Nitric Oxide and its utility
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Nitric oxide (NO) is an endogenous signaling molecule generated from L-arginine by nitric oxide synthase. It is a key signaling molecule in the cardiovascular, nervous, and immune systems. NO activates guanylate cyclase, increasing cyclic GMP levels to cause smooth muscle relaxation and inhibit platelet aggregation. The physiological role of NO was discovered in the vasculature, where it was shown that endothelium-derived relaxing factor causing vasodilation was NO. NO has diverse functions and is involved in processes like neurotransmission, host defense, and inflammation.
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Nitric Oxide and its utility
- 1. Nitric Oxide and Its Utility By Dr Ketan Asawalle JR1 Dept of Pharmacology SVNGMC Yavatmal
- 3. Formula: NO IUPAC ID: Nitric oxide Molar mass: 30.01 g/mol Density: 1.34 kg/m³ Boiling point: -152 °C Soluble in: Water
- 4. Oxide (NO) is a novel mediator with diverse function generated from L-argenine by nitric oxide synthase(occurs in endothelial, neuronal and inducible
- 5. a FREE RADICAL gas that forms during lightening NO NO NO NO NO NO NO NO NO NO NO
- 6. cultures of MACROPHAGES were subjected
- 7. VASCULAR STUDIES also indicated towards the like acetylcholine were known to relax blood LUMINAL ENDOTHELIAL CELLS near SMOOTH They secreted EDRF
- 8. The physiological function of NO was discovered in the vasculature when it was shown that the endothelium derived relaxing factor was FURCHGOTT ZAWADZKI NO
- 9. formed by an enzymatic catalysed reaction between
- 10. Key role as a signalling molecule in • CARDIOVASCULA SYSTEM • NERVOUS SYSTEM Also has a role in HOST DEFENCE
- 11. NO is endogenous activator of Guanylyl cyclase Activates cGMP Secondary Messenger Nerves, smooth muscles, monocytes and platelets
- 12. Nitrogen and oxygen are neighbours in periodic so they have a few similar properties For instance HAEM
- 13. important for activation of guanylyl cyclase as it has mechanism acts in inactivation of NO by Haemoglobin
- 14. BIOSYNTHESIS OF NITRIC OXIDE
- 15. Enzyme in central control of Nitric Oxide biosynthesis NITRIC OXIDE SYNTHASE iNOS NOS-II nNOS NOS-I eNOS NOS-III i = Inducible e = Endothelial n = Neuronal
- 16. iNOS NOS-II nNOS NOS-I eNOS NOS-III •Macrophages •Kupffer cells •Neutrophills •Fibroblasts •Vascular smooth muscles •Endothelium •Cardiac myosites •Osteoblasts •Osteoclasts •Neurons CONSTITUTIVE FORMS PHYSIOLOGICAL PATHOLOGICAL
- 20. activity of constitutive isoforms of NOS is controlled CALCIUM CALMODULIN by TWO ways
- 21. Endothelium dependent Agonists like Acetycholine,bradykinin,Substance P Cytoplasmic Calcium ions Calcium Calmodulin Activates eNOS and nNOS
- 22. absence of any change in calcium ion concentration Phosphorylation of specific resides on eNOS Controls Calcium-Calmodulin concentration
- 23. important stimulus controlling endothelial NO SHEAR STRESS mechanoreceptors and transduced via SERINE-THREONINE
- 24. cAMP eNOS Protein Kinase A-mediated phosphorylation e.g. ß2 agonists Protein C kinase eNOS Phosphorylation of residues in calmodulin binding domain INSULIN eNOS Tyrosine Kinase Activation
- 25. constitutive NOS, iNOS does not depend on Calcium iNOS is activated by • Bacterial Lipopolysaccharides Cytokines synthesised in response to Lipopolysaccharides
