VIETNAM NATIONAL UNIVERSITY - HCMC INTERNATIONAL

UNIVERSITY SCHOOL OF BIOTECHNOLOGY

CLINICAL OF BIOCHEMISTRY
ASSIGNMENT 2
“Clinical biochemistry in Drug profile”

Instructors: PhD. Hoàng Lê Sơn

Name of student: Nguyễn Thị Cẩm Tiên
Student ID: BTBCIU20070
I. INTRODUCTION
Drug profile means a complete and comprehensive summary of a patient's
current drugs and details of each drug including information such as active
ingredient, strength and form, dose and directions for use, and other
supplementary information. Drugs work in the body in a variety of ways. They
can interfere with microorganisms (germs) that invade the body, destroy
abnormal cells that cause cancer, replace deficient substances (such as
hormones or vitamins), or re-regulating the work. Biochemical Pharmacology
is concerned with the effects of drugs on biochemical pathways underlying the
pharmacokinetic and pharmacodynamic process and the subsequent therapeutic
and toxicological processes realms.
1.1 DRUG CLASSIFICATION
Drugs have three or more names including a: chemical name, brand or trade
name, and generic or common name. The chemical name is assigned according
to rules of nomenclature of chemical compounds. The brand name is always
capitalized and is selected by the manufacturer. The generic name refers to a
common established name irrespective of its manufacturer. In most cases, a
drug bearing a generic name is equivalent to the same drug with a brand name.
However, this equivalency is not always true. Although drugs are chemically
equivalent, different manufacturing processes may cause differences in
pharmacological action. Several differences may be crystal size or form,
isomers, crystal hydration, purity (type and number of impurities), vehicles,
binders, coatings, dissolution rate, and storage stability.
1.2 MODE OF DRUG ACTION
One major problem of pharmacology is that no drug produces a single effect.
The primary effect is the desired therapeutic effect. Secondary effects are all
other effects beside the desired effect which may be either beneficial or harmful.
Drugs are chosen to exploit differences between normal metabolic processes
and any abnormalities which may be present. Since the differences may not be
very great, drugs may be nonspecific in action and alter normal functions as
well as the undesirable ones. This leads to undesirable side effects.
The biological effects observed after a drug has been administered are the result
of an interaction between that chemical and some part of the organism.
Mechanisms of drug action can be viewed from different perspectives, namely,
the site of action and the general nature of the drug-cell interaction.
 • Killing Foreign Organisms: chemotherapeutic agents act by killing or
weakening foreign organisms such as bacteria, worms, viruses. The main
principle of action is selective toxicity, i.e. the drug must be more toxic to
the parasite than to the host.
• Stimulation and Depression: drugs act by stimulating or depressing
normal physiological functions. Stimulation increases the rate of activity
while depression reduces the rate of activity.

II. SITE OF DRUG ACTION

2.1 ENZYME INHIBITION
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme.
In a normally functioning cell, enzymes are regulated by a variety of inhibitors.
Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the
enzyme’s active site, while others inhibit enzymatic activity by binding to other
sites on the protein structure.
Normal Enzyme Reaction: in a normal reaction, a substrate binds to an enzyme
(via the active site) to form an enzyme-substrate complex. The shape and
properties of the substrate and active site are complementary, resulting in
enzyme-substrate specificity. When binding occurs, the active site undergoes a
conformational change to optimally interact with the substrate (induced fit).
This conformational change destabilized chemical bonds within the substrate,
lowering the activation energy. As a consequence of enzyme interaction, the
substrate is converted into product at an accelerated rate.

