Drug Physicochemical Properties and Biological Action

Posted on Feb 20, 2026 in Biotechnology

Physicochemical Properties in Relation to Biological Action

Physicochemical Properties refer to the physical and chemical characteristics of a drug molecule that influence its behavior in biological systems. These properties play a crucial role in determining the drug’s absorption, distribution, metabolism, and excretion (ADME). They include:

• Ionization
• Solubility
• Partition Coefficient
• Hydrogen Bonding
• Protein Binding
• Chelation
• Bioisosterism
• Optical and Geometrical Isomerism

1. Ionization

Ionization is a key physicochemical property that refers to the ability of a molecule to gain or lose protons (H+), leading to the formation of charged species (ions). The extent of ionization is determined by the pKa of the drug and the pH of the surrounding environment.

Relation to Biological Action

1. Solubility: Ionized drugs are more soluble in water, aiding in dissolution in aqueous environments like the gastrointestinal tract.
2. Membrane Permeability: Non-ionized forms of a drug are more lipophilic and cross membranes easily, whereas ionized forms struggle to penetrate lipid bilayers.
3. Absorption & Distribution: Drugs must balance ionization to be absorbed efficiently. Weak acids absorb better in acidic environments, while weak bases absorb better in basic environments.
4. Excretion: Ionized drugs are more water-soluble and are excreted more easily via the kidneys, while non-ionized drugs may undergo reabsorption.

By understanding ionization, medicinal chemists can optimize drug properties for better therapeutic action and bioavailability.

2. Solubility

Solubility is the ability of a substance (solute) to dissolve in a solvent to form a homogenous solution. In the context of Medicinal Chemistry, drug solubility refers to the extent to which a drug dissolves in biological fluids (e.g., gastric juice, blood, or intestinal fluid). Drugs must be sufficiently soluble in aqueous fluids to be absorbed, distributed, and transported effectively in the body.

Biological Significance

1. Drug Absorption & Bioavailability: A drug must dissolve in GIT fluids before it can be absorbed into the bloodstream. Poorly soluble drugs have low dissolution rates, leading to reduced bioavailability.
2. Drug Distribution: Once absorbed, a drug circulates in plasma, which is mostly water. Highly water-soluble drugs remain in the blood, while lipophilic drugs distribute over body tissues.
3. Drug Metabolism & Excretion: Water-soluble drugs are easily metabolized and excreted via the kidneys. Poorly soluble drugs require metabolism to increase solubility for excretion.

Solubility is a critical factor in drug design and formulation, affecting absorption, distribution, metabolism, and excretion. Medicinal Chemists optimize drug solubility to enhance bioavailability, therapeutic action, and patient compliance while minimizing side effects.

3. Partition Coefficient

The Partition Coefficient (P) is the ratio of a compound’s concentration in a lipophilic solvent to its concentration in a hydrophilic solvent at equilibrium. It is expressed as: P = [Drug]_LIPID / [Drug]_WATER. The hydrophilic and lipophilic nature of a drug is indicated by its log P value.

Biological Importance

A moderate log P enhances absorption through biological membranes, as cell membranes are lipophilic. Drugs with very high log P are too lipophilic and may become trapped in membranes. Drugs with very low log P are too hydrophilic and may not cross lipid membranes effectively. Lipophilic drugs are metabolized in the liver before excretion, while hydrophilic drugs are excreted directly by the kidneys.

4. Hydrogen Bonding

Hydrogen Bonding is a type of weak chemical interaction that occurs when a hydrogen atom (H) is shared between a hydrogen bond donor and an electronegative acceptor atom.

It is of two types: Intermolecular Hydrogen Bonding and Intramolecular Hydrogen Bonding.

Importance in Biological Relation

1. Solubility: Drugs that form hydrogen bonds dissolve better in water, improving their solubility. Example: Paracetamol forms hydrogen bonds, making it highly water-soluble.
2. Membrane Permeability: Too many hydrogen bonds make a drug less lipophilic, reducing its ability to cross cell membranes.
3. Receptor Binding: Many drugs interact with proteins through hydrogen bonds, affecting their potency.
4. Metabolism & Excretion: Hydrogen bonding can influence how drugs bind to liver enzymes for metabolism and how easily they are excreted.

Hydrogen bonding is essential for drug-target binding, metabolism, and absorption. Balancing hydrogen bonds is crucial when designing effective drugs.

5. Protein Binding

Protein Binding refers to the ability of a drug to bind to plasma proteins (such as albumin, $\alpha$1-acid glycoprotein, and lipoproteins) in the bloodstream. Drugs exist in two forms: Bound Drug (inactive, stored in the bloodstream) and Free Drug (active, available for biological action).

