PHARMACOLOGY – III PREPAIRED BY: MR.

RAHUL SINGH SHAKTAWAT

[UNIT – II, CHAPTER – 3] WEBSITE LINK: https://drugee.wordpress.com/

[UNIT – II, CHAPTER – 3]

Chemotherapy
Antibiotics- Penicillins, cephalosporins, chloramphenicol, macrolides, quinolones
and fluoroquinolins, tetracycline and aminoglycosides

Introduction to Antibiotics

1. Definition of Antibiotics: Antibiotics are chemical substances produced by

microorganisms (or synthesized chemically) that inhibit the growth of or destroy other
microorganisms, especially bacteria, at low concentrations without harming the host
cells.
Standard Definition (Waksman, 1942): “An antibiotic is a chemical substance produced by
microorganisms that, in small concentrations, can inhibit or destroy the growth of other
microorganisms.”
2. Origin of Antibiotics
Antibiotics were originally discovered as natural products: Many were isolated from soil
bacteria (Streptomyces spp.) and fungi (Penicillium spp.).
Historical Milestone:
• 1928 – Alexander Fleming discovered penicillin, the first true antibiotic, from
Penicillium notatum.
• 1940s – Florey and Chain purified and mass-produced penicillin during WWII,
revolutionizing treatment for bacterial infections.
3. Importance of Antibiotics
• Saved millions of lives by turning once-deadly infections (like pneumonia,
tuberculosis, and sepsis) into treatable conditions.
• Enabled safe surgical procedures, cancer chemotherapy, and organ transplants
by preventing/treating secondary infections.
• Paved the way for modern infection control and public health improvements.
4. Characteristics of Ideal Antibiotics
An ideal antibiotic should:
• Be selectively toxic (kill microbes without harming host).
• Have broad-spectrum activity.

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• Not cause resistance easily.

• Be stable, affordable, and safe for human use.

Penicillins

1. Definition: Penicillins are a group of β-lactam antibiotics derived from Penicillium

species. They act by inhibiting bacterial cell wall synthesis, leading to bactericidal
effects, especially on actively dividing Gram-positive bacteria.
According to KD Tripathi: “Penicillins are the earliest antibiotics discovered and are β-
lactam compounds that inhibit bacterial cell wall synthesis selectively.”
2. Classification with Dose
Penicillins are classified based on their spectrum of activity and resistance to β-
lactamase:
Category Examples Typical Adult Dose
Penicillin G: 1–4 million units
Natural Penicillins Penicillin G (IV), Penicillin V (oral)
IV every 4–6 hrs
Penicillinase-resistant Cloxacillin, Nafcillin Cloxacillin: 250–500 mg QID
Aminopenicillins (Broad-
Amoxicillin, Ampicillin Amoxicillin: 500 mg TID
spectrum)
Extended-spectrum Piperacillin: 3–4 g IV every 6–8
Piperacillin, Ticarcillin
(Antipseudomonal) hrs
β-lactam + β-lactamase Amoxicillin + Clavulanic acid,
Augmentin: 625–1000 mg TID
inhibitors Piperacillin + Tazobactam
Source: KD Tripathi – Essentials of Medical Pharmacology, Chapter on β-lactam Antibiotics
3. Mechanism of Action of Penicillin
a. Structural Target: The Bacterial Cell Wall
• The bacterial cell wall is made of peptidoglycan, a lattice-like polymer of N-
acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) cross-linked by short
peptide chains.
• This structure is essential for bacterial rigidity, shape, and resistance to osmotic
stress.
• In Gram-positive bacteria, this peptidoglycan layer is thick, making them more
susceptible to penicillins.
b. Penicillin Structure and the β-lactam Ring
• Penicillin molecules contain a β-lactam ring, which is crucial for their activity.

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• The β-lactam ring mimics the D-Ala-D-Ala terminal of the peptidoglycan

precursors that bacterial enzymes use during cell wall synthesis.
• This mimicry is what confuses the bacterial enzymes and allows penicillin to
interfere with their function.
Labeled in the diagram:
• The β-lactam ring is highlighted in red.
• This part is chemically reactive and binds to bacterial enzymes irreversibly.
c. Target Enzymes: Penicillin-Binding Proteins (PBPs)
• Penicillin-Binding Proteins (PBPs) are bacterial enzymes like transpeptidase,
which catalyze the final step in peptidoglycan synthesis — cross-linking adjacent
NAM-NAG chains via peptide bridges.
• PBPs are located in the periplasmic space (between the inner membrane and cell
wall in Gram-negative bacteria, or near the membrane in Gram-positives).
In the diagram:
• The PBPs are shown interacting with the β-lactam ring, leading to enzyme
inhibition.
d. Inhibition of Transpeptidation Reaction
• Normally, transpeptidase binds to the D-Ala-D-Ala terminal on a peptidoglycan
precursor and links it to another peptide chain.
• Penicillin binds to the transpeptidase instead, forming a covalent bond with the
active site serine.
• This irreversibly inactivates the enzyme.
Consequences:
• No cross-linking of peptidoglycan.
• Accumulation of uncrosslinked chains.
• Weak and unstable cell wall.
e. Activation of Autolysins (Bacterial Self-Destruction)
• Bacteria have enzymes called autolysins, which normally remodel the cell wall
during growth and division.
• When penicillin disrupts peptidoglycan cross-linking, autolysins are unopposed
and digest the existing cell wall.
Outcome:

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• The bacterium loses structural integrity.

• Osmotic lysis occurs → cell bursts and dies.
f. Selective Toxicity
• Mammalian (human) cells do not have peptidoglycan and lack PBPs.
• Therefore, penicillins do not affect human cells, making them highly selective.
This is a textbook example of selective toxicity — a core principle in chemotherapy.
Summary of MOA in Stepwise Form
Step Action
1️⃣ Penicillin enters bacterial periplasm
2️⃣ Binds to penicillin-binding protein (PBP)
3️⃣ Inhibits transpeptidase enzyme
4️⃣ Prevents cross-linking of peptidoglycan
5️⃣ Activates autolysins (cell wall degradation)
6️⃣ Causes osmotic lysis of bacterium (cell death)
Final Note: Why This MOA is Clinically Important
• Works only on actively dividing bacteria.
• Resistance arises through:
o β-lactamase enzymes (destroy β-lactam ring).
o Mutated PBPs (e.g., MRSA).
o Reduced permeability (especially in Gram-negative organisms).
Combining penicillin with β-lactamase inhibitors (e.g., clavulanic acid) overcomes many
resistance mechanisms.
4. Therapeutic Effects
• Bactericidal action against susceptible bacteria.
• Effective in treating acute and chronic infections caused by Gram-positive and
some Gram-negative cocci.
• Combination with β-lactamase inhibitors broadens spectrum and protects against
resistance.
5. Clinical Uses
Disease/Condition Penicillin(s) of Choice
Pharyngitis, tonsillitis Penicillin V
Syphilis Penicillin G
Streptococcal skin infections Cloxacillin, Amoxicillin
Otitis media, sinusitis Amoxicillin + Clavulanic acid
Pneumonia (CAP) Amoxicillin or Penicillin G
Urinary Tract Infections Ampicillin (limited use due to resistance)
Pseudomonas infections Piperacillin + Tazobactam
Bite wounds, dental infections Amoxicillin + Clavulanic acid

