Drugs and the Kidney

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Drugs and the Kidney
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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 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)

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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

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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
Serum creatinine
Glomerular filtration rate (GFR)
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GFR Estimation

• Cockroft-Gault Formula
• CrClFx(140-age)xweight/CreaP
• F?1.04
• F?1.23
• Example
• 85?, 55kg, Creatinine95
• CrCl33ml/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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The nephron and electrolyte handling
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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, Bumetanide
• Indication
• Fluid overload
• Hypertension
• Hypercalcaemia
• Mechanism of action
• Blockade 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 gt200µM)
• T ½ 3-5 hours

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Thiazides

• Indications
• Antihypertensive especially in combination with
  ACE inhibitor/ARB (AD)
• 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 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. 20022882981-2997
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Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
Chlorthalidone Amlodipine Lisinopril
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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.
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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 343180-184

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Prescribing in Kidney Disease

• Patients with renal impairment
• Patients on Dialysis
• Patients with renal transplants

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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

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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

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Past Papers

• Write short notes on the following
• Spironolactone (Dec2000)
• Amphotericin (June99)
• Cyclosporin (June99)

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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?

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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

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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)

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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)

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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

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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

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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

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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.