Medication for urinary stones
Currently, there are various treatment methods for urinary stones, including medications, extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy, various intracavitary lithotripsy, and surgical stone removal by incision. The choice of treatment method is based on medical conditions, the patient’s condition, the size, location, shape and composition of the stone, the length of history and the presence of complications. It is generally accepted that the following conditions can be preferred or drug-based treatment can be used: (1) stone diameter less than 0.6 cm; (2) smooth surface and relatively regular shape; (3) no serious infection; (4) no obstruction or stricture in the urinary tract below the stone; (5) pure uric acid stones and cystine stones (6) not long duration of disease, urography shows good renal function; (7) metabolic diseases with clear diagnosis.
An effective and widely accepted medical treatment option has not been obtained. The main reason is that the means to modify the urinary lithogenic composition and crystal formation factors are not yet an effective internal medicine treatment and prevention method; secondly, most studies have not been done with prospective, placebo-controlled and randomized criteria, and the follow-up time is often insufficient, the number of observed cases is low and the treatment analysis is not well developed. The most important aim of effective internal therapy is not to correct the urinary composition but to reduce stone recurrence.
Stone dissolution and volume reduction are the best evidence that drug therapy is effective because this evidence of efficacy is obvious and easily measured and evaluated, but there are many problems with the evaluation of stone drug efficacy. The main ones are 1) errors in the evaluation of stone dissolution and volume reduction, including the measurement method and the measurer, and 2) deviations in the assessment of stone recurrence from the true nature again.
There are other problems with the pharmacological treatment of urinary stones: 1) side effects, such as D-penicillamine, curettage and citrate preparations, etc. 2) poor tolerance of long-term administration. 3) It is difficult to do long-term studies of relevant drugs. It is more difficult to obtain meaningful results because of the large sample size and the high rate of patient withdrawal from long-term studies.4) For uric acid stones and cystine stones, reduction of urine is the preferred treatment option. However, strict monitoring of urine pH is required; otherwise, it is difficult to demonstrate the therapeutic effect of urinary alkalinization.
Stone components are often mixed and are divided into four categories according to their chemical composition: calcium-containing stones, uric acid stones, infected stones, and cystine stones. The pharmacological treatment of each of these four types of stones is discussed below.
Calcium-containing stones
The main components of calcium-containing stones are calcium oxalate and calcium phosphate. Among them, pure calcium oxalate stones and mixed calcium oxalate + calcium phosphate stones are the most common. Pure calcium phosphate stones are rare, and their formation is often caused by renal tubular acidosis.
Pharmacological treatment of calcium-containing stones has been used for many years, with alkaline citrate and thiazide (class) diuretics being the most commonly used.
1) Alkaline citrate preparations
Mechanism of action: A small portion of citrate absorbed from the intestine is excreted in the urine, and most of it enters the bloodstream and is metabolized. Alkaline citrate preparations increase urinary citrate mainly by increasing the pH of tubular cells. Increased levels of urinary citrate reduce the saturation of calcium oxalate and calcium phosphate, and also inhibit the growth and aggregation of stone crystals. In addition, citrate preparations can also decrease the saturation of uric acid. Therefore, citrate preparations can inhibit the formation of calcium oxalate, calcium phosphate and uric acid stones.
Side effects: 42% of patients treated with citrate preparations experienced mild side effects, 26% experienced moderate side effects, and 12% experienced severe side effects (usually diarrhea).
2) Thiazide (class) diuretics
Mechanism of action: Thiazide (class) diuretics combined with low sodium intake can reduce urinary calcium excretion. Studies have shown that thiazide (class) diuretics can also reduce urinary calcium in patients with normal urinary calcium and can reduce urinary oxalic acid and intestinal absorption of calcium. Urinary calcium can be reduced by 20-30% with the use of this drug. It can also reduce osteoporosis and decrease the risk of fracture.
