9autacoids

1. Autacoids Greek : autos = self Akos = medicinal agents or remedy naturally occurring chemical substances produced within the body transported to the other parts of the body where they exert their effects protect the body from adverse situations.

2. Classification of autacoids In the basis of structure autacoids can be divided into three categories: a) Decarboxylated amino-acid Histamine Serotonin (5-HT) b) Polypeptides : Angiotensin Plasma kinins ( Bradykinin and kallidin ) Vasopressin VIP c) Ecosanoids : Prostaglandin thromboxanes leukotrienes Platelet activating factor (PAF)

3. Histamine Imidazole ethylamine Important inflammatory mediator potent biogenic amine and plays an important role in inflammation, anaphylaxis , allergies, gastric acid secretion and drug reaction Histidine Enzyme histidine decarboxylase Histamine

4. Sites of histamine release 1 ) Mast cell site: Pulmonary tissue (mucosa of bronchial tree) Skin GIT(intestinal mucosa) Conc. Of histamine is particularly high in these tissues

5. 2) Non-mast cell sites: CNS (neurons) Epidermis of skin. GIT(gastric cells) Cells in regenerating or rapidly growing tissues Basophils (in the blood)

6. Sites of histamine Storage Mast cell in most tissues. Basophils in the blood. Other storage site includes (non-mast cell sites): Epidermis of skin. Cells in the gastric mucosa Neurons in the CNS.

7. Metabolism of histamine The bound form of histamine is biologically inactive. There are two major paths of histamine metabolism in man. The more important of these involves ring methylation . Alternatively histamine undergoes oxidative deamination . The products of metabolism are imidazole acid and its ribosides . The metabolites are excreted in urine. Granules of mast cell contain glycosaminoglycans , acidic protein in histamine.

8.   Release of histamine Antigen-antibody reactions Mechanical trauma. Stings and venom. Fragments of complements (c 3a and c 5a ) Lysosomal protein (protease) Proteolytic enzyme( trypsin ) Surface acting antigen (bile salt, lysolecithin ) High molecular weight compound( dextran , ovomucoid )

9. Drugs: Chemotherapeutic agents Centrally acting drugs Spasmolytic drugs Sympathomimetic drugs Vasodilator drugs NM blocking agents Anticoagulants

10. Mechanism of Histamine release immunological . lgE antibody sensitized mast or basophil cells +antigen- > Fall of intracellular c AMP and an influx of ca ++ occurs- > degranulation  Histamine released Histamine held by an acidic protein and heparin within intracellular granules, when granules are extruded by exocytosis , Na+ gets exchanged for histamine Substance release during IgG or lgM immunoreactions also release histamine from the mast cells & basophil .

11. Chemical and mechanical mast cells injury causes degranulation of cytoplasmic granules & histamine is released. Certain amines ( E.g. morphine, d- tubocurarine ) accumulate in the mast cells due to affinity for heparin, displace histamine and form a heparin liberator complex. This complex increases the permeability of the mast cell membrane and diffuse histamine. Loss of granules from mast cells relapsed histamine by ion exchange. Na + in the extra-cellular fluid rapidly displace histamine from the complex. Compound 48/80 releases histamine from tissue from tissue mast cells by an exocytotic degranulation process requiring energy and ca ++

12. Histamine release inhibitors Guanidine, papaverine Thiamine Histamine itself Corticosteroids β- adrenoceptor agonist aminophylline LSD Monoamine oxidase inhibitors

13. Histamine receptors Type /location Agonist drugs H 1 receptor (H 1 -R) Bronchus Adrenal medulla skin Blood vessels urinary bladder Gastrointestinal tract CNS(post-synaptic) Hypothalamus cerebellum Histamine> 2-thiazolyle-thylamine>2-beta-histine>2-pyridylethyl-amine. **G-protein coupled PIP2 hydrolysis---increased IP3/DAG Release of Ca++ Protein Kinase C activation

14. H 2 receptor (H 2 -R ) Gastric parietal cells Heart Uterus CNS (postsynaptic) some blood vessels Mast cells. Impromadine > Histamine> Dimaprit > 4-methylhistaine > Betazole . **G- protein coupled H 2 – R acts by increase cAMP Adenyl cyclase activation---increase cAMP H 3 receptor (H 3 -R ) Pre-synaptic ( Brain) myenteric plexus other neurons . α- methyl-histamine **G protein coupled Decrease Ca++ influx K+ channel activation Decrease cAMP

15. Physiologic role of Histamine Play an important role in gastric HCl secretion by stimulating H 2 receptor. Endogenous histamine plays a central role in the immediate hypersensitivity and allergic reaction. In regulation of microcirculation through its vasoactive properties. Histamine acts as a neurotransmitter in the CNS . Inflammation Tissue growth and repair Headache Histamine helps in implantation of fertilized ovum by increasing blood supply to the myometrium .

