This document provides information about antidiuretic drugs. It begins by defining antidiuretics as drugs that inhibit water excretion without affecting salt excretion. It then lists common antidiuretic drugs including antidiuretic hormone, desmopressin, thiazide diuretics, and others. The document discusses the mechanism of action of antidiuretic hormone, its effects on various organs like the kidneys and blood vessels, and conditions it can be used to treat like diabetes insipidus. It also covers antidiuretic hormone receptors, interactions with other drugs, and potential adverse effects.
3. Antidiuretics or Anti- Aquarectics?
What are Anti-Diuretics??
Hint: Remember the term diuretics??
Antidiuretics essentially:
Inhibit water excretion
“Without” affecting salt excretion
So which term would you prefer??
5. Antidiuretic Hormone(ADH)
Hormone (protein) secreted by posterior pituitary
(neurohypophysis)
Where is it formed?
What are the other hormones secreted by neurohypophysis?
Rate of ADH Release controlled by:
Osmoreceptors present in hypothalamus
Volume receptors present in left atrium, ventricles and
pulmonary veins
Physiological Stimuli for ADH release:
Rise in plasma osmolarity
Contraction of plasma extracellular fluid (e.c.f.) volume
6. ADH 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
7. 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
8. GIT:
Increased peristalsis: evacuation and expulsion of gases
Uterus:
Contracted by acting on oxytocin receptors
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 von Willebrand’s factor from vascular
endothelium : V2 mediated
ADH: Action on Various Organs
9. ADH: Mechanism of Action
V2R
ed
cAMP
Activation of
cAMP
dependent
Protein
kinase A
Water permeability of CD cells increased in proportion of aquaporin-2 channels
inserted in the apical membrane
Continued V2 stimulation upregulates aquaporin-2 systhesis through cAMP response
element of the gene encoding aquaporin-2
Protein
phosphor
ylation
Exocytosis of
aquaporin-2
WCVs
Rate of endocytosis
and concurrent
degradation reduced
More aqueous
channels gets inserted
11. ADH: Mechanism of Action
V2R:
Principal cells of Collecting Duct: increased aquaporins expression leading to
increased water absorption decreased urine formed.
Augmented by concurrent decrease in endocytosis and degradation of aquaporins
Continued stimulation leads to increased production of aquaporins
Increased Vasopressin regulated urea transporter expression in terminal CD cells
increased medullary hypertonicity increased water absorption decreased
urine formed
Increased translocation and synthesis of Na+K+2Cl- channels in ascending limb of
loop of Henle increased medullary hypertonicity concentrated urine formed
V1R
Constricts vasa recta: diminished blood flow to inner medulla: reduces washing off
effect and helps in maintaining high osmolarity; contributing to antidiuresis
12. AVP Interactions
Lithium, demelocycline: partially antagonise AVP action
(limiting cAMP formation)
Used in patients with inappropriate ADH secretion
NSAIDs (Indomethacin): augments AVP (increased renal
PG synthesis)
Carbamazepine, chlorpropamide: potentiates AVP
action on kidney
13. VASOPRESSIN ANALOUGES
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)
14. AVP: USES
Based on V2 Actions:
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
15. Vasopressin: 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
Contraindicated in patients with Ischaemic heart disease,
hypertension, chronic nephritis, psychogenic polydipsia
16. 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 in PT
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
17. 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
Effective in neurogenic DI: sensitizes kidney to ADH
Carbamazepine
Antiepileptic
Effective in neurogenic DI (? M/A)
Higher Doses needed: marked adverse effects
Hypothalamus: supraoptic and paraventricular nerve cell bodies: precursor peptide with its binding protein neurophysin
Osmoreceptors also present in hepatic portal system: senses ingested salt and releases ADH before plamsa osmolarity increases due to ingested salt.
Opiods:
Low dose morphine: inhibits ADH secretion
High doses: enhances it
Opioid peptides: inhibitory
Nicotine and imipramine: stimulate
Alcohol, haloperidol, phenytoin, glucocorticoid: decrease ADH release
G protein coupled cell membrane receptors
V1 receptors:
phospholipase C-IP3/DAG pathway: release of Ca++ from intracellular stores: vasoconstriction, visceral smooth muscle contraction, glycogenolysis, platelet aggregation, ACTH release etc.
