Drugs acting on the kidney Flashcards
List the types of drugs which act on the kidney
Diuretics Vasopressin receptor agonist Vasopressin receptor antagonists Inhibitor of sodium-glucose co-transporter 2 Uricosuric drugs Renal failure drugs pH altering drugs
What are uricosuric drugs?
Drugs which increase excretion of uric acid
What do diuretics do?
Increase urine flow by inhibiting reabsorption of electrolytes at various points within the nephron (water follows salt)
Why are diuretics useful?
The help correct conditions where the interstitial fluid volume is too high (e.g oedema)
What is oedema?
An imbalance in the rate of formation and the rate of absorption of interstitial fluid causing tissue swelling
What is the equation for formation of interstitial fluid?
(Capillary hydrostatic pressure - hydrostatic pressure of interstitial fluid) - (capillary oncotic pressure - interstitial oncotic pressure)
Which disease states induce oedema and by affecting which starling forces?
Nephrotic syndrome
Congestive heart failure
Hepatic cirrhosis + ascites
Increased capillary hydrostatic pressure
Decreased capillary oncotic pressure
What is nephrotic syndrome?
Disorder of nephrotic filtration allowing proteins such as albumin to appear in the filtrate (albuminuria and proteinuria)
Describe how nephrotic syndrome causes oedema
Decreased capillary oncotic pressure –>
Increased formation of interstitial fluid (oedema)–>
Decreased blood volume and cardiac output –>
Activation of RAAS –>
Sodium and water retention –>
Increased capillary hydrostatic pressure and decreased capillary oncotic pressure (oedema)
What is congestive heart failure?
Heart failure caused by decreased cardiac output
How does congestive heart failure cause oedema?
Reduced cardiac output –>
Reduced renal perfusion –>
Activation of RAAS –>
Increased blood volume –>
Increased capillary and venous hydrostatic pressure & reduced capillary oncotic pressure –>
Increased interstitial fluid volume (pulmonary and peripheral oedema)
How does hepatic cirrhosis cause oedema?
Increased hepatic portal veinous pressure (inc hydrostatic) &
Decreased production of albumin & protein (dec oncotic) ->
Loss of fluid into peritoneal cavity (i.e ascites) –>
Decreased circulating volume activates RAAS
When does risk of circulatory collapse and thrombosis occur with diuretic use?
Overuse of diuretics
Describe the major sites and methods of sodium absorption within the nephron
Proximal tubule - sodium hydrogen exchanger & sodium channels
Loop of Henle - thick ascending limb has triple cotransporter
Distal tubule - sodium hydrogen exchanger & sodium chlorine cotransporter
Collecting duct - sodium potassium exchanger
Describe how sodium absorption is blocked by each class of diuretics
Loop - blocks triple co-transporter within loop of Henle
Thiazide - block sodium chloride co-transporter
Carbonic anhydrase inhibitors - blocks sodium hydrogen exchanger
Potassium sparing diuretics - blocks sodium potassium exchanger
Nb - remember where these transporters are found within the nephron
How does small inhibition of transport mechanisms affect sodium reabsorption?
Marked increased in excretion (sodium usually reabsorbed)
Which membrane of tubular cells do diuretics act upon? Why is the relevant?
Apical membrane
Drugs must enter the tubular filtrate
How do diuretics enter the filtrate?
Glomerular filtration (not bound to plasma protein) Secretion in the proximal tubule (organic anion and cation transporters)
Which type of drugs do organic anion and cation transporters secrete respectively?
Anion - acidic
Cation - basic
Explain how organic anion transporters work
Organic anions enter cells via diffusion or OATs when exhanged for an alpha-ketoglutarate –>
Alpha-ketoglutarate transported into the cell against its concentration gradient via sodium dicarboxylate cotransporter –>
At apical membrane anion enters the lumen via multidrug resistant protein 2 OR OAT4 (exchanged for alpha-ketoglutarate)
Explain how organic cation transporters work
Organic cation enter cells via diffusion or OCT driven by negative intracellular charge concentration gradient –>
At apical membrane cation enters lume via multidrug resistant protein 1 OR cation hydrogen antiporters (OCTN)
How do loop diuretics work? What effect does this have?
They block the triple cotransporter (sodium, potassium and two chloride ions) by binding to the chloride site at the thick limb of the ascending loop of Henle
Decreases tonicity of medulla meaning that fluid thus preventing hypotonic distal tubule filtrate formation –>
Inc sodium, potassium, calcium and magnesium excretion
Name two loop diuretics
Furosemide
Bumetanide
Loop diuretics act rapidly. T/F
True
What indirect effect do loop diuretics have?
