S1 drugsandthe kidney_000 /certified fixed orthodontic courses by Indian dental academy

Drugs and the Kidney
INDIAN DENTAL ACADEMY
Leader in continuing dental education
www.indiandentalacademy.com


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 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 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

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 Formula
CrCl=Fx(140-age)xweight/CreaP
F♀=1.04
F♂=1.23
Example
85♀, 55kg, Creatinine=95
CrCl=33ml/min

• MDRD Formula

Tests of renal function cont.
•

24h Urine sample-Creatinine
clearance
•
chromium EDTA Clearance
•
gold standard Inulin clearance


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


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, Bumetanide
Indication
– Fluid overload
– Hypertension
– Hypercalcaemia

Mechanism of action
Blockade 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

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
Institute (NHLBI)
JAMA. 2002;288:2981-2997

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
www.indiandentalacademy.com 11,362
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

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.


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 ( antihypertensives, 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
– Amphotericin
– Cyclosporin

(Dec2000)
(June99)
(June99)


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?


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.

Thank you
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