clinical pharmacy in nephrology. drugs and the kidney 1 renal physiology and pharmacokinetics 2...
Post on 04-Jan-2016
225 Views
Preview:
TRANSCRIPT
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 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)
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
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
Seru
m
creatinin
e
Glomerular filtration rate (GFR)
GFR Estimation
• Cockroft-Gault FormulaCrCl=Fx(140-age)xweight/CreaP
F♀=1.04F♂=1.23Example85♀, 55kg, Creatinine=95CrCl=33ml/min
• MDRD Formula
Tests of renal function cont.
• 24h Urine sample-Creatinine clearance
• chromium EDTA Clearance
• gold standard Inulin clearance
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
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, BumetanideIndication
– Fluid overload– Hypertension– Hypercalcaemia
Mechanism of actionBlockade 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
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
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
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; 343:180-184
top related