Pharmacology of diuretics including renal physiology.ppt

Review of Renal Physiology High ceiling (loop) diuretics
Thiazide diuretics
Carbonic anyhdrase inhibitors
Potassium – sparing diuretics
Osmotic diuretics
Novel diuretics

1. Diuretics
Haftom G. (B.Pharm., MSc.)
[email protected]

2. Diuretics
Chemicalsthatincreaseurineoutput
UrineformationandSodiumandwaterexcretion.
•These agents have the following major applications
–Rx of hypertension
–Mobilization of edematous fluid (heart failure, cirrhosis & kidney disease)
•Natriuretic
•Aquaretic

3. Review of Renal Physiology
Kidney:make0.5%oftotalbodyWt;consume7%oftotalbodyoxygen
Nephron:basicurineformingunit
–Functionally four distinct regions
1.Glomerulus
2.Proximal convoluted tubule (PCT)
3.Loop of Henle
4.Distal Convoluted Tubule (DCT)
5.Collecting ducts play a critical role in kidney Function.
RBF:650ml/min,GFR=125ml/minonly1ml/minofurineformed

6. Review of renal Physiology…
–The kidney serves
•Cleansingof the ECFalong with maintenance of ECF volume &
composition
•Maintenance of acid–basebalance, &
•Excretionof metabolic wastes and foreign substances (drugs, toxins).
•Hormone secretion

7. Review of renal Physio….
•The three renal processes
–The effects of the kidney upon the ECF volume and composition are
the net results of three basic processes.
•Filtration
•Reabsorption
•Active secretion

8. Processes of reabsorption occurring at specific sites along the nephron

9. Processes of reabsorption occurring at specific sites along the nephron
1.Proximal Convoluted Tubule (PCT)
60–70% of the total reabsorption of Na
+
(Na
+
Cl
-
& Na
+
HCo
3
-
) present in the filtrate are
reabsorbed at this site.
As Na
+
& Cl
-
as well as other solutes are actively reabsorbed water follows passively.
HCo
3
-
itself is poorly reabsorbed through the luminal membrane,
Converted in to CO
2Pass membrane then HCo
3
-
regenerated fromCO
2
Carbonic anhaydrase (CA) required for this process
When filtrate leaves PCT Na
+
& Cl
-
remain in significant amount.
Most relevant to diuretic action are Na
+
, Cl
-
& Hco
-
3

10. CA-mediated Na
+
-H
+
exchange in proximal convoluted tubule

11. 2. Loop of Henle
25%offilteredloadofNa
+
reabsorbed.
a)ThinDescendingLoop:
permeabletowater,permeabilitytoNaCl&ureaislow
ConcentratedUrine(concentratingsegment)
Osmoticdiureticsexerttheiractioninthisregion
b)ThickAscendingLoop:
PermeabletoNaCl&Ureabutisimpermeabletowater
ActivereabsorptionofNa
+
,K
+
,andCl
-
ismediatedbyaNa
+
/K
+
/2Cl
-
cotransporter.
Reabsorptioninthethickascendinglimbdilutesthetubularfluid(Diluting
segment)
•Thistransportisselectivelyblockedbyloopdiuretics

12. Loop diuretics block the Na
+
/K
+
/2CI
-
co-transporter there by
–increasing the excretion of Na
+
& CI
-
–decrease the potential difference across the tubule cells, which
arise from the recycling of K
+
leads to
•Increased excretion of Ca
2+
& Mg
2+
by inhibiting Para cellular diffusion

14. 3. Distal convoluted tubule (DCT)
Impermeable to water
10 % of filtered Na
+
reabsorbed /actively/ via Na
+
-Cl
-
cotransporter (NCC)
Sensitive to Thiazide Diuretics
The main source of urinary K
+
is tubular secretion by DCT and collecting ducts
Reciprocal relation between the direction and magnitude of ca
++
and Na
+
transport
Ca
2+
is actively reabsorbed DCT epithelial cell via an apical ca
2+
channel &
basolateral Na
+
/Ca
2+
exchanger. The process in regulated by PTH.

16. 4. late distal convoluted tubule and collecting duct
2% to 5%of filtered Na
+
& Cl
-
reabsorbed.
The principalcellsare responsible for Na
+
, K
+
, and watertransport, whereas the intercalatedcells
affect H
+
secretion.
Plays an important role in volume regulation (through mineralocarticoid)
Water permeability: modulated by ADH.
In the absence of ADH, the collecting ducts are essentially impermeable to water.
Major site for K
+
secretion by the kidney: is the site of two important processes:
–Exchange of Na
+
for K
+
and is under the influence of aldosterone.
–Process determines the final concentration of the urine & is regulated by ADH.

