DRUGS TO INCREASE BLADDER ACTIVITY
Drugs that increase bladder activity (e.g. muscarinic agonists, such as bethanechol, or anticholinesterases, such as distig- mine) have been used to treat patients with chronic retention of urine, but catheterization is usually preferable.
DRUGS FOR URINARY INCONTINENCE
Stress incontinence is usually managed without drugs, often surgically, although duloxetine(an amine uptake inhibitor) is licensed for use in women with moderately severe stress incontinence in conjunction with pelvic floor exercises. Alpha blockers (e.g. doxazosin, see Chapter 28) can worsen inconti- nence in women with pelvic floor pathology and should be discontinued if possible.
Urge incontinence is common. Infection should be excluded.
When unstable detrusor contraction is responsible, drug treat- ment to reduce bladder activity is of limited use, combined with pelvic floor exercises and bladder training. Antimuscarinic drugs, such as oxybutynin, have a high incidence of antimus- carinic side effects (e.g. dry mouth, dry eyes, blurred vision, constipation, confusion). These may be minimized by starting with a low dose and by slow release formulation. Solifenacinis a newer and more expensive drug.
DRUGS THATAFFECT THEBLADDER ANDGENITO-URINARYSYSTEM 279
Key points
Drugs and plasma potassium
• Hypokalaemia (and hypomagnesaemia) predisposes to digoxin toxicity and to torsades de pointes caused by drugs that prolong the QT interval (e.g. amiodarone, sotalol). Mild hypokalaemia associated with thiazide or loop diuretics is common and seldom harmful per se.
• Where hypokalaemia is clinically important it can be corrected and/or prevented with Ksupplements or more conveniently with K-retaining diuretics.
However, these predispose to hyperkalaemia.
• Hyperkalaemia can cause dysrhythmias that can be fatal. ACEI predispose to hyperkalaemia, especially when there is renal impairment.
• Emergency treatment of broad complex tachycardia caused by hyperkalaemia includes i.v. calcium gluconate.
• Glucose and insulin i.v. cause redistribution of potassium into cells.
• Sodium bicarbonate i.v. can cause redistribution of potassium into cells in exchange for hydrogen ions.
• β2-Agonists i.v./high-dose nebulized cause intracellular shift of K.
• Haemodialysis or haemofiltration is frequently indicated in acute hyperkalaemic emergencies.
• Ion-exchange resins administered by mouth are useful.
DRUGS THAT ALTER URINE pH
ACIDIFICATION
Ammonium chloridegiven orally results in urinary acidifica- tion and is used in specialized diagnostic tests of renal tubular
DRUGS FOR PROSTATIC OBSTRUCTION
Prostatic obstruction is often managed surgically. Symptoms of benign prostatic hypertrophy may be improved by a 5α- reductase inhibitor (e.g. finasteride, Chapters 41 and 48) or by anα1-adrenoceptor antagonist (e.g. doxazosin, Chapter 28).
Tamsulosin, an α1-adrenoceptor antagonist selective for the α1A-adrenoceptor subtype, produces less postural hypotension than non-selective α1-adrenoceptor antagonists. Hormonal manipulation with anti-androgens and analogues of luteiniz- ing hormone-releasing hormone (LHRH) is valuable in patients with prostatic cancer (Chapter 48).
ERECTILE DYSFUNCTION
Erectile failure has several organic, as well as numerous psy- chological, causes. Replacement therapy with testosterone, given by skin patch, is effective in cases caused by proven androgen deficiency. Nitric oxide is involved in erectile func- tion both as a vascular endothelium-derived mediator and as a non-adrenergic non-cholinergic neurotransmitter. This has led to the development of type V phosphodiesterase inhibitors as oral agents to treat erectile dysfunction. Sildenafil(Viagra™) was the first of these to be introduced, there are several other longer-acting agents in this class currently. These drugs are discussed in Chapter 41.
FURTHER READING
Brater DC. Pharmacology of diuretics. American Journal of Medical Science2000;319: 38–50.
Clark BA, Brown RS. Potassium homeostasis and hyperkalemic syn- dromes. Endocrinology and Metabolism Clinics of North America1995;
24: 573–91.
