Drugs Acting on Urinary

System
Unit 2

1
Objectives

At the end of the chapter you will be able to understand:

1. Physiology of urine formation
2. Definition of diuretics
3. Classification of diuretics
4. Pharmacology of different diuretics
5. Complications of diuretic use

2
 Physiology of urine formation
• Steps
• Glomerular
filtration
• Tubular
reabsorption
• Tubular
secretion

Parts of Nephron
3
Glomerular Filtration
• As blood flows through the kidney, it
passes into glomerular capillaries
located within the cortex (outer zone
of the kidney).
• These glomerular capillaries are highly
permeable to water and electrolytes.
• Glomerular capillary hydrostatic
pressure drives (filters) water and
electrolytes into Bowman's space and
into the proximal convoluting tubule
(PCT).
• About 20% of the plasma that enters
the glomerular capillaries is filtered
(termed filtration fraction).

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Major Segments of the Nephron and Functions

5
PCT-Site I
• More than99% of filtrate reabsorbed
• At PCT
• Na+ reabsorbed along with
water
• Glucose,Potassium,Calcium,
Aminoacids etc also get
reabsorbed
• Composition of the glomerular
fluid changes
• However, water is also absorbed
to maintain osmotic pressure-
fluid is isosmotic

Isotonic tubular fluid with major

changes in composition enters
desc. limb of Henle

6
Descending limb of loop of Henle
• Permeable to water only
• No ions reabsorbed

The luminal fluid becomes hypertonic

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Ascending limb of loop of Henle-Site II
• Medullary part
• Na+- K+- 2Cl-
transported- non
electrogenic
• Na+ pumped to ecf
thru basolateral
membrane
• Na+- Cl- symporter
carriers them to ecf
Fluid in tubule becomes
progressively hypotonic while
interstial fluid becomes
hypertonic
•This draws water from desc.
Limb into interstial space
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Ascending limb of loop of Henle- Site III
• Cortical part
• Impermeable to water
• Continues to reabsorb salts
• Na+- Cl- Symporter

Fluid becomes progressively

hypotonic

9
Distal Tubule & Collecting Duct- Site IV
• In late DT and CD
• Na+ is actively reabsorbed- aldosterone
dependent, thru a specific channel
• Cl- passively follows
• K+ and H+ are secreted out
• K+ secretion is dependent on:
• Na load delivered to distal segment
• Presence /absence aldosterone
• Availability of K+ intracelluraly
• Availability of H+
• CD cells are sensitive to ADH
• In presence of ADH cells become permeable to
water and water is reabsorbed- less urine
• In absence of ADH no reabsorption of water-
more urine

10
Definitions
• Diuretics
• Diuretic drugs increase urine output by the kidney (i.e., promote diuresis)
• Drugs that accelerate the rate of urine formation act by removing sodium and water
• Free water clearance
• Volume of urine excreted per unit time in excess of that required to excrete the contained
solute iso-osmotically with plasma.

+ Dilute urine
- Conc.urine
0 Isotonic urine

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Classification
• High efficacy/Loop diuretics (inhibitors of Na+- K+- 2Cl- )
• Sulphomoyl der.- Furosemide, bumetanide

• Medium efficacy (inhibitors of Na+- Cl- )

• Thiazide –Hydrochlorthiazide, benzthiazide
• Thiazide like- Chlorthalidone, metolazone, xipamide, indapamide

• Weak/adjuvant
• Carbonic anhydrase inhibitors- acetazolamide
• Potassium-sparing diuretics
• Aldosterone antagonist- spiranolactone
• Inhibitors of renal epithelial Na+ channel- triamterene, amiloride
• Osmotic diuretics – Mannitol, isosorbide, glycerol
12
Site of action of various classes

13
Loop diuretics
• MOA
• No transport systems in descending loop of Henle
• Ascending loop contains Na+ - K+ - 2Cl- cotransporter from lumen to
ascending limb cells
• Loop diuretic blocks cotransporter  Na+, K+, and Cl- remain in lumen,
excreted along with water
• Attaches to CL- binding site of the transport protein

14
Loop diuretics- Furosemide
• Additional activity
• Increase in PG synthesis
• Weak CAase activity- ↑HCO3- excretion- urinary pH may
rise but no acidosis
• Little action on PCT

