Pharmacology Lecture Slides on Antidiuretics by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. ANTIDIURETICS
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Introduction
Drugs are used to reduce the urine volume
especially in diabetes insipidus (DI), they are
grouped as anti-diuretic agents.
Types:
 Antidiuretic Hormone: Vasopressin or ADH
 Congeners of ADH: Desmopressin, Lypressin,
Terlipressin
 Thiazide Diuretics: Hydrochlorthiazide
 K+ Sparing Diuretics: Amiloride
 Others: Indomethacin, Carbamazepine

3. Diabetes Insipidus
DI is a clinical condition due to a deficit of
ADH or due to the kidney’s resistance to the
effects of ADH and is characterized by the
passage of copious amounts of dilute urine.
DI may be either:
central (neurogenic) –Failure of secretion
Nephrogenic--Receptor insensitivity to ADH
DI may be a transient or a permanent
condition.

5. Etiologies of DI
CNS disorders that damage or create pressure in the area
of the hypothalamus, pituitary stalk, or posterior pituitary
gland
Head Injuries
CNS infections
Intraventricular Hemorrhage
Neurosurgical Procedures: common postoperatively with
resection of craniopharyngiomas, pituitary gland tumors, or
suprasellar tumors.
Associated with certain drugs: Ethanol, phenytoin,
halothane, opiate antagonists, lithium

6. Signs and Symptoms of DI
POLYURIA- first sign
Low Urine osmolality (less than 100-200 mOsm/L)
Urine specific gravity <1.010
Hypernatremia (serum sodium greater than 145
mEq/L)
Serum hyperosmolar (greater than 300 mOsm/L)
Thirst, polydipsia
Irritability or mental status changes
Dehydration
Shock

7. Clinical Management of DI
Goal is to prevent circulatory failure and
hyperosmolar encephalopathy.
Replace volume deficit and ongoing losses
Replace ADH
Close monitoring of serum and urine
osmolality

8. Fluid Replacement
Correct Hypernatremia slowly
Bolus infusion with NS if hypotensive
Volume deficit replaced over 24 to 48 hours
Replace ongoing urine losses

9. ADH
ADH is also known as arginine vasopressin (AVP
= ADH) because of its vasopressive activity, but its
major effect is on the kidney in preventing water
loss.
It is synthesized as pre-prohormones and
processed into a nonapeptide, that is secreted by
posterior pitutary (neurohypophysis).

10. ADH Deficiency
Mechanical disruption of the neurohypohyseal
tract by trauma, tumor, or surgery temporarily
causes ADH deficiency.
ADH will be restored after regeneration of the
axons (about 2 weeks).
But if disruption happens at a high enough level,
the cell bodies die in the hypothalamus resulting
in permanent ADH deficiency.

11. ADH & water
The biological action of ADH is to conserve body
water and regulate tonicity of body fluids.
It is primarily regulated by osmotic stimuli
(>280mOsm/L) and volume stimuli.
Water deprivation increases osmolality of plasma
which activates hypothalamic osmoreceptors to
stimulate ADH release.
Conversely, water ingestion suppresses
osmoreceptor firing and consequently shuts off ADH
release.
Plasma ADH then declines further after water is
absorbed and osmolality falls.

12. ADH Secretion Is Inhibited By
Alcohol
Oropharyngeal water reflex
Beta-adrenergic stimulants
ANF-Atrial Natriuretic factor
Phenytoin

13. Pathway by
which ADH
secretion is
lowered and
water excretion
raised when
excess water is
ingested
Pathway by
which ADH
secretion and
tubular
permeability to
water is
increased when
plasma volume
decreases

14. If plasma osmolality is directly increased by administration
of solutes, only those solutes that do not freely or rapidly
penetrate cell membranes, such as sodium, cause ADH
release.
Conversely, substances that enter cells rapidly, such as
urea, do not change osmotic equilibrium and thus do not
stimulate ADH release.
ADH secretion is exquisitely sensitive to changes in
osmolality.
Changes of 1-2% result in increased ADH secretion.
ADH and Solutes

