Vasopressin and its pharmacology

Pharmacology of vasopressin

1. Vasopressin and other agents affecting the renal conservation of water Presented by: Yasmeen Mir M. Pharm ist year ( Pharmacology-II) Roll no.:18155110001

2. Contents Physiology (including anatomical considerations; the synthesis, transport, and storage of vasopressin; and the regulation of vasopressin secretion), Chemistry (including the chemistry of vasopressin agonists and antagonists), Basic pharmacology (including vasopressin receptors and their signal-transduction pathways, renal actions of vasopressin, pharmacological modification of the antidiuretic response to vasopressin, and nonrenal actions of vasopressin), Diseases affecting the vasopressin system (diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, and other water-retaining states), and Clinical pharmacology of vasopressin peptides (therapeutic uses, pharmacokinetics, toxicities, adverse effects, contraindications, and drug interactions).

3. Precise regulation of body fluid osmolality is essential. It is controlled by a finely tuned, intricate homeostatic mechanism that operates by adjusting both the rate of water intake and the rate of solute-free water excretion by the kidneys— i.e., water balance. Abnormalities in this homeostatic system can result from genetic, acquired diseases, or may cause serious and potentially life-threatening deviations in plasma osmolality. With the emergence of life on land, vasopressin became the mediator of a remarkable regulatory system for the conservation of water. The hormone is released by the posterior pituitary whenever water deprivation causes an increased plasma osmolality or whenever the cardiovascular system is challenged by hypovolemia and/or hypotension. In amphibians, the target organs for vasopressin are skin and the urinary bladder, whereas in other vertebrates, including humans, vasopressin acts primarily in the renal collecting duct. It increases the permeability of the cell membrane to water, thus permitting water to move passively down an osmotic gradient across skin, bladder, or collecting duct into the extracellular compartment.

4. Anatomy It involves two anatomical components: CNS component for the synthesis, transport, storage, and release of vasopressin Renal collecting-duct system composed of epithelial cells that respond to vasopressin by increasing their permeability to water. The CNS component ( hypothalamiconeurohypophyseal system) consists of neurosecretory neurons with perikarya located predominantly in two specific hypothalamic nuclei, the supraoptic nucleus (SON) and the paraventricular nucleus (PVN). The long axons of magnocellular neurons transverse the external zone of the median eminence to terminate in the neural lobe of the posterior pituitary (neurohypophysis ), where they release vasopressin and oxytocin. In addition, axons of parvicellular neurons project to the external zone of the median eminence and release vasopressin directly into the pituitary portal circulation. Source;Kovacs , L., and Robertson, G.L. Syndrome of inappropriate antidiuresis. Endocrinol . Metab . Clin . North Am., 1992, 21:859–875.

5. Synthesis Synthesized mainly in the perikarya of magnocellular and Parvicellular neurons in the SON and PVN. Vasopressin synthesis appears to be regulated solely at the transcriptional level. In human beings, a 168–amino acid preprohormone is synthesized, and a signal peptide (residues –23 to –1) ensures incorporation of the nascent polypeptide into ribosomes. During synthesis, the signal peptide is removed to form the vasopressin prohormone, which then is processed and incorporated into the Golgi compartment and then into membrane-associated granules. The prohormone contains three domains: vasopressin (residues 1 to 9), vasopressin (VP)–neurophysin (residues 13 to 105), (sometimes referred to as neurophysin II or MSEL–neurophysin) and VP– glycopeptide (residues 107 to 145) (sometimes called copeptin). The vasopressin domain is linked to the VP– neurophysin domain through a glycine–lysine– arginine–processing signal , and the VP–neurophysin is linked to the VP–glycopeptide domain by an arginine processing signal . In the secretory granules, an endopeptidase, exopeptidase, monooxygenase, and lyase act sequentially on the prohormone to produce vasopressin The synthesis and transport of vasopressin depend on the conformation of the preprohormone. In particular, VP– neurophysin binds vasopressin and is critical to the correct processing, transport, and storage of vasopressin. Genetic mutations in either the signal peptide or VP– neurophysin give rise to central diabetes insipidus.

