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Introduction to Diuretics


Classification:
 
High efficacy diuretics (LOOP DIURETICS)
(lnhibitors of Na+-K+-2Cl- - cotransport)
Medium efficacy diuretics
(lnhibitors of Na+-Cl-- symport)
Weak or adjunctive diuretics
Furosemide,
Bumetanide,
Torasemide
Axosemide
(Ethracynic acid and Organomercurials are only historical)
 
 
 
 
 
 
 
a) Thiazides 
Hydrochlorothiazide,
Benzthiazide,
Hydroflumethiazide,
Clopamide
b) Thiazide like
Chiorthalidone,
Metolazone,
 Xipamide,
 Indapamide
(a) Carbonic anhydrase inhibitors
Acetazolamide,  Methazolamide , Dichlorphenamide
b) Potassium sparing diuretics
(i) Aldosterone antagonists:
Spironolactone, Eplerenone, Canrenone
(ii) Inhibitors of renal epithelial Na* channel
Triamterene, Amiloride.
 (c) Osmotic diuretics (Aqurectics)
 Mannitol,
Isosorbide,
Glycerol
Urea
(d) Adenosine A1 antagonist
Caffeine
(e) ADH antagonist
Conivaptan
Tolvaptan



 
 
 
 
 
 
 




 










 






Thiazides

MOA EFFECTS CLINICAL APPLICATION TOXICITY
Inhibition of the Na/Cl transporter in the Distal Convoluted Tubule
 
Modest increase in Na/Cl excretion
Some K wasting
Hypokalemic metabolic alkalosis
Decreased urine Ca/Mg
Hypertension,
Mild CHF,
Nephrolithiasis,
Nephrogenic diabetes insipidus
 
Hypokalemic metabolic alkalosis,
Hyperuricemia,
Hyperglycemia,
Hyponatremia
 

  1. MC used                              
  2. Sulfonamides (Sulfanilamides)              
  3. Slowest diuretics
  4. Act upon DCT (early)            
  5. Inhibit Na+ 2Cl cotransport

P/K

  1. Well absorbed; HCT absorption is increased by meals
  2. Metolazone, indapamide—eliminated by bile
  3. Both are vasodilatory thiazides
  4. Others eliminated by tubular secretion
  5. Thiazides are safe upto GFR 35 ml/min 

Uses

  1. DOC
  • Hypertension (25 mg of HCT)
  1. Slow acting  
  2. No postural hypotension    
  3. Conserve calcium; hence slow down bone loss 

Other uses (DOC)

  1. Nephrogenic DI
  2. Renal stones of calcium oxalate
  3. Idiopathic hypercalciuria (William’s syndrome)
  4. Liddle’s syndrome
  5. 1* hyperparathyroism
  • Prevent renal stones

S/E

  1. MC hypokalemia
  2. Hyperglyecemia (inhibit conversion of proinsulin to insulin)
  3. Hyperuricemia
  4. Hyperlipedemia
  5. Hypercalcemia
  6. Renal cell cancer (Rare)
  7. Impotence (MC drugs causing impotence) 

D/I

  1. Thiazides reduce renal clearance of lithium
  2. xCan precipitate toxicity of digoxin  
  1. Loop diuretics

MOA EFFECTS CLINICAL APPLICATION TOXICITY
 
Inhibition of the Na/K/2Cl transporter in the Ascending limb of Henle’s loop
 
Marked increase in Na/Cl excretion,
Some K wasting,
Hypokalemic metabolic alkalosis,
Increased urine Ca/Mg
 
Pulmonary Edema,
Peripheral Edema,
Hypertension,
Acute Hypercalcemia Or Hyperkalemia,
Acute Renal Failure,
Anion Overdose
Ototoxicity,
Hypovolemia,
K+ Wasting,
Hyperuricemia,
Hypomagnesemia
 

  1. Fastest, most efficacious drugs
  2. Contain sulphanilamide moeities
  3. Act upon thick ascending segment of LOH
  4. Inhibit Na+K+ 2Cl cotransport (also called as Tamm-Harshphall protein)
  5. Also activate tubule-glomerular feedback and hence can reduce free water clearance  

P/k

  1. Well absorbed
  2. Toresemide has earliest onset of action
  3. Bumetanide is most potent
  4. Furosemide (LASIX)-acts for 6 hours
    1. Increases RBF; even effective in anuria
    2. NSAIDs inhibit this action 

