Maciej Niewada Clinical and Experimental Pharmacology Email: [email protected] Maciej Niewada Clinical and Experimental Pharmacology Email: [email protected]

Maciej NiewadaMaciej NiewadaClinical and Experimental PharmacologyClinical and Experimental PharmacologyEmail: [email protected]: [email protected]

Maciej NiewadaMaciej NiewadaClinical and Experimental PharmacologyClinical and Experimental PharmacologyEmail: [email protected]: [email protected]

Leki moczopędneLeki moczopędneLeki moczopędneLeki moczopędne

Critical group of drugs used to adjust the composition of plasma Critical group of drugs used to adjust the composition of plasma electrolytes and/or volume of circulating fluids in various disorders electrolytes and/or volume of circulating fluids in various disorders affecting large population.affecting large population.

EdemaEdemaTThat accompanies CHF, renal failure, liver failure (cirrhosis)hat accompanies CHF, renal failure, liver failure (cirrhosis)..

HypertensionHypertensionReduce blood volume (increase HReduce blood volume (increase H22O excretion)O excretion)..

Reduce NaReduce Na++ reabsorption (increase reabsorption (increase NaNa++ excretion excretion).).

Critical group of drugs used to adjust the composition of plasma Critical group of drugs used to adjust the composition of plasma electrolytes and/or volume of circulating fluids in various disorders electrolytes and/or volume of circulating fluids in various disorders affecting large population.affecting large population.

EdemaEdemaTThat accompanies CHF, renal failure, liver failure (cirrhosis)hat accompanies CHF, renal failure, liver failure (cirrhosis)..

HypertensionHypertensionReduce blood volume (increase HReduce blood volume (increase H22O excretion)O excretion)..

Reduce NaReduce Na++ reabsorption (increase reabsorption (increase NaNa++ excretion excretion).).

DiureticsDiureticsDiureticsDiuretics

Diuretic:Diuretic: includes diuresis and natriuresis. includes diuresis and natriuresis.

Diuresis:Diuresis: increased urine flow. increased urine flow.Natriuresis:Natriuresis: increased sodium excretion. increased sodium excretion.

Diuretic:Diuretic: includes diuresis and natriuresis. includes diuresis and natriuresis.

Diuresis:Diuresis: increased urine flow. increased urine flow.Natriuresis:Natriuresis: increased sodium excretion. increased sodium excretion.

TermsTermsTermsTerms

NaNa++ Sodium (Natrium)Sodium (Natrium)KK++ Potassium (Kalium)Potassium (Kalium) - Hyperkalemia - Hyperkalemia (increased K+ in blood)(increased K+ in blood)

- Hypokalemia - Hypokalemia (reduced K+ in blood)(reduced K+ in blood)

Acidosis - AcidsAcidosis - AcidsAlkalosis - Bases (Alkaline)Alkalosis - Bases (Alkaline)

NaNa++ Sodium (Natrium)Sodium (Natrium)KK++ Potassium (Kalium)Potassium (Kalium) - Hyperkalemia - Hyperkalemia (increased K+ in blood)(increased K+ in blood)

- Hypokalemia - Hypokalemia (reduced K+ in blood)(reduced K+ in blood)

Acidosis - AcidsAcidosis - AcidsAlkalosis - Bases (Alkaline)Alkalosis - Bases (Alkaline)

OsmosisOsmosis:: tthe passage of water or another solvent across a he passage of water or another solvent across a semi-permeable membrane into a compartment that has a semi-permeable membrane into a compartment that has a higher concentration of solutes; this tends to regulate the higher concentration of solutes; this tends to regulate the concentration of solutes in the two compartmentsconcentration of solutes in the two compartments

Osmotic pressureOsmotic pressure:: tthe pressure created when water flows by he pressure created when water flows by osmosis through a semiosmosis through a semi--permeable membrane into a chamber permeable membrane into a chamber containing a high concentration of solutes.containing a high concentration of solutes.

Hypo/Hyper tonicHypo/Hyper tonic:: anyany solution that has a lower solution that has a lower/higher/higher osmotic pressure than another solution (i.e. has a lowerosmotic pressure than another solution (i.e. has a lower/higher/higher concentration of solutes than another solution).concentration of solutes than another solution).

OsmosisOsmosis:: tthe passage of water or another solvent across a he passage of water or another solvent across a semi-permeable membrane into a compartment that has a semi-permeable membrane into a compartment that has a higher concentration of solutes; this tends to regulate the higher concentration of solutes; this tends to regulate the concentration of solutes in the two compartmentsconcentration of solutes in the two compartments

Osmotic pressureOsmotic pressure:: tthe pressure created when water flows by he pressure created when water flows by osmosis through a semiosmosis through a semi--permeable membrane into a chamber permeable membrane into a chamber containing a high concentration of solutes.containing a high concentration of solutes.

Hypo/Hyper tonicHypo/Hyper tonic:: anyany solution that has a lower solution that has a lower/higher/higher osmotic pressure than another solution (i.e. has a lowerosmotic pressure than another solution (i.e. has a lower/higher/higher concentration of solutes than another solution).concentration of solutes than another solution).

TermsTermsTermsTerms

Functions of the KidneysFunctions of the KidneysFunctions of the KidneysFunctions of the KidneysMajor function of kidneys is the formation of urine.Major function of kidneys is the formation of urine.

Regulation of the volume of extracellular fluid.Regulation of the volume of extracellular fluid.Regulation of ion concentration (electrolyte homeostasis, pH of body fluids).Regulation of ion concentration (electrolyte homeostasis, pH of body fluids).Excretion of nitrogenous waste products of metabolism (urea, creatinin)Excretion of nitrogenous waste products of metabolism (urea, creatinin)

Major function of kidneys is the formation of urine.Major function of kidneys is the formation of urine.Regulation of the volume of extracellular fluid.Regulation of the volume of extracellular fluid.Regulation of ion concentration (electrolyte homeostasis, pH of body fluids).Regulation of ion concentration (electrolyte homeostasis, pH of body fluids).Excretion of nitrogenous waste products of metabolism (urea, creatinin)Excretion of nitrogenous waste products of metabolism (urea, creatinin)

Nephron (basic unit of the kidney) allows formation of urine.Nephron (basic unit of the kidney) allows formation of urine.

Glomerular FiltrationGlomerular FiltrationGlomerulus consists of a specialized spherical tuft of capillaries enclosed in an Glomerulus consists of a specialized spherical tuft of capillaries enclosed in an epithelial cell capsule which empties tubular fluid into the nephron tubular system.epithelial cell capsule which empties tubular fluid into the nephron tubular system.Serves as “sieve” for plasmaServes as “sieve” for plasma through fenestrated endothelium & podocytes. through fenestrated endothelium & podocytes. Filtration Filtration rate is affected by renal blood flow (afferent/efferent renal arterioles). Small molecules rate is affected by renal blood flow (afferent/efferent renal arterioles). Small molecules are freely filtered. Large ones no. 130-150 liters/day. Approx 10 x volume of are freely filtered. Large ones no. 130-150 liters/day. Approx 10 x volume of extracellular fluid, 60 x plasma. Large proportion must be reabsorbed. extracellular fluid, 60 x plasma. Large proportion must be reabsorbed.

Tubular ReabsorptionTubular ReabsorptionActive transport of electrolytes and other solutes from lumen of tubules, to peritubular Active transport of electrolytes and other solutes from lumen of tubules, to peritubular fluid (blood). Hfluid (blood). H22O is likely to be reabsorbed by osmotic processes.O is likely to be reabsorbed by osmotic processes.

Tubular SecretionTubular SecretionOrganic acids and bases secreted. Mainly in proximal tubule.Organic acids and bases secreted. Mainly in proximal tubule.