Venodilator (beneficial to pulmonary oedema caused by heart failure)
Do loop diuretics bind to plasma proteins? How do they enter the nephron?
Yes! Organic anion transporter
List the clinical indications for loop diuretics
Reduce salt and water overload
Increase urine volume in acute kidney failure
Treat hypertension (resistance to other drugs - renal insufficiency)
Reduce acute hypercalcaemia
Which conditions are associated with salt and water overload (oedema)?
Acute pulmonary oedema Chronic heart failure Chronic kidney failure Nephrotic syndrome Hepatic cirrhosis with ascites
What are the side effects of loop diuretics?
Hypokalemia Increased toxicity of digoxin & class III antirhythmatics Hypocalcaemia and hypomagnesium Hypovolaemia and hypotension (elderly) Metabolic acidiosis (inc. H+ secretion) Hyperuricaemia
How can hypokalaemia cause by loop diuretics be corrected?
Concomitant use of potassium sparing diuretic
Potassium supplement
How do thiazide diuretics work?
Block of the sodium chloride cotransporter in the distal tubule by binding to cholride site –>
Decreases tonicity of medullary fluid, increase sodium and potassium excretion and increase calcium reabsorption
Name two thiazide diuretics
Bendoflumethiazide (bendrofluazide)
Hydrochlorothiazide
Which diuretic is more effective loop or thiazide?
Loop causes greater excretion of sodium (& hence water)
What indirect effect do thiazide diuretics have? Why is this relevant?
Vasodilator. Useful in the management of hypertension
How do thiazide diuretics enter the nephron?
Organic anion transporter
What are the clinical indications for thiazide use?
Mild heart failure Hypertension Resistant oedema (with loop) Nephrolithiasis (dec excretion of calcium) Nephrogenic diabetes insipidus
What causes nephrogenic diabetes insipidus?
Reduced responsiveness to vasopressin by collecting ducts
What are the side effects of thiazide diuretics?
Hypokalaemia Metabolic acidosis Hypovolaemia and hypotension (elderly) Hypomagnesium Decreased male sexual function Impaired glucose tolerance Hyperuricaemia (gout)
What type of hormone is aldosterone and what does it do?
Steroid
Increases synthesis of sodium potassium channels
Increases synthesis of protein which produces epithelial sodium channels (ENaC)
What type of hormone is vasopressin and what does it do?
Peptide
Increases aquaporins in the cell membrane
What type of receptors do aldosterone and vasopressin act on respectively?
Aldosterone - cytoplasmic
Vasopressin - g-protein coupled
What do potassium channels (ROMK) do?
Secrete potassium into the collecting tubule (recycling of potassium helps with sodium absorption)
How do loop and thiazide diuretics cause potassium loss?
Increased sodium caused by diuretics caused increased reabsorption of sodium –>
Lumen becomes more negative and depolarises apical & basolateral membrane –>
Potassium follows charge gradient and secretion is increased (same for hydrogen)–>
Increased urinary flow rate washes away potassium (& hydrogen) –>
Hypokalaemia & metabolic acidosis
Name four potassium sparing diuretics and explain how they work respectively
Amiloride
Triamterene
Block apical sodium channel thus decrease sodium reabsorption
Spironolactone
Eplerenone
Compete with aldosterone for binding to intracellular receptors –>
decrease gene expression for protein which activates sodium channels & decreases number of sodium potassium bumps in basolateral membrane
What are the effects of spironolactone and similar drugs modulated by?
Aldosterone levels
Is amiloride well or poorly absorbed from the GI tract?
Poorly absorbed
How do amiloride and similar drugs enter the collecting tubules?
Organic cation transport system
What are the clinical indications of potassium sparing diuretics and aldosterone antagonists respectively?
In conjunction with other diuretics (given alone will cause hyperkalemia)
Increase affect of diuretics by blocking RAAS system
Primary hyperaldosteronism (conn’s)
Secondary hyperaldosteronism (cirrhosis & ascites)
Resistant hypertension
Heart failure
Name an aldosterone antagonist
Spironolactone
Name two osmotic diuretics
Mannitol
Sorbitol
How are osmotic diuretics administered? Why?
IV. They cannot cross the plasma membrane as they are polyhydric alcohols
Osmotic diuretics are filtered and reabsorbed in equal measure. T/F
False - they are filtered but not reabsorbed
How do osmotic diuretics affect the tubular filtrate? What effect does this have?
They make the filtrate hyperosmotic thereby attracting water into the filtrate
Where within the nephron do osmotic diuretics have their effect? Why?
Proximal tubule
This is normally where most iso-osmotic water reabsorption occurs (because it’s freely permeable)
What secondary effect do osmotic diuretics have? Why?
