Short Note: Sulphonamides, Cotrimoxazole, Cephalosporins & Macrolides

1. SULPHONAMIDES

Mechanism of Action

Human cells are unaffected because they obtain folate from diet rather than synthesising it de novo — this is the basis of selective toxicity.

Pharmacokinetics

Uses

• Urinary tract infections (E. coli)
• Nocardiosis (sulphadiazine)
• Toxoplasmosis (sulphadiazine + pyrimethamine — drug of choice)
• Burn wound prophylaxis — silver sulfadiazine cream
• Inflammatory bowel disease — sulfasalazine
• Ophthalmic infections — sulfacetamide eye drops
• Malaria — in combination (fansidar = sulfadoxine + pyrimethamine)

Adverse Effects

1. Crystalluria — acetylated metabolite precipitates in acidic urine → kidney damage; prevented by adequate hydration + alkalization of urine
2. Hypersensitivity — rashes, urticaria, angioedema, Stevens–Johnson syndrome, toxic epidermal necrolysis; photosensitivity
3. Haematological — haemolytic anaemia (especially in G6PD deficiency), granulocytopenia, thrombocytopenia, aplastic anaemia (rare)
4. Kernicterus — displaces bilirubin from albumin → brain damage in neonates; contraindicated in neonates and late pregnancy
5. Drug interactions — potentiate warfarin, methotrexate, hypoglycaemics

2. COTRIMOXAZOLE (TMP-SMX)

Mechanism of Action

PABA → Dihydrofolic acid → Tetrahydrofolic acid
        ↑                     ↑
     SMX blocks           TMP blocks
 (dihydropteroate        (dihydrofolate
   synthetase)            reductase)

Pharmacokinetics

Uses

• UTI — first-line for uncomplicated urinary tract infections
• PCP (Pneumocystis jirovecii pneumonia) — drug of choice for both treatment and prophylaxis in immunocompromised/HIV patients
• MRSA — cotrimoxazole has activity against community-acquired MRSA
• Traveller's diarrhoea (Shigella, E. coli)
• Nocardia infections
• Stenotrophomonas maltophilia infections (drug of choice)
• Toxoplasmosis prophylaxis in HIV
• Listeria, Salmonella typhi

Adverse Effects (same as sulfonamides + TMP-specific)

• All sulphonamide side effects (crystalluria, hypersensitivity, haemolytic anaemia in G6PD deficiency)
• TMP can cause folate deficiency → megaloblastic anaemia (countered by folinic acid, not folic acid)
• Hyperkalaemia — TMP blocks renal potassium secretion (resembles amiloride)
• Hyponatraemia — TMP resembles antidiuretic effect in some patients
• Contraindicated: neonates, late pregnancy, severe renal/hepatic failure

3. CEPHALOSPORINS

Mechanism of Action

Generations (Key Examples)

Pharmacokinetics

• Most are renally cleared → dose reduction in renal failure
• Ceftriaxone is excreted in bile (safe in renal failure; once-daily dosing, t½ ~8 h)
• Oral agents: cephalexin, cefaclor, cefuroxime axetil, cefixime
• Most do not penetrate CSF well except 3rd generation (ceftriaxone, cefotaxime) — used in bacterial meningitis
• Tubular secretion blocked by probenecid → increases serum levels

Uses (Summary)

• Surgical prophylaxis — cefazolin (1st gen) is gold standard
• Community-acquired pneumonia — ceftriaxone
• Bacterial meningitis — ceftriaxone/cefotaxime
• Gonorrhoea — ceftriaxone (IM, single dose)
• Typhoid — ceftriaxone/cefotaxime
• PID, intra-abdominal — cefoxitin (2nd gen)