Nephron (basic unit of the kidney) allows formation of urine.Nephron (basic unit of the kidney) allows formation of urine.

Glomerular FiltrationGlomerular FiltrationGlomerulus consists of a specialized spherical tuft of capillaries enclosed in an Glomerulus consists of a specialized spherical tuft of capillaries enclosed in an epithelial cell capsule which empties tubular fluid into the nephron tubular system.epithelial cell capsule which empties tubular fluid into the nephron tubular system.Serves as “sieve” for plasmaServes as “sieve” for plasma through fenestrated endothelium & podocytes. through fenestrated endothelium & podocytes. Filtration Filtration rate is affected by renal blood flow (afferent/efferent renal arterioles). Small molecules rate is affected by renal blood flow (afferent/efferent renal arterioles). Small molecules are freely filtered. Large ones no. 130-150 liters/day. Approx 10 x volume of are freely filtered. Large ones no. 130-150 liters/day. Approx 10 x volume of extracellular fluid, 60 x plasma. Large proportion must be reabsorbed. extracellular fluid, 60 x plasma. Large proportion must be reabsorbed.

Tubular ReabsorptionTubular ReabsorptionActive transport of electrolytes and other solutes from lumen of tubules, to peritubular Active transport of electrolytes and other solutes from lumen of tubules, to peritubular fluid (blood). Hfluid (blood). H22O is likely to be reabsorbed by osmotic processes.O is likely to be reabsorbed by osmotic processes.

Tubular SecretionTubular SecretionOrganic acids and bases secreted. Mainly in proximal tubule.Organic acids and bases secreted. Mainly in proximal tubule.

IsotonicIsotonic

HypertonicHypertonic

HighHigh NoneNone VariableVariable

Water PermeabilityWater Permeability

1

ThindescendingLimb ofHenle

Major site (2/3) of NaMajor site (2/3) of Na++ and H and H22O O

reabsorption. Bicarb. Reabsorption.reabsorption. Bicarb. Reabsorption.Carbonic Anhydrase Inhibitors.Carbonic Anhydrase Inhibitors.

Major site (2/3) of NaMajor site (2/3) of Na++ and H and H22O O

reabsorption. Bicarb. Reabsorption.reabsorption. Bicarb. Reabsorption.Carbonic Anhydrase Inhibitors.Carbonic Anhydrase Inhibitors.

Tubular ReabsorptionTubular Reabsorption

Impermeable to HImpermeable to H22O. 25% NaO. 25% Na++ reabsorb. reabsorb.

Fluid becomes hypotonic.Fluid becomes hypotonic.Loop Diuretics.Loop Diuretics.


Fluid becomes hypotonic.Fluid becomes hypotonic.Loop Diuretics.Loop Diuretics.


Active CaActive Ca++++ reabsorption. reabsorption.Thiazides.Thiazides.


Active CaActive Ca++++ reabsorption. reabsorption.Thiazides.Thiazides.

““Fine-tuning”Fine-tuning” of electrolyte balance. of electrolyte balance. Final site of NaFinal site of Na++ reabsorb. reabsorb.KK++ excretion (correl to amt. Na excretion (correl to amt. Na++ reabs). reabs).Controlled by Aldosterone.Controlled by Aldosterone.Potassium Sparing.Potassium Sparing.

““Fine-tuning”Fine-tuning” of electrolyte balance. of electrolyte balance. Final site of NaFinal site of Na++ reabsorb. reabsorb.KK++ excretion (correl to amt. Na excretion (correl to amt. Na++ reabs). reabs).Controlled by Aldosterone.Controlled by Aldosterone.Potassium Sparing.Potassium Sparing.

2

3

4

11

22

33

44

Proximal Convoluted Tubule & Thin Proximal Convoluted Tubule & Thin Descending Limb.Descending Limb.Osmotic Diuretics.Osmotic Diuretics.

Proximal Convoluted Tubule & Thin Proximal Convoluted Tubule & Thin Descending Limb.Descending Limb.Osmotic Diuretics.Osmotic Diuretics.

55

Natrecor - hormon natriuretyczny

rekomendowany do rejestracji przez FDA

Wskazania: krótkotrwałe wlewy dożylne w zaostrzeniu

niewydolności serca

J Am Coll Cardiol 1999 Jul;34(1):155-62

LumenLumen(Urine)(Urine)

InterstitiumInterstitium(Blood)(Blood)

NaNa++

NaNa++ChannelChannel

NaNa++

XX--SymportSymport

NaNa++

HH++AntiportAntiport

Transcellular Transcellular HH22OO

Paracellular Paracellular HH22OO

RenalRenalEpithelial CellEpithelial Cell

General NaGeneral Na++/H/H22O reabsorptionO reabsorptionGeneral NaGeneral Na++/H/H22O reabsorptionO reabsorption

NaNa++

KK++

ATPATP

ApicalApicalCell MembraneCell Membrane

BasolateralBasolateralCell MembraneCell Membrane

- - W W kanaliku bliższym, kanaliku bliższym, końcowej części końcowej części kanalika dalszego (dystalnego) i kanalika dalszego (dystalnego) i początkowej części kanalika początkowej części kanalika zbiorczego jony sodowe są zbiorczego jony sodowe są wymieniane na jony potasowe i wymieniane na jony potasowe i wodorowe, które przechodzą do wodorowe, które przechodzą do światła kanalika.światła kanalika.- - W niedoborze potasu wzrasta W niedoborze potasu wzrasta wydalanie jonów wodorowych; w ten wydalanie jonów wodorowych; w ten sposób powstaje zasadowica sposób powstaje zasadowica metaboliczna w hipokaliemii metaboliczna w hipokaliemii

Proximal Convoluted TubuleProximal Convoluted TubuleProximal Convoluted TubuleProximal Convoluted Tubule

Major site of NaMajor site of Na++ and H and H22O reabsorption O reabsorption

(as much as 2/3 reabsorbed)(as much as 2/3 reabsorbed); blocked by ; blocked by ANF ANF

Major site of bicarbonate (HCOMajor site of bicarbonate (HCO33--) reab. ) reab.

Fluid stays isotonic.Fluid stays isotonic.

Driving force for NaDriving force for Na++ reabsorption is reabsorption is NaNa++/ATP/ATPasease pump at basement membrane pump at basement membrane

of tubular cell. of tubular cell.

NaNa++ reabsorption is performed by reabsorption is performed by NaNa++/H/H++ exchanger.exchanger.

Conservation of HCOConservation of HCO33-- is accomplished is accomplished

through through CACA at luminal surface. at luminal surface.

Major site of NaMajor site of Na++ and H and H22O reabsorption O reabsorption

(as much as 2/3 reabsorbed)(as much as 2/3 reabsorbed); blocked by ; blocked by ANF ANF

Major site of bicarbonate (HCOMajor site of bicarbonate (HCO33--) reab. ) reab.

Fluid stays isotonic.Fluid stays isotonic.



NaNa++ reabsorption is performed by reabsorption is performed by NaNa++/H/H++ exchanger.exchanger.

