Pharmacology of Antidiuretics

1. Pharmacology of Antidiuretics
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DR.R.Lavanya,FOP

2. Antidiuretics
Antidiuretics or anti-aquaretics essentially:
• Inhibit water excretion
• ―Without‖ affecting salt excretion
They are the drugs that reduce urine volume, particularly
in diabetes insipidus (DI)- their primary indication
Drugs include:
• Antidiuretic hormone (ADH, Vasopressin),Desmopressin,
Lypressin, Terlipressin
• Thiazide diuretics, Amiloride.
• Miscellaneous: Indomethacin,Chlorpropamide, Carbamazepine
2DR.R.Lavanya,FOP

3. ANTIDIURETIC HORMONE
(Argenine Vasopressin-AVP)
• nonapeptide secreted by posterior pituitary (neurohypophysis)
along with oxytocin
• Osmoreceptors (present in hypothalamus) and Volume
receptors (present in left atrium, ventricles and pulmonary
veins) regulate the rate of ADH release governed by body
hydration.
• Osmoreceptors present in the hepatic portal system senses
ingested salt and release ADH even before plasma osmolarity
is increased by the ingested salt.
• Impulses from baroreceptors and higher centres also impinge
on the nuclei synthesizing ADH and affect its release.
• Physiological Stimuli for ADH release:
 Rise in plasma osmolarity
 Contraction of plasma extracellular fluid (e.c.f.) volume 3DR.R.Lavanya,FOP

4. ANTIDIURETIC HORMONE
• Neurotransmitters, hormones and drugs modify ADH
secretion.
• Enhanced by angiotensin II, prostaglandins (PGs), histamine,
neuropeptide Y and ACh.
• Decreased by GABA and atrial natriuretic peptide (ANP).
• Opioids have agent-specific and dose dependent action
Low-dose morphine inhibits , but high doses enhance
secretion.
• Opioid peptides are mostly inhibitory.
• Nicotine and imipramine stimulate, while alcohol, haloperidol,
phenytoin and glucocorticoids decrease ADH release.
• The human ADH is 8-arginine-vasopressin (AVP); 8-lysine-
vasopressin (lypressin) is found in swine and has been
synthetically prepared
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6. ADH action
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7. ADH (Vasopressin) receptors
V1 Receptors
At all sites except for sites of V2 (i.e. Collecting Duct cells)
Further classified as V1a and V1b
V1a: vascular smooth muscles (including that of vasa recta in renal
medulla), uterine, visceral smooth muscles, interstitial cells in renal medulla,
cortical CD cells, adipose tissue, brain, platelets, liver, etc.
V1b : anterior pituitary, certain areas in brain and in pancreas
V2 Receptors: More sensitive
Collecting Duct Principal cells in Kidney: Regulates their water permeability
Also present in AscLH cells: Activates Na+K+2Cl- cotransporter
Endothelium: vasodilator
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8. ADH: Action on Various Organs
Kidneys:
Acts on CD principal cells  renders them water permeable water absorbed 
concentrated urine (equilibrating with hyperosmolar medulla) passed
Blood Vessels:
Constricts through V1 receptors : raises blood pressure
Dilates through V2 receptors: endothelium dependent NO production
Uterus:
Contracted by acting on oxytocin receptors
GIT:
Increased peristalsis: evacuation and expulsion of gases
Central Nervous System:
Endogenous AVP may be involved in regulation of temperature, systemic
circulation, ACTH release, learning of tasks
Others: Induces platelet aggregation, hepatic glycogenolysis
Release of factor VIII and VonWillebrand’s factor from vascular endothelium :
V2 mediated
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10. 10
V2R
Increases urea
permeability in
terminal CD in
inner medulla
by stimulating
vasopressin
regulated urea
transporter
Medullary
hypertonicity
DR.R.Lavanya,FOP

