Drugs And The Kidney
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Transcript of Drugs And The Kidney
Drugs and the Kidney
Drugs and the Kidney
1 Renal Physiology and Pharmacokinetics2 Drugs and the normal kidney3 Drugs toxic to the kidney4 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 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
Serum
creatinine
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 diureticsFrusemide, 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, MetolazoneSite of action distal convoluted tubuleblocks 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 ConclusionsALLHAT
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 toxicityFollowing 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.