Conservation of HCOConservation of HCO33-- is accomplished is accomplished

through through CACA at luminal surface. at luminal surface.NaHCONaHCO33 Sodium BicarbonateSodium Bicarbonate

HCOHCO33-- BicarbonateBicarbonate

HH22COCO33 Carbonic AcidCarbonic Acid

NaHCONaHCO33 Sodium BicarbonateSodium Bicarbonate

HCOHCO33-- BicarbonateBicarbonate

HH22COCO33 Carbonic AcidCarbonic Acid

From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250

70%70%

20%20%

5%

4.5%4.5%

0.5%0.5%Volume 1.5 L/day

Urine Na 100 mEq/LNa Excretion 155 mEq/day

100%100%GFR 180 L/day

Plasma Na 145 mEq/LFiltered Load 26,100 mEq/day

CA InhibitorsProximal tubule

Loop DiureticsLoop of Henle

ThiazidesDistal tubule

Antikaliuretics

Collecting duct

Thick Ascending Limb

• • I.I. Leki modyfikujące transport kanalikowyLeki modyfikujące transport kanalikowy• • 1. O wysokiej efektywności (Do 25 -30%) zwane inaczej diuretykami pętlowymi1. O wysokiej efektywności (Do 25 -30%) zwane inaczej diuretykami pętlowymi• a) pochodne sulfonamidowe (furosemid, torasemid, bumetanid, piretanid)a) pochodne sulfonamidowe (furosemid, torasemid, bumetanid, piretanid)• b) pochodne kwasu fenoksyoctowęgo (kwas etakrynowy)b) pochodne kwasu fenoksyoctowęgo (kwas etakrynowy)• c) związki organiczne rtęci - diuretyki rtęciowe (mersalyl)c) związki organiczne rtęci - diuretyki rtęciowe (mersalyl)• • 2. O umiarkowanej efektywności (do 15%) zwane również diuretykami korowego odcinka pętli nefronu2. O umiarkowanej efektywności (do 15%) zwane również diuretykami korowego odcinka pętli nefronu• a) pochodne benzotiadiazyny czyli tiazydy moczopędne (chlorotiazyd, hydrochlorotiazyd)a) pochodne benzotiadiazyny czyli tiazydy moczopędne (chlorotiazyd, hydrochlorotiazyd)• b) związki tiazydopodobne (chlortąlidon, indapamid, klopamid)b) związki tiazydopodobne (chlortąlidon, indapamid, klopamid)• C) antagoniści wazopresyny C) antagoniści wazopresyny

• 3. O miernej efektywności (<5%)3. O miernej efektywności (<5%)• • a)środki moczopędne oszczędzające potas (spironolakton, triamteren, amilorid)a)środki moczopędne oszczędzające potas (spironolakton, triamteren, amilorid)• b) inhibitory anhydrazy węglanowej (acetazolamid)b) inhibitory anhydrazy węglanowej (acetazolamid)

• II.II. Inne leki moczopędneInne leki moczopędne• • 1. diuretyki osmotyczne (mannitol)1. diuretyki osmotyczne (mannitol)• 2. środki pochodzenia roślinnego2. środki pochodzenia roślinnego•


NaNa++

HH++


NaNa++

KK++

ATPATP

HCOHCO33--

HH22COCO33

COCO22 HH22OO

HH++HCOHCO33--

HH22COCO33

HH22OO COCO22

Cl Cl --

Base Base --

CACACACA

NaNa++/ATP/ATPase ase pump keeps i.Napump keeps i.Na+ + low.low.

NaNa++/H/H++ exchanger exchanger reabsorbs Na reabsorbs Na++ and and secretes Hsecretes H+ + in lumen.in lumen.

HH++ ions combine w/ filtered HCO ions combine w/ filtered HCO33-- to to

form Hform H22COCO33..

HH22COCO33 is dehydrated w/ is dehydrated w/ CACA to H to H22O O

and COand CO22..

HH22O and COO and CO22 cross membrane and cross membrane and

are rehydrated w/ are rehydrated w/ CACA to H to H22COCO33..

HH22COCO33 dissociates to H dissociates to H+ + and HCOand HCO33--

providing another Hproviding another H++ to be used in to be used in NaNa++/H/H++ exchanger and allows exchanger and allows regenerated HCOregenerated HCO33

-- to be reabsorbed to be reabsorbed

in plasma.in plasma.


NaNa++/H/H++ exchanger exchanger reabsorbs Na reabsorbs Na++ and and secretes Hsecretes H+ + in lumen.in lumen.

HH++ ions combine w/ filtered HCO ions combine w/ filtered HCO33-- to to

form Hform H22COCO33..

HH22COCO33 is dehydrated w/ is dehydrated w/ CACA to H to H22O O

and COand CO22..

HH22O and COO and CO22 cross membrane and cross membrane and

are rehydrated w/ are rehydrated w/ CACA to H to H22COCO33..

HH22COCO33 dissociates to H dissociates to H+ + and HCOand HCO33--

providing another Hproviding another H++ to be used in to be used in NaNa++/H/H++ exchanger and allows exchanger and allows regenerated HCOregenerated HCO33

-- to be reabsorbed to be reabsorbed

in plasma.in plasma.

Proximal Convoluted TubuleProximal Convoluted TubuleProximal Convoluted TubuleProximal Convoluted Tubule

CA InhibitorsCA InhibitorsCA InhibitorsCA Inhibitors


NaNa++

HH++


NaNa++

KK++

ATPATP

HCOHCO33--

HH22COCO33

COCO22 HH22OO

HH++HCOHCO33--

HH22COCO33

HH22OO COCO22

Cl Cl --

Base Base --

CACACACA

Inhibit enzyme CA.Inhibit enzyme CA.Decrease availability of HDecrease availability of H+ + for Nafor Na++/H/H++ exchanger.exchanger.

NaNa++ secreted with HCO secreted with HCO33--. Decreased H. Decreased H22O O

and COand CO22 formation in lumen. formation in lumen.

High tolerance develops (not used as High tolerance develops (not used as diuretics or antihypertensives).diuretics or antihypertensives).

Increased HCOIncreased HCO33--excretion excretion Acidosis.Acidosis.

Alkalinize urine (attn. renal stones form).Alkalinize urine (attn. renal stones form).Tx. Metabolic acidosis., epilepsy, Tx. Metabolic acidosis., epilepsy, Prevent acute mt. Sickness (Prevent acute mt. Sickness (ΔΔ pressure may pressure may cause respiratory alkalosis).cause respiratory alkalosis).Tx. High intraocular pressure (glaucoma), Tx. High intraocular pressure (glaucoma), because aqueous humor has high bicarb.because aqueous humor has high bicarb.Hyperphosphatemia Hyperphosphatemia Loss of appetite, drowsiness, confusion (CA Loss of appetite, drowsiness, confusion (CA in CNS).in CNS).Hepatic encephalopathy (due to increased Hepatic encephalopathy (due to increased plasma ammonia).plasma ammonia).Sulphonamide derivativeSulphonamide derivative

Inhibit enzyme CA.Inhibit enzyme CA.Decrease availability of HDecrease availability of H+ + for Nafor Na++/H/H++ exchanger.exchanger.

NaNa++ secreted with HCO secreted with HCO33--. Decreased H. Decreased H22O O

and COand CO22 formation in lumen. formation in lumen.

High tolerance develops (not used as High tolerance develops (not used as diuretics or antihypertensives).diuretics or antihypertensives).

Increased HCOIncreased HCO33--excretion excretion Acidosis.Acidosis.

Alkalinize urine (attn. renal stones form).Alkalinize urine (attn. renal stones form).Tx. Metabolic acidosis., epilepsy, Tx. Metabolic acidosis., epilepsy, Prevent acute mt. Sickness (Prevent acute mt. Sickness (ΔΔ pressure may pressure may cause respiratory alkalosis).cause respiratory alkalosis).Tx. High intraocular pressure (glaucoma), Tx. High intraocular pressure (glaucoma), because aqueous humor has high bicarb.because aqueous humor has high bicarb.Hyperphosphatemia Hyperphosphatemia Loss of appetite, drowsiness, confusion (CA Loss of appetite, drowsiness, confusion (CA in CNS).in CNS).Hepatic encephalopathy (due to increased Hepatic encephalopathy (due to increased plasma ammonia).plasma ammonia).Sulphonamide derivativeSulphonamide derivative

Proximal Convoluted TubuleProximal Convoluted TubuleProximal Convoluted TubuleProximal Convoluted TubuleAcetazolamideAcetazolamideAcetazolamideAcetazolamide

Thick Ascending LimbThick Ascending LimbThick Ascending LimbThick Ascending LimbImpermeable to HImpermeable to H22O, but 25-35%NaO, but 25-35%Na++

reabsorption.reabsorption.



