CLINICAL PHARMACY IN NEPHROLOGY

Drugs and the Kidney 1 Renal Physiology and Pharmacokinetics 2 Drugs and the normal kidney 3 Drugs toxic to the kidney 4 Prescribing in kidney disease

Normal Kidney Function 1 Extra Cellular Fluid Volume control 2 Electrolyte balance 3 Waste product excretion 4 Drug and hormone elimination/metabolism 5 Blood pressure regulation 6 Regulation of haematocrit 7 regulation of calcium/phosphate balance (vitamin D3 metabolism)

Clinical Estimation of renal function Clinical examination pallor, volume status, blood pressure measurement, urinalysis Blood tests Routine Tests haemoglobin level electrolyte measurement (Na,K, Ca, PO 4 ) urea creatinine normal range 70 to 140 μmol/l

Serum Creatinine and GFR Muscle metabolite- concentration proportional to muscle mass –High: muscular young men –Low: conditions with muscle wasting elderly muscular dystrophy Anorexia malignancy “Normal” range 70 to 140 μmol/litre

Serum Creatinine and GFR Serum creatinine Glomerular filtration rate (GFR)

GFR Estimation Cockroft-Gault Formula CrCl=Fx(140-age)xweight/Crea P F ♀=1.04 F♂=1.23 Example 85♀, 55kg, Creatinine=95 CrCl=33ml/min MDRD Formula

Tests of renal function cont. 24h Urine sample-Creatinine clearance chromium EDTA Clearance gold standard Inulin clearance

The nephron and electrolyte handling

Pharmacokinetics Absorption Distribution Metabolism Elimination – filtration – secretion

Diuretics Loop Thiazide Aldosterone antagonist Osmotic

Diuretics Indications for use – heart failure ( acute or chronic ) –pulmonary oedema –hypertension –nephrotic syndrome –hypercalcaemia –hypercalciuria

Loop diuretics Frusemide, Bumetanide Indication –Fluid overload –Hypertension –Hypercalcaemia Mechanism of action Blockade of NaK2Cl (NKCC2) transporter in the thick ascending loop of Henle

Loop diuretics Frusemide – oral bioavailability between 10 and 90% –Acts at luminal side of thick ascending limb(NaK2Cl transporter) –Highly protein bound –Rebound after single dose –Half-life 4 hours

Loop diuretics continued Caution –Electrolyte imbalance - hypokalaemia –Volume depletion (prerenal uremia) –Tinitus (acts within cochlea – can synergise with aminoglycoside antibiotics)

Thiazide diuretics Bendrofluazide, Metolazone Site of action distal convoluted tubule blocks electroneutral Na/Cl exchanger (NCCT) Reaches site of action in glomerular filtrate – Higher doses required in low GFR (ineffective when serum creatinine >200μM) – T ½ 3-5 hours

Thiazides Indications –Antihypertensive: especially in combination with ACE inhibitor/ARB (A+D) –In combination with loop diuretic for profound oedema –Cautions Metabolic side effects – hyperuricaemia, impaired glucose tolerance & electrolyte disturbance (hypokalaemia and hyponatraemia) Volume depletion

Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) ALLHAT JAMA. 2002;288:

Years to CHD Event Cumulative CHD Event Rate Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group RR (95% CI)p value A/C0.98 ( )0.65 L/C0.99 ( )0.81 ALLHAT Chlorthalidone Amlodipine Lisinopril

Overall Conclusions ALLHAT Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.

Amiloride and Spironolactone Amiloride –Blocks ENaC (channel for Na secretion in collecting duct under aldosterone control) Spironolactone –Aldosterone receptor antagonist –Reaches DCT via blood stream (not dependent on GFR) Often Combined with loop or thiazides to capitalise on K-sparing action

Nephrotoxic Drugs Dose dependant toxicity –NSAIDs including COX 2 –Aminoglycosides –Radio opaque contrast materials Idiosyncratic Renal Damage –NSAIDs –Penicillins –Gold, penicillamine

NSAIDs (Non-steroidal anti inflammatory drugs) Commonly used –Interfere with prostaglandin production, disrupt regulation of renal medullary blood flow and salt water balance Chronic renal impairment –Habitual use –Exacerbated by other drugs ( anti- hypertensives, ACE inhibitors) –Typical radiological features when advanced

Aminoglycosides Highly effective antimicrobials –Particularly useful in gram -ve sepsis –bactericidal BUT –Nephrotoxic –Ototoxic –Narrow therapeutic range

Prescribing Aminoglycosides Once daily regimen now recommended in patients with normal kidneys – High peak concentration enhances efficacy – long post dose effect – Single daily dose less nephrotoxic Dose depends on size and renal function – Measure levels!

Intravenous contrast Used commonly –CT scanning, IV urography, Angiography –Unsafe in patients with pre-existing renal impairment –Risk increased in diabetic nephropathy, heart failure & dehydration –Can precipitate end-stage renal failure –Cumulative effect on repeated administration Risk reduced by using Acetylcysteine ? – see N Engl J Med 2000; 343: