Pharmacology - Kidney & Diuretics Flashcards
Kidney Function - 5
- Renal pelvis: Collects urine, which is excreted via the ureter to the urinary bladder & out of the body.
- Regulates body fluid volume & balance.
- Maintains ion balance (e.g. sodium, chloride) & pH.
- Excretes foreign substances, including waste products like urea.
- Secretes renin, which activates the renin-angiotensin-aldosterone system (RAAS) for BP regulation.
Ultrafiltration: Normal & Opposing forces
Blood is filtered from the Glomerular Capillaries into the Bowman’s Capsule
Driving force:
PGC - Glomerular Capillary hydrostatic pressure
πBS - oncotic pressure in the Bowman’s Space (negligible in normal kidney)
Opposing forces:
πGC - oncotic pressure of blood plasma
PBS - Pressure in the Bowman’s Space
Tubular reabsorption, secretion & excretion - 5
- Reabsorption or absorption: movement of solutes & water from tubular filtrate into interstitial fluid & plasma.
- Secretion: movement of solutes & water from plasma & interstitial fluid into tubular filtrate.
Reabsorption / absorption or secretion can be: - Transcellular (through epithelial cell & across luminal & the basolateral membrane)
- Paracellular (through tight junctions between epithelial cells)
- Excretion: extrusion of solutes & water in the tubular filtrate by the kidneys
Major sites for Tubular Sodium Reabsorption
- 4
- The Proximal Convoluted Tubule (PCT)
- The Thick Ascending Limb (TAL) of the loop of Henle
- The Distal Tubule (DT)
- The Collecting Tubule (CT)
& the Collecting Duct (CD)
Diuretics: Ranked by ability to produce natriuresis and diuresis:
- 5
- Loop Diuretics:
Act on Thick Ascending Limb (TAL) of Loop of Henle - Thiazides & Thiazide-like diuretics:
Act on Distal Tubule - Potassium Sparing Diuretics:
Act on: Collecting Tubule & Collecting Duct - Osmotic Diuretics
Act on: Proximal Convoluted Tubule & Thin Descending Limb of the loop of Henle - Carbonic Anhydrase Inhibitors:
Act on Proximal Convoluted Tubule
Tubular Sodium Reabsorption in the PCT - 9
On the Luminal membrane:
1. Na+/H+ exchanger (H+ secretion)
2. Na/H exchanger activity enhanced by Ang II via AT-1 receptors increasing Na+ reabsorption in the PCT
3. Na+-coupled co-transporters (X = glucose, amino acids)
4. Uses these mechanisms to enter PCT from Tubular lumen
On the Basolateral membrane:
5. Driving force is activity of the basolateral Na+-K+ ATPase (Creates Na+ [gradient] between the tubular lumen & interstitial space)
6. Renal K+ channels
7. Moves from PCT to Interstitial fluid
Tight Junctions: (gaps in Basolateral membrane)
8. Water permeable
9. Reabsorption of Ca2+, Mg2+, K+, Cl-
Tubular Sodium Reabsorption in the PCT: - 8
On the Luminal membrane:
1. Na+/H+ exchanger (H+ secretion) – maintains pH balance
2. Na+-coupled co-transporters (X = glucose, amino acids)
On basolateral membrane:
3. Na+-K+ ATPase on basal membrane pumps out sodium, & creates Sodium [gradient], drives reabsorption of ions, glucose, amino acids, & other substances.
4. Potassium is recycled via potassium channels.
5. Tight junctions (not very tight): allow Ca, Mg, K, Cl, & H20 to pass through.
6. Increased osmolarity in interstitial space by drugs can pull ions along, aiding in reabsorption
7. 99% of glucose reabsorbed via sodium-glucose transporters (important in diabetes treatment).
8. Drugs can interact with organic anion & cation transporters, influencing each other’s excretion pathways & potentially causing DI.
Carbonic Anhydrase Inhibitors: Acetazolamide - 6
- Inhibition of carbonic anhydrase in the PCT
- The enzyme reversibly converts carbonic acid into H2O & CO2 in the lumen, & CO2 &+ H2O to bicarbonate (HCO3-) & protons (H+) inside the epithelial cell.
