Diuretics
-goal
increase urine volume
increase excretion of sodium and water
“Natriuretic” vs. “Aquaretic”
“Natriuretic” - increase renal sodium excretion
-directly act on the cells of the nephron by blocking enzymes and carriers
“Aquaretic” - increase water excretion
-modify the content of the filtrate
Where does Mannitol acts on? Which parts of the nephron?
proximal convoluted tubule
thin descending limb
collecting duct
Where do Thiazides acts on? Which parts of the nephron?
Proximal straight tubule
Distal convoluted tubule
Where does Adenosine acts on? Which parts of the nephron?
glomerulus
proximal convoluted tubule
thick ascending limb
collecting duct
In which part of the nephron water easily crosses the membrane (urine –> interstitium)?
proximal convoluted tubule
thin descending limb
collecting duct
Juxtaglomerular apparatus
- main parts
- macula densa cells - mechanism of action
- afferent arteriole (contains granular cells), distal tubule (contains macula densa cells) and efferent arteriole
- macula densa cells recognize the amount of sodium in the ruine and based on the level of it, they are capable of activating granular cells and either increase or decrease the release of renin
ex: too much sodium in the urine –> macula densa cells detect it –> granular cells are activated –> granular cells release renin –> deactivation of the RAAS
Medullary counter-current
-brings electrolytes into the interstitium
- Ascending limb –> impermeable to water, electrolytes co-transporter
- Descending limb –> permeable to water, no electrolytes transporter
Proximal convoluted tubule (6)
- sodium and bicarbonate re-absorption from urine
- Carbonic anhydrase plates an imp. role in the exchange of hydrogen and bicarbonate
- Chlorine is exchanged with a base
- Na+/K+ in the membrane maintains intracellular sodium and potassium levels
- Na+/H+ exchange via NHE3
- uric acid is mainly secreted here as well as ammonia and some other drugs
Carbonic anhydrase inhibitor
- name
- mechanism
-Acetozalomide
- activated when urine pH is alkaline –> decrease formation of aqueous humor in eyes, CSF in brain
- when carbonic anhydrase is inhibited –> bicarbonate levels in the urine will increase
- no indication as a diuretic agents because they are weak drugs –> effect wouldnt last long because increase levels of sodium will cause other parts of the nephron to compensate
Carbonic anhydrase inhibitor
- indications
- unwanted effects
- glaucoma, infantile epilepsy, metabolic alkalosis
- metabolic acidosis, hypoK+, kidney stones
Why is hypokalemia a side effect of many diuretics?
- sodium levels would reach the collecting tubules and lead to a increased reabsorption in exchange of potassium
- increase sodium reabsorption in collecting tubules = loss of potassium and hydrogen
Which diuretic drug is the strongest?
Loop diuretics - Furosemide
Thick ascending limb (3)
- NKCC2 is the primary transporter in the luminal membrane - sodium, potassium and chlorine are actively reabsorbed
- reabsorption –> NaCl, Mg, Ca
- intracellularly is more negative and the lumen is more positive –> movement of magnesium and calcium to negative side
Loop diuretics
- name
- mechanism of action
-Furosemide
- secretion of many electrolytes - most powerful
- increase PG production –> vasodilation –> increase blood supply to kindeys –> hypotensive effect!
- inhibit NKCC12 receptor
Loop diuretics
- indications
- unwanted effects
- hyperK+, pulmonary edema, heart failure, ascites, nephrotic syndrome, hypertension
- hypoK+, hypoNa+, metabolic alkalosis, hyperuricemia, hearing loss
The paradoxical effect of thiazide diuretics in diabetes insipidus. Why loop diuretics wont work in this case?
- they are given
- decrease sodium reabsorption in distal tubule
- increase urinary excretion
- decrease volume of blood and extracellular volume in general
- increase proximal sodium and water reabsorption
- decrease distal delivery of sodium and water
- decrease urine output
Because there would be disruption in the osmotic gradient in the medulla
too much sodium would be left in the tubules, water wouldn’t be reabsorbed = more water in the urine
Distal convoluted tubule
- NCC –> the primary sodium and chlorine transporter in the luminal membrane
- reabsorption –> nacl, ca
- PTH –> maintains calcium levels in the blood by regulating the amount of calcium channels
Thiazide diuretics
- name
- mechanism
-Hydrochlorothiazide
- secretion –> sodium, Cl, K, Mg, H, water
- vasodilation –> secondary effect
- inhibit NCC receptor –> sodium levels in urine increase and sodium levels intracellularly decrease –> increase activity of Na+-Ca2+ levels –> increased levels of calcium will be reabsorbed in exchange for sodium –> beneficial in hypercalciuria
- should be used carefully in patients with type 2 diabetes –> decrease insulin secretion because causes hyperpolarization of pancreatic beta cells
Thiazide diuretics
- indication
- side effects
- hypertension, pulmonary edema, hypercalciuria, heart failure (mild)
- hypoK+, hypoCa2+, hyperglycemia
Furosemide and Hydrochlorothiazide
- which one is more potent?
- which one is more efficient?
- Hydrochlorothiazide - lower amount is needed to cause a response
- Furosemide - cause much higher sodium elimination in the urine
Collecting tubule
- inward diffusion of sodium leaves lumen negative which drives reabsorption of chlorine and efflux of K
- ADH increases the number of aquaporin channels –> reabsorption of water is increased
-Principle cells: responsible for sodium reabsorption by the activity of aldosterone.
- Intercalated cells: alpha and beta
- alpha –> responsible for the secretion of hydrogen, maintains acid levels
- beta –> regulate bicarbonate secretion and reabsorption
What happens when aldosterone activates principal cells in the collecting tubule?
- rapid effects –> increase number of sodium channels opening, increase activity of ATP pump, increase sodium reabsorption
- delayed effects: active the synthesis of different proteins, leading to a increase in the number of sodium channels
Why do we pee a lot when we drink alcohol?
Alcohol inhibits the secretion of ADH in the pituitary gland –> low amount of water is reabsorbed back in the collecting tubule
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Introduction lecture5
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Pharmacodynamics17
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Pharmacokinetics26
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Cholinergic transmission30
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Adrenergic transmission29
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Opioids27
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Anaesthetics23
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Antiepileptics35
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Sedatives and Hypnotics10
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Anti-depressants15
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Anti-psychotics and mood-stabilizing drugs17
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Agents used in cardiac arrhythmias27
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Agents used in heart failure15
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Treatment of Angina25
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Anti-hypertensive agents. Vasodilators12
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NSAIDs26
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Gout, Migraine20
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Hemostasis and Thrombosis44
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Haemopoietic System14
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Diuretics34
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Respiratory system46
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GI diseases37
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Anti-histamines13
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Antibiotics47
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Anti-fungal agents18
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Anti- helminthic agents15
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Anti-viral drugs27
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Tuberculosis16
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Anti-malarial drugs27