NaNa++ reabsorption is performed by reabsorption is performed by NaNa++/K/K++/2Cl/2Cl-- co-transport.co-transport.

RECYCKLING OF NaRECYCKLING OF Na+ + produces osmotic produces osmotic gradient – fluid becomes hypotonic.gradient – fluid becomes hypotonic.

Impermeable to HImpermeable to H22O, but 25-35%NaO, but 25-35%Na++

reabsorption.reabsorption.



NaNa++ reabsorption is performed by reabsorption is performed by NaNa++/K/K++/2Cl/2Cl-- co-transport.co-transport.

RECYCKLING OF NaRECYCKLING OF Na+ + produces osmotic produces osmotic gradient – fluid becomes hypotonic.gradient – fluid becomes hypotonic.


NaNa++


NaNa++

KK++

ATPATP

Mg Mg ++++

CaCa++++

KK++

2Cl2Cl--


NaNa++/K/K++/2Cl/2Cl-- cotransporter cotransporter reabsorbs. reabsorbs.

Great buildup of i.KGreat buildup of i.K++ (coming from (coming from lumen and interstitium).lumen and interstitium).

Result: backward diffusion of KResult: backward diffusion of K++ into into lumen, creating net + charge in lumen.lumen, creating net + charge in lumen.

This + charge causes electrostatic This + charge causes electrostatic repulsion with + ions, encouraging repulsion with + ions, encouraging absorption of + ions Mgabsorption of + ions Mg++++, Ca, Ca++++. .


NaNa++/K/K++/2Cl/2Cl-- cotransporter cotransporter reabsorbs. reabsorbs.

Great buildup of i.KGreat buildup of i.K++ (coming from (coming from lumen and interstitium).lumen and interstitium).

Result: backward diffusion of KResult: backward diffusion of K++ into into lumen, creating net + charge in lumen.lumen, creating net + charge in lumen.

This + charge causes electrostatic This + charge causes electrostatic repulsion with + ions, encouraging repulsion with + ions, encouraging absorption of + ions Mgabsorption of + ions Mg++++, Ca, Ca++++. .

Thick Ascending LimbThick Ascending LimbThick Ascending LimbThick Ascending Limb

KK++ KK++

ClCl--

HH22OO

(+)(+)


NaNa++


NaNa++

KK++

ATPATP

Mg Mg ++++

CaCa++++

KK++

2Cl2Cl--

Thick Ascending LimbThick Ascending LimbThick Ascending LimbThick Ascending Limb

KK++ KK++

ClCl--

HH22OO

(+)(+)

Compete with Cl- for a binding site on the Compete with Cl- for a binding site on the NaNa++/K/K++/2Cl/2Cl-- cotransporter. Block transporter. cotransporter. Block transporter.Prevent NaPrevent Na+ + reabsorption (increase secretion).reabsorption (increase secretion).

Impermeable to HImpermeable to H22O so no great changes in HO so no great changes in H22O O reabsorption at this site, but increased luminal reabsorption at this site, but increased luminal NaNa++ prevents H prevents H22O reabsorption in collecting duct.O reabsorption in collecting duct.

Increased NaIncreased Na++ in collecting duct will increase K in collecting duct will increase K++ and Hand H++ excretion. Therefore excretion. Therefore induce hypokalemia induce hypokalemia and metabolic alkalosisand metabolic alkalosis (used tx. hyperkalemia).(used tx. hyperkalemia).Decreased NaDecreased Na++ and Cl and Cl- - reabsorption & Kreabsorption & K++ excretion prevents absorption of Caexcretion prevents absorption of Ca++++ and Mg and Mg++ ++

(electrical gradient).(electrical gradient).May be used to tx. HypercalcemiaMay be used to tx. Hypercalcemia (do not induce (do not induce hypocalcemia as Cahypocalcemia as Ca++++ is absorbed in distal c. t.) . is absorbed in distal c. t.) .Hypomagnesemia.Hypomagnesemia.Hypochloremia.Hypochloremia.Hyponatremia and/or dehydration.Hyponatremia and/or dehydration.Hyperuricemia (excess uric acid in bloodHyperuricemia (excess uric acid in blood, gout, gout).).Ototoxicity; more severe with use of ototoxic Ototoxicity; more severe with use of ototoxic antibiotics (e.g. aminoglycosides)antibiotics (e.g. aminoglycosides) unknown mech. unknown mech.

Compete with Cl- for a binding site on the Compete with Cl- for a binding site on the NaNa++/K/K++/2Cl/2Cl-- cotransporter. Block transporter. cotransporter. Block transporter.Prevent NaPrevent Na+ + reabsorption (increase secretion).reabsorption (increase secretion).


Increased NaIncreased Na++ in collecting duct will increase K in collecting duct will increase K++ and Hand H++ excretion. Therefore excretion. Therefore induce hypokalemia induce hypokalemia and metabolic alkalosisand metabolic alkalosis (used tx. hyperkalemia).(used tx. hyperkalemia).Decreased NaDecreased Na++ and Cl and Cl- - reabsorption & Kreabsorption & K++ excretion prevents absorption of Caexcretion prevents absorption of Ca++++ and Mg and Mg++ ++

(electrical gradient).(electrical gradient).May be used to tx. HypercalcemiaMay be used to tx. Hypercalcemia (do not induce (do not induce hypocalcemia as Cahypocalcemia as Ca++++ is absorbed in distal c. t.) . is absorbed in distal c. t.) .Hypomagnesemia.Hypomagnesemia.Hypochloremia.Hypochloremia.Hyponatremia and/or dehydration.Hyponatremia and/or dehydration.Hyperuricemia (excess uric acid in bloodHyperuricemia (excess uric acid in blood, gout, gout).).Ototoxicity; more severe with use of ototoxic Ototoxicity; more severe with use of ototoxic antibiotics (e.g. aminoglycosides)antibiotics (e.g. aminoglycosides) unknown mech. unknown mech.

Loop DiureticsLoop DiureticsLoop DiureticsLoop Diuretics

Induce dilation of venous system and renal vasodilation - increase in renal flow (prob. Induce dilation of venous system and renal vasodilation - increase in renal flow (prob. mediated by prostaglandings). Increases glomerular filtration.mediated by prostaglandings). Increases glomerular filtration. Fall in left ventr. press. Fall in left ventr. press.

Edema. Edema. PulmonaryPulmonary and others (CHF, cirrhosis). and others (CHF, cirrhosis).

Antihypertensives, esp. in patients w/ impaired renal function.Antihypertensives, esp. in patients w/ impaired renal function.

NSAIDS decrease diuretic effects (block prostaglandins). Probenecid inhibits NSAIDS decrease diuretic effects (block prostaglandins). Probenecid inhibits secretion of drugs & decreases diuretic action.secretion of drugs & decreases diuretic action.

Short latency of action onset (20 min). Very efficacious “high ceiling”.Short latency of action onset (20 min). Very efficacious “high ceiling”.

May impair glucose tolerance (hyperglycemia). Attn. patients with diabetes melliuts.May impair glucose tolerance (hyperglycemia). Attn. patients with diabetes melliuts.

Symptoms secondary to electrolyte imbalance; hypokalemia may exacerbate some.Symptoms secondary to electrolyte imbalance; hypokalemia may exacerbate some.

