Diuretics & Anti-Diuretics.pptx

Diuretics & Anti-Diuretics.pptx

• 1.
  DIURETICS Dr.Arka Mondal Assistant Professor
• 2.
  Introduction  Diuresis:- ↑Urinevolume  Natriuresis:-↑Na excretion  Kaliuresis:- ↑K excretion  Diuretics:-drugs that ↑renal excretion of water & solutes (mainly Na salt) to ↓fluid volume of the body & adjust the water electrolyte balance  Use for –  Pathological condition like-  Edema,  CHF  Renal disease  Hypertension
• 4.
  Classification of diuretics Highefficacy/high- ceiling/Loop diuretics/ Inhibitors of Na+K+2Cl - symport  Furosemide  Torsemide  Bumetanide Medium efficacy diuretics/ Inhibitors of Na+ Cl- symport  Benzothiadiazines :- Chlorothiazide, Hydrochlorothiazide Hydroflumethiazide Benzthiazide  Thiazide like- Chlorthalidone, Metolazone, Xipamide Indapamide Clopamide Low efficacy/weak diuretics  Carbonic anhydrase Inhibitors:-Acetazolamide  Potassium sparing diuretics:-  1. Aldosterone antagonist: Spironolactone Eplerenone  2. Renal epithelial Na+  channel inhibitors:- Amiloride, Triamterene  Osmotic diuretics:- Mannitol, Glycerol, Isosorbide
• 5.
  CARBONIC ANHYDRASE INHIBITORS(CA-Inhibitors) Drug-Acetazolamide,Methazolamide, Dorzolamide, Brinzolamide Systemic (oral route use as diuretics) Topical (Use in Glaucoma) Acetazolamide, Methazolamide Dorzolamide, Brinzolamide  Carbonic Anhydrase Enzyme-  Distribution-Kidney, CNS, Eye, Gastric mucosa, Pancreas & RBC  In kidney:-  Present in luminal & basolateral membrane (membrane bound) & in cytoplasm of proximal tubular epithelial cell(PCT)
• 6.
  :- • Site ofAction-PCT Inhibit HCO3- reabsorption in the PCT(↓availability of H+ ion in PCT) Also- Inhibits Cl-,Na, Bicarbonate reabsorption →less water reabsorbed Resulted-↑Na concentration in tubular fluid↔ Partially compensated by ↑NaCl reabsorption in later segments of tubule thus its (low efficacy diuretics) Inhibit both the membrane – bound and cytoplasmic forms of carbonic anhydrase CA-inhibitors
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  Mechanism of Action:-
• 8.
  Other Actions:- Aqueous humor:-↓the rate of formation →consequently ↓ IOP CSF:-↓ the rate of formation (sedation & paresthesia) ↑seizure threshold Pharmacokinetics:- Absorption-well orally (Acetazolamide) t1/2-6-10hrs Oral BA-100% Excretion- unchanged in urine
• 9.
  Therapeutic Uses:- Glaucoma- asadjuvant in narrow angle glaucoma (Local action so less side effect) Acute Mountain sickness(High altitude sickness)- Above 10,000ft. Symptoms:- Cerebral edema, Headache, Dizziness due to hypoxia followed by respiratory alkalosis ℞-Tab. Acetazolamide-250 mg(prophylaxis) 24hr.before the ascent –cont.2days after returning to ground level Mechanism:- Acetazolamide→↓pH by metabolic acidosis which counteract respiratory alkalosis
• 10.
  It ↑ventilation withacclimatization & maintain oxygenation Familial periodic paralysis- Occur due to sudden fall in plasma K+ level which is corrected by Acetazolamide Metabolic alkalosis:- In Heart failure pt.→ alkalosis occur due to excessive use of diuretics Preferred drug- Acetazolamide Epilepsy:- in absence seizure as adjuvant Acetazolamide→↑seizure threshold
• 11.
  Side effect:- Hypokalemia-due toloss of K+ Acidosis Renal Stone formation due to precipitation of calcium phosphate salts in an alkaline urine Drowsiness, paresthesia Contraindications:- Hepatic cirrhosis:- due to alkaline urine→ interfering with excretion of ammonia Acidosis or severe chronic obstructive pulmonary disease
• 12.
