Drugs acting on the Kidney

Question 1

List drugs that act on the kidney

Answer 1

Diuretics
Vasopressin Receptor Agonists/Antagonists
SGLT2
Uricosuric Drugs (promote urate excretion via urine)
Those used in renal failure
Those that alter urine pH

Question 2

What is the general mechanism of all diuretics?

Answer 2

Increase urine flow by inhibiting electrolyte (mainly Na and Cl) absorption
Enhance salt and water excretion where ECF increases cause tissue swelling

Question 3

How does oedema occur?

Answer 3

It results from an imbalance between the rate of formation and absorption of interstitial fluid

Question 4

What are the 4 forces that are important in oedema

Answer 4

Hydrostatic capillary pressure (Pc)
Hydrostatic IF pressure (Pi)
Oncotic plasma pressure (Op)
Oncotic IF pressure (Oi)

Question 5

What conditions in the body will cause oedema?

Answer 5

Anything that increases Pc will push water out into the tissues
Anything that decreases Op will bring water into the tissues

Question 6

Give examples of disease states that increase Pc or decrease Op

Answer 6

Nephrotic Syndrome
CCF
Hepatic Cirrhosis with Ascites

Question 7

What is Nephrotic Syndrome?

Answer 7

A disorder of glomerular filtration, allowing large protein (mainly albumin) to appear in the urine (proteinuria) as the reabsorption mechanisms are overwhelmed by the vast quantities of urine

Question 8

Can protein normally appear in filtrate?

Answer 8

Yes, especially after exercise but these proteins are small and are rapidly reabsorbed so do NOT present in urine

Question 9

How does Nephrotic Syndrome occur?

Answer 9

Decreased Op caused Increased IF formation, resulting in a degree of oedema.
IF formation also reduces blood volume and cardiac output, which in turn activates RAAS.
This results in Na and H2O retention, increasing Pc and reducing Op, worsening oedema

Question 10

Why does CCF cause oedema?

Answer 10

Reduced cardiac output (kidneys get 25% normally) and subsequent renal Hypoperfusion activates the RAAS
Expansion of blood volume contributes to increased venous and capillary pressures, which combined with reduced Op, causes pulmonary and peripheral oedema

Question 11

How does Ascites occur in hepatic cirrhosis?

Answer 11

Increased pressure in the hepatic portal vein, combined with decreased production of albumin, causes loss of fluid into the peritoneal cavity and oedema (ascites)

Activation of the RAAS occurs in response to decreased circulating volume, worsens oedema

Question 12

How do Loop Diuretics work?

Answer 12

In the AL of LoH.
Block the Triple Cotransporter by binding to the Cl binding site, causing powerful diuresis and reducing Na, K and Cl movement into the tubular cell

Also reduce Ca and Mg reabsorption across the Zona Accludens Gap Junctions

Question 13

How do Thiazide diuretics work?

Answer 13

In the early DCT
Block the Na and Cl cotransporter on the Apical Membrane, producing modest diuresis and increasing Na and Cl excretion from the body

Question 14

What must be remembered about diuretics (2)?

Potassium-sparing diuretics are barred from Point 1

Answer 14

Any diuretic that increases the amount of Na in the DCT will cause K loss, producing potential for hypokalaemia

Even in modest inhibition of Na reuptake, Diuretics cause marked increases in Na excretion

Question 15

What extra-renal treatment are carbonic anhydrase inhibitors used for?

Answer 15

Relieve altitude sickness and intra-ocular pressure

Question 16

What must hydrophilic diuretics enter in order to act on the apical membrane?

Answer 16

Filtrate

Question 17

How does diuretic entry into the glomerular filtrate occur?

Answer 17

Glomerular filtration for diuretics NOT bound to large plasma proteins.

Any diuretic that is bound to protein cannot bind to nephron via filtration and so, must be secreted via several transport processes at the PCT.

As filtrate passes through the nephron, it becomes more conc. hence diuretic conc. also goes up.

Question 18

What are the main transport processes that occur for diuretics at the PCT, to allow them to act on the Apical Membrane?

Answer 18

Organic anion transporters (OATs) – transport acidic drugs (e.g. thiazides and loop agents)

Organic cation transporters (OCTs) – transport basic drugs (e.g. triamterene and amiloride)

Question 19

Why is diuretic secretion important for its mechanism?

Answer 19

Secretion results in the concentration of diuretic in the filtrate being higher than that in blood, contributing to pharmacological selectivity

Question 20

How does secretion of organic anions occur in the PCT?

Answer 20

At the basolateral membrane, organic anions enter the tubular cell against the conc. gradient in exchange for Alpha-Ketoglutarate (a-kg).

Organic anions then pass into the lumen across the apical membrane via 2 transporter proteins

Question 21

How does secretion of organic cations occur in the PCT?

Answer 21

At the basolateral membrane, organic cations enter the tubular cell against a concentration gradient
(The transport is driven by voltage in which the positive ion is moved into the cell)

Organic cation enters lumen across apical membrane via 2 transport proteins

Question 22

How can interaction of multiple drugs occur due to the organic anion transporter?