- 26. Tumour Necrosis factor alpha Interlukin-1 Involved in induction of iNOS But Not Alone INTERFERON GAMMA
- 28. DEGRADATION OF NITRIC OXIDE 2NO + O2 ——> N2O4 N2O4 + H2O ——> NO3- + NO2- + 2H+ NO2- + HbO ——> NO3- + Hb
- 29. Nitric Oxide is inactivated by • Combination with haem of haemoglobin • Oxidation to Nitrite or Nitrate Excreted through MAJOR ROUTE
- 30. unstable and combine reversibly with CYSTINE NO + Cystine residues of Albumin and Globulin Stable Nitrosothiols They act as circulation O2 sensitive NO carriers
- 31. reactions with a variety of oxides of nitrogen that NO + PEROXISIDES ––> PEROXYNITRATE(ONOO-) • DNA damage • Nitration of tyrosine • Oxidation of Cystine
- 32. EFFECTS OF NITRIC OXIDE
- 33. volatile gas and it reacts with various metals, function of NO is activation of soluble Gyanylyl combining with haem group which is important for
- 34. BIOCHEMICAL AND CELLULAR ASPECTS NO can be studied with NO gas dissolved donors od NO can also be used to study the • Nitroprusside • S-nitrosoacetylpenicillamine(SNAP) • S-nitroglutathine(SNOG)
- 35. BIOCHEMICAL AND CELLULAR ASPECTS activate Gyanylyl Cyclase in the same cell that AUTOCRINE EFFECTS e.g. Barrier function of endothelium
- 36. BIOCHEMICAL AND CELLULAR ASPECTS site of synthesis and activate Guanylyl Cyclase protein G, cyclic nucleotide phosphodiesterase, induced smooth muscle contraction and platelet
- 37. BIOCHEMICAL AND CELLULAR ASPECTS Inhibits Smooth muscle and Fibroblast proliferation Migration adhesion and aggregation of platelets Monocyte adhesion ANTIATHEROSCLEROTIC
- 38. BIOCHEMICAL AND CELLULAR ASPECTS receptors when stimulated excessively produce Nitric Oxide HOST DEFENCE NEURONAL DESTRUCTION Through DIRECT EFFECT PEROXYNITRATE ANIONS
- 39. VASCULAR EFFECTS Argenine/NO pathway is tonically active in resistance keeps vasodilation in resistance vessels thus It is Anti-Atherosclerotic Anti-Thrombotic
- 40. NEURONAL EFFECTS Cholinergic mediators in many tissues like upper airway, Important for neuronal development Helps in synaptic Plasticity
- 41. HOST DEFENCE NO has Cytotoxic/Cytostatic effects This has been proved experimentally in mice without iNOS were susceptible to Leishmania
- 42. SEPTIC SHOCK Systemic inflammatory response TNF-alpha Endotoxins Cytokines Macrophages Neutrophils T cells Hepatocytes Smooth muscle cells Endothelial cells Fibroblasts NO HYPOTENSION
- 45. Actions of NO
- 46. Actions of NO
- 48. NITRIC OXIDE
- 49. Inhalation of large quantities of nitric oxide • ACUTE PULMONARY OEDEMA • METHAEMOGLOBINEMIA 300 ppm has bronchodilatory action
- 50. MAIN ACTION PULMONARY VASODILATATION NO preferentially acts on VENTILATED ARDS
- 51. different reasons causing shunting of arterial PERFUSED areas and causing VASODILATION ETHYL NITRIC gas is being used to reduce
- 52. NITRIC OXIDE DONORS/PRECURSORS • NITROPRUSIDE • GLYCERYL TRINITRATE(GTN) • S-NITROSOGLUTATHIONE(SNOG) • S-NITROSOACETYLPENICILLAMINE(SNAP)
- 53. common mode of action of these drugs DONATION of NO more potent on VASCULAR SMOOTH selectively INHIBITS PLATELET FUNCTION
- 54. lowers arterial BP parallel to rise in plasma causes lowering of nitrites in body leading
- 55. Sodium Nitropruside Rapidly acting Consistantly acting Brief duration of action - 2 to 5 minutes Dose can be TITRATED
- 56. Sodium Nitropruside both RESISTANCE and CAPACITANCE TOTAL PERIPHERAL RESISTANCE and Myocardial work Reduced