16. Role of Histamine in Inflammation Histamine induces action of prostaglandin as well as bradykinin to produce pain. Histamine helps in the release of proteolytic & hydrolytic enzymes from the lysosomes . Histamine causes vasodilation and increases capillary permeability. So, Increase exudation of serum & plasma to surrounding area ( oedema ). Increase migration of polymorph leucocyte to the traumatic area. Increase migration of inflammatory cell to other places. All the processes are in the favour of inflammation

17. Indications of Histamine Diagnostic use: Diagnosis of pernicious anaemia (vit-B 12 deficiency). Pernicious anaemia -> Achlorohydria (no HCI) ->Histamine administered -> if no HCI(diagnostic) Diagnosis of phaechromocytoma : phaechromocytoma ->histamine administered -> excessive adrenaline release from adrenal medulla-> hypertensive crisis. Diagnosis of integrity of reflex arc.

18. Therapeutic use Meniere's disease .( non suppurative disease of labyrinth ) --- betahistine Various vascular headache.

19. Contraindication of histamine Bronchial asthma. Patient with active peptic ulcer disease . Gastrointestinal bleeding. Angina with hypotension.

20. Adverse effect of Histamine Dyspnoea due to bronchospasm . Hypotension (histaminic shock) Headache. Itching and pain Flushing Abdominal cramps. Diarrhea. Visual disturbance Metallic test

21. Histaminic Shock

22. Histamine Antagonists Actions of histamine opposed in 3 ways : Adrenaline type Release inhibition Adrenal steroids Sodium cromoglycate iii) Direct histamine receptor antagonists

23. H 1 -receptor blockers : Chlorpheniramine , promethazine , Diphenhydramine , citirizine , Terfenadine , Loratadine , Desloratadine . H 2 -receptor blocker: Cimetidine Ranitidine Famotidine Nizatidine H 3 -receptor blockers: Thioperamide Impromidine

24. Individual H1 receptor antagonist classification 1) Sedative (first generation) antihistamines: Highly lipid soluble and easily enters into the CNS: a ) Potent and marked sedative : Promethazine ( phenergan ) :widely used Diphenhydramine Dimenhydrinate b) Potent and moderate sedative: Chloryclizine Chlorpheniramine Tetrahydeoxy carboline c ) Less potent and less sedative : Mepyramine Pheniramine ( avil )

25. 2) Non-sedative (second generation ) antihistamines : Less lipid soluble therefore cannot enter into the CNS: Cetrizine Terfenadine Astemizole Loratadine Ketotifen Cyclizine

26. 3) Antihistamines having anti-cholinergic action a) Anti-emetic and anti-motion sickness. Promethazine Diphenhydramine b) Anti-parkinsonism: Orphenadrine Phenindamine Central action: anti- emetic, anti-motion sickness and anti- parkinsonism. Peripheral action: Atropine like side effects. 4) Anti-histamines having anti-serotonin action Cyproheptadine -5-HT antagonist action. 5) Antihistamine having local anaesthetic property: Promethazine Diphenhydramine :

27. Pharmacological action of H 1 blocker H 1 receptor blockade action Action not caused by histamine receptor blockade: Sedation Anti nausea and anti emetic Anti parkinsonism Anti cholinergic Alpha adrenoceptor block( orthostatic hypotension) Anti serotonin Local anesthetic action

28. 2 nd generation anti histamines (newer antihistamines ) Fexofenadine Loratadine Cetrizine Azelastine , mizolastine Mequitazone Terfenadine astemizol ebastine