Major Proteins Involved

• Albumin: Binds to acidic drugs.
• $\alpha$1-Acid Glycoprotein: Binds to basic drugs.
• Lipoprotein: Binds to lipophilic drugs.

Importance in Biological System

1. Drug Distribution: Highly protein-bound drugs stay in circulation longer and distribute more slowly into tissues.
2. Drug Activity: Only the free drug is available to interact with receptors and produce effects.
3. Metabolism & Excretion: Bound drugs are not easily metabolized or excreted. The liver and kidneys primarily remove free drugs.

Protein binding influences drug distribution, activity, interactions, metabolism, and excretion. Understanding it helps in dosing adjustments and avoiding drug interactions.

6. Chelation

Chelation happens when a drug binds tightly to metal ions like calcium, iron, magnesium, or zinc, forming a stable complex.

Relation with Biological System

1. Affects Absorption: Some drugs bind to metals in food, making them harder to absorb.
2. Removes Toxic Metals: Some drugs are used to trap and remove toxic metals from the body.
3. Block Enzymes: Binding drugs stop enzymes from working by blocking the metals they need.

Chelation can affect drug absorption, remove toxins, or block enzymes. Understanding it helps in making drugs work better and avoiding food or metal interactions.

7. Bioisosterism

Before discussing Bioisosterism, let’s first discuss Isosterism. Isosterism is the phenomenon where molecules or ions have the same number of atoms and a similar arrangement of electrons, leading to comparable physical and chemical properties.

Example: N$_2$ (Nitrogen) and CO (Carbon Monoxide). Both have the same number of total electrons (14). Both molecules have a triple bond between the two atoms. They have similar bond lengths and ionization energies. The concept of isosterism was first introduced by Irving Langmuir in 1919.

Bioisosterism

Bioisosterism is a concept in Medicinal Chemistry where one functional group or molecule is replaced with another that has similar physical and chemical properties. This helps improve the drug’s effects, reduce side effects, or make it last longer in the body.

Detailed Explanation: In drug design, scientists often change parts of a drug to make it better. However, if they replace the part with something too different, the drug might stop working. So, they use Bioisosteres.

Classification of Bioisosterism

Bioisosteres are mainly categorized into two main types:

1. Classical Bioisosteres
2. Non-Classical Bioisosteres

1. Classical Bioisosteres

These are the bioisosteres which have the same valency, shape, and electronic properties. Example: -OH, -NH$_2$, -H, -F.

Classification

They are further classified as follows:

• A. Monovalent Bioisosteres
• B. Tetravalent Bioisosteres
• C. Trivalent Bioisosteres
• D. Ring Equivalents

2. Non-Classical Bioisosteres

Non-Classical Bioisosteres are those that do not have the same valency or electronic properties but still produce similar biological effects. Example: Carboxyl (-COOH) $\approx$ Tetrazole (-C(N$_4$H)).

Significance in Biological Relation

1. Improved Pharmacokinetics: Substituting bioisosteres can enhance a drug’s absorption, distribution, metabolism, and excretion, leading to better efficacy and stability.
2. Reduced Toxicity: Toxic functional groups can be replaced with safer alternatives while maintaining effects.
3. Increased Selectivity: Bioisosteric modifications can enhance a drug’s specificity for its target, reducing side effects.
4. Enhanced Metabolic Stability: Some bioisosteric replacements prevent rapid degradation, prolonging the drug’s half-life.

8. Geometrical Isomerism

Geometrical Isomers are stereoisomers that have a different arrangement of groups or atoms around double bonds. They are of two types: Cis-Isomer and Trans-Isomer.

Relation to Biological Action

Geometrical Isomers can have different activities. For example: Cis-platin is an effective anticancer drug, while trans-platin is inactive.

Metabolism

It is also known as Biotransformation. It is a process by which the body transforms a drug into more readily excretable forms. The primary site for metabolism is the Liver. Other sites include the kidney, intestines, lungs, and plasma. Metabolism usually involves enzymatic reactions in the liver that alter (change) the chemical structure of the drug. These reactions make the drug more water-soluble, and these drugs become easier to be eliminated from the urine or bile. Metabolism usually converts:

• Lipid Soluble $\rightarrow$ Water Soluble
• Unionized $\rightarrow$ Ionized

Metabolism is crucial for the drug’s duration and intensity of action, as well as for its overall safety profile.

Drug metabolism usually leads to the conversion of:

1. Active Drug $\rightarrow$ Active Metabolite
2. Active Drug $\rightarrow$ Inactive Metabolite
3. Inactive Drug $\rightarrow$ Active Metabolite

Cytochrome P450 Enzymes

Cytochrome P450 enzymes are a group of proteins in the body that help break down drugs, toxins, and other substances. In Cytochrome P450, ‘P’ stands for pigment that has maximum light absorption at wavelength 450 nm. Several families of CYP enzymes are involved in the metabolism of drugs. These are named as CYP followed by a number (denoting family), then an alphabet (subfamily), and again a number (specific isoform of the enzyme).

