ANTIDIURETIC HORMONE (ADH, AVP, VASOPRESSIN)

ANTIDIURETIC HORMONE by  Ray I. Ozolua

    Definition

    This refers to the basic physiology and site of synthesis. It differs from oxytocin only in the amino acids at positions 3 and 8, both being made up of 9 amino acids.

     Factors that influence release of ADH

    i) Hyperosmolality of plasma (say beyond 290 mOsm/kg) cause release.

    ii) Hypovolaemia and hypotension regardless of the cause (such as haemorrhage, sodium depletion,diuresis, heart failure, hepatic cirrhosis with ascites and use of antihypertensive drugs.

    Hormones and neurotransmitters: Release can be accentuated or attenuated by several agents. ACh,(via nicotinic receptors), histamine (via H1), dopamine via D1 and D2), substance P, PGs, and angiotensin II, all cause release. Inhibitors include ANP, GABA, and dynorphin (via κ). These influences derive from the supraoptic and/or the paraventricular nuclei.

    iii) Drugs: These may influence one or more of the CNS structures or by direct alteration in haemodynamics. Vincristine, nicotine, cyclosphosphamide, adrenaline and high doses of morphine stimulate release. Li+ inhibits renal effect of ADH but enhances its release. Inhibitors of release include ethanol, phenytoin, low dose of morphine, glucocorticoids, fluphenazine, haloperidol,promethazine, and butorphanol. Carbamazepine has anti-diuretic effect by increasing ADH release.

    In the kidneys, ADH increases the permeability of the cortical and medullary segments leading to reabsorption of water by osmotic processes. Consequently, the osmolality of the urine is increased significantly.

    Other actions of ADH

    1. CVS: Vasoconstriction occurs at doses in excess of what may be required for maximal antidiuresis. Pressor effect involves all vascular beds. It may help in the maintenance of vascular tone and may also contribute to vascular resistance in CHF although there is as yet no convincing evidence for the role of ADH in human hypertension. In the heart, patientsn with coronary insufficiency may suffer from vasoconstrictive responses. It can also produce positive inotropic effects.

    2. BLOOD: It stimulates aggregation and degranulation of platelets. It increases the plasma concentration of factor VIII and von Willebrand’s factor.

    3. PITUITARY: It can cause the release of ACTH

    4. CNS: Neuromodullatory and possibly a neurotransmitter.

    Aside from all these, ADH may promote cortisol release, function as an antipyretic and hasten the breakdown of glycogen in liver cells.

    Two types of receptors have been described (see fig. 3): V1 and V2. V1 now has subtypes V1a and V1b. The V1a receptors are located on vascular smooth muscle cells, hepatocytes, platelets, adrenal gland, the bladder, myometrium, and the vasa recta. V1b receptors are found in the adenohypophysis and the adrenal medulla. V1 receptors are coupled to G-proteins leading to the production of IP3 and DAG both of which enhance Ca2+ mobilisation. 

    There is also the activation of PLD via Ca2+ and protein kinase C leading to phosphorylation of key proteins. Activation of PLA2 leads to metabolism of arachidonic acid. In all,biological effects mediated through V1 receptors include: vasoconstriction, glycogenolysis, platelet aggregation, ACTH release, and growth of vascular smooth muscle cells.

    V2 receptors are however located predominantly in the principal cells of the renal collecting duct system.

    These receptors are coupled to adenylate cyclase leading to the production of cAMP. Activation of cAMPmediated protein kinase (Protein kinase A) mediates the hydroosmotic effects of ADH. There is increased production of aquaporins in the renal collecting ducts.

    The half-life of circulating ADH is 17 – 35 minutes. As a drug, it may be given, i.v., i.m., or s.c. or by nasal sprays. Effects are usually brief and when desired a depo-preparation which effect lasts 48 – 96 hours may be given i.m.

    There are different preparations with alterations in the amino acids and consequently in the selectivity for

    either V1 or V2.


    Immediate Responses

    Figure 1. Schematic representation of the mechanisms involved in the actions of ADH. V1, V2, vasopressin receptors;

    phospholipase A; PLC, phospholipase C; PLD, phospholipase D; IP3, inositol-1,4,5-triphosphate; DAG, diacylglycerol; AA,arachidonic acids; PGs, prostaglandins; LTs, leukotrienes; cAMP, cyclic adenosine monophosphate.

    Medical Uses of Antidiuretic Hormone(ADH)

    1. ADH-sensitive (central or neurogenic) diabetes insipidus. Nephrogenic diabetes insipidus can be managed (paradoxically) by use of thiazides

    2. Nocturnal eneuresis

    3. As an adjunct in the treatment of bleeding oesophageal varices, acute haemorrhagic gastritis and

    during abdominal surgery in patients with portal hypertension.

    4. As a prophylactic treatment of haemophilia.

    Side Effects

    Side effects include marked facial pallor in large doses, increased GIT activity, which may lead to nausea,belching and cramps, and an urge to defecate and uterine cramps in women. Urticaria, allergic rash and water intoxication are possible. Most serious of all is effect on coronary circulation and only very low doses if a must should be used in patients with cardiac problems.

    Preparations

    i. Vasopressin injection (PITRESSIN) is a synthetic derivative.

    ii. Desmopressin acetate is an aqueous solution and may administer intranasally.

    iii. Lyspressin (8-lysyl vasopressin) may also be given intranasally.

    iv. Vasopressin tannate (Pitressin tannate in oil) is available as intramuscular injection.

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