YANET-LIYANA HEALTH SCIENCE

COLLEGE
PHARMACY PHARMACOLOGY
 TABLE CONTENT
I. Introduction ……………………………………………… 1

II. Vasopressin receptors……………………………………. 1

III. Vasopressin Actions on different Organs………………... 3

IV. Pharmacokinetics of Vasopressin…………………......… 5

V. Vasopressin Analogues………………………………….. 6

VI. Clinical Uses……………………………………………..7

VII. Adverse Effects………………………………………….8

VIII. Vasopressin Receptor Antagonists…………………… 8

IX. Diseases Affecting the Vasopressin System…………….9

X. Reference………………………………………………..14
 Vasopressin and Other Agents Affecting Renal
Conservation of Water

I. Introduction
Antidiuretic hormone (Vasopressin) It is a nonapeptide secreted by posterior
pituitary (neurohypophysis) along with oxytocin. It is synthesized in the hypothalamic
(supraoptic and paraventricular) nerve cell bodies as a large precursor peptide along
with its binding protein ‘neurophysin’, and is transported down the axons to nerve
endings in the median eminence and pars nervosa. Osmoreceptors present in
hypothalamus and volume receptors present in left atrium, ventricles and pulmonary
veins primarily regulate the rate of ADH release governed by body hydration.
Impulses from baroreceptors and higher centres also impinge on the nuclei
synthesizing ADH and affect its release. The two main physiological stimuli for ADH
release are rise in plasma osmolarity and contraction of e.c.f. volume.

ADH secretion is enhanced by angiotensin II, prostaglandins (PGs), histamine,

neuropeptide Y and ACh. No. It is inhibited by GABA and atrial natriuretic peptide
(ANP). Opioids have agentspecific action: while morphine stimulates ADH secretion,
endogenous opioid peptides are mostly inhibitory. These humoral mediators may play
a role in the modulation of ADH secretion.

The mammalian ADH is 8argininevasopressin (AVP); 8lysinevasopressin (lypressin)

is found in swine and has been synthetically prepared. Other more potent and longer
acting peptide analogues of ADH having agonistic as well as antagonistic action have
been prepared.

II. Vasopressin (ADH) Receptors

These are G protein coupled cell membrane receptors; two subtypes V 1 and V2 have
been identified, cloned and structurally characterized.

a) V1 Receptors: All vasopressin receptors except those on renal

CD(collecting duct) cells and some blood vessels are of the V1 type.

These are further divided into:

V1a present on vascular and other smooth muscles, platelets, liver, etc. and
V1b localized to the anterior pituitary.

The V1 receptors function mainly through the phospholipase C–IP3/DAG pathway—

release Ca2+ from intracellular stores—causing vasoconstriction, visceral smooth
muscle contraction, glycogenolysis, platelet aggregation, ACTH release, etc. These

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actions are augmented by enhanced influx of Ca2+ through Ca2+ channels as well as
by DAG mediated protein kinase C activation which phosphorylates relevant proteins.
V1 receptors, in addition, activate phospholipase A2—release arachidonic acid
resulting in generation of PGs and other eicosanoids which contribute to many of the
V1 mediated effects. Persistent V1 receptor stimulation activates protooncogenes
(possibly through IP 3/DAG pathway) resulting in growth of vascular smooth muscle
and other responsive cells.

b) V2 Receptors

These are located primarily on the collecting duct (CD) cells in the kidney—regulate
their water permeability through cAMP production. Vasodilatory V 2 receptors are
present in blood vessels.

The V2 receptors are more sensitive (respond at lower concentrations) to ADH than
are V1 receptors.

 Selective peptide agonists and antagonists of the subtypes of vasopressin

receptors are:

 Some orally active nonpeptide V1a and V2 receptor antagonists have

been produced and are under clinical trial.