29. Properties of newer antihistamine They are highly selective for H 1 receptors Less lipid soluble; hence no or poor penetration into CNS. They are devoid of significant anti-cholinergic actions like older antihistamines. They are usually active orally. Their metabolites are also active H 1 antagonist Astemizole are extensively plasma protein bound(t1/2:20hrs) These drugs are able to suppress the wheal and flare response to histamine or allergen for more than 12hours Low incidence of side effects

30. Indication of H 1 blockers 1)Dermatitis of all types. 2)Allergic reaction : Urticaria,Rhinitis,Conjunctivitis and 3)Anaphylactic shock 4)Anti-motion sickness: diphenhydramine 5)Anti- emetic:Cyclizine,Meclizine,Doxylamine (in pregnancy) 6) Anti- parkinsonism: Diphenhydramine is used. 7) Preanesthetic medication 8) As sedative agent: Promethazine 9)Cough depressant. 10) Otitis media. 11)common cold.

31. Adverse effect of H 1 blockers CNS : sedation Drowsiness Fatigue Irritability Incoordination Nervousness Tinnitus Ocular :disturbance of ocular accommodation anti- muscarinic action. Dryness of mouth Blurring of vision. Constipation. Urinary retention GIT : gastrointestinal upset. Teratogenicity : Cyclizine ( teratogenic ) Doxylamine (no teratogenicity ) Others : Dermatitis, skin rashes Agranulocytosis

32. 5-HYDROXYTRYPTAMINE (SEROTONIN): regulator of smooth muscle in the cardiovascular system and the gastrointestinal tract, an enhancer of platelet aggregation, and a neurotransmitter in the CNS 5-HT is found in high concentrations in enterochromaffin cells throughout the gastrointestinal tract, in storage granules in platelets, and broadly throughout the CNS widely distributed in the animal and plant kingdoms It occurs in vertebrates; mollusks, arthropods, and coelenterates; and in fruits and nuts. It also is present in venoms, including those of the common stinging nettle and of wasps and scorpions

33. Synthesis and metabolism of serotonin essential amino acid tryptophan 2 steps Tryptophan hydroxylase , a mixed-function oxidase converts tryptophan to 5-hydroxytryptophan. aromatic L-amino acid decarboxylase converts to 5-hydroxytryptamine Released by exocytosis from the serotonergic neurons metabolism of 5-HT involves oxidative deamination by monoamine oxidase (MAO), forming an acetaldehyde intermediate and then to 5-hydroxyindole acetic acid (5-HIAA) by a ubiquitous enzyme, aldehyde dehydrogenase

34. Serotonin receptors The 5-HT 1 , 5-HT 2 , and 5-HT 4-7 receptor families are members of the superfamily of GPCRs. The 5-HT 3 receptor, on the other hand, is a ligand -gated ion channel that gates Na + and K + similar to nicotinic receptors. 5-HT 1 Receptors. All 5 members of the 5-HT 1 -receptor subfamily inhibit adenylyl cyclase.decrease cAMP , autoreceptors , inhibit serotonergic receptors 5-HT 2 Receptors. The 3 subtypes of 5-HT 2 receptors are linked to phospholipase C with the generation of two second messengers, diacylglycerol (a cofactor in the activation of protein kinase C) and inositol trisphosphate (which mobilizes intracellular stores of Ca 2+ ).

35. 5-HT 3 receptor- corresponding to M type receptor gating cation channel , present in somatic and autonomic nerve endings, nerve endings in myenteric plexus, and area postrema . 5-HT 4 receptor is thought to evoke secretion in the alimentary tract and to facilitate the peristaltic reflex. 5-HT 4 receptors couple to G s to activate adenylyl cyclase , leading to a rise in intracellular levels of cyclic AMP ( cAMP )

36. Sites of 5-HT Action 1) Enterochromaffin Cells: gi mucosa , highest density in duodenum, synthesize 5-HT from tryptophan and store 5-HT and other autacoids. Basal release of enteric 5-HT is augmented by mechanical stretching. 2) platelets: not synthesized in platelets, but is taken up from the circulation and stored in secretory granules by active transport, regulates thrombosis and hemostasis (5-HT2a)

37. 3) Cardiovascular System: The classical response of blood vessels to 5-HT is contraction, particularly in the splanchnic , renal, pulmonary, and cerebral vasculatures, Contraction – large vessels Relaxation( due to release of EDRF) Bradycardia - activation of coronary chemoreflex Hypotension and apnoea positive inotropic and chronotropic actions 4) Central Nervous System. A multitude of brain functions are influenced by 5-HT, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception , mood, appetite, sexual behavior, and hormone secretion.( but injected serotonin doenot have CNS effects) A) sleep and wake cycles B) anxiety and depression C) Aggression and Impulsivity