Decrease in sodium reabsorption
Increased fluid in filtrate dilutes sodium and deceases the electrochemical gradient for reabsorption
When are osmotic diuretics indicated?
Prevention of acute hypovolaemic renal failure (maintain urine flow)
Raised intracranial pressure
Raised intraocular pressure
How do osmotic diuretics decrease intracranial/ocular pressure?
Increased plasma osmolarity causes water to move from these compartments into the blood
When does osmotic diuresis occur outside of pharmacological induction?
Hyperglycaemia
Use of iodine-based radio-contrast dyes in imaging
How does osmotic diuresis occur in diabetes?
Glucose levels are so high that the active transport mechanisms reach transport maximum and hence cannot reabsorb all glucose. Hypertonic filtrate attracts water and urine volume is massively increased
How do iodine-based radio-contrast dyes cause osmotic diuresis?
Dye filtered but not absorbed. Hypertonic fluid attracts water and urine volume is increased
What is the risk of iodine-based radio-contrast dyes in relation to osmotic diuresis?
Reduction of intravascular volume (as water moves into tubule) may cause hypotension in patients with CVS conditions
Name a carbonic anhydrase inhibitor
Acetazolemide
What is the problem with carbonic anhydrase inhibitors as diuretics?
Weak diuretics which lose their effectiveness over time
What do carbonic anhydrase inhibitors do?
Inhibit carbonic anhydrase resulting in
- Increased excretion of bicarbonate
- Increased excretion of sodium
- Increased excretion of potassium
- Increased excretion of water
Eventually causing alkaline urine and metabolic acidosis
What are carbonic anhydrase inhibitors used for?
Glaucoma
Post eye surgery
Infantile epilepsy (occasionally)
Altidude sickness prophylaxis
Why are carbonic anhydrase inhibitors useful in eye pathology?
Reduce intra-ocular pressure by suppressing production of aqueous humour by reducing it’s bicarbonate dependent sodium induced formation
Why are carbonic anhydrase inhibitors useful in altitude sickess?
Altitude sickness has been linked to CSF disturbance
CSF production by the choroid plexus is dependent on carbonic anhydrase
Why can alkaline urine be useful? How can it be induced?
Relief of dysuria
Prevention of crystallization of weak, poorly soluble acids (i.e stone formation)
Excretion of weak acids (e.g aspirin overdose)
Carbonic anhydrase inhibitors
Citrate calls
Degree of ionisation of weak acid increases with pH. T/F
True
Where is aldosterone secreted from?
Adrenal cortex (zona glomerulosa)
Where is vasopressin secreted from?
Posterior pituitary gland
Which two factors induce aldosterone secretion?
Increased potassium concentration
Activation of RAAS (angiotensin II)
What does aldosterone do? How?
Increases sodium (& salt) reabsorption Decreases potassium reabsorption
Binds to cytoplasmic steroid receptor –>
- increased synthesis of sodium potassium ATPase &
- increased synthesis of mediator protein activating ENac &
- prevents internalisation of ENaC
What does vasopressin do? How?
Increased water reabsorption
Binds to vasopressin 2 g-protein coupled receptors on basolateral membrane –>
- increase in intracellular cyclic AMP –>
- increase in number of aquaporins on apical membrane
How does diabetes insipidus present?
Polydipsia
Polyuria
Urine copious and dilute
What is diabetes insipidus?
Disturbance of vasopressin either neurogenic or nephrogenic in origin
Explain neurogenic and nephrogenic diabetes insipidus respectively
Neurogenic - lack of ADH production
Nephrogenic - lack of ADH sensitivity
How is neurogenic diabetes insipidus treated?
Desmopressin (i.e vasopressin analogue)
Desmopressin’s effect on vasopressin receptors can induce hypetension. T/F
False - desmopressin is V2 specific and it is V1 receptors which are involved in hypertension
How do nicotine and alcohol effect ADH activity?
Alcohol decreases activity
Nicotine increases activity
Nb - ecstasy also decreases activity hence the dehydration risk
Desmopressin can be used for enuresis in children over 10. T/F
True - NOT recommended for use in those over 65
What causes nephrogenic diabetes insipidus? How common is it?
Mutations (usually X-linked) in V2 receptor
Uncommon
How is nephrogenic diabetes insipidus treated?
No pharmacological treatment available
What external factors can induce nephrogenic diabetes?
Lithium (bipolar disorder)
Democlocycline (antibiotic / block to vasopressin in excessive secretion)
“-vaptans”
Which sex is affected by nephrogenic diabetes insipidus?
Male
What are vaptans?