CYP3A4 forms the maximum hepatic content (26%) of CYP enzymes and is involved in the metabolism of the maximum percentage of drugs (33%).

Example of CYP Enzymes

• CYP3A4
• CYP2D6
• CYP2C19
• CYP2C9
• CYP1A2

Types of Metabolism Reaction

There are mainly two types of Biotransformation reactions:

1. Phase I Reaction
2. Phase II Reaction

1. Phase-I Reactions

These reactions introduce functional groups into the drug and include:

• Oxidation
• Reduction
• Hydrolysis
• Cyclization
• Decyclization

1. Oxidation

Oxidation is the process of addition of oxygen to a drug molecule or removal of hydrogen from a drug molecule. Oxidation is primarily mediated by enzymes like CYP450s and results in the formation of more polar metabolites, which can be easily excreted from the body. Example: Phenytoin, Phenobarbitone, Propranolol.

2. Reduction

Reduction is the process of addition of Hydrogen or removal of Oxygen from a drug molecule. It is less common than Oxidation. Example: Chloramphenicol, Warfarin.

3. Hydrolysis (Breakdown)

Breakdown of a drug molecule by the addition of water is known as hydrolysis. This is common among esters and amides. It is mediated by enzymes such as esterases, amidases, and peptidases.

4. Cyclization

In this, a straight-chain compound is converted into a ring structure. Example: Cycloguanil from Proguanil.

5. Decyclization

It involves the opening up of the ring structure of a cyclic drug molecule. Example: Barbiturates.

2. Phase-II Reactions

Phase II Reactions are also known as Conjugation Reactions. These reactions attach polar groups (e.g., glucuronic acid, sulfate, acetyl, methyl) to the drug, making it highly water-soluble. These reactions include:

• Glucuronide Conjugation
• Acetylation
• Methylation
• Sulfate Conjugation
• Glycine Conjugation
• Glutathione Conjugation

1. Glucuronide Conjugation

It is the process of addition of Glucuronic Acid. It is mediated by UDP-glucuronosyl transferases (UGTs). Examples: Chloramphenicol, Aspirin, Paracetamol.

2. Acetylation

It is the process of addition of an Acetyl Group. It is mediated by N-Acetyltransferases. Example: Sulfonamides, Isoniazid.

3. Methylation

It is the process of addition of a Methyl Group. It is mediated by Methyltransferases. Example: Methyldopa, Mercaptopurine.

4. Sulfate Conjugation

It is the process of addition of a Sulfate Group. It is mediated by Sulfotransferases. Example: Chloramphenicol, Methyldopa, etc.

5. Glycine Conjugation

It is the process of addition of Glycine to the drugs. It is mediated by Glycine N-Acetyltransferases. Example: Salicylates, Nicotinic Acid, etc.

6. Glutathione Conjugation

It is mediated by S-Transferases. Example: Paracetamol.

Factors Affecting Drug Metabolism

There are various factors affecting drug metabolism as follows:

1. Age
2. Genetics
3. Liver Health
4. Gender
5. Diet and Lifestyle
6. Drug Interactions

1. Age

Newborn babies show slow metabolism as liver function is not fully developed. Elderly people also show slow metabolism with age.

2. Genetics

Some people naturally break down drugs faster or slower due to differences in their genes.

Sympathomimetic Agents

Sympathomimetic Agents are drugs or substances that mimic the effects of the sympathetic nervous system by stimulating adrenergic receptors ($\alpha$ and $\beta$ receptors). They either directly activate these receptors or increase the levels of natural neurotransmitters like norepinephrine or epinephrine.

Sympathomimetic Agents:

• (Direct Acting): Phenylephrine, Isoproterenol
• (Indirect Acting): Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine
• (Mixed Acting): Ephedrine, Metaraminol

SAR of Sympathomimetic Agents

The general structure of Sympathomimetic Agents is $\beta$-Phenyl ethylamine.

• Any additional group on the $\beta$ carbon atom of the $\beta$-receptor agonist activity greatly increases $\alpha$ activity.
• Any additional group on the $\alpha$ carbon atom increases the half-life by inhibiting MAO and also allows the drug to act as an indirect sympathomimetic agent.
• Presence of an amino group on phenyl ethylamines is essential for direct agonist activity.
• Presence of a methyl group on the amine increases $\alpha$ selectivity. The smaller the group, the more $\alpha$ effect there is.
• Presence of -OH groups on both $\alpha$ and $\beta$ receptors is important.

1. Norepinephrine

MOA

Norepinephrine mainly acts on $\alpha$ receptors by causing vasoconstriction, increasing blood pressure. It also acts a little on $\beta$1 receptors, increasing heart rate and strength.

