1. Organic Chemistry Foundations 🧪

Understanding functional groups and their properties is essential for predicting drug behavior, metabolism, and interactions.

Functional Group	Structure	Properties	Drug Examples
Hydroxyl (-OH)	R-OH	↑ Water solubility, H-bonding	Acetaminophen, Morphine
Carboxyl (-COOH)	R-COOH	Acidic, ionized at physiological pH	Aspirin, Ibuprofen
Amine (-NH2)	R-NH2	Basic, can be protonated	Amphetamine, Lidocaine
Ester (-COO-)	R-COO-R'	Hydrolyzable, prodrug design	Aspirin, Enalapril
Amide (-CONH-)	R-CONH-R'	Stable, H-bonding capability	Lidocaine, Acetaminophen
Sulfhydryl (-SH)	R-SH	Nucleophilic, can form disulfide	Captopril, N-acetylcysteine

💡 Clinical Relevance:

Acidic drugs (with -COOH) tend to bind to albumin, while basic drugs (with -NH2) bind to alpha-1 acid glycoprotein. This affects drug distribution and interactions!

2. Stereochemistry and Chirality 🔄

Many drugs exist as enantiomers (mirror images) that can have different pharmacological effects. Understanding stereochemistry is critical for drug safety.

R/S Nomenclature:

Based on Cahn-Ingold-Prelog priority rules
R (Rectus): Clockwise arrangement
S (Sinister): Counterclockwise arrangement
Chiral center = carbon with 4 different groups

Clinical Importance:

Thalidomide: S-isomer causes teratogenicity
Omeprazole: S-isomer (esomeprazole) more potent
Ibuprofen: S-isomer is active form
Propranolol: S-isomer has beta-blocking activity

Key Terms:

Enantiomers: Non-superimposable mirror images (same physical properties except optical rotation)
Diastereomers: Stereoisomers that are not mirror images (different physical properties)
Racemic mixture: 50:50 mixture of enantiomers (optically inactive)
Eutomer: More active enantiomer; Distomer: Less active enantiomer

3. Structure-Activity Relationship (SAR) 🧬

SAR studies how chemical structure modifications affect biological activity. This is the basis of rational drug design and developing new therapeutic agents.

Structural Change	Effect	Example
Add alkyl groups	↑ Lipophilicity, ↑ duration	Methylation of morphine → codeine
Add hydroxyl (-OH)	↑ Water solubility, ↓ BBB penetration	Norepinephrine vs Epinephrine
Add halogen (F, Cl)	↑ Lipophilicity, ↑ metabolic stability	Fluoroquinolones
Bioisosteric replacement	Maintain activity, alter properties	-COOH → tetrazole (losartan)
Ring modifications	Alter receptor binding, selectivity	Benzodiazepine variations

Lipinski's Rule of Five (Drug-likeness):

For good oral bioavailability, a drug should have:

Molecular weight ≤ 500 Da
LogP ≤ 5 (lipophilicity)
H-bond donors ≤ 5
H-bond acceptors ≤ 10

4. Drug Stability and Degradation 🔬

Understanding drug degradation pathways is essential for proper storage, formulation, and shelf-life determination.

Degradation Type	Mechanism	Susceptible Drugs	Prevention
Hydrolysis	Water cleaves bonds (esters, amides)	Aspirin, Penicillins	Control moisture, anhydrous formulation
Oxidation	Loss of electrons, free radicals	Vitamin C, Adrenaline	Antioxidants, N2 atmosphere
Photolysis	Light-induced degradation	Nifedipine, Nitroprusside	Amber containers, protect from light
Racemization	Conversion between enantiomers	Epinephrine, Pilocarpine	pH control, proper storage

💡 Storage Guidelines:

Refrigerate (2-8°C): Insulin, Vaccines, most biologics
Room temp (15-30°C): Most oral medications
Protect from light: Nitrofurantoin, Amphotericin B, Metronidazole
Keep dry: Aspirin, Effervescent tablets

5. Major Drug Classes by Chemical Structure 💊

Board exams often test knowledge of drug classes based on their chemical structures and naming conventions.

Beta-Lactam Antibiotics:

Four-membered ring containing nitrogen

Penicillins: Amoxicillin, Ampicillin
Cephalosporins: Cefazolin, Ceftriaxone
Carbapenems: Imipenem, Meropenem
Monobactams: Aztreonam

Sulfonamides:

Contain -SO2NH2 group

Antibiotics: Sulfamethoxazole
Diuretics: Furosemide, Thiazides
Hypoglycemics: Glipizide, Glyburide
COX-2 inhibitors: Celecoxib

Steroids:

Four fused rings (cyclopentanoperhydrophenanthrene)

Corticosteroids: Prednisone, Dexamethasone
Sex hormones: Estradiol, Testosterone
Cardiac glycosides: Digoxin
Vitamin D: Calcitriol

Common Drug Suffixes:

-olol: Beta-blockers
-pril: ACE inhibitors
-sartan: ARBs
-statin: HMG-CoA reductase inhibitors
-prazole: Proton pump inhibitors
-mab: Monoclonal antibodies

6. Practice Questions 📝

Question 1: Functional Groups

Which functional group in aspirin is responsible for its susceptibility to hydrolysis?

Answer: The ester group (-COO-). Aspirin contains an acetyl ester that hydrolyzes to salicylic acid and acetic acid, especially in the presence of moisture. This is why aspirin should be kept in dry conditions and has a characteristic vinegar smell when degraded.

Question 2: Stereochemistry

What is the clinical significance of the R and S enantiomers of thalidomide?

Answer: The R-enantiomer has sedative effects (desired), while the S-enantiomer is teratogenic (causes birth defects). However, even pure R-thalidomide racemizes in vivo, making it dangerous during pregnancy. This tragedy led to stricter drug testing requirements worldwide.

Question 3: SAR

Why does adding a methyl group to morphine (forming codeine) decrease analgesic potency?

Answer: Methylation of the 3-OH group in morphine forms codeine, which has lower affinity for opioid receptors. Codeine acts mainly as a prodrug - it must be converted to morphine by CYP2D6 for analgesic effect. About 10% of population are poor CYP2D6 metabolizers and get little benefit from codeine.

Question 4: Drug Stability

Why must nitroglycerin sublingual tablets be stored in the original glass container?

Answer: Nitroglycerin is volatile and can be absorbed by plastic containers. It is also sensitive to light, heat, and moisture. Glass containers minimize loss through absorption and containers should be tightly closed. Patients should discard tablets 6 months after opening.

Pharmaceutical Chemistry