Drugs And The Kidney

1. Drugs and the Kidney

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

3. 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)

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, PO
4
)
• urea
• creatinine normal range 70 to 140 μmol/l

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

6. Serum Creatinine and GFR
S
e
r
u
m

c
r
e
a
t
i
n
i
n
e
Glomerular filtration rate
(GFR)

7. GFR Estimation
•Cockroft-Gault Formula
CrCl=Fx(140-age)xweight/Crea
P

F♀=1.04
F♂=1.23
Example
85♀, 55kg, Creatinine=95
CrCl=33ml/min
•MDRD Formula

8. Tests of renal function cont.
•24h Urine sample-Creatinine
clearance
•chromium EDTA Clearance
•gold standard Inulin clearance

9. Na
+
60%
K
+
2%
Na
+
-K
+
, H
+
Liddle’s syndrome
Pseudohypoaldosteronism
type-I
Amiloride sensitive
1%
Na
+
-Cl
-
Gitelman's syndrome
Thiazide sensitive
7%
30%
Na-K-2Cl
ROMK
Bartter's syndrome
Bumetanide
sensitive
The nephron and electrolyte
handling

11. Pharmacokinetics
• Absorption
•Distribution
•Metabolism
•Elimination
– filtration
– secretion

12. Diuretics
•Loop
•Thiazide
•Aldosterone antagonist
•Osmotic

13. Diuretics
•Indications for use
–heart failure ( acute or chronic )
–pulmonary oedema
–hypertension
–nephrotic syndrome
–hypercalcaemia
–hypercalciuria

14. Loop diuretics
Frusemide, Bumetanide
Indication
–Fluid overload
–Hypertension
–Hypercalcaemia
Mechanism of action
Blockade of NaK2Cl (NKCC2) transporter in the
thick ascending loop of Henle

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

17. Loop diuretics continued
•Caution
–Electrolyte imbalance - hypokalaemia
–Volume depletion (prerenal uremia)
–Tinitus (acts within cochlea – can synergise
with aminoglycoside antibiotics)

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

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

21. 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)
ALLHAT
JAMA. 2002;288:2981-2997

22. Years to CHD Event
0 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
0.810.99 (0.91-1.08)L/C
0.650.98 (0.90-1.07)A/C
p valueRR (95% CI)
ALLHAT
Chlorthalidone
Amlodipine
Lisinopril

23. 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.

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

26. Nephrotoxic Drugs
•Dose dependant toxicity
–NSAIDs including COX 2
–Aminoglycosides
–Radio opaque contrast materials
•Idiosyncratic Renal Damage
–NSAIDs
–Penicillins
–Gold, penicillamine

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 ( anti-
hypertensives, ACE inhibitors)
–Typical radiological features when advanced

29. Aminoglycosides
•Highly effective antimicrobials
–Particularly useful in gram -ve sepsis
–bactericidal
• BUT
–Nephrotoxic
–Ototoxic
–Narrow therapeutic range

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!

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

32. Prescribing in Kidney Disease
•Patients with renal impairment
•Patients on Dialysis
•Patients with renal transplants

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

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

35. Past Papers
•Write short notes on the following
–Spironolactone(Dec2000)
–Amphotericin (June99)
–Cyclosporin (June99)

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?

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

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)

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)

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

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

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

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.