Figure 1. Normal enzyme reaction

Competitive inhibitors occupy the active site of enzymes, making them unable
to accommodate the substrate. However, sufficiently high concentrations of the
substrate can outcompete the inhibitor; as a result, competitive inhibitors slow
an enzyme's initial reaction rate but do not impact the enzyme’s maximum rate.
One example of a competitive inhibitor is the drug disulfiram, used to treat
chronic alcoholism. When alcohol is ingested, it is normally converted to
acetaldehyde, which is then converted to acetyl coenzyme A by acetaldehyde
dehydrogenase. Disulfiram binds to and occupies the active site of acetaldehyde
dehydrogenase, making the enzyme unable to perform this conversion. As a
result, a patient taking disulfiram immediately begins to experience hangover-
like symptoms, such as headache, thereby decreasing alcohol consumption.

Figure 2. Competitive inhibitors

Noncompetitive inhibitors bind to distinct sites on the enzyme, away from the
active site. These are called allosteric sites and when molecules bind to them,
the shape of the active site is changed such that the enzyme has a lower affinity
for the substrate. Because noncompetitive inhibitors do not occupy the active
site, the presence of additional substrate is unable to overcome noncompetitive
inhibition and the enzyme is unable to achieve its maximum reaction rate.

Figure 3. Competitive inhibitors

Covalent binding between an inhibitor and an enzyme is usually irreversible, as
in the case of some toxins. Most regulatory inhibitors normally active in the cell
interact with enzymes by weak interactions. This type of binding is reversible
and useful for the regulation of metabolic processes. The exploration of new
molecules to competitively and non-competitively inhibit enzymes regulating
cell growth in cancer is an active area of research.
 Figure 4. Examples of interactions due to enzyme inhibition
2.2 DRUG-RECEPTOR INTERACTION
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. Few if any
drugs are specific for one receptor or subtype, but most have relative selectivity.
Selectivity is the degree to which a drug acts on a given site relative to other
sites; selectivity relates largely to physicochemical binding of the drug to cellular
receptors. 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). The lifetime of the drug-
receptor complex is affected by dynamic processes (conformation changes) that
control the rate of drug association and dissociation from the target. A longer
residence time explains a prolonged pharmacologic effect. Drugs with long
residence times include finasteride and darunavir. A longer residence time can
be a potential disadvantage when it prolongs a drug's toxicity. For some
receptors, transient drug occupancy produces the desired pharmacologic effect,
whereas prolonged occupancy causes toxicity.
Ligands bind to precise molecular regions, called recognition sites, on receptor
macromolecules. The binding site for a drug may be the same as or different
from that of an endogenous agonist (hormone or neurotransmitter). Agonists
that bind to an adjacent site or a different site on a receptor are sometimes called
allosteric agonists. Nonspecific drug binding also occurs—ie, at molecular
sites not designated as receptors (eg, plasma proteins). Drug binding to such
nonspecific sites, such as binding to serum proteins, prohibits the drug from
binding to the receptor and thus inactivates the drug. Unbound drugs are
available to bind to receptors and thus have an effect.
• 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.
III. DRUG INTERACTION

