ANTIDIURETICS

GROUP 7
Group members
definition
• Antidiuretics are substances that inhibit water excretion with low or
without effect on salt excretion
• Majoring acting on the kidney
• Antidiuretics include:
ADH and its analogues
Natriuretics
Other antidiuretics
The primary and principle antidiuretic is ADH
Antidiuretic Hormone (ADH)
• Endogenous substance released by the posterior lobe pf the pituitary gland
• Also known as vasopressin due to its constriction effect of the blood vessels

Synthesis
• Produced by magnocellular neurons in the supraoptic and paraventricular
nuclei of the hypothalamus
• Produced as a preprohormone
• The hormone bound to neurophysin is through axons of these neurons to
the posterior pituitary gland for storage ( hypothalamoneurohyophyseal
system)
• ADH is also synthesized in small quantities in
 walls of the heart
Adrenal glands
Release
• ADH released from posterior pituitary gland is under regulation by ;
• Plasma osmolarity
Increased osmolarity (osmoreceptors) ↑ release
• Blood volume and blood pressure
Hypovolemia and hypotension ↑ release
• Hormones and neurotransmitters
Stimulators
 Ach, histamine, dopamine, glutamine, aspartate
Inhibitors
 ANP, GABA, opioids

• Pharmacological agents
Pharmacokinetics
• administered by intravenous or intramuscular injection.
• The half-life of circulating vasopressin is approximately 15 minutes.
• undergoes renal and hepatic metabolism via reduction of the
disulfide bond and peptide cleavage.
Pharmacodynamics
ADH binds to its receptors in different tissues to carry out its roles
These receptors are G protein coupled and these include;
V1 and V2
V1 are classified into V1a and V1b
• V1a is found in vascular smooth muscle, adrenal gland, myometrium,
bladder,
• adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa
• recta in the renal microcirculation, epithelial cells in the renal cortical
collecting duct, spleen, testis, and many CNS structure
Receptors cont…..
• V1b is found in anterior pituitary, several brain regions, pancreas, and
adrenal medulla.
• V2 is distributed predominantly in principal cells of the renal
collecting duct system but also are present on epithelial cells in TAL
and on vascular endothelial cells.
Vasopressin binding to V1 receptors
• activates the Gq -PLC-IP3 pathway, thereby mobilizing intracellular
Ca2+ and activating PKC, ultimately causing;
• biological effects that include immediate responses e.g.,
vasoconstriction, glycogenolysis, platelet aggregation, and ACTH
release
• and growth responses in smooth muscle cells
ADH binds have V2 receptors on their basolateral membranes of
Principal cells in renal collecting duct that couple to GS to stimulate
adenylyl cyclase activity
The resulting activation of the cyclic AMP/PKA pathway triggers an
increased rate of insertion aquaporins into the apical membrane
Their net shift into apical membranes in response to V2 receptor
stimulation greatly increases water permeability of the apical
membrane
V2 receptor activation also increases Na+ transport in TAL and
collecting duct. Increased Na+ transport in TAL is mediated by three
mechanisms that affect the Na+-K+-2C1− symporter:
• rapid phosphorylation of the symporter,
• translocation of the symporter into the luminal membrane, and
increased expression of symporter protein.
Actions of ADH
Renal actions (V2)
• Increased water permeability in the collecting ducts through insertion
of aquaporin 2 into the apical membrane
• Increased urea permeability in intramedullary collecting ducts
• Increased Na+ transport in TAL and the cortical collecting ducts
Cardiovascular system
• Vasoconstriction mainly the resistance vessels in the skin, skeletal
muscle, fat, pancreas, and thyroid gland.
• Mediated by V1 in the vascular smooth muscle
• Occurs at higher concentration than those required for maximal
antidiuresis
• Acts by inhibiting sympathetic efferents and potentiation of
baroreflexes
• V2 causes vasodilation
• Cardiac effects (reduced cardiac output and heart rate) are indirect as
a result of coronary vasoconstriction, decreased coronary blood flow,
and alterations in vagal and sympathetic tone.
CNS effects
• Vasopressin likely plays a role as a neurotransmitter by modulating
CNS autonomic systems controlling heart rate, arterial blood pressure,
respiration rate, and sleep patterns, though the physiological
significance is unclear.
• vasopressin may provide for sustained activation of the hypothalamic-
pituitary-adrenal axis during chronic stress.
Blood coagulation
• Activation of V2 stimulates the release of the clotting factor VIII and
von Willebrand factor form the vascular endothelium.
• This facilitates blood clotting
• Vasopressin is stored in platelets, and activation of V1 receptors
stimulates platelet aggregation

Uterus
• Stimulates oxytocin receptors and causes contraction of the uterus
Vasopressin agonists
1. Desmopressin
• A V2 selective agonist
• Desmopressin can be administered intravenously, subcutaneously, intranasally, or
orally.
• The half-life of circulating desmopressin is 1.5–2.5 hours.
• Nasal bioavailability of desmopressin is 3–4%, whereas oral bioavailability is less
than 1%
• desmopressin is the preferred drug for the treatment of central DI
• Also used in treatment coagulopathy in hemophilia A and von Willebrand disease
• Used in managing Bed wetting in children and nocturia in adults
2. Terlipressin
Administered as IV injection (terlipressin acetate)
Used to treat bleeding esophageal varices
Used caution in patients with chronic renal failure
3. Lypressin
Activates both V1 and V2
Less potent than vasopressin
Used in treatment of central diabetes insipidus and hepatorenal
syndrome
Therapeutic use
• V1 receptor agonists are indicated for the treatment of hypotension in
patients with vasodilatory shock that responds insufficiently to
therapy with fluids and catecholamines
• also used during abdominal surgery in patients with portal
hypertension to diminish the risk of hemorrhage during the
procedure
• V1 receptor–mediated GI smooth muscle contraction has been used
to treat postoperative ileus and abdominal distension
Therapeutic use
• V2 agonists have the same usage as desmopressin
Side effects and contraindications
• Headache, nausea, abdominal cramps, agitation, and allergic
reactions occur rarely.
• Overdosage can result in hyponatremia and seizures.
• Vasopressin can cause vasoconstriction and should be used
cautiously in patients with coronary artery disease
Natriuretics
• Mainly include; thiazides and amiloride
• These increase urinally excretion of Na+ ions resulting into
hyponatremia. This induces a state of sustained electrolyte depletion
• Results into complete reabsorption of the glomerular filtrate in PCT
• Also reduce the GFR and thus less load on the tubules
• Mostly used thiazide is hydrochlorothiazide and it reduces polyuria
• K+ supplements should be given with the use of thiazide
Amiloride is epithelial Na+ channel blocker (K+ sparing diuretic)
It blocks entry of Na+ into the principle cells
It also block lithium entry
It is majorly used in treatment of lithium induced nephrogenic DI
Other antidiuretics
Indomethacin
• Reduces PG synthesis hence used to reduce polyuria
• Combined with thiazides in treatments of nephrogenic DI
Chlorpropamide
• Long acting sulfonylurea
• Reduces urine volume in neurogenic DI but not in renal DI
• Sensitizes the kidney to ADH
Carbamazepine
• Antiepileptic
• Also reduces urine volume in neurologic DI
• Higher doses are needed
Thank you