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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 60% + K 2% + + + Na -K , H 30% Liddle’s syndrome Pseudohypoaldosteronism Na-K-2Cl type-I ROMK Amiloride sensitive 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 JAMA. 2002;288:2981-2997 Institute (NHLBI) Cumulative Event Rates for the Primary ALLHAT Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group .2 RR (95% CI) p value .16 A/C 0.98 (0.90-1.07) 0.65 Cumulative CHD Event Rate L/C 0.99 (0.91-1.08) 0.81 .12 Chlorthalidone Amlodipine Lisinopril .08 .04 0 0 1 2 3 4 5 6 7 Years to CHD Event Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195 Overall ALLHAT 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 ( 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; 343:180-184 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 (Dec2000) – Amphotericin (June99) – Cyclosporin (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.
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