280 NEPHROLOGICAL AND RELATED ASPECTS
Case history
A 35-year-old woman has proteinuria (3 g/24 hours) and progressive renal impairment (current serum creatinine 220μmol/L) in the setting of insulin-dependent diabetes mellitus. In addition to insulin, she takes captopril regularly and buys ibuprofen over the counter to take as needed for migraine. She develops progressive oedema which does not respond to oral furosemide in increasing doses of up to 250 mg/day. Amiloride (10 mg daily) is added without bene- fit and metolazone (5 mg daily) is started. She loses 3 kg over the next three days. One week later, she is admitted to hospital having collapsed at home. She is conscious but severely ill. Her blood pressure is 90/60 mmHg, heart rate is 86 beats/minute and regular, and she has residual periph- eral oedema, but the jugular venous pressure is not raised.
Serum urea is 55 mmol/L, creatinine is 350μmol/L, K is 6.8 mmol/L, glucose is 5.6 mmol/L and albumin is 3.0 g/dL.
Urinalysis shows 4protein. An ECG shows tall peaked T- waves and broad QRS complexes.
Question
Decide whether each of the following statements is true or false.
(a) Insulin should be withheld until the patient’s metabolic state has improved.
(b) Metolazone should be stopped.
(c) The furosemide dose should be increased in view of the persistent oedema.
(d) Ibuprofen could have contributed to the hyperkalaemia.
(e) Captopril should be withheld.
Answer (a) False (b) True (c) False (d) True (e) True Comment
Although highly effective in causing diuresis in patients with resistant oedema, combination diuretic treatment with loop, K-sparing and thiazide diuretics can cause acute prerenal renal failure with a disproportionate increase in serum urea compared to creatinine. Resistance to furosemide may be related to the combination of reduced GFR plus albuminuria. The combination of an NSAID, captopril and amiloride is extremely dangerous, especially in diabetics, and will have contributed to the severe hyperkalaemia. The NSAID may also have led to reduced glomerular filtration. Glucose with insulin would be appropriate to lower the plasma K.
Case history
A 73-year-old man has a long history of hypertension and of osteoarthritis. Three months ago he had a myocardial infarc- tion, since when he has been progressively oedematous and dyspnoeic, initially only on exertion but more recently also on lying flat. He continues to take co-amilozide for his hypertension and naproxen for his osteoarthritis. The blood pressure is 164/94 mmHg and there are signs of fluid over- load with generalized oedema and markedly elevated jugu- lar venous pressure. Serum creatinine is 138μmol/L and Kis 5.0 mmol/L. Why would it be hazardous to commence furosemide in addition to his present treatment? What alter- native strategy could be considered?
Comment
The patient may go into prerenal renal failure with the addition of the loop diuretic to the two more distal diuret- ics he is already taking in the co-amilozide combination.
The NSAID he is taking makes this more likely, and also makes it more probable that his serum potassium level (which is already high) will become dangerously elevated.
It would be appropriate to consider hospital admission, stopping naproxen (perhaps substituting paracetamol for pain if necessary), stopping the co-amilozide and cautiously instituting an ACE inhibitor (which could improve his prog- nosis from his heart failure as described in Chapter 31) fol- lowed by introduction of furosemide with close monitoring of blood pressure, signs of fluid overload and serum creati- nine and potassium levels over the next few days.
Greger R, Lang F, Sebekova, Heidland A. Action and clinical use of diuretics. In: Davison AMA, Cameron JS, Grunfeld J-P et al (eds).
Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 2619–48.
Reid IR, Ames RW, Orr-Walker BJ et al. Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a random- ized controlled trial. American Journal of Medicine 2000; 109:
362–70.
Saggar-Malik AK, Cappuccio FP. Potassium supplements and potassium-sparing diuretics. A review and guide to appropriate use.Drugs1993;46: 986–1008.
Shankar SS, Brater DC. Loop diuretics: from the Na-K-2Cl transporter to clinical use. American Journal of Physiology. Renal Physiology2003;
284: F11–21.
Weinberger MH. Eplerenone – a new selective aldosterone receptor antagonist.Drugs of Today2004;40: 481–5.
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PART VIII