15
Furosemide- P’cological actions

• Natriuretic effect greater than other classes

• Active even in renal failure
• Prompt onset of action
• Secreted thru organic ion transport system-reaches site thru luminal side
• Abolishes corticomedullary osmotic gradient-blocks +ve as well as –ve free
water clearance
• Increase in K+ excretion but less than thiazides
• Changes in renal and systemic blood flow- PG related
• Renal flow transiently increases after iv infusion- no drastic change in gfr
• More blood to midcortical zone
• Decreased PT reabsorption
• Increases Ca++ & Mg++ excretion
• Raises blood uric acid level (but lesser than thiazides)-competes with it PT
secretion
• Hyperglycaemia (but lesser than thiazides)

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Furosemide- P’kinetics
• Prompt onset of action
• Dose dependent diuretic action
• Rapidly absorbed orally- bioavailability 60%
• Highly bound to plasma proteins
• Excreted unchanged (majorly) , partly conjugated with glucoronic acid
• Plasma t1/2 1-2 hrs but prolonged in pulmonary edema, renal/hepatic insuffiency
• Bumetanide
• 40 times mire potent that Furosemide
• Very effective in pulmionary edema
• May be effective in cases where furosemide fails
• Fewer side effects Vs furosemide
• Bioavailability 80%
• Torasemide
• 3 times mire potent that Furosemide
• More compelete and rapid oral abs.
• Longer duration of action
• Used in edema & HT

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Uses of Loop Diuretics
• Edema
• Cardiac/hepatic/renal
• 1st choice in CHF, renal edema, resistant edema
• Used for rapid mobilization of edema fluid, thiazides for maintenance
• Cerebral edema-osmotic preferred but furosemide can be used
• Hypertension- only in presence of renal insufficiency
• Along with blood transfusion to prevent vulume overload
• Hypercalcemia and renal stones

18
Thiazide and Related
• MOA
• Site- cortical diluting segment (Site III)
• Inhibit Na+- Cl- co transport
• Molecular MOA not clear
• No action on ascending limb- no effect on corticomedullary osmotic gradient
• Some agents may have additional CAse activity- clinically insignificant
• Secreted by organic acid secretary pathway

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P’cological actions
• Increased Na+ delivered to DT- K+ excretion increases
• Moderately efficacious-90% already reabsorbed
• Flat dose response
• No significant change in acid-base balance
• Reduces blood vol- ↓gfr- not effective in patients with low gfr
• ↓ Ca++ excretion while Mg++ excretion
• ↓ urate excretion
• Decreased insulin release
• Relaxes arterioles

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P’kinetics
• Well absorbed orally
• Onset 1hr
• Lipid soluble agents- larger vol of distribution- tissue bound-longer
acting
• Excreted unchanged (majorly)
• Filtered at glomerulus, secreted in PT, lipid soluble agents reabsorbed

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Agents
• Chlorthalidone
• Long acting, t1/2 40-50 hrs, used as anti-hypertensive
• Metazolone- Effective even in renal failure
• Xipamide- pronounced action //r to furosemide, hypokalemia
prominent
• Indapamide- little diuretic action at usual doses but retains
antihypertensive action.

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Uses
• Edema
• For mild to moderate edema- preferred for maintenance
• Best for cardiac edema, not useful for hepatic/renal edema
• Hypertension-1st choice
• Diabetes insipidus- reduce urine vol
• Hypercalciuria-kidney stones. Reduce Ca++ excretion

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Comparison of Loop and thiazide diuretics

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Complications of high ceiling & thiazides
• Hypokalemia
• Weakness, fatigue, muscle cramps, cardiac arrhythmia.
• Less prominent in loop due to short duration of action
• High dietary K+, supplements of K+, concurrent use of K sparing diuretics
• Kcl-diuretic not recommended together
• Gut ulceration
• Insifficient K+
• K+ retained more if given after diuresis

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Complications of high ceiling & thiazides
• Acute saline depletion-dehydration and low BP
• Dilutional hyponatremia- in CHF with high ceiling. Kidneys try to retain water (but
not salts due to drug) ecf diluted- edema inspite of natriuresis.
• GIT disturbances- nausea- vomitting, diarrhoea
• Hearing loss- rarely especially with ethacrynic acid
• Allergic manifestations
• Aggrevates renal insufficiency

