6.9: Gastrointestinal & Renal Therapeutics

6.9 Gastrointestinal & Renal Therapeutics

Gastrointestinal and renal diseases are common clinical scenarios that require complex drug management, strict dosing modifications, and chronic condition monitoring. Pharmacists must be competent in managing GERD, peptic ulcers, H. pylori, IBD, and chronic kidney disease.

---

1. Gastro-Oesophageal Reflux Disease (GERD) & Peptic Ulcer Disease (PUD)

Proton Pump Inhibitors (PPIs) and H2-Receptor Antagonists (H2RAs)

PPIs (e.g., esomeprazole, pantoprazole, omeprazole) are the most effective agents for suppressing gastric acid secretion by irreversibly inhibiting the H+/K+-ATPase pump in parietal cells.

• GERD Management: Standard guidelines recommend a "step-down" approach. Start with a standard daily PPI dose for 4-8 weeks to allow mucosal healing. If symptoms resolve, reduce to the lowest effective dose, transition to as-needed ("PRN") therapy, or cease.
• Long-Term PPI Risks: Long-term PPI use (> 1 year) is associated with several adverse outcomes:
  • Hypomagnesaemia: Impaired intestinal magnesium absorption. Monitor magnesium levels periodically.
  • Vitamin B12 Deficiency: Gastric acid is required to cleave B12 from dietary protein.
  • Osteoporosis and Fractures: Reduced calcium absorption; PPIs can inhibit osteoclast proton pumps.
  • Infection Risk: Increased susceptibility to Clostridioides difficile associated diarrhoea (CDAD) and community-acquired pneumonia due to loss of the gastric acid barrier.
• H2RAs (e.g., Famotidine): Alternative for mild GERD. Reversible blockers of H2 receptors. Long-term use can lead to tachyphylaxis (tolerance).

Helicobacter pylori Eradication

For patients with peptic ulcer disease confirmed to have H. pylori infection, eradication therapy is mandatory.

• First-Line Triple Therapy (7-day regimen in Australia):
  • PPI (e.g., Esomeprazole 20 mg, Omeprazole 20 mg, or Pantoprazole 40 mg) twice daily AND
  • Amoxicillin 1 g twice daily AND
  • Clarithromycin 500 mg twice daily.
• Penicillin Allergy Alternative: Replace amoxicillin with metronidazole 400 mg twice daily.
• Bismuth-based Quadruple Therapy: PPI + Bismuth subsalicylate + Tetracycline + Metronidazole for 10–14 days. Used if initial triple therapy fails or in areas of high clarithromycin resistance.

---

2. Inflammatory Bowel Disease (IBD)

IBD comprises Ulcerative Colitis (UC) and Crohn's Disease (CD). Medical therapy is divided into induction of remission and maintenance of remission.

Ulcerative Colitis (UC)

UC characteristically involves continuous inflammation of the colon and rectum.

• Mild-to-Moderate Active Disease:
  • Distal Disease (Proctitis/Left-sided colitis): Topical (rectal) 5-aminosalicylates (5-ASA) (e.g., mesalazine suppositories or enemas) are first-line. Rectal administration delivers high drug concentrations directly to the inflamed mucosa, offering superior efficacy and fewer side effects compared to oral routes.
  • Extensive/Pancolitis: Combine oral mesalazine (e.g., 2–4 g daily) with topical mesalazine.
• Moderate-to-Severe Flare:
  • Oral Corticosteroids (e.g., prednisolone 40 mg daily, tapered over 8 weeks) are used for the induction of remission only. They should never be used for maintenance therapy due to systemic adverse effects (osteoporosis, adrenal suppression, cataracts, metabolic disturbance).
  • Severe acute colitis requires hospitalization and intravenous methylprednisolone or hydrocortisone. If refractory, rescue therapy with infliximab (TNF-alpha inhibitor) or ciclosporin is initiated.
• Maintenance of Remission:
  • First-line: Mesalazine (oral or rectal, depending on disease extent).
  • Steroid-dependent or refractory cases: Thiopurines (azathioprine or mercaptopurine). Prior to initiation, check thiopurine methyltransferase (TPMT) activity to avoid severe myelosuppression in patients with genetic deficiencies.