Induce dilation of venous system and renal vasodilation - increase in renal flow (prob. Induce dilation of venous system and renal vasodilation - increase in renal flow (prob. mediated by prostaglandings). Increases glomerular filtration.mediated by prostaglandings). Increases glomerular filtration. Fall in left ventr. press. Fall in left ventr. press.

Edema. Edema. PulmonaryPulmonary and others (CHF, cirrhosis). and others (CHF, cirrhosis).

Antihypertensives, esp. in patients w/ impaired renal function.Antihypertensives, esp. in patients w/ impaired renal function.

NSAIDS decrease diuretic effects (block prostaglandins). Probenecid inhibits NSAIDS decrease diuretic effects (block prostaglandins). Probenecid inhibits secretion of drugs & decreases diuretic action.secretion of drugs & decreases diuretic action.

Short latency of action onset (20 min). Very efficacious “high ceiling”.Short latency of action onset (20 min). Very efficacious “high ceiling”.



Ethacrynic Acid Ethacrynic Acid (Edecrin)(Edecrin)Not sulfonamide derivative. Not sulfonamide derivative. V. ototoxic. V. ototoxic. Oral use; salt for i.v. use.Oral use; salt for i.v. use.

Furosemide Furosemide (Lasix)(Lasix)Sulfonamide derivative. Prescribed v. commonly.Sulfonamide derivative. Prescribed v. commonly.

Bumetanide Bumetanide (Bumex)(Bumex)Sulfonamide derivative. V. potent (40x lowed doses than furosemide enough).Sulfonamide derivative. V. potent (40x lowed doses than furosemide enough).

Torsemide Torsemide (Demadex)(Demadex)Sulfonamide derivative. Newer, longer lasting.Sulfonamide derivative. Newer, longer lasting.

Ethacrynic Acid Ethacrynic Acid (Edecrin)(Edecrin)Not sulfonamide derivative. Not sulfonamide derivative. V. ototoxic. V. ototoxic. Oral use; salt for i.v. use.Oral use; salt for i.v. use.

Furosemide Furosemide (Lasix)(Lasix)Sulfonamide derivative. Prescribed v. commonly.Sulfonamide derivative. Prescribed v. commonly.

Bumetanide Bumetanide (Bumex)(Bumex)Sulfonamide derivative. V. potent (40x lowed doses than furosemide enough).Sulfonamide derivative. V. potent (40x lowed doses than furosemide enough).

Torsemide Torsemide (Demadex)(Demadex)Sulfonamide derivative. Newer, longer lasting.Sulfonamide derivative. Newer, longer lasting.

Thick Ascending LimbThick Ascending LimbThick Ascending LimbThick Ascending Limb Loop DiureticsLoop DiureticsLoop DiureticsLoop Diuretics

Allergies to sulfonamidesAllergies to sulfonamidesAllergies to sulfonamidesAllergies to sulfonamides

Distal Convoluted TubuleDistal Convoluted TubuleDistal Convoluted TubuleDistal Convoluted Tubule

Impermeable to HImpermeable to H22O, but NaO, but Na++

reabsorption continues (5-10%).reabsorption continues (5-10%).

Site of active CaSite of active Ca++++ reabsorption reabsorption (regulated by parathyroid hormone).(regulated by parathyroid hormone).



NaNa++ reabsorption is performed by reabsorption is performed by NaNa++/Cl/Cl-- co-transport.co-transport.

Impermeable to HImpermeable to H22O, but NaO, but Na++

reabsorption continues (5-10%).reabsorption continues (5-10%).

Site of active CaSite of active Ca++++ reabsorption reabsorption (regulated by parathyroid hormone).(regulated by parathyroid hormone).



NaNa++ reabsorption is performed by reabsorption is performed by NaNa++/Cl/Cl-- co-transport.co-transport.


NaNa++


NaNa++

KK++

ATPATP

ClCl--


CaCa++++NaNa++

CaCa++++

HH22OO


NaNa++/Cl/Cl-- cotransporter cotransporter reabsorbs. reabsorbs.

CaCa++ ++ reabsorption occurs (regulated by reabsorption occurs (regulated by parathyroid hormone).parathyroid hormone).

Once inside the cell, CaOnce inside the cell, Ca++++ is absorbed is absorbed via Navia Na++/Ca/Ca++++ exchanger. exchanger.


NaNa++/Cl/Cl-- cotransporter cotransporter reabsorbs. reabsorbs.

CaCa++ ++ reabsorption occurs (regulated by reabsorption occurs (regulated by parathyroid hormone).parathyroid hormone).

Once inside the cell, CaOnce inside the cell, Ca++++ is absorbed is absorbed via Navia Na++/Ca/Ca++++ exchanger. exchanger.


NaNa++


NaNa++

KK++

ATPATP

ClCl--


CaCa++++NaNa++

CaCa++++

HH22OO

ThiazidesThiazidesThiazidesThiazides

Compete with Cl- for a binding site on the NaCompete with Cl- for a binding site on the Na++/Cl/Cl-- cotransporter. Block transporter.cotransporter. Block transporter.Prevent NaPrevent Na++and Cl- reabsorption (increase and Cl- reabsorption (increase secretion).secretion).


Increased NaIncreased Na++ in collecting duct will increase K in collecting duct will increase K++ and Hand H++ excretion. Therefore excretion. Therefore induce hypokalemia induce hypokalemia and metabolic alkalosis.and metabolic alkalosis.Decreased NaDecreased Na++ reabsorption increases Ca reabsorption increases Ca++++ reabsorption (electrical gradient).reabsorption (electrical gradient).Renal stones. May help tx. of Osteoporosis.Renal stones. May help tx. of Osteoporosis.Hypomagnesemia (unknown mechanism).Hypomagnesemia (unknown mechanism).Hypochloremia.Hypochloremia.Hyponatremia and/or dehydration.Hyponatremia and/or dehydration.Hyperuricemia (excess uric acid in blood).Hyperuricemia (excess uric acid in blood).Hyperlipidemia; increase LDL cholesterol.Hyperlipidemia; increase LDL cholesterol.

Compete with Cl- for a binding site on the NaCompete with Cl- for a binding site on the Na++/Cl/Cl-- cotransporter. Block transporter.cotransporter. Block transporter.Prevent NaPrevent Na++and Cl- reabsorption (increase and Cl- reabsorption (increase secretion).secretion).


Increased NaIncreased Na++ in collecting duct will increase K in collecting duct will increase K++ and Hand H++ excretion. Therefore excretion. Therefore induce hypokalemia induce hypokalemia and metabolic alkalosis.and metabolic alkalosis.Decreased NaDecreased Na++ reabsorption increases Ca reabsorption increases Ca++++ reabsorption (electrical gradient).reabsorption (electrical gradient).Renal stones. May help tx. of Osteoporosis.Renal stones. May help tx. of Osteoporosis.Hypomagnesemia (unknown mechanism).Hypomagnesemia (unknown mechanism).Hypochloremia.Hypochloremia.Hyponatremia and/or dehydration.Hyponatremia and/or dehydration.Hyperuricemia (excess uric acid in blood).Hyperuricemia (excess uric acid in blood).Hyperlipidemia; increase LDL cholesterol.Hyperlipidemia; increase LDL cholesterol.

Moderately potent diuretics (most salts have already been absorbed, only 5-10% NaModerately potent diuretics (most salts have already been absorbed, only 5-10% Na++ reabsorbed here).reabsorbed here).

Most commonly prescribed class of diuretics.Most commonly prescribed class of diuretics.

Antihypertensives (mild-moderate).Antihypertensives (mild-moderate).

Increase efficacy of other antihypertensive agents, esp. ACE inhibitors.Increase efficacy of other antihypertensive agents, esp. ACE inhibitors.