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Complications of high ceiling & thiazides
• Mental disturbance in cirrhotics due to brisk diuresis
• Hyperuricaemia- gout
• Hyperglycemia- reversible
• Hyperlipidemia- LDL, ↓HDL
• Hypercalcemia with thiazides/hypocalcemia with loop
• Mg depletion- with prolonged use of thiazides & loop- increase risk of
arrhythmia after MI

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Interactions
• Potentiate anti- hypertensive agents
• Potentiate digitalis toxicity
• Potentiate Ototoxicity of aminoglycosides
• NSAIDs diminish action of loop diuretics
• Probencid reduces concentration in tubular fluid

28
CAse inhibitors- MOA
• CAIs work on cotransport of Na+, HCO3- and Cl- that is coupled to H+ countertransport
• Acts to block carbonic anhydrase (CA),

1.CA converts HCO3- + H+ to H2O + CO2 in tubular lumen

2.CO2 diffuses into cell (water follows Na+), CA converts CO2 + H2O into HCO3- + H+
3.H+ now available again for countertransport with Na+, etc)
4.Na+ and HCO3- now transported into peritubular capillary

• CA can catalyze reaction in either direction depending on relative concentration of substrates

29
CAse inhibitors- MOA

30
Acetazolamide
• Sulfonamide derivative
• Non-competitively but reversible inhibits CAse in PT
• Slows hydration of CO2- decreased availability of H+ with luminal Na+
• Less CO2 diffuses back into cell
• HCO3- reabsorbtion is inhibited-causes acidosis- less HCO3- filtered-self limiting
action
• Secretion of H+ in DT is also inhibited- Na+ exchange with K+ only.
• Alkaline urine rich in HCO3- &K+

31
Acetazolamide
• Extra renal actions
• Lowers formation of aq. humour-lowers IOT
• At very high doses, redcues gastric acid secretion and pancreatic NaHCO 3
• Raises CO2 level in blood- decreases pH-increases seizure threshold
• Alters CO2 transport in lungs and tissues- masked by compensatory mechanisms
• P’kinetics
• Well absorbed orally, excreted unchanged in urine
• Action lasts for 8-12 hrs

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CAase inhibitors

• Uses
• Glaucoma
• metabolic alkalosis
• To alkalinise urine- UTI, promote excretion of acidic drugs
• Epilepsy

• Adverse effects
• Acidosis
• Hypokalemia
• Drowsiness, fatigue, parasthesias abdominal discomfort
• Rare but serious bone marrow depression

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Potassium sparing diuretics
• Conserve K+
• Aldosterone/ directly acting agents on DT
• Have most downstream site of action (collecting tubule)
• Reduce K loss by inhibiting Na/K exchange
• Not a strong diuretic because action is furthest downstream
• Often used in combination with thiazide diuretics to restrict K loss

34
Potassium sparing diuretics
• Two cell types in collecting tubule
1.Principal cells – transport Na, K, water
• Blocking Na+ movement in also prevents K+ movement out
2.Intercalated cells – secretion of H+ and HCO3

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Potassium sparing diuretics
• Triamterene
• Incompletely absorbed orally, partly bound to plasma proteins, metabolised
in liver, excreted thru urine
• Nausea, vomitting, increase in blood urea are common side effects
• Amiloride
• More potent than triamterene
• At higher doses action at site1-inhibits Na+ reabsorption- clinically
insignificant
• urate excretion, ↓in Ca++ excretion

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• Aldosterone acts on the late DT and CD cells by combining with an
intracellular mineralocorticoid receptor
• It induces the formation of 'aldosterone-induced proteins' (AIPs)
• The AlPs include Na+K+ A TPase and amiloride sensitive Na+ channels
• Promote Na+ reabsorption by a number of mechanisms and K+ secretion

37
Spironolactone
• Steroid- related to aldosterone
• Acts from interstitial side- combines with aldosterone receptor in a
competitive manner and inhibits formation of AIP (aldo. induced protein-
promotes Na+ reabs. & K+ sec.)
• No effect in absence of aldosterone
• Mild saluretic- major Na+ already absorbed
• Antagonises K+ loss induced by other diuretics
• Effect develops after 2-3 days

