This document provides an overview of vasopressin agonists and antagonists. It begins with an introduction to vasopressin and its synthesis, transport, and regulation in the body. It then discusses vasopressin's actions in various organ systems like the kidney, blood vessels, gastrointestinal tract, and liver. The document reviews the pharmacokinetics of vasopressin and lists various vasopressin agonists and antagonists. It describes the use of desmopressin and other vasopressin drugs in treating conditions like diabetes insipidus and SIADH. Finally, it mentions several clinical trials investigating vasopressin antagonists.

1. Vasopressin agonists and antagonists
Dr Prasheeta V Praviraj
Department of Pharmacology
Rangaraya Medical College
1

2. Contents
 Introduction
 Synthesis , transport & regulation
 Action on body
 Pharmacokinetics
 Agonists & Antagonists
 Pharmacotherapy of Diabetes Insipidus
 Pharmacotherapy of SIADH
 Conclusion
 References
2

3. Introduction
 Vasopressin is also called Antidiuretic hormone
(ADH).
 The two main hormones released from
neurohypophysis (posterior pituitary ) are Oxytocin
& ADH .
 Structure of mammalian vasopressin – nonapeptide
hormone3

4. Synthesis & transport
 Supraoptic nucleus(SON) – 75%
 Paraventricular nuclei (PVHN) -3%
 Large precursor peptide + neurophysin+glycopeptide
= neurosecretory granule (axon terminals )
 They pass down the hypothalamic – hypophyseal
tract formed by the long axons which end in pars
nervosa lying in close contact with pitiutary
capillaries .
 While being transported the precursors get cleaved
into products in these microtubule track .
Magnocellular
neuron
4

5. 5

6.  Phasic firing of vasopressin neurons is the most
most efficient pattern of release
This phasic activity is controlled by
 Glutamate stimulation
 Opiod inhibition
 Control of hormone synthesis
 Stimuli for hormone synthesis
At the level of transcription
6

7. Factors affecting ADH release
(Courtesy: Williams endocrinology;13th edition ; Pg 302)
 Osmolality – osmoreceptors
 Volume
 Blood pressure
Other stimuli
 Nausea , pain , stress
 Hypoglycaemia , hypoxia
 Cytokines , IL-6 , oxytocin
baroreceptors
7

8. Receptors
Vasopressin receptors
V1
V1a V1b/V3
V2
•Smooth muscle of
blood
vessels
•Smooth muscle of
other
visceral organs
•Myometrium
•Platelets
•Liver
•Anterior pitiutary
•Hypothalamic
circumventricular
organs
•Pancreas
•Adrenal medulla
Renal - Epithelial cells
of collecting ducts in
kidney: luminal side
Extrarenal –
•Blood vessels
•Platelets
•Vascular
endothelium
8

9. Action of ADH
 KIDNEY
 V2 Inc c AMP
intracellulary
Activation of
protein kinase
A
Phosphorylatio
n of proteins
Promotes
exocytosis of
Aquaporin 2 in
apical membrane
Increases
water
permeability
Antidiuresis
Activates vasopressin
regulated urea
transporter (VRUT/UT-
1)
Inc urea permeability of
terminal parts of CD
Inc medullary
hypertonicity
Present in asc.
Loop of henle
Activate Na/K/Cl
cotranporter
Inc synthesis (longterm)
Inc medullary
hypertonicity
9

10. KIDNEY
 V1a constrict vasa recta dec. bloodflow
to
inner medulla
inc. production of prostaglandins
from interstitial cells
inc osmolality
Dec. responsiveness of CD cells to
V2 receptor stimulation
Antidiuresis
Diuresis
10

11. Other actions
Organ
system
Recep
tors
Actions Remarks
Blood
vessels
V1a
V2
Vasoconstriction
Vasodilatation EDRF(NO) mediated
G.I. V1a Increases peristalsis of
large bowel
Expulsion of gases
Uterus V1a Contraction Non pregnant uterus ; AVP & oxy
have similar sensitivity
At term : oxy selectivity appears
Liver V2 Enhances
glycogenolysis
Platelet V2 Increases aggregation Releases coagulation factor VIII &
vWF
C.N.S V1b/V3
V1a
Neurotransmitter
Neuromodulator
Cerebral vessel
constriction
Temperature , Circulation
ACTH release , Learning of task
C.V.S V1a Constricts coronary
blood vessels
Initial tachycardia & hypotension
Final bradycardia11

12. Pharmacokinetics
 Orally inactive : metabolised by “trypsin”
 Vasopressin when given SC / IM remains in body for
few hours
 When given IV – rapidly metabolised by liver and
some in kidney
 Plasma t1/2 = 20min
12

