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List drugs that act on the kidney

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


What is the general mechanism of all diuretics?

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


How does oedema occur?

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


What are the 4 forces that are important in oedema

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


What conditions in the body will cause oedema?

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


Give examples of disease states that increase Pc or decrease Op

Nephrotic Syndrome
Hepatic Cirrhosis with Ascites


What is Nephrotic Syndrome?

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


Can protein normally appear in filtrate?

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


How does Nephrotic Syndrome occur?

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


Why does CCF cause oedema?

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


How does Ascites occur in hepatic cirrhosis?

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


How do Loop Diuretics work?

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


How do Thiazide diuretics work?

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


What must be remembered about diuretics (2)?
Potassium-sparing diuretics are barred from Point 1

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


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

Relieve altitude sickness and intra-ocular pressure


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



How does diuretic entry into the glomerular filtrate occur?

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.


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

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)


Why is diuretic secretion important for its mechanism?

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


How does secretion of organic anions occur in the PCT?

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


How does secretion of organic cations occur in the PCT?

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


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

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


What do Loop Diuretics increase the probability of?

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


Which catecholamines are transported via the organic cation transporter?



What is Barrter's Disease?

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


What are other effects of loop diuretics?

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


How can the efficacy of loop diuretics be increased?

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


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

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


How may nephrotic syndrome reduce the efficacy of Loop Diuretics?

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


What are clinical indications of loop diuretics?

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)


What are contraindications for loop diuretics?



What are side effects of loop diuretics?



What is Gitelman's Disease?

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


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

Thiazide drug = a true thiazide
Thiazide-like drug = drug with a different structure but same action

Thiazide - Bendroflumethiazide
Thiazide-like - Chlortalidone, Indapamide


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

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


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

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


When are Thiazide and Thiazide-like diuretics contraindicated?

Be cautious in Gout and Hyponatraemia


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

Erectile Dysfunction (low dose to reduce risk)
Impaired glucose tolerance (binds to KATP channels)


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

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.


Give examples of K sparing diuretics



How do K sparing diuretics work?

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


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



What is important to remember regarding Spironolactone metabolism?

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


What are clinical indications of K sparing diuretics?

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


What are contraindications for K sparing diuretics?

Addison's Disease
Severe Renal Impairment


What are Osmotic Diuretics?

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


Where is the site of action for Osmotic Diuretics?



What is another effect of Osmotic Diuretics?

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


What are clinical indications for Osmotic Diuresis?

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


In what conditions does Osmotic Diuresis occur?

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


What do carbonic anhydrase inhibitors do?
Give an example?

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



What does alkaline diuresis do?

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

Relieves dysuria


When are carbonic anhydrase inhibitors indicated?


Following eye surgery (to reduce intraocular pressure by suppressing formation of aqueous humour)

Prophylaxis of altitude sickness

Some forms of infantile epilepsy


What are Aquaretics/Vaptans?

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


Give examples of Vaptans?

Tolvaptan = Selective V2 Blocker
Conivaptan = V1 and V2 Blocker


What are clinical indications for Vaptans?

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


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

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


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

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)


What do SGLT2 Antagonists do?
Give examples of them.

Block SGLT2 preventing glucose reabsorption in the kidney ONLY

Canagliflozin, dapagliflozin and empagliflozin


What are other effects of SGLT2 Antagonists?

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


What is Familial Renal Glycosuria?

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


What are the major prostaglandins secreted by the kidneys?

PGE2 – medulla
PGI2 (Prostacyclin) – glomeruli


What do Prostaglandins do?

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


How do Prostaglandins implement their effect?

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


How do Prostaglandins affect the GFR?

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


What drugs may precipitate renal failure?

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