S4 Diuretics and Renal pharmacology

Question 1

what are the functions of the kidneys ?

Answer 1

regulation
excretion
endocrine - renin, erythropoietin, prostaglandins
Metabolism - active form of Vit D, catabolism of insulin, PTH calcitonin
control ; volume, PH

Question 2

in which section of the nephron do different diuretics work ?

Answer 2

PT - carbonic anhydrase inhibitors ( e.g acetozoloamide) and osmotic diuretics (e.g mannitol) but not really used any more
LoH - loop diuretics (inhibit NaK2Cl symport furosemide, bumetanide)
DCT - thiazide diuretics (inhibit NaCL symport e.g metolazone)
CD- K+ sparing diuretics (EnaC blockers e.g amiloride), aldosterone antagonists - also spare K+ (e.g spironolactone), ADH antagonist (lithium)

Question 3

what is the effect of aldosterone on channels ?

Answer 3

increase expression of NaK ATPase and ENaC and K+ channels
alcohol inhibits ADH release, caffeine increases GFR and decreases Na reabsorption and both have diuretic actions
ADH antagonists - lithium, tolvaptan

Question 4

what are the ADRS for diuretics

Answer 4

generic : anaphylaxis, hypotension (which activates RAAS), electrolyte disturbance
Thiazide : gout, hyperglycaemia
Spironolactone : Hyperkalaemia, impotence
Frusemide : ototoxicity, alkalosis
Bumetanide : myalgia

Question 5

what are uses of diuretics ?

Answer 5

hypertensions : TD, spironolactone
Heart failure : LD
decompensated liver disease : spironolactone, LD
Nephrotic syndrome : LD, add TD if high K+
Chronic kidney disease : LD

Question 6

describe what is meant by diuretic resistance ?

Answer 6

during delivery to the renal tubule, diuretics are absorbed through the gut, so gut cant be oedematous. Diuretic enters bloodstream so cant have HF, furosemide is albumin bound so cant have albumin deficiency. Fursoemide secreted into PT via OATs, then LoH so PTand LoH must be functioning

Question 7

describe all the diuretics in summary with usage and main side effect

Answer 7

drug - usage - main side effect
carbonic anhydrase inhibitor - glaucoma, altitude sickness - acidosis, renal stones
osmotic diuretics - reduce high intracerebral pressure - allergic reactions
Loop diuretic - oedema ( may be hypertension in CKD)- alkalosis, metabolic effects (increase urate, lipids)
thiazides - hypertension - electrolyte disturbance, metabolic effects (increased urate, glucose , lipids, impotence)
potassium- sparing diuretics (amiloride )- low potassium where diuretic required - hyperkalaemia
aldosterone antagonist - heart failure, ascites, hypertension, hyperadrenalism - hyperkalaemia, gynaecomastia (spironolactone)
ADH antagonist - hyponatremia - hypernatraemia, deranged liver function

Question 8

why can drugs cause pre-renal AKI ?

Answer 8

NSAIDS : inhibit prostaglandins, which normally dilate the afferent arteriole
ACEi/ARB : reduce ANG II so less vasoconstriction of efferent
both drop the perfusion pressure so GFR falls much faster than normal

Question 9

what precautions should be taken in patients with CKD

Answer 9

avoid nephrotoxins
dose carefully with vancomyocin
side effects of drugs are more common in renal disease

Question 10

what are causes of hyperkalaemia?

Answer 10

excessive intake
movement out of cells e.g acidosis
reduced urine loss
diabetic ketoacidosis
Drugs - ACEi, NSAIDS

Question 11

what is seen in the ECG in hyperkalaemia?

Answer 11

life threatening arrhythmias, tall T small P waves , sine waves

Question 12

how is hyperkalaemia managed

Answer 12

reduced effect on heart with IV Ca2+ gluconate, remove excess K+ by dialysis or calcium resonium, reduce intake

Question 13

how is blood pressure controlled ?

Answer 13

controlled by ANS and RAAS

Question 14

what is hypertension ?

