Renal pharmacology and diuretics

kidney functions

• regulation of water, salts, acid-base balance

• removal of metabolic waste

• removal of foreign chemicals

• gluconeogenesis

• production of hormes/enzymes

what hormones/enzymes does the kidney produce and what for

• erythropoietin- controls red blood cell production

• renin- controls blood pressure and sodium balance

• activates vitamin D- regulates calcium

kidney anatomy

capsule, cortex, medulla, renal pelvis, ureter

what parts of the nephron is in the cortex?

glomerulus, proximal and distal convoluted tubule

what parts of the nephron is in the medulla

loop of henle and collecting duct

how is glomerular filtration rate regulated

adjusting blood pressure within glomerulus

what is glomerular filtration rate

volume of fluid filtered from glomeruli to bowman’s space per unit time

how to reduce/increase GFR

reduce- constrict afferent flow, reduced pressure

dilate efferent flow and reduced pressure

reduces water and salt loss through excretion

increase- opposite

which diuretic acts on the glomerulus

2

which diuretic acts on proximal convoluted tubule

1

which diuretic acts on ascending loop of henle

5

which diuretic acts on distal convoluted tubule

3+4

which diuretic acts on collecting duct

6

sites of water reabsorption

descending loop of henle and proximal convoluted tubule

sites of sodium reabsorption

everywehere but descending loop of henle and the bowman’s capsule/glomerulus

number 2 on drug list

decreases water reabsorption, increases sodium excretion through retention, increases osmolarity of tubular filtrate. acts on water permeable parts- proximal convoluted tubule, descending loop of henle, collecting duct. weak. limited use in certain patients (acute renal failure).

non-renal use of number 2

increases osmolarity of blood plasma→ cerebral oedema (reduce intracranial pressure) and glaucoma (reduce intraocular pressure)

sodium reabsorption in PCT

Na+ moved into tubule cells through Na+/H+ counter-transporter. Na+ moved from cell to interstitial space via Na+/K+ ATPase pump. 5% Na+ reabsorption. overall PCT 65-70% Na+ reabsorption

H+ secretion in PCT

•Carbonic anhydrase produces carbonic acid from  H₂O and CO₂

•Carbonic acid breaks down into H⁺ and HCO₃

•H⁺ promotes Na⁺ reabsorption through Na⁺/H⁺ counter transporter

•HCO₃ reabsorbed

•Replaces HCO₃ lost through filtration

•Control of acid-base balance

1 diuretic on drug sheet

•Inhibit carbonic anhydrase

•Na⁺ /H⁺ counter transporter shuts down

•Moderate decrease in Na⁺ reabsorption

•Mild plasma acidosis

•Urine alkalosis

•Due to increased bicarbonate secretion

•Rarely used as a diuretic

•Weak diuretic (5% Na excretion)

•Self-limiting

•Carbonate in tubular fluid acts to increase osmolarity

•Acidosis suppresses carbonate loss through filtration

•Therefore, reduced carbonate reduces H₂O retention in tubules

•Increased sodium reabsorption elsewhere in nephron

non-renal use of number 1

•Glaucoma- Reduced production of aqueous humour

•Altitude sickness- Reduced respiratory alkalosis by making plasma more acidic

Na+ reabsorption in ascending loop of henle

•Na⁺ moved from tubules into cells through cotransport  with K⁺ and Cl^-

•Na-K-Cl cotransporter (NKCC)

•Na⁺/K⁺ ATPase moves Na⁺ out to interstitial space

•15-25% of Na⁺ reabsorption

5 on drug list

•Inhibit NKCC co-transporter

•Decreased reabsorption of Na⁺ and Cl^-

•Increased K⁺ excretion

•Absorbed in gut

•Secreted into tubular filtrate by Organic anion transporters (OAT) in PCT

•Excreted in urine

Therapeutic use

•Most powerful class of diuretics

•Acute pulmonary oedema

•Resistant oedema

•Resistant hypertension

•Impaired kidney function

•Liver cirrhosis with ascites

Na+ reabsorption in distal convoluted tubule

•Na⁺ moved from tubules into cells through cotransport  with Cl^-

•Na/Cl co-transporter

•Na⁺/K⁺ ATPase moves Na⁺ out to interstitial space

•7% of Na⁺ reabsorption

•Ca²⁺ secretion occurs here

3 and 4 on the drug list

•Inhibition of Na⁺/Cl^- co-transporter

•Decreased reabsorption of Na⁺ and Cl^-

•Increased Ca²⁺ reabsorption

Comparison to loop diuretics

•Less powerful than loop diuretics (loop 15-25% Sodium reabsorption, DCT 7%)