Competative antagonists of vasopressin receptors (V1a,b & 2)
What is the difference between an aquaretic and a diuretic?
Aquaretic - water loss without sodium loss
Diuretic - sodium loss causing water loss
What effect on plasma osmolarity do aquaretics have?
Increase
How do vaptans work?
Binds to vasopressin receptors causing G protein coupling to activate adenylate cyclase –>
Cyclic AMP activates protein kinase A –>
Causes vesicles containing aquaporin 2 channels to insert into apical membrane –>
Increased water reabsorption
What do the different vasopressin receptors do?
V1A - arteriolar smooth muscle (vasoconstriction)
V2 - kidney tubules (water balance)
What is the effect of vasopressin 2 receptor antagonism?
Excretion of water without sodium loss (aquaresis) –>
Increased sodium plasma concentration
Name two vaptans and state which receptors they act on
Conivaptan - V1A & 2
Tolvaptan - V2 specific
When are vaptans useful?
Possibly heart failure - hypervolaemic hyponatraemia
Syndrome of inappropriate ADH secretion to increase sodium (tolvaptan)
Where and how is glucose reabsorbed in the nephron?
Proximal tubule
Sodium glucose co-transporter 1 & 2
When does glucose appear in the urinary filtrate?
Transport maximum of renal tubule reached
Where are SGLT 1 & 2 found respectively? How is this relevant to clinical practive?
SGLT 1 - intestine (enterocytes) and kidney (more distal than SGLT 2)
SGLT 2 - proximal tubule (kidney)
SGLT 2 selective drugs will only affect renal absorption of glucose
SGLT 1 is responsible for most of renal glucose reabsorption. T/F
False - SGLT 2
Is reabsorption of glucose by active transport or facilitated diffusion?
Secondary active transport - apical/tubular membrane
Facilitated diffusion - basolateral membrane
Describe the secondary active transport of glucose
Glucose reabsorbed against concentration gradient coupled to electrochemical gradient of sodium
State the stoichiometry of the SGLT transporters
SGLT 1 - two sodium to one glucose
SGLT 2 - one sodium to one glucose
State the respective affinities and capacities of the SGLT transporters
SGLT 1 - high affinity low capacity
SGLT 2 - low affinity high capacity
Remember - glucose is highest in proximal tubule
What does SGLT2 inhibition result in? What condition might this be confused for?
Glucosuria
Familial renal glucosuria (benign)
Name three SGLT2 inhibitors
Canagliflozin
Dapagliflozin
Empaggliflozin
Are SGLT2 inhibitors insulin dependent or independent?
Independent
What are the effects of SGLT2 inhibitors?
Excretion of glucose (glucosuria)
Lowered HbA1c
Weight loss (calorific and mild osmotic diuresis)
What is the commonest side effect of SGLT2 inhibitors? Why?
Fungal infections (thrush) Increased colonisation of genital bacteria due to increased glucose
What are prostaglandins?
Molecules derived from arachidoinic acid (membrane fatty acid) by COX enzymes
What type of molecules are prostaglandins?
Prostanoids
COX2 is expressed during inflammation and tissue trauma. T/F
True
Name the two main kidney prostaglandins and where they are produced within the kidney
Prostaglandin E2 - medulla
Prostaglandin I2/prostacyclin - glomeruli (macula densa)
What do the renal prostaglandins do?
Naturetic (promote sodium loss)
Vasodilators (local effect on kidney)
What are the synthesised in response to?
Angiotensin II Mechanical trauma Ischemia ADH Bradykinin
What effects do the renal prostaglandins have on the renal blood flow and glomerular filtrate rate?
Normally - minimal
Vasoconstriction +/- decreased blood flow - vasodilation
How do prostaglandins affect glomerular filtration rate?
Vasodilation of afferent arteriole
Vasoconstriction of efferent arteriole (activate RAAS)
What type of drugs may precipitate acute renal failure? When? How?
NSAIDS in conjunction with
- cirrhosis
- heart failure
- nephrotic syndrome
Inhibit COX which is essential for prostaglandin formation ->
Decreased GFR
What drugs make up the “triple whammy” effect on the liver which causes acute renal failure in individuals with pathology? Why?
ACE/ARBS (RAAS blocking)
Diuretics (dec volume)
NSAIDs (inhibit COX)
All decrease GFR in some way
What is metabolised to produce uric acid?
Purines
What condition does high uric acid predispose to?
Gout
Name two uricosuric agents
Probenecid
Sulfinpyrazole
How might uricosuric agents be useful in the treatment of gout?
Block reabsorption of urate in the proximal tubule
What is a better drug, in managing gout, than uricsuric acids? Why?
Allopurinol
Inhibits urate production