Figure 5. Drug interaction

3.1 PHARMACODYNAMIC
Pharmacodynamics is the study of the biochemical, physiologic, and molecular
effects of drugs on the body and involves receptor binding (including receptor
sensitivity), postreceptor effects, and chemical interactions.
Pharmacodynamics, with pharmacokinetics (what the body does to a drug, or
the fate of a drug within the body), helps explain the relationship between the
dose and response, ie, the drug's effects. The pharmacologic response depends
on the drug binding to its target. The concentration of the drug at the receptor site
influences the drug’s effect. Pharmacodynamics occurs when two drugs given
together act at the same or similar receptor site and lead to a greater (additive
or synergistic) effect or a decreased (antagonist) effect. For example, when
chlorpromazine, sometimes used to help prevent nausea and vomiting, and
haloperidol, an antipsychotic medication for schizophrenia, are given together
there may be a greater risk for causing a serious, possibly fatal irregular heart
rhythm. In pharmacodynamics, there are two term to evaluate the extent of drug
reaction to the body:
• Efficacy: Maximum functional response produced by a drug-receptor
complex.
 • Potency: the strength of a drug at a particular dosage. Or say, the amount
of the drug required to produce a particular effect.
A drug’s pharmacodynamics can be affected by physiologic changes due to
• A disorder or disease
• Aging process
• Other drugs
Disorders that affect pharmacodynamic responses include genetic mutations,
thyrotoxicosis, malnutrition, myasthenia gravis, Parkinson disease, and some
forms of insulin-resistant diabetes mellitus. These disorders can change receptor
binding, alter the level of binding proteins, or decrease receptor sensitivity.
Aging tends to affect pharmacodynamic responses through alterations in
receptor binding or in postreceptor response sensitivity.
3.2 PHARMACOKINETIC
Pharmacokinetics (PK) is the study of how the body interacts with administered
substances for the entire duration of exposure. This is closely related to but
distinctly different from pharmacodynamics, which examines the drug’s effect
on the body more closely. The four main parameters generally examined by this
field include absorption, distribution, metabolism, and excretion (ADME).
Wielding an understanding of these processes allows practitioners the
flexibility to prescribe and administer medications that will provide the greatest
benefit at the lowest risk and allow them to make adjustments as necessary,
given the varied physiology and lifestyles of patients. Examples can help to
explain these complicated mechanisms:
a. Absorption: Absorption is the process that brings a drug from the
administration, e.g., tablet, capsule, into the systemic circulation.
Absorption affects the speed and concentration at which a drug may arrive
at its desired location of effect, e.g., plasma. There are many possible
methods of drug administration, including but not limited to oral,
intravenous, intramuscular, intrathecal, subcutaneous, buccal, rectal,
vaginal, ocular, otic, inhaled, nebulized, and transdermal. Each of these
methods has its own absorption characteristics, advantages, and
disadvantages.
The process of absorption also often includes liberation, or the process by
which the drug is released from its pharmaceutical dosage form. This is
especially important in the case of oral medications. For instance, oral
medication may be delayed in the throat or esophagus for hours after being
taken, delaying the onset of effects, or even causing mucosal damage.
Once in the stomach, the low pH may begin to chemically react with these
drugs before they even arrive in the systemic circulation.
Some drugs can alter the absorption of another drug into your
bloodstream. For example, calcium can bind with some medications and
block absorption. The HIV treatment dolutegravir (Tivicay) should not be
taken at the same time as calcium carbonate (Tums, Maalox, others),
because it can lower the amount of dolutegravir absorbed into the
bloodstream and reduce its effectiveness in treating HIV infection.
Dolutegravir should be taken 2 hours before or 6 hours after medications
that contain calcium or other minerals to help prevent this interaction. In
the same manner, many drugs cannot be taken with milk or dairy products
because they will bind with the calcium. Drugs that affect stomach or
intestine motility, pH, or natural flora can also lead to drug interactions.
• Bioavailability: Bioavailability is the fraction of the originally
administered drug that arrives in systemic circulation and depends
on the properties of the substance and the mode of administration.
It can be a direct reflection of medication absorption. For example,
when administering medication intravenously, 100% of the drug
arrives in circulation virtually instantly, giving this method a
bioavailability of 100%. This makes intravenous administration
the gold standard regarding bioavailability. This concept is
especially important in orally administered medications.
Oral medications, once swallowed, must navigate the acidity of the
stomach and be taken up by the digestive tract. The digestive enzymes
begin the process of metabolism for oral medications, already diminishing
the amount of drug arriving in circulation before being taken up. Once
absorbed by gut transporters, the medications then often have to undergo
"first-pass metabolism." When oral medication is administered, it is often
processed in large quantities by the liver, gut wall, or digestive enzymes,
subsequently lowering the amount of medication that arrives in
circulation; therefore, having a lower bioavailability.
These processes will be discussed in greater detail under metabolism.
Other modes of administration may delay certain quantities of drugs to
arrive in circulation at the same time (intramuscular, oral, transdermal),
 giving rise to the use of the area under the plasma concentration curve
(AUC). The AUC is a method of calculating the drug bioavailability of
substances with different dissemination characteristics, and this observes
the plasma concentration over a given time. By calculating the integral of
that curve, bioavailability can be expressed as a percentage of the 100%
bioavailability of intravenous administration.
b. Distribution: Distribution describes how a substance is spread
throughout the body. This varies based on the biochemical properties of
the drug as well as the physiology of the individual taking that medication.
In its simplest sense, the distribution may be influenced by two main
factors: diffusion and convection. These factors may be influenced by the
polarity, size, or binding abilities of the drug, the fluid status of the patient
(hydration and protein concentrations), or the body habitus of the
individual.
The goal of the distribution is to achieve what is known as the effective
drug concentration. This is the concentration of the drug at its designed
receptor site. To be effective, a medication must reach its designated
compartmental destination, described by the volume of distribution, and
not be protein-bound in order to be active.
Protein-binding interactions can occur when two or more highly protein-
bound drugs compete for a limited number of binding sites on plasma
proteins. One example of an interaction is between fenofibric acid
(Trilipix), used to lower cholesterol and triglycerides in the blood, and
warfarin, a common blood thinner to help prevent clots. Fenofibric acid
can increase the effects of warfarin and cause you to bleed more easily.
• Protein Binding: In the body, a drug may be protein-bound or free.
Only free drug can act at its pharmacologically active sites, e.g.,
receptors, cross into other fluid compartments, or be eliminated. In
the clinical setting, the free concentration of a drug at receptor sites
in plasma more closely correlates with effect than is the total
concentration in plasma. The protein binding of the substance
largely determines this. Any reduction in plasma protein binding
increases the amount of drug available to act on receptors, possibly
leading to greater effect or an increased possibility of toxicity. The
principal proteins responsible for binding drugs of interest are
albumin and alpha--acid glycoprotein.
 These proteins may fluctuate depending on the age and development of
the patient, any underlying liver or kidney disease, or nutrition status. One
example in which this is relevant is renal failure. In renal failure, uremia
decreases the ability of acidic drugs, such as diazepam to bind to serum
proteins. Even though the same amount of drug is initially given, there is
far more drug in the "active" space, unbound by serum protein. This will
increase the effect of the medication and increase the possibility of
toxicity, e.g., respiratory depression.

