1. Drugs and the Kidney
INDIAN DENTAL ACADEMY
Leader in continuing dental education
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2. 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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3. Normal Kidney Function
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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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4. 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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5. 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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6. Serum Creatinine and GFR
Serum creatinine
Glomerular filtration rate
(GFR)
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7. 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
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8. Tests of renal function cont.
•
24h Urine sample-Creatinine
clearance
•
chromium EDTA Clearance
•
gold standard Inulin clearance
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9. The nephron and electrolyte
handling
Na+-ClGitelman's syndrome
Thiazide sensitive
7%
Na
+
K
+
60%
2%
30%
Na-K-2Cl
ROMK
Bartter's syndrome 1%
Bumetanide
sensitive
Na+ -K+, H+
Liddle’s syndrome
Pseudohypoaldosteronism
type-I
Amiloride sensitive
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16. 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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17. Loop diuretics continued
• Caution
– Electrolyte imbalance - hypokalaemia
– Volume depletion (prerenal uremia)
– Tinitus (acts within cochlea – can synergise
with aminoglycoside antibiotics)
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18. 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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20. 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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21. 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
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Institute (NHLBI)
JAMA. 2002;288:2981-2997
22. ALLHAT
Cumulative Event Rates for the Primary
Outcome (Fatal CHD or Nonfatal MI) by
ALLHAT Treatment Group
.2
Cumulative CHD Event Rate
RR (95% CI)
A/C
0.98 (0.90-1.07)
0.65
L/C
.16
p value
0.99 (0.91-1.08)
0.81
Chlorthalidone
Amlodipine
Lisinopril
.12
.08
.04
0
0
Number at Risk:
Chlorthalidone
Amlodipine
Lisinopril
15,255
9,048
9,054
1
2
3
4
Years to CHD Event
14,477
13,820
13,102
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8,576
8,218
7,843
6,824
8,535
8,123
7,711
6,662
5
6
6,340
3,870
3,832
2,956
1,878
1,770
7
209
215
195
23. ALLHAT
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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24. 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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27. 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 ( antihypertensives, ACE inhibitors)
– Typical radiological features when advanced
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29. Aminoglycosides
• Highly effective antimicrobials
– Particularly useful in gram -ve sepsis
– bactericidal
• BUT
– Nephrotoxic
– Ototoxic
– Narrow therapeutic range
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30. 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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31. 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
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32. Prescribing in Kidney Disease
• Patients with renal impairment
• Patients on Dialysis
• Patients with renal transplants
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33. 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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34. 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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35. Past Papers
• Write short notes on the following
– Spironolactone
– Amphotericin
– Cyclosporin
(Dec2000)
(June99)
(June99)
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36. 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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37. 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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38. 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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39. 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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40. 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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41. 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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42. 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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43. 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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44. Thank you
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