DiureticsDiuretics

NephronNephron

Speed of primary urine formation – 120–127 ml/minSpeed of primary urine formation – 120–127 ml/minThere are about 1mln. nephrons in a kidney, reabsorbtive surface of which is – 6-8 mThere are about 1mln. nephrons in a kidney, reabsorbtive surface of which is – 6-8 m22..Along the nephron 99% of ultrafiltrate is reabsorbed and 1.2-1.5 l of secondary urine Along the nephron 99% of ultrafiltrate is reabsorbed and 1.2-1.5 l of secondary urine forms from 150-200 l of primary urine.forms from 150-200 l of primary urine.

Apical (lumenal) membraneApical (lumenal) membrane

NaNa++ enters a cell enters a cell 1) with the concentration gradient1) with the concentration gradient2) with the help of protein transporters – 2) with the help of protein transporters – permeases (synthesized under the influence of permeases (synthesized under the influence of aldosterone)aldosterone)

Basal membraneBasal membrane

NaNa++ enters interstitial space against enters interstitial space against concentration gradient with energy concentration gradient with energy consumption and with the help of specific consumption and with the help of specific transport systemstransport systems ( (KK++, Na, Na++--ATPases, cАMP-ATPases, cАMP-adenilatcyclases and phosphodiesterases,adenilatcyclases and phosphodiesterases, etc.)etc.)

Na+

Na+

Quantity of Quantity of didiuuresis resis

(secondary (secondary urine)urine)

Increasing of Increasing of filtration filtration for for 10%10%

( 1% of volume ( 1% of volume of primary urine)of primary urine)

NormNorm

Decreasing of Decreasing of reabsorbtion for 10%reabsorbtion for 10%

Rea

bso

rbti

on

Primary Primary

urineurine

Filt

rati

on

Classification of diuretics according to place of dominant actionI Mostly act on beginning part of distal nephral canalicules :

dichlothiasid, cyclomethiasid, clopamid (brinaldix), oxodolin (chlortalidon, hygroton) ІІ Act on ascendent part of loop of Henle (“loop” diuretics) : furosemide (lasix), etacrynic acid (uregit), bufenoxІІІ Act on ending part of distal nephral canalicules and collective tubules (potassium sparing diuretics): triamterene, amiloride, spironolactoneІV Act along the whole nephral canalicules: mannitol, urea (carbamide)V Act on proximal nephral canalicules: euphylline

5 – distal tubule; 6 – collective tubules.

1 – vascular glomerulus with capsule;

2 – proximal tubule;

3 – descendent part of loop of Henle;

4 – ascendent part of loop of Henle;

ClassificClassificaation of diuretics according totion of diuretics according to

power of actionpower of action

І І StrongStrong (slowing down of (slowing down of NaNa+ + reabsorbtion reabsorbtion forfor

10 – 2010 – 20 %)%) – – loop diureticsloop diuretics

furosemide, etacrynic acid, clopamide, bfurosemide, etacrynic acid, clopamide, buufenoxfenox

ІІ ІІ Medial powerMedial power of action (slowing down of of action (slowing down of NaNa++

reabsorbtion forreabsorbtion for 5 – 85 – 8 %)%)

dichlotdichlothhiaside, oxodolineiaside, oxodoline

ІІІ ІІІ LightLight (slowing down of (slowing down of NaNa+ + reabsorbtion no more than reabsorbtion no more than

for for 33 %)%)

diacarb, spironolactone, amiloride, triamteren, diacarb, spironolactone, amiloride, triamteren,

xantines (theophylline)xantines (theophylline)

MannitolMannitol

15 % solution15 % solution

rapid intravenous rapid intravenous introductionintroduction

intravenous dropping intravenous dropping introductionintroduction

dehydrating dehydrating actionaction

diuretic diuretic actionaction

diureticdiuretic actionaction

MannitolMannitolIndicatiIndicatioonsns

1.1. Brain oedema (in case of maintaining ofBrain oedema (in case of maintaining of HEB permeability)HEB permeability)2.2. Toxic lung oedema (poisoning with gasoline, gass, formaline, Toxic lung oedema (poisoning with gasoline, gass, formaline,

skipidar etc.)skipidar etc.)3. Larynx oedema of allergic or inflammatory genesis3. Larynx oedema of allergic or inflammatory genesis4. 4. PerformPerforming of forced diuresis (poisoning with barbiturates, ing of forced diuresis (poisoning with barbiturates,

salycylates, sulphonamides, PASA, metanole, boric acid, haemolytic salycylates, sulphonamides, PASA, metanole, boric acid, haemolytic poisons, antifreezers; in case of trapoisons, antifreezers; in case of trannsfusisfusioon of incompatible blood, n of incompatible blood, massive hemoglobinuria etc. massive hemoglobinuria etc.