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 III. Vasopressin Actions on different Organs

 Kidney
AVP acts on the collecting duct (CD) cells to increase their water permeability—
water from the lumen diffuses to the interstitium by equilibrating with the
hyperosmolar renal medulla (see Fig. IX.1). In man, maximal osmolarity of urine that
can be attained is 4 times higher than plasma. When ADH is absent, CD cells remain
impermeable to water → dilute urine (produced by the diluting segment) is passed as
suCh. No. Graded effect occurs at lower concentration of ADH: urine volume closely
balances fluid intake.

Mechanism Of Action: On V2 receptors

 The V2 subtype of ADH receptors are present on the basolateral side of

collecting duct cell membrane.
Activation of these receptors increases cAMP formation
intracellularly → activation of cAMP dependent protein kinase
A → phosphorylation of relevant proteins which promote exocytosis
of ‘aquaporin2’ water channel containing vesicles (WCVs) through the

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 apical membrane → more aqueous channels get inserted into the
apical membrane.

The rate of endocytosis and degradation of WCVs is concurrently reduced. The water
permeability of collecting duct cells is increased in proportion to the population of
aquaporin2 channels in the apical membrane at any given time. Continued
V2 receptor stimulation (during chronic water deprivation) in addition upregulates
aquaporin2 synthesis through cAMP response element of the gene encoding
aquaporin2.

Other aquaporins like aquaporin1 (in PT) and aquaporin 3, 4 (on basolateral
membrane of collecting duct cells) also participate in water transport at these sites.

To achieve maximum concentration of urine, activation of V2 receptors increases urea

permeability of terminal part of of collecting duct s by stimulating a vasopressin
regulated urea transporter (VRUT or UT1)—which in turn augments medullary
hypertonicity. Recently, V2 receptor mediated actions of AVP on AscLH have been
demonstrated which further reinforce medullary hypertonicity by activating the
Na+K+2Cl¯ cotransporter in the shortterm and increasing its synthesis in the long-
term.

Mechanism Of Action: On V1 receptor

 The V 1 receptors also participate in the renal response to ADH. While

V1a receptor activation constricts vasa recta to diminish blood flow to inner
medulla which will help in maintaining high osmolarity in this region and thus
contribute to antidiuresis; other V1 actions augmenting PG production from
interstitial cells and directly diminishing responsiveness of of collecting duct
cells to V2 receptor stimulation tend to restrain V2 mediated water
permeability. Since V2 action is produced at much lower concentration of
AVP, physiologically V1 renal actions may serve to restrict V2 effect when
blood levels of AVP are very high.

Mechanism Of Action: ADH Antagonists

 Lithium and demeclocycline partially antagonize ADH action (probably by

limiting cAMP formation), reduce the urine concentrating ability of the
kidney, produce polyuria and polydipsia. They have been used in patients with
inappropriate ADH secretion. On the other hand NSAIDs (especially
indomethacin) augment AVP induced antidiuresis by inhibiting renal PG
synthesis. Carbamazepine and chlorpropamide also potentiate AVP.

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  Blood Vessels
AVP constricts blood vessels through V1 receptors and can raise BP (hence the name
vasopressin), but much higher concentration is needed than for maximal antidiuresis.
The cutaneous, mesenteric, skeletal muscle, fat depot, thyroid, and coronary beds are
particularly constricted. Though vasoconstrictor action of AVP does not appear to be
physiologically important, some recent studies indicate that it may play a role in CHF,
haemorrhage, hypotensive states, etc. Prolonged exposure to AVP causes vascular
smooth muscle hypertrophy.

The V2 receptor mediated vasodilatation can be unmasked when AVP is administered

in the presence of a V1 antagonist. It can also be demonstrated by the use of selective
V2 agonist desmopressin, and appears to be EDRF (NO) mediated.

 Other Actions
Most visceral smooth muscles contract. Increased peristalsis in gut (especially large
bowel), evacuation and expulsion of gases may occur.

