Write a short note on mechanism of action, pharmacokinetics, Indications and adverse effects of aminoglycosides 2nd yr mbbs refer kdt

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Aminoglycosides — Short Note

(Based on Katzung's Basic & Clinical Pharmacology 16e + Medical Microbiology 9e)

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Streptomycin, Gentamicin, Tobramycin, Amikacin, Neomycin, Kanamycin, Netilmicin

1. Mechanism of Action

Aminoglycosides are bactericidal, irreversible inhibitors of protein synthesis. Their action involves two phases:

Step 1 — Entry into the cell:

Drug passively diffuses through porin channels in the outer membrane (gram-negative bacteria)
Then actively transported across the cytoplasmic membrane via an oxygen-dependent, energy-dependent process driven by the transmembrane electrochemical gradient (coupled to a proton pump)
This explains why anaerobes are inherently resistant (no O₂ → no energy → no uptake)
Cell wall–active drugs (penicillin, vancomycin) enhance aminoglycoside entry → basis of synergism

Step 2 — Intracellular action (30S ribosome binding): Once inside, aminoglycosides bind irreversibly to 30S ribosomal subunit proteins and inhibit protein synthesis in three ways:

Blockade of initiation complex formation (no peptide chain starts)
Misreading of mRNA → wrong amino acids incorporated → nonfunctional proteins
Breakup of polysomes into monosomes → protein synthesis halts

The overall effect is irreversible and leads to cell death (bactericidal).

Katzung's Basic and Clinical Pharmacology 16e, pp. 1286–1287

2. Pharmacokinetics

Parameter	Details
Absorption	Poorly absorbed from GIT (highly polar, cationic) → must be given parenterally (IV/IM) for systemic infections. Neomycin used orally for gut decontamination.
Distribution	Distributed in extracellular fluid; Vd ≈ 0.25 L/kg. Do not cross BBB (even in meningitis). Accumulate in renal cortex and perilymph/endolymph of inner ear (basis of toxicity).
Protein binding	Very low (< 10%)
Metabolism	Not metabolised — excreted unchanged
Excretion	Entirely by glomerular filtration; excretion directly proportional to creatinine clearance. Half-life = 2–3 hours (normal renal function); prolonged in renal impairment. Dose adjustment required in renal failure.
Post-antibiotic effect (PAE)	Prolonged PAE (several hours) → supports once-daily dosing
Concentration-dependent killing	Efficacy depends on peak:MIC ratio → higher single doses are more effective

Dosing:

Once-daily (extended interval) dosing preferred — equally effective, less toxic
Traditional dosing: Gentamicin/Tobramycin peak 5–10 mcg/mL, trough <2 mcg/mL
Trough >2 mcg/mL predictive of toxicity

Katzung's Basic and Clinical Pharmacology 16e, pp. 1288–1290

3. Indications

Clinical Use	Notes
Severe gram-negative infections	Enterobacteriaceae (E. coli, Klebsiella, Proteus), Pseudomonas, Acinetobacter — septicaemia, pneumonia, peritonitis
Enterococcal/streptococcal endocarditis	Combined with penicillin/ampicillin (synergism)
Staphylococcal endocarditis (prosthetic valve)	Combined regimen
Tuberculosis	Streptomycin (first-line in some regimens); Amikacin/Kanamycin for MDR-TB
Plague, tularaemia, brucellosis	Streptomycin / Gentamicin
Urinary tract infections	Gentamicin (severe/complicated cases)
Surgical bowel prep	Neomycin oral (reduces aerobic flora)
Hepatic encephalopathy	Neomycin oral (reduces coliform-ammonia production; now largely replaced by lactulose)
Topical	Neomycin — skin/eye infections; ear drops (gentamicin)
Leishmaniasis	Paromomycin (parenteral for visceral; topical for cutaneous)

Katzung's Basic and Clinical Pharmacology 16e, p. 1291; Medical Microbiology 9e, p. 202

4. Adverse Effects

A. Ototoxicity ⚠️ (Most important)

Affects cochlear (auditory) and vestibular divisions of CN VIII
Cochlear toxicity (hearing loss) — more common with neomycin, kanamycin, amikacin
Vestibular toxicity (vertigo, ataxia, nystagmus) — more common with streptomycin, gentamicin
Damage is irreversible — due to accumulation in perilymph/endolymph and destruction of hair cells
Risk factors: prolonged therapy (>5 days), high doses, elderly, renal impairment, concurrent loop diuretics (furosemide)

B. Nephrotoxicity ⚠️

Acute tubular necrosis (proximal tubule) — accumulation in renal cortex
Manifests as rising serum creatinine, casts in urine, reduced GFR
Usually reversible if drug stopped early
Risk factors: prolonged therapy, pre-existing renal disease, dehydration, concurrent nephrotoxins (amphotericin B, vancomycin, NSAIDs, cisplatin)

C. Neuromuscular Blockade

Rare but life-threatening — curare-like block → respiratory arrest
Occurs after rapid IV infusion, intraperitoneal instillation (post-operative), or in patients with myasthenia gravis
Mechanism: inhibition of Ca²⁺-dependent acetylcholine release at NMJ
Antidote: Calcium gluconate IV + Neostigmine

D. Hypersensitivity

Rare — more common with neomycin (topical use → contact dermatitis)
Cross-allergenicity within the class

E. Teratogenicity

Category D — can cause VIII nerve damage in the fetus; use with caution in pregnancy (streptomycin historically caused fetal deafness)

Summary Table

Feature	Detail
Class	Aminocyclitol-amino sugar antibiotics
Spectrum	Gram-negative bacilli, some gram-positive (synergy)
Mechanism	30S ribosome binding → bactericidal
Route	Parenteral (IV/IM); topical/oral for special uses
Excretion	Renal (unchanged)
Key toxicities	Ototoxicity, nephrotoxicity, NMJ blockade
Monitoring	Serum levels (peak & trough), renal function, hearing

Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition, Ch. 45 | Medical Microbiology 9e, Ch. 17 (KD Tripathi not available in the library; Katzung covers the same content as KDT for 2nd yr MBBS pharmacology)

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