Amoxicillin

Pharmacological Actions
Amoxicillin is a beta-lactam antibiotic belonging to the aminopenicillin class, primarily exerting its pharmacological action by inhibiting bacterial cell wall synthesis. It achieves this by competitively binding to penicillin-binding proteins (PBPs), specifically PBP1 and other high molecular weight PBPs, which are crucial for glycosyltransferase and transpeptidase reactions. These reactions cross-link D-alanine and D-aspartic acid in the bacterial cell wall, and their inhibition prevents proper cell wall formation. As a result, bacteria upregulate autolytic enzymes, leading to cell wall disruption and bactericidal activity against susceptible gram-positive and some gram-negative bacteria, such as Streptococcus species, Listeria monocytogenes, and Enterococcus spp.
While its primary action is antibacterial, amoxicillin does not exhibit significant pharmacological effects on human cells beyond potential side effects, which are not considered intended actions. Its spectrum of activity includes coverage against beta-lactamase-negative isolates, making it effective for infections like ear, nose, throat, lower respiratory, and urinary tract infections, as well as Helicobacter pylori eradication.
Pharmacokinetic Parameters
The pharmacokinetic profile of amoxicillin is well-documented, with the following key parameters:

Half-Life: The elimination half-life is approximately 61.3 minutes, indicating rapid clearance from the body, which necessitates frequent dosing to maintain therapeutic levels.
Bioavailability: Oral bioavailability is reported to vary across studies, with values ranging from 60% to 93%. Recent sources, such as DrugBank and the electronic medicines compendium (emc), suggest approximately 60-70%, while older studies (e.g., a 1977 PMC article) reported 93% based on AUC comparisons with intravenous administration. This discrepancy may reflect differences in formulations or study conditions, with the consensus leaning toward 60-70% for standard oral administration. The absorption is rapid, with peak plasma concentrations (Tmax) typically reached within 1-2 hours, and is not significantly influenced by food intake, though some sources suggest taking it with food for better absorption.
Detailed Pharmacokinetic Values:

For a 250 mg oral dose: Cmax 3.93 ± 1.13 mg/L, Tmax 1.31 ± 0.33 hours, AUC 27.29 ± 4.72 mg*h/L.
For an 875 mg oral dose: Cmax 11.21 ± 3.42 mg/L, Tmax 1.52 ± 0.40 hours, AUC 55.04 ± 12.68 mg*h/L.
Volume of distribution: 27.7 L, indicating moderate distribution into body tissues.
Protein binding: Approximately 17-20%, suggesting minimal binding and high free drug availability.
Clearance: Mean clearance is 21.3 L/h, with 70-78% excreted unchanged in urine within 6-8 hours, primarily via renal elimination.

Other Routes: Intramuscular administration shows high bioavailability, with AUC 92% of intravenous, and urinary recovery at 91%, indicating complete and reliable absorption compared to oral routes.

Dosage Guidelines
Dosing recommendations vary by age, weight, infection severity, and renal function, with the following details:

For mild to moderate infections (e.g., ear, nose, throat, genitourinary, skin): 500 mg every 12 hours or 250 mg every 8 hours.
For severe infections: 875 mg every 12 hours or 500 mg every 8 hours, with durations typically 10-14 days for certain conditions.
For Helicobacter pylori (triple therapy): 1 g every 12 hours with lansoprazole and clarithromycin for 14 days.
For prophylaxis (e.g., infective endocarditis): 2 g 30-60 minutes before procedure.

For infants <3 months: Up to 30 mg/kg/day divided every 12 hours.
For children >3 months and <40 kg, mild to moderate: 25 mg/kg/day divided every 12 hours or 20 mg/kg/day divided every 8 hours; severe: 45 mg/kg/day divided every 12 hours or 40 mg/kg/day divided every 8 hours.
For community-acquired pneumonia (off-label, ≥3 months): Up to 90 mg/kg/day divided every 12 hours, not exceeding 4,000 mg/day, for 10 days.

The safe range aligns with standard doses, typically 250-875 mg every 8-12 hours for adults, depending on severity. The minimum effective dose varies by infection, often starting at 250 mg every 8 hours for mild cases.

The usual maximum is 875 mg per dose or 2 g/day for suspension, but in high-risk cases (e.g., acute bacterial sinusitis), doses up to 4 g/day (2 g twice daily) may be used, though not routinely recommended without medical oversight.

LD50 in rats is >15 g/kg orally and >2000 mg/kg dermally, indicating low acute toxicity. For humans, therapeutic doses are far below these levels, suggesting a wide safety margin.

Research, including a prospective study of 51 pediatric patients, suggests overdoses <250 mg/kg are not associated with significant clinical symptoms. For a 70 kg adult, this equates to ~17.5 g, far above typical doses. Higher doses may lead to renal issues like interstitial nephritis or crystalluria, potentially causing kidney failure, but these are reversible with cessation and supportive care. Poison control notes that overdoses are rarely dangerous, with symptoms like stomach upset and diarrhea, and serious effects require very high doses.