c. Metabolism: Metabolism is the processing of the drug by the body into

subsequent compounds. This is often used to convert the drug into more
water-soluble substances that will progress to renal clearance or, in the
case of prodrug administration such as codeine, metabolism may be
required to convert the drug into active metabolites. Different strategies
of metabolism may occur in multiple areas throughout the body, such as
the gastrointestinal tract, skin, plasma, kidneys, or lungs, but the majority
of metabolism is through phase I (CYP450) and phase II (UGT) reactions
in the liver. Phase I reactions generally transform substances into polar
metabolites by oxidation allowing conjugation reactions of Phase II to
take place. Most commonly, these processes inactivate the drug, convert
it into a more hydrophilic metabolite, and allow it to be excreted in the
urine or bile.
Drugs are usually eliminated from the body as either the unchanged
(parent) drug or as a metabolite that has been changed in some way.
Enzymes in the liver, usually the CYP450 enzymes, are often responsible
for breaking down drugs for elimination from the body. However, enzyme
levels may go up or down and affect how drugs are broken down. For
example, using diltiazem (a blood pressure medication) with simvastatin
(a medicine to lower cholesterol) may elevate the blood levels and side
effects of simvastatin. Diltiazem can inhibit (block) the CYP450 3A4
enzymes needed for the breakdown (metabolism) of simvastatin. High
blood levels of simvastatin can lead to serious liver and muscle side
effects.
o Phase I: Modification of the drug molecule via oxidation,
reduction, and hydrolytic reactions
o Phase II: Conjugation with endogenous compounds via the activity
of transferases
d. Excretion: Excretion is the process by which the drug is eliminated from
the body. The kidneys most commonly conduct excretion, but for certain
drugs, it may be via the lungs, skin, or gastrointestinal tract. In the
kidneys, drugs may be cleared by passive filtration in the glomerulus or
secretion in the tubules, complicated by reabsorption in some
compounds.
Some nonsteroidal antiinflammatory drugs (NSAIDs), like indomethacin,
may lower kidney function and affect the excretion of lithium, a drug used
for bipolar disorder. You may need a dose adjustment or more frequent
monitoring by your doctor to safely use both medications together.
Major modes are biotransformation to inactive metabolites to inactive
metabolites, renal excretion and excretion via the bile duct, lungs, and
sweat.
• Zero–Order Elimination Rate:
o Rate is independent of plasma concentration (or amount in the
body).
o A constant amount of drug is eliminated per unit time.

