Transcript Loop Diuretics

DIURETICS
Prof. R. K. Dixit
Pharmacology
K.G.M.U. Lucknow
[email protected]
Objectives of today’s Lecture
After completion of this lecture you will be able to
know
– Diuretics
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Definition
Classification
Names of members in classes
Mechanism of action
Major indications
Major side effects and Precautions
Major drug interactions
MCQs related to Diuretics
Facts of Renal Physiology
• Kidney-
– Weight- 0.5% of Body,
– Receive 25% of cardiac output (50 times)
• Kidney functions
– Balance of electrolytes, Plasma volume, Acid Base
– Activation of Vitamin D
– Synthesis of Erythropoietin, Urokinase
– Excretion of Urea, Uric acid, Creatinine etc.
• Transport types
– Passive
• Simple, channel mediated and facilitated diffusion, solvent
drag
– Active
• Primary and Secondary (Symports and Secondary Counter
transport)
Facts related to Renal Physiology
• Pressure difference at Bowman’s Capsule20mm Hg
• Filter= Plasma-Proteins
• Volume of
– Filter- 180 liters
– Urine- 1.5 liters (1%)
• Kidneys
– Renal Blood Flow- 1200ml/min
– Renal Plasma Flow- 650 ml/min
– GFR- 120 ml/min
– Reabsorb – Sodium, Chloride and Bicarbonates >
99% while Potassium about 85%
Terminology
• Natriuresis- increased sodium excretion
• Kaliuresis- Increased Potassium excretion
• Diuretics- Drugs which cause a net loss of
Na+ and water in urine. (Exception- Osmotic
diuretics (Mannitol) don't cause natriuresis but
produce diuresis
Nephron Parts and Characters
Proximal Tubule
• Leaky- Freely permeable to water, solutes
• Active absorption of
– Sodium Chloride,
– Sodium Bicarbonate
– Glucose
– Amino Acids
– Organic Solutes
• Followed by passive absorption of water
Loop Of Henle
• Descending limb– Permeable to water
• Thick ascending limb –
– Impermeable to water but
– Permeable to sodium by Na+K+2Cl- Co transport
– About 25% of filtered sodium is absorbed here
Macula Densa and Juxtaglomerular Apparatus
• Contact between Ascending limb with afferent
arterioles – by specialized columnar epithelial
cells Macula Densa
• Macula Densa sense NaCl conc. in filtrate
• Give signal to J.G. Cells present in afferent
arterioles
• J.G. Cells of afferent arterioles secrete Renin
RAAS in response to low BP, or Low Na
Renin– Angiotensinogen - Angiotensin I
ACE– Angiotensin II– Sympathetic, Aldosterone
Vasoconstriction, Sodium and water retention,
Early Distal Tubule
• Active transport of sodium by NaCl symport
• Calcium excretion is regulated (Parathomone and
Calcitriol, increase absorption of calcium)
Collecting Tubule and Collecting Duct
• Aldosterone- On membrane receptor and
cause sodium absorption by Na+/H+/ K+
Exchange
• ADH- Collecting tubular epithelium permeable
to water (Water enters through aquaporin-2)
Nephron parts and their functions
SEGMENT
FUNCTION
Glomerulus
Formation of glomerular filtrate
Proximal convoluted
tubule (PCT)
Reabsorption of 65% of filtered Na+/K+/ Ca2+, and Mg2+; 85% of NaHCO3,
(activity of Carbonic an-hydrase enzyme) and nearly, 100% of glucose and
amino acids.
Iso-osmotic reabsorption of water., Secretion and reabsorption of organic acids
and bases, including uric acid and most diuretics
Thin descending limb of
Henle’s loop
Passive reabsorption of water
Thick ascending limb of
Henle’s loop (TAL)
Distal convoluted tubule
(DCT)
Active reabsorption of 25% of filtered
re-absorption of Ca2+ and Mg2+
Na+/K+/2Cl−
Active reabsorption of 4–8% of filtered
under parathyroid hormone control
; , secondary
Na+ Cl− Ca2+ reabsorption
;
Cortical collecting tubule
(CCT)
Na+ reabsorption (2–5%) coupled to K+ and H+ secretion (under
Medullary collecting duct
Water reabsorption under Vasopressin control
Aldosterone)
The relative magnitudes of
Na+ reabsorption at sites
• PT
- 65%
• Asc LH - 25%
• DT
- 9%
• CD
- 1%.