Side effects: Treatment with thiazide (class) diuretics has more side effects such as normocalcemic hyperparathyroidism, hyperlipidemia and gout. Thiazide (class) diuretics may also cause fatigue and weakness, and in rare cases may lead to erectile dysfunction (impotence). Especially in the early stages of treatment, the patient’s blood calcium, potassium, uric acid and glucose should be reviewed regularly. A decrease in glucose tolerance can lead to diabetes or exacerbate it. This side effect is dose-dependent and is mainly caused by a decrease in the insulin-releasing capacity of the pancreas or a decrease in peripheral glucose utilization. Potassium loss due to thiazide (class) diuretics can lead to metabolic alkalosis and should be noted. Other symptoms caused by low potassium, such as weakness and fatigue, should also be noted. A small percentage of patients treated with thiazide (class) diuretics develop severe hyponatremia, which may be associated with excessive drinking, hypokalemia and congestive heart failure. In addition, some allergic reactions such as rash, hemolytic anemia, thrombocytopenia, acute pancreatitis, obstructive jaundice and acute pulmonary edema should be noted. Thiazide (class) diuretics should be used with caution in patients with liver cirrhosis. It may also aggravate the renal impairment, etc. Thiazide (class) diuretics for the treatment of urolithiasis in early studies applied in larger doses, but later proved that low doses of once-daily administration of long-acting thiazide (class) diuretics have better safety, tolerability and convenience, and better clinical results.
3) Orthophosphate
Mechanism of action:There are two types of orthophosphates for clinical treatment of calcium-containing stones: acid orthophosphates and neutral orthophosphates. Its mechanism of action is to reduce the synthesis of 1,25(OH)2-vitD, thus reducing the absorption of calcium from food and lowering urinary calcium. In addition, bone decalcification is reduced. The effect of neutral orthophosphate is more pronounced, as it both decreases urinary calcium and increases urinary citrate by increasing the secretion of phosphate in the urine. This results in increased secretion of urinary orthophosphate and citrate and increased ability to inhibit crystal formation.
Side effects: Common side effects include diarrhea, painful abdominal cramps, nausea and vomiting. The adverse effects of orthophosphate on parathyroid hormone should also be noted.
4) Cellulose phosphate
Mechanism of action: cellulose phosphate (also includes sodium cellulose phosphate) can be combined with calcium in the intestine to form a complex and reduce the absorption of calcium, ultimately reducing urinary calcium.
Side effects: Diarrhea is a common side effect of cellulose phosphate sodium. As sodium cellulose phosphate forms complexes with calcium and magnesium cations in the intestine, it can lead to high oxaluria and low magnesium urine in patients. And the metabolism of other cations is also affected. The patient’s compliance with sodium cellulose phosphate treatment is poor, because every meal has to be taken, and magnesium preparations have to be taken between meals.
5) magnesium preparation
Mechanism of action: because the magnesium in the urine can combine with oxalic acid, so that the saturation of calcium oxalate is reduced; magnesium can inhibit the growth of calcium oxalate crystals; increased excretion of magnesium in the urine can increase citrate and raise pH, so magnesium preparations can inhibit the formation of stones. Magnesium can also directly inhibit the growth of calcium phosphate crystals.
Side effects: diarrhea and abdominal discomfort are the main side effects and are dose dependent. The use of magnesium preparations will increase urinary calcium excretion
6) allopurinol
Mechanism of action: allopurinol reduces the production of uric acid in the body, thus reducing the excretion of uric acid in the urine. Hyperuricuria can lead to the formation of uric acid or sodium urate crystals. These crystals could theoretically reduce heterologous nucleation of calcium oxalate crystals or induce homologous nucleation through a salt release mechanism. Uric acid or colloidal uric acid inhibits the activity of glucosaminoglycans. Allopurinol has also been reported to reduce urinary oxalic acid secretion. Therefore, allopurinol is a therapeutic agent for patients with high uric acid urinary calcium-containing stones.