6. Transport and Storage The process of axonal transport of vasopressin- and oxytocin-containing granules is rapid, and these hormone- laden granules arrive at their destinations within 30 minutes, ready for release by exocytosis when the magnocellular or parvicellular neurons are stimulated appropriately. Maximal release of vasopressin occurs when impulse frequency is approximately 12 spikes per second for 20 seconds. Higher frequencies or longer periods of stimulation lead to diminished hormone release (fatigue). Appropriately, vasopressin-releasing cells demonstrate an atypical pattern of spike activity characterized by rapid phasic bursts (5 to 12 spikes per second for 15 to 60 seconds) separated by quiescent periods (15 to 60 seconds in duration). This pattern is orchestrated by activation and inactivation of ion channels in the magnocellular neurons and provides for optimal release of vasopressin. Vasopressin Synthesis Outside the CNS . Heart (Hupf et al., 1999) and adrenal gland (Guillon et al., 1998). In the heart, elevated wall stress increases vasopressin synthesis. Cardiac synthesis of vasopressin is predominantly vascular and perivascular and may contribute to impaired ventricular relaxation and coronary vasoconstriction. Vasopressin synthesis in the adrenal medulla stimulates catecholamine secretion from chromaffin cells and may promote adrenal cortical growth and stimulate aldosterone synthesis.

7. Regulation of Vasopressin Secretion . Increase in plasma osmolality Severe hypovolemia/hypotension Pain, nausea, and hypoxia Several endogenous hormones and pharmacological agents can modify vasopressin release Source; Goodman Gillman, the pharmacological basis, 11 th edition, page no. 773

8. The osmolality threshold for secretion is approximately 280 mOsm/kg. Below the threshold, vasopressin is barely detectable in plasma, and above the threshold, vasopressin levels are a steep and relatively linear function of plasma osmolality. A small increase in plasma osmolality leads to enhanced vasopressin secretion. Indeed, a 2% elevation in plasma osmolality causes a two- to three fold increase in plasma vasopressin levels, which, in turn, causes increased solute-free water reabsorption, with an increase in urine osmolality Increases in plasma osmolality above 290 mOsm/kg lead to an intense desire for water(thirst).

9. Several CNS structures are involved in osmotic stimulation of vasopressin release by the posterior pituitary; these structures are collectively referred to as the osmoreceptive complex . The SON and PVN receive projections from the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) either directly or indirectly via the median preoptic nucleus (MnPO). Subgroups of neurons in the SFO, OVLT, and MnPO are either osmoreceptors or osmoresponders (i.e., are stimulated by osmoreceptive neurons located at other sites). Thus a web of interconnecting neurons contributes to osmotically induced vasopressin secretion.

10. Aquaporin 4 , a water-selective channel, is associated with CNS structures involved in osmoregulation and may confer osmosensitivity. In the CNS, aquaporin 4 resides on glial and ependymal cells rather than on neurons, suggesting that osmotic status may be communicated to the neuronal cell by a glial–neuron interaction (Wells, 1998). Source;Wells , T. Vesicular osmometers , vasopressin secretion and aquaporin-4: A new mechanism for osmoreception ? Mol. Cell. Endocrinol ., 1998, 136:103–107.

11. Hepatic Portal Osmoreceptors . An oral salt load activates hepatic portal osmoreceptors leading to increased vasopressin release. Hypovolemia and Hypotension. Regardless of the cause (e.g., hemorrhage, sodium depletion, diuretics, heart failure, hepatic cirrhosis with ascites, adrenal insufficiency, or hypotensive drugs), reductions in effective blood volume and/or arterial blood pressure may be associated with high circulating concentrations of vasopressin. However, unlike osmoregulation, hemodynamic regulation of vasopressin secretion is exponential; i.e., small decreases (5% to 10%) in blood volume and/or pressure have little effect on vasopressin secretion, whereas larger decreases (20% to 30%) can increase vasopressin levels to 20 to 30 times normal levels (exceeding the concentration of vasopressin required to induce maximal antidiuresis).