Answer 22

Many drugs compete for the transporter so one drug may influence the secretion of another

e.g. diuretics (amiloride, triamterene), atropine, metformin, morphine, procainamide, endogenous catecholamines

Question 23

What do Loop Diuretics increase the probability of?

Answer 23

Gout

Decrease urate secretion via urine as transport is reduced, which causes urate build-up in the body

Question 24

Which catecholamines are transported via the organic cation transporter?

Answer 24

Adrenaline
Noradrenaline
Dopamine

Question 25

What is Barrter's Disease?

Answer 25

Autosomal Recessive disease with symptoms similar to an individual taking Loop Diuretic, showing Na, Cl and H2O wasting Types 1, 2, 3 and 4 exist, depending on which transport channel is mutated i.e. K Channel, Cl Channel and Triple Cotransporter

Question 26

What are other effects of loop diuretics?

Answer 26

Decrease the tonicity of the interstitium of the medulla, reducing the capacity to absorb H2O Prevents the diluting function of the AL of the LoH Possess a venodilator action which helps with hypertension and CCF

Question 27

How can the efficacy of loop diuretics be increased?

Answer 27

Giving IV with Nitrate and O2 increases onset of action to within 30mins Nitrates reinforce venodilating action of loop diuretics which can be used in pulmonary oedema in CCF

Question 28

In chronic heart failure, which loop diuretic is better: Furosemide or Bumetanide?

Answer 28

Bumetanide | Intestinal Oedema from chronic heart failure may reduce the capacity of furosemide to work due to impaired absorption

Question 29

How may nephrotic syndrome reduce the efficacy of Loop Diuretics?

Answer 29

Diuretics may bind to the large proteins secreted in nephrotic syndrome and so, cannot bind to a protein transporter simultaneously, reducing their action.

Question 30

What are clinical indications of loop diuretics?

Answer 30

Acute Pulmonary Oedema in CCF (O2 and Nitrates too) Chronic heart failure (or raise urine output in acute kidney failure) Chronic kidney failure Ascites (Liver Cirrhosis) Nephrotic syndrome Acute hypercalcaemia Resistant hypertensions (other diuretics used previously)

Question 31

What are contraindications for loop diuretics?

Answer 31

Hypokalaemia | Dehydration

Question 32

What are side effects of loop diuretics?

Answer 32

``` Hypokalaemia Hypocalcaemia Hypomagnesaemia Hypovolaemia Hypotension ```

Question 33

What is Gitelman's Disease?

Answer 33

Autosomal recessive disease due to mutations in the Na/Cl Cotransporter

Question 34

What is the difference between the Thiazide and Thiazide-like diuretics? Give examples of both

Answer 34

Thiazide drug = a true thiazide Thiazide-like drug = drug with a different structure but same action Thiazide - Bendroflumethiazide Thiazide-like - Chlortalidone, Indapamide

Question 35

What are other effects of Thiazide and Thiazide-like diuretics?

Answer 35

Promote reabsorption of Ca Prevent diluting ability of filtrate in early DCT Venodilator mechanism

Question 36

What are clinical indications of Thiazide and Thiazide-like diuretics?

Answer 36

``` Mild HF Hypertension (Thiazide-like) Severely Resistant Oedema Renal Calculi Disease Nephrogenic DI ```

Question 37

When are Thiazide and Thiazide-like diuretics contraindicated?

Answer 37

Hypokalaemia | Be cautious in Gout and Hyponatraemia

Question 38

What are side effects of Thiazide and Thiazide-like diuretics?

Answer 38

Hypovolaemia Hypokalaemia Hypotension Hypomagnesaemia Erectile Dysfunction (low dose to reduce risk) Impaired glucose tolerance (binds to KATP channels)

Question 39

How do Loop, Thiazide and Thiazide-like diuretics cause K loss?

Answer 39

Loop diuretics prevent Na reabsorption in the AL of the LoH while Thiazide and Thiazide-like diuretics prevent Na reabsorption in the EARLY DCT. Therefore, the is increased Na in the LATE DCT and Collecting Tubule, causing enhanced reabsorption of Na in the Late DCT and collecting tubule. Tubular lumen becomes negatively charged as a result, depolarising apical membrane, causing enhanced K secretion.

Question 40

Give examples of K sparing diuretics

Answer 40

Amiloride Triamterene Eplerenone Spironolactone

Question 41

How do K sparing diuretics work?

Answer 41

Amiloride and Triamterene block the apical sodium channel (ENaC) and decrease Na reabsorption Eplerenone and spironolactone compete with aldosterone for binding to cytoplasmic intracellular receptors preventing aldosterone action

Question 42

All diuretics are well absorbed in the GI Tract except for which one?

Answer 42

Amiloride

Question 43

What is important to remember regarding Spironolactone metabolism?

Answer 43

Spironolactone is a pro-drug that is metabolised in the GI Tract to become its active form; Canrenone

Question 44

What are clinical indications of K sparing diuretics?

