Pharmacology 9: Diuretics and drugs in kidney failure Flashcards

1
Q

You are looking to treat a patient with severe pulmonary and peripheral oedema with a diuretic in hospital, which diuretic might you choose and by which route, and why.

A

Loop diuretic- potency- inhibit Na+/K+/2Cl- cotransporter in ATL of LOH, so about 5% of Na+ reabsorption inhibited. Bumetanide may be given as has 90% uptake, and with severe oedema, gut wall oedema will compromise furosemide uptake, and give IV as want to have effect quickly.

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2
Q

diuretics used in heart failure?

A

loop diuretic e.g. furosemide, and bumetanide- better absorption (90%) so may be better if gut wall oedema
thiazide diuretic. High Na+ reabsorption capacity of ATL makes them 1st line for acute relief of pulmonary and peripheral oedema in HF. Reduce pre-load, hence filling pressure on heart, reduce pulmonary oedema.
aldosterone antagonist= K+ sparing= combat ADR of hypokalaemia assoc with loop and thiazide, e.g. spironolactone or eplerenone

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3
Q

diuretics used in hypertension?

A

thiazide and aldosterone antagonist e.g. spironolactone, possible loop

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4
Q

diuretics used in liver failure?

A

aldosterone antagonist and loop

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5
Q

diuretic used in Conn’s syndrome?

A

aldosterone antagonist e.g. spironolactone

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6
Q

why might combination diuretic therapy e.g. loop and thiazide, be used?

A

patients have oedema which is resitant to tment with 1 diuretic, but vigorous tment, espec with loop, may cause acute hypotension.

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7
Q

why is spironolactone chosen to treat oedema arising from liver cirrhosis?

A

K+ sparing and hypokalaemia can precipitate encephalopathy that is associated with liver cirrhosis

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8
Q

Other than encephalopathy, what else can diuretics increase the risk of in a patient with alcoholic liver cirrhosis?

A

arrythmias as increased risk of hypomagnesaemia

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9
Q

why are thiazides usually given at start of day?

A

so diuresis induced doesn’t interfere with sleep

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10
Q

mechanism of action of thiazide diuretics?

A

inhibit Na+/Cl- co-transporter at beginning of DCT, so more Na+ and H20 excreted from body. This lowers circulating blood volume, hence preload of heart, force of myocardial contraction and SV, so CO reduced and aBP reduced.
so at low doses used in hypertension.
can be used in chronic heart failure to reduce oedema if mild HF and renal function intact.

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11
Q

ADRs of thiazides?

A

postural hypotension
hypokalaemia *increased tubular flow rate, increased K+ secretion by principal cells as more Na+ to move through ENaC, creating +ve luminal potential for K+ movement out into filtrate.
hypercalcaemia
hyponatraemia
gout- hyperuricaemia
hyperglycaemia- possibly due to drug-induced impairment of insulin secretion and/or reduced insulin sensitivity
erectile dysfunction

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12
Q

example of a thiazide diuretic used in mild to moderate heart failure

A

bendroflumethiazide

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13
Q

when might a thiazide diuretic be used in heart failure?

A

if mild to moderate HF and good renal function, but ineffective in patients with eGFR of < 30ml/min

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14
Q

why is the natriuresis produced by thiazides less than that produced by loop diuretics?

A

thiazides act downstream to loop, where 90% of Na+ reabsorption has occurred upstream of their site of action

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15
Q

how might thiazides decrease BP, other than inhibiting Na+/Cl- reabsorption at the DCT?

A

direct vasodilatory effect

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16
Q

The DCT is a site of PTH regulated reabsorption of Ca2+, how do thiazides promote increased transcellular Ca2+ reabsorption?

A

By inhibiting Na+ reabsoprtion, there is increased activity of NCX on BL membrane as more Na+ moved into cell from ECF down conc gradient as less Na+ in cell from movement across apical membrane, so more Ca2+ moved into ECF.
Also, reduced Na+ reabsoprtion creates -ve luminal potential promoting Ca2+ movement across apical membrane into cell, and then across BL membrane into ECF.

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17
Q

why should thiazides not be administered alongside anti-arrhythmic agents that prolong the QT interval e.g. amiodarone?

A

as predispose to torsades de pointes, possible due to thiazide induced hypokalaemia which increases risk of cardiac arrhythmias.

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18
Q

key kidney functions in terms of REEM?

A

regulatory- fluid balance, electrolyte balance, acid-base
excretory- waste products and drugs- glom filtration and tubular secretion
endocrine- erythropoietin, RAAS and PGs
metabolic- Vit D and polypeptides- insulin and PTH

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19
Q

5 actions of Ang II?

A
activate SNS
stimulate aldosterone release
increase Na/CL reabsorption by PCT of kidney
increase ADH release
arteriolar vasoconstriction
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20
Q

3 factors that stimulate renin release?

A

reduced perfusion pressure to kidney
SNS activation
reduced NaCl delivery to DCT

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21
Q

specific ADR of furosemide? (loops in general?)

A

ototoxicity- electrolyte disturbance in endolymph

22
Q

specific ADR of bumetanide?

A

myalgia

23
Q

general ADRs of diuretics?

A

hypovolaemia/hypotension, leading to acute renal failure (pre-renal cause)
electrolyte disturbances- hyponatraemia, hypokalaemia
metabolic abnormalities
anaphylaxis/rash

24
Q

common specific ADRs of spironolactone?

A
painful gynaecomastia (also caused by cimetidine)
hyperkalaemia
25
Q

potential interactions of an ACEI and K+ sparing diuretic e.g. amiloride or spironolactone?

A

hyperkalaemia, which can cause cardiac disturbances

26
Q

potential interactions of an aminoglycoside and loop diuretic?