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Control of Renal Function
Sympathetic- Increase Na reabsorption, Renin
RAAS- Renin in response to Low sodium, Low BP
ADH – Water reabsorption at collecting duct
Atrial Natriuretic Peptide/Factor- Released when
atrial pressure is high and causes solute and water
diuresis and reduces blood volume and BP. Inhibits
synthesis of Renin, Aldosterone, ADH and
overcomes the long term persistent effect of
aldosterone (Opposite of RAAS)
• Prostaglandins- maintain renal circulation
Breath for a minute
Pharmacology copy by student
Diuretics
• Carbonic Anhydrase Inhibitors (Site I)
– Brinzolamide, Acetazolamide, Dorzolamide
• Osmotic Diuretic (Site II)
– Glycerine, Urea, Mannitol, Isosorbide
• Loop Diuretics (Site III)- TALH
– Frusemide/ Furosemide, Bumetanide, Torasemide,
Ethacrynic acid
• Thiazide Diuretics (Site IV)
– Hydrochlorothiazide, Clopamide, Benzthiazide,
Chlorthalidone, Metolazone, Xipamide, Indapamide
• Potassium Sparing Diuretics (Site V)
– Aldosterone Antagonist
• Spironolactone, Canrenone, Eplerone
– Direct Acting (Inhibition of renal epithelial Nq+ channel
• Triamterene, Amiloride (more potent)
Carbonic An-hydrase Inhibitors
Thiazide diuretics
Osmotic Diuretics
Potassium Sparing Diuretics
Loop Diuretics (High Ceiling)
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors
Loop Diuretics
Thiazides
Spironolactone
Amiloride
A GMBrings FruTECuts MIXs with Big HandsAnd Starts Taking-
A GMBrings FruTEAcetazolamide
Carbonic Anhydrase Inhibitors (Site I)
Glycerine, Mannitol Osmotic Diuretics (Site I, II and…)
Torasemide, Ethacrynic acid
Bumetanide, Furosemide,
Loop Diuretics (Site III)
Cuts MIXs with Big HandsClopamide, Chlorthalidone, Metolazone, Indapamide, Xipamide,
Benzthiazide, Hydrochlorthiazide,
Thiazide Diuretics (Site IV)
And Starts TakingSpironolactone, Triamterene
Amiloride,
Potassium Sparing Diuretics (Site V)
Diuretic
Site of Action
Adverse Effects
Special points
Carbonic
anhydrase
inhibitors
PTC
(inhibition of CAE)
Metabolic Acidosis
Weak, Used in Glaucoma, Petit mal epilepsy,
Acute mountain sickness, to alkaline the urine
Osmotic
Diuretics
PTC, LOH, DCT
(Osmotic retention of water,
Dilates Afferent arterioles,
Increased hydrostatic
pressure in glomerulus
Shifting of fluid from
intracellular to
extracellular,
Hyponatremia,
Pulmonary edema
Potent
Used in Glaucoma, Poisoning, Increased ICT,
impending ARF
Loop
Diuretics
Thick Ascending Limb of
Henle
(NaK2Cl inhibition)
Weak CAI action
Hyponatremia
Hypomagnesaemia
Hypocalcaemia
Hyperuricemia
Hyperglycemia
Hyperlipidemia
Hyperuricemia
Ototoxic (ECA)
Most potent, Most Potent is Bumetanide,
Effective even in low GFR, All except Ethacrynic
acid are sulphonamide related,
Venodilatation, Decrease Left Ventricle Pressure,
Used in Acute LVF, Pulmonary Edema, Nephrotic
syndrome, ARF, NSAIDS blunt effect, Cerebral
edema, short term tt of Hypertension, to reduce
volume overload during transfusion,
Thiazide
Diuretics
DCT
(NaCl)
Hypokalemic
metabolic alkalosis
(Gitelman’s
Syndrome)
Hypercalcemia
Moderate, Chlorthalidone is Longest acting,
Paradoxical effect in Diabetes Insipidus
First line in Hypertension,
Potassium
Sparing
Diuretics
CD
HyperKalemia
Antiandrogenic effect
Weak, As supplement to other to counter the
hypokalemia, Canrenone is active metabolite, used in
Conn’s syndrome (Primary Hyperaldosteronism) cirrhotic
edema, polycystic ovary
Breathing Please……………..
Pharmacology teacher grfom where you passed
Special mention
• Don’t use diuretics overenthusiastically.
(dehydration, hypotension)
• Brisk diuresis in cirrhosis may precipitate
hepatic coma. (hypokalemia, alkalosis and
increased NH3 levels)
• Diuretics not used in Toxaemia of Pregnancy.
(Blood volume is low despite edema. Diuretics will
compromise placental circulation)
• Most of Loop and Thiazide diuretics are
sulphonamide derivatives. (Think of allergic
manifestations)
• Hypokalemia by diureitcs precipates digitalis,
quinidine side effects
• Hypokalemia by diuretics decrease
sulfonylurea action (reduced insulin release
due to reduced action of ATP dependent
potassium channel)
• High ceiling not given with Amino-glycosides
• ACE inhibitors with Thiazides reduce the chances of
hypokalaemia (FDC)
• Probenicid inhibits tubular secretion of Frusemide
and Thiazides and reduce action
• Potency of producing hypokalaemia
CAsI>Thiazides>Loop
• NSAIDS reduce diuretic action due to PG inhibition
and affecting glomerular blood flow
• CAsE is present in PT, gastric mucosa, exocrine
pancreas, ciliary body, arachnoid plexus & RBC
• Acetazolamide action is self limiting
• Spironolactone breaks the Thiazide resistance
• Aspirin blocks Spironolactone action by
inhibiting tubular secretion of canrenone
• Spironolactone can produce dangerous
hyperkalaemia when used along with ACEI
and ARBs
• Spironolactone has antiandrogenic side
effects
• Eplirenone is new potassium sparing diuretics
with less antiandrogenic effects
• Osmotic diuretics indicated in impending ARF.