Answer 44

``` Used with other diuretics to prevent Hypokalaemia and potentiate their actions by blocking the counteractive RAAS Conn's Syndrome Secondary Aldosteronism HF Resistant primary hypertension ```

Question 45

What are contraindications for K sparing diuretics?

Answer 45

Hyperkalaemia Addison's Disease Severe Renal Impairment

Question 46

What are Osmotic Diuretics?

Answer 46

Membrane impermeable drugs which increase the osmolality of the filtrate, opposing the absorption of water in parts of the nephron that are freely permeable to water

Question 47

Where is the site of action for Osmotic Diuretics?

Answer 47

PCT

Question 48

What is another effect of Osmotic Diuretics?

Answer 48

Secondarily decrease sodium reabsorption in the PCT (larger fluid volume decreases sodium concentration and electrochemical gradient for reabsorption)

Question 49

What are clinical indications for Osmotic Diuresis?

Answer 49

Prevention of acute hypovolaemic renal failure to maintain urine flow Treatment of acutely raised intracranial and intraocular pressure. The solute does not enter the eye, or brain, but increased plasma osmolality extracts water from these compartments

Question 50

In what conditions does Osmotic Diuresis occur?

Answer 50

Hyperglycaemia – reabsorptive capacity of the proximal tubule for glucose (by SGLT1 and SGLT2) is exceeded Consequence of the use of iodine-based radiocontrast dyes in imaging

Question 51

What do carbonic anhydrase inhibitors do? | Give an example?

Answer 51

Increase excretion of HCO3- with Na+, K+ and H2O – alkaline diuresis and metabolic acidosis result Acetalozamide

Question 52

What does alkaline diuresis do?

Answer 52

Discourages the formation of urate stones as crystallisation of weak acids is prevented and weak acids are excreted Relieves dysuria

Question 53

When are carbonic anhydrase inhibitors indicated?

Answer 53

Glaucoma Following eye surgery (to reduce intraocular pressure by suppressing formation of aqueous humour) Prophylaxis of altitude sickness Some forms of infantile epilepsy

Question 54

What are Aquaretics/Vaptans?

Answer 54

Drugs that act as competitive antagonists of vasopressin receptors (which occur as V1A, V1B and V2 GPCR subtypes) Promotes excretion of water but not sodium, by increasing the permeability of the apical membrane to water

Question 55

Give examples of Vaptans?

Answer 55

``` Tolvaptan = Selective V2 Blocker Conivaptan = V1 and V2 Blocker ```

Question 56

What are clinical indications for Vaptans?

Answer 56

Treatment of HH-associated HF and they increase Na concentration whilst losing water and therefore, reducing the preload on the heart Tolvaptan can be used to treat SIADH

Question 57

Where are the SGLT found in the body? | What do they do?

Answer 57

SGLT1 is found in the intestines and in the distal part of the PCT SGLT2 is found in the proximal part of the PCT Responsible for efficient glucose reabsorption, coupled with Na transport

Question 58

What is the difference in the functional aspects of the SGLT1 and SGLT2?

Answer 58

SGLT2 appears in the early PCT where glucose concentration is maximal so has a lower affinity for glucose but higher transport capacity (1 Glucose, 1 Na). SGLT1 appears in the late PCT where glucose concentration is ~10% so has a higher affinity for glucose but lower transport capacity (1 Glucose, 2 Na)

Question 59

What do SGLT2 Antagonists do? | Give examples of them.

Answer 59

Block SGLT2 preventing glucose reabsorption in the kidney ONLY Canagliflozin, dapagliflozin and empagliflozin

Question 60

What are other effects of SGLT2 Antagonists?

Answer 60

Decrease HbA1c Cause weight loss due to calorific loss via glucose excretion and mild osmotic diuresis However, glucose urine in bladder can increase risk of UTI

Question 61

What is Familial Renal Glycosuria?

Answer 61

Benign condition in which patients lead completely normal life despite having no functioning SGLT2 receptors.

Question 62

What are the major prostaglandins secreted by the kidneys?

Answer 62

PGE2 – medulla | PGI2 (Prostacyclin) – glomeruli

Question 63

What do Prostaglandins do?

Answer 63

act as vasodilators, are natriuretic, and are synthesised in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin

Question 64

How do Prostaglandins implement their effect?

Answer 64

Under normal conditions, prostaglandins have little effect upon RBF or GFR Prostaglandins gain importance under conditions of vasoconstriction, or decreased effective arterial blood volume, where they cause compensatory vasodilation

Question 65

How do Prostaglandins affect the GFR?

Answer 65

Direct vasodilator effect upon the afferent arteriole Releasing renin leading to increased levels of angiotensin II that vasoconstricts the efferent arteriole, causing the filtration pressure to increase

Question 66

What drugs may precipitate renal failure?

Answer 66

NSAIDS inhibit COX and may precipitate acute renal failure (greatly decreased GFR) in conditions where RBF is dependent upon vasodilator prostaglandins e.g. liver cirrhosis, heart failure, nephrotic syndrome Combination of ACEI (or ARB), diuretic and NSAID may be detrimental via the ‘triple whammy’ effect