38. Pathophysiological roles Neurotransmitter -sleep, temperature regulation, thought, cognitive function, behaviour and mood, vomiting and pain perception Precursor of melatonin Neuroendocrine function Nausea and vomiting Migraine- methysergide , sumatriptan Haemostasis Raynaud’s disease- ketanserin Variant angina Hypertension- ketanserin Intestinal motility Carcinoid syndrome

39. Serotonin agonists 5-HT 1A receptor Azapirones such as buspirone , gepirone , and tandospirone are 5-HT 1A agonists marketed primarily as anxiolytics , but also recently as antidepressants, 8-OH DPAT( hydroxydipropylaminotetraline ) 5-HT 1B receptor Triptans such as sumatriptan , rizatriptan , and naratriptan , are 5-HT 1B receptor agonists that are used to abort migraine and cluster headache attacks. 5-HT 1D receptor In addition to being 5-HT 1B agonists, triptans are also agonists at the 5-HT 1D receptor, which contributes to their antimigraine effect. 5-HT 1F receptor . Lasmiditan has successfully completed Phase II clinical trials in early 2010.

40. 5-HT 2A receptor Psychedelic drugs such as LSD, mescaline, psilocin, , act as 5-HT 2A agonists. Their action at this receptor is responsible for their hallucinogenic effects. It is now known that many of these drugs act as agonists at many other 5HT receptors in addition to the 5-HT2A including the 5-HT2C and others. 5-HT 2C receptor Lorcaserin is a thermogenic and anorectic weight-loss drug which acts as a selective 5-HT 2C agonist. 5-HT 4 receptor Cisapride is a 5-HT 4 partial receptor agonist that has been used to treat disorders of gastrointestinal motility. Prucalopride is a highly selective 5-HT 4 receptor agonist that can be used to treat certain disorders of gastrointestinal motility

41. other drugs affecting 5-HT system 1) 5-HT precursor - tryptophan 2) synthesis inhibitors - p- chlorophenylalanine 3) uptake inhibitors : TCA, SSRIs 4) storage inhibitors- reserpine 5) degradation inhibitors – tranylcypromine , clorgyline 6) neuronal degeneration- 5,6-dihydroxytryptamine

42. 5-HT-Receptor Antagonists 5-HT1 antagonist: 5-HT2 antagonist: metergoline , Ketanserin (2C) Clozapine , Cyproheptadine , Methysergide ,. 5-HT3 antagonist : Ondansetron , dolasetron , and granisetron

43. ' Ketanserine ' blocks 5 HT2A,5 HT2C and alpha 1 receptors. ' Ondansetron,Dolansetron,Granisetron ' are 5 HT3 receptor antagonist.they are efficacious in treating chemotherapy induced emesis. ‘ Clozapine ' blocks 5 HT2A,5 HT2C,D4 receptors. Quetiapine ' blocks 5 HT2A,5 HT1A,D1-2,HI,alpha 1 receptors. Methsergide ' is 5 HT2A-2C antagonist and nonselective 5 HT 1 receptor blocker.it causes retrperitoneal fibrosis and mediastinal fibrosis. Cyproheptadine ' blocks 5 HT2A, HI and it is a mild anticholinergic . Pizotifen ' is a 5 HT2A-2C , H1 blocker and anticholinergic used for migraine prophylaxis

44. Cyproheptadine 5-HT2a, H1 antagonist Allergy, pruritus Increase appetite in children Weight gain Carcinoid Postgastrectomy dumping syndromes Antagonise priapism and orgasmic delays caused by SSRIs

45. Clozapine Clozapine , a 5-HT 2A/2C -receptor antagonist, represents a class of atypical antipsychotic drugs reduced incidence of extrapyramidal side effects compared to the classical neuroleptics , and possibly a greater efficacy for reducing negative symptoms of schizophrenia Also has a high affinity for subtypes of dopamine receptors.

