General Principles of Chemotherapy

What is Chemotherapy?

Derived from "Chemo" (Chemical) and "Therapy" (Treatment).

It refers to the use of chemical agents to destroy disease-causing microorganisms or target cancerous cells selectively.

Antimicrobial Agents

1. Antibiotics

Naturally produced by microorganisms to inhibit or kill other microbes at low concentrations.

2. Chemotherapeutic Agents

Can be synthetic, semi-synthetic, or natural compounds that eliminate pathogens while causing minimal harm to the host.

3. Anti-Microbial Agents

Combination of chemotherapeutic agents and antibiotics that selectively act against microbial infections.

History of Chemotherapy

Paul Ehrlich (1908) – Father of Chemotherapy (Developed Arsphenamine).

Alexander Fleming (1928) – Discovered Penicillin.

Gerhard Domagk (1932) – Developed Sulfonamides.

Principles of Antimicrobial Therapy

1. Accurate Diagnosis

Identify site of infection.

Determine causative microorganism.

Select effective antimicrobial agents.

2. Necessity of Chemotherapy

Acute infections → Require chemotherapy.

Chronic infections → May need surgical intervention.

3. Drug Selection Criteria

Antimicrobial activity.

Pharmacokinetics (Absorption, distribution, metabolism, excretion).

Patient factors (Allergy, renal function, immune status).

4. Dosage & Duration

Use optimized doses to prevent resistance.

Inadequate dosing → Leads to drug resistance.

5. Continuous Therapy

Some infections resolve in 5–10 days, while others require prolonged treatment:

Typhoid Fever

Tuberculosis

Infective Endocarditis

6. Prophylactic Chemotherapy

Used before surgery to prevent infections.

Classification of Antimicrobial Agents

A. Based on Chemical Structure

1. Sulfonamides & Related Drugs → Dapsone, Sulfadiazine

2. Diaminopyrimidines → Trimethoprim, Pyrimethamine

3. Quinolones → Nalidixic acid, Ciprofloxacin

4. Beta-Lactams → Penicillins, Cephalosporins

5. Tetracyclines → Doxycycline, Oxytetracycline

6. Aminoglycosides → Streptomycin, Gentamicin, Amikacin

7. Macrolides → Erythromycin, Azithromycin

8. Glycopeptides → Vancomycin

9. Oxazolidinones → Linezolid

10. Nitroimidazoles → Metronidazole, Tinidazole

B. Based on Mechanism of Action

1. Inhibits Cell Wall Synthesis → Penicillins, Cephalosporins, Vancomycin

2. Inhibits Protein Synthesis → Tetracyclines, Macrolides, Aminoglycosides

3. Disrupts Cell Membrane → Polymyxins

4. Inhibits DNA/RNA Synthesis → Rifampin, Quinolones

5. Blocks Essential Metabolites → Sulfonamides, Trimethoprim

C. Based on Target Organisms

Antibacterial → Penicillin, Erythromycin

Antiviral → Acyclovir, Zidovudine

Antifungal → Griseofulvin, Amphotericin B

Antiprotozoal → Metronidazole, Chloroquine

Antihelmintic → Mebendazole, Niclosamide

D. Based on Spectrum of Activity

Narrow Spectrum → Penicillin G, Streptomycin

Broad Spectrum → Tetracycline, Chloramphenicol

Penicillin: A Breakthrough Antibiotic

Discovered by: Alexander Fleming (1928)

Source: Penicillium notatum & Penicillium chrysogeum

First clinical use: 1941

Classification of Penicillins

1. Penicillin G Variants (Acid-sensitive)

Benzylpenicillin (Penicillin G)

Phenoxymethyl penicillin (Penicillin V) (Acid-resistant alternative to Pen G)

2. Penicillinase-Resistant Penicillins

Methicillin, Cloxacillin, Dicloxacillin

3. Extended-Spectrum Penicillins

Ampicillin, Amoxicillin, Piperacillin

4. Beta-Lactamase Inhibitors (Enhance Penicillin Activity)

Clavulanic Acid, Sulbactam, Tazobaco

Mechanism of Action of Penicillin

1. Inhibits Cell Wall Synthesis

Binds to Penicillin-Binding Proteins (PBPs) → Prevents cross-linking → Bacterial cell lysis.

2. Inhibits Transpeptidase

Prevents peptidoglycan cross-linking, weakening the cell wall.

3. Activates Autolysins

Induces self-destruction of bacterial cell walls.

Resistance to Penicillin

1. Enzyme-Mediated Resistance

Penicillinase (β-lactamase) inactivates Penicillin G.

Found in Staphylococci, E. coli, H. influenzae.

2. Target Modification

Altered PBPs reduce penicillin binding → Common in MRSA (Methicillin-Resistant Staphylococcus Aureus).

3. Decreased Permeability

Gram-negative bacteria have outer membranes, preventing penicillin entry.

Pharmacokinetics of Penicillin G

Acid-labile (Destroyed by gastric acid).

Rapid absorption (IM route preferred).

Short half-life (~30 min in adults).

Does not cross BBB easily (Except in meningitis).

Excreted via kidneys (Renal impairment affects clearance).

Adverse Effects of Penicillin

1. Local & Systemic Toxicity

Pain at injection site (IM)

Thrombophlebitis (IV)

Neurotoxicity (High doses → Confusion, seizures)

2. Hypersensitivity Reactions

Mild: Rash, itching, fever.

Severe: Anaphylaxis, Angioedema.

3. Jarisch–Herxheimer Reaction

Occurs in syphilis treatment → Fever, muscle pain, vascular collapse.

Therapeutic Uses of Penicillin

A. Bacterial Infections

Streptococcal Infections → Pharyngitis, Rheumatic fever

Pneumococcal Infections → Pneumonia, Meningitis

Meningococcal Meningitis

Syphilis (Drug of Choice)

Diphtheria, Tetanus, Anthrax

B. Prophylactic Uses

Rheumatic fever prevention

Bacterial endocarditis prevention

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