Volume regulators

Question 1

Diuretics: definition, different types

Answer 1

Medications that act on the kidneys to increase production of urine
There are five main types:
- carbonic anhydrase inhibitors
- osmotic diuretics
- thiazide & thiazide- like diuretics
- loop diuretics
- K+ sparing diuretics
For diuretics, the therapeutic class is limited to those affecting volemia but acting directly on the nephron. Thus ACE ihibitors are not classified as diuretics

Question 2

Digoxin

Answer 2

Act on the alpha 2 and 3 of Na/K pump, which are mainly expressed in the heart. (Alpha 1 isoform mostly in the nephron)

Question 3

Osmotic diuretics

Answer 3

E.g. Mannitol
Do not have a specific target. They are easily filtered through the glomerulus and act as osmolites in the tubules.
Indications: brain edema, crushing syndromes (rhabdomyolysis)
Side effect: hypernatremia

Question 4

Carbonic anydrase inhibitors

Answer 4

Inhibit CA at the proximal tubule. Inhibiting the absorption of sodium and bicarbonate.
Not a strong diuretics due to compensatory mechanisms present in the distal portion.
Indications: glaucoma, edema when there is also alkalosis.
Side effects: hyperchloremia, calcium phosphate stones, acidosis, hyperammonia, hypokalemia, drowsiness and peripheral neuropathy.
Examples: acetazolamide, brinzolamide, dorzolamide.

Question 5

Loop diuretics

Answer 5

Block the na/k/cl symporter on the apical side of the thick ascending loop of Henle. They are very efficacious.
Examples: furosamide (lasix) – a reversible blocker of the transporter. Etacrynic acid is of the same therapeutic class of furosemide, less potent.
Indications: acute conditions as pulmonary edema, brain edema, immediately after myocardial infarcion to hypervolemia, most severe forms of heart failure. In cirrhotic patients (ascites – portal hypertension and reduced albumin).
Side effects: hypocalcemia, low Mg, hypokalemia

Question 6

Thiazide diuretics

Answer 6

Inhibition of Na+/Cl- cotransporters in the distal convoluted tubule → ↑ excretion of Na+ (saluresis) and Cl- → ↑ excretion of potassium (kaliuresis) → diuresis.
Indications: hypertension
Very important in fixed combinations with other anti-hypertensive like ACE inhibitors, statins, and beta-blockers
Side effects: accumulation of uric acid, photo-sensitivity, potentially tumorigenic

Question 7

K sparing diuretics

Answer 7

Drugs acting on aldosterone receptor or on ENaC (Amiloride).

Not powerful on their own, usually given in combination with other diuretics.

Question 8

Aldosterone antagonists

Answer 8

Intefere with the activity of principal cells. K+ sparing diuretics.
Competitively bind to aldosterone receptors in the late distal tubule and the collecting duct → inhibit effects of aldosterone → decreased Na+ reabsorption and K+ excretion → diuresis
Spironolactone: not specific, also acts (nonspecifically) on sex hormone receptors → endocrine side effects (-> skin problems and beard in women)
→ spironolactone is no more used
Eplerenone: more specific, used nowadays

Question 9

ADH agonists

Answer 9

ADH causes aquaporins exocytosis, their insertion in the PM.
Agonists can be used against nocturnal enuresis, the bladder is emptied. But the patient can drink after having taken the drug, otherwise risk of brain edema.

Question 10

Aldosterone action

Answer 10

Regulates ENaC and Na/K pump (alpha 1 isoform). It increases the transcrition of ENaC, leading to an increased expression of this channel. Since it is a genomic regulation, it takes time.
Increased activity of na/K pump.
When this mechanism is forced, an excess of potassium is released, leading to hypokalemia.

Question 11

RAAS

Answer 11

Renin Angiotension Aldosterone System
Angiotensinogen is produced by the liver and converted by renin in angiotensin I. Renin is produced by juxtaglomerular cells. The angiotensin I is converted to angiotensin II by ACE. 2 Forms of ACE:
- Anchored on the PM of the endothelial cells in the general circulation. Endothelial cells of pulmonary vessels express a lot of ACE
- Circulating

Question 12

Mechanism of renin release

Answer 12

3 mechanisms:

• Baroreceptor mechanism: increased pressure in afferent arteriole inhibits renin release from JG cells, decreased pressure promotes renin release
• Sympathetic nerve mechanism: B1 adrenergic nerves stimulates renin release
• Macula densa mechanim: increase NaCl in distal nephron inhibits renin release; decreased load promotes renin release

Question 13

Angiotensin II action

Answer 13

• Altered peripheral resistance
• Altered renal function
• Altered CV structure

Question 14

NSAIDs on urine formation

Answer 14

NSAIDs block prostaglandins production (they normally induce dilation of afferent arterioles) which lead to an important decrease in urine formation

Question 15

ACE inhibitors are appropriate in primary or secondary hypertension

Answer 15

in primary hypertension.

In case of secondary hypertensionusing an ACE inhibitors could induce renal insufficiency

Question 16

Angiotensin II receptors

Answer 16

Type 1 are involved in most regulatory processes. Main target of ATII R inhibitors.
Type 2 not clearly defined.
All couples PLC, leading to an increase in Ca2+ levels -> SMC contraction -> vasoconstriction

Question 17

ACE inhibitors use, actions, adverse effect

Answer 17

Disease-modifying drugs. Mostly used in HT and HF. Also immediately after a MI.

• Direct action on BP
• Inhibition of kininase II (inactivator of bradykinin that would lead to vasodilation)

Adverse effect: cough, hypotension, angioedema, acute renal failure, hyperkalemia

Question 18

Sartans

Answer 18

Block AT1 which are responsible for vasoconstriction.
Prototype: losartan
Pregnancy is a contraindication.
No coughing.