Uterus is contracted by AVP acting on oxytocin receptors. In the nonpregnant and

early pregnancy uterus, AVP is equipotent to oxytocin. Only at term sensitivity to
oxytocin increases selectively.

CNS Exogenously administered AVP does not penetrate blood-brain barrier.

However, it is now recognized as a peptide neurotransmitter in many areas of brain
and spinal cord: may be involved in regulation of temperature, circulation, ACTH
release, and in learning of tasks.

AVP induces platelet aggregation and hepatic glycogenolysis. It releases coagulation

factor VIII and von Willebrand’s factor from vascular endothelium through
V2 receptors.

IV. Pharmacokinetics of Vasopressin

 AVP is inactive orally because it is destroyed by trypsin. It can be

administered by any parenteral route or by intranasal application. The peptide
chain of AVP is rapidly cleaved enzymatically in many organs, especially in
liver and kidney; plasma t½ is short~25 min. However, the action of aqueous
vasopressin lasts 3– 4 hours.

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Aqueous vasopressin (AVP) inj: POSTACTON 10 U inj; for i.v., i.m. or s.c.
administration.

V. Vasopressin Analogues
Lypressin:It is 8-lysine vasopressin. Though somewhat less potent than AVP, it acts
on both V1 and V2 receptors and has longer duration of action (4–6 hours). It is being
used in place of AVP—mostly for V1 receptor mediated actions.

PETRESIN, VASOPIN 20 IU/ml inj; 10 IU i.m. or s.c. or 20 IU diluted in 100–

200 ml of dextrose solution and infused i.v. over 10–20 min.

Terlipressin: This synthetic prodrug of vasopressin is specifically used for bleeding

esophageal varices; may produce less severe adverse effects than lypressin.

Dose: 2 mg i.v., repeat 1–2 mg every 4–6 hours as needed. GLYPRESSIN 1 mg

freeze dried powder with 5 ml diluent for inj.

Desmopressin (dDAVP): This synthetic peptide is a selective V2 agonist; 12

times more potent antidiuretic than AVP, but has negligible vasoconstrictor activity. It
is also longer acting because enzymatic degradation is slow; t½ 1–2 hours; duration of
action 8–12 hours. Desmopressin is the preparation of choice for all V 2 receptor
related indications. The intranasal route is preferred, though bioavailability is only
10–20%. An oral formulation has been recently marketed with a bioavailability of 1–
2%; oral dose is 10–15 times higher than intranasal dose, but systemic effects are
produced and nasal side effects are avoided. Most patients find oral tablet more
convenient.

Dose: Intranasal: Adults 10–40 μg/day in 2–3 divided doses, children 5–10 μg at bed
time.

Oral: 0.1–0.2 mg TDS.

Parenteral (s.c. or i.v.) 2–4 μg/day in 2–3 divided doses. MINIRIN 100 μg/ml
nasal spray (10 μg per actuation); 100 μg/ml intranasal solution in 2.5 ml
bottle with applicator; 0.1 mg tablets; 4 μg/ml inj.

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 VI. Clinical Uses
A) Based on V2 Actions (Desmopressin is the drug of choice)
1. Diabetes Insipidus

DI of pituitary origin (neurogenic) is the most important indication for vasopressin. It

is ineffective in renal (nephrogenic) DI, since kidney is unresponsive to ADH.
Lifelong therapy is required, except in some cases of head injury or neurosurgery,
where DI occurs transiently.

The dose of desmopressin is individualized by measuring 24 hour urine volume.

Aqueous vasopressin or lypressin injection is impracticable for long-term treatment. It
can be used in transient DI and to differentiate neurogenic from nephrogenic DI—
urine volume is reduced and its osmolarity increased if DI is due to deficiency of
ADH, but not when it is due to unresponsiveness of kidney to ADH. Desmopressin
2 μg i.m. is the preparation of choice now for the same purpose.