46. Ondansetron Selective serotonin (5-HT 3 ) receptor antagonist that inhibits serotonin receptors in GI tract or chemoreceptor trigger zone. Prevention of nausea and vomiting with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin ; prevention of postoperative nausea or vomiting

47. Eicosanoids Eicosanoids are 20-carbon fatty acid derivatives Consist of prostaglandins, related thromoboxanes and leukotrienes derived from the oxidative metabolism of arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid) arachidonic acid cascade

48. Nomenclature Eicosanoids --- eicosa ( 20C fatty acid) Prostate gland derived----prostaglandin PGA, PGB---ring structure 1, 2, 3--no of double bonds Leukocyte and 3 double bonds- leukotrienes

49. Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases ): PGG2, and PGH2 2 enzymes: COX-1 – constitutive, levels always same COX-2--- normally insignificant but induced by cytokines, and growth factors COX-1 inhibitors: COX-2 inhibitors: The prostaglandins, thromboxane, and prostacyclin, collectively termed the prostanoids, are generated from PGH 2 through the action of isomerases and synthases

50. Products of Lipoxygenase Lungs, WBC, and platelets hydroperoxyeicosatetraenoic acids (HPETEs), which rapidly convert to hydroxy derivatives (HETEs) and leukotrienes FLAP (5-lipo-oxygenase activating protein) associated with asthma, anaphylactic shock, and cardiovascular disease. LTA 4 , the primary product of 5-LOX, can be converted via 12-LOX in platelets to the lipoxins LXA 4 and LXB 4 Lipo-oxygenase inhibitor: zileuton

51. Epoxygenase Products (cytp450 enzymes) four epoxyeicosatrienoic acids (EETs) The epoxygenase products are synthesized in endothelial cells, and cause vasodilation in a number of vascular beds by activating the smooth muscle large conductance Ca 2+ -activated K + channels

52. Isoprostanes Prostaglandin isomers Degradation of eicosanoids : Fastest in lungs Oxidation of side chains and reduction of double bonds Metabolites excreted in urine

53. Prostaglandin synthesis inhibitors Nonsteroidal anti-inflammatory drugs NSAIDS , block enzymes that convert arachidonic acid to prostaglandins. Corticosteroids : by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. inhibit phospholipase A 2 activity, probably by interfering with phospholipid binding and thus preventing the release of arachidonic acid.

54. Prostaglandins Basic structural unit is referred to as a prostanoic or prostenoic acid. Each PG differs from the others in the substitution pattern in the cyclopentane ring and the sidechains Prostaglandins are broadly classified as PGA, PGB,PGC, PGD, PGE, PGF, PGG, and PGH based on their cyclopentane /pentene ring substitution pattern subclassified based on the degree of unsaturation (i.e. PGE1, PGE2)

55. Physiologic actions of prostaglandins inflammation, pain, pyrexia, cardiovascular disease, renal disease, cancer, glaucoma, allergic rhinitis, asthma preterm labor, male sexual dysfunction osteoporosis.

56. Prostaglandin receptors eight prostanoid receptors have been cloned and characterized. receptors are coupled to either phospholipase C (PLC) or adenylate cyclase in the case of adenylate cyclase , the action of the PGs may be stimulatory or inhibitory.

57. Prostaglandin receptors

58. Pharmacologic actions powerful vasodilators; especially PGI 2 and PGE 2 , promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium, In kidney: increased excretion of salt in the urine. inhibit the action of vasopressin on the kidney tubules, mediate the control of GnRH over LH secretion, modulate ovulation, and stimulate uterine muscle contraction and facilitate fertilization dysmenorrhoea inducing labor in pregnant Administration of either PGE 2 or PGF 2 results in colicky cramps

59. Low concentrations of PGE 2 enhance, whereas higher concentrations inhibit, platelet aggregation. Both PGD 2 and PGI 2 inhibit aggregation PGE 2 promotes the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH. increase bone turnover, ie, stimulation of bone resorption and formation PGE and PGF derivatives lower intraocular pressure Mediate fever and malaise

