Pharmacology lecture 1 Dr. Sameer AlRekabi Autacoids = local hormones DEFINITION These are heterogeneous group of chemical substances with wide spectrum of biological effects , synthesized by different tissues and exerting local effect with no or very minute serum level. Autacoids' include histamine , serotonin , prostaglandins , leukotriens , vaso-active intestinal polypeptides (VIPs), kinins, Angiotensin , Nitric oxide (NO), endothelin,…………etc. HISTAMINE and ANTI-HISTAMINES Histamine : is a bioactive amine , widely distributed in animal and plant tissues. In human body, histamine present in skin , GIT , lungs , CNS , CVS, basophiles. It is stored in granules in mast cell, it is released in response to many physical and chemical agents that lead to degranulation of the mast cells. Synthesis: Histamine is synthesized by 2 enzymes: 1- Histidine de-carboxylase that converts histidine to histamine. This enzyme is inhibited by methyl histidine. 2- Aromatic amino acid decarboxylase which is non specific enzyme and inhibited by methyl-dopamine . Release: Histamine is released by the process of degranulation in response to: 1- Immunological reactions : Ag-Ab complex stimulates mast cell de-granulation. 2- Chemical and mechanical reactions like histamine release by drugs like morphine codeine ,Vancomycin , polymexin,……….etc. Mechanical reaction like in triple response of Lewis. Metabolism : By 2 routs 1- By histaminase or di-amine oxidase. 2- By histamine methylating enzymes. Mechanism of action of histamine: Histamine acts by binding to 4 subclasses of receptors [ H1 , H2 , H3 , H4] which distributed in different tissues. Physiological role of histamine: 1- neurotransmitter in CNS. 2- Micro-circulatory regulation. 3- control sleep and alertness . 4- correlates with fetal development . 5- wounds healing. 6- Has a role in thermal and body weight regulation. 7- WBC chemotaxis. 8- Gastric acid secretion. Pharmacological action of histamine: 1- CVS : ↓ in systolic and diastolic blood pressure. On heart : -ve inotropic effect through H1 receptor . +ve inotropic and chronotrpic effect through H2 receptor. 2- Gastric acid secretion: histamine is a potent stimulator of gastric acid secretion , and to lesser extent pepsin and intrinsic factor. 3- Effect on smooth muscles: It has a stimulatory action , it causes profound bronchiospasm in patient with bronchial asthma .It increases intestinal motility and may causes diarrhea in large dose. Histamine has no significant action on smooth muscle of genitorurinary tract and eyes. 4- Gland secretion : has no significant action. 5- Suprarenal medulla : stimulates the release of adrenalin and noradrenalin in normal subject. It causes massive secretion of catecholamines in patients with pheochromocytoma. 6- On nerve endings: It stimulates the sensory nerve endings causing pain and itching. Triple response of Lewis: Injection of small dose of histamine (10 micrograms) intradermally causes the triple response of Lewis which includes: 1- Local redness due to local vasodilatation . 2- Wheal (oedema) due to increase in the permeability of blood capillaries. 3- Diffused redness ( flare) due to general vasodilatation related to neural mechanism ( axonal reflex). Clinical indication of histamine: Histamine has no therapeutic roles but can be used clinically in: 1- Diagnosis of pernicious anemia. 2- Measurement of gastric acid secretion . 3- Diagnosis of pheochromocytoma. Side effects of histamine : Headache , flushing , hypotension , tachycardia , bronchiospasm , GI upset. Contraindications : 1- Bronchial asthma . 2- Active peptic ulcer. 3- Pheochromocytoma. Histamine agonists : 1- Betazole : Isomer of histamine and acts on H2 receptor . It is used for diagnosis of gastric acid secretion but it is contraindicated in case of bronchial asthma. 2- Betahistine : It is analogue of histamine and acts on H1 receptor , it is used in the treatment of Meneire,s disease . IT should be used cautiously in patients with bronchial asthma and pheochromocytoma. Histamine antagonists : The action of histamine can be antagonized by : 1- Physiological antagonist : By adrenalin . 2- Competitive pharmacological antagonists : we have H1 and H2 blockers . 