diuretics Flashcards
what are diuretics
drugs which have direct actin on the kidney which increase the excretion of salt and water in urine
what are uses of diuretics
treatment of cardiac failure and other conditions that give rise to oedema and also treatment of hypertension
what are ways of reducing generalised oedema
remove of primary cause (e.g cardiac glycosides in treatment of heart failure)
reduce intake of salt
increase excretion of salt and water via kidney using a diuretic
what is the mechanism of action of diuretics
in principle there are 3 ways:
increase amount filtered into urine through nephrons
increase amount secreted into urine through nephrons
reduce reabsorption from filtrate
diuretics all work be reducing reabsorption of solutes and water from tubular lumen
normally how much is reabsorbed from urine in terms of solutes
normally a lot is reabsorbed: 99+% of sodium, chloride and water is reabsorbed
100% of HCO3 (bicarbonate) and 93+% of potassium
hence small impairments in reabsorption can lead to great increase in excretion
how does reabsorption occur from proximal convoluted tubule
proximal convoluted tubule:
NaCl is retrieved via:
passive entry of sodium from tubular fluid into tubular cells via their luminal membrane, excess sodium is expelled via active transport on the other face of the tubular cells
HCO3 is reabsorbed by a mechanism which involves exchange of sodium in the filtrate for H+ from the cell, supply of H+ is rate limited by carbonic anhydrase activity
carbonic anhydrase is blocked by acetazolamide which is a weak diuretic
how does reabsorption occur from thick part of ascending limb of loop of hence
NaCl is reabsorbed:
NaCl enter tubular cells via co-transport mechanism Na/K/2Cl in the luminal membrane
sodium is actively expelled via sodium pump in the basolateral membrane
the cotransporter which pumps sodium into tubular cells is blocked by loop diuretics such as furosemide
how does reabsorption in the distal convoluted tubule occur
further reabsorption of NaCl occurs here
NaCl enters tubular cells via Na/Cl transporter
thiazides block this transporter
how does reabsorption in the collecting ducts occur
these cells are impermeable to water in absence of vasopressin and to sodium in absence of aldosterone
chloride ions exit the tubule through the paracellular pathway
potassium and hydrogen ions are added to the filtrate here
a sodium pump in the basolateral membrane is the main source of energy for ion movements in collecting duct
aldosterone acts on nuclear receptor within tubule cell and on membrane receptors to increase the sodium pumps
aldosterone action is inhibited by spironolactone, a compeitive blocker, causing less sodium to be reabsorbed from urine, this is known as a ptoassium sparing diuretic
amiloride blocks the sodium channels and is another potassium sparing diuretic
vasopressin acts via V2 receptors which increase expression of aquaporins
when are thiazide diuretics used, where do they act
treatment of hypertension, use of high doses may be used to treat heart failure
sodium/chloride pump of distal convoluted tubule
what are physiological affects of thiazide diuretics
reduction in blood pressure partly due to direct consequence of diuretic action reducing plasma volume and partly due to vasodilator effects in vascular smooth muscle
relative importance of diuretic/vasodilator effect is difficult to establish
side effects:
hypokalaemia,more likely to be significant at higher doses for heart failure, a hazard since reduction in plasma potassium increases toxicity of cardiac glycosides which are sometimes used together in treatment of heart failure
may also increase plasma glucoses, uric acid and lipids though changes are usually small for hypertension doses, may cause diabetes to be made worse
plasma increase in uric acid may cause or intensify gout
adverse effects are relatively uncommon and are thiazides are usually well tolerated
what are physiological features of loop diuretics
e.g furosemide
features shared w thiazides:
orally active
lowers blood pressure (loop ones mechanism is unknown either by plasma volume reduction or vasodilation through potassium channels)
can cause potassium loss
can increase plasma uric acid and glucose
differences between loop diuretics and thiazides:
site of action: loop diuretics target thick part of ascending limb of loop of henle, thiazides target the distal convoluted tubule
maximum natriuresis (nutrients such as sodium in urine) attainable is much greater in loop diuretics than thiazides
loop diuretics increase excretion of calcium whereas thiazides reduce it (furosemide can be used in treatment of hypercalcaemia)
loop diuretics can cause deafness which is usually but not alway reversible, ototoxicity may be related to changes in electrolyte composition of endolymph
