CHAPTER 1

INTRODUCTION
Physicians prescribe drugs on the basis of the characteristics of the medications
and on the probability that reliable and reproducible clinical effects will result.
However, differences in drug response among patients are common, often leading
to challenges in optimizing a dosage regimen for an individual patient. Most
major drugs are effective in only 25 to 60 percent of patients, 1 and more than 2
million cases of adverse drug reactions occur annually in the United States,
including 100,000 deaths.2 Such variability in drug response among patients is
multifactorial, including environmental, genetic, and disease determinants that
affect the disposition (absorption, distribution, metabolism, and excretion) of a
given drug.
An unusual effect on the drug is one result of the variability in response to the use
of certain medications. There are many kinds of effects of drugs. The mechanism
is quite complex and involves a wide range of unique processes. The mechanisms
include variations in drug pharmacokinetics pathway, pharmacodynamic drug,
receptor, the way drugs work in the body and how variations in biological systems
can affect the performance of the drug in the body.
Drugs are substances that interact with a system of living through a chemical
process, mainly bound to the regulatory molecules, and stimulate or inhibit the
normality body's processes. 3 Medicine is chemical substances that give beneficial
effects for giving therapeutic or can be toxic that injured the human body. In
general the molecule of drugs interacts with the specific molecule in human body
called Receptor. In some cases, a drug known as chemical antagonists can interact
with other drugs, while some drugs (such as osmotic agent) is almost always
interact with water molecules. Toxins also include drugs; toxic substances are
usually defined as initial biological toxins which are synthesized by plants or
animals, or inorganic toxins such as tin and arsenic.
Chemical interaction with the receptor of drugs, the molecule of drug should have
suitable size, electrical charge, shape and composition.

a. The physical properties of the drugs

In high temperature drug in solid (aspirin, atropine), liquids (nicotine, ethanol)
or gas (nitrogen oxides).
b. The size of the drugs
Molecular size of drugs commonly used in varian form. In general, these drugs
molecular weight between 100-1000.
c. Reactivity of drugs and drug receptor binding
Drugs interact with receptors depend on the strength or chemical bonds, there
are three types of chemical bonds that are: covalent, electrostatic and
hydrophobic.
d. Shape of the drugs
Shape of drug molecule must specific. Optimally the shape of the drug and th
shape of the molecule receptor must look like the Lock and Key.
1.1

PHARMACOKINETICS
Pharmacokinetics is the action of the body to the drugs. There are 4 steps of
Pharmacokinetics4:
a. Absorbtion

: entering the drug molecule to the blood

b. Distribution

: distribute the drug molecule in blood circulation

c. Metabolism

: transformation of the drugs which using oxidation,

reduction, hydrolysis, or conjugation

d. Excretion

: excrete the molecule of the drug from blood usually using

kidney, hepar
1.2

PHARMACODYNAMICS
Pharmacodynamics is the action of the drugs on the body. The action of the
drugs depend on4 :
a. The mechanism of the drugs:
1. Interaction Drugs-Receptor : Adrenergic, steroid, colonergic, opioid.
2. Substrate-enzyme

: Allopurinol, aspirin, catropil, digoksin

3. Opened-closed channel ion : Calsium antagonist

4. Destroy the cell system (Cytotoxic) : Antibiotic, anticancer

b. Receptor : The specific molecule protein in the cell that have the
interaction with specific ligand/drugs which have the specific, afinity, and
sensitifity.
c. Ligand-Receptor (Lock and Key)
1. Agonist

: a drug capable of fully activating the effector systems

when it binds to the receptor

2. Partial Agonist: a drug capable produce less than the full effect, when it
saturated the receptors.
3. Antagonist : block the receptor and the agonist can enter, so the
receptor bind the drug but unactive
i. Competitive antagonist : drugs that bind to the receptor in a

reversible way without activating the effector system for that

receptor (veraoamil and nifedipine)
ii. Physilogic Antagonist : drugs that binds to a different receptor,

producing and effect opposite to that produced by the drug it is

antagonizing
iii. Chemical Antagonist

: drugs that interact directly with the drugs

being antagonized to remove it or to prevent it form reaching its

target.
d. Side effect of Drugs : the other effect that appeared with the therapeutic
effect when given the wrong dosage.
e. Therapeutic effects of Drugs
1. Effectiveness : the drug capacity to make the receptor active.
2. Potency

: the drug capacity to increase the effect (therapeutic

effects)