3- Mast cells stabilizers (drugs that prevent mast cell de-granulation ) like chromolyin and nedochromil. Anti-histamines (H1 blockers) These are heterogeneous group of drugs that antagonize the effect of histamine on H1 receptor , rapidly absorbed from GIT , extensively metabolized by liver , excreted by kidney , also secreted into milk of lactating woman. Pharmacological actions of H1 blockers: 1- they produce CNS depression in therapeutic doses BUT may produce CNS stimulation , convulsion and hyperthermia when they are given in large doses especially in children. 2- they have anti-nausea and anti-vomiting effects. 3- Anti-cholinergic effect (dry mouth, constipation , urine retention , glaucoma ,….) 4- Local anesthetic effect. 5- Anti- parkinsonism effect. 6- Antiserotoninergic effect 7- α- adrenoceptor blocking effects. 8- they inhibit P-glycoprotein (P-glycoprotein responsible for cytotoxic drugs efflux outside of tumor cells). Classification of H1-blockers : 1- 1st generation H1-blockers General properties include : a- Great CNS depression . b- relatively of short duration of action. c- relatively of little dangerous drug interaction with macrolides antibiotics and antifungal drugs. 1st generation H1 blockers includes : 1- Ethanolamine group : like Diphenhydramine (allermin) . 2- Ethylenediamine group : like Antazoline. 3- Alkylamine group: like chlorpheneramine (Histadine). 4- Piperazin group: like Hydroxyzine , cyclizine. 5- Phenothiazines group: like promethazine. 6- Miscellaneous group : like cyproheptadine (periactin) which used as appetite stimulant especially in children , in carcinoid syndrome (it has antiserotoninergic effect), in hay fever , in dumping syndrome after gasterectomy, as prophylactic in migraine . Other drugs like acrivastin , clemastin , loratidine ,desloratidine , ketotifen,……… 2- 2nd generation H1 blockers : General properties includes: a- Low or no CNS depression. b- relatively of long duration of action. c- relatively of dangerous drug interaction with macrolides antibiotics(erythromycin and Clarithromycin) and anti-fungal (Ketocanazole) drugs that may lead to prolonged QT interval and ventricular arrhythmias. nd 2 generation H1 blockers includes : Astimazole , Terfenadine , Fexofenadine, Cetrizine. Clinical indications : 1- Angio-noretic oedema ., 2- Allergic dermatosis , 3- Urticaria , 4- Hay fever , 5- Motion sickness , 6- insect bite , 7- anaphylactic shock, 8- blood transfusion allergic reactions. Side effects of H1-blockers Sedation , dizziness , insomnia , blurred vision, tinnitus , parasthesia . Drug interactions : 1- Non- specific CNS depressants like Alcohol , Barbiturates . 2- Anti-cholinergic drugs. 3- α- adrenoceptor blockers. Contraindications of H1 blockers : 1- Hypersensitivity to the drugs. 2- Sever bronchial asthma. 3- Prostatic hyperplasia. 4- Closed angle glaucoma. 5- Bladder neck obstruction . 6- breast feeding. Serotonin and anti-serotonin Serotonin is a bioactive amine that can be synthesized by hydroxylation of amino acid tryptophan to 5hydroxy tryptophan ( by enzyme = tryptophan hydroxylase) then by enzyme aromatic amino acid decarboxylase to 5-hydroxy tryptamine= serotonin. Serotonin is one of most important autacoid , has many physiological roles and serotonin agonists and antagonists have many clinical applications . Serotonin is widely distributed in plants and animal tissues. In human , about 90% of total body serotonin present in enterochromaffin tissues , 8% in platelets and 2% in CNS . Serotonin metabolism : By mono-amino oxidase enzyme to form 5hydroxy indol acetic acid which is excreted in the urine in amount of about 3-10 mg /day. The excretion of 5-hydroxy indol acetic acid ↑ in the following conditions : 1- Carcinoid syndrome ( tumor of enterochromaffin cells). 2- in case of using some of old anti-hypertensive drugs (reserpine). 3- ingestion of banana. Physiological roles of serotonin: 1- It acts as a neurotransmitter in the brain. 2- Regulation of temperature. 3- Pain perception . 4- In pathogenesis of migraine. 5- In pathogenesis of depression. 6- In pathogenesis of anxiety. 7- Involved in intestinal motility . 8- Control of vomiting. 9- Control of appetite. 10- Pathogenesis of carcinoid syndrome. Mechanism of action of serotonin: Serotonin exerts its action by binding to 7 subtypes of receptor [ 6 of them are G-protein coupled and one of them "5-HT3" is ionic channels coupled. The second messenger of G-protein coupled receptors is either cyclic AMP or IP3 and DAG. Pharmacological action of serotonin: 1- CVS: - On heart : serotonin has small +ve inotropic and +ve chronotropic effect on the heart. Elevated plasma level of serotonin in carcinoid syndrome lead to pathogenic endocardial changes. - On blood vessels : serotonin produces triphasic response which includes: 1- early depressor phase due to ↓ heart rate and cardiac output due to chemoreceptor reflex. 