12. Source; Goodman Gillman, the pharmacological basis, 11 th edition, page no. 774-775

13. The neuronal pathways that mediate hemodynamic regulation of vasopressin release are different from those involved in osmoregulation. Baroreceptors in the left atrium, left ventricle, and pulmonary veins sense blood volume (filling pressures), and baroreceptors in the carotid sinus and aorta monitor arterial blood pressure. Nerve impulses reach brainstem nuclei predominantly through the vagal trunk and glossopharyngeal nerve ; these signals are relayed to the solitary tract nucleus, then to the A1-noradrenergic cell group in the caudal ventrolateral medulla, and finally to the SON and PVN.

14. Hormones and neurotransmitters can modulate vasopressin secretion by stimulating or inhibiting neurons in nuclei that project, either directly or indirectly, to the SON and PVN.

15. Angiotensin II, applied directly to magnocellular neurons in the SON and PVN, increases neuronal excitability; when applied to the MnPO, angiotensin II indirectly stimulates magnocellular neurons in the SON and PVN. In addition, angiotensin II stimulates angiotensin-sensitive neurons in the OVLT and SFO (circumventricular nuclei lacking a blood–brain barrier) that project to the SON/PVN. Thus angiotensin II synthesized in the brain and circulating angiotensin may stimulate vasopressin release. Inhibition of the conversion of angiotensin II to angiotensin III blocks angiotensin II–induced vasopressin release, suggesting that angiotensin III is the main effector peptide of the brain renin–angiotensin system controlling vasopressin release ( Reaux et al., 2001).

16. Pharmacological Agents . A number of drugs alter urine osmolality by stimulating or inhibiting the secretion of vasopressin. Stimulators of vasopressin secretion Vincristine , Cyclophosphamide , Tricyclic antidepressants, Nicotine, epinephrine, and high doses of morphine. Lithium, which inhibits the renal effects of vasopressin, also enhances vasopressin secretion. Inhibitors of vasopressin secretion Ethanol, Phenytoin , Low doses of morphine, Glucocorticoids, Fluphenazine , haloperidol, promethazine , oxilorphan , and butorphanol . Carbamazepine has a renal action to produce antidiuresis in patients with central diabetes insipidus but actually inhibits vasopressin secretion via a central action.

17. Vasopressin Receptors The cellular effects of vasopressin are mediated mainly by interactions with the three types of receptors, V1a, V1b, and V2. V1a receptor most widespread subtype of vasopressin receptor ; found in vascular smooth muscle, the adrenal gland, myometrium , the bladder, adipocytes , hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting-duct, spleen, testis, and many CNS structures. V1b receptors limited distribution found in the anterior pituitary, several brain regions, the pancreas, and the adrenal medulla. V2 receptors are located predominantly in principal cells of the renal collecting-duct system but also are present on epithelial cells in the thick ascending limb and on vascular endothelial cells.

18. V1 Receptor – Effector Coupling . Source; Goodman Gillman, the pharmacological basis,11 th edition, page no. 778

19. V 2 vasopressin receptor Kidney Distal Tubule Cell Cytoplasm Aquaporin-2 Apical membrane H 2 O H 2 O H 2 O Protein Kinase A Pathway ADP ATP cAMP cAMP cAMP cAMP (active) PKA cAMP ATP PKA (inactive) Basolateral membrane Vasopressin G s protein Adenylyl cyclase Nephrogenic Diabetes Insipidus: defective receptor causes ADH resistance ADH biochemical action in the distal renal tubule via activation of PKA H 2 O H 2 O H 2 O H 2 O H 2 O Phosphorylates Aquaporin-2 subunits in vesicles bound to microtubular subunits Source; KD Tripathi, essentials of medical pharmacology, 8 th edition

20. Renal Actions of Vasopressin V1 receptors mediate contraction of mesangial cells in the glomerulus, contraction of vascular smooth muscle cells in the vasa recta and efferent arteriole. Indeed , V1-receptor-mediated reduction of inner medullary blood flow contributes to the maximum concentrating capacity of the kidney .V1 receptors also stimulate prostaglandin synthesis by medullary interstitial cells. Since prostaglandin E2 inhibits adenylyl cyclase in the collecting duct, stimulation of prostaglandin synthesis by V1 receptors may counterbalance V2-receptor-mediated antidiuresis. V1 receptors on principal cells in the cortical collecting duct may inhibit V2- receptor-mediated water flux via activation of protein kinase C (PKC ). V2 receptors mediate the most prominent response to vasopressin, i.e., increased water permeability of the collecting duct. Indeed, vasopressin can increase water permeability in the collecting duct at concentrations as low as 50 f M.