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KD Tripathi notes that penicillins are still first-line agents for many infections due to their
safety and efficacy.
6. Side Effects
System Adverse Effects
Hypersensitivity Rashes, urticaria, anaphylaxis (most common side effect of penicillin)
Gastrointestinal Nausea, diarrhea, antibiotic-associated colitis (especially with broad-spectrum use)
Hematologic Hemolytic anemia, neutropenia (rare)
CNS (high doses) Seizures (especially in renal failure)
Anaphylaxis risk is high in penicillin-allergic patients → always check history before use.
7. Indications and Contraindications
Indications
• Bacterial infections caused by penicillin-sensitive organisms.
• Prophylaxis in rheumatic fever, dental procedures (endocarditis risk), and surgery.
Contraindications
• Penicillin allergy/hypersensitivity
• Cross-reactivity with cephalosporins in ~10% of penicillin-allergic patients.
• Renal impairment → requires dose adjustment for certain penicillins.
8. Pharmacological Actions on Organ Systems
System Pharmacological Action
Bacterial cell wall Inhibition → bactericidal effect
Immune system Can trigger hypersensitivity reactions
Renal system Mostly excreted unchanged → adjust dose in renal impairment
GI tract Alters gut flora → may cause superinfection (e.g., C. difficile colitis)
9. Role of Penicillins in Prevention & Treatment (Chemotherapy Perspective)
Principles of Chemotherapy Applied:
• Selective toxicity: Penicillins selectively target bacterial cell walls → minimal host
toxicity.
• Minimal inhibitory concentration (MIC): Achieved with proper dosing for time-
dependent killing.
• Spectrum adjustment: From narrow (Pen G) to broad (amoxicillin, piperacillin) via
chemical modification.
• Resistance management: Overcome β-lactamase production by combining with
clavulanic acid or tazobactam.
Contribution to Public Health:
• Made diseases like syphilis, pneumonia, strep infections easily curable.
• Reduced mortality during World War II and beyond.

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• Still first-line in many pediatric and obstetric infections due to low toxicity.
WHO – Antibiotics classification and global use

Cephalosporins

1. Definition of Cephalosporins: Cephalosporins are a large group of broad-spectrum

β-lactam antibiotics derived from the fungus Cephalosporium acremonium. Like
penicillins, they contain a β-lactam ring, but with a 7-aminocephalosporanic acid
nucleus rather than the 6-aminopenicillanic acid of penicillins.
Core activity: Inhibit bacterial cell wall synthesis → cause bactericidal effect.
They are among the safest and most commonly used antibiotics worldwide and are
classified into five generations based on their antimicrobial spectrum.
2. Classification of Cephalosporins (With Typical Doses)
Cephalosporins are classified into five generations, with increasing activity against
Gram-negative organisms and β-lactamase resistance.
Generation Examples Typical Dose Spectrum & Notes
250–500 mg PO Gram-positive cocci (e.g., Strep, Staph);
1st Cephalexin, Cefazolin
QID; 1g IV 8hr minor Gram-negative
250–500 mg PO; Better Gram-negative coverage (H.
2nd Cefuroxime, Cefaclor
750 mg IV influenzae, Neisseria)
Ceftriaxone, 1–2 g IV once/twice Broad Gram-negative; CNS penetration
3rd
Cefotaxime, Ceftazidime daily (meningitis); less Gram-positive
1–2 g IV every 8– More resistant to β-lactamases; used in
4th Cefepime
12h nosocomial infections
Ceftaroline, Covers MRSA and penicillin-resistant
5th 600 mg IV every 12h
Ceftobiprole pneumococci
KD Tripathi notes that cephalosporins are highly stable in vivo and well tolerated.
3. Mechanism of Action (MOA) of Cephalosporins
1. Molecular Level: β-Lactam Ring and Structural Mimicry
• Cephalosporins, like all β-lactam antibiotics, contain a β-lactam ring fused to a
dihydrothiazine ring (7-aminocephalosporanic acid nucleus).
• The β-lactam ring structurally mimics the D-Ala-D-Ala dipeptide that forms the
terminal end of peptidoglycan precursors in bacterial cell walls.
Molecular Interaction:
• This mimicry allows cephalosporins to bind competitively to the active site of
bacterial enzymes known as penicillin-binding proteins (PBPs) — the same

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enzymes that normally catalyze peptidoglycan cross-linking during cell wall

formation.
Key Point: PBPs are essential for maintaining bacterial cell wall integrity.
2. Subcellular Level: Inhibition of Transpeptidation in Cell Wall Synthesis
Step-by-Step Explanation:
Step 1: Binding to Penicillin-Binding Proteins (PBPs)
• PBPs are transpeptidase and carboxypeptidase enzymes embedded in the
bacterial cytoplasmic membrane.
• Cephalosporins bind irreversibly to these PBPs.
Step 2: Inhibition of Peptidoglycan Cross-Linking
• In normal bacteria, PBPs link the peptide chains of adjacent peptidoglycan layers.
• When cephalosporins are bound to PBPs, cross-linking is halted, leading to
accumulation of weak, uncross-linked peptidoglycan.
Step 3: Autolysin Activation
• Bacteria naturally produce autolysins to remodel the cell wall.
• In the absence of proper cross-linking, autolysins uncontrollably degrade the
existing peptidoglycan.
• This causes cell wall breakdown and bacterial lysis.
End Result: The bacterial cell loses its shape, becomes osmotically fragile, and ruptures
— this is a bactericidal effect.
KD Tripathi notes that cephalosporins are time-dependent bactericidal agents that act most
effectively during active bacterial growth.
3. Systemic/Organ-Level Action: Because cephalosporins target cell wall synthesis,
which only occurs in actively dividing bacteria, their systemic effect is more
pronounced in acute, replicative infections.
• Examples:
o In bacterial meningitis, third-generation agents (like ceftriaxone) cross the
blood-brain barrier and inhibit bacterial replication in the CNS.
o In pneumonia, cephalosporins accumulate in the lung tissue and act on
replicating Streptococcus pneumoniae or Haemophilus influenzae.