2- Presser effect due to ↑ peripheral vascular resistance and cardiac output. 3- Late depressor phase : related to vasodilatation in skeletal muscle. 2- Respiratory system: Serotonin produces a small direct stimulation to bronchial smooth muscle in normal person but produce a bronchiospasm in patients with carcinoid syndrome. Serotonin produces hyperventilation due to stimulation of bronchial sensory nerve endings. 3- GIT: serotonin has a potent stimulation on the smooth muscle of the gut which increases the tone and facilitate peristalsis that related to the action of serotonin on 5HT receptor in smooth muscle and ganglionic stimulation of the enteric plexus . 4- CNS : Stimulation of sensory nerve endings leads to pain and itching. 5- Glandular secretion: Serotonin has little inhibitory effects on exocrine glands. 6- Uterus: Large dose of serotonin impairs placental blood supply and may lead to fetal distress. Serotonin syndrome : It is related to the interactions of serotonin re-uptake inhibitors with mono-amino oxidase inhibitors (MAOIs) or interactions of serotonin agonists with MAOIs. It is a clinical emergency with high mortality rate and characterized by rigidity , hyperthermia , myoclonus , mental changes, tachycardia. Treatment is supportive. Serotonin agonists : 1- Buspirone : acts on 5-HT1A receptor .It is an anxiolytic drug ( non benzodiazepines non barbiturates anxiolytic). 2- Dexfenfluramine : Suppresses appetite and used to ↓ body weight. 3- Sumatriptan ,Amlotriptan , Eletriptan , Naratriptan , Rizatriptan , Zolmitryptan : They act on 5-HT 1 B and D receptors and used in treatment of acute migraine. 4- Cisapride : It is used in the management of reflux esophagitis but now rarely used because it causes serious ventricular arrhythmias .It acts on 5-HT4 receptors .Other 5-HT4 receptor agonists are: Tagaserol and metaclopromide . Serotonin antagonists: 1- Cyproheptadine (periactin): It is H1 and 5-HT2 blocker , used mainly as appetite stimulant. Other uses include : Allergic rhinitis , cold urticaria , prophylaxis of migraine , in Dumping syndrome after gasterectomy and in carcinoid syndrome. 2- Ketanserin: It is 5-HT 2 and α-blocker . It was used in the treatment of hypertension . 3- Ritanserin : It is 5-HT2 blocker and has no αblocking effect. 4- Ondansetron , Granisetron ,Tropisetron and Alosetron: Acts on 5-HT3 receptor as antagonists and used mainly in cytotoxic induced nausea and vomiting. 5- Ergot Alkaloids : They are produced by fungus that infects grain . Ergots act on the following receptors: a- Serotonin receptor. b- α adrenoceptor. c- Dopamine receptor. Ergots act as agonist , partial agonist or antagonist. Ergotism: It is the clinical manifestation of ergot alkaloid poisoning and characterized by nausea , vomiting , abdominal pain , abortion of pregnant woman , gangrene , hallucination , confusion and convulsion. Ergot alkaloid drugs and their clinical uses: 1- Bromocriptine: used in acromegaly and hyperprolactinaemia. 2- Ergotamine : used in acute migraine . 3- Ergonovine: used in post-partum hemorrhage and diagnosis of Varian angina . 4- Lysergic acid diethylamide (LSD) :It is a hallucinogenic agent. 5- Methysergide: used in migraine prophylaxis. 6- Dihydroergotoxin : Used in cerebral insufficiency. Side effects of Ergot Alkaloids: Nausea , vomiting , abdominal pain , drowsiness , hallucination , confusion , abortion, retro-peritoneal fibrosis, gangrene. Migraine Syndrome: It is a syndrome of recurrent throbbing unilateral headache with or without aura ( visual halos) with nausea , vomiting , phonophobia and photophobia. Aetiology: It is poorly understood , it is precipitated by stress , anger , fatigue , diet , rich in chocolate and cheese , alcohol , menses in female or using contraceptive , hypoglycemia. Changes in vascularity between intra and extracranial blood vessels and stimulation of trigeminal nerve by calcitonin genes related peptides are the most popular concept concerning Aetiology of migraine. Treatment of migraine : 1- Treatment of acute attack : by using Paracetamol , NSAIDs (aspirin), serotonin agonists like Sumatriptan , ……..other serotonin agonists or by ergot alkaloid derivatives like ergotamine. Other supportive treatment like antiemetic , sedative. 