2) Bedwetting In Children And Nocturia In Adults

Intranasal or oral desmopressin at bedtime controls primary nocturia by reducing

urine volume. Nocturnal voids are reduced to nearly half and first sleep period in
adults is increased by ~2 hr. Fluid intake must be restricted 1 hr before and till 8 hr
after the dose to avoid fluid retention. Monitor BP and body weight periodically to
check fluid overload. Withdraw for one week every 3 months for reassessment.

3. Renal Concentration Test

5–10 U i.m. of aqueous vasopressin or 2 μg of desmopressin causes maximum urinary

concentration.

4. Haemophilia, Von Willebrand’s Disease

AVP may check bleeding by releasing coagulation factor VIII and von Willebrand’s
factor. Desmopressin is the preferred preparation in a dose of 0.3 μg/kg diluted in 50
ml saline and infused i.v. over 30 min.

B) Based on V1 Actions
1. Bleeding Esophageal Varices

Vasopressin/ terlipressin often stop bleeding by constricting mesenteric blood vessels

and reducing blood flow through the liver to the varices, allowing clot formation.
Terlipressin stops bleeding in ~80% and has been shown to improve survival. It has
replaced AVP because of fewer adverse effects and greater convenience in use.

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Octreotide (a somatostatin analogue) injected i.v. is an alternative. However,
definitive therapy of varices remains endoscopic obliteration by sclerotherapy.

2. Before Abdominal Radiography

AVP/lypressin has been occasionally used to drive out gases from bowel.

VII. Adverse Effects

Because of V2 selectivity desmopressin produces fewer adverse effects than
vasopressin, lypressin or terlipressin. However, transient headache and flushing are
frequent.

Nasal irritation, congestion, rhinitis, ulceration and epistaxis can occur on local
application. Systemic side effects are: belching, nausea, abdominal cramps, pallor,
urge to defecate, backache in females (due to uterine contraction). Fluid retention and
hyponatraemia may develop.

AVP can cause bradycardia, increase cardiac afterload and precipitate angina by
constricting coronary vessels. It is contraindicated in patients with ischaemic heart
disease, hypertension, chronic nephritis and psychogenic polydipsia. Urticaria and
other allergies are possible with any preparation.

VIII. Vasopressin Receptor Antagonists

Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule.
Conivaptan and tolvaptan are direct ADH receptor antagonists, while both lithium and
demeclocycline reduce ADH-induced cAMP.

Vasopressin antagonists or vasopressin receptor antagonists (VRA) are a new group

of nonpeptide drugs used to treat hyponatremia (low sodium levels in the blood)
which is the most common electrolyte abnormality observed in hospitalized patients.
These drugs work by binding to vasopressin receptors and inhibit the action of
vasopressin. The pituitary gland releases vasopressin, an antidiuretic hormone that
constricts blood vessels and increases the reabsorption of water by the kidneys.

 Conivaptan is a nonselective V1a receptor/V2 receptor antagonist that is

FDA-approved for the treatment of hospitalized patients with euvolemic and
hypervolemic hyponatremia. Conivaptan is available only for intravenous
infusion. Expert panels have yet to reach a consensus regarding the
appropriate use of V receptor antagonists.
 Tolvaptan is the first oral VRA, also known as aquaretics. Tolvaptan works
by selectively inhibiting vasopressin V2-receptors in the kidneys and cause an
increase in urine water excretion. This increases electrolyte-free water

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 excretion (aquaresis) and decreases urine osmolality and correctshyponatremia
by increasing serum sodium concentration.

IX. DISEASES AFFECTING THE VASOPRESSIN

SYSTEM
 DIABETES INSIPIDUS (DI)
 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).
 Very rarely, DI can be caused by an abnormally high rate of degradation of
vasopressin by circulating vasopressinases. Pregnancy may accentuate or
reveal central and/or nephrogenic DI by increasing plasma levels of
vasopressinase and by reducing the renal sensitivity to vasopressin.
 Patients with DI excrete large volumes (>30 mL/kg/day) of dilute (<200
mOsm/kg) urine and, if their thirst mechanism is functioning normally, are
polydipsic.
 The diagnosis of DI rests on demonstrating that the patient is unable to
reduce urine volume and increase urine osmolality during a period of
carefully observed fluid deprivation.
 Central DI can be distinguished from nephrogenic 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.