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Selective Toxicity at Systemic Level: Human cells lack peptidoglycan and PBPs, so
cephalosporins have no effect on host tissues, demonstrating high therapeutic
selectivity.
4. Key Chemotherapeutic Concepts Illustrated by Cephalosporin MOA
Concept How Cephalosporins Apply
Selective Toxicity Only bacteria have PBPs and peptidoglycan → no effect on human cells
Target Specificity Acts only on actively dividing bacteria (during cell wall synthesis)
Bactericidal Action Causes direct bacterial lysis, not just inhibition
Time-Dependent Drug must be maintained above MIC (minimum inhibitory concentration) for
Killing effectiveness
Summary of MOA (Textual Flow)
[ Bacterial Cell Wall Synthesis ]
↓
Peptidoglycan precursors → D-Ala-D-Ala ends
↓
Transpeptidase (PBP) cross-links peptidoglycan strands
↓
Cephalosporin (β-lactam) binds PBP → inhibits cross-linking
↓
Weak cell wall + autolysin activity
↓
Osmotic lysis → Bacterial death
Resistance Considerations (Related to MOA)
Bacterial resistance to cephalosporins occurs via:
Mechanism How It Interferes With MOA
β-lactamase production Hydrolyzes the β-lactam ring → prevents PBP binding
Altered PBPs (e.g., MRSA) Mutation reduces affinity for cephalosporins → drugs can't bind
Efflux pumps Reduce intracellular cephalosporin concentration
Porin changes (Gram-negatives) Block entry of drug → fails to reach PBPs
Newer cephalosporins (e.g., 5th gen ceftaroline) are designed to bind mutated PBPs in
MRSA.
Supporting Evidence
• Electron microscopy: Treated bacteria show cell wall rupture and cytoplasmic
leakage.
• Time-kill assays: Demonstrate time-dependent bacterial reduction.

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• Mutant studies: Bacteria lacking PBPs or producing β-lactamase are resistant,

validating the MOA.
Clinical Implications of MOA
• Best used in infections with rapid bacterial growth (e.g., pneumonia, sepsis).
• Should be administered at regular intervals to maintain concentration above MIC.
• Ineffective against dormant or intracellular bacteria (like Mycobacterium
tuberculosis).
4. Therapeutic Effects
• Rapid bactericidal action against susceptible organisms.
• Generations 3–5 are effective even in severe systemic infections like sepsis or
meningitis.
• Good tissue penetration, including lungs, kidneys, skin, bones, and CSF (for some
drugs).
• Some agents are active even against β-lactamase-producing bacteria.
Tripathi emphasizes their use in both prophylactic and curative contexts.
5. Clinical Uses
Condition Cephalosporin Used
Tonsillitis, URTI Cephalexin, Cefuroxime
Otitis media, sinusitis Cefaclor, Cefuroxime
Gonorrhea Ceftriaxone (single 250–500 mg IM dose)
Typhoid fever Ceftriaxone, Cefixime
Meningitis Cefotaxime, Ceftriaxone (cross BBB)
Septicemia Cefepime, Ceftazidime
MRSA infections Ceftaroline, Ceftobiprole (5th gen)
Surgical prophylaxis Cefazolin (esp. in orthopedic, GI surgeries)
CDC – Cephalosporin Use in STI and Meningitis Guidelines
6. Side Effects
System Affected Adverse Reactions
Skin Urticaria, rash, rarely Stevens-Johnson syndrome
GI tract Nausea, vomiting, diarrhea, C. difficile-associated diarrhea
Blood Thrombocytopenia, neutropenia (rare)
Renal Nephrotoxicity (especially with aminoglycoside combination)
Liver/Bleeding Cefoperazone and Ceftriaxone may cause hypoprothrombinemia and bleeding
Alcohol interaction Disulfiram-like reaction with Cefoperazone (avoid alcohol)
Cephalosporins are overall well tolerated; hypersensitivity is the most common issue.
7. Indications and Contraindications
Indications:

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• Susceptible bacterial infections involving skin, bone, respiratory tract, genitourinary

tract, blood, CNS.
• Prophylaxis before surgical or dental procedures.
• First-line therapy in gonorrhea, typhoid, and community-acquired pneumonia
(CAP).
Contraindications:
• Anaphylaxis to penicillins or cephalosporins (cross-reactivity ~5–10%)
• History of severe β-lactam allergy
• Caution in renal impairment, pregnancy, and newborns (ceftriaxone risk of
biliary sludging)
8. Pharmacological Actions on Different Body Systems
Pharmacological Actions of Cephalosporins:
1. Respiratory System
• Action: Cephalosporins eradicate bacteria responsible for upper and lower
respiratory tract infections.
• Targeted pathogens: Streptococcus pneumoniae, Haemophilus influenzae,
Moraxella catarrhalis.
• Effective drugs:
o 2nd gen (Cefuroxime) – effective for bronchitis, sinusitis.
o 3rd gen (Ceftriaxone, Cefotaxime) – for community-acquired pneumonia
(CAP) and hospital-acquired infections.
• Clinical outcome: Resolution of pneumonia, reduction in fever, and clearance of
infection.
2. Central Nervous System (CNS)
• Action: Cross the blood-brain barrier (BBB) during meningitis to kill pathogens in
cerebrospinal fluid (CSF).
• Drugs used: Cefotaxime, Ceftriaxone (3rd gen), due to excellent CSF penetration.
• Targeted organisms: Neisseria meningitidis, Streptococcus pneumoniae,
Haemophilus influenzae.
• Effect: Rapid bactericidal activity leads to reduction of inflammation, CSF cell
count, and symptoms of meningitis.
3. Gastrointestinal System

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• Action: Eradicate enteric pathogens in diseases like typhoid, shigellosis, and

enteric fever.
• Common drugs: Ceftriaxone, Cefixime.
• Spectrum: Active against Salmonella typhi, Shigella, Escherichia coli.
• Systemic outcome: Normalization of temperature, reduction in GI symptoms,
clearance of stool cultures.
4. Genitourinary System
• Action: Eliminate bacteria from urinary tract (bladder, kidneys) and reproductive
organs.
• Used in: UTIs, gonorrhea, pyelonephritis, pelvic inflammatory disease (PID).
• Effective agents:
o Cefixime, Cefuroxime – uncomplicated UTIs.
o Ceftriaxone – single-dose treatment for gonorrhea.
• Pharmacological result: Restoration of normal urination, resolution of infection,
prevention of complications.
5. Bone and Joint System
• Action: Penetrate synovial fluid and bone tissue to act against pathogens causing
osteomyelitis and septic arthritis.
• Effective drugs: Cefazolin (1st gen) for Staph aureus; Ceftriaxone (3rd gen) for
Gram-negatives.
• Clinical effect: Reduced inflammation, joint mobility improvement, and infection
resolution.
6. Bloodstream (Systemic Infections/Sepsis)
• Action: Rapid killing of bacteria in the bloodstream.
• Common drugs: Cefepime (4th gen), Ceftriaxone (3rd gen).
• Targets: Klebsiella, E. coli, Pseudomonas (with later-generation drugs).
• Result: Stabilization of vitals, resolution of systemic inflammatory response,
improved organ function.
7. Immune and Prophylactic Role
• Prevents infections during surgical interventions by eliminating potential
pathogens in mucosa or blood.
• Example: Cefazolin used preoperatively in orthopedic and GI surgeries.

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• Outcome: Reduced postoperative infection rates, faster recovery.