18. How diuretics work?
Blockade of Na+ (& cl-) reabsorption
By blockingthe reabsoprtioncreate an osmoticpressurewith in the
nephron that prevents the passive reabsorption of water.
–Hence, diuretics cause water and solutes to be retained with in the nephron 
promoting their excretion

19. Classification of the diuretics
•High ceiling (loop) diuretics
–Furosemide, Torsemide
–Bumetanide, Ethacrynic acid
•Thiazide diuretics
–Hydrochlorthiazide,
–Chlorthalidone, Chlorthiazide
–Hydroflumethiazide
•Carbonic anyhdrase inhibitors
–acetazolamide
–Methazolamide
–dorzalamide
•Potassium –sparing diuretics
–Spironolactone
–Eplerenone
–Amiloride
–Triamterene
•Osmotic diuretics
–Mannitol
–urea
–Isosorbide
–glycerol
•Novel diuretics?

21. 1. Inhibitors of Carbonic anhydrase
Acetazolamide, methazolamide, dichlorphenamide,dorzolamide
Site of action: Proximal Tubule
MOA: Inhibition of Carbonic Anhydrase activity.

22. http://tmedweb.tulane.edu/pharmwiki/doku.php/diuretic_pharm

23. Pharmacological effects
Urinary excretion of HCO
3
-
(35% of filtered load)
Increased urinary pH & metabolic acidosis
Excretion of 5% of filtered Na
+
& 70% of filtered K
+
Increased phosphate excretion
Reduce intraocular pressure

24. Pharmacokinetics
All are orally effective
Protein binding moderate to high
Distributed to site of action: glomerular filtration & proximal tubular
secretion
Eliminated as unchanged or as metabolites in urine

25. Adverseeffects
Metabolicacidosis(mild),potassiumdepletion,renalstone
formation,drowsiness,andparesthesiamayoccur.
Therapeuticuses
Rarelyusedasdiuretics
Glaucoma
Epilepsy
metabolicalkalosis
Acutemountainsickness
Urinealkalization

26. Osmotic Diuretics
Properties and MOA
Water soluble and are hence freely filtered
Insoluble in lipids and hence are poorly reabsorbed
Pharmacologically inert
Hence increase the osmolarity of tubular fluid
Drugs: Mannitol, Urea, Glycerin, Isosorbide
Site of action -Nephron segments which are freely permeable to water

27. http://tmedweb.tulane.edu/pharmwiki/doku.php/diuretic_pharm

28. Pharmacokinetics
Glycerin & Isosorbide: orally effective
Mannitol & urea: orally ineffective (hence IV.)
Elimination:
Renal: Isosorbide, urea, Mannitol
Metabolism: glycerin, Mannitol (-10%)

29. Adverseeffects
Headache,nausea,vomiting
Dehydration
Pain(urea)
Hyperglycemia(glycerin)
Therapeuticuses
Treatment&prevention:-acuteglaucoma&Cerebraledema(sed
ICP)

30. Loop Diuretics (high ceiling diuretics)
InhibitorsofNa
+
-K
+
-2Cl
-
Cotransporter
Drugs:Furosemide,Torsemide,Ethacrynicacid
Siteofaction:-thickascendinglimb
M.O.A:
–Loop diuretics inhibit the Na+/K+/2Cl-contransport of the luminal membrane in
the ascending loop of henlereabsorption of Na+, K+, & cl-

31. Loop Diuretics….
the amount of Na+ reaching the collecting duct & there by increased K
+
-secretion.
Ca
2+
& Mg
2+
reabsorption is also inhibited, due to the decrease in potential difference
across the cell normally generated from the recycling of K
+
.
Loop diuretics (furosemide) increase renal blood flow & cause redistribution of blood
flow with in the renal cortex (believed to be due to release of PGS)

32. http://tmedweb.tulane.edu/pharmwiki/doku.php/diuretic_pharm

33. Pharmacological effects.
ed urinary excretion of Na
+
& Cl
-
ed excretion of Ca
++
and Mg
++
ed excretion of HCO
3
-
& Phosphate –
Furosemide
Some carbonic anhydrase inhibition
activity
ed excretion of K
+
Pharmacokinetics
All are orally effective (bioavailability 60-
100%)
Given Iv in emergencies
All are highly protein bound:
Eliminated in the urine by both glomerular
filtration and tubular secretion (organic acid
secretory system in proximal tubule)
Elimination: metabolism and also renal as
unchanged