11. All V2 receptor (V2R) mediated actions are exerted through the adenylyl cyclase (AC)-
cyclic AMP (cAMP) pathway,
while the V1a receptor (V1aR) mediated action is exerted via the phospholipase C—IP3:
DAG pathway.
Rapid actions
(1) Translocation of water channel containing vesicles (WCVs) and exocytotic insertion
of aquaporin 2 water channels into the apical membrane of principal cells of collecting
ducts; the primary action responsible for antidiuresis.
(2) Inhibition of endocytotic removal of aquaporin 2 channels from the apical
membrane.
(3) Activation of vasopressin regulated urea transporter (VRUT) at apical membrane of
collecting ducts in the inner medulla.
(4) Translocation of Na+K+2Cl¯ cotransporter to the luminal membrane of cells in thick
ascending limb of loop of Henle (AscLH).
(5) Activation of Na+K+2Cl¯ cotransporter in AscLH cells
 increased medullary hypertonicity  increased water absorption concentrated
urine formed(decreased urine)
(6) V1a receptor (V1aR) mediated vasoconstriction of vasa recta-diminished blood flow
to inner medulla: reduces washing off effect and helps in maintaining high osmolarity;
contributing to antidiuresis
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12. Long-term actions
(7) Gene mediated increased expression of aquaporin 2 channels in collecting duct
cells.
(8) Gene mediated increased expression of Na+K+2Cl¯ cotransporter in AscLH cells.
PKA—cAMP dependent protein kinase.
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14. 1.The atria have stretch receptors that are excited by overfilling.
2. When excited, they send signals to the brain to inhibit ADH secretion.
3. Conversely, when the receptors are unexcited as a result of under filling, the
opposite occurs, with greatly increased ADH secretion.
4. Decreased stretch of the baroreceptors of the carotid, aortic, and pulmonary
regions also stimulates ADH secretion
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15. Interactions:
• Lithium, demelocycline: partially antagonise AVP action (limiting cAMP
formation) reduce the urine concentrating ability of the kidney, produce
polyuria and polydipsia. -- Used in patients with inappropriate ADH
secretion
• NSAIDs (Indomethacin): augments AVP induced antidiuresis by inhibiting
renal PG synthesis.
• Carbamazepine, chlorpropamide: potentiates AVP action on kidney
Pharmacokinetics
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. Action of aqueous vasopressin lasts 3–4 hours.
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16. VASOPRESSIN ANALOGUES
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Lypressin Terlipressin Desmopressin (dDAVP)
8-lysine vasopressin
Synthetic prodrug of
vasopressin Synthetic peptide
Less potent than AVP Bleeding esophageal
varices
Selective V2 agonist
V1 and V2 activity
Less severe adverse
effects
that lypressin
12 times more potent than AVP
Longer duration of action
4-6 hrs
Negligible vasoconstrictor activity
Substitute for AVP for V1
actions
Longer duration of action 8-12 hrs
Preparation of choice for all V2 mediated actions
Intranasal route preferred (bioavailability 10-20%) oral
(1- 2%; avoids nasal side effects)
DR.R.Lavanya,FOP

17. Uses
• Based on V2 Actions:(Desmopressin is the drug of choice)
• Diabetes Insipidus (Neurogenic)
• Bedwetting in children and nocturia in adults
• Renal Concentration Test
• Hemophilia, von Willebrand’s Disease
• Based on V1 Actions:
• Bleeding Esophageal Varices
• Before abdominal radiography
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18. Adverse effects
• Selective drugs produce lesser side effects
• Transient headache and flushing: frequent
• Local Application: Nasal irritation, congestion, rhinitis, ulceration, epistaxis
• Systemic Side effects: belching, nausea, vomiting, abdominal cramps, pallor, urge
to defecate, backache in females (uterine contraction)
• Fluid retention, hyponatremia
AVP:
• Bradycardia, increased cardiac afterload, precipitate angina
• Urticaria and other allergies are possible with any preparation
• Contraindicated in patients with Ischaemic heart disease, hypertension, chronic
nephritis, psychogenic polydipsia
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19. Thiazide- Hydrochlorthiazide
• Paradoxical Effect
• Furosemide: effective but less desirable: short and brisk action
• Effective in both neurogenic as well as nephrogenic DI
• Mechanism of Action:
1. similar to salt restriction
• State of sustained electrolyte depletion
• Glomerular filtrate completely reabsorbed iso-osmotically inPT
• Urine passing has low solutes  presented to cortical DT  salt
reabsorption decreases  less dilute urine presented to CD  same
is passed out
2. Reduces glomerular filtration rate  reduced fluid load on tubules
• Amiloride: Lithium induced nephrogenic DI
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20. Other Antidiuretics
Indomethacin
Reduces renal PG synthesis  reduced polyuria in nephrogenic DI.
Combined with thiazide +/- amiloride
Other NSAIDs less active
Chlorpropamide
Long acting sulfonylurea oral hypoglycaemics. reduce urine volume in DI
of pituitary origin but not in renal DI
Effective in neurogenic DI: sensitizes kidney to ADH. Its efficacy
depends on small amounts of the circulating hormone; it is not active
when ADH is totally absent.
Carbamazepine - Antiepileptic
Effective in neurogenic DI
Higher Doses needed: marked adverse effects
20DR.R.Lavanya,FOP

21. Vasopressin Antagonists
Tolvaptan
orally active nonpeptide selective V2 receptor antagonist used in the
treatment of hyponatraemia due to CHF, cirrhosis of liver or syndrome
of inappropriate ADH secretion (SIADH).
It increases free water clearance by the kidney (aquaretic) and helps to
correct the low plasma Na+ levels. Symptoms of worsening heart failure
were improved.
Too rapid correction of hyponatraemia should not be attempted attempted,
possibility of thrombotic complications due to haemoconcentration.
Frequent side effect: Thirst and dry mouth.
Others are fever, g.i. upset and hyperglycaemia.
Metabolized by CYP3A4; contraindicated in patients receiving inhibitors of
this isoenzyme. The t½ is 6–8 hours, once daily dose.
Mozavaptan (V2 selective antagonist) and Conivaptan (V1a+V2 antagonist)
are the other vasopressin antagonists clinically used. 21DR.R.Lavanya,FOP

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Reference:
Essentials of Medical Pharmacology, Seventh Edition, KD Tripathi
DR.R.Lavanya,FOP

23. Thank you
23DR.R.Lavanya,FOP