CHF (loop diuretics are drug of choice).CHF (loop diuretics are drug of choice).

Most drugs are benzothiazides (shortened to thiazides), some are sulfonamides.Most drugs are benzothiazides (shortened to thiazides), some are sulfonamides.

NSAIDS decrease diuretic effects. Probenecid inhibits secretion of drugs.NSAIDS decrease diuretic effects. Probenecid inhibits secretion of drugs.



Allergy to sulfonamides (many drugs are sulfonamide derivatives).Allergy to sulfonamides (many drugs are sulfonamide derivatives).

Moderately potent diuretics (most salts have already been absorbed, only 5-10% NaModerately potent diuretics (most salts have already been absorbed, only 5-10% Na++ reabsorbed here).reabsorbed here).

Most commonly prescribed class of diuretics.Most commonly prescribed class of diuretics.

Antihypertensives (mild-moderate).Antihypertensives (mild-moderate).

Increase efficacy of other antihypertensive agents, esp. ACE inhibitors.Increase efficacy of other antihypertensive agents, esp. ACE inhibitors.

CHF (loop diuretics are drug of choice).CHF (loop diuretics are drug of choice).

Most drugs are benzothiazides (shortened to thiazides), some are sulfonamides.Most drugs are benzothiazides (shortened to thiazides), some are sulfonamides.

NSAIDS decrease diuretic effects. Probenecid inhibits secretion of drugs.NSAIDS decrease diuretic effects. Probenecid inhibits secretion of drugs.



Allergy to sulfonamides (many drugs are sulfonamide derivatives).Allergy to sulfonamides (many drugs are sulfonamide derivatives).

Chlorthiazide Chlorthiazide (Diuril, Hygorton)(Diuril, Hygorton)Hydrocholrothiazide Hydrocholrothiazide (Esidrex)(Esidrex)Chlorthalidone Chlorthalidone ((HygrotonHygroton))Metolazone Metolazone (Mykrox, Zaroxolyn)(Mykrox, Zaroxolyn)Indapamide Indapamide (Lo(Lozzol)ol)

Chlorthiazide Chlorthiazide (Diuril, Hygorton)(Diuril, Hygorton)Hydrocholrothiazide Hydrocholrothiazide (Esidrex)(Esidrex)Chlorthalidone Chlorthalidone ((HygrotonHygroton))Metolazone Metolazone (Mykrox, Zaroxolyn)(Mykrox, Zaroxolyn)Indapamide Indapamide (Lo(Lozzol)ol)

Distal Convoluted TubuleDistal Convoluted TubuleDistal Convoluted TubuleDistal Convoluted Tubule ThiazidesThiazidesThiazidesThiazides

Mechanism of action of the paradoxical effect of thiazide diuretics on diabetes insipidus

http://ndt.oupjournals.org/content/vol15/issue12/images/large/ND71588.39.1.jpeg

Collecting TubuleCollecting TubuleCollecting TubuleCollecting Tubule

Final site of electrolyte adjustment Final site of electrolyte adjustment (“fine-tuning” of ion secretion).(“fine-tuning” of ion secretion).

Only 2-5% NaOnly 2-5% Na++ reabsorption. reabsorption.

Major site of KMajor site of K++ excretion. excretion.

2 types of cells2 types of cellsPrincipal cells: NaPrincipal cells: Na++, K, K++, H, H22O transport. O transport.

Intercalated cells: HIntercalated cells: H++ transport. transport.


of tubular cell.of tubular cell.

NaNa++ and K and K++ transport is performed by transport is performed by NaNa++ and K and K++ channels. channels.

Regulated by Aldosterone.Regulated by Aldosterone.

Final site of electrolyte adjustment Final site of electrolyte adjustment (“fine-tuning” of ion secretion).(“fine-tuning” of ion secretion).

Only 2-5% NaOnly 2-5% Na++ reabsorption. reabsorption.

Major site of KMajor site of K++ excretion. excretion.

2 types of cells2 types of cellsPrincipal cells: NaPrincipal cells: Na++, K, K++, H, H22O transport. O transport.

Intercalated cells: HIntercalated cells: H++ transport. transport.


of tubular cell.of tubular cell.

NaNa++ and K and K++ transport is performed by transport is performed by NaNa++ and K and K++ channels. channels.

Regulated by Aldosterone.Regulated by Aldosterone.


NaNa++


NaNa++

KK++

ATPATP

KK++


HH22OO

ClCl--

HCOHCO33--

HH++

ATPATP

HH22O ChannelO Channel

MoleculesMolecules

ADHADH

AldosteroneAldosteroneRR

RR


Passive influx of NaPassive influx of Na+ + (channels).(channels).

To lesser extent efflux KTo lesser extent efflux K+ + (channels).(channels).

Drive for NaDrive for Na+ + influx higher than Kinflux higher than K+ + efflux.efflux.

Negative charge builds in lumen pushes Negative charge builds in lumen pushes ClCl-- out, and K out, and K++ in. in.

The more NaThe more Na++ delivered in, the more K delivered in, the more K++ goes out.goes out.

AldosteroneAldosterone stimulates production of stimulates production of NaNa++/ATP/ATPase ase pump, Napump, Na+ + channels, Kchannels, K+ +

channels.channels.

ADHADH regulates (increases) H regulates (increases) H22O O

permeability.permeability.


Passive influx of NaPassive influx of Na+ + (channels).(channels).

To lesser extent efflux KTo lesser extent efflux K+ + (channels).(channels).

Drive for NaDrive for Na+ + influx higher than Kinflux higher than K+ + efflux.efflux.

Negative charge builds in lumen pushes Negative charge builds in lumen pushes ClCl-- out, and K out, and K++ in. in.

The more NaThe more Na++ delivered in, the more K delivered in, the more K++ goes out.goes out.

AldosteroneAldosterone stimulates production of stimulates production of NaNa++/ATP/ATPase ase pump, Napump, Na+ + channels, Kchannels, K+ +

channels.channels.

ADHADH regulates (increases) H regulates (increases) H22O O

permeability.permeability.

ClCl--


NaNa++


NaNa++

KK++

ATPATP

KK++


HH22OO

ClCl--

HCOHCO33--

HH++

ATPATP

HH22O ChannelO Channel

MoleculesMolecules

ADHADH

AldosteroneAldosteroneRR

RR

ClCl--

K+ sparingK+ sparingK+ sparingK+ sparing

Inhibit NaInhibit Na+ + reabsorptionreabsorption (therefore indirectly K (therefore indirectly K+ +

excretion)excretion)..Channel blockers/Aldosterone antagonists.Channel blockers/Aldosterone antagonists.

Decreased NaDecreased Na++ reabsorption decreases H reabsorption decreases H22O O reabsorption.reabsorption.Diuretic Diuretic activity weak (most salts have already activity weak (most salts have already been absorbed only 3% Nabeen absorbed only 3% Na++ reabsorbed here). reabsorbed here).Used in combination with loop diuretics or Used in combination with loop diuretics or thiazides for tx. thiazides for tx. hypertension.hypertension.Decreased NaDecreased Na++ reabsorption ( reabsorption ( lumen negative) lumen negative) will will decreases Kdecreases K++ excretionexcretion (potassium sparing). (potassium sparing).Correct Hypokalemia induced w/ other diuretics.Correct Hypokalemia induced w/ other diuretics.Hyperkalemia (life threatening).Hyperkalemia (life threatening). Decrease HDecrease H++ secretion. secretion. Metabolic Acidosis.Metabolic Acidosis.Glucose intolerance/Hyperglycemia.Glucose intolerance/Hyperglycemia.

