Diuretics and Antidiuretics PDF

 Diuretics Carbonic Anhydrase Inhibitors (Site I) – Brinzolamide, Acetazolamide, Dorzolamide Osmotic Diuretic (Site II) – Glycerine, Urea, Mannitol, Isosorbide Loop Diuretics/High Ceiling (Site III)- TALH – Frusemide/ Furosemide, Bumetanide, Torasemide, Ethacrynic...

 Diuretics Carbonic Anhydrase Inhibitors (Site I) – Brinzolamide, Acetazolamide, Dorzolamide Osmotic Diuretic (Site II) – Glycerine, Urea, Mannitol, Isosorbide Loop Diuretics/High Ceiling (Site III)- TALH – Frusemide/ Furosemide, Bumetanide, Torasemide, Ethacrynic acid Thiazide Diuretics (Site IV) – Hydrochlorothiazide, Clopamide, Benzthiazide, Chlorthalidone, Metolazone, Xipamide, Indapamide Potassium Sparing Diuretics (Site V) – Carbonic An-hydrase Thiazide Inhibitors diuretics Osmotic Diuretics Potassium Sparing Diuretics Loop Diuretics (High Ceiling) Carbonic Anhydrase Inhibitors Carbonic Anhydrase Inhibitors Loop Diuretics Thiazides  Spironolactone Amiloride Furosemide  Its maximal natriuretic effect is much greater than that of other classes.  The diuretic response goes on increasing with dose: upto 10 L  of urine may be produced in a day.  It is active even in patients with relatively severe renal failure.  The onset of action is prompt (i.v. 2–5 min., i.m. 10–20 min., oral 20– 40 min.) and duration short (3–6 hours). Weak CAse inhibitory action:  Furosemide has weak CAse inhibitory action; increases HCO3¯ excretion as well Renal and systemic haemodynamics:  After 5 min of i.v. injection, renal blood flow is transiently increased and there is redistribution of blood flow from outer to midcortical zone; g.f.r. generally remains unaltered due to compensatory mechanisms despite increased renal blood flow.  Pressure relationship between vascular, interstitial and tubular compartments is altered, the net result of which is decreased PT reabsorption.  The intrarenal haemodynamic changes are brought about by increased local PG synthesis. Blood vessels and CVS:  Intravenous furosemide causes prompt increase in systemic venous capacitance and decreases left ventricular filling pressure.  This action also appears to be PG mediated and is responsible for the quick relief it affords in LVF and pulmonary edema. Other Effects:  Furosemide increases Ca2+ and Mg2+ excretion (contrast thiazides which reduce it) by abolishing transepithelial potential difference in the thick AscLH which drives their reabsorption.  It tends to raise blood uric acid level by competing with its proximal tubular secretion as well as by increasing reabsorption in PT which is a consequence of reduced e.c.f. volume.  The magnitude of hyperuricaemia is lower than that with thiazides.  A small rise in blood sugar level may be noted after regular use of furosemide, but is again less marked compared to thiazides. Mechanism of salt reabsorption in the thick ascending limb of loop of Henle (AscLH) cell, and site of action of furosemide on the Na +-K+-2Cl¯ cotransporter Mechanism:  The major site of action is the thick AscLH (therefore called loop diuretics) where furosemide inhibits Na+- K+-2Cl¯ cotransport. (Site- II).  Furosemide attaches to the Cl¯ binding site of this protein to inhibit its transport function.  It is secreted in PT by organic anion transport and reaches AscLH where it acts from luminal side of the membrane.  The corticomedullary osmotic gradient is abolished.  K+ excretion is increased mainly due to high Na+ load reaching DT. Pharmacokinetics:  Furosemide is rapidly absorbed orally but bioavailability is about 60%. In severe CHF oral bioavailability may be markedly reduced necessitating parenteral administration.  Lipid-solubility is low, and it is highly bound to plasma proteins.  It is partly conjugated with glucuronic acid and mainly excreted unchanged by glomerular filtration as well as tubular secretion.  Some excretion in bile and directly in intestine also occurs. Plasma t½ averages 1–2 hour but is prolonged in patients with pulmonary edema, renal and hepatic insufficiency. Use of high ceiling diuretics: 1. Edema: Diuretics are used irrespective of etiology of edema— cardiac, hepatic or renal. 2. Acute pulmonary edema (acute LVF, following MI): Intravenous administration of furosemide or its congeners produces prompt relief. 3. Cerebral edema Though osmotic diuretics are primarily used to lower intracranial pressure 4. Hypertension High ceiling diuretics are indicated in hypertension only in the presence of renal insufficiency, CHF, or in resistant cases and in hypertensive emergencies. 5. Along with blood transfusion in severe anaemia, to prevent volume overload. 6. Hypercalcaemia of malignancy This condition may present as a medical emergency with severe volume depletion. Rapid  Antidiuretics Antidiuretics (more precisely ‘anti-aquaretics’, because they inhibit water excretion without affecting salt excretion) 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, Carbamazepine.  