38
Spironolactone

• Uses
• Edema- in chronic liver failure & renal failure.
• Breaks resistance to thiazides due to secondary aldosteronism
• Along with loop and thiazide diuretics to counteract K+ loss
• Hypertension but in selected cases only
• Interactions
• Hyperkalemia with potassium supplements
• Increases plasma digoxin levels
• Aspirin blocks spironolactone action by blocking inhibiting tubular secretion
• Adverse effects
• Hyperkalemia, drowsiness, confusion, hirsutism, gynaecomastia, menstrual irregularities

39
Potassium sparing diuretics
• Directly action agents- Triamterene & Amiloride
• Non-steroidal
• Decrease K+ excretion- when intake is high or due to other diuretics
• Increase in Na+ excretion accompanied with Cl- & HCO3-
• Urine slightly alkaline
• Action independent of aldosterone
• Acts from luminal side, inhibits Na+ reabsorption- thus driving force for K+
secretion is lost
• Both drugs used in conjunction with loop diuretics/thiazides
• Shd not be given with K+ supplements

40
Osmotic diuretics
• No interaction with transport systems
• All activity depends on osmotic pressure exerted in lumen
• Blocks water reabsorption in proximal tubule, descending loop, collecting duct
• Results in large water loss, smaller electrolyte loss  can result in hypernatremia
• Mannitol
• Low molecular weight, can be given in large quantities, not metabolised, filtered at glomerulus
• Osmotic pressure of mannitol inhibits water reabsorption
• Has to be administered iv
• Isosorbide
• Orally active
• Used to reduce intraoccular & intracranial pressure

41
Osmotic diuretics
• Uses
• Acute renal failure- to maintain gfr
• Reduce preoperative intraocular or intracranial pressure
• Reduce pre-surgical or post-trauma intracranial pressure
• Prompt removal of renal toxins
• One of the few diuretics that do not remove large amounts of Na+
• Can cause hypernatremia

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43
Anti-Diuretics

44
Definition and Classification

• These are drugs that reduce urine volume.

• Specially used in condition like diabetes insipidus (DI).
• Classification of Anti diuretic Agents:
1. Antidiuretic hormone: ADH,Vasopressin), Desmopressin,Lypressin, Terlipressin
2. Thiazide diuretics, Amiloride.
3. Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine

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ADH
• https://www.youtube.com/watch?v=xkfEfx4g5QI
• https://www.youtube.com/watch?v=JBPOGgCp5Cw
• https://www.youtube.com/watch?v=odayMhgkYG8 (part1)
• https://www.youtube.com/watch?v=I5w_Zss6pyU (part 2)

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47
ADH Receptors

48
ADH: Actions
• Kidney: Reduces Urine output

V2 receptor on basolateral V1 receptor action on Vasa

side of CD cell membrane Recta-

Increases cAMP formation Constrict Vasa Recta

Promotes exocytosis of auaporin 2

Diminish blood flow to inner
water channel containing vesicles in
medulla-
apical membrane

Water permeability of CD cell

Prevent Urine formation
increased and prevent urination

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ADH: Actions Kidney

• AVP acts on the collecting duct (CD) principal cells to increase their
water permeability— water from the duct lumen diffuses to the
interstitium by equilibrating with the hyperosmolar renal medulla
• When AVP is absent, CD cells remain impermeable to water → dilute
urine (produced by the diluting segment) is passed as such.
• Graded effect occurs at lower concentrations of AVP: urine volume
closely balances fluid intake.
• In addition to increase in aquaporin channels (details slide 47) , V2
receptors increases urea permeability of terminal part of CDs in inner
medulla by stimulating a vasopressin regulated urea transporter (VRUT
or UT-1)—which in turn augments medullary hypertonicity
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ADH: Actions Kidney
• Activation of V1 receptors constricts vasa recta
to diminish blood flow to inner medulla which
reduces washing off effect and helps in
maintaining high osmolarity in this region.
Thus, it contributes to antidiuresis.
• On the other hand, activation of medullary
interstitial cell V1 receptors enhance PG
synthesis which decerase cAMP generation in
CD cells and oppose V2 mediated antidiuresis. Vasa Recta- V1- constricts Vasa recta-
• V1 receptors are also present on CD cells. Their
antidiuresis
stimulation activates PKc which directly Medullary Cells- V1- PG synthesis-opose
diminishes responsiveness of CD cells to V2 antidiuresis
receptors and restrains V2 mediated water CD cells- V1- decreases responsiveness
permeability. toV2 receptors mediated increase in
• The logic of this apparent paradox may lie in water permeability
the fact that these V1 actions are produced at
much higher concentrations of AVP, so that
physiologically they may serve to restrict V2
effects only when blood levels of AVP are very
high.