60. Prostaglandin agonists 1 ) Alprostadil (PGE1) produces vasodilation , inhibits platelet aggregation and stimulates intestinal and uterine smooth muscle. ductus arteriosus erectile dysfunction Adverse Reactions: ♦ Cardiovascular: Flushing, bradycardia , hypotension, tachycardia, edema , less commonly more severe effects such as cardiac arrest, congestive heart failure, second degree heart block, shock, supraventricular tachycardia and ventricular fibrillation. ♦ CNS : Fever, seizures, cerebral bleeding, hyperextension of the neck, hyperirritability, hypothermia,lethargy and stiffness . ♦ GI: Diarrhea, gastric regurgitation and hyperbilirubinemia . Hematologic : Disseminated intravascular coagulation, anemia, bleeding, thrombocytopenia ♦ Renal : Anuria and hematuria ♦ Respiratory : Apnea, bradypnea , bronchial wheezing, hypercapnia , respiratory depression, respiratory distress and tachypnea

61. 2) Prostaglandin E2 ( Dinoprostone ) PGE2 stimulates the production of PGF2α which in turn sensitizes the myometrium to endogenous or exogenously administered oxytocin . Indications : 1)initiation or continuation of cervical ripening in pregnant women at or near term with a medical or obstetrical need for labor induction (cervical ripening) 2) the management of missed abortion or intrauterine fetal death up to 28 weeks gestational age and, 3) management of nonmetastatic gestational trophoblastic disease (benign hydatidiform mole).

62. 3) Misoprostol , Enprostil - for peptic ulcer as anti secretory and cytoprotective agents) Antisecretory Actions: decreased HCl and pepsin secretion( basal or stimulus) • Cytoprotective Activities: increased gastric blood flow, increased mucous and bicarbonate protection • Immunologic Actions: inhibit basophilhistamine release, thus it has a potential role as immunotherapy designed to reduce early-phase and late-phase allergic inflammation • Reproductive Effects: Misoprostol produces uterine contractions that may endanger pregnancy

63. 4) Prostaglandins for Treatment of Pulmonary Hypertension: Epoprostenol , Treprostinil and Beraprost

64. Clinical Pharmacology of Eicosanoids 1) Female reproductive system : Abortion— mifepristone pretreatment misoprostol + methotrexate b) Post partum hemorrhage– carboprost , dinoprostine , gemeprost c) Facilitation of labour -- d) Dysmenorrhoea e) Menstruation inducing contraceptive--

65. 2) Male reproductive system: erectile dysfunction-- alprostadil 3) Pulmonary hypertension 4) Patent ductus arteriosus 5) Peripheral vascular diseases 6) Blood platelet aggregation 7) GIT 8 ) Immune system a) Cell-mediated organ transplant rejection b) Inflammation c) Rheumatoid arthritis 9) Glaucoma 10) Bronchial asthma

66. Thromboxanes process of clot formation begins with an aggregation of blood platelets (TXA2). This process is strongly stimulated by thromboxanes and inhibited by prostacyclin . Prostacyclin --- vasodilation and lowers BP

67. Leukotrienes LTB4- neutrophils LTC4 and LTD4- macrophages LTC 4 and LTD 4 are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis

68. Effects of leukotrienes : CVS and blood : brief rise in BP followed by a prolonged fall, due to coronary constriction induced decrease in cardiac output and reduction in circulating volume due to increased capillary permeability Inflammation = redness ( rubor ), heat ( calor ), pain (dolor), swelling (tumor), migration of neutrophils to the inflammatory site promoted by LTB4 3 ) Smooth muscle- contraction, potent bronchoconstrictors , and also increase bronchial secretions 4) Afferent nerves- sensitizes afferent neurons carrying pain impulses

69. Leukotriene receptors All function through IP3/DAG transducer mechanism.

70. Leukotriene receptor antagonists Monteleukast Zafirleukast Adverse effects CNS : Headache; dizziness. GI : Nausea; diarrhea; dyspepsia; abdominal pain; vomiting. HEPATIC : Elevation in transaminase levels. OTHER : Infection; fever; asthenia; generalized pain; myalgia ; back pain

71. Leukotriene synthesis inhibitor Nedocromil Sodium

72. Vasoactive peptides 1) vasoconstrictors angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin 2) vasodilators bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide (CGRP) , and adrenomedullin.

