Pharmacology of vasopressin

1. Presented by:
Yasmeen Mir
M. Pharm ist year (Pharmacology-II)
Roll no.:18155110001

2. Contents
(1) Physiology (including anatomical considerations; the synthesis, transport, and storage
of vasopressin; and the regulation of vasopressin secretion),
(2) Chemistry (including the chemistry of vasopressin agonists and antagonists),
(3) 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),
(4) Diseases affecting the vasopressin system (diabetes insipidus, syndrome of
inappropriate secretion of antidiuretic hormone, and other water-retaining states), and
(5) 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:
1. CNS component for the synthesis, transport, storage, and release
of vasopressin
2. 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.

7. 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.

8. 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, 11th edition, page no. 773

9. 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).

10. 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.

11. 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.

12. 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).

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

14. 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.

15. 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.

16.  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).

17. 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.

18. 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.

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

21. V2 vasopressin
receptor
Kidney Distal Tubule Cell
Cytoplasm
Aquaporin-2
Apical
membrane
H2O
H2O
H2O
Protein Kinase A Pathway
ADP
ATP
cAMP
cAMP
cAMP
cAMP
(active)
PKA
cAMP
ATP
PKA
(inactive)
Basolateral
membrane
Vasopressin
Gs protein
Adenylyl cyclase
Nephrogenic Diabetes Insipidus:
defective receptor causes ADH resistance
ADH biochemical action in the distal renal tubule via activation of PKA
H2O
H2O
H2O
H2O
H2O
Phosphorylates
Aquaporin-2
subunits in
vesicles bound to
microtubular
subunits
Source; KD Tripathi, essentials of medical pharmacology, 8th edition

23. 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 fM.

24. 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.

25. 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.

26. 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.

27. 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,11th edition,
page no. 781

28. 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.

29. Vasopressin Receptor Agonists

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

31. V1b receptor agonists

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

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

34. Nonpeptide Vasopressin Antagonists as Pharmacological Tools and Therapeutic Agents

35. CLINICAL SUMMARY; PHARMACOLOGY OF
VASOPRESSIN PEPTIDES

36. 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.

37. 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.

38. 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.

39. 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.

40. Based on V2 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.

41. Based on V1 actions
1. Bleeding esophageal verices; terlipressin stops bleeding in ~80%.
2. Before abdominal radiography; AVP/lypressin used to drive out gasses from bowel.
Pharmacokinetics
 AVP is inactive orally, destroyed by trypsin.
 T1/2 ~25 min
 duration of action lasts for 4-5 hours.

42. Adverse effects
Local
1. Nasal irritation.
2. Congestion.
3. Rhinitis
4. Ulceration and epistaxis
Systemic side effects
1. Belching
2. Nausea
3. Abdominal cramps
4. Pallor
5. Urge to defecate
6. Backache in females
7. Fluid retention and hyponatremia.
8. CVS complications, bradycardia, precipitate angina, increase cardiac
afterload.

43. Contraindications
1. Hypertension
2. Ischeamic heart disease
3. Chronic nephritis
4. Psychogenic polydipsia.
5. 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.

44. 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.

45. 1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Bankir, L. Antidiuretic action of vasopressin: Quantitative aspects and interaction between V1a and V2 receptor
mediated effects. Cardiovasc. Res., 2001, 51(suppl.):372–390.
9. Goodman Gillman, the pharmacological basis,11th edition,
10. KD Tripathi, essentials in medical pharmacology, 8th Edition.
References