A

ototoxicity and nephrotoxicity

27
Q

potential interactions of digoxin, and thiazide and loop diuretics?

A

hypokalaemia, causing increased digoxin binding and toxicity

28
Q

potential interactions of beta blockers and thiazide diuretics?

A

Hyperglycemia, hyperlipidemia,

hyperuricaemia.

29
Q

potential interactions of steroids, and loop and thiazide diuretics?

A

increased risk of hypokalaemia

30
Q

potential interactions of carbamazepine and thiazide diuretics?

A

increased risk of hyponatraemia

31
Q

why might diuretics be ineffective in a patient?

A

Incomplete treatment of the primary disorder
Continuation of high Na+intake
Patient non-compliance
Poor absorption e.g. GI gut wall oedema
Volume depletion decreases filtration of diuretics
Volume depletion increases serum aldosterone
which enhances Na+ reabsorption.
NSAIDs - can reduce renal blood flow

32
Q

2 key issues of prescribing in renal disease?

A

drugs may reduce kidney function by direct or indirect toxicity
drugs at normal doses may accumulate to toxic levels if excreted through kidneys and renal function impaired

33
Q

potentially nephrotoxic drugs?

A
ACEIs
NSAIDs
gentamicin and other aminoglycosides
penicillins
cyclosporin A
metformin- can use in stage III CKD, but must be stopped if eGFR becomes <30ml/min
34
Q

Hyperkalaemia ECG changes?

A

reduction/absent P waves
widening QRS complex
tall and tented T waves
increased PR interval

35
Q

tment of hyperkalaemia?

A

establish cause!
calcium gluconate- cardioprotection, prevent arrythmic disturbances
calcium resonium- binds K+ in gut to prevent absorption, polystyrene sulfonate resin
insulin and dextrose- insulin moves K+ into cells through Na+pump stimulation, and dextrose prevents hypoglycaemia.
nebulised salbutamol- also makes K+ enter cells as beta 2 agonist- stimulates Na+ pump which moves K+ into cells
sodium bicarbonate

36
Q

why can loop diuretics cause low Ca2+ and Mg2+?

A

by inhibiting Na+/Cl- reabsorption via Na+/K+/2Cl- co-transporter, this creates a lumen +ve potential which inhibits Ca2+ and Mg2+ reabsorption across apical membrane.

37
Q

why does hypokalaemia occur with loop diuretics?

A

increase Na+ load presented to principal cells of CD: increase electrical gradient for K+ excretion as increase +ve luminal potential, and chemical gradient as increase activity of BL Na+ pump.
Also increase tubular flow rate maintaining conc gradient for K+ secretion.

38
Q

how are the clinical consequences of loop diuretic tment together often described?

A

volume-contraction alkalosis

39
Q

how is potency of bumetanide compared to other loop diuretics?

A

bumetanide approx. 40X more potent than other loops.

40
Q

how does activity of furosemide and bumetanide differ with route of administration?

A

act within 1 hr if given orally, peak effect within 30 mins if given IV

41
Q

ADRs of loop diuretics?

A
hypovolaemia, postural hypotension
hypokalaemia, hyponatraemia
hyperglycaemia- though less likely than with thiazides
ototoxicity- tinnitus and deafness
myalgia- bumetanide
hypersensitivity reactions
42
Q

when might low-dose loop diuretics be used, other than in hypertension or HF?

A

liver disease causing hypoalbuminaemia, decreasing IV oncotic pressure, or nephrotic syndrome.

43
Q

how does spironolactone act as a K+ sparing diuretic?

A

aldosterone antagonist, inhibits biosynthesis of new Na+ channels in prinicipal cells of CD to inhibit Na+ reabsorption, and this decreases normal lumen -ve transepithelial potential do decreases driving force for K+ secretion.

44
Q

why can spironolactone cause gynaecomastia?

A

inhibits androgen receptor in addition to mineralocorticoid receptor

45
Q

why can aldosterone antagonists cause metabolic acidosis?

A

inhibt Na+ uptake through ENaC can diminish H+ secretion

46
Q

what are carbonic anhydrase inhibitors used for?

A

glaucoma

47
Q

what are osomotic diuretics e.g. mannitol used for?

A

cerebral oedema

48
Q

how can ADH antagonists have a diuretic effect?

A

e.g. lithium
inhibt action of ADH on CD which normally causes insertion of AQP-2 channels on apical membrane to increase H20 reabsorption by CD.
Used in SIADH

49
Q

how do digoxin and amiloride have diuretic activity?

A

digoxin- Na+ pump tubular inhibitor

amiloride- inhibits ENaC in principal cells in DCT and CD, K+ sparing- affect electrochemical gradient for K+ secretion

50
Q

general advice about prescribing drugs to patients with renal failure?

A

avoid nephrotoxins if at all possible
reduce dosages in line with GFR if emt or elim via kidneys
monitor renal function (eGFR, creatinina and urea) and drug levels if narrow therapeutic range
hyperkalaemia more likely
uraemic pateints have greater tendence to bleed

51
Q

why should metformin not be used if eGFR<30ml/min?

A

metformin excreted via kidneys, with reduction in kidney function it can accumulate to toxic levels producing lactic acidosis- will alter function of important enzymes in body.

52
Q

why are NSAIDs CI if bilateral renal artery stenosis?

A

can cause renal failure and accumulate to toxic levels in body, produce GI ADRS e.g. gastric ulceration, abdom pain, diarrhoea, nausea, and CVS effects e.g. hypertension and heart failure.
As naproxen is eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients.
Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding.
When renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, patients should have renal function assessed before and during naproxen therapy. Dose dependant reduction in prostaglandin formation can precipitate renal failure already compromised function- renal artery stenosis.