73. RENIN AND ANGIOTENSIN pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy Circulating renin angiotensin system Tissue (local) renin-angiotensin system Extrinsic local RAS- blood vessels Intrinsic local RAS- heart , blood vessels, brain, kidneys, adrenal glands

74. Angiotensinogen Synthesized in liver Glycoprotein with a molecular weight 57, 000 Synthesis increased by: a) corticosteroids b) estrogens c) thyroid hormones d) angiotensin II Elevated during pregnancy and in women taking OCP

75. Components of RENIN-ANGIOTENSIN SYSTEM Angiotensinogen Renin Angiotensin I Angiotensin coverting enzyme Angiotensin II angiotensinase

76. Renin aspartyl protease within kidney synthesized by JG cells Renin secretion controlled by : Renal vascular receptor : decreased stretch =increased renin Macula densa : sensitive to Na+ and Cl - delivery to distal tubule, signal transmission by: adenosine( inhibits renin ) , prostaglandins ( stimulates renin ) and nitric oxide. Decrease= increased renin Sympathetic nervous system : increased nerve activity= increased renin beta1 receptors (renal) etrarenal beta receptors angiotensin : Angiotensin II inhibits renin secretion Pharmacologic alteration of renin release : stimulated by : vasodilators beta agonists Alpha antagonists Phosphodiesterase enzyme inhibitors ( theophylline , milrinone , amrinone )

77. Angiotensin I No biologic activity Must be converted to angiotensin II

78. Angiotensin converting enzyme Peptidyl dipeptidase ( PDP) ACE Kininase II Carboxypeptidase Substrates: angiotensin I bradykinin also cleaves enkephalins and substance P Distributed widely in body , mostly on luminal surface of vascular endothelial cells

79. Angiotensin II Potent pressor agent 40 times more potent than norepinephrine Pressor response due to Direct contraction of vascular smooth muscle Reset baroreceptor reflex control Stimulates autonomic ganglia Facilitate sympathetic transmission Direct positive inotropic action on heart

80. In adrenal cortex: acts on zona glomerulosa to stimulate aldosterone biosynthesis, also glucocorticoid biosynthesis In Kidney: renal vasoconstriction increase proximal tubular reabsorption inhibit secretion of renin

81. CNS: stimulate drinking ( dypsogenic ) increased secretion of vasopressin and ACTH Cell Growth : mitogenic causes cardiovascular hypertrophy

82. Angiotensin receptors AT1 high affinity for losartan and low for PD123177, predominant in vascular smooth muscle , GPCR activation of phospholipase C and IP3/DAG- smooth muscle contraction Vascular and cardiac growth mediated by tyrosine kinases and increased transcription of specific genes

83. AT2 Fetal tissue development Inhibition of growth and proliferation Cell differentiation Apoptosis vasodilation

84. Angiotensinogenase Angiotensin II having very short half life Most vascular beds ( except lungs) Metabolites biologically inactive aminopeptidases , endopeptidases , and carboxypeptidases .

85. Drugs acting on renin angiotensin system Drugs blocking renin secretion: clonidine , propranolol Direct renin inhibitors: remikiren , enalkiren ACE inhibitors captopril , enalapril Angiotensin antagonists : a) peptide: saralasin b) non peptide: losartan , valsartan , erposartan , irbesartan , candensartan , telmesartan

86. KININS potent vasodilator peptides formed enzymatically by the action of enzymes known as kallikreins or kininogenases acting on protein substrates called kininogens . metabolised by nonspecific exopeptidases or endopeptidases, commonly referred to as kininases

87. Kallikreins present in plasma and in several tissues, including the kidneys, pancreas, intestine, sweat glands, and salivary glands. Plasma prekallikrein can be activated to kallikrein by trypsin, Hageman factor, and possibly kallikrein itself. Kallikreins can convert prorenin to active renin Kininogens precursors of kinins and substrates of kallikreins present in plasma, lymph, and interstitial fluid. Two kininogens are known to be present in plasma: A) low-molecular-weight form (LMW kininogen) - crosses capillary walls and serves as the substrate for tissue kallikreins B) high-molecular-weight form (HMW kininogen) ( 15–20% of the total plasma kininogen ) . confined to the bloodstream and serves as the substrate for plasma kallikrein.

