Cardio renal L6

Question 1

the water-permeability of the collecting duct is under the control of …

Answer 1

the water-permeability of the collecting duct is under the control of ADH (antidiuretic hormone, otherwise known as vasopressin, arginine vasopressin or AVP).

Question 2

with out ADH - describe the permeability of the collecting duct - and how this facilitates dilute urine?

Answer 2

lack of ADH makes collecting duct impermeable.

Na+ actively pumped out, without water following = dilute urine

Question 3

Diuretics do what?

Answer 3

Diuretics cause an increase in urine output

Question 4

how do diuretics increase urine output?

Answer 4

All diuretic drugs increase Na+ excretion (this phenomenon is called ‘natriuresis’), as Na+ enters the lumen of the renal tubule water follows to maintain osmotic equilibrium

Question 5

bothdiuretics and drinking fack loads of water increase urinary output - whats the differnece?

Answer 5

drinking: urine = mainly water, solute excretion is not increased
diuretics: both solute and water excretion are increased

Question 6

overall end effect of diuretics?

Answer 6

As diuretic therapy leads to loss of Na+ and water, their effect is to reduce the volume of the body’s extracellular fluid (ECF) compartment.

This results in alleviation of oedema, reduction of blood volume, and as a result these drugs are useful in the treatment of heart failure and/or hypertension.

They can also be useful in maintaining kidney function in various renal diseases.

Question 7

The sites of action in the nephron of the different types of diuretic drugs

Answer 7

Question 8

where do loop diuretics act?

Answer 8

the loop of henle

Question 9

are loop diuretics powerful?

Answer 9

yes - called high ceiling diuretics as they can cause upto 4 litres per day of urine excretion

Question 10

2 main loop diuretics?

Answer 10

The main drugs are furosemide and bumetanide - they are sulphonamides (like some antibacterial drugs)

Question 11

how do loop diuretics work?

Answer 11

loop diuretics block Na+-K+-2Cl- co-transport in the apical (luminal) membrane of cells of the thick ascending limb

can cause 15-20% of filtrate to be excreted

very powerful

Question 12

diuretics are mainly used to treat ?

why?

Answer 12

acute heart failure

as well as diuresis furosemide also causes venodilation and thus reduces atrial filling pressure. This venodilator mechanism also increases the effect of furosemide on the nephron by increasing renal blood flow without a change in GFR, i.e. by decreasing the fraction of the blood flow that is filtered at the glomer

Question 13

give some problems with loop diuretics?

Answer 13

• continued administration can lead to hypokalaemia
• Concurrent metabolic alkalosis (as a result of increased H+ loss into filtrate partly as a result of enhanced Na+/H+ exchange and partly due to stimulated renal synthesis of NH3 and secretion as NH4+).
• Ca2+ and Mg2+ loss increased
• Uric acid excretion in urine is decreased - can lead to gout

Question 14

which are the most common Thiazide diuretics

Answer 14

hydrochlorothiazide and bendroflumethiazide.

Question 15

Like loop diuretics thiazides can produce some inhibition of ….

Answer 15

Like loop diuretics thiazides can produce some inhibition of carbonic anhydrase

Question 16

thiazide diuretics compared to high cieling diuretics?

Answer 16

They have a lesser effect than high-ceiling loop diuretics, but can still result

in the loss of 10 to 15% of the filtered load

Question 17

where do thiazide diuretics act?

Answer 17

act in the cortical segment of the thick ascending limb or in the distal tubule

Question 18

how do thiazide loop diruetics work

Answer 18

location: cortical segment of the thick ascending limb or in the distal tubule.

early distal tubule: by blocking Na+-Cl- cotransport, probably by binding at the Cl- site

Question 19

like loop diuretics, thiazides also have ______ effects.

Answer 19

like loop diuretics, thiazides also have vasodilator effects.

Question 20

describe gout?

Answer 20

The symptoms of gout result from excessive production of purines leading to deposition of sodium urate crystals in the synovial tissue of joints.

The condition is treated with probenecid, which competes for the same carrier as uric acid in the proximal tubule and thereby inhibits uric acid reabsorption.

Question 21

describe Diazoxide

Answer 21

Diazoxide is a non-diuretic thiazide which has vasodilator action.

