DIURETI
CS
GUIDE : CANDIDATE :
Dr. Shiv shankar sharma Dr. Mayank soni
Professor , Dept. Of Medicine RMO II nd Year
MGMMC , INDORE (M.P) Dept. of Medicine MGMMC , INDORE
(M.P)
CLASSIFICATION :-
• High ceiling :- Loop & Osmotic diuretics
• Medium ceiling :- Thiazides
• Low ceiling :- Carbonic anhydrase inhibitors
Potassium sparing diuretics
DRUGS ACTING ON PROXIMAL
TUBULE :-
• CARBONIC ANHYDRASE INHIBITORS
• SGLT-2 INHIBITORS
CARBONIC ANHYDRASE INHIBITORS
:-
Inhibit carbonic anhydrase in proximal tubule as well as intercalated cells of collecting
tubules.
Drugs :-
• Acetazolamide ( Diamox )
• Methazolamide
• Dichlorphenamide
• Self- limiting effect.
• Side effects :-
o Metabolic acidosis , Hypokalemia ( maximum as compared to other diuretics at equal
naturetic doses )
o Renal stones ( Calcium phosphate )
o Hypersenstivity reactions
o Bone marrow suppression ( rare )
o C/I in liver diseases
Uses :-
• Glaucoma ( topical agents – Dorzolamide , Brinzolamide )
In angle closure glaucoma : - 500 mg of oral or I/V Acetazolamide along with other agents .
• Alkalinization of urine
• Mountain sickness
• Idiopathic intracranial hypertension :
Adult dosing is oral 500 mg BD , can go up to 2-4 gm/day in 2-
3 divided doses, if tolerated.
Young children : 25mg/kg/day in 2-3 divided doses ; Max. 100
mg/kg or 2 gm/day .
• Metabolic alkalosis
• Meniere’s disease
• Weaning off from ventilatory support
Acute mountain sickness / High altitude cerebral edema :-
• In Mild symptoms – conservative management ( Avoid further ascent , limit activity ) with symptomatic treatment
( analgesic / anti-emetic )
• In Moderate to severe symptoms – Acetazolamide – 125 to 250 mg BD / TDS
Dexamethasone 4mg oral or I/M 6th hourly x 1-2 days .
• Prophylaxis :-
- T. acetazolamide 125 mg BD .
• Advice :-
•Climb slowly so that enough time is available for the body to adjust to the changes
•Get adequate carbohydrates
•Drink plenty of water
•Do the higher climb during the day and get back to the lower altitude at night for
sleeping
• ADVOR Trail : Acetazolamide in Acute Decompensated Heart Failure with
Volume Overload
• Acetazolamide reduces proximal tubular sodium reabsorption and may improve
diuretic efficiency when added to loop diuretics, thereby potentially facilitating
decongestion.
• The addition of acetazolamide (at a dose of 500 mg administered intravenously
once daily) to intravenous loop-diuretic therapy increased urinary sodium
excretion.
• Addition of acetazolamide to standardized intravenous loop-diuretic therapy
improve the incidence of successful decongestion among patients with acute
decompensated heart failure.
• POINT TO REMEMBER :
• Drugs with CA inhibitors like activity :-
• Cyclophosphamide
• Tenofovir disaproxil
• Topiramate
• Gentamycin
• Outdated tetracycline
SGLT-2
INHIBITORS
Blocks SGLT-2 in PCT . :-
Previously known as “Glorified diuretics” .
Drugs :-
Dapagliflozin, Canagliflozin, Empagliflozin, Ertugliflozin , Ipragliflozin
• Reduction in HbA1c by 0.5-1 %
• Average weight loss by 3-3.5 kg.
• Drop in Systolic blood pressure by 5 mmHg .
• Cardio-protective & Reno-protective effect.
• Reduces the incidence of ESRD in patients with non-diabetic proteinuric CKD.
• Recent trails shows - Oral administration of SGLT 2i appears to be an effective treatment for
hyponatremia.
• SGLT2 inhibitors have been shown to improve magnesium levels in patients with urinary
magnesium wasting.
• Side effects :-
Increased incidence of UTI & Genital infections
DRUGS ACTING ON LOOP OF HENLE :-
• LOOP DIURETICS
• OSMOTIC DIURETICS
LOOP DIURETICS
:-
• Inhibition of Na+ k+ 2cl- symporter at luminal
membrane of Thick ascending LOH
Drugs :
• Furosemide
• Torsemide
• Bumetanide ( Most potent )
• Ethacrynic acid
• Maximal Natriuretic effect than all other diuretics.
Uses :-
• To Remove the edema fluid in Hepatic , cardiac , Renal diseases
• Prompt relief of Acute pulmonary edema .