88. Three kinins have been identified in mammals: bradykinin, lysylbradykinin (also known as kallidin ), and methionyl - lysylbradykinin Bradykinin is released by plasma kallikrein, lysylbradykinin by tissue kallikrein, and methionyl - lysylbradykinin by pepsin and pepsin-like enzymes

89. Actions of kinins Effects on the Cardiovascular System marked vasodilation direct inhibitory effect of kinins on arteriolar smooth muscle mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE 2 and PGI 2 Venous constriction direct stimulation of venous smooth muscle or from the release of venoconstrictor prostaglandins such as PGF 2 Dual action Bradykinin also increases blood pressure when injected into the central nervous system water and solutes pass from the blood to the extracellular fluid, lymph flow increases, and edema may result.

90. Effects on Endocrine & Exocrine Glands prekallikreins and kallikreins are present in several glands, including the pancreas, kidney, intestine, salivary glands, and sweat glands Local modulators of blood flow modulate the tone of salivary and pancreatic ducts and help regulate gastrointestinal motility influence the transepithelial transport of water, electrolytes, glucose,and amino acids, and may regulate the transport of these substances in the gastrointestinal tract and kidney physiologic activation of various prohormones, including proinsulin and prorenin

91. Role in Inflammation Kallikreins and kinins can produce redness, local heat, swelling, and pain Effects on Sensory Nerves elicit pain by stimulating nociceptive afferents in the skin and viscera.

92. Kinin Receptors & Mechanisms of Action B 1 and B 2 B 2 widespread distribution G protein–coupled and agonist binding sets in motion multiple signal transduction events, including calcium mobilization, chloride transport, formation of nitric oxide, and activation of phospholipase C, phospholipase A 2 , and adenylyl cyclase B 1 Limited distribution important in long-lasting kinin effects such as collagen synthesis and cell multiplication.

93. Drugs Affecting the Kallikrein-Kinin System anti-inflammatory and antinociceptive agents. Peptides- Icatibant is a second-generation B 2 receptor antagonist third generation of B 2 -receptor antagonists was developed; examples are FR 173657, FR 172357 , and NPC 18884 the kallikrein inhibitor aprotinin

94. Pentagastrin a synthetic polypeptide that has effects like gastrin when given parenterally . stimulates the secretion of gastric acid, pepsin, and intrinsic factor, used as a diagnostic aid in the pentagastrin -stimulated calcitonin test. binds to the cholecystokinin -B receptor, which is expressed widely in the brain. Activation of these receptors activates the phospholipase C second messenger system. When given intravenously it causes panic attacks.

95. Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Also called pancreozymin CCK also causes the increased production of hepatic bile, and stimulates the contraction of the gall bladder and the relaxation of the Sphincter of Oddi , resulting in the delivery of bile into the duodenal part of the small intestine. CCK administration causes nausea and anxiety, and induces a satiating effect

96. CCK receptors influence neurotransmission in the brain, regulating anxiety, feeding, and locomotion. regulation of dopamine activity in the brain. CCK-B activation appears to possess a general inhibitory action on dopamine activity in the brain, opposing the dopamine-enhancing effects of CCK-A. Activation enhances GABA release CCK-B receptors modulate dopamine release, and influence the development of tolerance to opioids CCK-B activation decreases amphetamine-induced DA release, and contributes to individual variability in response to amphetamine.

97. Cholecystokinin agonists : cholecystokinin gastrin pentagastrin Cholecystokinin antagonist: proglumide

98. Substance P belongs to the tachykinin family of peptides, Other members of this family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and B are decapeptides. present in the central nervous system, where it is a neurotransmitter, and in the gastrointestinal tract, where it may play a role as a transmitter in the enteric nervous system and as a local hormone . Effects in behavior, anxiety, depression, nausea, and emesis. It is a potent arteriolar vasodilator, producing marked hypotension . The vasodilation is mediated by release of nitric oxide from the endothelium. substance P causes contraction of venous, intestinal, and bronchial smooth muscle. It also stimulates secretion of the salivary glands and causes diuresis and natriuresis by the kidneys.

99. The actions of substance P and neurokinins A and B are mediated by three G protein-coupled tachykinin receptors designated NK 1 , NK 2 , and NK 3 . Substance P is the preferred ligand for the NK 1 receptor, the predominant tachykinin receptor in the human brain. neurokinins A and B also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NK 1 receptors. Several nonpeptide NK 1 receptor antagonists have been developed. These compounds are highly selective and orally active, and enter the brain. these antagonists may be useful in treating depression and other disorders and in preventing chemotherapy-induced emesis. Eg . aprepitant .