Answer 14

defined as 140/90 mmhg

Question 15

what are the causes of hypertension

Answer 15

primary hyp : no known cause, affects 90% of hyp people. Causative agents include oral contraceptive pill, corticosteroids or high alcohol intake
Secondary Hyp : has a discrete, identifiable underlying cause

Question 16

what is the treatment of hypertension

Answer 16

identify and treat underlying cause if present
lifestyle advice/non-pharmacological therapy
Pharmacological therapy (bp > 160/100)

Question 17

what are examples of lifestyle therapy

Answer 17

patient education, reduce salt, exercise and reduce alcohol

Question 18

what are Ace Inhibitors

Answer 18

usually given in under 55s E.g Lisinopril or Ramipril
Stop Ang1 —> Ang2 causing less vasoconstriction, Na retention and aldosterone release
also increases bradykinin (vasodilator) and has some venodilation
side effects cough other adverse side effects : angio-oedema , renal failure and hyperkalaemia

Question 19

what angiotensin receptor blockers

Answer 19

e.g losartan, candersartan
Bind to Ang1 receptor preventing Ang2 formation so no vasoconstriction or aldosterone release
side effects : renal failure, Hyperkalaemia

Question 20

what are some calcium channel blockers

Answer 20

usually in over 55’s
bind to specific alpha subunit of L - tyoe calcium chanel reducing cellular calcium entry
vasodilates peripheral, coronary and pulmonary arteries

Question 21

what are the three groups of CCBS ?

Answer 21

Dihydropyridines (Nifedipine, Amlodipine) - have good oral absorption and are metabolised by the liver - adverse effects - sympa NS activation
Phenylalkylamines (verapamil) - acts on the myocardial and smooth muscle membrane reducing Ca transport- causes vasodilation and reduces myocardial contractility adverse effects - constipation and bradycardia ( so cant be given beta blockers)
Benzothiazepines (Diltiazem) - acts on the myocardial and smooth muscle membrane reducing Ca transport
Causes - vasodilation and reduces myocardial contractility
Adverse effects - bradycardia and slight negative inotropy

Question 22

how are thiazide diuretics used to control BP ?

Answer 22

e.g indapamide , Bendroflumethiazide
reduce distal tubular sodium reabsorption by blocking NaCl symporter
reduces bp by reducing blood volume and then TPR
Adverse effects : hypokalaemia , increased urea and impaired glucose tolerance and increased cholestrol

Question 23

what are some other anti - hypertensive drugs

Answer 23

other diuretics - spironolactone (ARB) amiloride (k+ sparing)

Question 24

how do alpha blockers treat hypertension

Answer 24

e.g doxazosin
act via selective antagonism at post-synaptic a1 adrenoreceptors and antagonise the contractile effects of noradrenaline on vascular smooth muscle so reducing TPR
adverse effects - postural hypotension and oedema

Question 25

how do beta - blockers treat hypertension

Answer 25

e.g atenolol , bisoprolol, nebivolol antagonise the action of B1 - adrenoreceptors on the ventricular myocardium reducing HR and CO. inhibit renin release adverse effects : lethargy, bradycardia and raynauds

Question 26

what is aliskiren ?

Answer 26

direct renin inhibitor | binds to renin preventing cleavage of Ang1 --> Ang2

Question 27

what are centrally acting agents

Answer 27

these include methylodopa (potent a2 - adrenoreceptor agonist), clonidine (pre-synaptic a2 - adrenoreceptor agonist) or moxonidine (some a2 - adrenoreceptor agonism) all reduce sympathetic outflow to reduce bp adverse effects : lethargy , depression

Question 28

how is combination therapy used to treat hypertension

Answer 28

thiazide diuretics lower Bp but can raise glucose or lower K+ amiloride lowers bp but has no effect on glucose combination of two shall lower Bp and have no effect on glucose or K+

Question 29

describe heart failures aetiology and management

Answer 29

ischaemic heart disease, hypertension, cardiomyopathies (e.g alcohol) management : correct underlying cause pharmacological therapy diuretics ACEi, B blocker , Ivabradine and sacubtril ( increase natriuretic peptides), hydralazine, digoxin, inotropes and phosphodiesterase inhibitors lifestyle ; reduce salt and alcohol and increase exercise beta blockers reduce HR and Bp so reduces the heart workload. they also reduce mobilisation of glycogen

Question 30

how is mean arterial BP measured ?

