Drugs and the kidney

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


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/litrewww.freelivedoctor.com

Serum Creatinine and GFR

Seru

m

creatinin

e

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 diuretics

Frusemide, 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, 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


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)www.freelivedoctor.com

Years to CHD Event0 1 2 3 4 5 6 7

Cum

ula

tive

CH

D E

vent

Rat

e

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

ChlorthalidoneAmlodipineLisinopril


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 ( 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


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.


From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250

70%

20%

5%

4.5%

0.5%Volume 1.5 L/dayUrine Na 100 mEq/LNa Excretion 155 mEq/day

100%GFR 180 L/day Plasma Na 145 mEq/LFiltered Load 26,100 mEq/day

CA InhibitorsProximal tubule

Loop DiureticsLoop of Henle

ThiazidesDistal tubule

Antikaliuretics

Collecting duct

Thick Ascending Limb


Principles important for understanding effects of diuretics

• Interference with Na+ reabsorption at one nephron site interferes with other renal functions linked to it

• It also leads to increased Na+ reabsorption at other sites

• Increased flow and Na+ delivery to distal nephron stimulates K + (and H +) secretion


• Diuretics act only if Na+ reaches their site of action. The magnitude of the diuretic effect depends on the amount of Na+ reaching that site

• Diuretic actions at different nephron sites can produce synergism

• All, except spironolactone, act from the lumenal side of the tubular cellular membrane

Principles important for understanding effects of diuretics


N NSO2

NH2

SO2NH2NH2

NH2

NH2

SO2NH2Cl

Cl

SO2NH2

SO2NH2

Cl

SO2NH2

N C

N

SO2

Prontosil

Sulfanilamide

p-chlorobenzene sulfonamide

1,3 disulfonamide 6 cholrobenzene

Cholrothiazide www.freelivedoctor.com

THIAZIDE DIURETICS

• Secreted into the tubular lumen by the organic acid transport mechanisms in the proximal tubule

• Act on the distal tubule to inhibit sodium and chloride transport and result in a modest diuresis

• Increase renal excretion of potassium, magnesium• Reduce calcium and urate excretion• Not effective at low glomerular filtration rates• Impair maximal diluting but not maximal concentrating

ability


General Structure of Thiazide Diureticswww.freelivedoctor.com

Ion % Control

NaF 143±9

LiCl 4±1

NaCl 20±0.5

KCl 44±2

Choline chloride 36±7

NaBr 24±2

NaI 25±1

KI 12±2

Na acetate 82±5

K acetate 95±5

Disodium sulfate 152±22

Dipotassium sulfate 118±12

Trisodium citrate 112±5

Inhibition of high-affinity 3H-metolazone binding by ions


Correlation of the daily clinical doses of thiazide diuretics with their affinity for high-affinity 3H-metolazone binding sites in rat kidney. Correlation coefficient r=0.7513.


Thiazides - Pharmacokinetics

• Rapid GI absorption• Distribution in extracellular space• Elimination unchanged in kidney• Variable elimination kinetics and therefore

variable half-lives of elimination ranging from hours to days.


CLINICAL USES Of THIAZIDES-1

1) HYPERTENSION

• Thiazides reduce blood pressure and associated risk of CVA and MI in hypertension

• they should be considered first-line therapy in hypertension (effective, safe and cheap)

• Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect


Schematic drawing of temporal changes in mean arterial pressure (MAP), total peripheral vascular resistance (TPR), cardiac output (CO) and plasma volume (PV) during thiazide treatment of a hypertensive subject


CLINICAL USES OF THIAZIDES-2

2) EDEMA (cardiac, liver renal)

3) IDIOPATHIC HYPERCALCIURIA• condition characterized by recurrent stone

formation in the kidneys due to excess calcium excretion

• thiazide diuretics used to prevent calcium loss and protect the kidneys

4) DIABETES INSIPIDUS


ADVERSE EFFECTS OF THIAZIDES-1

Initially, they were used at high doses which caused a high

incidence of adverse effects. Lower doses now used cause

fewer adverse effects. Among them are:• HYPOKALEMIA• DEHYDRATION (particularly in the elderly) leading to

POSTURAL HYPOTENSION• HYPERGLYCEMIA possibly because of impaired insulin

release secondary to hypokalemia• HYPERURICEMIA because thiazides compete with urate

for tubular secretion



• HYPERLIPIDEMIA; mechanism unknown but cholesterol increases usually trivial (1% increase)

• IMPOTENCE

• HYPONATREMIA due to thirst, sodium losloss, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use


Less common problems

• HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare)

• METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen

• HYPERCALCEMIA



LOOP DIURETICS• Secreted in proximal tubule by acid mechanisms• Act on the ascending loop of Henle to inhibit

sodium and chloride transport• Cause a greater natriuresis than thiazides• Effective at low glomerular filtration rates (as occur

in chronic renal failure), where thiazides are ineffective

• Increase potassium, calcium and magnesium excretion

• Decrease urate excretion• Impair maximal concentrating and diluting capacity


LOOP DIURETICS

• Additional non-tubular effects1. Renal Vasodilation and

redistribution of blood flow2. Increase in renin release3. Increase in venous capacitance

These effects mediated by release of prostaglandins from the kidney.


Loop Diuretics - Pharmacokinetics

• Rapid GI absorption. Also given i.m. and i.v.

• Extensively protein bound in plasma

• Short half-lives in general

• Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile.


CLINICAL USES OF LOOP DIURETICS

• EDEMA due to CHF, nephrotic syndrome or cirrhosis

• Acute heart failure with PULMONARY EDEMA

• HYPERCALCEMIA• not in widespread use for the treatment of

hypertension (except in a few special cases e.g. hypertension in renal disease)


• Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia

• Dehydration and postural hypotension• Hypocalcemia (in contrast to thiazides)• Hypersensitivity• OTOTOXICITY (especially if given by rapid IV

bolus)

Adverse Effects of Loop Diuretics similar to thiazides in many respects


Edema: Therapeutic Considerations

• Therapy is palliative (except with pulmonary edema).

• Need a mild sustained response. • Specific consideration to potassium

homeostasis, i.e. supplement with K-salt or use K-sparing diuretic.

• Therefore, in most cases start with a thiazide.• If resistant, move to Loop diuretic.


Conditions treated with Diuretics

• Edema

• Hypertension

• Nephrogenic Diabetes Insipidus

• Syndrome of Inappropriate ADH Secretion (SIADH)

• To increase or decrease Ca++, K+ or H+ ion excretion.


Diuretic Resistance

1. Compensatory Mechanisms (RAAS, SNS)2. Failure to reach tubular site of action

a - Decreased G.I. absorptionb - Decreased secretion into tubular lumen (e.g. uremia, decreased kidney perfusion)c - Decreased availability in tubular lumen (e.g. nephrotic syndrome)

3. Interference by other drugs (e.g. NSAID’s)4. Tubular adaptation (chronic Loop diuretic use)

Can Use Combination of Diuretics to Induce a Synergistic Effect


Clinical Condition Dose of furosemide (mg)

intravenous Oral

Renal Insufficiency 0 < ClCr < 50 80 160

Renal Insufficiency ClCr < 20 200 400

Nephrotic Syndrome 120 240

Cirrhosis 40 80Congestive Heart

Failure 40-80 80-160

Maximum Doses of Loop Diuretics


Drugs and the kidney

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