1) Define biotransformation and explain in detail phase 1 & phase 2 biotransformation.
Biotransformation, also known as drug metabolism, refers to the chemical modification of drugs and
other xenobiotics (foreign substances) by enzymes in the body to make them more water-soluble and
easier to excrete. Biotransformation can occur in various organs, including the liver, kidneys, lungs, and
intestines, but the liver is the main site of biotransformation.
Biotransformation can be divided into two phases:
Phase 1 Biotransformation: In this phase, the drug is modified by enzymes, such as cytochrome P450
enzymes, to create a more polar or water-soluble compound that can be easily excreted by the kidneys.
The reactions involved in phase 1 biotransformation include oxidation, reduction, and hydrolysis.
Oxidation is the most common reaction in phase 1 biotransformation, which involves adding an oxygen
atom to the drug molecule. This reaction is carried out by cytochrome P450 enzymes, which are a family
of enzymes that are responsible for metabolizing many drugs and xenobiotics. The oxidation can either
result in the formation of a more polar metabolite or the formation of a reactive metabolite, which can
lead to toxic effects.
Reduction involves the removal of oxygen or the addition of hydrogen to the drug molecule. This
reaction is carried out by enzymes such as aldo-keto reductases and carbonyl reductases.
Hydrolysis involves the cleavage of chemical bonds by adding water to the drug molecule. This reaction
is carried out by enzymes such as esterases and amidases.
Phase 2 Biotransformation: In this phase, the drug or its metabolite is conjugated or combined with a
polar molecule, such as glucuronic acid, sulfate, or amino acids, to make it even more water-soluble and
easier to excrete by the kidneys. The reactions involved in phase 2 biotransformation include
glucuronidation, sulfation, acetylation, methylation, and conjugation with amino acids.
Glucuronidation is the most common reaction in phase 2 biotransformation, which involves the addition
of a glucuronic acid molecule to the drug or its metabolite. This reaction is carried out by enzymes called
UDP-glucuronosyltransferases (UGTs).
Sulfation involves the addition of a sulfate molecule to the drug or its metabolite. This reaction is carried
out by enzymes called sulfotransferases (SULTs).
Acetylation involves thaddingn acetyl group to the drug or its metabolite. This reaction is carried out by
enzymes called N-acetyltransferases (NATs).
Methylation involves the addition of a methyl group to the drug or its metabolite. This reaction is carried
out by enzymes called methyltransferases.
Conjugation with amino acids involves the addition of an amino acid molecule to the drug or its
metabolite. This reaction is carried out by enzymes such as glutathione S-transferases (GSTs).
In summary, biotransformation is the process by which drugs and other xenobiotics are modified in the
body to make them more water-soluble and easier to excrete. Phase 1 biotransformation involves the
modification of the drug by oxidation, reduction, or hydrolysis, while phase 2 biotransformation involves
the conjugation of the drug or its metabolite with a polar molecule. The enzymes involved in
biotransformation are mainly located in the liver, and the rate of biotransformation can affect the drug's
efficacy and toxicity.
2) Define drug metabolism and explain in detail about factors affecting drug metabolism.
Drug metabolism, also known as biotransformation, refers to the chemical modification of drugs and
other xenobiotics by enzymes in the body to make them more water-soluble and easier to excrete. The
primary site of drug metabolism is the liver, although other organs such as the kidneys, lungs, and
intestines can also be involved.
Several factors can affect drug metabolism, including:
Genetics: Genetic differences can affect the activity and expression of drug-metabolizing enzymes,
leading to inter-individual variability in drug metabolism. For example, genetic variations in cytochrome
P450 enzymes can affect the rate of drug metabolism, leading to differences in drug efficacy and
toxicity.
Age: Drug metabolism can be affected by age-related changes in enzyme activity and expression. In
general, drug metabolism tends to decrease with age, leading to increased drug exposure and potential
toxicity in older adults.