Answer 30

Mean arterial BP = CO (SV X HR) X TPR

Question 31

describe short term regulation of BP

Answer 31

baroreceptor reflex. BP control for acute changes and can't sustain as the threshold for baroreceptor firing resets (accommodation) nerve endings in carotid sinus + aortic arch sensitive to stretch, increased arterial pressure increases stretch, increased firing of AP detected in medulla. Decreases sympathetic outflow so reduces HR, CO and TPR (bradycardia and vasodilatation). Vice versa for low BP

Question 32

describe long term regulation of BP

Answer 32

interaction of neuronal and hormonal responses which control Na + balance and therefore ECV : RAAS, sympathetic NS, ADH and natriuretic peptides hormonal response to low renal perfusion and to increase bp : RAAS, sympa NS, prostaglandins, ADH

Question 33

where is renin released from

Answer 33

granular cells of juxtaglomerular apparatus (JGA) of the afferent arteriole of the kidneys

Question 34

what are the factors that stimulate renin release

Answer 34

reduced NaCl delivery to distal tubule reduced perfusion pressure (blood volume) in the kidney, detected by baroreceptors in the afferent arteriole sympathetic stimulation decreased circulating volume stimulates renin release

Question 35

describe how renin stimulates Na+ reabsorption

Answer 35

Renin converts angiotensinogen to angiotensin 1 ACE converts angiotensin 1 to angiotensin 2 angiotensin 2 acts both directly on blood vessels causing vasoconstriction and also directly on kidneys to stimulate sodium reabsorption increasing blood volume and hence CO and Bp. Increases thirst in hypothalamus via ADH release from the pituitary Angiotensin 2 interacts with adrenal cortex to release aldosterone aldosterone increases Na reabsorption

Question 36

describe the nature of aldosterone receptors

Answer 36

two types of Ang II receptors - AT1 and AT2 main actions via AT1 receptor ; g protein coupled receptor there is vasoconstriction of efferent > afferent arteriole so enhanced Na+ reabsorption at the PCT

Question 37

what is the action of aldosterone on the kidney

Answer 37

acts in principal cells of collecting duct stimulates Na + and therefore water reabsorption via apical eNaC and ROMK also increases basolateral Na + excretion via Na/K/ATPase so bigger gradient for sodium to move in

Question 38

how does the sympathetic NS regulate BP

Answer 38

HIGH SNS activity decreases renal blood flow by vasoconstricting arterioles and decreasing GFR, so sodium excretion is decreased so blood pressure increases. stimulates renin release so increases Ang II, aldosterone and increases Na+ reabsorption. water follows so BP increases

Question 39

how does the introduction of prostaglandins regulate BP

Answer 39

causing vasodilation of the afferent arteriole so GFR increases. Produced by RAAS and SNS, decrease Na + reabsorption, important when Ang II is high

Question 40

describe how ADH can increase BP

Answer 40

ADH forms concentrate urine by retaining water to control plasma osmolarity - it increases water reabsorption through AQP2 and stimulates sodium reabsorption by acting on NAK2CL in thick ascending limb. released from posterior pituitary when there is high plasma osmolarity or severe hypovolaemia. causes vasoconstriction

Question 41

how does ANP reduce BP

Answer 41

acts via vasodilation of AA ( increases blood flow and thus GFR) and inhibits sodium reabsorption which causes natriuresis - sodium excretion in urine so would also lower BP

Question 42

what is hypertension defined as

Answer 42

a sustained increase in blood pressure which diastolic > 90 mmhg or systolic > 140 mmhg. often asymptomatic byt damages heart and vasculature so can lead to MI, stroke, HF primary - cause not definable may be genetic or environmental secondary - identifiable cause which needs treating

Question 43

what are examples of secondary hypertension

Answer 43

renal vascular disease : RA stenosis , fall in kidney perfusion, increased renin, RAAS activation, vasoconstriction and sodium retention, water follows and BP increases Renal parenchymal disease - early loss of vasodilation , later sodium and water retention due to inadequate glomerular filtration coarctation of the aorta adrenal causes : conns syndrome - aldosterone - secreting adenoma causing hypertension and hypokalaemia cushings syndrome - increased cortisol, acts on aldosterone receptors, sodium and water retention chronic kidney disease - inability to excrete excess salt and water due to reduced kidney function (reduced GFR), causing hypertension and oedema Nephrotic syndrome - massive proteinuria, hypoalbuminemia, oedema. often due to podocyte injury