2- prophylactic treatment : many drugs are used with different outcome like calcium channel blockers ( Verapamil), B-blockers (propranolol ) , ergot alkaloid ( Methysergide) , clonidine, tricyclic anti-depressant (imipramine), anti-serotonin ( cyproheptadine and pizotifen) . Eicosanoids: prostaglandins "PGs" , leukotriens "LTs" , thromboxanes "TXs" , lipoxines "LXs", isoprostanes, epoxides. They are the oxidation products of poly unsaturated long chain fatty acid. They are short lived , highly potent compounds with broad spectrum of biologic activity. They act in autocrine or paracrine fashion . Synthesis of eicosanoids : 1-Arachidonic acid is the source of eicosanoids . Arachidonic acid is formed by the action of phospholipase A2 which converts phospholipids in cell membrane into arachidonic acid. Arachidonic acid is converted to PGs endoperoxides by the help of 2 enzymes : a- Cyclo-oxygenase I "COX I " [ PGH synthase I] which is widely distributed in body tissues and has gastro-cytoprotection.] b-Cyclo-oxygenase II " COX II" [ PGH synthase II] which is inducible by inflammatory reactions and concerns with development of renal function. NOTE : Non-steroidal anti-inflammatory drugs [NSAIDs] exert their effects through inhibition of COX I and II. COX I and II produce both PGs and TXs. PGs are widely distributed in brain , lung , liver, kidney , adrenals , uterus , testis , and prostate . We have PGE1, PGE2 , PGE3 , PGF1α , PGF2α,…….. NOTE : Other types of PGs are derived from the above compounds. 2- The arachidonic acid and by the action of lipo-oxygenase enzyme produces LTs and LXs . LTs are biologically active compounds but lipoxines with no clear biological activity. 3- Epoxides : unstable compounds and have effects on smooth muscle that may concern with renal function. 4- Isoprostanes : They are considered as PGs isomers and they are concerned in the pathogenesis of hepato-renal syndrome [ complication of liver cirrhosis] . Mechanism of action of PGs: They bind to G-protein coupled receptor -------- ↑ cAMP Mechanism of action of thromboxane A2: They bind to G-protein coupled receptor-----------↑ IP3 and DAG Pharmacological actions of PGs and TX: 1- GIT: PGE2 and PGF2α cause contraction of the longitudinal muscle of the gut while PGI2 and PGF2α cause contraction of the circular muscle of the gut.PGE2 relaxes the circular muscles. In general , large dose of PGs inhibits gastric acid secretion. 2- vascular smooth muscles : PGE2 and PGI2 cause vasodilatation , while PGF2α and TX cause vasoconstriction . 3- platelets : PGE1 and PGI2 inhibit platelets aggregation while TX induces platelets aggregation. 4- Respiratory system: PGE1 , PGE2 and PGI2 cause bronchi dilatation while PGF2α and TX cause bronchi constriction. 5- Renal system: PGE1, PGE2 and PGI2 increase GFR (vasodilating effect ) and increase the Na excretion , also enhance the release of rennin. PGE2 is involved in renal phosphate excretion. TX reduces renal function and GFR. 6- Reproductive system: PGE2 and PGF2α causes contraction of uterus , PGI2 increases penile erection. NOTE: Seminal fluid containing less than 400 ug/ml of PG is considered an infertile man 7- CNS: -Fever : PGE1 and PGE2 when are injected into cerebral ventricles , they increase the body temperature. PGD2 when infused into cerebral ventricles produces sleepiness . - Neurotransmission: PG compounds inhibit the release of Nor-adrenalin from postganglionic sympathetic nerve endings. - Neuro-endocrine: PG compounds promote the secretion of prolactine , GH, TSH, ACTH, FSH and LH. 8- Bone : PGD2 increases bone turnover (bone formation and resorption) . PG is involved in bone loss in post-menopausal women. 9- Eyes: PGF2α decreases intra-ocular pressure . Clinical indications of PG preparations : 1- Reproductive indications: PGE2 and PGF2α when used in early pregnancy , they will cause abortion , they terminate pregnancy at any stage , facilitates labor if given at time of labor. Advantages of PG over Oxytocin [ which also used in labor] : a- PGs are more safe in pregnant women with pre-eclampsia , cardiac and renal diseases . b- PGs unlike Oxytocin, having no anti-diuretic effect. PGE2 and PGF2α are involved in primary dysmenorrhia. PGE1 is used in sexual dysfunction , injection of PGE1 in cavernosa is important in management of impotence in man. 2-CVS indications : PG compounds have antihypertensive effect due to their vasodilating and natriuretic effects. PGI2 is used in pulmonary hypertension. PGE1 and PGI2 are used in Ryanaud disease. 