Diuretics

Nephron Speed of primary urine formation – 120–127 ml/min There are about 1mln. nephrons in a kidney, reabsorbtive surface of which is – 6-8 m 2. Along the nephron 99% of ultrafiltrate is reabsorbed and l of secondary urine forms from l of primary urine.

Apical (lumenal) membrane Na + enters a cell 1) with the concentration gradient 2) with the help of protein transporters – permeases (synthesized under the influence of aldosterone) Basal membrane Na + enters interstitial space against concentration gradient with energy consumption and with the help of specific transport systems (K +, Na + -ATPases, cАMP- adenilatcyclases and phosphodiesterases, etc.) Na +

Quantity of diuresis (secondary urine) Increasing of filtration for 10% ( 1% of volume of primary urine) Norm Decreasing of reabsorbtion for 10% Reabsorbtion Primaryurine Filtration

Classification of diuretics according to place of dominant action I 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), bufenox ІІІ Act on ending part of distal nephral canalicules and collective tubules (potassium sparing diuretics): triamterene, amiloride, spironolactone ІV 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;

Classification of diuretics according to power of action І Strong (slowing down of Na + reabsorbtion for І Strong (slowing down of Na + reabsorbtion for 10 – 20 %) – loop diuretics 10 – 20 %) – loop diuretics furosemide, etacrynic acid, clopamide, bufenox furosemide, etacrynic acid, clopamide, bufenox ІІ Medial power of action (slowing down of Na + reabsorbtion for 5 – 8 %) dichlothiaside, oxodoline ІІІ Light (slowing down of Na + reabsorbtion no more than for 3 %) diacarb, spironolactone, amiloride, triamteren, xantines (theophylline)

Mannitol 15 % solution rapid intravenous introduction intravenous dropping intravenous droppingintroduction dehydratingactiondiureticaction diuretic action action

Mannitol Indications 1.Brain oedema (in case of maintaining of HEB permeability) 2.Toxic lung oedema (poisoning with gasoline, gass, formaline, skipidar etc.) 3. Larynx oedema of allergic or inflammatory genesis 4. Performing of forced diuresis (poisoning with barbiturates, salycylates, sulphonamides, PASA, metanole, boric acid, haemolytic poisons, antifreezers; in case of transfusion of incompatible blood, massive hemoglobinuria etc. 5.In oliguric phase of acute kidney insufficiency 6.Burns, osteomielitis, peritonitis, sepsis (to improve elimination out of the organism toxic compounds which formed from destroyed tissues) Contraindications Acute cardiac insufficiency, arterial hypertension, skull trauma, intracranial hemorrhages

Furosemide (lazix) Furosemide (lazix) Effective even in a case of decreased glomerular filtration less than 10 ml/min. (norm – ml/min) Effective even in a case of decreased glomerular filtration less than 10 ml/min. (norm – ml/min) Indications Indications 1.Acute left ventricular insufficiency, lung oedema 2.Chronic cardiac insufficiency 3.Arterial hypertension, especially hypertensive crisis 4.Brain oedema of any etiology 5.Acute kidney insufficiency 6.Performing of forced diuresis 7.For excretion of Calcium ions (hypervitaminosis D)

Furosemid

Side effects of furosemide Side effects of furosemide 1.Hypopotassiumaemia, hypopotassiumhystia 2.Hypovolemia, vascular collapse, hyposodiumaemia, hypocalciumaemia, hypochloraemia, metabolic alkalosis 3.Ototoxic action (deafness) 4.Contrinsulinic action (manifestation of latent diabetes mellitus) 5.Formation of oxalate and phosphate stones in urinary tract 6.Decreasing of secretion of uric acid (acute attack of gout) It should not be combined with antibiotics aminoglycosides and cephalosporines!

Furosemide

Furosemide Furosemide

Dichlothiaside (hydrochlorthiaside) Indications 1.Oedema in case of chronic cardiac insufficiency 2.Oedema in case of chronic pathology of liver and kidneys 3.Long-term treatment of arterial hypertension 4.Diabetes insipidus 5.Retention of Ca ions Side effects 1.Hypopotassiumaemia, hypopotassiumhystia 2.Hypochloraemic alkalosis 3.Retention of uric acid - artralgy, acute attack of gout, chronic nephropathy 4.Hyposodiumaemia of dilution: nausea, vomitting, diarrhea, weakness 5.Pancreatitis

THERAPEUTIC EFFECTS Increase Na Excretion to 5% of Filtered Load Treatment for Hypertension Decrease Ca Excretion Treatment for Calcium Nephrolithiasis Treatment for Nephrogenic Diabetes Insipidus Treatment for Mild Edema