Gender: Gender differences can affect drug metabolism due to differences in hormone levels and
enzyme activity. For example, women tend to have lower activity of cytochrome P450 enzymes than
men, leading to differences in drug metabolism.
Disease state: Many diseases can affect drug metabolism by altering the activity and expression of drugmetabolizing enzymes. For example, liver disease can lead to decreased activity of cytochrome P450
enzymes, leading to decreased drug metabolism and increased risk of drug toxicity.
Drug interactions: Co-administration of drugs can affect drug metabolism by altering the activity and
expression of drug-metabolizing enzymes. For example, some drugs can induce the activity of
cytochrome P450 enzymes, leading to increased drug metabolism and decreased efficacy of coadministered drugs.
Environmental factors: Exposure to environmental toxins such as cigarette smoke, alcohol, and
pollutants can affect drug metabolism by altering the activity and expression of drug-metabolizing
enzymes.
In summary, drug metabolism is the process by which drugs and other xenobiotics are modified in the
body to make them more water-soluble and easier to excrete. Several factors can affect drug
metabolism, including genetics, age, gender, disease state, drug interactions, and environmental factors.
Understanding these factors is important for predicting and minimizing the potential for drug
interactions and toxicity.
3) Define the drug and enlist physiochemical factors affecting drug action and explain each factor in
detail.
A drug is a substance that is used to diagnose, treat, or prevent disease. The physiochemical properties
of a drug can affect its absorption, distribution, metabolism, and excretion, as well as its mechanism of
action.
The following are some of the physiochemical factors that can affect drug action:
Molecular size and shape: The molecular size and shape of a drug can affect its ability to penetrate cell
membranes and interact with target molecules. Larger molecules may have difficulty crossing cell
membranes, while molecules with a specific shape may interact more selectively with target molecules.
Lipid solubility: The lipid solubility of a drug can affect its ability to penetrate cell membranes and
distribute throughout the body. Highly lipid-soluble drugs tend to be more rapidly absorbed and
distributed to tissues, while less lipid-soluble drugs may have slower onset and longer duration of
action.
Ionization state: The ionization state of a drug can affect its solubility, absorption, and distribution.
Acidic drugs tend to be more ionized in alkaline environments, while basic drugs tend to be more ionized
in acidic environments. This can affect the ability of a drug to cross cell membranes and interact with
target molecules.
Protein binding: Many drugs bind to plasma proteins, which can affect their distribution and elimination
from the body. Highly protein-bound drugs may have slower clearance rates and longer half-lives, while
drugs with low protein binding may be rapidly eliminated from the body.
Chemical stability: The chemical stability of a drug can affect its shelf-life and efficacy. Some drugs may
degrade over time or under certain environmental conditions, which can affect their potency and safety.
Route of administration: The route of administration can affect the onset, duration, and intensity of
drug action. Different routes of administration may result in different rates and extent of drug
absorption and distribution.
In summary, the physiochemical properties of a drug can have a significant impact on its
pharmacokinetics and pharmacodynamics. Understanding these factors can help in the design and
development of new drugs and in the optimization of drug therapy for individual patients.
4) Define sympathomimetic agents, classify them, and give SAR, MOA, and uses of each class.
Sympathomimetic agents are drugs that mimic the effects of the sympathetic nervous system by
stimulating adrenergic receptors. They are classified based on the type of adrenergic receptor they
target, which can be either alpha or beta adrenergic receptors. The following are the classes of
sympathomimetic agents:
Alpha-adrenergic agonists: These drugs target alpha-adrenergic receptors and can be further classified
into two subtypes:
Alpha-1 agonists: Examples include phenylephrine and methoxamine. They stimulate alpha-1 adrenergic
receptors, leading to vasoconstriction and increased blood pressure. They are used in the treatment of
hypotension, shock, and nasal congestion.
Alpha-2 agonists: Examples include clonidine and dexmedetomidine. They stimulate alpha-2 adrenergic
receptors, leading to decreased sympathetic outflow and decreased blood pressure. They are used in
the treatment of hypertension, pain, and opioid withdrawal.