Ethacrynic acid

  1. Phenoxyacetic acid derivative
  2. Loop diuretic
  3. Different chemical class
  4. Even effective when allergy to loop/thiaizde
    1. Ototoxic                
    2. Gastrotoxic          
    3. Poor oral absorption

Furosemide (DOC)

  1. Malignant hypertension                
  2. Hypertension with renal failure
  3. Renal failure with edema                      
  4. Hypercalcemia
  5. Hyperuricemia*                           
  6. Thiazide resistance

D/I

  1. NSAIDS blunt diuretic action of furosemide
  2. Ototoxic drugs increase ototoxicity
  3. Furosemide, does not interfere with renal clearance of lithium

S/E

  1. MC hypokalemia                  
  2. Hypovolumia                                
  3. Hyponatremia  
  4. Hyperuricemia                      
  5. Otoxicity (Furosemide specific)                     
  6. Hypomagnesia (Both with loop & thiazides) 
  1. Carbonic anhydrase inhibitors
MOA EFFECTS CLINICAL APPLICATION TOXICITY
 
Inhibition of the enzyme prevents dehydration of H2CO3 and hydration of CO2 in the Proximal Convoluted Tubule
 
Reduces Reabsorption Of HCO3−, causing Self-limited diuresis
Hyperchloremic Metabolic Acidosis Reduces Body pH,
Reduces Intraocular Pressure
Glaucoma,
Mountain Sickness ,
Edema With Alkalosis
 
Metabolic Acidosis,
Renal Stones,
Hyperammonemia In Cirrhotics
 

  1. Weakest diuretics                                                        
  2. Sulfonamides
  3. Inhibit HCO3- Absorption (loss of bicarbonate-metabolic acidosis)             
  4. Act upon PCT

p/k

  1. Well absorbed                      
  2. Half life of acetazolamide=1 hour
  3. Dorzolamide is topical          
  4. Metabolized in liver, eliminated by tubular secretion

Use

  1. Acetazolamide (DOC)
  2. Acute mountain sickness (Prophylaxis)
     
    i. HAPE-furosemide, HABE-oxygen
  3. Familial periodic paralysis
  4. Cystinuria
  5. Uric acid stones
  6. Acute narrow angle glaucoma

C/I

  • Liver cirrhosis

S/E

  • HSP
  1. Hypersensitivity            
  2. Stones (phosphate, calcium stones)
  3. Paresthesia (MC)          
  4. Hypokalemia (Severe) Contraindications  
  5. Liver cirrhosis  
  1. Ostomotic diuretics
MOA EFFECTS CLINICAL APPLICATION TOXICITY
 
Physical Osmotic Effect On Tissue Water Distribution Because It Is Retained In The Vascular Compartment.
 
Marked Increase In Urine Flow,
Reduced Brain Volume,
Decreased Intraocular Pressure,
Initial Hyponatremia, Then Hypernatremia
Renal Failure Due To Increased Solute Load (Rhabdomyolysis, Chemotherapy),
Increased Intracranial Pressure,
Glaucoma
Nausea,
Vomiting,
Headache
 

  1. Mannitol              
  2. Isosorbide            
  3. Urea                    
  4. Glycerol 

A. Mannitol

  1. Freely filtered carbohydrate          
  2. Not metabolized          
  3. Not a sulfonamide

MAO

  1. Act upon thin descending segment of LOH
  2. Earlier, it was believed to be PCT diuretic
  3. Expands ECF

p/k

  1. Not absorbed orally              
  2. Not metabolized   
  3. Half life-1 hour            
  4. Laxative-causes diarrhea

Uses

  • DOC
  1. Acute narrow angle glaucoma        
  2. Oliguric renal failure (Increases RBF)
  3. Brain edema                              
  4. Cisplatin induced nephropathy

C/I

  1. Intracerebral haemorrhage            
  2. ATN              
  3. Pulmonary edema with LVF

S/E

  • MC
  • Hypovolumia
  1. Hypernatremia
  2. Hyperkalemia
  MOA EFFECTS CLINICAL APPLICATIONS TOXICITY
SPIRONOLACTONE Pharmacologic antagonist of aldosterone in collecting tubules
Weak antagonism of Androgen receptors
 
