NATIONAL RIBAT UNIVERSITY

Drug response variations

Bashir Alsiddig Yousef
B. Pharm., MSc. Molecular Medicine, Ph.D. Pharmacology
Department of Pharmacology
Email: bashiralsiddiq@outlook.com
2017 - 2018
 Introduction
• Therapeutics would be a great easier if responses to the same dose of drug
were always the same.
• In reality, inter- and even intra-individual variation is often substantial.
• Variation can be caused by different concentrations at sites of drug action
(pharmacokinetic variation) or by different responses to the same drug
concentration (pharmacodynamics variation).
• Variation either is (quantitative variation) in which the drug produces a
larger or smaller effect, or acts for a longer or shorter time.
• OR (qualitative variation) also known as ‘idiosyncratic reactions ’.
Factors Responsible For Quantitative
Individual Variation:
• The main causes of variability are:
1. Ethnicity
2. Age
3. Genetic factors
4. Immunological factors
5. Pathological states (e.g. kidney or liver disease)
6. Drug interactions.
Ethnicity
• Citizens of several modern societies are asked to define their race or ethnicity
from a list of options (e.g. ‘white’, ‘black’, ‘mixed’, ‘Chinese’, ‘Asian’ or ‘other’).
• Members of such self-defined groups share some characteristics on the basis of
common genetic and cultural heritage.
1. Change in ethnicity can lead to variation of drug responsiveness. EXAMPLES:
African-Americans with heart failure gain a benefit (decrease mortality) from
treatment with a combination of hydralazine plus a nitrate, whereas white
Americans may not.
2. Some adverse effects may also be predicted on the basis of race; EXAMPLE:
many Chinese subjects differ from Europeans in the way that they metabolize
ethanol, producing a higher plasma concentration of acetaldehyde, which can
cause flushing and palpitations
• Other examples:
• Chinese subjects are considerably more sensitive to the cardiovascular
effects of propranolol than white Europeans, whereas Afro-Caribbean
individuals are less sensitive.
• Overall effectiveness of gefitinib in treating patients with advanced lung
tumors has been disappointing, but in about 10% of patients lung
tumors shrink rapidly in response to this drug. Japanese patients are
three times as likely as whites to respond in this way.
Age
• The main reason that age affects drug action is that drug elimination is
less efficient in newborn babies and in old people, so that drugs
commonly produce greater and more prolonged effects at the extremes
of life.
• Other age-related factors, such as:
1. Variations in pharmacodynamic sensitivity, are also important with
some drugs.
2. Physiological factors (e.g. altered cardiovascular reflexes).
3. Pathological factors (e.g. hypothermia), which are common in elderly
people, also influence drug effects.
4. Body composition changes with age, fat contributing a greater
proportion to body mass in elderly, with consequent changes in
distribution volume of drugs.
5. Elderly people consume more drugs than do younger adults (poly-
pharmacy), so the potential for drug interactions is also increased.
A- Effect Of Age On Renal Excretion Of Drugs:
• Glomerular filtration rate (GFR) in the newborn, normalized to body
surface area, is only about 20% of the adult value, and tubular function is
also less.
• Accordingly, plasma elimination half-lives of renally eliminated drugs are
longer in neonates than in adults.
• Glomerular filtration rate declines slowly from about 20 years of age, falling
by about 25% at 50 years and by 50% at 75 years.
B- Effect Of Age On Drug Metabolism:
• Several important enzymes, including hepatic microsomal oxidase,
glucuronyl-transferase, acetyltransferase and plasma esterases, have low
activity in neonates, especially if premature.
• The relative lack of conjugating activity in the newborn can have serious
consequences, as in kernicterus caused by drug displacement of bilirubin
from its binding sites on albumin,
• And in the grey baby syndrome caused by the antibiotic chloramphenicol.
• Slow conjugation is also one reason why morphine is not used as an
analgesic in labor, because drug transferred via the placenta has a long
half-life in the newborn baby and can cause prolonged respiratory
depression.
C- Age-related Variation In Sensitivity To Drugs:
• The same plasma concentration of a drug can cause different effects in
young and old subjects.
• Benzodiazepines, producing more confusion and less sedation in elderly
than in young subjects
• Hypotensive drugs cause postural hypotension more commonly in
elderly than in younger adult patients.
Pregnancy
• Pregnancy causes physiological changes that influence drug disposition
in mother and fetus.
• Maternal plasma albumin concentration is reduced, influencing drug
protein binding.
• Cardiac output is increased, leading to increased renal blood flow and
GFR, and increased renal elimination of drugs.
• Lipophilic molecules rapidly traverse the placental barrier, whereas
transfer of hydrophobic drugs is slow, limiting fetal drug exposure
following a single maternal dose.
Disease
• Disease can cause pharmacokinetic or pharmacodynamic variation.
• Common disorders such as impaired renal or hepatic function predispose
to toxicity by causing unexpectedly intense or prolonged drug effects as a
result of increased drug concentration following a standard dose.
• Drug absorption is slowed in conditions causing gastric stasis (e.g.
migraine, diabetic neuropathy) and may be incomplete in patients with
malabsorption owing to ileal or pancreatic disease or to edema of the ileal
mucosa caused by heart failure or nephrotic syndrome.
• Nephrotic syndrome alters drug absorption because of edema of intestinal
mucosa; alters drug disposition through changes in binding to plasma
albumin.
• Hypothyroidism is associated with increased sensitivity to several widely
used drugs (e.g. pethidine), for reasons that are poorly understood.
• Hypothermia (to which elderly persons, in particular, are predisposed)
markedly reduces the clearance of many drugs.