Uses

It raises blood pressure and helps the heart pump better.

2. Epinephrine

MOA

It acts on alpha and beta receptors in the body:

• $\alpha$1: Narrows blood vessels to raise blood pressure.
• $\beta$1: Increases heart rate and strength of heart beat.
• $\beta$2: Relaxes airway muscles to make breathing easier.

Uses

It makes the heart beat stronger, opens the lungs, and raises blood pressure.

3. Phenylephrine

MOA

It acts on $\alpha$1 receptors only. It causes vasoconstriction (tightening of blood vessels). It has little or no effect on the heart or lungs.

Properties

It is a white crystalline powder. It is freely soluble in ethanol and water. It is resistant to COMT.

Uses

It increases blood pressure in acute hypotension. It is also used sometimes for treating nasal decongestion and shock.

4. Dopamine

MOA

Dopamine works by improving blood flow and helping the heart pump better, depending on the dose:

• Low Dose: Increases kidney blood flow (acts on dopamine receptors).
• Medium Dose: Strengthens heartbeat (acts on $\beta$1 receptors).
• High Dose: Vasoconstriction + Blood Pressure (acts on $\alpha$1 receptors).

Adrenergic Antagonists

Adrenergic Antagonists are drugs that block the effect of adrenaline and noradrenaline on adrenergic receptors in the body. They work by binding to adrenergic receptors without activating them, thus preventing stimulation by the body’s natural catecholamines.

Adrenergic Antagonists:

• ($\alpha$-Blockers): Tolazoline, Phentolamine, Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide.
• ($\beta$-Blockers): Propranolol, Metoprolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Mexiletine, Labetalol, Carvedilol.

1. Alpha-Adrenergic Blockers

Alpha-Adrenergic blockers, also known as $\alpha$ blockers, are drugs that inhibit the stimulation of $\alpha$ adrenergic receptors by Adrenaline or Noradrenaline.

MOA

Alpha blockers prevent the constriction of blood vessels, relaxation of smooth muscles, and lowering of blood pressure, leading to desired effects.

Drugs

1. Tolazoline
2. Phentolamine
3. Phenoxybenzamine
4. Methysergide

2. Phentolamine – Uses

It is used in the treatment of Hypertension. It is also used in the treatment of erectile dysfunction.

3. Phenoxybenzamine – Uses

It is used in the treatment of urinary retention. It is used in the treatment of hypertension.

4. Prazosin – Uses

It is used in the treatment of Heart failure.

5. Methysergide – Uses

It is used in the treatment of severe migraine.

6. Dihydroergotamine – Uses

It is used in the treatment of Migraine.

2. Beta-Adrenergic Blockers

Beta Adrenergic blockers, also known as $\beta$ blockers, are drugs that block the stimulation of $\beta$-adrenergic receptors by Adrenaline and Noradrenaline. They mainly block $\beta$1 receptors and lead to a slower heart rate, reduced force of heart contraction, and lower blood pressure.

The $-\text{O-CH}_2-$ group between the aromatic ring and ethylamino side chain is responsible for antagonistic property. The -OH group at the $\beta$ position is essential for activity. The nitrogen atom should be a secondary amine for optimum $\beta$-blocking activity. The most effective substituents at the amino group are isopropyl and tertiary butyl groups.

1. Propranolol – Uses

Propranolol is used in the treatment of tremors, angina, hypertension. It is also used in the prevention of heart attack.

Biosynthesis of Acetylcholine

Biosynthesis of Acetylcholine refers to the biological process by which the neurotransmitter Acetylcholine (ACh) is produced. It occurs mainly in the nerve terminals of Cholinergic Neurons. The reaction is catalyzed by the enzyme choline acetyltransferase (ChAT). Choline (obtained from the diet or recycled from ACh breakdown) combines with Acetyl-CoA (produced in the mitochondria) to form Acetylcholine. The reaction is:

Choline + Acetyl-CoA $\xrightarrow{\text{ChAT}}$ Acetylcholine + CoA

Catabolism of Acetylcholine

Catabolism of Acetylcholine refers to the breakdown of Acetylcholine after it has carried out its function at a synapse. It mainly happens in the synaptic cleft and involves:

The enzyme acetylcholinesterase (AChE) rapidly breaks down acetylcholine. The choline is taken back into the neuron to be reused for making new acetylcholine. This breakdown occurs very fast (within milliseconds).