(Don’t use if ARF has set in)
Acetazolamide, CAIs, Alkaline urine, S/E Acidosis
Clopamide, Metolazone, Indapamide, Xipamide, Benzthiazide,
Hydrochlorthiazide, Hypercalcaemia
A
GM
Brings FruTE
Cuts MIXs with Big Hands
And Starts Taking
Amiloride, Spironolactone, Triamterene
Bumetanide, Frusemide, Torasemide, Ethacrynic acid- Loop,
Most potent, Hypocalcimia
Glycerine, Mannitol, Osmotic, Hyponatremia, Not when ARF already sets in
MCQs on Diuretics
• Reabsorption of which of the following is
affected maximum by action of vasopressin?
– Water
– Chloride
– Potassium
– Hydrogen
A
• Bumetanide belongs to which of the following
class of diuretics?
– Carbonic anhydrase inhibitor
– Aldosterone antagonist
– Thiazide diuretics
– Loop diuretics
D
• All of the following compounds produce diuretic
action by acting on thick ascending part of loop of
henle EXCEPT
– Ethacrynic acid
– Torasemide
– Furosemide
– Clopamide
D
• Which of the following is thiazide like diuretics?
– Spironolactone
– Triameterene
– Metolazone
– Acetazolamide
C
• Which of the following is carbonic anhydrase
inhibitor?
– Acetazolamide
– Spironolactone
– Benzthiazide
– Clopamide
A
• Which of the following is NOT an aldosterone
antagonist?
– Spironolactone
– Canrenone
– Eplerenone
– Triameterene
D
• Among all of the following which is most potent?
– Frusemide
– Bumetanide
– Torasemide
– Ethracrynic acid
B
• Spirnolactone may be beneficial in all of the
following clinical conditions EXCEPT
– Nephrotic edema
– Hypertension
– Congestive heart failure
– Hyperkalaemia
D
• Among following which is most ototoxic?
– Metolazone
– Clopamide
– Ethacrynic acid
– Chlorthalidone
C
• Which of the following is not an adverse effect of
Furosemide?
– Hyperuricaemia
– Hyperglycaemia
– Hyperlipidemia
– Hypermagnesaemia
D
• Which of the following drugs can precipitate
hypercalcaemia?
– Spironolactone
– Hydrochlorthiazide
– Furosemide
– Mannitol
B
• Thiazides induced hyperuricaemia may be
prevented by administration of which of the
following?
– Allopurinol
– Probenecid
– Mannitol
– Furosemide
A
• Which of the following condition is
contraindication for Mannitol administration?
– Acute congestive glaucoma
– Head injury
– Impending acute renal failure
– Acute Pulmonary Edema
D
• Among following which compound has maximum
potency?
– Chlorthiazide
– Chlorthalidone
– Hydroflumethozide
– Clopamide
B
• Which of the following is most appropriate
mechanism of action of Triametrene
– Inhibition of Miniralocorticoid receptors
– Inhibition of Na+K+2Cl- channels
– Inhibition of Na+Cl– channels of DCT
– Inhibition of renal epithelial Na+ channels
D
• Which of the following drug is used in acute
mountain sickness
– Acetazolamide
– Spironolactone
– Domperidone
– Ethacrynic acid
A
• Site of action of spironolactone is
– Proximal Convoluted Tubule
– Descending limb of Loop of Henle
– Collecting Duct
– Ascedning limb of loop of henle
C
• Which of the following is converted by Angiotensin
Converting Enzyme
– Angiotensinogen to Angiotensin I
– Angiotensin I to Angiotensin II
– Angiotensin II to Angiotensin III
– Inactivation of Angiotensin III
B
• Renin is secreted from
– Macula Densa cells
– Juxta Glomerular Cells
– Specialized cells of Ascending limb of henle
– Specialized cells of efferent arterioles
B
• Which of the follwing is NOT an indication of
Acetazolamide
– Petit mal epilepsy
– Periodic Paralysis
– To acidfy urine
– To alkalinise urine
C
• In loop of henle what percentage of sodium is
reabsorbed
– 65%
– 25%
– 9%
– 1%
B
• Which of the following diuretics is not a
sulphonamide derivative
– Ethacrynic acid
– Furosemide
– Bumetanide
– Torasemide
A
• Which of the follwing diuretic is active even when
GFR is less than 20ml/min
– Chlorthiazide
– Chlorthalidone
– Metolazone
– Clopamide
C
• Which of the following drug does not produce
hypokalaemic metabolic alkalosis
– Furosemide
– Hydrochlorthiazide
– Acetazolamide
– Indapamide
C
• Which of the following is NOT indicated in
Diabetes Insipidus?
– Desmopressin
– Hydrochlorthiazide
– Chlorpropamide
– Mannitol
D
Thanks