ANTIDIURETIC HORMONE (Argenine Vasopressin-AVP) 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’. Both are transported down the axons to the 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. Osmoreceptors are also present in the hepatic portal system which sense 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. The two main physiological stimuli for ADH release are rise in plasma osmolarity and contraction of e.c.f. volume. ADH (Vasopressin) receptors These are G protein coupled cell membrane receptors; two subtypes V1 and V2 have been identified, cloned and structurally characterized. V1 Receptors All vasopressin receptors except those on renal CD cells, AscLH cells and vascular endothelium are of the V1 type. These are further divided into V1a and V1b subtypes V1a receptors are present on vascular smooth muscle (including that of vasa recta in renal medulla), uterine and other visceral smooth muscles, interstitial cells in renal medulla, cortical CD cells, adipose tissue, brain, platelets, liver, etc. The V receptors are localized to the anterior pituitary, certain areas in brain and in pancreas. The V1b 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 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 IP3/DAG pathway) resulting in growth (hypertrophy) of vascular smooth muscle and other responsive cells. V2 Receptors These are located primarily on the collecting duct (CD) principal cells in the kidney —regulate their water permeability through cAMP production. Some V2 receptors are also present on AscLH cells which activate Na+ cotransporter. Vasodilatory V2 receptors are present on endothelium of blood vessels. The V2 receptors are more sensitive (respond at lower concentrations) to AVP than are V2 receptors Mechanism of action Vasopressin is instrumental in rapid adjustments of water excretion according to the state of body hydration, as well as in dealing with conditions prevailing over long subtype of ADH receptors are present on the basolateral membrane of principal cells in CDs. Activation of these receptors increases cAMP formation intracellularly → activation of cAMP dependent protein kinase A → phosphorylation of relevant proteins which promote exocytosis of ‘aquaporin-2’ water channel containing vesicles (WCVs) through the 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 CD cells is increased in proportion to the population of aquaporin-2 channels in the apical membrane at any given time. The V2 receptor stimulation (during chronic water deprivation) in addition upregulates aquaporin-2 synthesis through cAMP response element of the gene encoding aquaporin-2 Mechanisms of rapid and long-term anti-aquaretic action of vasopressin 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. 6. V1a receptor (V1aR) mediated vasoconstriction of vasa recta 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. Actions Kidney AVP acts on the collecting duct (CD) principal cells to increase their water permeability— water from the duct lumen diffuses to the interstitium by equilibrating with the hyperosmolar renal medulla. To achieve maximum concentration of urine, activation of V2 receptors increases urea permeability of terminal part of CDs in inner medulla by stimulating a vasopressin regulated urea transporter (VRUT or UT-1)—which in turn augments medullary hypertonicity. Blood vessels AVP constricts blood vessels through V receptors and can raise BP (hence the name vasopressin), but much higher concentration is needed than for maximal antidiuresis. The V2 receptor mediated vasodilatation can be unmasked when AVP is administered in the presence of a V1 antagonist. 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. CNS Exogenously administered AVP does not penetrate blood-brain barrier. 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. However, the action of aqueous vasopressin lasts 3–4 hours. 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). Terlipressin This synthetic prodrug of vasopressin is specifically used for bleeding esophageal varices; may produce less severe adverse effects than lypressin. Desmopressin (dDAVP) This synthetic peptide is a selective V 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. Substance P (SP) SP is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. Substance P is released from the terminals of specific sensory nerves. It is found in the brain and spinal cord and is associated with inflammatory processes and pain. The endogenous G-protein coupled receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R). Other neurokinin subtypes and neurokinin receptors that interact with SP have been reported as well. Binding of SP to NK-1 results in internalization by the clathrin-dependent mechanism to the acidified endosomes where the complex disassociates. Subsequently, SP is degraded and NK-1 is re-expressed on the cell surface. Substance P and the NK1 receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray). They are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs. Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise biological integrity. SP is thus regarded as an immediate defense, stress, repair, survival system. Vasodilation Substance P is a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release. Substance P is involved in the axon reflex-mediated vasodilatation to local heating and wheal and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium. Inflammation SP initiates expression of almost all known immunological chemical messengers (cytokines). Also, most of the cytokines, in turn, induce SP and the NK1 receptor. SP is particularly excitatory to cell growth and multiplication, via usual, as well as oncogenic driver. Pain Preclinical data support the notion that Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation. Mood, anxiety, learning Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, pain, and nociception. Vomiting The vomiting center in the medulla, called the Area Postrema, contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Cell growth, proliferation, angiogenesis, and migration Substance P has been known to stimulate cell growth in normal and cancer cell line cultures, and it was shown that substance P could promote wound healing of non-healing ulcers in humans.