5.5. In oliguric phase of acute In oliguric phase of acute kidneykidney insufficiency insufficiency6.6. Burns, osteomielitis, peritonitis, sepsBurns, osteomielitis, peritonitis, sepsiiss (to improve elimination out of (to improve elimination out of

the organism toxic compounds which formed from destroyed tissues)the organism toxic compounds which formed from destroyed tissues)

Contraindications Contraindications

Acute cardiac insufficiency, arterial hypertensionAcute cardiac insufficiency, arterial hypertension,, skull trauma, intracranial hemorrhagesskull trauma, intracranial hemorrhages

Furosemide (lazix)Furosemide (lazix)

Effective even in Effective even in a a case of decreased glomerular case of decreased glomerular filtration less than 10 ml/min. (norm – filtration less than 10 ml/min. (norm – 120-120-127ml/min)127ml/min)

IndicationsIndications

1.1. Acute left ventricular insufficiency, lung oedemaAcute left ventricular insufficiency, lung oedema2.2. Chronic cardiac insufficiency Chronic cardiac insufficiency 3.3. Arterial hypertension, Arterial hypertension, especiallyespecially hypertensive crisis hypertensive crisis 4.4. Brain oedema of any etiologyBrain oedema of any etiology5.5. Acute Acute kidneykidney insufficiency insufficiency6.6. Performing of forced diuresisPerforming of forced diuresis7.7. For excretion of Calcium ions (hypervitaminosis D)For excretion of Calcium ions (hypervitaminosis D)

THERAPEUTIC EFFECTS

Increase Na Excretionto 25% of Filtered Load

Treatment forOliguric ARF

Increase Ca ExcretionTreatment for Hypercalcemia

Impair Free WaterReabsorption

Treatment forHyponatremia

Increase VenousCapacitance

Treatment forPulmonary

Edema

Increase Urine Volume

Treatment forSevere Edema

Furosemid

Side effects of furosemideSide effects of furosemide

1.1. Hypopotassiumaemia, hypopotassiumhystiaHypopotassiumaemia, hypopotassiumhystia2.2. Hypovolemia, vascular collapse, hyposodiumaemia, Hypovolemia, vascular collapse, hyposodiumaemia,

hypocalciumaemia, hypochloraemia, metabolic hypocalciumaemia, hypochloraemia, metabolic alkalosisalkalosis

3.3. Ototoxic actionOtotoxic action (deafness) (deafness)4.4. ContrinsulContrinsulinicinic action (manifestation of latent diabetes action (manifestation of latent diabetes

mellitus)mellitus)5.5. Formation of oxalate and phosphate stones in urinary Formation of oxalate and phosphate stones in urinary

tracttract6.6. Decreasing of secretion of uric acid (acute attack of Decreasing of secretion of uric acid (acute attack of

gout)gout)

It should not be combined with antibioticsIt should not be combined with antibiotics aminoglycosides and cephalosporines!aminoglycosides and cephalosporines!

ADVERSE EFFECTS

Hypomagnesemia

MetabolicAlkalosis

Hypokalemia

Profound ECFVDepletion

Hyperglycemia

Hyperuricemia

Ototoxicity

Hypocalcemia

FurosemideFurosemide

FurosemideFurosemide

FurosemideFurosemide

DichlotDichlothhiaside iaside (h(hyydrdroochlorchlorthiaside)thiaside)

IndicationsIndications1.1. Oedema in case of Oedema in case of chronicchronic cardiac insufficiency cardiac insufficiency2.2. Oedema in case of Oedema in case of chronicchronic pathology of liver and kidneys pathology of liver and kidneys 3.3. Long-term tLong-term treatment of arterial hypertensionreatment of arterial hypertension4.4. DDiabetes insipidusiabetes insipidus5.5. Retention of Ca ionsRetention of Ca ions