Adverse Effects

1. Hypersensitivity — rashes, urticaria; ~1–2% cross-reactivity with penicillin (anaphylaxis rare)
2. Haematological — hypoprothrobinaemia, bleeding (MTT side chain: cefoperazone, cefotetan) — due to vitamin K antagonism
3. GI upset — nausea, diarrhoea; C. difficile colitis with broad-spectrum agents
4. Nephrotoxicity — especially when combined with aminoglycosides
5. Ceftriaxone — biliary sludge/pseudolithiasis (precipitates in bile as calcium salt); avoid in neonates (displaces bilirubin)
6. Disulfiram-like reaction — with alcohol (cefoperazone, cefotetan, moxalactam — MTT side chain)
7. Seizures — rare, at high doses or in renal failure

4. MACROLIDES

Mechanism of Action

Key Drugs

Pharmacokinetics (Azithromycin — most commonly used)

• Well absorbed orally; food may affect absorption
• Excellent tissue and intracellular (phagocyte) penetration
• Does not penetrate CSF
• Long t½ (~3 days) → 3-day or single-dose courses effective
• Primarily excreted in bile/faeces (minimal renal excretion)
• Does not inhibit CYP3A4 (unlike erythromycin and clarithromycin)

Uses

• Atypical pneumonia — drug of choice: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella
• Chlamydial infections — azithromycin 1 g single dose (urethritis/cervicitis)
• Whooping cough (Bordetella pertussis) — azithromycin/clarithromycin
• Diphtheria — erythromycin (drug of choice)
• Campylobacter gastroenteritis — azithromycin
• H. pylori eradication — clarithromycin-based triple therapy
• MAC (M. avium complex) prophylaxis in AIDS — azithromycin/clarithromycin
• Rheumatic fever prophylaxis — in penicillin-allergic patients
• Acne — topical erythromycin
• Scrub typhus (Orientia tsutsugamushi) — azithromycin
• Gastroparesis — erythromycin (prokinetic via motilin receptor agonism)

Adverse Effects

1. GI effects — most common; nausea, vomiting, diarrhoea, abdominal cramps (especially erythromycin — motilin receptor agonism); less with azithromycin
2. Hepatotoxicity — cholestatic jaundice (erythromycin estolate — most common); avoid in liver disease
3. QT prolongation — all macrolides block cardiac K⁺ channels → risk of torsades de pointes (especially with other QT-prolonging drugs); azithromycin associated with small increased risk of cardiac death
4. Drug interactions — erythromycin and clarithromycin are strong CYP3A4 inhibitors → increase levels of statins (↑ myopathy), warfarin, digoxin, cyclosporine, theophylline; azithromycin is safe (no CYP3A4 inhibition)
5. Ototoxicity — rare; high-dose IV erythromycin
6. Thrombophlebitis — IV administration

Quick Comparison Table

Short Note: Rheumatoid Arthritis — Pharmacological Basis & Methotrexate

PART 1: Pharmacological Basis of Treatment in Rheumatoid Arthritis

Pathogenesis (Brief)

1. An unknown trigger activates autoreactive CD4+ T cells in the synovium
2. Activated T cells stimulate macrophages → release of pro-inflammatory cytokines: TNF-α, IL-1, IL-6, IL-17
3. Cytokines activate synovial fibroblasts → produce matrix metalloproteinases (MMPs) → cartilage destruction
4. RANKL (expressed on T cells and fibroblasts) activates osteoclasts → bone erosion
5. B cells produce autoantibodies — Rheumatoid Factor (RF) and Anti-Citrullinated Protein Antibodies (ACPA/anti-CCP) — forming immune complexes that amplify inflammation

Pharmacological Rationale

• Immune cell overactivation (T cells, B cells, macrophages)
• Pro-inflammatory cytokine excess (TNF-α, IL-1, IL-6)
• Persistent synovial inflammation and pannus formation

NSAIDs and glucocorticoids relieve symptoms only. DMARDs actually retard structural (radiographic) progression — hence the cornerstone of RA management.