21. Cardiovascular System Vasopressin is a potent vasoconstrictor (V1-receptor-mediated ), Vascular smooth muscle in the skin, skeletal muscle, fat, pancreas, and thyroid gland appear most sensitive, with significant vasoconstriction also occurring in the gastrointestinal tract, coronary vessels, and brain. To a large extent, this is due to circulating vasopressin actions on V1 receptors to inhibit sympathetic efferents and potentiate baroreflexes. V2 receptors cause vasodilation in some blood vessels. The effects of vasopressin on the heart (reduced cardiac output and heart rate) are largely indirect and result from coronary vasoconstriction, decreased coronary blood flow, and alterations in vagal and sympathetic tone.

22. Central Nervous System (CNS It plays a role as a neurotransmitter and/or neuromodulator . Vasopressin may participate in the acquisition of certain learned behaviors ( Dantzer and Bluthe , 1993), in the development of some complex social processes (Young et al., 1998), and in the pathogenesis of specific psychiatric diseases such as depression (Scott and Dinan , 2002). Many studies support a physiological role for vasopressin as a naturally occurring antipyretic factor ( Cridland and Kasting , 1992 ). Although vasopressin can modulate CNS autonomic systems controlling heart rate, arterial blood pressure, respiration rate, and sleep patterns, the physiological significance of these actions is unclear. secretion of ACTH is enhanced by vasopressin released from parvicellular neurons in the PVN and secreted into the pituitary portal capillaries from axon terminals in the median eminence. Although vasopressin is not the principal corticotropin -releasing factor, vasopressin may provide for sustained activation of the hypothalamic–pituitary–adrenal axis during chronic stress (Aguilera and Rabadan -Diehl, 2000) . The CNS effects of vasopressin appear to be mediated predominantly by V1 receptors.

23. Blood Coagulation . Activation of V2 receptors by desmopressin or vasopressin increases circulating levels of procoagulant factor VIII and of von Willebrand factor. Other Nonrenal Effects of Vasopressin At high concentrations, vasopressin stimulates contraction of smooth muscle in the uterus ( via oxytocin receptors) and gastrointestinal tract ( via V1 receptors ). Vasopressin is stored in platelets, and activation of V1 receptors stimulates platelet aggregation. activation of V1 receptors on hepatocytes stimulates glycogenolysis . The physiological significance of these effects of vasopressin in not known.

24. Mechanisms by which vasopressin increases the renal conservation of water .( IMCD, inner medullary collecting duct; TAL, thick ascending limb; VRUT, vasopressin regulated urea transporter. Thick and thin arrows denote major and minor pathways, respectively .) Source; Goodman Gillman, the pharmacological basis,11 th edition, page no. 781

25. VASOPRESSIN RECEPTOR AGONISTS AND ANTAGONISTS A number of vasopressin like peptides occur naturally All are nonapeptides, contain cysteine residues in positions 1 and 6, have an intramolecular disulfide bridge between the two cysteine residues (essential for agonist activity), have additional conserved amino acids in positions 5, 7, and 9 ( asparagine , proline , and glycine, respectively), contain a basic amino acid in position 8, and are amidated on the carboxyl terminus. In all mammals except swine, the neurohypophyseal peptide is 8- arginine vasopressin.