what are general mechanisms of diuretics
all of them impaire reabsorptive activity of nephron
many diuretics (thiazides and loops) increase excretion of potassium thus causing hypokalaemia, this may be countered with a potassium sparing diuretic or potassium supplements
all effective diuretics sustain reduction in plasma volume, some may also cause vasodilation however these mechanisms are poorly understood
indomethacin and other NSAIDs attenuate and may even abolist the natriuretic and direct vascular effects of diuretics, mechanism is unclear
which sites do the different types of diuretics target
osmotic diuretics modify glomerular filtrate content at glomerulus
loop diuretics target thick part of ascending limb of loop of henle
acetazolamide: proximal convoluted tubule
thiazides: distal convoluted tubule
potassium sparing diuretics: collecting duct
give an example of a loop diuretic and a potassium sparing diuretic
loop: furosemide
potassium sparing: spironolactone and amiloride
what causes renin release
dropping of rate of glomerular filtration, fall in sodium content of fluid entering distal tubule, increased sympathetic activity
where is renin secreted from
granular juxtaglomerular cells
what is function of ACE
converts angiotensin 1 (inactive) to angiotensin 2 (causes vasoconstriction and aldosterone secretion)
also converts bradykinin (vasodilator, increased sensitivity of pain fibres) into inactive products
what are physiological effects of aldosterone
potassium excretion increases because aldosterone promotes reabsorption of sodium from tubular fluid in exchange for potassium
causes release of vasopressin from posterior pituitary, this contributes to retention of water
increased sodium reabsorption
how does renin-angiotensin-aldosterone system effect hypertension
overactivity of renin-angiotensin-aldosterone system may contribute to hypertension by:
promoting vasoconstriction (angiotensin 2)
sodium and water retention (aldosterone)
give examples of ACE inhibitors, how do they affect people
captopril (first discovered)
enalapril (commonly used)
small drop in blood pressure in normals, much large reduction in hypertensives especially is plasma renin is high
administered alongside diuretics in heart failure, causes reduction in mean arterial pressure and vasodilation, meaning both pre and after load are reduced
if a thiazide is already being used ACE inhhibitors can cause large reductions in blood pressure to care is needed
what are side affects of ACE inhibitors
cough due to increased bradykinin concentration, also causes activity of pain nerve endings in bronchial mucosa
what are angiotensin 2 antagonists used for
treatment of hypertension
e.g losartan, orally active, causes less coughing cause bradykinin metabolism not affected
where and when in vasopressin released
peptide hormone released from posterior pituitary
released in response to an increase in plasma osmolality and decrease in circulating blood volume
what physiological effects does vasopressin have
makes collecting duct more water permeable, allowing for more reabsorption of water
at higher concentrations causes vasoconstriction
what drugs affect vasopressin release
release is inhibited by alcohol
release is increased by angiotensin 2 and nioctine
what is vasopressin used to treat
cranial diabetes insipidus (production of vassopressin is deficient)
since it is peptide hormone must be given via injection or nasal spray
desmopressin is more often used because it causes less vasoconstriction
what is felypressin used for
analogue of vasopressin, more vasoconstrictor activity and antidiuretic
used as vasoconstrictor in conjunction with local anaesthetics in dentistry
what vasopressin receptors are found where
V2 in renal tubules
V1 in blood vessels
what are osmotic diuretics
high molecular weight compounds that are filtered but not reabsorbed
cause water retention within nephron by reducing osmotic gradient (lower water potential of urine) and hence diuresis e.g mannitol
only given by injection
used to reduce intracranial pressure and to increase rate of elimination of renal toxins
how do thiazides and loop diuretics get to site of action
inside tubular lumen, via weak acid transport system;
proximal tubular cells secrete weak acids into lumen
in what situations may change of urine ph be wanted
when some antibiotics are used to treat urinary tract infection (penicillin and tetracycline are more active in acid solution, sulphonamides are more active and soluble in alkaline solution)
in attempting increase of exretion of salicylate or phenobarbitone when taken in overdose
what effect do carbonic anhydrase inhibitors have on urine ph
make urine more alkaline since they block bicarbonate reabsorption
what is given to alkalinise urine
citrate
