Antidiuretics (Dr. Shivani Sainani's slides), explained simply

1. What are antidiuretics? (Page 2)

• "Diuresis" means making urine. Antidiuretics reduce the amount of urine.
• Their main use is diabetes insipidus (DI). In DI, the body can't hold on to water, so the person passes huge amounts of dilute urine and is always thirsty.
• They are really "anti-aquaretics". They stop the body from losing water but don't change how much salt is lost.

1. Hormone-based: ADH (vasopressin), desmopressin, lypressin, terlipressin
2. Thiazide diuretics and amiloride. These are odd because diuretics usually increase urine. In DI they reduce urine volume indirectly.
3. Miscellaneous: indomethacin, chlorpropamide, carbamazepine

2. What is ADH? How is it made? (Page 3)

• Human ADH is 8-arginine-vasopressin (AVP).
• Lypressin is the pig version (8-lysine-vasopressin). It is now made synthetically.
• ADH is a nonapeptide, meaning a small protein of 9 amino acids.
• It is released by the posterior pituitary along with oxytocin.
• It is made in nerve cell bodies of the hypothalamus (supraoptic and paraventricular nuclei). It is made as a large precursor together with a carrier protein called neurophysin.
• Both travel down the nerve fibres to the nerve endings (median eminence and pars nervosa). From there ADH is released into the blood.

3. What controls ADH release? (Page 4)

• Osmoreceptors in the hypothalamus sense how concentrated the blood is.
• Volume receptors in the left atrium, ventricles and pulmonary veins sense how much fluid is in the body.
• Osmoreceptors in the liver's portal system sense salt you have just eaten. They release ADH early, before blood concentration actually rises.
• Baroreceptors (pressure sensors) and higher brain centres also affect ADH release.
• The two main triggers for ADH release are:
  • Rise in plasma osmolarity (blood becomes too concentrated)
  • Fall in extracellular fluid volume (dehydration or blood loss)

4. ADH receptors (Pages 5 to 8)

V1 receptors (Pages 6 and 7)

• They are found almost everywhere except the kidney collecting duct cells, the ascending limb of the loop of Henle (AscLH), and the blood vessel lining.
• V1a is on blood vessel smooth muscle, uterus and other smooth muscle, brain, platelets, liver and fat tissue.
• V1b is on the anterior pituitary, parts of the brain and the pancreas.
• How V1 works: it uses the phospholipase C pathway. This makes IP3 and DAG, which raise intracellular calcium and activate protein kinase C.
• Results: blood vessel constriction, smooth muscle contraction, glycogen breakdown in the liver, platelet clumping and ACTH release.
• V1 also activates phospholipase A2. This produces arachidonic acid and then prostaglandins, which add to these effects.
• Long-term V1 stimulation turns on growth genes. This thickens and enlarges (hypertrophy) the blood vessel muscle.

V2 receptors (Page 8)

• They are mainly on the principal cells of the kidney collecting duct. They raise cAMP, which makes the duct permeable to water.
• Some are on AscLH cells, where they activate the Na⁺-K⁺-2Cl⁻ cotransporter.
• Some are on blood vessel lining, where they cause vasodilation.
• V2 receptors are more sensitive than V1. They respond to very low ADH levels, so a small amount of ADH is enough to concentrate urine.

5. Actions of ADH

Kidney (Pages 9 to 11)

• ADH makes collecting duct cells permeable to water. Water moves out of the duct into the salty (hyperosmolar) kidney medulla and goes back into the body.
• The most concentrated urine a person can make is about 4 times the concentration of plasma.
• Without ADH: the duct stays waterproof and the person passes dilute urine.
• At low ADH levels the effect is graded, so urine volume matches fluid intake.

1. Vesicles carrying aquaporin-2 water channels move to the cell surface and fuse in. This is the main reason urine is reduced.
2. The removal of aquaporin-2 channels from the surface is blocked, so they stay longer.
3. A urea transporter (VRUT) is activated in the inner medulla. This helps keep the medulla salty.
4. The Na⁺-K⁺-2Cl⁻ cotransporter moves to the cell surface in the thick ascending limb.
5. That cotransporter is activated. More salt reabsorption keeps the medulla concentrated.
6. V1a receptors constrict the vasa recta (the kidney's medullary blood vessels). This stops the medullary concentration from being washed away.

Blood vessels (Page 12)

• AVP narrows blood vessels through V1 and can raise blood pressure. That is where the name vasopressin comes from.
• This needs much higher doses than the dose needed to reduce urine.
• Vessels in the skin, gut, skeletal muscle, fat, thyroid and heart are narrowed most.
• This doesn't seem important in normal life. It may matter in heart failure, bleeding and low blood pressure states.
• Long exposure thickens the vessel muscle.
• V2 vasodilation appears if V1 is blocked, or if desmopressin is used. It works by releasing nitric oxide (NO) from the vessel lining.

Other actions (Page 13)

• Gut: smooth muscle contracts and the bowel moves more, especially the large bowel. This can cause an urge to pass stool and gas.
• Uterus: AVP acts on oxytocin receptors and contracts the uterus. In non-pregnant women and early pregnancy it is as strong as oxytocin. Only near full term does the uterus become more sensitive to oxytocin.
• Brain: AVP given as a drug does not cross the blood-brain barrier. The brain also makes its own AVP as a neurotransmitter. It may play a role in temperature control, circulation, ACTH release and learning.
• Liver: it breaks down glycogen.
• Clotting: it releases factor VIII and von Willebrand factor from the blood vessel lining, and platelets clump.

6. Pharmacokinetics (Page 14)

• Not taken by mouth. It is destroyed by trypsin in the gut. It is given by injection (IV, IM or SC) or as a nasal spray.
• It is rapidly broken down, mainly in the liver and kidney. Its plasma half-life is only about 25 minutes, but the effect of aqueous vasopressin lasts 3 to 4 hours.
• The brand shown is Postacton 10 U injection.

7. Uses (Pages 15 and 16)

8. Adverse effects, contraindications and precautions (Page 17)

• Desmopressin has fewer side effects than vasopressin, lypressin or terlipressin because it is V2-selective. Short-lived headache and flushing are still common.
• Local (nasal use): irritation, congestion, runny nose, ulcers and nosebleeds.
• General: belching, nausea, stomach cramps, pallor, urge to pass stool, and backache in women (from uterine contraction).
• Water retention and low blood sodium (hyponatraemia) can develop.
• Contraindications: AVP slows the heart rate, increases the heart's workload and narrows coronary vessels, which can trigger angina. Avoid it in:
  • Ischaemic heart disease
  • Hypertension
  • Chronic nephritis
  • Psychogenic polydipsia (compulsive water drinking)
• Precaution: allergies such as hives can occur with any preparation.

Quick memory summary

• V1 is for Vessels. It causes constriction and bleeding control.
• V2 is for Water (kidney) and also works on clotting factors. It causes less urine, less bedwetting and DI control.
• ADH works by inserting aquaporin-2 water channels into the collecting duct.
• ADH is destroyed when swallowed, so use injection or nasal spray, or oral desmopressin.
• The main danger is water retention with low sodium, plus heart problems with vasopressin.