Cholinergic Receptors

Cholinergic Receptors are specialized proteins located on the surface of cells (mainly neurons, muscles, and glands) to which Acetylcholine binds and mediates its effect. Cholinergic Receptors are broadly classified into two types:

1. Nicotinic Receptors
2. Muscarinic Receptors

Muscarinic Receptors

They belong to the G-Protein coupled receptors family. They are further divided into five subtypes:

• (a) M1 Receptors
• (b) M2 Receptors
• (c) M3 Receptors
• (d) M4 Receptors
• (e) M5 Receptors

Nicotinic Receptors

They are ligand-gated ion channels. They are of two types:

• (a) Nm Receptors
• (b) Nn Receptors

Distribution of Cholinergic Receptors

Parasympathomimetic Agents

Parasympathomimetic Agents are drugs that stimulate or mimic the effect of the Parasympathetic Nervous System by either directly activating Cholinergic Receptors (Muscarinic/Nicotinic) or by increasing Acetylcholine levels.

Parasympathomimetic Agents:

• (Direct Acting): Acetylcholine, Carbachol, Bethanechol, Methacholine, Pilocarpine
• (Indirect Acting) (Irreversible): Isoflurophate, Echothiophate, Diisopropyl fluorophosphate (DFP), Parathion, Malathion

SAR of Parasympathomimetic Agents

The general structure of Parasympathomimetic agents is as follows:

1. Substitution On Acyloxy Group: Acetate with Carbamate Group increases activity & stability. Replacement of the ester group by ether & ketone group gives chemically stable & potent compounds.
2. Substitution on Ethylene Group: Increase in chain length will lead to a decrease in activity. Branching on $\beta$ substitution leads to reduction in nicotinic activity but increase in muscarinic activity.
3. Substitution On Quaternary Ammonium Compound: Placement of Primary, secondary, or tertiary amines leads to a decrease in activity. Replacement of more than 1 methyl group of the Quaternary Ammonium group leads to complete loss of Cholinergic activity. Quaternary Ammonium Group is essential for activity.

2. Direct Acting Parasympathomimetic Agents

Direct Acting Parasympathomimetic Agents are drugs that directly stimulate cholinergic receptors by mimicking the effect of Acetylcholine.

MOA

These agents bind directly to cholinergic receptors (Nicotinic & Muscarinic) found in organs like the heart, lungs, eyes, GIT. Once the receptor is activated, it triggers intracellular pathways leading to:

• Smooth Muscle Contraction
• Increased Secretion
• Decreased Heart Rate
• Pupil Constriction, etc.

Drugs

Acetylcholine, Carbachol*, Bethanechol, Methacholine, Pilocarpine

1. Carbachol

MOA

Carbachol binds with both Muscarinic and Nicotinic receptors. It is not inactivated by Cholinesterase, so its actions are more prolonged.

USES

Used in cases of severe chronic glaucoma.

2. Acetylcholine

Uses

Used as eye drops to cause miosis. Used as a Vasodilator & cardiac depressant.

3. Bethanechol

Cholinesterase Reactivator

A Cholinesterase Reactivator is a type of drug specifically designed to restore the activity of Cholinesterase enzymes (Acetylcholinesterase) that have been inhibited by Organophosphate or carbamate compounds. These reactivators are mainly used as Antidotes in cases of poisoning by pesticides (organophosphates) or nerve agents.

Pralidoxime Chloride MOA

Pralidoxime Chloride is a specific antidote that reactivates Acetylcholinesterase and allows normal nerve function to resume.

Uses

Used for the treatment of poisoning from organophosphorus compounds.

Cholinergic Blocking Agents

They are also known as:

• Cholinolytic Agents
• Anticholinergic Agents
• Cholinergic Antagonists
• Parasympatholytic Agents
• Muscarinic Agents

These are those drugs or Agents which inhibit Acetylcholine or Parasympathomimetic action by blocking the Cholinergic receptors.

Classification:

• (Solanaceous Alkaloids): Atropine Sulphate, Hyoscyamine Sulphate, Scopolamine hydrobromide, Homatropine hydrobromide, Ipratropium bromide.
• (Synthetic Cholinergic Blockers): Tropicamide, Cyclopentolate hydrochloride, Clidinium bromide, Dicyclomine hydrochloride, Glycopyrrolate, Methantheline bromide, Propantheline bromide, Benztropine mesylate, Orphenadrine citrate, Biperiden hydrochloride, Procyclidine hydrochloride, Trihexyphenidyl chloride, Isopropamide iodide, Ethopropazine hydrochloride.

SAR of Cholinergic Blocking Agents

The general structure of Cholinergic Blocking Agents is as follows:

1. Substitution On Alkyl Group: Substituents R1 & R2 must be carbocyclic or heterocyclic rings for maximal antagonist activity. Replacement of a heterocyclic ring with an aromatic ring decreases activity. The rings could be identical, but the most potent compounds are found to have different ring substitutions.
2. Substitution On Carbon Chain: The length of the carbon chain can be from two to four carbons, but most potent anticholinergic agents have two methylene units in this chain. The substitution may be ester, ether, or alcohol amine. The nature of group X affects the duration of action, physicochemical properties, and side effects but has no effect on the drug’s ability to bind with the receptor.

Sedatives & Hypnotics

Sedatives are drugs/medicines that help calm you down or make you feel relaxed. Hypnotics are medicines that help you fall asleep. Both are often used to treat anxiety or sleep problems. Hypnotics are strong depressants of the CNS, cause sleep, and are used in insomnia.

Classification (Sedatives & Hypnotics)

• (Benzodiazepines): Chlordiazepoxide, Diazepam, Oxazepam, Chlordiazepoxide, Lorazepam, Alprazolam, Zolpidem.
• (Barbiturates): Barbital, Phenobarbital, Mephobarbital, Amobarbital, Butabarbital, Pentobarbital, Secobarbital.
• (Miscellaneous): Alcohol and their derivatives, Carbamate derivatives, Meprobamate, Ethchlorvynol, Amides and Imides, Glutethimide, Aldehyde and their derivatives, Triclofos sodium, Paraldehyde.

Benzodiazepines

Benzodiazepines are drugs that help reduce anxiety, relax muscles, and make it easier to sleep. They work by calming the brain. They were accidentally synthesized in 1961. They include:

1. Chlordiazepoxide
2. Diazepam
3. Oxazepam
4. Chlorazepate
5. Lorazepam
6. Alprazolam
7. Zolpidem

Mechanism of Action

Benzodiazepines work by increasing the effect of a brain chemical GABA, which calms down brain activity. This helps reduce anxiety, relax muscles, and cause sleepiness.

SAR of Benzodiazepines

• Ring A: It is essential for proper binding to the GABA-A receptor. Electron Withdrawing substituents at position 7 generally enhance activity. Substitution at positions 6, 8, or 9 also enhances activity.
• Ring B: It is a diazepine ring containing two ‘N’ atoms. Substitution at N1 by alkyl, haloalkyl, or aminoalkyl increases potency. A Hydroxy group at position 3 increases water solubility, improves metabolism, but shortens the duration of action. A Phenyl group at position 5 is essential for activity.
• Ring C: Important for binding affinity to GABA-A receptors. Substituents at the ortho position (2′) increase potency (e.g., electron-withdrawing groups). Para substitution (4′) typically reduces activity.

Uses

1. Anxiety
2. Insomnia
3. Muscle spasm

Chlordiazepoxide – Uses

Used in treatment of anxiety & insomnia. Used in treatment of withdrawal symptoms (Nausea, Muscle spasm, etc.) from Alcohol.

Oxazepam – Uses

Used in treatment of insomnia & anxiety disorder.

Antipsychotics

Antipsychotics are drugs that have a specific sedative effect and which improve the attitude and calm behavior of psychotic patients. They are also called as neuroleptics or major tranquilizers. They do not eliminate the disorder; they only decrease the symptoms.

Psychosis

A mental disorder characterized by a disconnection from reality.

Types of Psychotic Disorder

Psychosis occurs due to:

1. Schizophrenia
2. Bipolar disorder
3. Psychotic depression
4. Schizoaffective disorder
5. Drug-induced psychosis

Classification (Antipsychotic drugs)

• (Phenothiazines): Promazine, Chlorpromazine, Triflupromazine, Thioridazine, Piperazine derivatives, Prochlorperazine maleate, Trifluoperazine.
• (Ring analogues of Phenothiazines): Chlorprothixene, Thiothexene, Loxapine succinate, Clozapine.
• (Fluro Butyrophenones): Haloperidol, Droperidol, Risperidone.
• (Butyroamino ketones): Molindone hydrochloride.
• (Benzamides): Sulpiride.

Phenothiazines

They are non-selective, competitive antagonists of D1 and D2 receptors and block dopamine activity at this receptor site. These drugs are also known as Tricyclic antipsychotics. These act on the CNS by causing moderate sedative and autonomic effects. These include:

1. Promazine hydrochloride
2. Chlorpromazine hydrochloride
3. Triflupromazine
4. Thioridazine hydrochloride
5. Piperazine derivative
6. Prochlorperazine maleate
7. Trifluoperazine

Mechanism of Action

They work by blocking dopamine (D1, D2) receptors in the brain or CNS and help reduce symptoms like hallucinations, delusions, and agitation, making them helpful to treat mental health conditions like Schizophrenia.

SAR of Phenothiazines

1. Tricyclic Ring System: The phenothiazine nucleus is essential for activity. It consists of two benzene rings linked by an external ring containing Sulfur and nitrogen atoms.
2. Substitution at Position 2: A Cl or other electron-withdrawing group at position 2 increases potency by enhancing receptor binding.
3. Side Chain at Nitrogen: The nitrogen at position 10 is typically substituted with a 3-Carbon side chain ending in a terminal amine. The nature of the side chain determines the type of phenothiazine and receptor binding affinity.