3- Blood: PGI2 is very effective in preventing platelets aggregation . 4- Respiratory indications: PGE2 is used as aerosol to relieve bronchiospasm. 5- GIT indications : PGE1 analogue (Misoprostol)is cytoprotective and used for treatment of gastric ulcer. 6- Immune indications: PGE2 and PGI2 inhibit T-cell proliferation and clonal expansion by inhibiting interleukin I and II. While TX and platelet activating factor (PAF)stimulate T-cell proliferation and clonal expansion by stimulating IL-I and II. NOTE: PGs in general decrease incidence of organ transplantation rejection . 7- Eyes : PGF2α analogue is used in treatment of glaucoma . Side effects of PGs : GIT upset , headache , dizziness , bronchiospasm , allergic reactions , syncope , hypo or hypertension , uterine laceration . Some PGs preparations : Dinoprost = PGF2α Dinoprostone = PGE2 Alprostadil = PGE1 Epoprostenol = Prostacyclin = PGI2 Misoprostol = PGE1 analogue Latanoprost = PGF2α ( eye preparation) Leukotriens Potent biologically active compounds are synthesized from arachidonic acid with the help of 5-lipo-oxygenase in neutrophiles , monocytes , macrophages and keratinocytes. LTs present in brain , heart , lung and spleen . The slow reacting substance A released as result of immunological reactions contains LTC4 , LTD4 and LTE4 Pharmacological effects of LTs: 1- CVS : These agents reduce myocardial contractility and coronary blood flow. 2- GIT : LTB4 : are implicated with inflammatory bowel disease and their amount is largely increased by epithelial cells of colon. 3- Respiratory system: LTC4 and LTD4 are bronchio-constrictor , they increase the intravascular permeability and plasma exudates and also increase mucus secretion. Drugs that block leukotriens receptors like Zafirleukast and Monteleukast and are highly effective in management in bronchial asthma 4- Blood : LTB4 is a potent chemo attractant of neutrophiles , LTC4 and LTD4 are chemo attractant of eosinophiles . Lipoxins : Act on specific receptor on PMN cells , inhibits NK cells. PAF: Has role in Pathophysiology of asthma and shock. Lexipafant is PAF antagonist and used in management of acute pancreatitis . Vaso-active amines and peptides: These are heterogeneous group of peptides that act in autocrine and paracrine fashion and include vasodilators and vasoconstrictors and play a major roles in pathogenesis of many diseases with increasable understanding in causation of many pathologies . 1- vaso-dilator amines and peptides: a- Nitric oxide [NO]: Nitric Oxide, Donors, & Inhibitors: Nitric oxide (NO) is a gaseous signaling molecule that readily diffuses across cell membranes and regulates a wide range of physiologic and patho-physiologic processes including cardiovascular, inflammation, immune and neuronal functions. The endothelium released a short-lived vasodilator, which unlike endothelium-derived prostacyclin was not blocked by cyclo-oxygenase inhibitors. They named this vasodilator endothelium-derived relaxing factor (EDRF). Biologic Synthesis It is synthesized by a family of enzymes that are collectively called nitric oxide synthase, NOS Three isoforms of NOS have been identified.(NOS-1, NOS-2, NOS-3). These isoforms are heme-containing flavoproteins employing L-arginine as a substrate Nitric oxide generation. Activation of NOS by the influx of extracellular calcium and binding of calmodulin Inhibitors of Nitric Oxide Drugs may inhibit the uptake of Larginine into cells, thus depriving the NOS isoforms of substrate. Other methods include deprivation of the cofactors and calmodulin antagonists, inhibitors of NOS synthesis, inhibitors of binding of arginine to NOS, and scavengers of nitric oxide Role of Nitric Oxide Nitric oxide has major effects that are mediated by activation of cytoplasmic soluble guanylyl cyclase and stimulated production of cGMP, an important second messenger. Vascular Effects Nitric oxide., it is released by acetylcholine and other endothelium-dependent vasodilators. Infusion of NOS inhibitors increases vascular tone and elevates mean arterial pressure.Vasodilatation mediated of cGMP synthesis results in smooth muscle relaxation. Also it a potent inhibitor of neutrophiles adhesion to the vascular endothelium. Respiratory Disorders Pulmonary artery hypertension: NO is approved for this indication, and acute respiratory distress syndrome, use