ADVERSE EFFECTS Hypomagnesemia Metabolic Alkalosis Hypokalemia Hyperglycemia Hyperuricemia Hyponatremia Hypercalcemia ImpotenceIncreased LDL (Renal Cell Carcinoma??) ECFV Depletion Dichlothiaside (hydrochlorthiaside)

Post diuresis Sodium Retention!! – ricochet effect

Indapamide (ariphone – sulphamoil benzamide)

Drug Way of administration Latent period (onset) Duration of action Sulfonyl derivates Sulfonyl derivates Oxodolin (chlortalidon, hygroton) orally 2-4 hours 3 days Clopamide orally 1-3 hours 8-18 (till 24) hours Bufenox (bumetanide) In muscle i. V min. 2-5 min. 4-6 hours 1-3 hours Potassium-, magnesium-sparing Potassium-, magnesium-sparing Spironolactone orally 2-5 days 2-3 days Triamteren (pterophen) orally min. 6-8 hours Amiloride orally 2 hours 24 hour Pharmacokinetics of some diuretics

K-Sparing Diuretics Amiloride Triamterene Spironolactone

THERAPEUTIC 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 EFFECTS Renal Stones Interstitial Nephritis Megaloblastosis Hyperkalemia Amiloride Triamterene

MINERALOCORTICOID RECEPTOR ANTAGONISTS Also Called: K-Sparing Diuretics Aldosterone Antagonists Spironolactone Eplerenone

THERAPEUTIC 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 for Hypertension Treatment for Heart Failure

spironolactone ADVERSE EFFECTS Impotence Gynecomastia Metabolic Acidosis Hyperkalemia Hirsutism CNS Side Effects Peptic Ulcers Gastritis Menstrual Irregularities Deepening of Voice

Spironolactone

Combined administration of diuretics 1.Mannitol + furosemide (etacrynic acid) 2.Dichlothiaside + triamteren (spironolactone) 3.Furosemide + spironolactone 4.Furosemide (excretes Calcium ions) + dichlothiaside (retains Calcium ions)

Triampur (triamteren + hydrochlorthiaside) Triampur (triamteren + hydrochlorthiaside)

IMPORTANT DRUG INTERACTIONS NSAIDS Salt Decongestants Probenecid Hyperkalemia- Induced by K-Sparing Diuretics Enhanced Ototoxicity of Loop Diuretics Diminished Diuretic Response ACE Inhibitors Beta-Blockers K Supplements K-Sparing Diuretics Heparin Ototoxic Drugs

kidney tea Fol. Orthosiphoni

Shots of birch tree (Gemmae Betulae)

Leaves of red bilberries (fol.Vitisidaeae)

Horse-tail Herba Equiseti

Blue corn-flowers (Flores Centaureae cyani)

Juniper berries (Fructus Juniperi)

Drugs effecting uterus contraction І Influence mostly on myometrium contraction І Influence mostly on myometrium contraction 1. Increase rhythmic contraction Oxytocine, Pituitrine, Hyphotocine Oxytocine, Pituitrine, Hyphotocine Dinoprost (prostaglandine F 2α ), Dinoprost (prostaglandine F 2α ), Dinoproston (prostaglandine E 2 ), Dinoproston (prostaglandine E 2 ), 2. Decrease contractions (tokolytic substances) Salbutamol, Fenoterol, Salbutamol, Fenoterol, Sodium oxybutyrate, Magnesium sulphate Sodium oxybutyrate, Magnesium sulphate Diazoxide Diazoxide ІІ Increase mostly myometrium tone ІІ Increase mostly myometrium tone Ergometrini maleasCotarnine chloride Ergometrini maleasCotarnine chloride Ergotamine hydrotartrate Ergotamine hydrotartrate Ergotal Ergotal ІІІ Decrease tone of uterus cervix Atropine sulphate DinoprostDinoproston Atropine sulphate DinoprostDinoproston

For labour stimulation (rhythmic contraction of uterus): - i. v. dropply – 1 ml (5 Units) dissolve in 500 ml 5 % glucose - i. m or in cervix of uterus 0,5- 2,0 Units for single injection For post labor atonic bleeding (it is necessary to provoke spastic contraction of uterus) 1-2 ml i. m.

Dinoprost (prostaglandin F2α ) Dinoproston (prostaglandin E2) They cause rhythmic contractions of uterusThey cause rhythmic contractions of uterus For stimulation of labor, i. v. dropplyFor stimulation of labor, i. v. dropply Initiate uterus contractions independently of the term of pregnancyInitiate uterus contractions independently of the term of pregnancy Uses only after hospital admission!Uses only after hospital admission!

Ergometrini maleas – for stopping after labor atonic (hypotonic) bleedings Absolutely contraindicated for labour stimulation !!! Fungi Claviceps purpurea (Ergot) - Secale cornutum