It acts by opening ATP-sensitive K+ channels and is used as an antihypertensive- but only in hypertensive emergency.

Opening of ATP-sensitive K+ channels in pancreatic ß cells produces hyperpolarisation and inhibition of insulin release leading to a rise in blood glucose.

Thiazides increase blood glucose levels and this may reflect their ability to open ATP-K+ channels.

Question 22

Potential problems with thiazides?

Answer 22

• Hypokalaemia and metabolic alkalosis (as for furosemide)
• The average fall in plasma K+ is reported to be 0.7 mM. This is quite significant and would be a problem if thiazides were combined with cardiac glycosides in therapy for heart failure as described (under ‘ heart failure’) above, lower plasma K+ can potentiate action of cardiac glycosides, which compete with K+ for binding to the Na+/K+-pump
• Thiazides increase Mg2+ excretion, but decrease that of Ca2+
• Uric acid excretion is also decreased

Question 23

Thiazides _______ Mg2+ excretion, but _______ that of Ca2+

Answer 23

Thiazides increase Mg2+ excretion, but decrease that of Ca2+

Question 24

give the main drugs in Potassium-sparing diuretics

Answer 24

amiloride, triamterene and spironolactone

Question 25

As their name implies Potassium sparing diuretics do not have the side-effect of ______ loss that occurs with loop diuretics and thiazides

Answer 25

As their name implies these drugs do not have the side-effect of **potassium** loss that occurs with loop diuretics and thiazides

Question 26

potasssium sparing diuretics depend on the fact that ...

Answer 26

t in the late distal tubule Na+ enters cells through a channel in the apical membrane, down the concentration gradient generated by the Na+-K+ ATPase pump in the basolateral membrane. K+ or H+ are drawn into the lumen by the potential gradient across the apical membrane (which in turn is created by Na+ movement). This is a major site of K+ loss into the urine.

Question 27

how do Amiloride and triamterene work?

Answer 27

Amiloride and triamterene prevent Na+ reabsorption by blocking apical trimeric Na+ channels

Question 28

how do ## Footnote Spironolactone and canrenone work?

Answer 28

Spironolactone and canrenone act as antagonists of the action of aldosterone. block aldosterone = decreased membrane sodium conductance

Question 29

can Potassium-sparing diuretics be used with thiazides or loop diuretics to counteract hypokalaemia?

Answer 29

yep!

Question 30

Spironolactone is metabolised to _______ in the liver.

Answer 30

Spironolactone is metabolised to canrenone in the liver.

Question 31

how does aldosterone increase apical membrane sodium conductance?

Answer 31

The release of aldosterone is induced by angiotensin II (see below). Aldosterone migrates across the cell membrane into the cell and there combines with the cytoplasmic steroid receptor. The whole complex is translocated to the nucleus where it leads to synthesis of Na+ channels and Na+-K+ ATPase pumps.

Question 32

The effect of spironolactone is only significant when distal tubule cells are under the influence of \_\_\_\_\_\_.

Answer 32

The effect of spironolactone is only significant when distal tubule cells are under the influence of aldosterone.

Question 33

why is the rate of onset for spironolactone so slow?

Answer 33

Because the mechanism depends on the turnover of Na+ channels, the rate of onset of diuresis produced by spironolactone is slow.

Question 34

Carbonic anhydrase inhibitors: give a major example

Answer 34

Acetazolamide

Question 35

The carbonic anhydrase inhibitors were the first diuretics to be introduced but are now, to all intents and purposes \_\_\_\_\_\_.

Answer 35

The carbonic anhydrase inhibitors were the first diuretics to be introduced but are now, to all intents and purposes obsolete.

Question 36

how do carbonic anhydrase inhibitors work?

Answer 36

* work only in proximal tubule * Carbonic anhydrase inhibitors decrease the availability H+ in the cell * This is because 33% of proximal tubule Na+ reabsorption occurs in exchange for H+ (through the Na+-H+ antiporter) * The urine pH rises as HCO3- content is increased (Na+ excreted as the major counterion)

Question 37

It is necessary to block more than \_\_\_% of carbonic anhydrase to produce an appreciable effect.