for defective gas exchange in the newborn . Septic Shock Increased urinary excretion of nitrate, is reported in gramnegative bacterial infection, resulting in exaggerated hypotension, This hypotension is reversed by NOS inhibitors. Atherosclerosis In vitro, NO carriers and donors and cGMP analogs inhibit smooth muscle cell proliferation. In addition, it may blocks the oxidation of low-density lipoproteins (LDL) and thus preventing the formation of foam cells in the vascular wall. Platelets Nitric oxide is a potent inhibitor of platelet adhesion and aggregation. NO affects blood coagulation by enhancing fibrinolysis via an effect on plasminogen. Organ Transplantation High concentrations of NO may be detrimental during acute organ rejection due to upregulation of inducible NOS by cytokines. The Central Nervous System It has a major role in the central nervous system as a neurotransmitter, as a modulator of ligand-gated receptors, plays a role in neuronal degeneration in some conditions. cellular targets include presynaptic and postsynaptic nerve terminals, it act to yield cGMP and thus facilitate transmitter release. It also causes destruction of photoreceptor cells in the retina. The Peripheral Nervous System Non-adrenergic, noncholinergic (NANC) neurons are widely distributed in peripheral tissues, especially the gastrointestinal and reproductive tracts , some NANC neurons appear to release NO and cause penile erection, it promotes relaxation in the corpora cavernosa. Inflammation: NO promotes edema and vascular permeability, dietary L- arginine supplementation exacerbates arthritis. Psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of NO. Also it stimulates the synthesis of inflammatory prostaglandins by activating cyclo-oxygenase isoenzyme II (COX-2). Hypertension associated with pregnancy. Manifestation of pre- eclampsia result from inadequate physiological response of pregnancy and combined with deficiency of NO and prostacyclin. enhancement of NO level through nutritional supplement of L- arginine may be effective. b- Kinins (bradykinin): It is a well known vasodilator , it is 10 times more vasodilator than histamine In addition to their CV effects , they have an effects on endocrine , exocrine glands, inflammatory response and sensory nerve endings Note : Kininase are ACE and inhibition of ACE by ACEIs like Captopril cause high persistent level of bradykinin causing dry cough in about 10-15% of patients taking ACEIs. c- Natriuretic peptides which include : Atrial natriuretic peptide(ANP)and Brain type natriuretic peptide (BNP). They are increased by atrial and blood vessel stretching by ↑ blood volume. They cause vasodilatation , ↑ GFR and Na+ excretion . they act on different receptors [A , B, C] receptors and metabolized by endopeptidase. Their levels are increased in HF and used as diagnostic and prognostic markers in HF. NOTE: Nesiritide is BNP analogue and can be used in HF. Other vasodilators: Substance P (also plays role in pain perception), Neurotensin , PGI2,vasoactive intestinal peptide (VIP), calcitonin gene related peptide which is the strongest vasodilator discovered yet. 2- vaso-constrictor amines and peptides: a- Angiotensin : It is a well known vasoconstrictor. It is formed by Renin – Angiotensin –Aldosterone [ RAA] system. It acts on 2 types of receptor [ AT1 ] which the most important one and [AT2] which is less well understood . Renin is a glycoprotein , synthesized , stored and released from juxta-glomerular apparatus of the kidney in response to ↓ renal perfusion. Physiological role of Angiotensin: It is a potent vasoconstrictor. It stimulates adrenal cortex to secrete Aldosterone. It stimulate thirst It inhibits Renin release ( -ve feedback) NOTE: Blockage of Angiotensin synthesis ( ACEIs) or Angiotensin receptors (ARBs) are widely used drugs in medicine (HF , ↑ HT , IHD , diabetic nephropathy) b- Vasopressin [ ADH]: It acts through 2 types of receptors V1 and V2 V1 is divided into 2 subtypes V1a and V1b. V1a = Vasoconstriction . V1b = ↑ ACTH V2 = Anti-diuretic effect. Vasopressin and its analogues are indicated in treatment of portal hypertension Desmopressin is indicated in treatment of Hemophilia c- Endothelin : It is a potent vasoconstrictor . It acts through 2 types of receptor (ET1 and ET2 ) Endothelin receptor blocker (Bosentan) is a new drug that proved for treatment of HF , ↑ HT , IHD NOTE: Other vasoconstrictors : Neuropeptide Y and Urotensin.