Inhibit NaInhibit Na+ + reabsorptionreabsorption (therefore indirectly K (therefore indirectly K+ +

excretion)excretion)..Channel blockers/Aldosterone antagonists.Channel blockers/Aldosterone antagonists.

Decreased NaDecreased Na++ reabsorption decreases H reabsorption decreases H22O O reabsorption.reabsorption.Diuretic Diuretic activity weak (most salts have already activity weak (most salts have already been absorbed only 3% Nabeen absorbed only 3% Na++ reabsorbed here). reabsorbed here).Used in combination with loop diuretics or Used in combination with loop diuretics or thiazides for tx. thiazides for tx. hypertension.hypertension.Decreased NaDecreased Na++ reabsorption ( reabsorption ( lumen negative) lumen negative) will will decreases Kdecreases K++ excretionexcretion (potassium sparing). (potassium sparing).Correct Hypokalemia induced w/ other diuretics.Correct Hypokalemia induced w/ other diuretics.Hyperkalemia (life threatening).Hyperkalemia (life threatening). Decrease HDecrease H++ secretion. secretion. Metabolic Acidosis.Metabolic Acidosis.Glucose intolerance/Hyperglycemia.Glucose intolerance/Hyperglycemia.

Collecting TubuleCollecting TubuleCollecting TubuleCollecting Tubule K+ sparingK+ sparingK+ sparingK+ sparing

Spironolactone Spironolactone (Aldactone, Alatone)(Aldactone, Alatone)GenGen Prototype of aldosterone antagonist. Needs to be metabolized to Prototype of aldosterone antagonist. Needs to be metabolized to

carnenone to have Kcarnenone to have K++ sparing activity sparing activity (i.e. is a prodrug).(i.e. is a prodrug).Generally ineffective if used alone as antihypertensive agent.Generally ineffective if used alone as antihypertensive agent.

UseUse In combination w/ loop diuretic or thiazide for hypertension. Correct In combination w/ loop diuretic or thiazide for hypertension. Correct hypokalemia induced by other agents. Liver cirrhosis (drug of choice). hypokalemia induced by other agents. Liver cirrhosis (drug of choice). Hyperaldosteronism. Edema (CHF, cirrhosis, nephrotic syndrome).Hyperaldosteronism. Edema (CHF, cirrhosis, nephrotic syndrome).

MOAMOA Competitive aldosterone antagonist. Binds to intracell. aldosterone Competitive aldosterone antagonist. Binds to intracell. aldosterone receptors (mineralocorticoid receptors). (Aldo. stimulates facilitates Nareceptors (mineralocorticoid receptors). (Aldo. stimulates facilitates Na++ reabsorption and Kreabsorption and K++ and H and H++ excretion). excretion).

SESE Most serious: Hyperkalemia (serum KMost serious: Hyperkalemia (serum K++ should be monitored regularly). should be monitored regularly).Metabolic acidosisMetabolic acidosis (aldo. Stimulates H (aldo. Stimulates H++ s secretion from intercalated cells)ecretion from intercalated cells)..Hyperglycemia (impairs insulin release & utilization glucose).Hyperglycemia (impairs insulin release & utilization glucose).Gynecomastia in men (prob. binding of carnenone to androgen receptors).Gynecomastia in men (prob. binding of carnenone to androgen receptors).Hirsutism & menstrual irregularities (it’s a steroid).Hirsutism & menstrual irregularities (it’s a steroid).

Spironolactone Spironolactone (Aldactone, Alatone)(Aldactone, Alatone)GenGen Prototype of aldosterone antagonist. Needs to be metabolized to Prototype of aldosterone antagonist. Needs to be metabolized to

carnenone to have Kcarnenone to have K++ sparing activity sparing activity (i.e. is a prodrug).(i.e. is a prodrug).Generally ineffective if used alone as antihypertensive agent.Generally ineffective if used alone as antihypertensive agent.

UseUse In combination w/ loop diuretic or thiazide for hypertension. Correct In combination w/ loop diuretic or thiazide for hypertension. Correct hypokalemia induced by other agents. Liver cirrhosis (drug of choice). hypokalemia induced by other agents. Liver cirrhosis (drug of choice). Hyperaldosteronism. Edema (CHF, cirrhosis, nephrotic syndrome).Hyperaldosteronism. Edema (CHF, cirrhosis, nephrotic syndrome).

MOAMOA Competitive aldosterone antagonist. Binds to intracell. aldosterone Competitive aldosterone antagonist. Binds to intracell. aldosterone receptors (mineralocorticoid receptors). (Aldo. stimulates facilitates Nareceptors (mineralocorticoid receptors). (Aldo. stimulates facilitates Na++ reabsorption and Kreabsorption and K++ and H and H++ excretion). excretion).

SESE Most serious: Hyperkalemia (serum KMost serious: Hyperkalemia (serum K++ should be monitored regularly). should be monitored regularly).Metabolic acidosisMetabolic acidosis (aldo. Stimulates H (aldo. Stimulates H++ s secretion from intercalated cells)ecretion from intercalated cells)..Hyperglycemia (impairs insulin release & utilization glucose).Hyperglycemia (impairs insulin release & utilization glucose).Gynecomastia in men (prob. binding of carnenone to androgen receptors).Gynecomastia in men (prob. binding of carnenone to androgen receptors).Hirsutism & menstrual irregularities (it’s a steroid).Hirsutism & menstrual irregularities (it’s a steroid).

Collecting TubuleCollecting TubuleCollecting TubuleCollecting Tubule K+ sparingK+ sparingK+ sparingK+ sparing

Triamterene Triamterene (Dyrenium, Maxzide)(Dyrenium, Maxzide)GenGen Weak folic acid antagonist (prob. for cirrhosis in patients). Generally Weak folic acid antagonist (prob. for cirrhosis in patients). Generally

ineffective if used alone as antihypertensive agent.ineffective if used alone as antihypertensive agent.UseUse In combination w/ loop diuretic or thiazide for hypertension & Edema. In combination w/ loop diuretic or thiazide for hypertension & Edema.

Correct hypokalemia induced by other agents.Correct hypokalemia induced by other agents.

MOAMOA Blocks NaBlocks Na++ channel of principal cells. Reduces Na channel of principal cells. Reduces Na++ conductance. conductance.

SESE Most serious: Hyperkalemia (serum KMost serious: Hyperkalemia (serum K++ should be monitored regularly). should be monitored regularly).Nausea, vomiting, leg cramps, dizziness.Nausea, vomiting, leg cramps, dizziness.Glucose intolerance.Glucose intolerance.Kidney stones (triamterene is poorly soluble and may precipitate in urine Kidney stones (triamterene is poorly soluble and may precipitate in urine forming kidney stones).forming kidney stones).Megaloblastic anemia in patients w/ cirrhosis.Megaloblastic anemia in patients w/ cirrhosis.Photosensitization.Photosensitization.Interacts w/ indomethacin; may induce acute renal failure.Interacts w/ indomethacin; may induce acute renal failure.

Triamterene Triamterene (Dyrenium, Maxzide)(Dyrenium, Maxzide)GenGen Weak folic acid antagonist (prob. for cirrhosis in patients). Generally Weak folic acid antagonist (prob. for cirrhosis in patients). Generally

ineffective if used alone as antihypertensive agent.ineffective if used alone as antihypertensive agent.UseUse In combination w/ loop diuretic or thiazide for hypertension & Edema. In combination w/ loop diuretic or thiazide for hypertension & Edema.

Correct hypokalemia induced by other agents.Correct hypokalemia induced by other agents.

MOAMOA Blocks NaBlocks Na++ channel of principal cells. Reduces Na channel of principal cells. Reduces Na++ conductance. conductance.