Summary Table: Systemic Actions
System Drug Examples Therapeutic Role
Respiratory Cefuroxime, Ceftriaxone Pneumonia, bronchitis, sinusitis
CNS Cefotaxime, Ceftriaxone Meningitis
GI Cefixime, Ceftriaxone Typhoid, shigellosis
GU Cefuroxime, Cefixime UTIs, gonorrhea
Bones/Joints Cefazolin, Ceftriaxone Septic arthritis, osteomyelitis
Blood Cefepime, Ceftazidime Sepsis, bacteremia
Surgical Sites Cefazolin Prophylaxis (e.g., before surgery)
9. Chemotherapy Principles Applied in Cephalosporins
a. Selective Toxicity: Cephalosporins target bacterial cell wall synthesis, which does
not exist in humans → minimal host toxicity.
b. Bactericidal Nature: Their ability to kill bacteria rather than just inhibit growth is
crucial in sepsis, meningitis, endocarditis.
c. Resistance Management
• Advanced generations are more stable to β-lactamases.
• Use of narrowest effective generation aligns with antimicrobial stewardship.
d. Pharmacokinetic Match: Different drugs allow for oral/IV use, CSF penetration,
renal or biliary elimination, allowing precision therapy.

Chloramphenicol

1. Definition: Chloramphenicol is a synthetic broad-spectrum antibiotic, originally

isolated from Streptomyces venezuelae in 1947. It is effective against a wide variety of
Gram-positive and Gram-negative bacteria, as well as anaerobes, rickettsiae, and
atypical organisms. It was once a front-line agent for serious infections but is now
reserved due to its dose-limiting hematological toxicity.
It is considered a bacteriostatic agent at standard doses, though it may be bactericidal
against select pathogens like Haemophilus influenzae, Neisseria meningitidis, and
Bacteroides fragilis.
2. Classification and Dosing
Pharmacological Class:
• Nitrobenzene derivative
• Protein synthesis inhibitor (bacteriostatic)

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Forms and Typical Doses:

Form Dose
Oral 250–500 mg every 6 hours
IV (succinate form) 50–75 mg/kg/day (divided doses)
Children 25–50 mg/kg/day
Topical (Eye/Ear) 0.5%–5% ointments and drops
Source: KD Tripathi – Essentials of Medical Pharmacology, Chapter on Antimicrobials
3. Mechanism of Action (MOA): Chloramphenicol disrupts bacterial protein synthesis,
which is critical for cell survival and replication.
Macromolecular Level:
• Binds to the 50S subunit of the bacterial ribosome.
• Inhibits peptidyl transferase enzyme, preventing the formation of peptide bonds.
• This blocks the elongation of the polypeptide chain, halting protein synthesis.
Subcellular Level:
• Specifically prevents peptidyl-tRNA in the P-site from transferring its peptide to
aminoacyl-tRNA in the A-site.
• Results in a stalled ribosome complex, eventually leading to bacterial growth
inhibition.
• Also inhibits mitochondrial ribosomes (70S type) in human bone marrow →
leading to myelosuppression.
Organ/System Level:
• Excellent CNS penetration: Crosses the blood-brain barrier (BBB) → effective for
meningitis.
• Ocular absorption: Penetrates aqueous humor → used in endophthalmitis.
• Bone marrow: Can interfere with protein synthesis in hematopoietic stem cells.
4. Therapeutic Effects
Effect Description
Active against a broad spectrum of pathogens, including Gram-positive, Gram-
Antibacterial
negative, anaerobic bacteria, and rickettsiae
Bacteriostatic Arrests bacterial growth by inhibiting protein synthesis
Bactericidal
Against H. influenzae, N. meningitidis, and B. fragilis in high concentrations
(selective)
CNS efficacy Ideal for meningitis due to high CSF penetration
5. Clinical Uses: Due to its toxicity, chloramphenicol is not a first-line antibiotic. It is
reserved for serious, life-threatening infections, particularly in situations where:
• The causative organism is resistant to safer antibiotics.
• The patient is allergic or intolerant to other drugs.

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Main Indications:
• Bacterial meningitis (especially in β-lactam-allergic patients)
• Anaerobic brain abscesses
• Rickettsial infections (when tetracyclines contraindicated)
• Brucellosis
• Typhoid fever (especially drug-resistant cases)
• Endophthalmitis (via intraocular injection or systemic)
• Topical for conjunctivitis and blepharitis
6. Side Effects
Dose-Dependent Toxicities:
• Bone marrow suppression: Reversible; seen with high or prolonged doses.
• Aplastic anemia: Rare but often fatal; idiosyncratic and unpredictable.
Other Adverse Effects:
System Effect
Gray baby syndrome: Due to immature liver metabolism → cyanosis, hypotension,
Neonates
shock
Gastrointestinal Nausea, vomiting, diarrhea
CNS Confusion, irritability (especially in renal dysfunction)
Hematological Leukopenia, thrombocytopenia (reversible); aplastic anemia (irreversible)
Drug Inhibits liver enzymes (CYP450): increases plasma levels of phenytoin, warfarin,
Interactions etc.
Requires close blood count monitoring if used for more than 7–10 days.
7. Contraindications
• Neonates (<2 weeks) – due to risk of Gray Baby Syndrome
• History of chloramphenicol-induced aplastic anemia
• Pre-existing bone marrow depression
• Pregnancy and lactation (systemic use)
• Use in minor infections or where safer alternatives are available
8. Pharmacological Actions Across Body Systems
System Pharmacological Action
CNS High CSF levels → useful in meningitis
Blood Suppresses hematopoiesis via mitochondrial inhibition
Eye Used topically for conjunctivitis and keratitis
Liver Metabolized by glucuronidation
Renal Not significantly excreted unchanged – dose adjustment not usually required in renal failure
GI Tract Effective in typhoid and anaerobic GI infections
9. Chloramphenicol and the Principles of Chemotherapy
Principle Application

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Targets bacterial 50S ribosome; minimal action on eukaryotic 80S ribosomes

Selective Toxicity
but affects mitochondria
Therapeutic Index Narrow – requires therapeutic monitoring to prevent serious toxicity
Spectrum of
Broad-spectrum coverage → useful in polymicrobial or unknown infections
Activity
Resistance Bacteria may produce chloramphenicol acetyltransferase, which inactivates
Mechanism the drug
Reserved for serious infections to avoid resistance and protect hematological
Stewardship Role
safety

Macrolides

1. Definition: Macrolides are a class of bacteriostatic antibiotics that inhibit bacterial

protein synthesis by binding to the 50S ribosomal subunit. They are named for their
large macrocyclic lactone ring (14-, 15-, or 16-membered), to which one or more sugar
moieties (usually desosamine and cladinose) are attached.
They are active against:
• Gram-positive cocci
• Atypical pathogens (Mycoplasma, Chlamydia, Legionella)
• Some Gram-negative organisms
Prototype: Erythromycin
Semisynthetic derivatives: Clarithromycin, Azithromycin, Roxithromycin
2. Classification & Dose
Classification Based on Structure:
Group Examples Ring Size
Natural macrolides Erythromycin 14-membered
Semisynthetic macrolides Clarithromycin, Roxithromycin 14-membered
Azalides Azithromycin 15-membered
Ketolides Telithromycin 14-membered with ketone
Doses:
Drug Dose
Erythromycin 250–500 mg every 6 hours (max 4 g/day)
Clarithromycin 250–500 mg twice daily
Azithromycin 500 mg OD for 3–5 days or 1 g once (STIs)
Dosing varies depending on infection site and severity.
Source: KD Tripathi – Essentials of Medical Pharmacology, Ch. 58
3. Mechanism of Action (MOA)
Macrolides inhibit bacterial protein synthesis at multiple biological levels.
Macromolecular Level

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• Target: 50S ribosomal subunit of bacterial 70S ribosome.