13. 13

14. Agonists/Antagonists
VASOPRESSIN ANTAGONISTS
 Conivaptan
 Tolvaptan
 Lixivaptan
 Relcovaptan
 Satavaptan
 Mozavaptan
 SSR-149415
VASSOPRESSIN
AGONISTS
Felypressin
Lypressin
Desmopressin
Terlipressin
14

15. Desmopressin
DDAVP- Deamino-8-D-arginine vasopressin
 SAR :
-substitution with D arginine ; reduced the pressor activity
-removal of terminal amino ; increased half life(13-22 hr)
 Formulations : oral , sublingual(melt) , parentral ,
intranasal
 Uses : diabetes insipidus
- diagnostic test : Differentiate between neurogenic &
nephrogenic DI
- nocturnal enuresis / bedwetting in children
- renal concentration test
- bleeding disorders : haemophila & vW disease15

16.  Vasopressin : asystole cardiac arrest
 Lypressin : 8-lysine vasopressin – more pressor activity
- postoperative ileus & Abdominal distension
- esophageal varices
- acute haemorrhagic gastritis
 Felypressin : as a local vasoconstrictor along with anaesthetic
.
 Terlipressin : is a prodrug of vasopressin
- exclusively for esophageal varices
- lesser side effects than lypressin
 Glypressin : triglycyl lysine vasopressin
- releases the hormone slowly in vivo (10hr)16

17. Conivaptan
 Non selective V1/V2 receptor antagonist
 Only I.V formulation available
 CYP3A4 inducers : several drug interactions
 Continuos electrolyte monitoring must – hospitalized
serum Mg , K ,Na ion.
 Uses : Euvolemic / hypervolemic hyponatremia
Heart failure – ongoing trials ( prevent cardiac
hypertrophy )
 Side effects : headache , thirst , dry mouth , hypokalemia ,
orthostatic hypotension ,
 When used in liver cirrhosis – chances of variceal bleeding
17

18. Mechanism of action of vaptans
18

19.  Tolvaptan : selective V2 receptor antagonist
- oral formulation available & effective
- P-glycoprotein substrate
- Uses : CHF , SIADH , Cirrhosis
 Lixivaptan : selective V2 selective , oral
 Relcovaptan : V1a selective antagonist
- raynaud’s disease ,Dysmenorrhea , tocolytic
 SSR-149415(Nelvivaptan ) : V1b selective ,
Psychiatric disorders
19

20. Pharmacotherapy of diabetes insipidus
Diabetes Insipidus a disorder of a large volume of
urine(diabetes) that is hypotonic, dilute, and
tasteless (insipid).
 Primary polydipsia
 Central Diabetes Insipidus
 Nephrogenic Diabetes Insipidus
 Diabetes Insipidus of pregnancy
20

21. Primary polydipsia
 Cause : -drugs that cause dry mouth
-peripheral disorders increasing RAAS
-psychiatric syndromes(42%) – cause??
-habitual polydipsia
 Treatment : Refractory
Propranolol – inhibition of RAS
21

22. Central Diabetes Insipidus
 Cause : genetic abnormality
malignancy/sarcoidosis/infection/
surgery/trauma
 Treatment : 1) Water
2) Water retaining agents :
Desmopressin , L-arginine vasopressin
Chlorpropamide , clofibrate , carbamazepine
Indomethacin
3) Natriuretic peptides :
Thiazide diuretics , amiloride , indapamide
22

23.  Desmopressin : dose is individualized a/c 24 hr urine
volume
- 0.2mg orally / 20ug intranasal 2-3 times daily
 Chlorpropamide : increases the hydro-osmotic action of
residual vasopressin
-250-500mg/day
- off label use
- side effect : hypoglycemia
 NSAIDS : prolongs the time the water channel remain in
the membrane , thus augmenting ADH action
- add on drug with desmopressin23

24. Nephrogenic Diabetes insipidus
 Cause : -genetic mutation in V2 receptor thus CD
cells
are completely / partially insensitive to ADH .
- drugs
 Treatment : 1) stop the offending drug
2) adequate water intake (partial)
3) Thiazide diuretics :
“paradoxical antidiuretic action”
Proposed mechanisms : Thiazides induce a
state of sustained electrolyte depletion – stimulates
Na & water reabsorption PT . The urine presented to
DT has less filtrate , it passes as such excreted.24

25. - Also thiazides reduce G.F.R : decreases the fluid
load on tubules
(2) They inhibit the the enzyme cyclonucleotide
phosphodiesterase thus increase 3,5-cyclic AMP
levels . Thus increase membrane permeability of CD
to water .
- Dose : 100mg/day P.O
- Potassium supplementation
25