Signs and Symptoms

 Feeling very thirsty and drinking more liquid than usual
 Losing weight without trying
 Dry skin
 Feeling confused, weak, and dizzy
 Fatigue
 Headaches and vision changes
 Children may have irritability, a loss of appetite, and slow growth

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These are drugs that reduce urine volume, particularly in diabetes insipidus (DI)
which is their primary indication. Drugs are:

1. Antidiuretic hormone (ADH, Vasopressin), Desmopressin, Lypressin, Terlipressin

2. Thiazide diuretics, Amiloride.

3. Miscellaneous: Indomethacin, Chlorpropamide, and Carbamazepine.

Central DI

 Cause

 Head injury, either surgical or traumatic, in the region of the pituitary and/or
hypothalamus may cause central DI.
 Postoperative central DI may be transient, permanent, or triphasic (recovery
followed by permanent relapse).
 Other causes include hypothalamic or pituitary tumors, cerebral aneurysms,
CNS ischemia, and brain infiltrations and infections.
 Finally, central DI may be idiopathic or familial. Familial central DI usually is
autosomal dominant (chromosome 20); vasopressin deficiency occurs several
months or years after birth and worsens gradually. Autosomal dominant
central DI results from mutations in the vasopressin gene that cause the
prohormone to misfold and oligomerize improperly, resulting in
accumulation of the mutant vasopressin precursor in the affected neuron and
neuronal death. Rarely, familial central DI is autosomal recessive owing to a
mutation in the vasopressin peptide itself that gives rise to an inactive
vasopressin peptide.

Drugs for Central DI

 Desmopressin

Antidiuretic peptides are the primary treatment for central DI, with desmopressin
being the preferred peptide. For patients with central DI who cannot tolerate
antidiuretic peptides because of side effects or allergic reactions,

Mechanism of Action: Upon binding of desmopressin to V2 receptors in the

basolateral membrane of the cells of the distal tubule and collecting ducts of the
nephron, adenylyl cyclase is stimulated. The resulting intracellular cascades in the
collecting duct lead to increased rate of insertion of water channels, called
aquaporins, into the lumenal membrane and enhanced the permeability of the
membrane to water.
Adverse Effect: less likely headache;dizziness;dry mouth;nausea; or mild stomach
pain.

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Other Treatment Options for Central DI

 Chlorpropamide
 Carbamazepine
 Clofibrate

 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 125–500 mg daily is
particularly effective in patients with partial central DI. If polyuria is not
controlled satisfactorily with chlorpropamide alone, addition of a thiazide
diuretic (see Chapter 28) to the regimen usually results in an adequate
reduction in the volume of urine.

 Carbamazepine (800–1000 mg daily in divided doses) and clofibrate (1–2 g

daily in divided doses) also reduce urine volume in patients with central DI.
Long-term use of these agents may induce serious adverse effects; therefore,
carbamazepine and clofibrate are used rarely to treat central DI.

The antidiuretic mechanisms of chlorpropamide, carbamazepine, and clofibrate are

not clear. These agents are not effective in nephrogenic DI, which indicates that
functional V2 receptors are required for the antidiuretic effect. Since carbamazepine
inhibits and chlorpropamide has little effect on vasopressin secretion, it is likely that
carbamazepine and chlorpropamide act directly on the kidney to enhance V2
receptor mediated antidiuresis.

Nephrogenic DI
 Cause

 Nephrogenic DI may be congenital or acquired. Hypercalcemia, hypokalemia,

postobstructive renal failure, lithium, foscarnet, clozapine, demeclocycline,
and other drugs can induce nephrogenic [Link] many as 1 in 3 patients treated
with lithium may develop nephrogenic DI.