- Protons excreted via luminal Na+/H+ exchanger on the proximal tubule
Renal effects of acetazolamide: - Moderate decrease in Na+ reabsorption
- Mild plasma acidosis (due to H+ retention)
- Urine alkalosis (due to increased bicarbonate secretion)
Carbonic Anhydrase Inhibitors: Acetazolamide: Uses -
Urine alkalisation
1. Reduces formation of uric acid & cystine stones
2. Increases excretion of weak acids (e.g. salicylates, barbiturates)
3. Decreases crystallisation of weak acids in the urine (e.g. anti-bacterial sulphonamides)
4. Altitude sickness (reduces respiratory plasma alkalosis by making plasma more acidic)
5. In glaucoma
Urine alkalisation: Drugs which can increase urine pH - 2
- Sodium bicarbonate (to treat aspirin overdose)
- Citrate (metabolised to bicarbonate increasing levels and its secretion)
Mechanism of diuretic action: e.g. Mannitol - 8
- Freely filtered in the glomerulus
- Pharmacologically inert and not reabsorbed
- Increases osmolarity of the tubular filtrate
- Decreases water reabsorption
- Increases sodium excretion (by retaining sodium ions in diluted filtrate – secondary effect)
- Act on areas freely permeable to water: PCT & Descending Limb of the loop of Henle
- Collecting tubule and Collecting duct in the presence of ADH
Osmotic Diuretics: Therapeutic applications. E.g. Mannitol - 5
- Weak diuretics, rarely used in the kidney
- May be used in acute renal failure
- Non-renal uses (increase osmolarity of blood plasma):
- Cerebral oedema (to reduce intracranial pressure)
- Glaucoma (to reduce intraocular pressure)
Effects of Loop Diuretics (e.g., Furosemide and Bumetanide) - 5
- Inhibit the NKCC2 cotransporter (Ion reabsorption), leading to:
- Reduced Na, Cl, Ca, & Mg (decreased reabsorption, secretion).
- Hypocalcaemia & hypomagnesemia in some patients due to disrupted absorption.
- Increased K excretion as K channels remain open.
- Diuretics reduce Na absorption, can result in low plasma Na levels, requiring supplementation.
Pharmacokinetics of Loop Diuretics (e.g. Furosemide, Bumetanide) - 4
- Absorbed in gut & secreted into filtrate by organic anionic transporters.
- Share these transporters with other drugs (e.g., uric acid), possible DIs affecting their excretion.
- Delivered to the site of action as filtrate flows to the Loop of Henle.
- Excreted in the urine
LOOP DIURETICS e.g. Furosemide, Bumetanide: Therapeutic uses
- 5
- Acute pulmonary oedema
- Diuretic resistant oedemas
- Resistant hypertension
- Patients with impaired kidney function or with CHF
- Liver cirrhosis with ascites
Thiazides & Thiazide-like diuretics: Effects of Diuretics on the Distal Tubule - 4
- Inhibits NCC, reducing Na & Cl reabsorption, causing Na loss & moderate increase in K excretion.
- Ca reabsorption increased because Na gradient for Ca transport is reduced.
- Basolateral Na+Ca” exchanger (NCX1) and the basolateral Ca-ATPase (Ca-pump) moves Ca into interstitial space and then into blood.
- Tight junctions in distal tubule are water-impermeable, so water does not follow the ions in this section.
Thiazides & Thiazide-like diuretics: Renal Effects of Diuretics in the Distal Tubule - 3
- Sodium (Na+) & chloride (Cl-) reabsorption are reduced.
- Increase in Potassium (K+) excretion.
- Calcium (Ca2+) reabsorption is increased, leading to decreased calcium excretion.
THIAZIDES & THIAZIDE-RELATED DIRETICS - 5
Thiazides:
1. Hydrochlorothiazide
2. Bendroflumethiazide
Thiazide-like:
1. Chlortalidone
2. Indapamide
3. Metolazone
THIAZIDES vs LOOP DIURETICS: Comparison - 4
- are less powerful, but better tolerated than loop diuretics
- have more prolonged action
- have vasodilating properties
- a greater risk of hypercalcemia
THIAZIDES & THIAZIDE-RELATED DIRETICS (e.g. Hydrochlorothiazide, Indapamide): Therapeutic Uses - 4
- Hypertension
- Severe resistant oedema
- Prevention of kidney stone formation in idiopathic hypercalciuria (reduced Ca accumulation)
- Nephrogenic diabetes insipidus
Loop and thiazide/thiazide-like diuretics (Hydrochlorothiazide, Indapamide): Common Adverse Effects
- 5
- Hypotension
- Gout due to hyperuricaemia (high levels of uric acid)
- Erectile dysfunction
- Tachyarrhythmias: cause: hypokalaemia can reduce rate of repolarisation, promote abnormal depolarizations
- Hyperglycaemia: cause:: dose-related glucose intolerance due to depletion of intracellular K+ in pancreatic beta-cells.
