Drugs acting on the Kidney Flashcards
List drugs that act on the kidney
Diuretics
Vasopressin Receptor Agonists/Antagonists
SGLT2
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
CCF
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?
Filtrate
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?
Gout
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?
Adrenaline
Noradrenaline
Dopamine
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?
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?
Hypokalaemia
Dehydration
What are side effects of loop diuretics?
Hypokalaemia Hypocalcaemia Hypomagnesaemia Hypovolaemia Hypotension
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?
Hypokalaemia
Be cautious in Gout and Hyponatraemia
What are side effects of Thiazide and Thiazide-like diuretics?
Hypovolaemia
Hypokalaemia
Hypotension
Hypomagnesaemia
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
Amiloride
Triamterene
Eplerenone
Spironolactone
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?
Amiloride
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 HF Resistant primary hypertension
What are contraindications for K sparing diuretics?
Hyperkalaemia
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?
PCT
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
Acetalozamide
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?
Glaucoma
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