Answer 37

It is necessary to block more than 99% of the enzyme to produce an appreciable effect.

Question 38

carbonic anhydrases are still used to treat what?

Answer 38

1. glaucoma is a result of raised intraocular pressure which can lead to blindness. The carbonic anhydrase inhibitors suppress HCO3- secretion, which is part of the process of formation of aqueous humour in the eye. 2. Acetazolamide can be used to help acclimatisation to high altitudes and can guard against mountain sickness and help to alleviate sleep apnoea that can occur at high altitudes.

Question 39

T o rF ## Footnote he actions of carbonic anhydrase inhibitors are self-limiting because excess HCO3- loss results in metabolic acidosis.

Answer 39

True

Question 40

classic example of osmotic diuretics?

Answer 40

mannitol

Question 41

are osmotic diuretics the simplest?

Answer 41

in their action, yes

Question 42

how do osmotic diuretics work

Answer 42

1. Low molecular weight substances filtered at the glomerulus, but not reabsorbed 2. They retain their osmotic equivalent of water and so increase urine volume. 3. They decrease Na+ reabsorption in the proximal tubule as concentration is lowered 4. Acutely mannitol rapidly reduces intracranial and intraocular pressure and so is useful in cerebral oedema

Question 43

does mannitol cross the BBB?

Answer 43

no

Question 44

why are diuretics useful for treating hypertension?

Answer 44

Their effectiveness in hypertension is because blood pressure is a function of the cardiac output and the total peripheral resistance. If either of these factors is altered, the blood pressure changes in the same direction. A reduction in circulating fluid volume reduces blood pressure.

Question 45

lebel the control of BP diagrma:

Answer 45

Question 46

BP diagram label

Answer 46

Question 47

Aldosterone is secreted from the ....

Answer 47

Aldosterone is secreted from the zona glomerulosa of the adrenal cortex.

Question 48

Renin release is induced by ....

Answer 48

Renin release is induced by a reduction in perfusion pressure to the kidneys and by sympathetic nerve stimulation

Question 49

Renin is released from cells of the ....

Answer 49

Renin is released from cells of the juxtaglomerular apparatus as a result of the rise in intracellular cAMP

Question 50

Sympathetic stimulation of the juxtaglomerula apparatus causes....

Answer 50

Sympathetic stimulation causes a rise in cAMP and of renin release

Question 51

Renin release is reduced by....

Answer 51

Renin release is reduced by **adenosine**, **atrial natriuretic peptide (ANP)** and by negative feedback by **angiotensin II**

Question 52

Answer 52

Question 53

describe ACE inhibitors

Answer 53

Antagonism of the renin-angiotensin system is mainly achieved by ACE inhibitors.

Question 54

ACE inhibitor exmaples?

Answer 54

common examples are ramipril, followed by lisinopril and perindopril (the latter a pro-drug)

Question 55

Saralasin - what does it do?

Answer 55

Saralasin is an angiotensin II partial agonist , but it is a peptide and so not suitable for oral administration and so is not really competitive with other antihypertensive drugs.

Question 56

T or F ## Footnote Some people cannot tolerate ACE inhibitors

Answer 56

T

Question 57

what losartan?

Answer 57

Non-peptide angiotensin II antagonists which works on the AT1 angiotensin II receptor)

Question 58

descibe what AT2 receptors do?

Answer 58

Activation of AT2 receptors causes vasodilatation by generation of nitric oxide with a subsequent increase in cGMP, and binding of angiotensin II to AT2 receptors inhibits, in certain cells, proliferation, mediates differentiation in neural tissue, and can induce apoptosis.

Question 59

ACE inhibitors are almost always combined with ....

Answer 59

ACE inhibitors are almost always combined with diuretics.

Question 60

cardiovascular role of AT2 receptors?

Answer 60

insifnificant

Question 61

ACE inhibitors are used for ....

Answer 61

ACE inhibitors are used for hypertension and congestive heart failure

Question 62

Theoretically ACE inhibitors should be of most benefit in heart failure associated with ____ renin levels.

Answer 62

Theoretically they should be of most benefit in heart failure associated with high renin levels.