Side effects: High doses of allopurinol may produce more serious side effects, but it is better tolerated at normal doses or in small measurements. In patients with gout, acute gouty arthritis may occur early in allopurinol treatment when uric acid crystals are detached from the tissues and blood uric acid concentrations are lower than normal. Gastrointestinal reactions including nausea, vomiting, and diarrhea may also occur. In addition, peripheral neuritis and necrotizing vasculitis, bone marrow suppression, etc. may also occur, and aplastic anemia is rare. Hepatotoxicity and interstitial nephritis have also been reported. Allergic dermatitis reactions such as pruritic maculopapular rash may occur in a small number of patients.
In conclusion: Thiazide (class) diuretics and alkaline citrate should currently be used for prophylaxis in patients with high recurrence of calcium oxalate stones. There is no evidence to support the effectiveness of these treatment regimens based on altering urinary metabolic factors. Alkaline citrate preparations may increase stone clearance in patients with large stones treated with ESWL or in patients with stones in difficult locations (e.g., lower calcium stones). The long-term use of these drugs in pediatric patients is more controversial and is generally considered to be used only in children with severe disease. Allopurinol is only effective in patients with calcium oxalate who have high uric acid urine.
Uric acid stones
Uric acid stones form due to low urine pH and/or high urinary uric acid concentration. Of these, low urine pH is the main cause, because the lower the urine pH, the less soluble uric acid is in the urine. Therefore, the main medical treatment for uric acid stones should include 1) increasing fluid intake to improve urine output, 2) maintaining urine pH between 6.3 and 7.0, for example, by taking medications such as sodium bicarbonate or potassium citrate, and 3) reducing the intake of purines in food.
Current common pharmacological treatment: There are several treatment options for lithotripsy of uric acid stones, with lithotripsy rates of 86%-100%. The literature reports the following options currently in clinical use: 1) use of a mixture of sodium potassium citrate and citrate (UrolytU, Youlet); 2) use of allopurinol and sodium bicarbonate; 3) use of 0.6 mol lactate intravenous infusion and use of sodium citrate or UrolytU and allopurinol; 4) use of 0.16 M lactate (in acute patients) or sodium bicarbonate IV infusion and allopurinol; 4) use of sodium citrate or sodium bicarbonate. All of the above regimens are accompanied by encouragement to drink more water to achieve a certain urine output.
Cystine stones
Cystine stones can form when the urinary excretion of cystine is greater than 250 mg/g (creatinine) in patients with cystinuria. The solubility of cystine increases with the alkalinity of the urine, so treatment for cystine stones should include reducing free cystine in the urine, maintaining urine pH greater than 7, and increasing urine volume.
Current medications: Medications to lower free cystine in the urine include D-penicillamine hydrochloride, alpha-mercaptopropionylglycine, and captopril. These drugs can combine with cystine in the urine to form a more soluble disulfide. Most studies agree that to achieve cystine stone dissolution or to prevent recurrence, urinary cystine levels should be less than 350 mg/g (creatinine) and urinary pH greater than 7.0.
Infected stones
Principles of treatment to prevent infected stones: 1) complete removal of existing stones by surgical means; 2) increased fluid intake to improve urine output; 3) . Rational antibiotic use; 4). Use of; urease inhibitor vinblastine;). Use of drugs such as levothyroxine to lower urinary pH.
1) Urease inhibitors: The use of vinblastine for 5-30 months has been reported in the literature to partially or completely dissolve infected stones.
2) Acidification of the urine: long-term acidification of the urine is much more difficult than alkalinization of the urine. Methionine (methionine) is a useful drug to choose.
3) Antibiotic therapy: The main difficulty with long-term antibiotic therapy is that the renal collecting system can develop resistant bacteria if stones or stone fragments are retained. Studies have shown that the combination of antibiotics and vinblastine may be more effective. The most common urea-producing bacteria causing magnesium phosphate stones are Aspergillus chimaera, Escherichia coli does not secrete urease, but it is the most common infecting bacteria for urinary stones.