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ADH: Actions

• Blood Vessels: ADH acts on V1 receptor- Constriction of blood vessels ( Hence name Vasopressin)
- Increases blood pressure
• The cutaneous, mesenteric, skeletal muscle, fat depot, thyroid, and coronary beds are particularly
constricted. Prolonged exposure to AVP causes vascular smooth muscle hypertrophy

• Other action:
• Smooth muscles- Most visceral smooth muscles contract.
• Gut- Increased peristalsis, evacuation and expulsion of gases
• Uterus- Constricted
• CNS- ADH not penetrate BBB
• Liver- Glyconeogenesis

52
Pharmacokinetics and Other Analogues

• Absorption- Orally inactive because destroyed by trypsin

• Metabolism- Liver
• Excretion- Kidney
ANALOGUES OF ADH/AVP ( VASOPRESSIN)
• Lypressin- 8-lysin analogues; acts on both receptor; longer duration of action;
• Terlipressin- Synthetic prodrug; mainly used for bleeding esophageal varices.
• Desmopressin- Synthetic peptide; selective V2 agonist; 12times more potent
than all; But produces systemic side effects which are overcomes by nasal
application.

53
Uses

A. Based on V2 action:
1. Diabetes insipidus (DI)- DI of pituitary origin (neurogenic) important indication for vasopressin but
ineffective in renal DI (nephrogenic).
2. Bedwetting in children & nocturia in adults- Desmopressin reduce urine volume resulting control
nocturia condition.
3. Renal concentration test- 5-10 U i/m causes maximum urine retention and urine concentration.
4. Haemophilia, Von Willebrand’s disease- It is genetic disorder where missing or defective
vonWillebrand factor (VWF), a clotting protein is observed. While ADP releases clotting factor.

B. Based on V1 action:
5. Bleeding esophageal varices: Vasopressin stops the bleeding by constricting mesenteric blood vesscles
and reducing blood flow though liver & allowing clot formation.
6. Before abdominal radiography: Lypressin used to drive out gases form bowel facilitate easy abdominal
radiography.

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Adverse Effects
• Vasopressin, lypressin or terlipressin are nonselsctive derivatives so shows more side effects as
compaire to desmopressin (V2 selective).
• Transient headache and flusing- common.
• Nasal irritation, congestion, rhinitis, ulceration and epistaxis(nose bleeding)
• Systemic effects- belching, nausea, abdominal cramps, pallor, urge to defecate, backache in
females (due to uterine contraction). • Fluid retention and hyponatraemia.
• ADP causes bradycardia, increase cardiac afterload and precipitate angina by constricting
coronary vessels.
• CONTRAINDICATION: Patients with-
• Ischemic heart disease,
• Hypertension,
• chronic nephritis
• psychogenic polydipsia.
• Urticaria and other allergies

55
2.Thiazides Derivatives

• Actually thiazide and high ceiling diuretics are diuretic drugs but which provides
antidiuretic effect in Diabetes insipidus. high ceiling diuretics are not used
because is having short and strong action.
• Actual mechanism is unknown; But thiazides may induce sustained electrolyte
depletion resulting glomerular filtrate getting completely reabsorbed- Continuous
electrolyte loss causes decreases plasma osmolarity- antidiuretic action.
• Thiazides reduce urine volume in both pituitary origin and renal diabetes
insipidus.
• Used when ADH is ineffective.

56
Miscellaneous Derivatives

• These all are supportive derivatives for antidiuretic activity:

• Amloride hydrochloride is a drug of choice for lithium induced nephrogenic
Diabetes insipidus.
• Indomethacin: Reduce polyuria in renal diabetes insipidus.
• Chlorpropamide: It sensitizes ADH to acts on kidney cells.

57
Questions
1. Define and classify diuretics.
2. Write notes on pharmacology of furosemide/thiazides.
3. Write a detailed note on complications of thiazides and loop diuretics.
4. Describe mechanism of action spironolactone and amiloride.
5. Justify combination of potassium sparing agents with thiazides.
6. Give MOA and uses of acetazolamide
7. Describe uses of mannitol
8. Describe pharmacology of ADH
9. Explain use of thiazides as anti diuretic agents.

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