• Diuretics of choice in presence of moderate to severe renal failure ( GFR < 30
ml/min/1.73 m2 )
• Treatment of Acute Hypercalcemia & Hyper-kalemia ( Selective ).
• Side effects :-
• Metabolic Alkalosis , Hypokalemia , Hypomagnesemia , Hyponatremia , Hyper-glycemia ,
Hyper-uricemia & Dyslipidemia .
• Worsen’s cast formation in Myeloma & Light chain nephropathy .
• Ototoxicity
• Increased risk of fractures ( On long term administration )
• Long term therapy may worsen thiamine deficiency in patients with heart failure.
Dosing :-
• Loop diuretics respond in an all-or-none fashion, meaning there is no way to gradually increase or
decrease the diuretic effect of these medications; they are either “on” or “off.” i.e For a given
individual, a dose is either effective or not
• Loop diuretics are highly protein bound drugs thus not filtered at glomerulus & reach to target site by tubular secretion .
• the effect of loop diuretics is dose dependant , being determined largely by the rate at which the diuretic is delivered to its
site of action .
• Loop diuretics have a threshold dose; no diuretic effect is shown when the dose is lower than the
threshold dose.
• Oral v/s IV :
o Oral bioavailability – 50 % .
o The bioavailability can be improved if it is taken before meals because food can disrupt its
absorption.
o In patients with severe edema, the effect of furosemide may be altered due to inadequate
gastrointestinal absorption. Patients unresponsive to oral furosemide should be switched to
intravenous therapy or oral torsemide.
o The dosage of intravenously administered furosemide is usually half of that of the oral dose.
• Continuous v/s Bolus infusion ?
• T ½ - 2 hours for furosemide and 3-4 hours for torsemide.
• The bolus therapy of furosemide rapidly increases sodium excretion. However, this excretion is at
its maximum for the first 1-2 hours and then it progressively declines .
• The peak natriuretic effect with the second dose is 25% less than that of the first dose. To avoid this
compensation, furosemide should be injected at short intervals or infused continuously.
• Continuous intravenous infusion is more effective than, intravenous bolus therapy. It maintains an
effective rate of furosemide excretion and inhibition of Na+ reabsorption over time.
• The maximum diuresis occurs 3 hours after continuous infusion has begun. Therefore, when
furosemide is administered by continuous infusion, an intravenous loading dose of furosemide is
required to increase the initial intratubular concentration of furosemide.
• The recommended loading dose of furosemide is 40-200 mg according to renal function. The
infusion rate is 10-20 mg/hr which can be increased to hourly 40 mg.
• Diuretic stress test :
• Testing of renal tubular integrity with furosemide in early AKI.
• furosemide is not filtered and thus its function is completely dependent on tubular function. In this context,
furosemide-induced urine output could be used a marker of AKI severity.
• Patients were challenged with a one-time dose of intravenous furosemide
(1.0 mg/kg for loop diuretic naïve patients and 1.5 mg/kg for those who had prior loop diuretic exposure).
• 2-hr urine output in response to a furosemide challenge is seen.
• A urinary response of less than 200 mL over the first 2 h post furosemide administration indicates for the
need of RRT in near future.
OSMOTIC DIURETICS :-
Drugs :- Mannitol (IV) , Glycerol , Urea .
Uses :-
• Cerebral edema
• Glaucoma
• Dialysis disequilibrium syndrome.
• Prevention of Cis-platin induced nephron-toxicity.
• Side effects :-
• Dehydration , Hyperkalemia , Hypernatremia
• Hyponatremia ( in patients with severe renal impairment )
• Acute renal failure.
• Precipitate heart failure.
• Contra-indications :
• Established anuria due to renal disease
• Pulmonary edema or severe pulmonary congestion
• Progressive heart failure
• How to give IV Mannitol ?
• A bolus of 1 g/kg f/b repeat dosing 0.25 to 0.5 g/kg as needed every 6-8 hourly .
• Should be administered as a rapid infusion over 15-30 mins .
• Effects usually present with a peak at approximate 1 hour & lasting upto 6 hours.
• Can never be used at low temperatures as Precipitate into crystals at low temperatures, which
can cause vascular and end-organ damage.
• Monitoring :
• Monitor cardiac function as the fluid shifts can precipitate heart failure.
• Electrolytes including sodium, potassium and Osmolality.
• urine output.
• Stop if significant electrolyte abnormalities develop or the osmolality reaches
320 mOsm or higher.
• Failure for urine output to increase after administration of mannitol should prompt
cessation of mannitol and evaluation for possible renal or genitourinary issues.
DRUGS ACTING ON DISTAL TUBULE &
COLLECTING DUCTS:-
• THIAZIDES & THIAZIDE LIKE DIURETICS
• POTASSIUM SPARING DIURETICS
THIAZIDE & THIAZIDE LIKE
DIURETICS :-
Blocks Na+-k+ symporter in early DT .