  OSMOTIC DIURETICS Freely filteredat the glomerulus Not reabsorbed by renal tubule Relatively inert pharmacologically Non – metabolizable Increase plasma osmolarity Currently available osmotic diuretics -Mannitol, Glycerin, Isosorbide, Urea
• 13.
  Site of action:Proximal tubule , Descending loop of Henle MOA:- Osmotic diuretics ↓ ↑osmolarity of plasma & tubular fluid ↓ ↑Urine volume ↓ ↑Renal Blood Flow ↓ ↓ Medullary hypertonicity → ↓ salt reabsorption Acts by an osmotic effect in the tubules as non-re-absorbable solutes
• 14.
  In general, osmoticdiuretics ↑↑ the urinary excretion of nearly all electrolytes including Na+, K+, Ca 2+, Mg2+, Cl-, HCO3 - & phosphate Mannitol→↓tubular water electrolyte reabsorption by following method 1.Due to osmotic effect-fluid is retained in the lumen of PT 2.Expand ECF- ↑Intravascular volume ↓ Draws water from the intracellular compartment to Ecf ↓ ↑↑ GFR & hydrostatic pressure in glomerular capillaries & inhibit rennin release ↓ (↑urine volume) 3.↑renal blood flow→ Specially in medulla
• 15.
  -:Therapeutic Uses:- In impendingrenal failure (e.g shock, ischemia, nephrotoxins, Hemoglobinuria, myoglobinuria)→↑urine volume Acute attacks of glaucoma-They draw fluid from eye, by osmotic effect into blood For short - term reductions in IOP (both pre-operatively and post- operatively) To reduce cerebral edema and brain mass (before and after neurosurgery) Head injury with ↑intracranial Tension→↓ICT  To produce forced diuresis in case of poisoning (barbiturate)
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  -:Adverse Effects:- Headache, nausea,vomiting Loss of water in excess of electrolytes can cause hyponatremia and dehydration I.V. urea- Pain & thrombosis (site of administ.) -:Contraindicated:-  Anuria due to severe renal disease/ATN  Heart failure / Acute LVF(left ventricular failure)-↑osmolality of ECF, may produce pulmonary edema  Cerebral hemorrhage
• 17.
  Na-K-2Cl SYMPORT INHIBITORS Also Called: •LoopDiuretics •High Ceiling Diuretics Ethacrynic Acid (EDECRIN) Torsemide (DEMADEX) Bumetanide (BUMEX) Furosemide (LASIX)  Process maximal Na+ excreting capacity when compared to thiazides & potassium-sparing diuretics so called as “High ceiling Diuretics”
• 18.
  MOA:-  Site ofaction:- thick ascending limb of loop of Henle • Enter proximal tubule via organic acid transporter • Inhibition of the apical Na+-K+-2Cl- cotransporter of the TALH • Result:- • ↓NaCl reabsorption • ↓K+ Accumulation in cell • ↓reabsorption of Mg/Ca • ↑Mg++, Ca++ excretion-hypomagnesaemia • Competition with Cl- ion for binding • Stimulate renal PG synthesis→ NSAIDs interfere with loop diuretics by ↓PG synthesis
• 20.
  Pharmacokinetics • Absorption:-Rapid orally, •BA- ranges from 65-100% • Extensively bound to plasma proteins • Furosemide and bumetanide-administered by oral, i.v., and i.m. routes. • Torsemide is given orally • Furosemide has a rapid onset of action—within 2–5 min of i.v. • The duration of action of furosemide is short (4-6 hours) • secreted by proximal tubule organic acid transporters • Bumetanide-40 time more potent than furosemides • Ethacrynic acid-100% BA
• 21.
  THERAPEUTIC EFFECTS Increase NaExcretion to 25% of Filtered Load Treatment for Oliguric Acute Renal Failure Increase Ca Excretion Treatment for Hypercalcemia Impair Free Water Reabsorption Increase Venous Capacitance Treatment for Pulmonary Edema Increase Urine Volume Treatment for Severe Edema  Furosemides → Diuretic of Choice in pt. with severe renal failure (Acute + chronic) IN CHF ↓pre-load due to potent natriuretic &diuretic action
• 22.
