Drugs and the Kidney

Drugs and the Kidney 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, PO4) • 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/CreaP 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 Na -Cl Gitelman's syndrome Thiazide sensitive 7% + + - Na + K 60% 2% Na -K , H Liddle’s syndrome Pseudohypoaldosteronism type-I Amiloride sensitive + + + 30% Na-K-2Cl ROMK Bartter's syndrome 1% Bumetanide sensitive 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 ALLHAT 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) JAMA. 2002;288:2981-2997 ALLHAT .2 Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group RR (95% CI) p value 0.65 0.81 .16 Cumulative CHD Event Rate A/C L/C 0.98 (0.90-1.07) 0.99 (0.91-1.08) Chlorthalidone Amlodipine Lisinopril .12 .08 .04 0 0 Number at Risk: Chlorthalidone Amlodipine Lisinopril 15,255 9,048 9,054 1 14,477 8,576 8,535 2 13,820 8,218 8,123 3 4 Years to CHD Event 13,102 7,843 7,711 11,362 6,824 6,662 5 6,340 3,870 3,832 6 2,956 1,878 1,770 7 209 215 195 ALLHAT Overall Conclusions 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 ( antihypertensives, 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; 343:180-184 Prescribing in Kidney Disease • Patients with renal impairment • Patients on Dialysis • Patients with renal transplants Principles • Establish type of kidney disease • Most patients with kidney failure will already be taking a number of drugs • Interactions are common • Care needed to avoid drug toxicity • Patients with renal impairment and renal failure • Antihypertensives • Phosphate binders Dosing in renal impairment • Loading dose does not change (usually) • Maintenance dose or dosing interval does T ½ often prolonged – Reduce dose OR – Increase dosing interval – Some drugs have active metabolites that are themselves excreted renally – Warfarin, diazepam Past Papers • Write short notes on the following – Spironolactone – Amphotericin – Cyclosporin (Dec2000) (June99) (June99) Past Papers • Discuss the treatment of patients with – Digoxin toxicity – Lithium toxicity Following both deliberate and Iatrogenic overdose. Which treatments have been shown to improve survival? Spironolactone • Class • Potassium sparing diuretic • Mode of action • Antagonises the effect of aldosterone at levels MR • Mineralocorticoid receptor (MR)–aldosterone complex translocates to nucleus to affect gene transcription • Indication • Prevent hypokalaemia in patients taking diuretics or digoxin • Improves survival in advanced heart failure (RALES 1999 Randomised Aldactone Evaluation Study) • Antihypertensive (adjunctive third line therapy for hypertension or first line for conns patients) • Ascites in patients with cirrhosis Spironolactone • Side effects – Antiandrogenic effects through the antagonism of DHT (testosterone) at its binding site. – Gynaecomastia, impotence, reduced libido • Interactions – Other potassium sparing drugs e.g. ACE inhibitors/ARBs & potassium supplements (remember „LoSalt‟ used as NaCl substitute in cooking) Amphotericin • Class • Anti fungal agent for topical and systemic use • Mode of action • Lipid soluble drug. Binds steroid alcohols (ergosterol) in the fungal cell membrane causing leakage of cellular content and death. Effective against candida species • Fungistatic or fungicidal depending on the concentration • Broad spectrum (candida, cryptosporidium) Amphotericin • Indications – iv administration for systemic invasive fungal infections – Oral for GI mycosis • Side effects – Local/systemic effects with infusion (fever) – Chronic kidney dysfunction » Decline in GFR with prolonged use » Tubular dysfunction (membrane permeability) » Hypokalaemia, renal tubular acidosis (bicarb wasting type 1/distal), diabetes insipidus, hypomagnesaemia » Pre hydration/saline loading may avoid problems Toxicity can be reduced substantially by liposomal packing of Amphotericin Lithium toxicity • Lithium carbonate - Rx for bipolar affective disorder • Toxicity closely related to serum levels • Symptoms – CVS arrhythmias (especially junctional dysrrythmias) – CNS tremor – confusion - coma • Treatment • Supportive - Haemodialysis and colonic irrigation for severe levels • Inadvertent intoxication from interaction with ACEI & loop/thiazide diuretic • Carbamezepine and other anti epileptics increase neurotoxicity Digoxin toxicity • Incidence – High levels demonstrated in 10% and toxicity reported in 4% of a series of 4000 digoxin samples • Kinetics – large volume of distribution (reservoir is skeletal muscle) – about 30% of stores excreted in urine/day Treatment of digoxin toxicity • Supportive – Correction of electrolyte imbalances – Atropine for bradycardia avoid cardio stimulants because arrythmogenic • Limitation of absorption – Charcoal effective within 8 hours (or cholestyramine) • Specific measures – DIGIBIND Fab digoxin specific antibodies. Binds plasma digoxin and complex eliminated by kidneys (used when OD is high/near arrest) • Enhanced elimination – Dialysis is ineffective. Charcoal/cholestyramine interrupt enterohepatic cycling.