Describe about Factors Modifying Drug Action.

1.0 Physiological Factors (Patient related factors)

1.1 Age
Different age groups have different responses to drugs. The organs such as kidney and
liver are not completely developed in children and their blood brain barriers are weak, therefore
they are vulnerable to the adverse effects of drugs. For instances, premature infants who are
exposed to corticosteroids will result in retardation of growth and development. In the elderly,
the drug doses have to be reduced due to the progressively decline in renal and hepatic function
and the degenerative changes in brain and heart causes slower drug absorption and metabolic
inactivation. Drugs like diazepam and chlordiazepoxide is used to treat insomnia and anxiety, but
it would greatly increases the risk of falls and confusion in elderly.

1.2 Gender - pregnancy, lactation and menstruation

Females have smaller body size and lower drug clearance compared to male, therefore
the dosage required are comparatively lower. Drugs prescription must be done cautiously during
lactation, menstruation and especially during pregnancy. Most drugs are contraindicated because
it harms the fetal development. Besides that, during third trimester of pregnancy, absorption of
orally administered drug is slower due to decrease gastrointestinal motility. Also, purgatives or
laxative drugs to treat and prevent constipation may increase menstrual blood loss. Moreover,
drugs such as amiodarone and phenobarbitone should be avoided during breastfeeding or
lactation.
1.3 Body weight or surface area and size
Body weight affects the drug concentration to reach the action site. The average adult
dose is intended for a medium built individual. However, the prescribed dose may be modified
using the body surface area or body weight because weight indicates enzyme activity status. The
lesser the body weight, the more the plasma concentration, therefore low amount of drug are
required.
1.4 Food intake
The intake food could alter the response of drug. Hypertensive crisis could occur after
eating foods contain tyramine if the patient taking Monoamine oxidase inhibitors (MAOI).
1.5 Drug Tolerance and Allergy/Idiosyncrasy
Drug tolerance has developed when larger than usual dose is used to obtain the same
response. There is natural and acquired tolerance. Indians are less susceptible to thiacetazone, an
antituberculosis drug than whites. Repetitive use of drugs for analgesia will reduce the effect of
drugs. Idiosyncrasy is the abnormal response to a drug. Some individuals are allergic to
penicillin without exact cause.
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2.0 Pathological (Disease) Factors

2.1 Gastrointestinal disease
It can alter absorption of orally administered drugs. The drug absorption may increase or
decrease. For example, in celiac disease, absorption of amoxicillin is decreased while cephalexin
and cotrimoxazole are increased.

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2.2 Congestive Heart Failure

Modifying volume of distribution. For example, expansion of extracellular fluid volume can
increase volume of distribution while reduced tissue perfusion can decrease volume of
distribution.
Mucosal edema and splanchnic vasoconstriction reduce drug absorption from gastrointestinal
tract.
Increases tubular reabsorption, reduces glomerular filtration rate and perfusion will reduce drug
elimination.
2.3 Liver disease
In liver diseases, prolonged duration of action occurs because of increased half-life. Plasma
protein binding for warfarin, tolbutamide is decreased leading to adverse effects.
Bioavailability of drugs having high first pass metabolism is increased as a result of loss of
hepatocellular function and portocaval shunting.
Impaired liver microsomal enzymes may lead to toxic levels of diazepam, rifampicin and
theophylline.
Metabolism and elimination of some drugs such as morphine, propranolol are decreased.
Decrease inactivation or decrease activation of prodrug.
2.4 Thyroid disease
Patients with hypothyroidism have decreased metabolism and are more sensitive to
digoxin, morphine and central nervous system depressants. Patients with hyperthyroidism not
only have increased metabolism but also resistant to inotropic action and more prone to
arrhythmic action of digoxin.

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2.5 Renal disease

Plasma proteins such as albumin often low in patients with renal disease. The binding of basic
drug is not much affected but that of acidic drug is reduced.
Permeability of blood-brain barrier is increased in renal failure. Barbiturates and opiates produce
more central nervous system depression.
The sensitivity of the target organ is increased. Antihypertensive drugs produce more postural
hypotension.