16. ADH: Mechanism in Kidney
ADH binds and activates V2 receptors present in the CD
membrane
 Increased intracellular c-AMP concentration
 Activation of PK-A
 Production of “aquaporin-2” in CD
 Reabsorption of water
Also stimulates VRUT at terminal part of CD
 Reabsorption of urea
 Medullary hypertonicity
 Water reabsorption.
VRUT-Vasopressin Regulated Urea Transporter

17. ADH: Mechanism in Blood Vessels
V1 receptors present in blood vessels responsible
for vasoconstriction
Rise in BP (vasopressin)
But antidiuresis is insignificant via V1.
Activation of V1 receptors
Stimulation of PLC-IP3/DAG pathway
Release of Ca2+
Contraction, glycogenolysis, platelet
aggregation, ACTH release, etc.

18. ADH: Other Actions
Uterus:
Contracts uterus via oxytocin receptors
Quite equipotent to oxytocin in non-pregnant or
early pregnant women.
Sensitivity less than oxytocin near term of
pregnancy.
Platelet:
Induces platelet aggregation, releases
coagulation factor VIII and Von Willebrand’s factor
from vascular endothelium (V2 actions)

19. ADH: Pharmacokinetics
Destroyed by trypsin in GI so administered only
via parenteral route or intra-nasal application.
Very short half-life (~25 min) because peptide
chain easily cleaved in many organs, esp. liver and
kidney.

20. ADH Related Drugs
Agent Potency Duration
of Action
Vasopressin (aqueous,
AVP)
V2 > V1 3-4 h
Lypressin Less potent than AVP;
V1 = V2
4-6 h
Desmopressin Selective V2 agonist;
12 times more potent
than AVP; can be
given orally
8-12 h
Terlipressin Prodrug of
vasopressin. Less
severe A/E than
lypressin
4-6 h

21. USES of ADH & Related Agents
V2-Mediated Uses:
Diabetes Insipidus of neurogenic origin:
Desmopressin is the DoC
Bedwetting in children and nocturia in adults:
Intranasal or oral Desmopressin
Renal Concentration Test:
AVP or Desmopressin
Hemophilia, Von Wilebrand’s Disease:
AVP, Desmopressin (preferred)

22. ADH: Side Effects
Desmopressin: selective V2 action; less A/E
than vasopressin, lypressin ad terlipressin.
Nasal irritation, congestion, rhinitis, ulceration and
epistaxis/nose bleeding with local application.
Belching, nausea, abdominal cramps, pallor, urge to
defecate, backaches.
Fluid retention, hyponatremia, Bradycardia, angina
Contraindicated in HTN, chronic nephritis and
psychogenic polydipsia.

23. THIAZIDES
Paradoxical effect as antidiuretic in DI
(nephrogenic).
Less desirable due to short and brisk action.
Reduce urine volume in both pitutary origin and
renal origin (mainly) but efficacy is low.
Mechanism of action not well clear.
Paradoxical Antidiuretic Effect of Thiazides in Diabetes
Insipidus: Another Piece in the Puzzle---Johannes Loffing
http://jasn.asnjournals.org/content/15/11/2948.full

24. THIAZIDES: MECHANISM
Unclear, possible mechanism(s):
Cause sustained electrolyte depletion:
Glomerular filtrate is more rapidly absorbed iso-
osmotically in PT
Reduced salt reabsorption in cortical diluting
segment
Less dilute urine passed out.
Also reduce GFR and thus fluid load on tubules.

25. THIAZIDES
Hydrochlorthiazide 25-50 mg TDS is more
convenient and cheap than ADH (AVP) and has
been used in DI (both neurogenic and
nephrogenic) to reduce polyuria; however, is
less efficacious.
It is known to be effective in renal DI, where
ADH fails to work.

26. Other Agents
Amiloride:
The drug of choice for lithium induced
nephrogenic DI.
Indomethacin:
Used in renal DI to reduce urine output by
reducing renal PG synthesis.

27. Other Agents
Carbamazepine:
An antiepileptic agent, reduces urine
volume in DI of pitutary origin only.
Mechanism not clear, may increase the
efficiency of ADH on CD cells.
Since higher doses required, not preferred.

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