Augumented by enhanced influx of Ca++ through Ca++ channels as well as by DAG mediated protein kinase C activation which phosphorylates relevant proteins.
Additionally, activates phospholipase A2- release arachidonic acid resulting in generation of PGs and other eicosanoids: V1 mediated effects.
Persistent V1 stimulation: activates proto-oncogenes: growth (hypertrophy) of vascular smooth muscles and other responsive cells
V2 receptors: regulates water permeability of CD principal cells by cAMP production
Kidney:
No ADH CD principal cells impermeable to water dilute urine passed
Graded effects seen
Blood Vessels:
Constricts through V1 receptors : raises blood pressure (vasopressin) : cutaneous, mesenteric, skeletal, fat depot, thyroid, coronary beds are constricted
Higher concentration need to see this effect
This effect not physiologically important: may have a role in CHF, haemorrhage, hypotensive states
Prolonged exposure: hypertrophy of vascular smooth muscles
Non pregnant and early pregnancy: AVP equipotent to oxytocin. At term sensitivity to oxytocin increases selectively
AVP:
Instrumental in rapid adjustment of water excretion
V2 receptors on basolateral membrane of CD principal cells
Other aquaporins: aq-1 (PT), aq-3,4 (CD)
Urea transportation in inner medulla.. Terminal regions of CD
AVP activity at Asc LH : translocating Na+K+2Cl- (short term) and increasing synthesis (long term).. Reinforces hypertonicity
Response of V1R:
Constricts vasa recta: diminished blood flow to inner medulla: reduces washing off effect and helps in maintaining high osmolarity.. Contributing to antidiuresis
Activation of medullary interstitial cell V1R: enhance PG synthesis- attenuates cAMP generation in CD cells: counterproductive.
V1R present in CD cells- stimulation activates Protien kinase c, diminished responsiveness of CD cells to V2 : decreased antidiuresis. However high concentration is needed. May be required to block V2 activity at persistently high ADH levels.
Lithium, demelocycline: partially antagonise AVP action (limiting cAMP formation)reduce urine concentrating ability polyuria and polydipsia)
Inactive orally: needs to be given parenterally
Diabetes Insipidus
Ineffective in Renal DI: kidney unresponsive to ADH
Usually life long therapy: short term therapy in head injury or neurosurgery
Desmopressin dose- individualised by measuring 24 hr urine volume
Aquaeous vasopressin/lysopressin injection: impracticable for long term use can be used to distinguish neurogenic and nephrogenic DI: response seen in neurogenic DI. Desmopressin 2microgm i.m. preferred these days
Bed wetting and nocturia
Intra nasal/oral, hS
Controls primary nocturia by decreasing urine volume
Nocturnal voids reduced to half… first sleep periods increased upto 2hrs in adults, fluid restriction 1hr before and upto 8 hrs after dosing required: avoids fluid retention
Check for fluid overload: BP, weight
Withdraw for 1 week every 3 months for reassessment
Renal Concentration test
5-10 U i.m. of aq. Vasopressin or 2 microgm of desmopressin maximal urinary concentration
Hemophilia, von Willebrand’s Disease
Releases factor VIII and vWf- controls bleeding
Desmopressin preferred 0.3 microgm/kg diluted in 50 mL saline infused iv over 30 mins
Bleeding Esophageal Varices
Vasopressin/terlipressin: constricts mesenteric blood vessles, reducing blood flow through the liver to the varices, allows clot formation
Terlipressin stops bleeding in ~80% cases; replaced AVP for fewer side effects and greater convinence in use
Octeotride can also be used
Before abdominal radiography
Drive out gases from gut.
Dose: 25-50 mg TDS or equivalent
Less effective than AVP in neurogenic DI, convenient and cheaper so thiazide used in neurogenic DI as well
K+ supplements needed
Prostaglandins: produced locally– modulators of renal circulation and renin release. PGE2 inhibits action of ADH– increases urine volume
Indomethacin: reduce local PG: action of ADH restored