Beta-adrenergic agonists: These drugs target beta-adrenergic receptors and can be further classified into
three subtypes:
Beta-1 agonists: Examples include dobutamine and dopamine. They stimulate beta-1 adrenergic
receptors, leading to increased cardiac output and heart rate. They are used in the treatment of heart
failure, shock, and cardiac arrest.
Beta-2 agonists: Examples include albuterol and salmeterol. They stimulate beta-2 adrenergic receptors,
leading to bronchodilation and relaxation of smooth muscle. They are used in the treatment of asthma,
chronic obstructive pulmonary disease (COPD), and preterm labor.
Beta-3 agonists: Examples include mirabegron. They stimulate beta-3 adrenergic receptors, leading to
relaxation of bladder smooth muscle and increased bladder capacity. They are used in the treatment of
overactive bladder.
The structure-activity relationship (SAR) of sympathomimetic agents depends on the specific class of
drug. Generally, alpha-adrenergic agonists have a basic amine group and an aryl or alkyl group, while
beta-adrenergic agonists have a catechol moiety or a similar structure that can interact with adrenergic
receptors.
The mechanism of action of sympathomimetic agents involves binding to adrenergic receptors and
stimulating the sympathetic nervous system. This leads to a variety of physiological responses, including
vasoconstriction, bronchodilation, increased heart rate, and increased contractility. The specific
response depends on the subtype of adrenergic receptor targeted by the drug.
In summary, sympathomimetic agents are drugs that mimic the effects of the sympathetic nervous
system by stimulating adrenergic receptors. They are classified based on the type of adrenergic receptor
they target and are used in the treatment of a variety of conditions, including hypertension, heart
failure, asthma, and overactive bladder.
5) Define adrenoreceptors classify them and give their distribution and pharmacological action.
Adrenoceptors, also known as adrenergic receptors, are a class of G protein-coupled receptors that bind
to the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). They are divided
into two main classes, alpha and beta adrenoceptors, based on their pharmacological and structural
characteristics.
Alpha adrenoceptors are further divided into two subtypes, alpha-1 and alpha-2, and beta
adrenoceptors are divided into three subtypes, beta-1, beta-2, and beta-3. The distribution and
pharmacological actions of each subtype are as follows:
Alpha-1 adrenoceptors:
Distribution: Found in smooth muscle cells of blood vessels, the prostate gland, and the iris of the eye.
Pharmacological actions: Stimulation of alpha-1 adrenoceptors leads to vasoconstriction, contraction of
the prostate gland, and mydriasis (pupil dilation).
Alpha-2 adrenoceptors:
Distribution: Found in presynaptic nerve terminals, platelets, and certain regions of the brain.
Pharmacological actions: Stimulation of alpha-2 adrenoceptors leads to inhibition of norepinephrine
release from presynaptic nerve terminals, platelet aggregation, and sedation.
Beta-1 adrenoceptors:
Distribution: Found primarily in the heart.
Pharmacological actions: Stimulation of beta-1 adrenoceptors leads to increased heart rate, increased
contractility, and increased conduction velocity in the heart.
Beta-2 adrenoceptors:
Distribution: Found in smooth muscle cells of the lungs, blood vessels, and skeletal muscle, as well as in
certain regions of the pancreas and liver.
Pharmacological actions: Stimulation of beta-2 adrenoceptors leads to bronchodilation, vasodilation,
relaxation of uterine smooth muscle, and glycogenolysis in the liver.
Beta-3 adrenoceptors:
Distribution: Found in adipose tissue and the bladder.
Pharmacological actions: Stimulation of beta-3 adrenoceptors leads to lipolysis in adipose tissue and
relaxation of bladder smooth muscle.
The distribution and pharmacological actions of adrenoceptor subtypes play a key role in the
therapeutic effects and side effects of drugs that target them. For example, drugs that stimulate beta-2
adrenoceptors are used in the treatment of asthma and COPD, while drugs that block alpha-1
adrenoceptors are used in the treatment of hypertension and benign prostatic hyperplasia.
