Core pharmacology

Class Group

ANTIBIOTIC:
ANTIFOLATE + SULFONAMIDE

Legacy Cicm Level

Level 3

Introduction

Sulphamethoxazole (an intermediate half life, slow oral absorbing sulfonamide) and trimethoprim

Mechanism of action

MOA: Selectively inhibits bacterial dihydrofolate reductase, which inhibits purine synthesis and therefore DNA synthesis

Antimicrobial Spectrum

1. Gram positives- including MSSA and MRSA (though increasing resistance)
2. Gram negatives- including Moraxella, Klebsiella, haemophilus and some E. Coli
3. Non-bacterial pathogens- pneumocystis and toxoplasma

Adverse Effects Toxicity

1. Megaloblastic anaemia through to aplastic anaemia and neutropenia
2. Sulfa cross reactivity hypersensitivity
3. Dermatological reactions
- Uncomplicated maculopapular through to life threatening TENs (SMX)
4. Pseudorenal failure- trimethoprim inhibits proximal secretion of creatinine
5. Hyperkalaemia and hyponatraemia
- Believed to be an anti-aldosterone effect
- Risk highest in renal failure or patients with HIV/AIDs
6. AIN or crystalluriea (SMX)
7. Potentiates warfarin

Absorption

100% BA

Distribution

Trimethoprim is more lipid soluble than sulphamethoxazole, and therefore has a larger Vd. The drugs are combined as 1:5 parts trimethoprim:sulphamethoxazole. This results in a plasma concentration ratio of 1:20, which is optimal for synergism

Protein binding

TMP 45% PB
SMX 66% PB

Volume of distribution

TMP Vd 2 L/kg
SMX Vd 0.23 L/kg

Metabolism

TMP 5-15% to inactive metab
SMX Extensive metabolism – major metab acetyl derivative

Excretion

Both eliminated renally (TMP unchanged, SMX as metabolites)

Half-life

TMP 11hrs
SMX 9 hrs
Dose reduction if CrCl < 30 ml/min