  • Acute pulmonaryoedema—loop diuretics act in the following way I.V. furosemide ↑PG synthesis and release ↑Renal blood flow ↑Systemic venous capacitance Results in shift of blood from central pulmonary to systemic vessels ↓left ventricular filling pressure Produces quick relief from pulmonary oedema
• 23.
  ADVERSE EFFECTS Hypomagnesemia Metabolic Alkalosis Hypokalemia Profound ECFV Depletion Hyperglycemia Hyperuricemia Ototoxicity Hypocalcemia Dueto ↓Na+ absorption at PT ℞- loop diuretic +K+-sparing diuretic Ethacrynic Acid ↑ urinary excretion of Ca2+ and Mg2+ ↓renal excretion of uric acid & may precipitate attacks of gout ↓ insulin secretion
• 24.
  Contraindications:-  Severe Na+and volume depletion  Hypersensitivity to sulfonamides Drug interaction:-  Loop diuretics × warfarin- Displacement of plasma protein binding of warfarin  Loop diuretics × Li+ →clearance is decreased for Li  Furosemide × aminoglycosides:- Both are ototoxic drugs(Additive effect)  Furosemide ×Probenecid, NSAID’s → Inhibitors of organic acid transport (OAT- 1,3) →↓concentration in tubular fluid→ (↓uricosuric action of probenecid)
• 25.
  Na-Cl SYMPORT INHIBITORS AlsoCalled: •Thiazide Diuretics •Thiazide-Like Diuretics Chlorthalidone (HYGROTON) Metolazone (ZAROXOLYN) Chlorothiazide (DIURIL) Hydrochlorothiazide (HYDRODIURIL)
• 26.
  MECHANISM OF ACTION •Site of action:-Early distal convoluted tubule (DCT) • Thiazides freely filtered and secreted in proximal tubule • Bind to the electroneutral Na-Cl cotransporter in renal cortex • Thiazides impair Na+ and Cl- reabsorption in the early distal tubule: “Medium efficacy” because 90% of filtered Na+ load is reabsorbed before reaching the site of action of thiazide (DCT) • Some of the thiazides also have weak carbonic anhydrase inhibitory action and ↑HCO3 - loss (except-indapamide) • ↑Ca++ reabsorption on DCT→ Because blocked of Na-Cl cotransporter will enhance basolateral Na/Ca exchanger • Thiazide action depends →On renal PG synthesis so (NSAIDs) ↓PG synthesis will inhibit thiazide action
• 29.
  Pharmacokinetics • Absorption- wellorally • BA-approx.100% • Diuresis within one hour • They have a long duration of action and are excreted in urine • T1/2 for chlorothiazide is 1.5 hours, chlorthalidone 44 hours – Whole Body Effects of Thiazides:- – Increased urinary excretion of: – Na+, Cl-,K+,Water,HCO3- (dependent on structure) – ↓ ECF volume (contraction) – ↓ blood pressure (lower CO) – ↓ GFR
• 30.
  THERAPEUTIC EFFECTS Increase NaExcretion to 5-10% of Filtered Load Treatment for Hypertension(moderate-severe) ↓ Ca Excretion & ↑Ca reabsorption Treatment for Calcium Nephrolithiasis Treatment for Nephrogenic Diabetes Insipidus Treatment for Mild Edema Due to diuretic effect & Vasodilatory effect ↓Ca containing Kidney stone Use along with loop diuretics in severe resistant oedema ↓responsiveness of ADH Thiazides ↓urine vol. upto-50% paradoxically
• 31.
  • “Thiazides usedas Anti-diuretics in Diabetes insipidus” Explain why..? Possible Mechanism- 1.Paradoxical effect:- Thiazides ↓↓ ↓effective circulatory volume ↓↓ ↓GFR Due to which there is more reabsorption of water from kidney tubules (Less excretion of Urine)
• 32.
  2. Thiazides ↓↓ inhibits cyclonucleotide phosphodiesteraseEnzyme ↓↓ ↑cAMP ↓↓ ↑Permeability of collecting Duct towards water ↓↓ ↓Volume of urine
• 33.