Epilepsy

Epilepsy is one of the most common chronic neurological disorders characterized by recurrent, unpredictable seizures due to disorders of brain cells. Seizures occur due to sudden, uncontrolled electrical disturbances in the brain that can cause changes in behavior, movement, sensation, or loss of consciousness. It is a Paroxysmal Disorder. It often occurs due to too much excitation or too little inhibition.

Types of Epilepsy

It is of mainly two types:

1. Generalized Epilepsy
2. Focal Epilepsy

1. Generalized Epilepsy

A Generalized Epilepsy is a type of seizure that involves abnormal electrical activity throughout the entire brain. It affects both Hemispheres. It is further subdivided as follows:

• Tonic-Clonic Seizure
• Absence Seizure
• Tonic Seizure
• Clonic Seizure
• Atonic Seizure
• Myoclonic Seizure

1. Tonic-Clonic

It is also known as Grand-Mal Seizure. It is characterized by loss of consciousness, stiffening of muscles (Tonic Phase), and jerking movements (Clonic Phase). It leads to Post-Seizure Depression.

2. Absence

It is also known as Petit Mal Seizures. It is characterized by sudden loss of consciousness (for 30-60 seconds) in the middle of an activity. In this, the patient shows absent-minded behavior, typically occurring in children.

3. Tonic

Tonic seizure involves sustained muscle stiffening/rigidity. It usually affects muscles in the back, arms, and legs.

4. Clonic

Characterized by repeated jerking movement of muscles. It usually affects the neck, face, and arms.

5. Atonic

It involves sudden loss of muscle control, leading to collapse or fall.

6. Myoclonic

These seizures involve sudden brief muscle contraction. It can occur in a specific muscle group or involve the entire body.

Focal Epilepsy

It is also known as Partial Epilepsy. In this, only a single/specific part of the brain is affected. It is further subclassified into two types:

1. Simple Partial Seizure
2. Complex Partial Seizure

1. Simple Partial

These seizures do not cause loss of consciousness. They may cause localized symptoms such as tingling, changes in emotion, sensation, or perception.

2. Complex Partial

These seizures involve loss of consciousness accompanied by unusual behavior or automatism. The person may not remember the seizure afterwards.

Causes/Etiology

General Anesthetics

General Anesthesia is a type of drug used during surgery to make a person unconscious and unable to feel pain. It affects the whole body, and the person doesn’t wake up until the surgery is over. They are depressant drugs that produce a partial or total loss of sensation.

General Mechanism of Action

The mechanism of action of general anesthetics involves multiple effects on the central nervous system that result in loss of consciousness, amnesia, analgesia, and immobility. The exact mechanisms are complex and not completely understood, but the general principles include:

1. Enhancement of Inhibitory Pathways: Most general anesthetics enhance the action of inhibitory neurotransmitters, especially Gamma-aminobutyric Acid (GABA) at the GABA-A receptor. This leads to:
   • Hyperpolarization of neurons
   • Reduced neuronal excitability
   • Sedation, amnesia, and unconsciousness.
2. Inhibition of Excitatory Pathways: Some anesthetics inhibit excitatory neurotransmitters such as glutamate, particularly at the NMDA (N-methyl-D-Aspartate) receptors. Example: Ketamine blocks NMDA receptors, contributing to its dissociative anesthetic effect.
3. Modulation of Ion Channels: General anesthetics also act on potassium (K+) and sodium (Na+) channels:
   • Promotes K+ efflux $\rightarrow$ Hyperpolarization
   • Inhibits Na+ influx $\rightarrow$ Reduced action potential generation.

Classification (General Anesthetics)

• (Inhalation Anesthetics): Halothane, Methoxyflurane, Enflurane, Sevoflurane, Isoflurane, Desflurane.
• (Ultra Short Acting Barbiturates): Methohexital Sodium, Thiamylal sodium, Thiopental sodium.
• (Dissociative Anesthetics): Ketamine Hydrochloride.

Inhalation Anesthesia

They are gases or volatile liquids which are mixed with oxygen and administered through inhalation. They cause CNS depression and anesthesia by rapidly reaching the blood-brain barrier in sufficient concentration.

Mechanism of Action

Inhalation anesthetics induce anesthesia by modulating synaptic transmission in the central nervous system, leading to unconsciousness, amnesia, and immobility. Most inhalation anesthetics enhance inhibitory effects by increasing chloride (Cl-) influx.

Narcotics and Non-Narcotics Analgesics

Narcotic Analgesics

These are strong painkillers that can make you feel sleepy or drowsy. They are often used for severe pain. Examples: Morphine, Codeine, etc.

