Renal Pharmacology

DIURETICS
PCL304
RALPH E. ISAAC (B.Pharm, MSc)
DEPT OF PHARMACOLOGY AND THERAPEUTICS
GOMBE STATE UNIVERSITY
[email protected]
 Objectives of today’s Lecture
After completion of this lecture you will be able to
know
– Diuretics
• Definition
• Brief renal anatomy and physiology
• Classification of diuretics
• Names of members in classes
• Mechanism of action
• Major indications
• Major side effects and Precautions
• Major drug interactions
• MCQs related to Diuretics
 INTRODUCTION
 The kidneys are organs specialized to filter the
blood.
 Thus they make an important contribution to the
removal of metabolic waste products as well as to
maintenance of fluid and electrolyte balance.
 This is the main organ by which drugs and their
metabolites are eliminated from the body and so
when they fail dosing regimens of many drugs
must be adapted.
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 Capsule-
20mm 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%
 FUNCTIONAL ANATOMY OF
KIDNEYS anatomy of kidneys
Functional
The kidneys lie outside the peritoneal cavity in the
posterior abdominal wall, one on each side of the
vertebral column, slightly above the waistline. In
the adult human, each kidney is approximately 11
cm long, 6 cm wide, and 3 cm thick.
These organs are divided into two regions: the
inner renal medulla and the outer renal cortex
 The functional unit of the kidney is the nephron
Approximately 1 million nephrons are in each
kidney
  The nephron has two
Functional anatomy of components:
kidneys  Vascular
 Tubular
 The nephron. The functional unit of the kidney is the nephron,
which has two components.
 The vascular component includes the afferent arteriole, which
carries blood toward the glomerulus where filtration of the
plasma takes place. The efferent arteriole carries the
unfiltered blood away from the glomerulus.

 The tubular component of the nephron includes Bowman’s

capsule, which receives
the filtrate; the proximal tubule; the Loop of Henle; and the
distal tubule.
The tubule processes the filtrate, excreting waste products and
reabsorbing nutrient
molecules, electrolytes, and water.
 Renal excretion: 3 processes

 The nephron performs three basic renal processes

• Filtration
• Reabsorption
• Secretion
 Renal excretion: 3 processes
(1) Filtration is the movement of fluid and solutes from the
glomerular capillaries into Bowman’s capsule.
(2) Reabsorption, which takes place throughout the nephron,
is the movement of filtered substances out of the tubule
and into the surrounding peritubular capillaries.
(3) Secretion is the movement of selected unfiltered
substances from the peritubular capillaries into the renal
tubule for excretion.
• Any substance that is filtered or secreted, but not
reabsorbed, is excreted in the urine
 Diuretic Agents: What are they?
• Any compound that causes the excretion of an increased volume of
urine

• More accurate: a drug that increases the excretion of both fluids and
solutes

• Natriuretic: increases Na+ excretion

• Kaliuretic: increases K+ excretion

• Most Diuretics increase excretion of Na+ and water by the kidneys

1) They reduce reabsorption of Na+ from the filtrate
2) Increased water loss is secondary to Na+ excretion

• Two modes of action of diuretics

1) Direct action on the cells of the nephron (more common)
2) Modification of content of the filtrate
 Why Use Diuretics?
• Two major applications of diuretic agents:

1) Reduce circulating fluid volume

2) Removal of excess body fluid (oedema)

Via actions on the kidney

- hypertension - increase elimination of drugs

- chronic heart failure - rapid weight loss (abuse)

- liver cirrhosis Other actions

- renal disease - glaucoma

(reduces intra-ocular pressure)
- premenstrual oedema
- epilepsy
- toxic oedema (reduces pressure of CSF?)
Nephron Parts and Characters
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 (Parathyroid homone
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 Reabsorption of 65% of filtered Na+/K+/ Ca2+, and Mg2+; 85% of NaHCO3 ,
tubule (PCT)
(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 Passive reabsorption of water

Henle’s loop

Thick ascending limb of

Henle’s loop (TAL) Active reabsorption of 25% of filtered Na+/K+/2Cl− ;,
secondary re-
absorption of Ca2+ and Mg2+

Distal convoluted tubule

(DCT) Active reabsorption of 4–8% of filtered Na+ Cl− Ca2+ reabsorption
;

under parathyroid hormone control

Cortical collecting tubule Na+ reabsorption (2–5%) coupled to K+ and H+ secretion (under
(CCT)
Aldosterone)
Medullary collecting duct Water reabsorption under Vasopressin control
The relative magnitudes of Na+
reabsorption at sites
• PT - 65%
• Asc LH - 25%
• DT - 9%
• CD - 1%.
 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 effects 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 Na+ channel
• Triamterene, Amiloride (more potent)
Carbonic An-hydrase Inhibitors Thiazide diuretics

Osmotic Diuretics

Potassium Sparing Diuretics

Loop Diuretics (High Ceiling)
A -
GM-
Brings FruTE-
Cuts MIXs with Big Hands-
And Starts Taking-
A - Acetazolamide
Carbonic Anhydrase Inhibitors (Site I)

GM- Glycerine, Mannitol Osmotic Diuretics (Site I, II and…)

Brings FruTE- Bumetanide, Furosemide,

Torasemide, Ethacrynic acid Loop Diuretics (Site III)

Cuts MIXs with Big Hands-

Clopamide, Chlorthalidone, Metolazone, Indapamide, Xipamide,
Benzthiazide, Hydrochlorthiazide, Thiazide Diuretics (Site IV)

And Starts Taking- Amiloride,

Spironolactone, Triamterene Potassium Sparing Diuretics (Site V)
 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
• Spironolactone 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