  ADVERSE EFFECTS Hypomagnesemia Metabolic Alkalosis Hypokalemia ECFV Depletion Hyperglycemia Hyperuricemia Hyponatremia Hypercalcemia Impotence IncreasedLDL Hyperlipidemia Due to ↑thirst, hypovolemia-induced ADH elevation Diluting effect Rx-↓dose ↓water intake
• 34.
  • Drug interaction:- •Thiazide × Digoxin, Li, Quinidine (due to hypokalaemia & increase binding capacity of digoxine to Na+K+ATP-ase (leading to digoxin toxicity) • Thiazide + loop diuretics × Anti-coagulants, uricosuric drugs, sulphonylurease & insulin-↓effect of those drugs • Thiazide-like Diuretics:- • Chlorthalidone:- • Frequently used thiazide-like diuretic in hypertension as it has a longest acting thiazide (48hr.) • Indapamide:- more potent, longer acting and produce fewer adverse effects than thiazides
• 35.
  • Use inhypertension. • Metolazone:- • More potent, longer acting and produce fewer adverse effects than thiazides. • Effective when GFR<20ml/min • Dose:-2.5-10mg OD • Xipamide:- • Structurally related to chlorthalidone & frusemide
• 36.
  Na+ CHANNEL INHIBITORS Also Called: •K-SparingDiuretics Amiloride (MIDAMOR) Triamterene (DYRENIUM)
• 37.
   Site ofAction:-late collecting tubule & collecting duct Mechanism of action:-  Blockade of apical Na+ channel in the principal cells  They directly block the Na+ channels in the luminal membrane of the cells of the late DCT and CD leading to blocked of electrogenic entry of sodium causes a drop in apical membrane potential (less negative), which is the driving force for K+ secretion  The net effect of these drugs is ↑Na+ excretion and retain potassium- hence these are called K+-sparing diuretics.
• 39.
  Pharmacokinetics • Triamterine – 50%absorption of oral dose – 60% bound to plasma proteins – Extensive hepatic metabolism with active metabolites – Secreted by proximal tubule via organic cation transporters • Amiloride – 50% absorption of oral dose – not bound to plasma proteins – not metabolized, excreted in urine unchanged – Secreted by proximal tubular cation transporters
• 40.
  THERAPEUTIC EFFECTS Enhance Natriuresis Causedby Other Diuretics Block Na Channels Prevent Hypokalemia Used in Combination with Loop & Thiazide Diuretics Treatment for Lithium- Induced Diabetes Insipidus -Amiloride augments hydration of respiratory secretions and thereby improves mucociliary clearance- cystic fibrosis
• 41.
  ADVERSE EFFECTS Renal Stones -leastsoluble in urine Hyperkalemia Hyperkalemia Amiloride Triamterene Headache, Nausea, vomiting
• 42.
  MINERALOCORTICOID RECEPTOR ANTAGONISTS Also Called: •K-SparingDiuretics •Aldosterone Antagonists Spironolactone Eplerenone
• 43.
  Spironolactone is analdosterone antagonist It is a synthetic steroid and structurally related to aldosterone Aldosterone enters the cell and binds to specific mineralocorticoid receptor (MR) in the cytoplasm of late distal tubule and collecting duct (CD) cells The hormone–receptor complex (MR–AL) enters the cell nucleus, where it induces the synthesis of aldosterone-induced proteins (AIPs) The net effect of AIPs is to retain sodium and excrete potassium Spironolactone competitively blocks the mineralocorticoid receptor and prevents the formation of AIPs Promotes Na+ excretion and K+ retention
• 44.
  Spironolactone is mosteffective when circulating aldosterone levels are high. It also increases Ca2+ excretion Low efficacy Diuretics-Mild ↑Na+ & Cl- excretion
• 45.
  Pharmacokinetics • Absorption:- 70%absorption in GI tract(oral BA-70-75%) • Food-↑Absorption • Distribution:-Extensively bound to plasma proteins-slow onset of Action • Metabolism:-Extensive first pass effect in liver and enterohepatic circulation • Active metabolite: Canrenone (active)-t1/2-17hr • Excretion:-100% metabolites in urine
• 46.