Non-Narcotic Analgesics

These are milder painkillers that don’t cause sleepiness. They are used for mild to moderate pain, like headaches or muscle pain. Examples: Paracetamol (Acetaminophen), etc.

Mechanism of Action

1. Narcotic Analgesics: They work by binding to opioid receptors in the brain and spinal cord, blocking pain signals and changing how your body feels pain.
2. Non-narcotic Analgesics: They work by blocking enzymes COX that produce prostaglandins, which are chemicals that cause pain and swelling.

Classification

(Narcotic and Non-narcotic analgesics)

• (Morphine and related drugs): Morphine Sulphate, Codeine, Meperidine HCl, Anileridine HCl, Diphenoxylate HCl, Loperamide HCl, Fentanyl Citrate, Methadone HCl, Propoxyphene HCl, Pentazocine, Levorphanol tartrate.
• (Narcotic Antagonists): Nalorphine HCl, Levallorphan tartrate, Naloxone HCl.
• (Anti-inflammatory drugs – NSAIDs): Sodium salicylate, Aspirin, Mefenamic Acid, Meclofenamate, Indomethacin, Sulindac, Tolmetin, Zomepirac, Diclofenac, Ketorolac, Ibuprofen, Naproxen, Piroxicam, Phenacetin, Acetaminophen, Antipyrine, Phenylbutazone.

Morphine and Related Drugs

Morphine is a naturally occurring alkaloid obtained from the Opium Poppy (Papaver Somniferum). It is the prototypical narcotic analgesic, meaning it serves as the standard against which other opioid (narcotic) analgesics are compared.

MOA

Morphine binds to mu opioid receptors in the brain and spinal cord. This leads to:

• Inhibition of Adenylate Cyclase.
• Inhibition of neurotransmitter release (Ca$^{2+}$ channel closure).
• Opening of K+ Channels $\rightarrow$ Hyperpolarization.

Result: Pain signals are blocked, leading to analgesia, sedation, and respiratory depression.

SAR of Morphine Analogues

1. Aromatic Ring: The phenolic -OH at position 3 is crucial for activity. Modification or removal leads to severe loss of activity due to loss of hydrogen bonding with the receptor.
2. Alcohol at Position 6: It is a hydrophilic group contributing to receptor binding. Oxidation of this -OH group affects activity.

Anti-Inflammatory Agents

They are medicines that reduce pain, swelling, and fever without making you sleepy. They are also known as NSAIDs, which are widely used for the treatment of minor pain and for the management of edema and tissue damage resulting from inflammatory joint disease.

Mechanism of Action

They block cyclooxygenase (COX) enzymes responsible for the production of prostaglandins, which promote inflammation, pain, and fever. Reduction of prostaglandins leads to reduced pain and fever.

Drugs

• Sodium salicylate
• Aspirin
• Mefenamic Acid
• Indomethacin
• Meclofenamate
• Sulindac
• Tolmetin
• Zomepirac
• Diclofenac
• Ketorolac
• Ibuprofen
• Naproxen
• Piroxicam
• Phenacetin
• Acetaminophen
• Antipyrine
• Phenylbutazone

1. Mefenamic Acid

MOA

As mentioned in Anti-inflammatory agents (COX inhibition).

Uses

Used mainly in muscle & back pain.

2. Ibuprofen

MOA

Mentioned in Anti-inflammatory Agents (COX inhibition).

Uses

Reduce Fever, Pain, Inflammation.

3. Sodium Salicylate

Uses

It is used as an analgesic & antipyretic. It induces apoptosis in cancer cells and necrosis.

4. Aspirin

Uses

It can be used for relieving pain & swelling in arthritis.

5. Meclofenamate

Uses

Used in rheumatoid arthritis & osteoarthritis. To stop excessive bleeding during menstruation.

6. Indomethacin

Uses

Treat moderate to severe osteoarthritis, rheumatoid arthritis, gouty arthritis, or ankylosing spondylitis (rare type of arthritis that causes pain and stiffness in the spine).

7. Sulindac

Uses

Treat pain or inflammation caused by arthritis, ankylosing spondylitis, tenosynovitis, bursitis, or gout.

8. Tolmetin

Uses

Relieve pain, swelling, tenderness, and stiffness in conditions such as osteoarthritis and rheumatoid arthritis, including juvenile rheumatoid arthritis.

9. Zomepirac

Uses

Managing mild to severe pain. More effective than aspirin and codeine alone.

10. Diclofenac

Uses

Used to treat pain and inflammatory disease such as gout or ankylosing spondylitis.

11. Ketorolac

Uses

Effective when administered with paracetamol to control pain in newborns because it does not depress respiration as opioids do.

12. Naproxen

Uses

Used for relieving mild pain.