Crohn's Disease (CD)

CD is characterized by transmural, patchy inflammation that can affect any part of the GIT.

• Induction: Corticosteroids (oral budesonide for ileocaecal disease; prednisolone for extensive disease). 5-ASAs are generally considered ineffective for Crohn's disease induction or maintenance.
• Maintenance: Azathioprine, mercaptopurine, methotrexate, or TNF-alpha antagonists (infliximab, adalimumab).

---

3. Chronic Kidney Disease (CKD) Management

CKD is defined by persistent kidney damage or eGFR < 60 mL/min/1.73m² for $\ge$ 3 months. Management focuses on slowing progression, treating complications, and modifying drug doses.

Slowing CKD Progression

• Renin-Angiotensin System (RAS) Blockade: ACE inhibitors (e.g., ramipril) or ARBs (e.g., irbesartan) are first-line for patients with hypertension and albuminuria (urine albumin-to-creatinine ratio, uACR $\ge$ 3 mg/mmol), with or without diabetes. RAS blockers dilate the efferent arteriole, reducing intraglomerular pressure and protein excretion.
  • Monitoring: Expect a serum creatinine rise of up to 30% and mild hyperkalaemia upon initiation. Exceeding a 30% rise or severe hyperkalaemia (> 5.5 mmol/L) requires dosage reduction or discontinuation.
• SGLT2 Inhibitors: Dapagliflozin or empagliflozin are now recommended in Australia to slow progression of CKD in patients with proteinuric CKD (eGFR $\ge$ 20–25 mL/min/1.73m²).

CKD-Mineral and Bone Disorder (CKD-MBD)

As kidney function declines, phosphate excretion drops, leading to hyperphosphataemia. Furthermore, impaired renal activation of vitamin D (conversion of calcidiol to calcitriol) causes hypocalcaemia. These disturbances stimulate excess Parathyroid Hormone (PTH) secretion, resulting in secondary hyperparathyroidism and high bone turnover.

• Phosphate Binders: Restrict dietary phosphate and initiate binders. Binders must be taken with or immediately after meals to bind dietary phosphate in the gut lumen, forming insoluble complexes excreted in faeces.
  • Calcium-Based Binders (e.g., Calcium Carbonate): Effective and low cost, but carry a risk of hypercalcaemia and vascular calcification.
  • Non-Calcium-Based Binders (e.g., Sevelamer, Lanthanum): Preferred in patients with hypercalcaemia or arterial calcification.
• Active Vitamin D (Calcitriol): Given to treat hypocalcaemia and directly suppress PTH secretion. Standard cholecalciferol (inactive Vitamin D3) is insufficient for treating secondary hyperparathyroidism in advanced CKD.

Renal Dosing Adjustments

Many drugs accumulate in renal impairment, increasing toxicity.

• Estimating Kidney Function: In Australia, the Cockcroft-Gault equation is traditionally used to calculate creatinine clearance (CrCl) for drug dosing, whereas eGFR (normalized for body surface area) is used for staging CKD.
• High-Risk Renal Drugs requiring adjustment/avoidance:
  • Metformin: Max dose 1 g daily if CrCl 30–60 mL/min; contra-indicated if CrCl < 30 mL/min (lactic acidosis risk).
  • Gabapentin / Pregabalin: Require substantial dose reductions due to neurotoxicity/somnolence risks.
  • DOACs (e.g., Apixaban, Rivaroxaban): Require dosing reductions or avoidance (especially dabigatran) in severe renal impairment.
  • Enoxaparin: Reduce dose or switch to unfractionated heparin when CrCl < 30 mL/min.