•More prolonged action

•Better tolerated

3 and 4 other uses

•Hypertension

•Mild heart failure

•Severe resistant oedema (can be combined with loop diuretics – synergy)

•Prevention of calcium-based kidney stones in idiopathic hypercalciuria

Nephrogenic diabetes insipidus

3,4,5 side effects

•Hypotension

•Volume contraction alkalosis

•Reduced plasma volume increases plasma bicarbonate concentration

•Gout

•Due to hyperuricaemia (high plasma uric acid)

•Usually secreted into kidneys via OAT, competition with diuretics reduces uric acid secretion/excretion

•Increased uric acid reabsorption as consequence of compensation for low plasma volume 

•Hypokalaemia

•Plasma [K⁺] < 3.5 mM

•Tachyarrhythmia (impaired repolarisation of heart action potentials)

•Hyperglycaemia (K⁺ required for insulin release in pancreas)

•Inhibition of sodium reabsorption in either loop of henle or distal collecting duct forces more sodium through the collecting duct

•Compensatory mechanisms here promote hypokalemia

Na+ reabsorption in collecting duct

•Na⁺ moves into cell and K⁺ moves out through ion channels

• Renal sodium channels (ENaC)

• Renal outer medullar potassium channels (ROMK)

•Na⁺/K⁺ ATPase moves Na⁺ out to interstitial space and K⁺ into cells

•Increased Na⁺ delivery increases reabsorption in collecting duct

•This increases K⁺ secretion

slide 19

aldosterone

•steroid hormone acting on the collecting duct

•Acts on mineralocorticoid receptors

•Increases expression of ENaC, ROMK and Na⁺/K⁺ ATPase

•Increased ROMK expression increases K⁺ secretion/excretion

6a on drugs list

block action of aldosterone

6 on drug list uses

•Are not potent diuretics

•Hypokalaemia

•Heart failure

•Resistant essential hypertension

•Aldosteronisms (too much aldosterone)

• Primary aldosteronism (Conn’s syndrome)

• Secondary aldosteronism (e.g., overactive RAAS)

side effects of number 6

hyperkalaemia plasma (K+)>5.5 mM

7 on drug list

•acts on V2 GPCR on cells of collecting duct

•This causes Aquaporin-2 rich vesicles inside cell to fuse with apical cell membrane

•Aquaporins -3 and -4 constitutively expressed on basolateral side

•Increases number of channels water can use to cross into body

ADH related disorders- Diabetes insipidus

•Production of copious amounts of diluted water

Two forms

Neurohypophyseal (central) DI

•Reduced ADH secretion

•Normal kidney response

•Causes – Brain injury, surgery, genetics

Nephrogenic DI

•Normal ADH levels

•Impaired kidney response

•Causes – Lithium poisoning, kidney disease, genetics

DI treatments

Neurohypophyseal (central) DI

•Desmopressin

•Synthetic ADH

Nephrogenic DI

•3

•Paradoxically reduced urine volume

•Compensatory increase in proximal reabsorption allows kidneys to reabsorb water (and reduce ultimate urine volume) in nephron prior to collecting duct

renin-angiotensin aldosterone system

renin (enzyme) released in response to reduced sodium in dct and sympathetic stimulation of the juxtaglomerular apparatus via beta 1 adrenoreceptors. inhibited by ANP in response to increase in bp

formation of angiotensin ll

angiotensinogen → angiotensin l → angiotensin ll (by ACE)

angiotensin ll in the kidneys

increase na+ reabsorption in the PCT. stimulates the release of aldosterone a steroid hormone that acts on the collecting duct- reabsorbs more sodium and decreases potassium

aldosterone

regulates bp by controlling na+ and k+. retains na- increases amount water reabsorbed . excrete potassium.