6) Define bio-asterism and explain it in detail.
Bioisosterism is a concept in medicinal chemistry that refers to the replacement of a functional group,
atom, or group of atoms in a drug molecule with a different group or atom that has similar physical and
chemical properties, while retaining the biological activity of the original compound. The substituted
groups or atoms are known as bioisosteres, and their replacement is intended to optimize the
pharmacological properties of the molecule, such as improved potency, bioavailability, selectivity, and
pharmacokinetic properties, while minimizing unwanted side effects.
The concept of bioisosterism is based on the idea that molecules with similar shapes, sizes, and
electronic properties can have similar biological activity. Therefore, by replacing a functional group or
atom in a drug molecule with a bioisostere, the molecule can be modified to improve its biological
activity, metabolic stability, solubility, and other pharmacological properties, without significantly
altering its structure.
For example, the replacement of an ester group (-COO-) in a drug molecule with a bioisostere such as an
amide group (-CONH-) can improve the molecule's metabolic stability, as amides are more resistant to
hydrolysis by enzymes. Similarly, the replacement of a hydrogen atom with a fluorine atom in a drug
molecule can improve its lipophilicity, bioavailability, and metabolic stability, as fluorine has similar
electronic properties to hydrogen but is more lipophilic and resistant to metabolic degradation.
The use of bio isosteres is a powerful tool in drug design and optimization, as it allows medicinal
chemists to modify the pharmacological properties of a drug molecule while retaining its biological
activity. However, the selection of appropriate bioisosteres requires a deep understanding of the
physicochemical and pharmacological properties of the molecule, as well as the biological target and the
pharmacokinetic properties required for the drug to be effective.
In summary, bioisosterism is an important concept in medicinal chemistry that plays a critical role in the
development of safer and more effective drugs. The replacement of functional groups or atoms with
bioisosteres can optimize the pharmacological properties of drug molecules while minimizing unwanted
side effects, leading to the development of more effective and potent drugs.
7) Write a short note on the partition coefficient.
Partition coefficient (P) is a measure of the solubility of a drug in different solvents, usually expressed as
the ratio of the concentrations of a drug in two immiscible solvents at equilibrium. The partition
coefficient plays a critical role in medicinal chemistry as it governs the pharmacokinetics and
bioavailability of a drug.
The partition coefficient is calculated as the ratio of the concentrations of a drug in two immiscible
solvents, usually octanol and water. Octanol is used to represent the lipid membrane of the cell,
whereas water is used to represent the aqueous environment outside the cell. The octanol-water
partition coefficient (logP) is a logarithmic scale that measures the distribution of the drug between
these two phases.
The logP value is an important parameter for drug design and optimization. Drugs with a high logP value
tend to be more lipophilic, and therefore, they have a greater tendency to partition into cell membranes
and penetrate the blood-brain barrier. However, such drugs may also have poor aqueous solubility and
may be subject to poor absorption, distribution, metabolism, and excretion (ADME) properties, leading
to poor pharmacokinetics.
Conversely, drugs with a low logP value tend to be more hydrophilic, making them more water-soluble
and more easily excreted from the body. However, such drugs may have poor permeability and
bioavailability, which can limit their effectiveness.
Therefore, medicinal chemists must consider the partition coefficient of a drug carefully during drug
design and optimization to achieve the optimal balance between solubility and permeability. A suitable
logP value can be achieved by modifying the structure of the drug to improve its ADME properties and
ultimately its efficacy.
8) Give structure, SAR, MOA, and uses of
i) Ephedrine ii) Terbutaline iii) Isoprenaline iv) Amphidal v) Clonidine
i)
ii)
iii)
iv)
v)
i) Ephedrine:
Structure: Ephedrine is a sympathomimetic amine that has a similar structure to adrenaline. It is a chiral
molecule, with two enantiomers: (1R,2S)-(-)-ephedrine and (1S,2R)-(+)-pseudoephedrine.