  THERAPEUTIC EFFECTS Enhances Natriuresis Causedby Other Diuretics Blocks Aldosterone Treatment for Primary Hyper- aldosteronism Prevents Hypokalemia Used in Combination with Loop & Thiazide Diuretics Treatment for Edema of Liver Cirrhosis Treatment for Hypertension Treatment for Heart Failure Hirsutism & PCOD Due to antiandrogenic action
• 47.
  ADVERSE EFFECTS Impotence Gynecomastia Metabolic Acidosis Hyperkalemia CNS Side Effects PepticUlcers Gastritis Menstrual Irregularities Deepening of Voice  ↑Testosterone clearance  Covert Testosterone to estradiol  Inhibit androgen production Inhibition of H+ secretion
• 48.
  IMPORTANT DRUG INTERACTIONS:- ACE Inhibitors× spironolactone→ dangerous Hyperkalemia  NSAID’s × spironolactone → ↓action of spironolactone Eplerenone:-  More selective aldosterone antagonist  less estrogenic A/E → low affinity for androgen receptor  Potent CYP3A4-inibitors  Well absorbed orally  Metabolism-liver  USE:- Hypertension, CHF
• 49.
  ANTI-DIURETIC DRUGS
• 50.
  • Antidiuretics→ drugsthat ↓ urine volume • “Anti-Aquaretics”→inhibit water excretion without affecting salt excretion ANTI-DIURETICS  Vasopressin (ADH)  Desmopressin  Lypressin  Terlipressin Antidiuretic hormone & its analogues  Thiazides  Amiloride Natriuretics  Carbamazepine  Chlorpropamide  Indomethacin Miscellaneous
• 51.
  • VASOPRESSIN(ADH):- • Poly-peptidehormone consisting of nine amino acid • synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in posterior pituitary • Stimulated by ↑plasma osmolality (due to H20 loss & ↑Na concentration) • Structurally similar to oxytocin & process cross biological activity like contraction of smooth muscle of uterus, as well as the GIT • ADH cause→↑permeability of the collecting ducts & distal tubules to water • Result→↑reabsorption of water by nephrons • T1/2- 15-20min • ADH (Vasopressin) receptors:- V1-receptor V2-receptor
• 52.
  V1-receptor V2-receptor Vasopressin Receptor V1aV1b Also called V3  Distribution:- Renal medullary interstitial cells Vasa recta, platelets, spleen, testis Renal cortical CD Myometrium, Adipocytes, Platelets Distribution:- Anterior pituitary, Certain areas in brain,Pancreas  Distribution:- Principal cells of collecting ducts (CDs) in the kidney More sensitive to ADH than V1
• 53.
  Pharmacological Action ofVasopressin V1 receptors  V1a-mediated:- • Blood vessels: Vasoconstriction • GIT: Increases peristalsis • Liver: Glycogenolysis • Platelets: Aggregation  V1b-mediated:- • CNS: Release of ACTH from anterior pituitary V2 receptors:- • ↑H20 permeability (↑ H20 reabsorption) in CD-↓ urinary output • Blood vessel-Vasodilatation (Release NO) • Release of clotting factor VIII & Von Willebrand’s factor from vascular endothelium
• 54.
  Drugs Affecting Therenal actions of Vasopressin Drugs ↑ Antidiuretic response  NSAIDS- Indomethacin  Carbamazepine,  Chlorpropamide,  Clofibrate Drugs ↓ Antidiuretic response  Lithium  Demeclocycline  Ethanol Pharmacokinetics:-  Inactive orally (Destroyed) by proteolytic Enzyme→ administered parentally (i.m.,i.v.,s.c. or intranasal)  Metabolized rapidly in liver
• 55.
  Vasopressin Analogues • Desmopressin:- •Selective V2 receptor agonist (Synthetic analogue) • 10 time More potent than vasopressin-antidiuretic • It has negligible V1 receptor mediated vasoconstrictor action • It is administered by oral, nasal and parenteral routes • t1/2 is 2hr. but duration of action is longer-10hr. • DOC in Central diabetic insipidus(i.m./S.c., intranasally) • Dose- 0.3-0.6 orally • Lypressin:- • It acts on both V1 and V2 receptors (Non-selective agonist) • It is less potent but longer acting • USE:-Oesophageal varices
• 56.