Side effectsSide effects1.1. Hypopotassiumaemia, hypopotassiumhystiaHypopotassiumaemia, hypopotassiumhystia2.2. Hypochloraemic alkalosisHypochloraemic alkalosis3.3. Retention of uric acid - artralgy, acute attack of gout, chronic Retention of uric acid - artralgy, acute attack of gout, chronic

nephropathy nephropathy 4.4. Hyposodiumaemia of dilution: nausea, vomitting, diarrhea, Hyposodiumaemia of dilution: nausea, vomitting, diarrhea,

weaknessweakness5.5. Pancreatitis Pancreatitis

THERAPEUTIC EFFECTSTHERAPEUTIC EFFECTS

Increase Na Excretionto 5% of Filtered Load

Treatment forHypertension

Decrease Ca ExcretionTreatment for

Calcium Nephrolithiasis

Treatment forNephrogenic

Diabetes Insipidus

Treatment forMild Edema

ADVERSE EFFECTSADVERSE EFFECTS

Hypomagnesemia

MetabolicAlkalosis

Hypokalemia

Hyperglycemia

Hyperuricemia

Hyponatremia

Hypercalcemia

Impotence Increased LDL

(Renal Cell Carcinoma??)

ECFVDepletion

DichlotDichlothhiaside iaside (h(hyydrdroochlorchlorthiaside)thiaside)

Post diuresis Sodium Retention!! – ricochet Post diuresis Sodium Retention!! – ricochet

effecteffect

IndapamideIndapamide (ariphone – sulphamoil benzamide) (ariphone – sulphamoil benzamide)

Drug Drug Way of Way of administrationadministration

Latent Latent periodperiod (onset)(onset)

Duration of Duration of actionaction

Sulfonyl derivates Sulfonyl derivates

OxoOxoddolin (chlortalidon, olin (chlortalidon, hyhyggroton) roton)

orallyorally 2-4 hours2-4 hours 3 days3 days

Clopamide Clopamide oraorallllyy 1-3 hours1-3 hours 8-18 (till 24) 8-18 (till 24) hours hours

Bufenox (bumetanide)Bufenox (bumetanide) In muscleIn muscle

ii. . VV..

20-40 min.20-40 min.

2-5 min. 2-5 min.

4-6 hours4-6 hours

1-3 hours1-3 hours

Potassium-, magnesium-Potassium-, magnesium-sparisparingng

SpironolactoneSpironolactone oraorallllyy 2-5 days2-5 days 2-3 days2-3 days

Triamteren (pterophen)Triamteren (pterophen) oraorallllyy 20-30 min.20-30 min. 6-8 hours6-8 hours

Amiloride Amiloride oralorallyly 2 hours2 hours 24 hour24 hour

Pharmacokinetics of some diureticPharmacokinetics of some diureticss

K-Sparing DiureticsK-Sparing Diuretics

Amiloride

Triamterene Spironolactone

THERAPEUTIC EFFECTSTHERAPEUTIC EFFECTS

Enhance Natriuresis Caused by Other Diuretics

Block Na Channels

Treatment for Liddle’s Syndromen

(pseudoaldosteronism)

Prevent Hypokalemia

Used in Combination with Loop &

Thiazide Diuretics

Treatment for Lithium-Induced Diabetes Insipidus

ADVERSE EFFECTSADVERSE EFFECTS

Renal Stones

InterstitialNephritis

Megaloblastosis

HyperkalemiaHyperkalemia

AmilorideTriamterene

MINERALOCORTICOID MINERALOCORTICOID RECEPTOR ANTAGONISTSRECEPTOR ANTAGONISTS

Also Called:•K-Sparing Diuretics

•Aldosterone Antagonists

Spironolactone Eplerenone

THERAPEUTIC EFFECTSTHERAPEUTIC EFFECTS

Enhances Natriuresis Caused by Other Diuretics

Blocks Aldosterone

Treatment for Primary Hyper-

aldosteronism

Prevents Hypokalemia

Used in Combination with Loop &

Thiazide Diuretics

Treatment for Edema of Liver

Cirrhosis

Treatment forHypertension

Treatment forHeart Failure

spironolactonespironolactone ADVERSE EFFECTSADVERSE EFFECTS

Impotence

Gynecomastia

MetabolicAcidosis

Hyperkalemia

Hirsutism

CNS SideEffects

Peptic Ulcers

Gastritis

MenstrualIrregularities

Deepening ofVoice

SpironolactoneSpironolactone

Combined administration of Combined administration of diureticsdiuretics

1.1. Mannitol + furosemide (etacrynic acid)Mannitol + furosemide (etacrynic acid)2.2. DichlotDichlothhiaiasside + triamteren (spironolactone)ide + triamteren (spironolactone)3.3. Furosemide + spironolactoneFurosemide + spironolactone4.4. Furosemide (excretes Calcium ions) + Furosemide (excretes Calcium ions) +

dichlotdichlothhiaiassideide (retains Calcium ions)(retains Calcium ions)