• Other disorders affecting receptors and signal transduction mechanisms.

• Example: myasthenia gravis, an autoimmune disease characterized by
antibodies to nicotinic acetylcholine receptors and increased sensitivity to
neuromuscular blocking agents (e.g. vecuronium) and other drugs that may
influence neuromuscular transmission (e.g. aminoglycoside antibiotics)
Genetic factors
• Genetic variation is an important source of pharmacokinetic variability.
• There are several clear examples where genetic variation influences drug
response, including:
1. Fast/slow acetylators (hydralazine, procainamide, isoniazid)
2. Plasma cholinesterase variants (suxamethonium)
3. Hydroxylase polymorphism (debrisoquine).

• In future, profiling an individual’s DNA (e.g. for combinations of single

nucleotide polymorphisms) could provide a way to anticipate drug
responsiveness. (Pharmacogenomics)
Idiosyncratic Reactions
• An idiosyncratic reaction is a qualitatively abnormal, and usually harmful, drug
effect that occurs in a small proportion of individuals.
• For example, chloramphenicol causes aplastic anemia in approximately 1 in
50000 patients.
• In many cases, genetic anomalies are responsible. Glucose 6-phosphate
dehydrogenase (G6PD) deficiency and the hepatic porphyrias are well-
understood examples of this.
• Malignant hyperthermia is a metabolic reaction to drugs including
suxamethonium and various inhalational anesthetics and antipsychotic drugs.
• Susceptibility to these drugs in affected individuals is caused by an inherited
abnormality in the Ca2+ release channel known as the ryanodine receptor
located in the sarcoplasmic reticulum of striated muscles
NATIONAL RIBAT UNIVERSITY

Drug interaction
Bashir Alsiddig Yousef
B. Pharm., MSc. Molecular Medicine, Ph.D. Pharmacology
Department of Pharmacology
Email: bashiralsiddiq@outlook.com
2017 - 2018
Introduction
• Drug interaction is one of the factors that can alter the response to drugs is the
concurrent administration of other drugs.
• Many patients, especially the elderly, are treated continuously with one or more
drugs for chronic diseases such as hypertension, heart failure, osteoarthritis and
so on. Acute events (e.g. infections, myocardial infarction) are treated with
additional drugs.
• The potential for drug interactions is therefore substantial, and poly-pharmacy is
an important factor to consider when prescribing in this group.
• Drugs can also interact with other dietary constituents (e.g. grapefruit juice,
which down-regulates expression of CYP3A4 in the gut) and herbal remedies
(such as St John's wort).
• There are several mechanisms by which drugs may interact.
• The administration of one drug (A) can alter the action of another (B) by one of
two general mechanisms:
1. Modification of the pharmacological effect of B without altering its
concentration in the tissue fluid (pharmacodynamic interaction)
2. Alteration of the concentration of B that reaches its site of action
(pharmacokinetic interaction).
• Combined pharmacodynamics with pharmacokinetic interactions also may
happen between two drugs when used concurrently.
• For such interactions to be important clinically, it is necessary that the
therapeutic range of one drug is narrow (i.e. that a small reduction in effect will
lead to loss of efficacy and/or a small increase in effect will lead to toxicity).
Consequences of Drug Interactions
• Their effect on patients can vary greatly, from no untoward effects to the most
extreme result of severe morbidity or death.
• Physicians face medical-legal liability if a poor patient outcome is the result of a
known drug interaction.
• Health care facilities face increased consumption of resources and increased
costs for diagnosing and treating patients with significant drug interactions.
(One study found that hospitalized patients who received interacting drugs had a
longer and more costly hospitalization than patients who did not experience such
interactions).
• The pharmaceutical industry faces loss of investment, time, and financial
resources if a drug is removed from the market, as well as potential litigation.
Risk Factors
• Use of multiple prescribers and/or multiple pharmacies increases the odds that
health professionals will have incomplete medical and drug information available
to them, and raises the chance that a potential drug interaction may go
undetected.
• Specific populations are at increased risk of experiencing drug interactions. For
example, the elderly patients.
• The genetic makeup of an individual determines his or her complement of
metabolizing enzymes and other proteins. Patients classified as slow metabolizers
appear to be at less risk for drug interactions than extensive metabolizers or
ultra-rapid metabolizers.
• Number of chronic illnesses, increased drug usage to manage those illnesses,
and age-related physiologic changes (e.g., decreased renal function, decreased
protein binding), are at higher risk for drug interactions and adverse events.
• Obese patients have altered levels of metabolizing enzymes, making them
more susceptible to drug interactions, as do malnourished patients.
• Other populations at risk include critically ill patients, patients with
autoimmune disorders, and transplant recipients.
• Drugs with a narrow therapeutic index, a steep dose-response curve, or
potent pharmacologic effects have been associated with greatest risk for
significant drug interactions.
Risk Factors for Drug Interactions
 DRUG INTERACTIONS
CLASSIFIED AS:
ENHANCED EFFICACY
A) USEFUL
WITHOUT TOXICITY

TOXICITY
B) HARMFUL
EFFICACY