feeding can lead to toxicity in the infant if the
drug enters the milk in pharmacological quantities.
• The milk concentration of some drugs (e.g. iodides)
may exceed the maternal plasma concentration, but
the total dose delivered to the baby is usually very
small.
• However, drugs in breast milk may cause
hypersensitivity reactions even in very low doses.
• Milk is weakly acidic, so drugs that are weak bases
are concentrated in breast milk by trapping of the
charged form of the drug (tetracyclines, opioids).
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DRUGS AND
AGE
OF PATIENTS
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DRUGS IN CHILDREN
• Absorption
• Gastro-intestinal absorption is slower in infancy, but
absorption from intramuscular injection is faster. Infant
skin is thin and percutaneous absorption can cause
systemic toxicity if topical preparations (e.g. of potent
corticosteroids) are applied too extensively.
• Distribution
• Body fat content is relatively low in children, whereas water
content is greater, leading to a lower volume of distribution
of fat-soluble drugs (e.g. diazepam) in infants. Plasma
protein binding of drugs is reduced in neonates due to a
lower plasma albumin concentration and altered binding
properties. The risk of kernicterus caused by displacement
of bilirubin from albumin by sulphonamides is well
recognized. The blood–brain barrier is more permeable in
neonates and young children, leading to an increased risk of
CNS adverse effects.
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DRUGS IN CHILDREN (cont.)

• Metabolism
• At birth, the hepatic microsomal enzyme system
is relatively immature, but after the first four
weeks it matures rapidly. Chloramphenicol can
produce ‘grey baby syndrome’ in neonates due to
high plasma levels secondary to inefficient
elimination.
• Excretion
• All renal mechanisms (filtration, secretion and
reabsorption) are reduced in neonates, and renal
excretion of drugs is relatively reduced in the
newborn.
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DRUGS IN CHILDREN (cont.)

• Pharmacodynamics changes

• Documented evidence of differences in receptor

sensitivity in children is lacking, and the
apparently paradoxical effects of some drugs
(e.g. hyperkinesia with phenobarbital, sedation
of hyperactive children with amphetamine) are
as yet unexplained.
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DRUGS IN ELDERLY
• Absorption
• Absorption of carbohydrates and of several
nutrients, including iron, calcium and thiamine, is
reduced in elderly people. Lipid-soluble drugs are
absorbed by simple diffusion down the
concentration gradient, and this is not impaired by
age.
• Distribution
• Ageing is associated with loss of lean body mass, and
with an increased ratio of fat to muscle and body
water. This enlarges the volume of distribution of
fat-soluble drugs, such as diazepam and lidocaine,
whereas the distribution of polar drugs such as
digoxin is reduced compared to younger adults.
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DRUGS IN ELDERLY (cont.)

• Metabolism
• Ageing reduces metabolism of some drugs (e.g.
benzodiazepines) by reduced hepatic clearance.
Slow accumulation may lead to adverse effects
whose onset may occur days or weeks after
initiating therapy.

• Renal excretion
• Declining renal function is the most important
cause of drug accumulation.
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DRUGS IN ELDERLY (cont.)

Pharmacodynamic changes in the elderly include:
• Increased sensitivity to central nervous system
(CNS) effects (e.g. benzodiazepines);
• increased incidence of postural hypotension (e.g.
beta-blockers, tricyclic antidepressants,
diuretics);
• Increased toxicity from NSAIDs;
• Increased incidence of allergic reactions to
drugs.
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Pathological Factors
• Diseases cause individual variation in drug’s response.
Renal and liver insufficiency are the main modulators of
drug’s effects.
• Renal failure decreases drugs elimination. Drugs (and
their metabolites) which are excreted predominantly by
the kidney accumulate in renal failure, e.g. digoxin,
aminoglycosides, penicillins.
• Liver failure decreases drugs metabolism. This causes
altered pharmacokinetics:
• a) increased bioavailability due to reduced first-pass
metabolism;
• b) decreased first-pass activation of pro-drugs;
• c) decreased protein binding due to decreased protein
synthesis in the liver;
• d) decreased hepatic elimination.
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Genetic Factors
• Pharmacogenetics is the study of the relationship between
genetic factors and drug response.
• Examples:
• Acetylation is an important route of metabolism for many
drugs that possess an amine group. Most individuals are
either rapid or slow acetylators but the proportion of each
varies greatly between races.
• Some 90% of Japanese are rapid acetylators whereas in
Western populations the proportion is 50% or less. In slow
acetylator phenotype antimycobacterial drug isoniazid may
cause peripheral neuropathy, in rapid acetylator phenotype –
hepatitis.
• In patients with pseudocholinesterase deficiency depolarizing
neuro-muscular blocking agent succinylcholine leads to
prolonged apnea because the duration of action of this drug is
determined by its metabolism by pseudocholinesterase.
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