3.0 Genetic Factors

Genetic abnormalities will influence the response to drugs and dose of a drug. Individual
get affected at 2 levels which are level of receptor and level of drugs metabolizing enzyme.
These interfere with the functions such as rate of plasma drug clearance.
3.1 Genetic polymorphism
The existence in a population of two or more phenotypes with respect to the effect of a
drug. For example, acetylation enzymes deficiency. Acetyltransferase (non-microsomal) affects
isoniazid, sulphonamides, and others. Slow acetylator phenotype may present peripheral
neuropathy while rapid acetylator phenotype may present hepatitis.
3.2 Pseudocholinesterase deficiency
It is an inherited enzyme dysfunction where metabolic degradation of exogenous choline
ester drugs such as succinylcholine, a muscle relaxant, is abnormally slow. For example, after
administration of standard doses of succinylcholine, respiratory paralysis persists for a prolonged
period. This happens because the body is lack of the enzyme, pseudocholinesterase to catalyst
the breakdown of the drug.
3.3 Malignant hyperthermia (MH)
MH is a potentially fatal pharmacogenetic (inherited) disorder of skeletal muscle calcium
regulation. It is characterised by hypermetabolism involving the skeletal muscle. The triggers
include volatile inhalation of anesthetic agents and succinylcholine, a muscle relaxant. The
ryanodine receptor, which controls the release of calcium, in skeletal muscle is abnormal. This
abnormality causes accumulation of calcium in skeletal muscle, resulting in a massive metabolic
reaction.
3.4 Oxidation Polymorphism
In case of Debrisoquine, extensive metabolizers (EM) need larger dose while poor
metabolizers (PM) only need smaller dose.
3.5 Deficiency of Glucose-6-phospate dehyfrogenase (G-6-PD)
G-6-PD deficiency in red blood cells will lead to haemolytic anaemia upon exposure to
some oxidizing agents such as antimalarial drug primaquine, long acting sulphonamides and fava
beans (favism).
4.0 Environmental Factors
In a secure environment such as the hospital, variables such as new or strange
environment, unfamiliar faces, noises, equipment and procedures, and lack of physical activity.
These factors may increase the need for some medication analgesics, laxatives and sedative3

hypnotics. For example, in a quiet, cool, low external stimuli environment to decrease tension
and stimulation enhances the anxiolytic effects of sedative drugs.
4.1 Microsomal enzyme inducers
For example hydrocarbon in tobacco smoke and charcoal broiled meat induces CYP1A.
Thus, smoker metabolizes drugs more rapidly than non-smoker.
4.2 Effect of climate
Many drugs are sensitive to the physical surrounding. For example, sudden change of
temperature or a humid condition can affect the stability of a drug. Drugs may lose their potency
and effectiveness when exposed to these extreme conditions. Another example is nitroglycerin, a
drug to treat angina pain, where its effect can be diminished when in contact with air, light and
moisture. Hence, the drug needs to be store in its original container and should be replaced
frequently. Also, body metabolism is also affected by the climate change. Metabolism is low in
hot and humid climate. For example, purgatives, a type of laxative, act better in summer while
diuretics act better in winters.
4.3 Adverse effects
The relationship between physiologic function, drug effects, and adverse effects or injury
is affected by the environment surrounding the patient. Substances such as alcohol, tobacco, or
pesticides are prone to altering the pharmacokinetics of some drugs and increase the risk of
adverse drug effects in patients. For example, lorazepam, if consume with alcohol, may causes
adverse effect of respiratory depression which could be fatal.
5.0 Interaction with other drugs
A drug interaction can be defined as an interaction between a drug and another substance
that prevents the drug for performing as expected. Drug interactions occur when two drugs that
have similar effects or opposite effects on the body are administered together and this interaction
will reduce or enhances the effect of the drug.
5.1 Distribution interactions
Drug interactions affecting distribution are those that alter protein binding. It depending
on relative plasma concentrations and protein-binding affinities, one drug may displace another
with clinically significant results. For example, using warfarin together with phenytoin may
cause to bleed more easily and increase phenytoin levels.
5.2 Metabolism interactions
Mechanisms of metabolism interactions include enzyme induction and enzyme inhibition.
In this interactions, these will increase or decrease of rate of metabolism. Example of drugs is
rifampicin, ciprofloxacin and protease inhibitors.

6.0 Route of administration

The drug dosage pattern is given by various route of administration. Despite the
pharmacological impact of the same drug administered by different route ought to make similar,
the route might influence both the speed at which the desired effect is attained and the intensity
of the effect. The route of administration will influence the onset of action, plasma concentration
is achieved, and the length of time that the drugs stays in circulation. The ideal route ensures that
an effective concentration of a drug is conveyed to its desired site of action, also that this
concentration maintained relentlessly until the condition is cured.
6.1 Parenteral Route
The drug introduced into the circulatory system through injection rather than GI
absorption. This route is chosen when fast drug action is desired, when the patient is unconscious
or unable to accept oral drugs. The drugs may be injected into the arteries, veins, muscles, joints
and spinal segments.
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Intravenous (IV)
An aqueous solution is injected directly under those veins, typically at the forearm.
Advantages of this administration include more rapid onset of drug action (does not encounter
absorption barrier) and extremely valuable in emergency situation. Disadvantages include
possible pain, irritation, and risk of infection in the blood stream and at the injection site.

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Intramuscular (IM)
The drug is administered directly into the skeletal muscle include gluteus medius, gluteus
maximus, deltoid, and vastus lateralis. The rate of absorption into the bloodstream depends on
the blood flow to the muscle and the formulation of the injection. This administration provides
sustained drug action while bypassing gastrointestinal problem. As with IV administration, the
disadvantages include pain, irritation and risk of infection.