  • Terlipressin:- • Prodrugof vasopressin with selective V1 action • i.v. administration • Less toxic than lypressin • Use:- oesophageal varices-control bleeding -:Therapeutic uses of Vasopressin Analogues:- • 1. For emergency control of bleeding esophageal varices: • Terlipressin is preferred (Safer) • Action:- Terlipressin ↓↓ acts on V1 receptor n constricts mesenteric blood vessels ↓↓ ↓↓ blood flow to portal vessels through liver
• 57.
  ↓↓ pressure inthe varices n stops bleeding • 2. Vasopressin used before abdominal radiography to expel intestinal gas by acting on V1 receptor in the intestine • 3.Abdominal surgery in pt. with Portal hypertension →↓hemorrhage • 4.Acute hemorrhagic gastritis →↓hemorrhage (V1 mediated vasoconstriction of gastric vascular bed) • 5. Central DI (Neurogenic)- Due to ↓↓ ADH secretion, • Desmopressin-↓urine volume & well tolerated, Long acting • 6.Primary nocturnal enuresis- Desmopressin (intranasally)+ restricted fluid intake at bed time • 7. Hemophilia and von Willebrand’s disease – i.v. Desmopressin, →controls bleeding by promoting release of factor VIII and von Willebrand’s factor (by acting on V2 receptors
• 58.
  • Adverse Effectsof Vasopressin Analogues:- • 1. Nausea, vomiting, diarrhoea, belching and abdominal cramps. • 2. Backache→ is due to uterine contraction. • 3. Vasopressin can precipitate an attack of angina by constricting coronary blood vessels • 4. Local irritation and ulceration due to Intranasal desmopressin use • 5. Fluid retention and hyponatremia can occur (V2-mediated) • 6.It should not be given to patients with acute renal failure  ADH receptor Antagonist:-  Vaptans like Conivaptans, Tolvaptan, Relcovaptan, Mozavaptan, Lixivaptan, Satavaptan  Tolvaptan:- orally effective non-peptide selective V2 blockers
• 59.
  • Metabolism- byCYP3A4 • T1/2-6-8hr. • USE:-  Hyponatraemia due to CHF-short term benefit by ↑water clearance by kidney  Liver cirrhosis  Syndrome of inappropriate ADH secretion (SIADH) • A/E- thirst and dry mouth, fever.,g.i. upset and hyperglycaemia • Conivaptan:- • V1a,V2 blockers  First non peptide antagonist approved for SIADH
• 60.
  Disease due toaltered Vasopressin secretion/response 1. Diabetes Insipidus:- • 1A.Central(neurogenic or pituitary) DI:- due to ↓ADH secretion • It may be idiopathic • Urine production-30ml/kg (low osmolality) • Symptoms- Polydipsia • Treatment:-(℞) life long • DOC-Desmopressin –Intranasal -5mcg BD • Other drugs:- Chlorpropamide:- ↑Antidiuretic effect of ADH on kidney by V2 receptor action Carbamazepine:-↓urine volume in high dose Thiazides-due to paradoxical effect
• 61.
  • 1B.Nephrogenic DI:- •ADH levels are normal, but renal tubules (CD) fail to respond to ADH • Result due to defect in V2 receptor • Congenital or Acquired(head injury & neurosurgery) • Drug Induced- Li, Demeclocycline, Clozapine • Treatment:- • Thiazide –due to paradoxical effect • Amiloride- lithium-induced nephrogenic DI (inhibit Li & Na entry into the renal epithelial cells) • Indomethacin→ ↓urine volume by inhibiting renal PG synthesis 2.SIADH:- (Syndrome of Inappropriate secretion of ADH)  Excess secretion of ADH  Impaired water excretion along with hyponatremia and low plasma osmolality
• 62.
  • Symptoms – •Anorexia, nausea, vomiting, muscle cramps, lethargy, coma, convulsions & death • Treatment(℞):- • 1. Restricted water intake • 2. Drugs:- Demeclocycline:- inhibits action of ADH in the CD  Dose-600-1200mg OD Vasopressin receptor antagonists:-  Conivaptan-i.v. (V1a/V2) and tolvaptan-(orally) (V2 selective)
• 63.
  Thank You