33.4 Genitourinary Pharmacology II: Kidney Stones, Nephrotic and Nephritic Disease, Drug Dosing in Kidney Disease and Hyperkalemia, Benign Prostatic Hyperplasia, Erectile Dysfunction, Renal Cell Carcinoma and Prostate Cancer Therapy

Why this area matters

The TOS genitourinary area also covers:

• kidney stones;
• nephrotic and nephritic disease;
• prostatic diseases;
• renal cell carcinoma and prostate cancer.

Chronic kidney disease is common in the Philippines and is a leading reason for dialysis. Drug dosing must therefore account for renal function, and nephrotoxic drugs must be avoided.

Kidney stones

• Acute renal colic:
  • NSAIDs (diclofenac, ketorolac) are first-line; they reduce ureteral spasm and work as well as or better than opioids;
  • antiemetics;
  • medical expulsive therapy with tamsulosin for distal ureteral stones of 5 to 10 mm;
  • urgent drainage if infection complicates obstruction.
• Prevention by stone type:
  • calcium oxalate or phosphate stones:
    • fluids (urine output over 2 to 2.5 L a day);
    • normal dietary calcium, but low salt and low animal protein;
    • thiazides for hypercalciuria;
    • potassium citrate for hypocitraturia;
    • allopurinol if there is hyperuricosuria;
  • uric acid stones: urinary alkalinization with potassium citrate and allopurinol;
  • struvite stones: removal and treatment of the urease-producing infection;
  • cystine stones: alkalinization, high fluid intake and chelators such as tiopronin.

Nephrotic and nephritic disease

• Supportive care in proteinuric disease:
  • ACE inhibitor or ARB to reduce proteinuria and slow progression, with SGLT2 inhibitors in diabetic and other CKD;
  • loop diuretics for edema, with salt restriction;
  • statins for hyperlipidemia;
  • anticoagulation for high thrombosis risk (membranous nephropathy with very low albumin);
  • vaccines.
• Disease-specific therapy:
  • minimal change disease: prednisone;
  • FSGS and membranous nephropathy: steroids with calcineurin inhibitors (tacrolimus, cyclosporine) or rituximab;
  • lupus nephritis: steroids with mycophenolate or cyclophosphamide, plus hydroxychloroquine;
  • rapidly progressive GN (ANCA vasculitis, anti-GBM disease): pulse steroids with cyclophosphamide or rituximab, plus plasma exchange for anti-GBM disease;
  • post-streptococcal GN: supportive care, diuretics and antihypertensives, with penicillin to eradicate the strain.
• Adverse effects:
  • corticosteroids: hyperglycemia, infection, osteoporosis, cataracts, adrenal suppression;
  • calcineurin inhibitors: nephrotoxicity, hypertension, hyperkalemia, tremor, gum hyperplasia (cyclosporine);
  • cyclophosphamide: hemorrhagic cystitis (prevented with mesna and hydration), infertility, bladder cancer;
  • mycophenolate: teratogenic.

Drugs in kidney disease and hyperkalemia

• Dosing: estimate renal function (Cockcroft-Gault creatinine clearance or eGFR) and reduce doses or lengthen intervals for renally cleared drugs. Examples are aminoglycosides, vancomycin, many beta-lactams, enoxaparin, metformin, lithium, digoxin, gabapentin and DOACs.
• Avoid nephrotoxins:
  • NSAIDs, especially combined with ACE inhibitors or ARBs and diuretics (the "triple whammy");
  • aminoglycosides;
  • iodinated contrast in high-risk patients without hydration;
  • amphotericin B;
  • calcineurin inhibitors.
• Avoid in advanced CKD: magnesium-containing antacids and laxatives, phosphate enemas, and meperidine (a seizure-causing metabolite).
• Emergency hyperkalemia:
  1. Stabilize the myocardium: IV calcium gluconate 10 mL of 10% over 5 to 10 minutes (or calcium chloride), repeated if ECG changes persist.
  2. Shift potassium into cells:
     • regular insulin 10 units IV with dextrose, monitoring glucose;
     • nebulized salbutamol;
     • sodium bicarbonate if there is acidosis.
  3. Remove potassium:
     • loop diuretics if the kidneys work;
     • potassium binders (sodium polystyrene sulfonate, patiromer, sodium zirconium cyclosilicate);
     • hemodialysis for refractory cases or renal failure.
  4. Stop potassium-raising drugs: ACE inhibitors, ARBs, spironolactone, trimethoprim, NSAIDs and potassium supplements.
• CKD complications:
  • anemia: erythropoiesis-stimulating agents with iron;
  • mineral bone disease: phosphate binders, active vitamin D (calcitriol) and cinacalcet;
  • metabolic acidosis: sodium bicarbonate.

Prostate disease and erectile dysfunction

• Benign prostatic hyperplasia:
  • alpha-1 blockers (tamsulosin, silodosin, doxazosin, terazosin) relax prostate and bladder-neck smooth muscle and work within days. They cause dizziness, orthostatic hypotension (especially non-selective alpha-blockers), ejaculatory dysfunction and intraoperative floppy iris syndrome;
  • 5-alpha-reductase inhibitors (finasteride, dutasteride) block conversion of testosterone to dihydrotestosterone, shrink the prostate over 6 to 12 months, reduce retention and surgery, and lower PSA by about 50% (double the measured value when screening). They cause decreased libido and are teratogenic: pregnant women must not handle crushed tablets;
  • combination therapy is used for large prostates;
  • tadalafil (a PDE-5 inhibitor) for BPH with erectile dysfunction;
  • antimuscarinics for storage symptoms if the residual volume is low;
  • avoid anticholinergics and decongestants, which can precipitate retention.
• Prostatitis: fluoroquinolones or TMP-SMX for 2 to 6 weeks.
• Erectile dysfunction:
  • PDE-5 inhibitors (sildenafil, tadalafil) raise cGMP;
  • contraindicated with nitrates, because of severe hypotension;
  • cause headache, flushing, nasal congestion and visual changes (sildenafil causes blue tinge).

Renal cell carcinoma and prostate cancer

• Renal cell carcinoma:
  • surgery (partial or radical nephrectomy) for localized disease;
  • advanced disease responds poorly to conventional chemotherapy and radiation, so it is treated with VEGF-targeted tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, cabozantinib), which cause hypertension, hand-foot syndrome, hypothyroidism and diarrhea, and with immune checkpoint inhibitors (nivolumab, ipilimumab, pembrolizumab), often combined.
• Prostate cancer:
  • localized disease is treated by active surveillance, radical prostatectomy or radiation;
  • advanced disease is treated with androgen deprivation therapy:
    • GnRH agonists (leuprolide, goserelin) first cause a testosterone flare that can worsen bone pain or cord compression, so an antiandrogen (bicalutamide) is given for the first weeks;
    • GnRH antagonists (degarelix, relugolix) cause no flare;
  • castration-resistant disease is treated with abiraterone (a CYP17 inhibitor, given with prednisone to prevent mineralocorticoid excess), enzalutamide (an androgen receptor blocker), docetaxel and radium-223 for bone metastases;
  • androgen deprivation causes hot flushes, loss of libido, osteoporosis (give calcium, vitamin D and bisphosphonates or denosumab), metabolic syndrome and cardiovascular risk.