Question 63

For treatment of heart failure ACE inhibitors _______ pre- and afterload

Answer 63

For treatment of heart failure ACE inhibitors decrease pre- and afterload

Question 64

T or F ## Footnote the failing heart leads to activation of renin-angiotensin system

Answer 64

T

Question 65

ACE inhibitors are almost always combined with .....

Answer 65

ACE inhibitors are almost always combined with diuretics. The reduction in aldosterone should, in principle, help to avoid hypokalaemia

Question 66

why is hypotension dangerous wiht any ACE inhibitor?

Answer 66

Hypotension is dangerous with any ACE inhibitor, since the risk of renal failure is increased by the blockade of glomerular efferent arteriolar constriction which is normally mediated by angiotensin II.

Question 67

net result for ACE inhibitors

Answer 67

The net result is a reduction in vascular resistance, not blood pressure (a compensating increase in cardiac output tends to maintain blood pressure)

Question 68

Aliskiren.... does hwat\>

Answer 68

Aliskiren is a renin inhibitor

Question 69

Angiotensin II and angiotensin III exhibit\_\_\_\_\_\_\_ affinity(s) for type 1 and type 2 angiotensin II receptors (AT1 and AT2)

Answer 69

Angiotensin II and angiotensin III exhibit the same affinity for type 1 and type 2 angiotensin II receptors (AT1 and AT2)

Question 70

Intracerebroventricular injection of either Angiotensin II or III causes ....

Answer 70

Intracerebroventricular injection of either peptide causes a similar increase in vasopressin release and blood pressure

Question 71

In vivo, angiotensin II is converted to angiotensin III (by the action of ....

Answer 71

In vivo, angiotensin II is converted to angiotensin III (by the action of **brain aminopeptidase A)**

Question 72

Angiotensin IV acts in the....

Answer 72

Angiotensin IV acts in the brain, where it seems to be involved in learning, memory and long-term potentiation

Question 73

where are AT4 receptors located?

Answer 73

AT4 receptors are located widely, not just in the brain and their activation has been proposed as a strategy for memory enhancement, particularly in Alzheimer’s disease.

Question 74

describe Bradykinin

Answer 74

Bradykinin is a short peptide released from various cells Bradykinin is a potent natriuretic agent and a renal vasodilator Bradykinin is degraded by angiotensin converting enzyme

Question 75

If very high Na+ reaches the distal tubule, then ________ is released, bradykinin is formed from kinogen and Na+ reabsorption inhibited

Answer 75

If very high Na+ reaches the distal tubule, then kallikrein is released, bradykinin is formed from kinogen and Na+ reabsorption inhibited

Question 76

Under normal physiological conditions the role of the kallikrein-kinin system may be \_\_\_\_\_\_\_,

Answer 76

Under normal physiological conditions the role of the kallikrein-kinin system may be minimal,

Question 77

Bradykinin - other effects?

Answer 77

Bradykinin is an inflammatory mediator and nociceptive agent most pain inducing agent known

Question 78

might bradykinin be the cause of ACE inhibitors bad side effects?

Answer 78

It may be that cause of the ‘dry cough' seen with some ACE inhibitors

Question 79

do ACE inhibitors lead to bradykinin buildup?

Answer 79

yes

Question 80

ANP is released from ______ in response to ....

Answer 80

ANP is released from heart in response to atrial stretch

Question 81

ANP acts via?

Answer 81

It acts via a membrane-bound guanylate cyclase (GC-A) receptor to form cGMP

Question 82

Responses to ANP are directed towards?

Answer 82

Responses are directed towards a reduction of blood pressure and blood volume (i.e. the reverse of those of the renin-angiotensin system

Question 83

t or F ## Footnote ANP is a directly-acting vasodilator, and it also reduces release of noradrenaline.

Answer 83

T

Question 84

ANP stimulates diuresis and natriuresis by increasing GFR and inhibition of Na+ absorption in the collecting duct.

Answer 84

T

Question 85

does ANP inhibit renin releasE?

Answer 85

yep

Question 86

drugs influencing ANP?

Answer 86

There are no useful drugs acting to influence ANP (or its receptors) and there is no clear evidence that a defect of this system is involved in any form of hypertension, but mice lacking the GC-A gene are hypertensive (which is not made worse by a high-salt diet).

Question 87

fat

Answer 87

mamba