26. Vasopressin Receptor Agonists

27. Potent and Selective Agonists for the Vasopressin V1a Receptor in the Rat

28. V1b receptor agonists

29. Potent and Selective Agonists for the Vasopressin V2 Receptor in the Rata

30. Nonselective and Selective Cyclic and Linear V2 ⁄ V1a Antagonists for Rat Receptors

31. Nonpeptide Vasopressin Antagonists as Pharmacological Tools and Therapeutic Agents

32. CLINICAL SUMMARY; PHARMACOLOGY OF VASOPRESSIN PEPTIDES

33. DISEASES AFFECTING THE VASOPRESSIN SYSTEM DI is a disease of impaired renal conservation of water owing either to an inadequate secretion of vasopressin from the neurohypophysis ( central DI ) or to an insufficient renal response to vasopressin (nephrogenic DI ). Patients with DI excrete large volumes ( more than 30 ml/kg per day) of dilute (less than 200 mOsm/kg) urine and, if their thirst mechanism is functioning normally, are polydipsic. In contrast to the sweet urine excreted by patients with diabetes mellitus, urine from patients with DI is tasteless, hence the name insipidus. DI by administration of desmopressin, which will increase urine osmolality in patients with central DI but have little or no effect in patients with nephrogenic DI DI can be differentiated from primary polydipsia by measuring plasma osmolality , which will be low to low-normal in patients with primary polydipsia and high to high-normal in patients with DI.

34. Antidiuretic peptides are the primary treatment for central DI , with desmopressin being the peptide of choice. Chlorpropamide , an oral sulfonylurea , potentiates the action of small or residual amounts of circulating vasopressin and will reduce urine volume in more than half of all patients with central DI. A dose of 125 to 500 mg daily is particularly effective in patients with partial central DI. Carbamazepine (800 to 1000 mg daily in divided doses) and clofibrate (1 to 2 g daily in divided doses) also reduce urine volume in patients with central DI. the mainstay of treatment of nephrogenic DI is assurance of an adequate intake of water, drugs also can be used to reduce polyuria. Amiloride blocks the uptake of lithium by the sodium channel in the collecting- duct system and is considered the drug of choice for lithium-induced nephrogenic DI despite the absence of Food and Drug Administration (FDA) approval. Paradoxically, thiazide diuretics reduce the polyuria of patients with DI and often are used to treat non-lithium-induced nephrogenic DI .

35. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is a disease of impaired water excretion with accompanying hyponatremia and hypo-osmolality caused by the inappropriate secretion of vasopressin. The clinical manifestations of plasma hypotonicity resulting from SIADH may include lethargy, anorexia, nausea and vomiting, muscle cramps, coma, convulsions, and death. Other water-retaining states . In patients with congestive heart failure, cirrhosis, or nephrotic syndrome, effective blood volume often is reduced, and hypovolemia frequently is exacerbated by the liberal use of diuretics. Since hypovolemia stimulates vasopressin release, patients may become hyponatremic owing to vasopressin- mediated retention of water.

36. Only two antidiuretic peptides are available for clinical use in the United States . (1) Vasopressin (synthetic 8-L-arginine vasopressin; PITRESSIN) is available as a sterile aqueous solution; it may be administered subcutaneously , intramuscularly, or intranasally . (2) Desmopressin acetate (synthetic 1-deamino-8-D-arginine vasopressin ; DDAVP, others) is available as a sterile aqueous solution packaged for intravenous or subcutaneous injection , in a nasal solution for intranasal administration with either a nasal spray pump or rhinal tube delivery system , and in tablets for oral administration.

37. Based on V 2 actions 1. Diabetes insipidus ; Desmopressin , The duration of effect from a single intranasal dose is from 6 to 20 hours; twice-daily administration is effective in most patients The usual intranasal dosage in adults is 10 to 40 μg daily either as a single dose or divided into two or three doses. Oral administration of desmopressin in doses 10 to 20 times the intranasal dose provides adequate blood levels of desmopressin to control polyuria. Subcutaneous administration of 1 to 2 μg daily of desmopressin also is effective in central DI. 2.Haemophilia , Von Wilebrand’s disease : In most patients with type-I von Willebrand’s disease (vWD) and in some with type IIn vWD, desmopressin will elevate von Willebrand factor and shorten bleeding time. it also releases coagulation factor VIII . Desmopressin in a dose of 0.3 μg /kg diluted in 50ml saline and infused i.v . over 30 min. 3.Bedwetting in children and nocturia in adults ; intranasal or oral desmopressin at bed time. 4.Renal concentration test ; 5-10 U i.m . of aqueous vasopressin or 2 μg of desmopressin causes maximum urinary concentration.