26.  Amiloride : drug of choice in “Lithium induced
nephrogenic DI”
 Vaptans : in rescuing the mutant receptors they act
as “pharmacological chaperons”
-they combine with the misfolded proteins and
change the conformation to allow complete
maturation of the V2 receptors which can then be
activated by AVP.
 Nonpeptide V2 receptor agonists : in case of partially
mutated receptors .
- they combine with the mutant receptor trapped in
the ER and allow maturation .26

27. Diabetes Insipidus in Pregnancy
 Cause : due to increased clearance of AVP by
enzyme vasopressinase
 Treatment : Desmopressin – only recommended
drug
- 25% oxytocic activity of AVP
- not metabolized by oxytocinase
 After delivery : generally recovers spontaneously
27

28. Pharmacotherapy of SIADH
Syndrome of inappropriate ADH is a clinical condition
where ADH is secreted in excess than physiological limit.
 Euvolemic hyposmolaity , hyponatremia
 Causes : 1) Tumors or CNS lesions
2) Paraneoplasia
3) Drugs
 Diagnosis : Barter & Schwartz clinical criteria
 Treatment : 1) Fluid restriction 500ml-1L
2) Demclocycline : tetracycline antibiotic
inhibits adenylyl cyclase thus dec. cAMP
28

29.  Saline infusion : 3% NaCl (hypertonic) is infused for
acute hyponatremia with severe neurological deficits.
 Offending agent is stopped
 Vasopressin antagonists(VAPTANS): chronic SIADH
- directly block the receptor mediated actionof
vasopressin
*Conivaptan - 20mg loading dose over 30 min
- 20-40mg/day continuous infusion (4days )
*Tolvaptan – starting dose 15mg first day
- 30mg & 60mg on 3rd ,4th day titrated according to
osmolality or sodium levels
29

30.  Oral urea : corrects osmolality by increasing solute
free water excretion
- chronic SIADH
- Disadvantages : poor palatability
- preferred in SAH , Critical care
 Desmopressin : in severe SIADH along with Saline
infusion to avoid rapid & overcorrection
- osmotic demyleniation
 Furosemide with NaCl : still needs validation
30

31. Clinical trials
Sl
no
Name of the
trial
Trial details Status
1 BALANCE
study
Treatment of hyponatremia
based on Lixivaptan in NYHA
class III/IV heart failure
Increased mortality on day
7
Study terminated
2 AQUAMARIN
E study
Tolvaptan compared with
standard furosemide therapy
in heart failure with renal
impairment (Multicentre trial)
Add on drug(ACEI,β blocker)
Ongoing trial
Japan
3 EVEREST
study
Efficacy of vasopressin
antagonism in heart failure
outcome study with tolvaptan
Decreased MI rate
Slight risk in stroke
4 ADVANCE
study
Double blind , placebo
controlled , randomized trial
to investigate conivaptans for
use in heart failure
Ongoing trial
31

32.  SALT 1 & 2 : Study of ascending levels of tolvapatan
in hyponatremia for cirrhosis , heartfailure & SIADH .
-This study's purpose is to determine whether
tolvaptan can safely and effectively return the body's
balance of sodium and water toward normal, and to
characterize and quantify the potential clinical
benefits of this treatment.
-Tolvaptan was effective in increasing serum sodium
levels in patients with diverse disease states in the
outpatient setting and serum sodium returned to
baseline levels after tolvaptan was discontinued.
32

33. Conclusion
 Vasopressin /ADH is a posterior pitiutary hormone
synthesized in hypothalamus .
 Currently its analogues & antagonists are being used
in the treatment of SIADH, DI , Bleeding esophageal
varices widely.
 Its role in Congestive heart failure is not fully
established as of yet . Further research and trials are
required for its complete validation.
33

34. References
 Robinson A.G ,Verbatus J.G , Posterior pitiutary,
Williams textbook of Endocrinology , Chapter 10, Pg
300-320
 Slotki I.N ,Skorecki K.L ;Disorders of Sodium
Balance ;Brenner & Rector’s The kidney ; edition 10
chapter15, pg390-459
 M.-C. Vantyghem et al. ; Hyponatremia and
antidiuresis syndrome; Annales d’Endocrinologie
72; published in 2011; pg 500–512
 K.D.Tripathi , Essentials of medical pharmacology ;
Antidiuretics;chapter 12 ;section 9; pg 574-578
 Satoskar R.S. , Antidiuretics , Pharmacology &
Pharmacotherapeutics ; chapter 38;Pg 575-577
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