Depletion of intracellular K (hypokalaemia) interferes with normal activation of insulin release, can cause hyperglycaemia & may lead to T2D Mellitus
Potassium Regulation & Hyperkalaemia - 6
- Primary mechanism for K excretion involves a coupling of Na reabsorption & K excretion. The more sodium is reabsorbed, the more potassium is lost.
- Hyperkalaemia occurs when large amounts of Na reach the distal tubule, leading to excessive K loss via this coupling.
- Aldosterone regulates K levels by increasing K excretion when plasma K levels are high. It acts on three components:
- Increased Enac expression (renal Na channels for Na reabsorption).
- Increased ROMK (K channels for K excretion)
- Increased activity of Na-K ATPase.
Potassium-Sparing Diuretics MoA - 4
- These diuretics aim to reduce potassium loss, counteracting the effects of aldosterone.
Two main classes: - Mineralocorticoid Receptor Antagonists (e.g., spironolactone): Block aldosterone’s action, reducing Na reabsorption & K excretion.
- Sodium-Potassium Channel Blockers (e.g., amiloride, triamterene): Inhibit Na reabsorption & prevent K loss by blocking sodium channels.
- Amiloride and triamterene are weaker diuretics but are used to preserve potassium levels
POTASSIUM-SPARING DIURETICS: Therapeutic uses - 5
- To treat hypokalaemia (with thiazides or loop diuretics)
- Heart failure (MRAs to improve survival)
Resistant essential hypertension (e.g. due to low renin) - Aldosteronisms (spironolactone & eplerenone):
- Primary hyperaldosteronism (Conn’s Syndrome)
- Secondary aldosteronism (e.g. overactive RAAS)
(ADH) Antidiuretic hormone: Vasopressin (Arginine-Vasopressin, AVP) Water Reabsorption - 2
- Vasopressin: regulator of water reabsorption in the kidneys, (collecting ducts), responding to hypertonic environment in the medulla.
- High salt levels or dehydration detected by pituitary gland, signalling hypothalamus to release Vasopressin
Mechanism of Action: Antidiuretic hormone (e.g. Vasopressin) - 2
- Vasopressin acts on V2 receptors in the kidneys, they are GS-coupled & activate cAMP pathway, leading to increased water reabsorption.
- In the absence of vasopressin, collecting ducts not highly permeable to water. However, vasopressin promotes insertion of aquaporin channels into the luminal membrane, allowing water to pass through & be reabsorbed.
Factors Influencing Anti-diuretic hormone (Vasopressin) Release -2
- Increased plasma osmolarity (high [salt]) stimulates vasopressin release.
- Alcohol, nicotine, & caffeine inhibit vasopressin release, potentially leading to increased urine output.
- Conditions (e.g. diabetes insipidus) can cause abnormal vasopressin function, either due to inadequate release or lack of kidney response.
Diabetes insipidus (DI):
Define, causes 2, Treatment 2
- Diabetes Insipidus: condition where body excretes excessive amount of water, leading to extreme thirst, but the body cannot compensate by drinking enough water. Produces hypotonic plasma & filtrate. This condition differs from diabetes mellitus (which involves high blood sugar).
Causes: - Central diabetes Insipidus: Caused by reduced secretion of vasopressin (antidiuretic hormone, ADH) due to trauma, surgery, or genetic factors.
- Nephrogenic Diabetes Insipidus: The brain releases normal levels of vasopressin, but the kidneys fail to respond to it due to diseases or medication (e.g., lithium salts used in psychiatric treatments).
Treatment: - Central Diabetes Insipidus: Supplementing vasopressin using synthetic forms (e.g., desmopressin).
- Nephrogenic Diabetes Insipidus: treated with diuretics.