PART 2: Methotrexate (MTX) in Rheumatoid Arthritis

Position in RA Therapy

Mechanism of Action (At Anti-inflammatory / Low Doses)

At High (Anti-cancer) Doses:

• MTX is a folic acid analogue that binds with high affinity to dihydrofolate reductase (DHFR)
• Inhibits conversion: Dihydrofolate → Tetrahydrofolate (THF)
• THF is essential for de novo synthesis of purines, thymidylate (dTMP), serine, methionine
• Result: impaired DNA/RNA synthesis → cell death (S-phase specific)
• MTX forms polyglutamate derivatives (catalysed by FPGS) → retained intracellularly → prolonged action

At Low (Anti-rheumatic) Doses (7.5–25 mg/week):

• Inhibits AICAR transformylase (amino-imidazole-carboxamide-ribonucleotide transformylase)
• This leads to extracellular accumulation of adenosine (AMP)
• Adenosine acts on A2A/A2B receptors → potent anti-inflammatory effects:
  • Suppresses neutrophil, macrophage, dendritic cell, and lymphocyte function
  • Inhibits polymorphonuclear chemotaxis
  • ↓ TNF-α, IL-1, IL-6, IL-8 production
• Also directly inhibits lymphocyte proliferation and stimulates T-cell apoptosis
• Effects on DHFR are relatively minor at rheumatic doses

MTX → inhibits AICAR transformylase
         ↓
   AMP accumulates extracellularly
         ↓
   Adenosine receptor stimulation
         ↓
   ↓ TNF-α, IL-1, IL-6, neutrophil/lymphocyte function
         ↓
   Anti-inflammatory effect in RA synovium

Pharmacokinetics

Uses of Methotrexate (4 Key Uses)

1. Rheumatoid Arthritis (Primary indication)

• Dose: starts at 7.5 mg once weekly orally/SC; titrated up to 15–25 mg/week
• Reduces joint inflammation, pain, and stiffness
• Decreases rate of new bone erosions (radiographic progression)
• Used as monotherapy or combined with biologics (anti-TNF, abatacept, tocilizumab)
• Response may take 4–6 weeks to months

2. Psoriasis & Psoriatic Arthritis

• Low-dose MTX is effective for severe plaque psoriasis and psoriatic arthritis (peripheral joints)
• Inhibits epidermal keratinocyte proliferation

3. Malignancies (Oncology)

• Acute lymphoblastic leukaemia (ALL) — key component of consolidation/maintenance; given intrathecally for CNS prophylaxis
• Burkitt lymphoma, breast cancer, head & neck carcinomas, osteosarcoma, mycosis fungoides
• At high doses, must be followed by leucovorin (folinic acid) rescue within 24–42 hours

4. Other Inflammatory / Autoimmune Conditions

• Crohn's disease / IBD — low-dose MTX effective for steroid-dependent/refractory Crohn's
• Juvenile idiopathic arthritis (JIA)
• Systemic sclerosis (SSc) — effective for skin thickening
• Granulomatosis with polyangiitis (Wegener's), vasculitis, polymyositis, giant cell arteritis, SLE
• Ectopic pregnancy — single-dose IM MTX destroys trophoblastic tissue (inhibits rapidly dividing cells)

Adverse Effects

Monitoring (Essential)

• FBC, LFTs, serum creatinine — before starting and periodically
• Folic acid 1–5 mg/day (not folinic acid) co-prescribed to reduce GI and hepatic side effects without significantly reducing efficacy (reduces efficacy by only 10–18% but greatly reduces toxicity)
• Leucovorin rescue used with high-dose MTX (oncology doses)

Contraindications

• Pregnancy / lactation
• Significant renal impairment (primary excretory route)
• Hepatic disease / active alcohol use
• Immunodeficiency
• Blood dyscrasias / bone marrow suppression

Quick Summary Diagram

RA Inflammation → T cell activation → TNF-α / IL-1 / IL-6 ↑
                                              ↑
                               MTX → ↑ Adenosine (via AICAR)
                                    → ↓ Lymphocyte proliferation
                                    → ↓ Cytokine production
                                    → ↓ Neutrophil chemotaxis
                                    → ↓ Bone erosion (radiographic)