38. Based on V 1 actions Bleeding esophageal verices ; terlipressin stops bleeding in ~80 %. Before abdominal radiography ; AVP/ lypressin used to drive out gasses from bowel . Pharmacokinetics AVP is inactive orally, destroyed by trypsin . T 1/2 ~25 min duration of action lasts for 4-5 hours.

39. Adverse effects Local Nasal irritation. Congestion. Rhinitis Ulceration and epistaxis Systemic side effects Belching Nausea Abdominal cramps Pallor Urge to defecate Backache in females Fluid retention and hyponatremia. CVS complications, bradycardia, precipitate angina, increase cardiac afterload.

40. Contraindications Hypertension Ischeamic heart disease Chronic nephritis Psychogenic polydipsia. Angina pectoris Patients receiving desmopressin to maintain hemostasis should be advised to reduce fluid intake. Also, it is imperative that these peptides not be administered to patients with primary or psychogenic polydipsia because severe hypotonic hyponatremia will ensue.

41. Future Directions in Vasopressin Analogues Recent randomized clinical trials demonstrate efficacy for YM 087 (CONIVAPTAN) and OPC-41067 (TOLVAPTAN), V1a/V2- selective antagonists, respectively, as aquaretics in heart failure patients (Udelson et al., 2001; Gheorghiade et al., 2003). The V2-selective antagonist VPA-985 (LIXIVAPTAN) is an effective aquaretic in patients with hyponatremia of various etiologies (Wong et al., 2003). In contrast, the V2-selective agonist OPC-51803 has strong antidiuretic effects in animals and is being developed for central DI, nocturnal enuresis, and urinary incontinence ( Nakamura et al., 2003). It is likely that a number of nonpeptide vasopressin receptor antagonists and agonists will become available clinically in the near future.

42. Bernat, A., Hoffmann, T., Dumas, A., et al. V2 receptor antagonism of DDAVP-induced release of hemostatis factors in conscious dogs. J. Pharmacol . Exp. Ther ., 1997, 282:597 602. Udelson , J.E., Smith, W.B., Hendrix, G.H., et al. Acute hemodynamic effects of conivaptan , a dual V1A and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation, 2001, 104:2417–2423. Cridland , R.A., and Kasting , N.W. A critical role for central vasopressin in regulation of fever during bacterial infection. Am. J. Physiol., 1992, 263:R1235–R1240. Dunser , M.W., Mayr , A.J., Ulmer, H., et al. Arginine vasopressin in advanced vasodilatory shock: A prospective, randomized, controlled study. Circulation, 2003, 107:2313–2319. Franchini , K.G., and Cowley, A.W., Jr. Renal cortical and medullary blood flow responses during water restriction: role of vasopressin. Am. J. Physiol., 1996, 270:R1257–R1264. Gheorghiade , M., Niazi , I., Ouyang , J., et al., for the Tolvaptan Investigators. Vasopressin V2-receptor blockade with TOLVAPTAN in patients with chronic heart failure: Results from a double-blind, randomized trial. Circulation, 2003, 107:2690–2696. Nakamura, S., Hirano, T., Yamamura, Y., et al. Effects of OPC-51803, a novel, nonpeptide vasopressin V2-receptor agonist, on micturition frequency in B rattleboro and aged rats. J. Pharmacol . Sci., 2003, 93:484–488. Bankir , L. Antidiuretic action of vasopressin: Quantitative aspects and interaction between V1a and V2 receptor mediated effects. Cardiovasc . Res., 2001, 51(suppl.):372–390. Goodman Gillman, the pharmacological basis,11 th edition, KD Tripathi, essentials in medical pharmacology, 8 th Edition. References