- 57. Sodium Nitropruside Endothelial cells RBCs Na Nitropruside Enzymatically NITRIC OXIDE Non Enzymatically
- 58. 50mg in 500 ml of 5% Dextrose Slow IV is covered with dark cloth to avoid oxidation
- 59. Sodium Nitropruside USES • Hypertensive emergencies HYPOTENSION in REFRACTORY CCF, Pump Maintenance of patients with hypertension
- 60. Sodium Nitropruside SIDE EFFECTS Palpitations Nervousness Vomiting Perspiration Abdominal pain Disorientation Weakness Lacti acidosis
- 61. GTN It a VOLATILE LIQUID SUBLINGUAL route of administration is 1 - 2 minutes and peaks in 3 - 6
- 62. GTN T1/2 is 2 minutes the amount of time the drug is in contact
- 63. GTN GTN is readily absorbed from skin produces hemodynamic effects in
- 64. TRANSDERMAL PATCH produces effect in administration produces stable titrable GTN
- 65. ISOSORBIDE DINITRATE SUBLINGUAL route gives peak in5 - 6 minutes minutes but sustained release can give ISOSORBIDE MOMONITRATE Active metabolite of Isosorbide dinitrate
- 66. USES • Angina Pectoris • Acute Coronary Syndrome • MI • CHF with acute LVH • Biliary colic • Esophagial spasm • Cyanide poisoning
- 67. CYANIDE POISONING Haemoglobin Methaemoglobin CYANIDE SODIUM NITRITE AMYL NITRITE Cyanomethhemoglobin SODIUM THIOSULPHATE Methaemoglobin + Na Thiocynate
- 68. INHIBITORS OF NITRIC OXIDE SYNTHESIS
- 69. NON SELECTIVE N-MONOMETHYL-L-ARGENINE(L-NMMA) NITRO-L-ARGENINE METHYL ESTER(L-NAME) ASSYMETRIC DIMETHYL GLYCERENE
- 70. infused slowly in brachial artery causes LOCAL VASOCONSTRICTION L-NMMA acts through nNOS When Given IV Vasoconstriction of Renal, Mesenteric and Cerebral Sustained muscle resistance and increased BP
- 72. SELECTIVE • iNOS - N-iminomethyl-L-lysine •nNOS - 7-nitroindazole S-methyl-L-thiocitruline
- 74. POTENTIATORS OF NITRIC OXIDE
- 75. SELECTIVE NO DONORS GTN SNOG SNAP DIETARY SUPPLIMENTS BEETROOT ANTIOXIDNTS Reduce free oxygen radicals and stabilise NO
- 76. ACE inhibitors, Statins, Insulins, Oestrogens RESTORE ENDOTHELIUM FUNCTION ß2 AGONISTS Activate L-Argenine/NO Pathway PHOSPHODIESTERASE V INHIBITORS Sildenafil, Tadanafil, Vardenafil
- 77. PHOSPHODIESTERASE V INHIBITORS Used in treatment of ERECTILE DYSFUNCTION SILDENAFIL TADANAFIL VARDENAFIL
- 78. Generates cGMP NO Dephosphorylates MLCK PD-5 SILDENAFIL TADANAFIL VARDENAFIL 5-GMP
- 79. SILDENAFIL Selective PD-5 Inhibitor Enhances NO activity in CORPORA CAVERNOSA Oral bioavailability is about 40% Peak blood levels attained in about 1 - 2 hours Metabolised by CYP3A4
- 80. SILDENAFIL SIDE EFFECTS Headache Nasal congestion Dizziness Facial flushing Fall in BP Pulmonary HTN
- 81. TADANAFIL Faster onset of action Longer lasting T1/2 18 hours Duration of action 24-36 hours Peak Plasma levels in 80 - 120 minutes
- 82. UTILITY OF NITRIC OXIDE HYPERTENSION Maintenance Nitroprusside Emegencies Na Nitroprusside GTN Isosorbide
- 83. UTILITY OF NITRIC OXIDE ERECTILE DYSFUNCTION Sildenafil Tadanafil Vardenafil
- 84. UTILITY OF NITRIC OXIDE PULMONARY HTN and GASTRIC STASIS NO is under investigaton NEONATAL RESPIRATORY DISTRESS SYNDROME INHALED NO and ETHYL NITRIC GAS
- 85. UTILITY OF NITRIC OXIDE there is excess NO production e.g. INFLAMMATION,
- 86. THANK YOU
- 87. References 1. Rang and Dale’s Pharmacology 6th edition 2. Basic and Clinical Pharmacology; Katzung 12th edition 3. Essential of Medical Pharmacology; K D Tripathi 7th edition