34. Drug Route
Time course of events Usualadultdosage
(mg/day)
Onset
Duration
Furosemide
Furosemide
Hydrochlorthiazide
Chlorthiazide
OralIV
Oral
Oral
60min
5min
2hrs
1-2hr
6-8hr
2hr
6-12hr
6-12hr
20to80mg
20 to 40 mg repeated in 1 to
2hrs if needed.
25-100mg
500-2000mg

35. Therapeutic use of loop diuretics
–Acute pulmonary edema (emergency situation)
–Edema due to CHF, liver disease or nephritic syndrome
–Oligouria due to renal failure
–Hypertension (not responding to other diuretics)
–Hyperkalemia or hypercalcaemia

36. Adverse effects loop diuretics
Fluid and electrolyte imbalance
dehydration
Hypokalemia & /or ECFV depletion
Cardiac arrhythmias: hypokalemia
Hypomagnesemia, hypocalcemia
Ototoxicity (electrolyte imbalance in the inner ear)
Hyperuricemia (2
o
gout)
Abnormalities in serum lipids: LDL & TGs; HDL

37. Thiazide & thiazide-like diuretics
Thiazide: Chlorothiazide, Hydrochlorothiazide,hydroflumethiazide, polythiazide,
methyclothiazide
Thiazide-like diuretics: Indapamide, Chlorthalidone, Metolazone
•Siteofaction:distalconvolutedtubule
•Mechanismofaction:
–Inhibit Na+/Cl-contransporter on the luminal membrane at DCT
–Because they act on luminal membrane, must be excreted into the tubular lumen to be effective
–Increase secretion of K
+
& H
+
–Decrease Ca
2+
excretion

38. http://tmedweb.tulane.edu/pharmwiki/doku.php/diuretic_pharm

39. Pharmacological effects
Na
+
& Cl
-
excretion
Also possess carbonic anhydrase inhibition
HCO
3
-
& Phosphate excretion
excretion of K
+
Reduce uric acid excretion

40. PharmacoKinetics
AllarewellabsorbedfromGITexceptchlorothiazide
Extensiveplasmaproteinbinding
EliminationmainlyRenalasintactdrug.
Allaresecretedbytheorganicacidsecretorysystem(competewithuricacid).
Reachtheirsiteofaction:-secretioninthePT&byglomerularfiltration.
–The reabsorption of Ca2+ is increase by a mechanism that may involve stimulation
of Na+/Ca2+ counter transport,
•due to an increase in concentration gradient for Na+ across the basolateral
membrane.

41. Therapeutic uses:
EdemaassociatedwithCHF,Hepaticcirrhosis,Nephroticsyndrome
HTN
Nephrolithiasisduetoidiopathichypercalciuria
Nephrogenicdiabetesinspidus????

42. Nephrogenic diabetes insipidus (NDI)
•Is characterized by inability to concentrate the urine, which results in polyuria
(excessive urine production) and polydipsia (excessive thirst).
•Affected untreated infants usually have poor feeding and failure to thrive, and rapid
onset of severe dehydration with illness, hot environment, or the withholding of
water.
•Short stature and secondary dilatation of the ureters and bladder from the high
urine volume is common in untreated individuals.

43. AdverseReaction
Vertigo,headache,NVD
Photosensitivity,skinrashes
Hyponatremia
Hyperglycemia
Hyperuricemia
seplasmalevelsofLDL,totalcholesterol&totalTGs

44. K
+
Sparing Diuretics
Not very efficacious diuretics: used in combination with other diuretics
Site of action: collecting duct system
Spironolactone and eplerenone (has better selectivity to aldosterone receptor)
MOA: aldosterone antagonists
Amiloride and triamterene
MOA:inhibitionofrenalepithelialNa
+
channels(ENaC).

45. Amiloride and triamterene
Pharmacological effect:
Mild in Na
+
& Cl
-
excretion (2% of filtered Na
+
load)
ed excretion of H
+
& K
+
Both triamterene and amiloride are commonly used in combination with other
diuretics, usually for their potassium sparing properties.
The side effects of triamterene include increased uric acid, renal stones, and K+
retention.