CHAPTER II
CONTENT
Unusual effect of drugs is a term which belongs to unusual or unique responds of
drugs. Its called by unique because this unusual effect on drugs is different from
usual and happen on irregular frequency in population. Usually, unusual effect of
drugs occured in low intensity in one population. Unusual effect of drugs is also
called by Idiosyncracy or Meta reactions. 5 In general, the causes of this unusual
effect of drugs cover the genetic differentiation in drugs metabolism or by
immunology mechanism, include allergy reaction. These are the kind of unusual
effect of drugs6:
1. Hypereactive
The term hyperreactive is used to describe people who gets normal effect of drug
in a very low dosage used. Here, the term hyperreactive should be different from
hypersensitivity. Its because hypersensitivity is more refer to drug allergys
symptoms.
2. Hyporeactive
Hyporeactive is one of quantitative variation in respond of drugs whose effect is
reversed from hyperreactive. Hyporeactive describe people who get the normal
effect of drug in a really high dosage of drug.
3. Tolerance
Tolerance is a quantitative changes of drug sensitivity which characterised by
decreasing drug effect after the same drug given repeatedly. The people who
suffered this tolerance should get a higher dosage than before to get a normal
effect of the drug. The tolerance degree is different from people to people. Drug
tolerance is often occured in certain drugs which is consist of organic nitrate,
opioid, and so on.
Based on the mechanism, drug tolerance divided into two types:7
a. Pharmacokinetic Tolerance
The process involves the induction of enzyme systems. The excretion of drug by
hepatic (involved hepatic) increasing if the giving of drugs repeatition.
b. Pharmacodynamic Tolerance
The process involves the changes of the cell or the receptor part.
4. Tachyphylaxis
Tachyphylaxis is a form of acute tolerance where there is a further development of
tolerant.7Tachyphylaxis can caused by changes in the sensitivity of the receptor or
cofactor exhaustion that occurs after the first exposure of a drug, although with a

relatively low dosage. Drugs work indirectly, for example by releasing

norephinephrine to make potentially tachyphylaxis.
5. Physical Dependency
Physical dependence is appearing of symptoms continued after the stop using or
postponed exposure of drugs.

There are some factors to make Physical

Dependency, they are dosage of drugs used (the intensity of drug effects), the
duration of drug used (monthly or yearly), totally dosage of drugs (Dosage of
drugs used The duration of drug used).
Physical Dependency have possibility involving the dependency subject opiete
(opiete dependent subject) in using naloxone (Narcon). It is the drugs that classify
in opiod antagonist.
There are many variation of unusual effects of drugs. Each individual have
possibility to show vary response on the same drug exposure, even a person can
show different responses to the exposure of a particular type of drug in time,
situations, and different conditions. Some factors to consider in prescribing drugs
associated with variations in the response to these drugs are age, gender, body
posture, the level of genetic diseases and the use of drugs or other types
simultaneously together.
Four mechanism that contributes to the variation of the response to drugs:6
1. Changes in the concentrations of drugs that successfully reach the
receptor.
There are different variation of pharmacokinetic process in the body. The
variation of pharmacokinetic involve the differentiate of absorbtion,
distribution, metabolism, and excretion. The different in pharmacokinetic
process make the different drugs concentration that can reach and bind to the
relevant receptors, otomatically there are appear many kinds of responses in the
body that using same drugs. The different process of pharmacokinetic depend
on the age, body weight, gender, level of disease, hepar and kidney function,
and genetic that show in the functional component of the enzym to catalyze in
drugs metabolism.
For example, Cythocrome P-450 is an enzyme that have important role in
pharmokokinetic process. Especially in drug metabolism. Cythocrome P-450 is
an enzyme that is needed in the biosynthesis and degradation of endogenous
components such as steroids, lipids, and vitamins. Cytochrome P-450

metabolize and oxidize a variety of chemical substances that enter through the
food and the environment, including drugs. 8 Cythocrome P-450 to reduce and
change the pharmacologic activity of drugs and facilitating the elimination
process of drugs. Cythocrome P-450 involved in approximately 80% in the
process of drug metabolism and oxidation of drugs. In human body there are 57
genes of Cythocrome P-450 has been indentified. But only some of them that
make protein code to metabolyze of drugs, CYP1, CYP2, CYP3. The different
of the cytochrome in the human body make the different responses of using
same drugs. 9
2. Variations in the concentration of endogenous receptor ligands
This mechanism involves drugs that have pharmacologic antagonists. Drugs
that are antagonistic to endogenous ligands in the body will decrease the
activity of specific receptor ligands. The concentration of endogenous ligand in
the body itself also contributes to the variation in response to drugs.6
For example, Saralasin is a weak partial agonist acting on the angiotensin II
receptor antagonist, whereas in this case the endogenous ligand is angiotensin
II, which has the effect of making blood pressure increase. Saralasin can be
antagonist and decrease the blood pressure in patients of hypertension due to
increasing production of angiotensin II, but Saralasin can be agonist and
increase the blood pressure in patients who produce angiotensin II in small
quantities.
3. Changes in receptor number and function.
Some experiment have found that changes in response to a particular drug is
caused by the addition or subtraction receptor complex (receptor site) or
because of changes in the efficiency of the receptor ability. The factors that
make the changes in receptor number and function are:
A. Hormone
Thyroid hormone that increases the quantity receptors in cardiac muscle of
mice as well as the sensitivity of the cardiac muscle cells to catecholamines
which in this case acts as an agonist ligand.6
B. Agonist Ligand
An agonist ligand itself that induces a reduction in the number (down
regulation) and the reduction efficiency desensitization of its own receptor.
Antagonik a substance may increase the number of receptors on cells or tissues