SESE Most serious: Hyperkalemia (serum KMost serious: Hyperkalemia (serum K++ should be monitored regularly). should be monitored regularly).Nausea, vomiting, leg cramps, dizziness.Nausea, vomiting, leg cramps, dizziness.Glucose intolerance.Glucose intolerance.Kidney stones (triamterene is poorly soluble and may precipitate in urine Kidney stones (triamterene is poorly soluble and may precipitate in urine forming kidney stones).forming kidney stones).Megaloblastic anemia in patients w/ cirrhosis.Megaloblastic anemia in patients w/ cirrhosis.Photosensitization.Photosensitization.Interacts w/ indomethacin; may induce acute renal failure.Interacts w/ indomethacin; may induce acute renal failure.

Amiloride Amiloride (Midamor)(Midamor)More potent More potent (10x lowe(10x lowerr doses than triamterene doses than triamterene)). Not assoc. Not associatediated w/ kidney stones. w/ kidney stones.

Amiloride Amiloride (Midamor)(Midamor)More potent More potent (10x lowe(10x lowerr doses than triamterene doses than triamterene)). Not assoc. Not associatediated w/ kidney stones. w/ kidney stones.

Osmotic DiureticsOsmotic DiureticsOsmotic DiureticsOsmotic DiureticsProximal Tubule &Proximal Tubule &Thin Descending LimbThin Descending Limb

Proximal Tubule &Proximal Tubule &Thin Descending LimbThin Descending Limb

These segments of tubule are highly These segments of tubule are highly permeable to Hpermeable to H22O. Osmotic agent not O. Osmotic agent not transported (reabsorbed) causes water to be transported (reabsorbed) causes water to be retained, promoting diuresis.retained, promoting diuresis.Do not interact w/renal transport mechanism Do not interact w/renal transport mechanism (inert drugs - osmotic pressure changes).(inert drugs - osmotic pressure changes).

Increases extracell.Increases extracell. fluid by attracting Hfluid by attracting H22O O from intracell. (intraocular, intracranial).from intracell. (intraocular, intracranial).Decrease blood viscosity & renin release Decrease blood viscosity & renin release (reflex sympathetic), causing vasodilation. (reflex sympathetic), causing vasodilation. Vasodilation may involve prostaglandins.Vasodilation may involve prostaglandins.Used as diureticsUsed as diuretics but not antihypertensivesbut not antihypertensives..Reduce intraocular pressure (short term tx. Reduce intraocular pressure (short term tx. Glaucoma).Glaucoma).Reduce intracranial pressure.Reduce intracranial pressure.

May cause pulmonary edemaMay cause pulmonary edema (extract H(extract H22O O from intracell. from intracell. ccompt. ompt. eexpanding extracell. xpanding extracell. ffluid volume.luid volume. Initially increase blood volume. Initially increase blood volume.Increase work load heart & complicate CHF.Increase work load heart & complicate CHF.Dehydration, headache, nausea, vomiting.Dehydration, headache, nausea, vomiting.

These segments of tubule are highly These segments of tubule are highly permeable to Hpermeable to H22O. Osmotic agent not O. Osmotic agent not transported (reabsorbed) causes water to be transported (reabsorbed) causes water to be retained, promoting diuresis.retained, promoting diuresis.Do not interact w/renal transport mechanism Do not interact w/renal transport mechanism (inert drugs - osmotic pressure changes).(inert drugs - osmotic pressure changes).

Increases extracell.Increases extracell. fluid by attracting Hfluid by attracting H22O O from intracell. (intraocular, intracranial).from intracell. (intraocular, intracranial).Decrease blood viscosity & renin release Decrease blood viscosity & renin release (reflex sympathetic), causing vasodilation. (reflex sympathetic), causing vasodilation. Vasodilation may involve prostaglandins.Vasodilation may involve prostaglandins.Used as diureticsUsed as diuretics but not antihypertensivesbut not antihypertensives..Reduce intraocular pressure (short term tx. Reduce intraocular pressure (short term tx. Glaucoma).Glaucoma).Reduce intracranial pressure.Reduce intracranial pressure.

May cause pulmonary edemaMay cause pulmonary edema (extract H(extract H22O O from intracell. from intracell. ccompt. ompt. eexpanding extracell. xpanding extracell. ffluid volume.luid volume. Initially increase blood volume. Initially increase blood volume.Increase work load heart & complicate CHF.Increase work load heart & complicate CHF.Dehydration, headache, nausea, vomiting.Dehydration, headache, nausea, vomiting.

Mannitol Mannitol (Osmitrol)(Osmitrol)Osmotic agent of choice. Not absorbed.Osmotic agent of choice. Not absorbed.

Not absorbed orally. Must be given i.v.Not absorbed orally. Must be given i.v.

Causes initial increase in BV (pulls from intracell. Causes initial increase in BV (pulls from intracell. tto extracell.)o extracell.)

May induce diarrhea if given orally.May induce diarrhea if given orally.

Mannitol Mannitol (Osmitrol)(Osmitrol)Osmotic agent of choice. Not absorbed.Osmotic agent of choice. Not absorbed.

Not absorbed orally. Must be given i.v.Not absorbed orally. Must be given i.v.

Causes initial increase in BV (pulls from intracell. Causes initial increase in BV (pulls from intracell. tto extracell.)o extracell.)

May induce diarrhea if given orally.May induce diarrhea if given orally.

Isosorbide Isosorbide (Ismotic)(Ismotic)Less efficient Less efficient beacusebeacuse penetrates cellular membranes - absorbed. penetrates cellular membranes - absorbed.

May be given orally.May be given orally.

Isosorbide Isosorbide (Ismotic)(Ismotic)Less efficient Less efficient beacusebeacuse penetrates cellular membranes - absorbed. penetrates cellular membranes - absorbed.

May be given orally.May be given orally.

Osmotic DiureticsOsmotic DiureticsOsmotic DiureticsOsmotic DiureticsProximal Tubule &Proximal Tubule &Thin Descending LimbThin Descending Limb

Proximal Tubule &Proximal Tubule &Thin Descending LimbThin Descending Limb

POTAS W DIECIE50 – 150 mEq/dobę

POTAS ZEWNĄTRZKOMÓRKOWY

Ogółem 65 mEqStężenie 3.5 – 5.3 mEq/L

POTAS WEWNĄTRZKOMÓRKOWY

Ogółem 4200 mEqStężenie 150 mEG/L

FILTRACJA KŁĘBKOWA

180 L/dobę osocza800 mEq/dobę K+ K+

WYDALANIE Z MOCZEM

50 – 150 mEq/dobę

KANALIK PROKSYMALNYNEFRONU

KANALIK PROKSYMaALNYNEFRONU

KANALIK ZBIORCZY800 mEq/dobę K+

50 – 150 mEq/dobę K+

Potas:- działa jak „diuretyk”, zmniejsza objętość osocza poprzez hamowanie resorbcji sodu w cewkach proksymalnych - wpływa na aktywność układu renina-angiotensyna-aldosteron i zmniejszanie oddziaływania angiotensyny na receptory w naczyniach krwionośnych, nadnerczach i nerkach- rozszerza naczynia krwionośne poprzez pobudzanie sodowo-potasowej-ATPazy w komórkach mięśni gładkich i w adrenergicznych zakończeniach nerwowych- oddziaływuje na centralne i obwodowe mechanizmy regulujące ciśnienie tętnicze krwi. - Dieta bogata w potas może dodatkowo obniżać ciśnienie tętnicze poprzez relaksację mięśni gładkich naczyń krwionośnych i bezpośrednie zmniejszanie oporu naczyń obwodowych.

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Maciej Niewada Clinical and Experimental Pharmacology Email: [email protected] Maciej Niewada Clinical and Experimental Pharmacology Email: [email protected]