46. Antagonists of mineralocorticoid receptors
Aldosterone antagonists: spironolactoneand eplerenone
•Aldosterone
–Binds to a cytoplasmic mineralocorticosteroidreceptor stimulating the production of
aldosterone induced proteins, which
•Activate Na
+
and K
+
channels
•Increase the synthesis of Na
+
/K
+
ATPase, &
•Increase mitochondrial production of ATP
•The effect of aldosterone is to ↓Na
+
excretion and ↑K
+
and H
+
secretion in urine.

47. Antagonists of mineralocorticoid receptors cont’d…
Aldosterone antagonists inhibit the binding of aldosterone to Mineralocorticoid
Receptors at the collecting duct system .
Pharmacokinetics: -
Partially absorbed from GIT
Extensive hepatic 1
st
pass: short half life

48. http://tmedweb.tulane.edu/pharmwiki/doku.php/diuretic_pharm

49. Antagonists of mineralocorticoid receptors cont’d…
Adverse effects
Hyperkalemia,
metabolic acidosis
Drowsiness, lethargy, headache
Gynacomastia , impotence
Diarrhea
Therapeutic uses:-
Combined with other diuretics (to decrease K
+
excretion)
Primary hyper-aldosteronism (adrenal adenoma)
Secondary hyper-aldosteronism (2
o
to CHF, CRF)

50. Novel diuretics
•A new class of diuretics which are referred as novel diuretics because of their
unusual mechanism of action are becoming a focus of research to develop
diuretics with better safety and efficacy profiles.
•It was all started with increased understanding of the actions of adenosine and ADH
on the kidney tubule.
–A
1R antagonists
–ADH antagonists

51. Novel diuretics…
•Adenosineis an important intermediary metabolite, acting as a building block for
nucleic acids and a component of the biological energy currency, ATP.
•In addition, adenosine functions as a signaling molecule by stimulating specific cell
surface receptors.
•There are four adenosine receptors among vertebrates, which have been
denoted as adenosine A
1, A
2A, A
2Band A
3receptors.

52. Novel diuretics…
•Orally active non-peptide ADH antagonists called the “vaptans,” have
emerged as potentially effective drugs to treat chronic water retaining
disorders like hyponatremia because of their aquaretic activity.
•Conivaptan (Vaprisol®) was the first medication of this class to be approved by the
FDA for the treatment of hyponatremia in syndrome of inappropriate
antidiuretic hormone (SIADH) and hypervolemic hyponatremia.
•Other drugs in this group include tolvaptan and lixivaptan

53. Diuretic resistance
•All the clinically useful diuretic drugs increase urinary solute and water excretion
as a mechanism to mobilize edema and reduce extracellular fluid (ECF) volume
•However, in some critically ill patients, conventional doses of diuretics do not always
result in optimal diuresis.
–In such cases, patients are considered “diuretic resistant.”
•Even though the mechanisms of diuretic resistance are complex and differ from
patient to patient, three mechanisms of the phenomenon of diuretic resistance have
been suggested

54. Diuretic resistance….
•1
st
mechanism: rebound sodium retention. For example, after administration of loop
diuretics, sodium absorption is blocked at the loop of Henle, leading to a pronounced
reabsorption of sodium at the distal sites of the nephron.
–This reabsorption may be sufficient to nullify the effects of the prior blockage.
•2
nd
mechanism: is post diuretic effect, a compensatory sodium retention process
that begins as the diuretic action wanes. The body has compensated by absorbing more
sodium, partially nullifying the effect of the drug.
•3
rd
mechanism: is “diuretic braking,” the decrease in a patient’s response to a diuretic
after receiving the first dose. In other words, the magnitude of response to each
administered dose of diuretic declines with time .

55. Management of diuretic resistance
•Attenuating neurohormonal compensation: ACE inhibitors, angiotensin receptor
blockers, β-blockers, and spironolactone
•Improving contractility with inotropes (heart failure)
•Regulating dietary fluid and sodium intake; avoiding NSAIDs; and bed rest.
•Common clinical approaches to diuretic resistance include sequential diuretic
blockade and continuous infusion loop diuretic therapy (CILT)
•Route of administration??
•Elucidating the resistance mechanism is the answer to optimal treatment.

56. Diuretics Vs doping
•As masking agents
•To regulate body mass (box, weight lifting, etc.)

57. Diuretics Vs doping

58. Any question?
Thank you!