TriampurTriampur (triamteren + hydrochlorthiaside)(triamteren + hydrochlorthiaside)

IMPORTANT DRUG INTERACTIONSIMPORTANT DRUG INTERACTIONS

NSAIDSSalt

DecongestantsProbenecid

Hyperkalemia-Induced by K-Sparing

Diuretics

Enhanced Ototoxicityof Loop Diuretics

DiminishedDiuretic

Response

ACE InhibitorsBeta-Blockers

K SupplementsK-Sparing Diuretics

Heparin

Ototoxic Drugs

kidney tea Fol.

Orthosiphoni

Shots of birch tree Shots of birch tree (Gemmae Betulae)(Gemmae Betulae)

Leaves of red bilberries

(fol.Vitisidaeae)

Horse-tail Herba

Equiseti

Blue corn-Blue corn-flowers flowers ((Flores Flores

Centaureae Centaureae cyani)cyani)

Juniper berries (Fructus Juniperi)

Drugs Drugs effectingeffecting uterus contractionuterus contraction

ІІ Influence mostly on m Influence mostly on myyometrium contractionometrium contraction

1. 1. IncreaseIncrease rhythmic rhythmic contractioncontraction

Oxytocine, Oxytocine, Pituitrine,Pituitrine, Hyphotocine Hyphotocine

Dinoprost (prostaglandine Dinoprost (prostaglandine FF22αα )),,

Dinoproston (prostaglandine Dinoproston (prostaglandine EE2 2 ),),

2. 2. DecreaseDecrease contraction contractionss (tokolytic substances) (tokolytic substances)

SalbutamolSalbutamol, , FenoterolFenoterol,,

SSodium oxybutyrateodium oxybutyrate, , Magnesium sulphateMagnesium sulphate

Diazoxide Diazoxide

ІІІІ Increase mostly m Increase mostly myyometrium toneometrium tone

Ergometrini maleasErgometrini maleas CotaCotarrnine chloridenine chloride

Ergotamine hydrotartrateErgotamine hydrotartrate

ErgotalErgotal

ІІІІІІ Decrease tone of uterus cervix Decrease tone of uterus cervix

Atropine sulphateAtropine sulphate DinoprostDinoprost DinoprostonDinoproston

For labour For labour stimulation stimulation ((rhythmic contraction of rhythmic contraction of

uterusuterus):):- - i. v. dropplyi. v. dropply – 1 – 1 mlml (5 (5 UnitsUnits) )

dissolve indissolve in 500 500 mlml 5 % 5 % glucoseglucose

- - i. m or in cervix i. m or in cervix of uterusof uterus 0,5- 0,5-22,0,0 UnitsUnits for single injectionfor single injection

For post labor atonic bleeding For post labor atonic bleeding ((it is necessary to it is necessary to provoke spastic contraction of uterusprovoke spastic contraction of uterus))

1-2 1-2 ml i. m.ml i. m.

Dinoprost Dinoprost ((prostaglandinprostaglandin F2F2αα ))

Dinoproston Dinoproston (prostaglandin(prostaglandin EE22))

•They cause rhythmic contractions of They cause rhythmic contractions of uterus uterus •For stimulation of labor, i. v. dropplyFor stimulation of labor, i. v. dropply•Initiate uterus contractions Initiate uterus contractions independently of the term of independently of the term of pregnancypregnancy•Uses only after hospital admissionUses only after hospital admission!!

Ergometrini maleasErgometrini maleas – for stopping – for stopping after labor atonic (hypotonic) bleedingsafter labor atonic (hypotonic) bleedingsAbsolutely contraindicated for Absolutely contraindicated for labour stimulation !!!labour stimulation !!!

Fungi Claviceps purpurea (Ergot) -Secale cornutum