related to the regulatory process and prevent receptor activation by endogenous

substances agonik.
For example, discontinuation of clonidine (a drug that has activity on 2adrenoceptors agonik and has the effect of decreasing blood pressure)
hypertension can cause problems because of a reduction in the number of 2adrenoceptors caused by exposure to the drug clonidine.6
C. Genetic
Genetic also have an important role in changing the number and function of
specific receptors. For example, a genetic variant of 2C-adrenoceptors. When
inherited together with a specific variant of the 1-adrenoceptors,- 2adrenoceptors variant will show an increased risk of congestive cardiac
failure.6
4. Changes in certain components of the response mechanism distal to the
receptor.
Although these drugs carry out its action by binding to the receptor, the
response to the drug to make metabolic changes in the patient's body depends
on the integrity or unity of biochemical processes in cells which give the
responses and physiological regulation of organ systems. The pascareseptor
process is the largest and most important mechanism that causes the variation
in the response to drug therapy.
There are some examples of drugs that often given to the patient as a medicine but
sometimes these drugs also give unusual effect physically and physicologically in
our body.
1. Tinidazole 1
Tinidazole belongs to nitroimidazole group of drugs, which also include
metronidazole, secnidazole, ornidazole and benznidazole1. These drugs have
activity

against

Peptococcus,

Peptostreptococcus,

Gardnella

vaginalis,

Clostridium, Propionibacterium, Eubacterium, Fusobacterium, Bacteroides,

Helico- bacterium, Campylobactor, Actinomyces and Spirochetes. It is effective
against Entamoeba histolytica and Trichomonas vaginalis and useful in Crohn's
disease and pseudomemberaneous colitis. It also helps easy extraction of Guinea

worm. It also sensitises hypoxic tumour cells to the effects of ion- ising radiation. 1
Unusul effects of tinidazole are :
a. Brownish black hyper pigmentation of the angles of the mouth and medial
canthus of both the eyes for 2 weeks duration.
b. Symptoms started as itching on both upper and lower lips which progressed to
burning sensation, ulceration, oedema and ultimately resulted in hyper
pigmentation of the lips. All these symptoms also involved the inner canthus of
the both the eyes. There was mild penile itching but it subsided in 3 days.
c. Pigmentation only occurs on the light exposed parts like angel of mouth and
inner canthus and not on the penis. 5
2. Barbiturat 5
Barbiturat is a medicine that give effects as depresan on our center neuron system,
and, with this basic information, they produce a general spektrum yang luas from
the effects, from mild sedation until total anestesy. They also effective as an
anxiolytics, as hipnotic, and as antikonvulsan. They have addictive potency, either
psychology and physicology. Unusual effects of Barbiturat are:
a. Dizziness, drowsiness, and unsteadiness or clumsiness. These symptoms are
only considered problematic when they persist or interfere with normal
activities.
b. Bleeding sores on the lips, chest pain or tightness in the chest, fever, muscle or
joint pain, skin problems.
c. Overdosing Barbiturates can result in symptoms such as difficulty thinking,
slow speech, sluggishness, in coordination, shallow breathing, faulty judgment
d. Bad side effects of Barbiturates include respiratory depression, hypotension,
fatigue, unusual excitement, irritability, sedation, confusion, addiction and the
main risk of Barbiturate poisoning abuse is respiratory depression. Respiratory
arrest which could cause death.
e. Psychological effect like high gives feelings of euphoria and relaxed
contentment.

CHAPTER III
CONCLUSION
Differentiation or variation in respond of drug between one patient to another
generally happened and become a challenge for physician to determine a right
quantitiy of drug dosage given to patient.
Unusual effect of drugs is term used to describe the unusual respond of drug
caused by variative reaction to drugs between one patient and another or even in
one same patient at different time and condition. Many kind of unusual effect of
drugs are Hyppereactive, Hyporeactive, Tolerance, which is divided to
Pharmacokinetic Tolerance and Pharmacodynamic tolerance, Tachyphylaxis,
Physical dependency.
Four main mechanisms which contribute to a different respond of drugs between
one people to another are changes in the concentrations of drugs that successfully
reach the receptor, variations in the concentration of endogenous receptor ligands,
changes in receptor number and function, changes in certain components of the
distal response mechanism to the receptor.

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