o No fixed half-life – straight line plasma decay vs. time

o Ethanol, phenytoin, salicylates

• First–Order Elimination Rate:

o Rate is directly proportional to plasma level (most drugs)

o A constant fraction of the drug is eliminated per unit time.

o Exponential plasma decay vs. time

o Elimination half-life (t1/2) is time needed to decrease plasma

level to 50% of a former level.
IV. CLINICAL TESTS FOR DRUG
4.1 URINE DRUG TEST
A urine drug test, also known as a urine drug screen or a UDS, is a painless
test. It analyzes your urine for the presence of certain illegal drugs and
prescription medications. The urine drug test usually screens for
amphetamines, methamphetamines, benzodiazepines, barbiturates, marijuana,
cocaine, PCP, methadone, opioids (narcotics)... Alcohol can also be included
in screening tests, but it is usually detected through breath tests rather than
urine screens. A urine drug test can help a doctor detect potential substance
abuse problems. After a drug test identifies drugs, you may be misusing,
doctors can help you start a treatment plan. Taking urine drug tests throughout
substance abuse treatment helps to ensure that the plan is working and that
you’re no longer taking drugs.
There are two types of urine drug screens. The first, called the immunoassay,
is cost-effective and gives results fairly quickly. However, it has drawbacks.
For example, it does not pick up on all opioids. Also, it sometimes gives false
positives. A false positive occurs when the test results come back positive for
drugs, but there has been no drug use. If your first test comes back positive, a
follow-up test known as gas chromatography/mass spectrometry (GC/MS) is
done for confirmation. This type of test uses the same procedure for getting a
urine specimen as the immunoassay. GC/MS results are more expensive and
take longer to give results, but they rarely produce false positives. Both types
of tests can create a false negative, which is when the test reports a negative
result even if there is drug use. Both tests can also fail to capture same- day
drug use. Each drug is cleared by the body at different rates. When you can
find drugs in the urine depends on the drug taken, how often the person takes
the drug, and how the drug was taken.
4.2 DRUG TESTING TYPES:
The three main new drug testing types can be separated into:
• in vitro

• in vivo

• in silico testing

a. In vitro
Testing carried out "in glass" or "in vitro” takes place apart from live things.
Cells or other biological material that has been extracted from an organism
is frequently used in this kind of examination.
b. In vivo
Testing carried out on a live thing is referred to as in vivo. Either animals or
people might be used in this. One kind of in vivo testing is clinical trials.
c. In silico
In silico testing is a type of computer aided testing that uses models to
simulate the behaviors of real-world systems, such as the human body.
V. REFERENCES

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metabolism-cell/untitled-6/enzyme-inhibition.html

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https://www.jove.com/science-education/11004/enzyme-inhibition

[3] Farinde, A. (2023, June 21). Drug–receptor interactions - clinical pharmacology.

MSD Manual Professional Edition.
https://www.msdmanuals.com/professional/clinical-
pharmacology/pharmacodynamics/drug%E2%80%93receptor-interactions

[4] Biological Chemistry. Chemistry LibreTexts. (2022, September 17).

https://chem.libretexts.org/Bookshelves/Biological_Chemistry

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