Reduces Na retention and K wasting in kidney
Poorly understood antagonism of aldosterone in heart and vessels
 
Aldosteronism from any cause
Hypokalemia due to other diuretics
Post-myocardial infarction
 
Hyperkalemia,
Gynecomastia (spironolactone, not eplerenone)
Additive interaction with other K-retaining drugs
 
AMILORIDE Blocks epithelial sodium channels in collecting tubules Reduces Na retention and K wasting
Increases lithium clearance
Hypokalemia from other diuretics
Reduces lithium- induced polyuria
Hyperkalemic metabolic acidosis


 


















 

Does Not Cause Inhibition Of Transpost Of Any Ion -only increases water diuresis (Increases free water clearance) 
  1. K+ SPARING DIURETICS
    1. Aldosterone receptor blockers
       
      i. Spironolactone              
       
      ii. Eplerenone
    2. Na+ channel blockers
       
      i. Amiloride                      
       
      ii. Triamterene
    3. K+ sparing are sulfonamides
    4. Slowly acting, weak diuretics

MAO

  1. Na+ blockers
     
    i. Late DCT
  2. Aldosterone blockers
     
    i. Late DCT
     
    ii. Collecting duct

p/k

  1. Well absorbed; high first pass metabolism
  2. Triamterene, spironolactone avoided in hepatic failure
  3. Spironolactone-prodrug-canrenone---half life=24 hours
  4. Accumulates in renal failure

Use

Spironolactone (DOC)

  1. Conn syndrome (1* hyperaldosteronism)
  2. Secondary hyperaldosteronism
  3. Hirsutism

Eflornithine is a new drug (antihelminthic drug, inhibits ORNITHINE DECARBOXYLASE ENZYME)

  1. ADH/VASOPRESSIN ANTAGONIST

  MOA EFFECTS CLINICAL APPLICATIONS TOXICITY
CONIVAPTAN Antagonist at V1a and V2 ADH receptors
 
Reduces water reabsorption,
Increase plasma Na concentration,
Vasodilation
 
Hyponatremia,
Congestive heart failure
 
Infusion site reactions,
Thirst,
Polyuria,
Hypernatremia
 
TOLVAPTAN Selective antagonist at V2 ADH receptors Reduces water reabsorption,
increases plasma Na concentration
Hyponatremia,
SIADH
Polyuria (frequency),
Thirst,
Hypernatremia








 





 

  1. Antidiuretics
    Desmopressin
    1. Synthetic analogue of vasopressin
    2. 9- amino acid peptide

S/E

  • MC
  1. Hyperkalemia              
  2. Sulfa allergy                
  3. Gynecomastia
    1. Spirolactone is MC drug causing
    2. Tamoxifen is DOC for painful gynecomastia

D/I

  1. Triamterene should not be given with indomethacin---renal failure
  2. K+ sparing diuretics not given with:
    1. NSAIDs          
    2. Beta-blockers              
    3. ACE I          
    4. ARBs          
    5. Potassium
  • Added risk of hyperkalemia occurs

MAO

  1. Acts upon V1 (IP3/DAG)  & V2 (increase cAMP)
  2. Both are GPCRs
  3. V1 (blood vessels); V2 (Collecting Duct)

Uses

  1. Craniogenic diabetes insipidus (DOC)
  2. Nocturnal enuresis ? Earlier drug (imipramine) (DOC)
  3. Also used in:
i. Cristmas Disease (Liver)
ii. Von-Willebrand disease (Endothelium)
iii. S/e-hypertension

 

Terlipressin-

  • V1 receptor agonist,and useful for the treatment of esophageal varices.
  • DOC for esophageal varices is octreotide(somatostatin analogue)
  • Prophylactic DOC for esophageal varices is non specific beta bloakcer like propanolol.

Recent Advances:

New drug named → Rolophylline

It is methylxanthine analogue and acts by inhibiting adenosine receptor.

Adenosine is mediater of JG reflex which causes afferent artery constriction.

Approved to prevent diuretic induced kidney failure in CHF patients by causing vasodilation.

  

SIADH

  1. Demeclocycline   DOC
  2. Vaptan group:
    1. Conivaptan(non specific inhibitor)(V1 and 2 both)
    2. Tolvaptan and lonivaptan(specific inhibitor)(V2)





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