• Action: Inhibit the translocation step of protein elongation.
• Mechanism:
o Peptidyl-tRNA cannot shift from the A-site to the P-site.
o Blocks exit of newly formed polypeptide chain.
o Causes accumulation of incomplete proteins → metabolic arrest.
Effect:
• Bacteriostatic at regular doses.
• Can be bactericidal at high doses or in organisms with high intracellular
accumulation (e.g., Mycoplasma pneumoniae).
Subcellular Level
• Impairs ribosomal functioning → interrupts protein biosynthesis, stopping
bacterial replication.
• Does not affect DNA or cell wall synthesis, unlike β-lactams or quinolones.
Systemic/Organ Level
• Excellent accumulation in lungs, skin, and soft tissues.
• Azithromycin accumulates in macrophages and fibroblasts, aiding in treatment
of intracellular infections.
• Limited CNS penetration → not used in meningitis.
[Reference: https://www.ncbi.nlm.nih.gov/books/NBK547636/
4. Therapeutic Effects
Effect Details
Effective against Streptococcus spp., Staphylococcus spp. (excluding MRSA),
Antibacterial
Mycoplasma, Chlamydia, Legionella, Helicobacter pylori.
Anti-
Azithromycin suppresses IL-6, TNF-α → useful in chronic lung diseases.
inflammatory
Post-antibiotic
Azithromycin continues working even after serum levels fall below MIC.
effect
5. Clinical Uses
Respiratory Tract Infections:
• Pharyngitis, tonsillitis, bronchitis, sinusitis
• Atypical pneumonia (e.g., Mycoplasma pneumoniae) → Azithromycin preferred
Skin and Soft Tissue Infections:
• Impetigo, cellulitis
• Particularly effective in penicillin-allergic patients

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Genital Tract Infections:

• Chlamydia trachomatis: Azithromycin 1 g single dose
• Gonorrhea (in combination)
Helicobacter pylori infection: Clarithromycin is part of triple therapy (with PPI and
amoxicillin/metronidazole)
Other:
• Whooping cough (erythromycin)
• Campylobacter enteritis
• Prophylaxis in HIV: Azithromycin for MAC (Mycobacterium avium complex)
Useful in both treatment and prevention of intracellular and atypical bacterial infections.
6. Side Effects
System Side Effect
GI Tract Nausea, vomiting, diarrhea (erythromycin stimulates motilin receptors)
Liver Cholestatic hepatitis (mainly with erythromycin estolate)
Cardiac QT prolongation → Torsades de Pointes (especially with azithromycin)
Auditory Temporary hearing loss at high doses (reversible)
Drug Inhibit CYP3A4 (Erythromycin > Clarithromycin) → increased warfarin, phenytoin
interactions levels
Azithromycin does not inhibit CYP3A4, making it safer with other drugs.
7. Indications and Contraindications
Indications:
• Respiratory tract infections (especially in penicillin allergy)
• Sexually transmitted infections (chlamydia, gonorrhea)
• Helicobacter pylori-associated ulcers
• Prophylaxis against MAC in HIV
Contraindications:
• History of macrolide allergy
• Liver dysfunction
• Concomitant QT-prolonging drugs (e.g., amiodarone)
• Use with strong CYP3A4 inhibitors (for erythro/clarithromycin)
8. Pharmacological Actions Across Systems
System Macrolide Action
Respiratory High lung tissue levels; excellent in pneumonia and bronchitis
GI Tract Prokinetic effect via motilin receptor activation (esp. erythromycin)
Liver Hepatic metabolism; some forms hepatotoxic (monitor LFTs)
Immune system Immunomodulatory; suppress pro-inflammatory cytokines
Cardiovascular Potential to prolong QT interval (esp. azithromycin, clarithromycin)

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9. Chemotherapy Principles and Macrolides

Principle Macrolide Application
Selective toxicity Binds to bacterial 50S subunit → no effect on human 80S ribosome
Tissue selectivity Accumulates in lung, macrophages → targets intracellular pathogens
Therapeutic index Moderate → higher with azithromycin, lower with erythromycin
Resistance Resistance via methylation of ribosomal RNA (erm gene), drug efflux (mef gene),
development enzymatic inactivation
Rational use Avoid in viral infections; monitor ECG and liver function in high-risk patients
KD Tripathi highlights macrolides as a valuable alternative when β-lactams cannot be used
and emphasizes responsible prescribing to delay resistance.

Quinolones

1. Definition: Quinolones are synthetic broad-spectrum antibacterial agents that

inhibit bacterial DNA replication, transcription, repair, and recombination by targeting
the enzymes DNA gyrase (topoisomerase II) and topoisomerase IV. The more advanced
fluoroquinolones (like ciprofloxacin, levofloxacin, and moxifloxacin) include a fluorine
atom that enhances antibacterial potency and tissue penetration.
Principle of chemotherapy applied: Selective toxicity – these drugs inhibit enzymes
unique to bacteria, making them selectively toxic to microbes, not humans.
2. Classification with Dose
Based on Antibacterial Spectrum and Generation:
Common Adult
Generation Examples Spectrum
Dose
1st Nalidixic acid Gram-negative bacilli (esp. UTIs) 500–1000 mg/day
Ciprofloxacin, Broader Gram-negative, limited Gram- 500–750 mg
2nd
Norfloxacin positive twice/day
Enhanced Gram-positive (e.g. S. 500–750 mg
3rd Levofloxacin
pneumoniae) once/day
4th Moxifloxacin Gram-positive, anaerobes, atypicals 400 mg once/day
Reference: KD Tripathi & Padmaja Udaykumar Pharmacology Textbooks.
3. Mechanism of Action
A. Macromolecular Level
• DNA Gyrase (Topoisomerase II): Unwinds supercoiled DNA ahead of replication
fork (especially targeted in Gram-negatives).
• Topoisomerase IV: Separates newly replicated DNA strands during bacterial cell
division (primarily targeted in Gram-positives).