 X-linked nephrogenic DI is caused by mutations in the gene encoding the V2

receptor, which maps to Xq28. A number of missense, nonsense, and frame-
shift mutations in this gene have been identified in patients with this disorder,
causing impaired routing of the V2 receptor to the cell surface, defective
coupling to G proteins, or decreased affinity of the receptor for vasopressin.

 Autosomal recessive and dominant nephrogenic DI result from inactivating

mutations in aquaporin 2. These findings establish that aquaporin 2 is essential
for the antidiuretic effect of vasopressin. Although the mainstay of treatment
of nephrogenic DI is assurance of an adequate intake of water, drugs also can
be used to reduce polyuria.

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Treatment Options for Nephrogenic DI

 Amiloride

Pharmacokinetics : Readily absorbed following oral administration and eliminated

predominantly by urinary excretion of intact drug.
Mechanism of Action: blocks the uptake of lithium by the Nachannel in the
collecting-duct system and is used off-label for lithium-induced nephrogenic DI.

Side effect: Ascites, Calcium Nephrolithiasis, Congestive Heart Failure (CHF),

Hypertension, Hypokalemia, Metabolic Alkalosis, Polyuria.

 Thiazide diuretics

Like Hydrochlorothiazide, is more potent.

Reduce the polyuria of patients with DI and often are used to treat non-lithium-
induced nephrogenic DI. In infants with nephrogenic DI, thiazides may be crucially
important because uncontrolled polyuria may exceed the child’s capacity to imbibe
and absorb fluids.

Pharmacokinetics: All thiazides can be administered orally, but there are differences
in their metabolism like Chlorothiazide.

Mechanism of Action: The natriuretic action of thiazides and resulting depletion of

extracellular fluid volume may play an important role in the thiazide-induced
antidiuresis since these effects appear to parallel the ability of thiazides to cause
natriuresis, and the drugs are given in doses similar to those used to mobilize edema
fluid. In patients with DI, a 50% reduction of urine volume is a good response to
thiazides. Moderate restriction of sodium intake can enhance the antidiuretic
effectiveness of thiazides.

Adverse Effects: extracellular volume depletion, hypotension, hypokalemia,

hyponatremia, hypochloremia, metabolicalkalosis, hypomagnesemia, hypercalcemia,
and hyperuricemia.

 Indomethacin and cyclooxygenase inhibitors

While case reports describe the effectiveness of indomethacin in the treatment of

nephrogenic DI, other cyclooxygenase inhibitors (e.g., ibuprofen) appear to be less
effective.

Pharmacokinetics: Indometacin displays a linear pharmacokinetics profile where the

plasma concentrations and area under the curve (AUC) are dose-proportional,
whereas half-life (T1/2) and plasma and renal clearance are dose-

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[Link] is readily and rapidly absorbed from the gastrointestinal tract.
The bioavailability is virtually 100% following oral administration and about 90% of
the dose is absorbed within 4 [Link] bioavailability is about 80-90% following
rectal administration.

Mechanism of Action: decrease in glomerular filtration rate, an increase in medullary

solute concentration, and/or enhanced proximal reabsorption of fluid. Also, since
prostaglandins attenuate vasopressin-induced antidiuresis in patients with at least a
partially intact V2 -receptor system, some of the antidiuretic response to indomethacin
may be due to diminution of the prostaglandin effect and enhancement of the effects
of vasopressin on principal cells of the collecting duct.

Adverse effect: acid or sour stomach, belching, diarrhea, heartburn, indigestion,

nausea, stomach discomfort, upset or pain, and vomiting.

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 X. Reference
Goodmand and Gilman’s: The Pharmacological Basis of Therapeutics;

13th edition.

Katzung B.G.: Basic and Clinical Pharmacology: 14th edition.

[Link]

[Link]

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