CLINICAL PHARMACY IN NEPHROLOGY. Drugs and the Kidney 1 Renal Physiology and Pharmacokinetics 2...

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CLINICAL PHARMACY IN NEPHROLOGY

Transcript of CLINICAL PHARMACY IN NEPHROLOGY. Drugs and the Kidney 1 Renal Physiology and Pharmacokinetics 2...

Page 1: 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.

CLINICAL PHARMACY IN NEPHROLOGY

Page 2: 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.

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

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Normal Kidney Function

1 Extra Cellular Fluid Volume control2 Electrolyte balance3 Waste product excretion4 Drug and hormone elimination/metabolism5 Blood pressure regulation6 Regulation of haematocrit7 regulation of calcium/phosphate balance

(vitamin D3 metabolism)

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Clinical Estimation of renal function

• Clinical examinationpallor, 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

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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

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Serum Creatinine and GFR

Seru

m

creatinin

e

Glomerular filtration rate (GFR)

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GFR Estimation

• Cockroft-Gault FormulaCrCl=Fx(140-age)xweight/CreaP

F♀=1.04F♂=1.23Example85♀, 55kg, Creatinine=95CrCl=33ml/min

• MDRD Formula

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Tests of renal function cont.

• 24h Urine sample-Creatinine clearance

• chromium EDTA Clearance

• gold standard Inulin clearance

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Na+ 60%K+

2%

Na+ -K+, H+

Liddle’s syndromePseudohypoaldosteronismtype-IAmiloride sensitive

1%

Na+-Cl-

Gitelman's syndromeThiazide sensitive

7%

30%

Na-K-2ClROMKBartter's syndromeBumetanidesensitive

The nephron and electrolyte handling

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Page 11: 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.

Pharmacokinetics

• Absorption

• Distribution

• Metabolism

• Elimination– filtration– secretion

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Diuretics

• Loop

• Thiazide

• Aldosterone antagonist

• Osmotic

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Diuretics

• Indications for use– heart failure ( acute or chronic )

– pulmonary oedema

– hypertension

– nephrotic syndrome

– hypercalcaemia

– hypercalciuria

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Loop diuretics

Frusemide, BumetanideIndication

– Fluid overload– Hypertension– Hypercalcaemia

Mechanism of actionBlockade of NaK2Cl (NKCC2) transporter in the thick ascending loop of Henle

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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

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Loop diuretics continued

• Caution– Electrolyte imbalance - hypokalaemia– Volume depletion (prerenal uremia)– Tinitus (acts within cochlea – can synergise

with aminoglycoside antibiotics)

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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

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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

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Major Outcomes in High Risk Hypertensive Patients Randomized to

Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs

DiureticThe 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;288:2981-2997

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Years to CHD Event0 1 2 3 4 5 6 7

Cumulative CHD Event Rate

0

.04

.08

.12

.16

.2

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

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

RR (95% CI) p value

A/C 0.98 (0.90-1.07) 0.65

L/C 0.99 (0.91-1.08) 0.81

ALLHAT

ChlorthalidoneAmlodipineLisinopril

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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.

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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

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Nephrotoxic Drugs

• Dose dependant toxicity– NSAIDs including COX 2– Aminoglycosides– Radio opaque contrast materials

• Idiosyncratic Renal Damage– NSAIDs– Penicillins– Gold, penicillamine

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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

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Aminoglycosides

• Highly effective antimicrobials– Particularly useful in gram -ve sepsis– bactericidal

• BUT– Nephrotoxic – Ototoxic – Narrow therapeutic range

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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!

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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