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Quinolones stabilize the enzyme-DNA complex after DNA cleavage, preventing re-
ligation, resulting in double-stranded DNA breaks that kill the bacteria.
Principle: Quinolones act at critical macromolecular targets essential to bacterial survival
and replication.
B. Subcellular Level
• Interrupts nucleoid formation in bacteria.
• Triggers bacterial SOS repair response, which fails due to persistent DNA damage,
leading to cell lysis or apoptosis-like death.
C. Organ System Level (in humans)
• Not active on human cells due to absence of bacterial topoisomerases.
• Achieves therapeutic levels in lungs, kidneys, prostate, bones, CSF (especially
levofloxacin and moxifloxacin).
4. Therapeutic Effects
• Bactericidal, concentration-dependent killing.
• Broad coverage:
o Gram-negatives: E. coli, Klebsiella, Pseudomonas.
o Gram-positives: Streptococcus pneumoniae (esp. newer generations).
o Atypicals: Mycoplasma, Legionella, Chlamydia.
o Anaerobes: (moxifloxacin).
Post-antibiotic effect (PAE): Bacterial suppression persists even after drug concentration
drops below MIC.
5. Clinical Uses
System Conditions Treated
Genitourinary UTIs, prostatitis, pyelonephritis
Respiratory CAP, HAP, sinusitis, bronchitis (esp. levofloxacin/moxifloxacin)
Gastrointestinal Traveller’s diarrhea, shigellosis, cholera
Soft tissue/Bone Skin infections, osteomyelitis
STDs Gonorrhea (limited use due to resistance)
Bioterrorism Anthrax prophylaxis (ciprofloxacin)
6. Side Effects
Common:
• GI upset (nausea, diarrhea)
• CNS: Headache, dizziness, insomnia
Serious:
• Tendon rupture (esp. Achilles tendon, more common in elderly)

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• QT prolongation → arrhythmias
• Peripheral neuropathy
• Seizures (in those predisposed)
• Hepatotoxicity
• C. difficile–associated diarrhea
FDA warns against unnecessary use due to these risks, especially for uncomplicated
infections (FDA safety update).
7. Indications and Contraindications
Indications:
• Severe or resistant bacterial infections
• Prophylaxis in high-risk exposure (e.g., anthrax)
Contraindications:
• History of tendon disorders with quinolones
• Children (growth plate concerns)
• Pregnancy and breastfeeding (animal data suggest cartilage damage)
• Myasthenia gravis (may exacerbate muscle weakness)
8. Pharmacological Actions on Different Body Systems
A. Nervous System
• Can cross BBB → useful in CNS infections.
• May cause seizures in epileptics or those on NSAIDs.
B. Musculoskeletal System
• Cartilage toxicity seen in juvenile animals.
• Risk of tendonitis/tendon rupture in elderly or steroid users.
C. Cardiovascular System: QT prolongation especially with moxifloxacin → avoid in
patients with arrhythmias.
D. Hepatic & Renal
• Adjust dose in renal impairment (except moxifloxacin – mainly hepatic).
• Rare hepatotoxicity.
9. Role in Prevention and Treatment of Diseases
• Used in preventive prophylaxis for:
o Anthrax exposure
o Traveler’s diarrhea

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o Neutropenic patients (occasionally)

• Used in empirical therapy for:
o Febrile neutropenia
o Multidrug-resistant Pseudomonas
Demonstrates chemotherapy principle of maximum selective action with minimal
resistance and toxicity.
10. Principles of Chemotherapy Applied
Principle Application in Quinolones
Selective Toxicity Targets bacterial topoisomerases not present in humans
Broad Spectrum Covers Gram +/−, atypicals, some anaerobes (4th gen)
Minimal Resistance Newer generations less prone, but resistance emerging
Favorable PK/PD Good bioavailability, tissue penetration
Oral & Parenteral Use Available in both forms; facilitates outpatient management
References
1. NCBI Bookshelf - Fluoroquinolones
2. FDA Safety Announcement
3. KD Tripathi - Essentials of Medical Pharmacology
4. Padmaja Udaykumar – Pharmacology for Pharmacy Students
5. DrugBank – Ciprofloxacin

Fluoroquinolones

1. Definition: Fluoroquinolones are synthetic, bactericidal antibiotics that act by

inhibiting bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, enzymes
essential for DNA replication and transcription. They are chemically derived from
quinolones, with a fluorine atom added to enhance potency, tissue penetration, and
spectrum.
Chemotherapy Principle: Selective toxicity—targets enzymes not present in humans,
thus harming bacteria without affecting host cells. Source – NCBI Bookshelf
2. Classification (with examples and dosage)
Generational Classification:
Generation Examples Activity Spectrum Typical Dose
500–1000
1st Nalidixic acid Gram-negative rods (UTIs)
mg/day
Ciprofloxacin, Broader Gram-negative, mild Gram-
2nd 500–750 mg BID
Norfloxacin positive

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Improved Gram-positive, respiratory

3rd Levofloxacin 500–750 mg OD
infections
Moxifloxacin,
4th Gram-positives, atypicals, anaerobes 400 mg OD
Gemifloxacin
Ciprofloxacin and levofloxacin are available in oral and IV forms.
Source – Medscape: Fluoroquinolones Overview
3. Mechanism of Action
A. Macromolecular Level
• Primary Targets:
o DNA Gyrase: Introduces negative supercoils into DNA (essential in Gram-
negative bacteria).
o Topoisomerase IV: Separates daughter DNA strands during replication (key
in Gram-positive bacteria).
Action: Fluoroquinolones trap these enzymes in a cleaved complex with DNA,
preventing re-ligation. This leads to double-stranded DNA breaks, replication arrest, and
cell death.
B. Subcellular Level
• Fluoroquinolones block DNA metabolism.
• Activation of the SOS response in bacteria → leads to halted cell cycle and
apoptosis-like bacterial death.
C. Organ System Level
• High tissue penetration:
o Lungs: For pneumonia, bronchitis
o Kidneys: For pyelonephritis
o Prostate: For prostatitis
o Bone: For osteomyelitis
Excellent oral bioavailability makes them suitable for step-down therapy.
4. Therapeutic Effects
• Bactericidal: Rapid killing of bacteria through DNA damage.
• Post-Antibiotic Effect (PAE): Continued bacterial suppression even after plasma
levels decline.
• Broad Spectrum: Active against:
o Gram-negative bacilli: E. coli, Klebsiella, Pseudomonas
o Gram-positive cocci: Streptococcus pneumoniae (esp. levo/moxi)

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o Atypicals: Mycoplasma, Chlamydia, Legionella

o Anaerobes: (mainly 4th gen like moxifloxacin)
5. Clinical Uses
System Indications
Urinary Tract Pyelonephritis, complicated UTIs, prostatitis
Respiratory CAP, HAP, sinusitis, bronchitis (levo/moxifloxacin)
Gastrointestinal Shigella, Salmonella, traveler's diarrhea
Bone/Joint Osteomyelitis, septic arthritis
Skin Diabetic foot infections, cellulitis
STDs Gonorrhea (resistance limits use)
Prophylaxis Anthrax exposure (Ciprofloxacin)
CDC Anthrax Guidelines
6. Side Effects
Common:
• Nausea, vomiting
• Headache, dizziness
• Rash
Serious:
• Tendon rupture (esp. Achilles tendon)
• QT prolongation → may cause torsades de pointes
• Peripheral neuropathy
• Seizures (in predisposed patients)
• CNS toxicity: Hallucinations, psychosis (elderly, renal impairment)
• Dysglycemia: Hypo-/hyperglycemia (esp. in diabetics)
FDA Safety Communication – Fluoroquinolones
7. Indications and Contraindications
Indications
• Serious infections caused by resistant Gram-negative bacteria
• Respiratory infections where alternatives are unsuitable
• Prophylaxis (e.g., anthrax, neutropenic patients)
Contraindications
• Allergy to fluoroquinolones
• Pregnancy and breastfeeding (cartilage toxicity risk)
• Children (<18 years) – unless no alternatives (e.g., cystic fibrosis, Pseudomonas)
• Myasthenia gravis – may exacerbate weakness