Drugs :-
Thiazide’s :-
• Chlorthiazide
• Hydrochlorthiazide
• Bendroflumethiazi
de
• Methichlothiazide
• Hydroflumethiazid
Thiazide like e
:-
• Chlorthalidone
• Indapamide
• metolazone
Uses :
• Anti-hypertensive :
• Low dose Thiazide / thiazide like diuretics are used to minimize
metabolic complications.
• Fall in BP is significantly larger with Chlorthalidone / Indapamide as
compared to Hydrochlorthiazide.
• Low dose Chlorthalidone ( 12.5-25 mg/day ) reduces cardiovascular
events ( ALLHAT Trail )
( Antihypertensive & lipid lowering treatment to prevent heart attack )
• Chlorthalidone is 1.5-2 times as effective as hydro-chlorthiazide at
lowering BP at same dose given for longer duration.
Other Uses :
• Heart failure
• Nephrogenic Diabetes Insipidus ( Hydro-chlorthiazide )
• Idiopathic Hyper-calciurea / Recurrent Calcium stones in kidney .
• Reduces the risk of osteoporotic fractures.
(Thus preferred in hypertensive elderly females with Strict sodium monitoring )
Side Effects :
Dose dependant:
• Metabolic Alkalosis , Hypokalemia , Hypomagnesemia , Hyponatremia ,
Hyper-glycemia , Hyper-uricemia , Dyslipidemia
Dose Independant:
• Erectile dysfunction , Sleep cycle disturbances.
C/I in patients with Renal failure ( Except –
Metolazone )
POTASSIUM SPARING
DIURETICS :-
• ENaC Blockers
• Aldosterone antagonist
Epithelial Na+ Channel Inhibitors:-
DRUGS :-
• Amiloride
• Triamterene
USES :
• Lithium induced diabetes insipidus
• Liddle syndrome
Side effects :-
Renal stones , interstitial nephritis , Megaloblastic anemia ,
photosensitivity , impairment of glucose tolerance
Aldosterone antagonists:-
DRUGS :-
• Spironolactone
• Eplerenone
• Finerenone
USES :
• Anti-hypertensive ( Drug resistant hypertension )
• Heart failure ( HFrEF )
• Cirrhotic edema
• Treatment of hirsutism
• Hyperaldosteronism ( Primary / secondary )
Side effects :-
Gynaecomastia , Hyperkalemia , Hyperchloremic metabolic acidosis
Finerenone Non-steroidal mineralocorticoid antagonist.
:
• The ADA & KDIGO recommened the use of finerenone in patients of diabetic kidney disease who
have increased albuminuria despite treatment with ACE Inhibitors and SGLT-2 Inhibitors.
( FIGARO-DKD TRAIL )
• Cardio-protective effect.
• The anti-hypertensive action is inferior to spironolactone / eplerenone.
When not to give ?
• Serum potassium > 4.8 mEq/L
• Estimated GFR <25 ml/min/1.73 m2
V2 Receptor
antagonists:-
DRUGS :-
• Tolvaptan (oral)
• Lixivaptan
• Mozavaptan
• Conivaptan ( V1a/V2 ) ( IV )
USES :
• SIADH
• ADPKD
• Heart failure ( IV Conivaptan )
Side effects :-
Nephrogenic DI , Hypotension , dry mouth , polyuria , Infusion site reactions ( conivaptan )
Tolvaptan : • SIADH , ADPKD
• TEMPO TRIAL ( Tolvaptan efficacy & safety in management of ADPKD & Its outcomes.
• REPRISE TRIAL ( Replicating evidence of preserved renal function : an investigation of tolvaptan
safety & efficacy in ADPKD )
Contraindicated :-
• Elevation in liver function tests ( C/I in Active hepatitis )
• If AST, ALT or Bilirubin >2 times of ULN , Tolvaptan should be immediately
stopped & repeat test after 48-72 hours.
• If laboratory abnormalities stabilize or resolve , tolvaptan may be reinitiated &
may be continued as long as AST & ALT remains <3 times of normal .
• Not to be restarted if AST/ALT > 3 times of normal.
References :
• Goodman & Gilman's The Pharmacological Basis of Therapeutics.
• Katzung & Vanderah pharmacology 15th edition.
• Loop Diuretics in Clinical Practice - PMC (nih.gov)
• (PDF) Loop Diuretics in Clinical Practice (researchgate.net)
• A profile of SGLT-2 inhibitors in hyponatremia: The evidence to date - PubMed (nih.gov)
• Improvement in Serum Magnesium Levels With Sodium-Glucose Cotransporter 2 Inhibitors | JCEM Case
Reports | Oxford Academic (oup.com)
Thank you !