SAR: The SAR of ephedrine involves the hydroxyl (-OH) group at the phenyl ring and the amino (-NH2)
group at the alpha carbon. The hydroxyl group confers alpha-agonistic activity, while the amino group
confers beta-agonistic activity. Substitutions at either of these positions can significantly affect the
activity of the molecule.
MOA: Ephedrine acts as a sympathomimetic agent by stimulating both alpha and beta adrenergic
receptors. It causes the release of norepinephrine, which increases heart rate and blood pressure. It also
relaxes bronchial smooth muscles, making it useful in the treatment of asthma and other respiratory
conditions.
Uses: Ephedrine is primarily used as a nasal decongestant and bronchodilator in the treatment of
asthma and other respiratory conditions. It is also used as a stimulant and weight loss aid.
ii) Terbutaline:
Structure: Terbutaline is a selective beta-2 adrenergic agonist that has a phenethylamine structure.
SAR: The SAR of terbutaline involves the presence of the hydroxyl (-OH) group at the phenyl ring and the
substitution at the beta-carbon of the amine group.
MOA: Terbutaline acts as a selective beta-2 adrenergic agonist, which leads to the relaxation of
bronchial smooth muscles and the dilation of the bronchi. It is also used to inhibit premature labor by
relaxing the uterine smooth muscles.
Uses: Terbutaline is primarily used as a bronchodilator in the treatment of asthma and other respiratory
conditions. It is also used as a tocolytic agent to delay premature labor.
iii) Isoprenaline:
Structure: Isoprenaline is a synthetic catecholamine that has a structure similar to adrenaline.
SAR: The SAR of isoprenaline involves the presence of the hydroxyl (-OH) groups at the meta and para
positions of the phenyl ring, and the amino (-NH2) group at the beta carbon of the amine group.
MOA: Isoprenaline acts as a non-selective beta-adrenergic agonist, stimulating both beta-1 and beta-2
receptors. It increases heart rate, cardiac output, and dilates bronchi and blood vessels, leading to the
relaxation of bronchial and vascular smooth muscles.
Uses: Isoprenaline is used to treat bradycardia, heart block, and other cardiac arrhythmias. It is also used
as a bronchodilator in the treatment of asthma and other respiratory conditions.
iv) Amphidal:
Structure: Amphidal is a bronchodilator that has a xanthine structure.
SAR: The SAR of Amphidal involves the presence of the xanthine nucleus, which confers bronchodilator
activity.
MOA: Amphidal acts as a non-selective phosphodiesterase inhibitor and adenosine receptor antagonist,
which leads to the relaxation of bronchial smooth muscles and the dilation of bronchi.
Uses: Amphidal is used as a bronchodilator in the treatment of asthma and other respiratory conditions.
v) Structure: Clonidine is an imidazoline derivative that has a central alpha-2 adrenergic agonist activity.
It is a chiral molecule with two enantiomers, (R)-clonidine and (S)-clonidine.
SAR: The SAR of clonidine involves the presence of an imidazoline nucleus, a phenyl ring, and a central
alpha-2 adrenergic receptor. The imidazoline nucleus and the phenyl ring are essential for the activity of
the molecule, while the central alpha-2 adrenergic receptor is responsible for its mechanism of action.
MOA: Clonidine acts as a centrally-acting alpha-2 adrenergic receptor agonist, which leads to the
inhibition of sympathetic nerve activity in the central nervous system. This leads to the lowering of
blood pressure, the reduction of heart rate, and the suppression of the release of norepinephrine.
Uses: Clonidine is used to treat hypertension, attention deficit hyperactivity disorder (ADHD), anxiety
disorders, and withdrawal symptoms in individuals undergoing drug detoxification. It is also used as
adjunctive therapy in the management of chronic pain conditions such as cancer pain and neuropathic
pain.