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8. Pharmacological Actions on Body Systems

System Effects
GI Tract Nausea, diarrhea, risk of C. difficile colitis
CNS Headache, insomnia, seizures (esp. in elderly or renally impaired)
Cardiovascular QT interval prolongation, arrhythmia risk (notably with moxifloxacin)
Musculoskeletal Tendonitis, tendon rupture (Black Box Warning)
Endocrine Glucose disturbances (gatifloxacin – withdrawn)
Renal Nephrotoxicity rare; adjust dose in renal impairment (except moxifloxacin)
9. Role in Prevention and Treatment
• Prophylactic Use:
o Anthrax exposure – 60-day course with ciprofloxacin.
o In neutropenic patients to prevent Gram-negative sepsis.
• Treatment: Key agents in hospital-acquired pneumonia, multi-resistant UTI,
and bone infections where other antibiotics fail.
Chemotherapy principle: Use of potent, tissue-penetrating, broad-spectrum agents with
cautious attention to resistance and toxicity.
10. Principles of Chemotherapy (Applied)
Principle Application in Fluoroquinolones
Selective toxicity Targets bacterial DNA gyrase/topoisomerase absent in humans
Broad-spectrum activity Acts on Gram +/−, atypicals, and some anaerobes
Bactericidal action Destroys bacteria rather than inhibiting growth
Resistance control Misuse can lead to rapid resistance (e.g., E. coli, Pseudomonas)
Pharmacokinetics/PD High oral bioavailability, wide tissue penetration, PAE
Rational Use Reserved for moderate-severe infections or resistant organisms

Tetracyclines

1. Definition: Tetracyclines are a group of broad-spectrum, bacteriostatic antibiotics that

inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, thereby
preventing aminoacyl-tRNA from attaching to the ribosome. They are active against a wide
range of organisms, including:
• Gram-positive and Gram-negative bacteria,
• Atypical organisms (Rickettsia, Chlamydia, Mycoplasma),
• Some protozoa (Plasmodium falciparum), and
• Anaerobes (partially).
Principle of chemotherapy applied: Selective toxicity — human cells lack the bacterial
30S ribosome, making tetracyclines highly selective. NCBI StatPearls: Tetracycline
2. Classification and Dose

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Tetracyclines are classified by duration of action, which depends on half-life and

pharmacokinetics.
A. Short-acting (6–8 hours)
• Tetracycline: 250–500 mg PO every 6 hours.
• Oxytetracycline: 250–500 mg PO every 6 hours.
B. Intermediate-acting (12 hours): Demeclocycline: 150 mg PO every 6 hours (used for
SIADH).
C. Long-acting (16–24 hours)
• Doxycycline: 100 mg PO/IV every 12 hours.
• Minocycline: 100 mg PO every 12 hours.
Long-acting tetracyclines are preferred due to better absorption, tissue penetration, and
convenience.
Cleveland Clinic – Tetracyclines
3. Mechanism of Action
A. Macromolecular Level
• Tetracyclines bind reversibly to the 30S ribosomal subunit.
• This blocks the attachment of aminoacyl-tRNA to the A site.
• As a result, elongation of the peptide chain is halted, leading to inhibition of
protein synthesis. Mechanism Explained – Wikipedia
B. Subcellular Level
• Accumulate in bacterial cytoplasm via active transport, a mechanism absent in
human cells.
• Once inside, they interrupt translation, leading to cessation of bacterial metabolism
and division.
• They are bacteriostatic, not bactericidal — do not kill bacteria directly, but prevent
multiplication.
C. Organ-System Level
Tetracyclines exhibit good tissue penetration:
• Accumulate in lungs, bronchial mucosa → used in respiratory infections.
• Cross placenta and enter breast milk.
• Bind to developing teeth and bones, leading to discoloration and growth
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4. Therapeutic Effects
• Inhibit bacterial growth across a broad range of organisms.
• Useful against atypical organisms (not responsive to β-lactams).
• Some tetracyclines (esp. doxycycline) have anti-inflammatory effects — helpful in
acne and rosacea.
Notable for intracellular penetration, effective against rickettsial and chlamydial
infections.
5. Clinical Uses
Indication Tetracycline Used
Rickettsial infections (e.g. typhus) Doxycycline
Chlamydial STDs Doxycycline
Acne vulgaris Doxycycline/Minocycline (oral)
Malaria prophylaxis Doxycycline
Brucellosis Doxycycline + rifampin
Helicobacter pylori (as part of regimen) Tetracycline
Cholera, plague, leptospirosis Tetracycline or doxycycline
MedlinePlus – Tetracycline Us
6. Side Effects
Common
• Nausea, vomiting, epigastric discomfort.
• Diarrhea due to alteration of normal gut flora.
Photosensitivity: Especially with doxycycline — increased risk of sunburn.
Teeth and Bone Effects
• Deposition in growing bones and teeth in children and fetuses.
• Causes permanent yellow-gray discoloration of teeth.
Hepatotoxicity: More common with high doses, especially in pregnancy.
Vestibular Effects: Minocycline → dizziness, ataxia (dose-dependent).
Renal Effects: Outdated tetracyclines cause Fanconi syndrome (proximal renal tubule
damage).
7. Indications and Contraindications
Indications
• Infections by atypical organisms (e.g., Chlamydia, Mycoplasma).
• Acne, periodontitis, rickettsial fevers.

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• Malaria prophylaxis (doxycycline).

• Alternative in penicillin allergy.
Contraindications
• Pregnancy: crosses placenta → fetal bone/teeth effects.
• Children <8 years: due to risk of dental staining.
• Hepatic failure: especially with doxycycline.
• Hypersensitivity to tetracyclines.
8. Pharmacological Actions on Body Systems
Body System Effect
GI System Nausea, diarrhea, superinfection (C. difficile)
Hepatobiliary System Dose-related hepatotoxicity, especially in pregnancy
Renal System Fanconi syndrome (with expired tetracycline)
CNS Vestibular toxicity (minocycline)
Integumentary System Photosensitivity, rash
Skeletal/Dental System Bone growth inhibition and dental discoloration in fetuses/young children
9. Prevention and Treatment of Diseases
Preventive Roles
• Malaria prophylaxis: especially in Plasmodium falciparum–endemic areas.
• Traveler's diarrhea: older practice; now rarely used due to resistance.
• Anthrax exposure: doxycycline used in post-exposure prophylaxis.
Treatment Roles
• Rickettsial diseases: preferred treatment.
• Chlamydial infections: doxycycline is first-line.
• Brucellosis and leptospirosis: part of combination therapy.
10. Principles of Chemotherapy Applied
Principle Tetracycline Application
Selective toxicity Targets bacterial ribosomes (30S), not human 80S ribosomes
Broad-spectrum Effective against many bacteria and atypicals
Bacteriostatic action Inhibits growth, allowing immune clearance
Resistance concern Widespread resistance due to efflux pumps, ribosome protection proteins
Pharmacokinetics Good oral absorption, wide tissue distribution; food impairs some absorption
Toxicity awareness Dose and population-specific toxicities must be considered
References
1. KD Tripathi – Essentials of Medical Pharmacology, 6th ed.
2. Padmaja Udaykumar – Pharmacology for Pharmacy Students
3. StatPearls – Tetracycline
4. Drugs.com – Tetracycline
5. Cleveland Clinic – Tetracycline

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6. Wikipedia – Tetracycline Antibiotics

Aminoglycosides

1. Definition: Aminoglycosides are a class of bactericidal antibiotics that inhibit

bacterial protein synthesis by irreversibly binding to the 30S subunit of prokaryotic
ribosomes. They are particularly effective against aerobic Gram-negative bacilli, though
synergistic with β-lactams against some Gram-positive organisms (e.g., Enterococcus).
Their activity depends on oxygen-dependent active transport, making them ineffective
against anaerobic organisms.
Principle of chemotherapy: Selective toxicity – they specifically target prokaryotic
ribosomes, which differ structurally from human ribosomes.
NCBI StatPearls – Aminoglycosides
2. Classification and Dose
Classification (by source or type):
Group Drugs
Natural (Streptomyces) Streptomycin, Neomycin
Natural (Micromonospora) Gentamicin, Sisomicin, Netilmicin
Semisynthetic Amikacin (from kanamycin), Tobramycin
Dosages (adjusted based on renal function):
Drug Dose Range Notes
Gentamicin 3–5 mg/kg/day IV or IM divided q8h Peak: 5–10 μg/mL, Trough: <2 μg/mL
Amikacin 15 mg/kg/day IV/IM divided q12h Broadest spectrum; reserved for resistance
Tobramycin Similar to gentamicin Preferred in Pseudomonas lung infections
Streptomycin 15 mg/kg/day IM Used in TB, plague, tularemia
Neomycin 1–2 g/day orally or topical only Toxic systemically; pre-surgical gut sterilization
3. Mechanism of Action
A. Macromolecular Level
Aminoglycosides bind irreversibly to the 16S rRNA portion of the 30S subunit, inhibiting
the initiation complex and causing:
• Misreading of mRNA → abnormal protein synthesis.
• Premature termination of translation.
• Formation of nonfunctional/misfolded proteins → cell membrane damage.
This action is bactericidal (unusual for protein synthesis inhibitors).
B. Subcellular Level

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• Transported actively into bacteria via oxygen-dependent transport → ineffective in

anaerobes or acidic, hypoxic tissues.
• Create pores in the bacterial cytoplasmic membrane, enhancing permeability and
accelerating cell death.
C. Organ-System Level
• Poor oral absorption → given parenterally for systemic infections.
• Distributes to extracellular fluid, renal cortex, and endolymph of inner ear,
explaining:
o Nephrotoxicity
o Ototoxicity
4. Therapeutic Effects
Pharmacological characteristics:
• Bactericidal, concentration-dependent killing.
• Exhibit post-antibiotic effect (PAE): persistent suppression of bacterial growth
after drug concentration falls below MIC.
• Synergy with β-lactam antibiotics against Gram-positive cocci.
5. Clinical Uses
Clinical Condition Aminoglycoside Used
Severe Gram-negative infections Gentamicin, Tobramycin
Tuberculosis (2nd-line) Streptomycin
Plague, Tularemia Streptomycin
Endocarditis (with penicillin/ampicillin) Gentamicin
Neonatal sepsis Amikacin
Cystic fibrosis (inhalation route) Tobramycin
Preoperative bowel sterilization Neomycin (oral)
Used in hospital-acquired infections, especially resistant Pseudomonas, Acinetobacter,
and Klebsiella.
6. Side Effects
Toxicity is dose- and duration-dependent:
Toxicity Type Details
Nephrotoxicity Proximal tubular necrosis; reversible; risk ↑ with cephalosporins, NSAIDs
Ototoxicity Irreversible cochlear (hearing) or vestibular (balance) damage
Neuromuscular Blockade Rare; may cause apnea, especially in patients on neuromuscular blockers
Hypersensitivity Rash, fever
FDA Label – Aminoglycoside Toxicity
7. Indications and Contraindications
Indications

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• Life-threatening aerobic Gram-negative infections

• Sepsis, peritonitis, pneumonia (hospital-acquired)
• Endocarditis (in synergy)
• Multidrug-resistant TB (streptomycin)
• MDR Gram-negative infections
Contraindications
• Renal failure (unless dose adjusted or monitored)
• Preexisting hearing impairment
• Myasthenia gravis (potentiates weakness)
• Pregnancy (Category D — ototoxicity in fetus)
8. Pharmacological Actions on Body Systems
System Action / Risk
Renal Accumulates in proximal tubules → nephrotoxicity
Auditory Inner ear hair cell damage → hearing loss
Vestibular Labyrinthine injury → vertigo, ataxia
Neuromuscular junction Inhibits acetylcholine release → paralysis (rare)
Gastrointestinal (oral Local flora suppression → ammonia reduction (hepatic
neomycin) encephalopathy)
9. Pharmacological Role in Prevention & Treatment
Prevention
• Pre-op GI decontamination (neomycin + erythromycin)
• Tuberculosis prevention in contacts (when isoniazid resistance present)
Treatment
• Nosocomial infections (e.g., ventilator-associated pneumonia)
• Multidrug-resistant Enterobacteriaceae
• Severe UTI in hospitalized patients
• Tularemia, plague, brucellosis: streptomycin
Rational Use Principle: Combine with β-lactams for synergy and avoid monotherapy to
reduce resistance.
10. Principles of Chemotherapy – Applied
Chemotherapy Principle Aminoglycoside Application
Selective toxicity Targets bacterial 30S ribosome — not present in human cells
Bactericidal Irreversible binding + misreading = cell death
Concentration-dependent killing Higher peak = better killing + longer PAE
Synergism With β-lactams → better Gram-positive activity
Resistance minimization Avoid prolonged monotherapy; monitor trough levels
Toxicity management Monitor renal function, auditory symptoms, and blood drug levels
References

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1. KD Tripathi – Essentials of Medical Pharmacology (6th ed.)

2. Padmaja Udaykumar – Pharmacology for Pharmacy Students
3. NCBI Bookshelf – Aminoglycosides
4. Drugs.com – Aminoglycosides
5. Merck Manual – Aminoglycosides

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