AUTACOIDS 1.Histamine 2.Bradykinin & Kallidin 3.5 Hydroxytryptamine (5HT) 4.Autacoids derived from membrane phospholipid a.Eicosanoids – arachidonic acid  (PG, PGI, TXA2, LT) b.Modified phospholipids – PAF

HISTAMINES Chemistry: imidazole ring + amino group connected by 2 methylene groups

Synthesis  Decarboxylation of amino acid L-histidine catalyzed by pyridoxal PO4-dependent L- histidine decarboxylase.  Ingested from food or formed by bacteria in the GIT  Storage sites:  perivascular tissue – mast cell  circulation – basophil (bound to chondroitin SO4)  others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids

Metabolism :  Major pathways  Deamination – small intestine, liver, kidney and monocytes  Methylation – small intestine, liver, skin, kidney, thymus & leukocytes  N-methylimidazole acetic acid - principal urinary metabolite

Metabolism :

Functions: 1.Role in allergic responses – Ag + IgE (bound to mast cells & basophils) 1.Preformed mediators 2.Most important mechanism of release/controlled by H2 esp. in skin & blood 2.Release of other autacoids 3.Release by drugs (morphine, urase, amines), peptides, venoms & other agents 4.Release by urticarias 5.Gastric secretagogue 6.Neurotransmitter  increased wakefulness, thermoregulation

Selected Actions of Histamine in Humans Organ Tissue ActionReceptor CARDIOVASCULARVascular Facial cutaneous Forearm Gastric mucosa Carotid artery Pulmonary artery Basilar artery Coronary artery Other pre & post cap Arterioles Postcapillary venules Heart  TPR Vasodilatation Vasodilatation  Blood flow  Blood flow,relaxation ConstrictionRelaxationConstrictionConstrictionVasodilatation  Permeability  SA rate  Force of contraction Atrial & vent automaticity H1, H2 H2 H2 (?) H1H2H2H1H1H2H2

Selected Actions of Histamine in Humans Organ Tissue ActionReceptor RESPIRATORY Bronchiolar smooth muscle Contraction (more prominent) RelaxationH1H2 GASTROINTESTINAL Oxyntic mucosa GI smooth muscle Gallbladder smooth muscle Acid and pepsin secretion, If Relaxation & Contraction (more prominent) (more prominent) Relaxation (?) H2H1 H2 (?) CUTANEOUS NERVE ENDINGS (Sensory) Pain & itching (esp to insect bites & needle stings) H1, H2 (?) ADRENAL MEDULLA Epinephrine release H1 BASOPHILS Inhibition of IgE – dependent degranulation H2

Selected Actions of Histamine in Humans  H1, H2 - located in post synaptic membrane  H3 – presynaptic  H1 - predominant in endotracheal & smooth muscle  H2 - facial veins, carotid a, pulm. a, heart  gastric mucosa, heart, smooth muscle & some immune cells  H3 - several ares in CNS  Triple response - wheal, flare & redness

H1 RECEPTOR ANTAGONISTS Pharmacokinetics:  Well absorbed from GIT (oral)  Onset – 30 minutes, duration – 3 to 6 hours  Widely distributed  Biotransformed in the liver; microsomal enzyme inducer  Excretion – kidneys

Adverse Effects: 1.CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & convulsions - common in first generation antihistamines 2.GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation - dryness of mouth, throat & airway, urinary retention - first generation 3.Headache, faintness 4.Chest tightness, palpitations, hypotension 5.Visual disturbances 6.Hematological - leukopenia, agranulocytosis, HA

Therapeutic Uses: 1.dermatosis 2.allergic rhinitis 3.motion sickness & emesis 4.Parkinson’s disease 5.EPS 6.Insomnia 7.Adverse reactions

Histamine Antagonists Histamine Antagonists I. First Generation Agents A. Ethanolamines A. Ethanolamines 1.Carbinoxamine maleate 2.Clemastine fumarate 3.Diphenhydramine HCl 4.Dimenhydrinate B. Ethylenediamines B. Ethylenediamines 1.Pyrilamine maleate 2.Tripelennemine HCL/citrate 3.PPA C. Alkylamines C. Alkylamines 1.Chlorpheniramine maleate 2.Brompheniramine maleate II. Second Generation Agents A. Alkylamines  Acrivastine B. Piperazines  Cetirizines HCl C. Piperidines  Astemizole  Levocabastine  Loratadine  Terfenadine  Fexofenadine

FIRST GENERATION AGENTS D. Piperazines 1. Hydroxyzine HCl/pamoate (long acting) 1. Hydroxyzine HCl/pamoate (long acting) 2. Cyclizine HCl/lactate 2. Cyclizine HCl/lactate 3. Meclizine HCl 3. Meclizine HCl 4. Chlorcyclizine 4. Chlorcyclizine E. Phenothiazines 1. Promethazine HCl 1. Promethazine HCl

Structural Class PrototypeCharacteristics First Gen. Agents: 1. Ethanolamine Diphenhydramine Significant antimuscarinic activity Sedation, somnolence  Incidence of GI symptoms  Incidence of GI symptoms Effective in emesis & motion sickness 2.Ethylenediamine/ Ethylamine EthylaminePyrilamineMepyraminePyranesamine Most specific H1 antagonist  Anticholinergic activity  Anticholinergic activity Feeble CNS effects Somnolence GI s/s common 3. Alkylamine ChlorpheniraminePheniramineChlorphenamine Most potent Not so prone to develop drowsiness More suitable for older patients Sedation/CNS stimulation 4. Piperazine Chlorcyclizine Oldest member More prolonged action  Incidence of drowsiness  Incidence of drowsiness

Structural Class PrototypeCharacteristics Hydroxyzine Hydroxyzine Long acting Widely used for skin allergies CNS depressant More prominent antipruritic action Cyclizine Counters motion sickness (primarily) Meclizine/Meclozine Counters motion sickness & emesis

Structural Class PrototypeCharacteristics 5. Phenothiazine Promethazine Promethazine Anticholinergic Anticholinergic Prominent sedation Prominent sedation Counters motion sickness primarily antiemetic Counters motion sickness primarily antiemetic Second Gen.Agents Second Gen.Agents 1. Piperidine Terfenadine Highly selective for H1 receptor Non-sedating (-) anticholonergic action (-) pass BBB  incidence of S/E  incidence of S/E 2. Alkylamine Acrivastine Rapid onset of action (30 mins) (-) anticholinergic effects Reduce both wheal & flare response  Potential to penetrate BBB  Potential to penetrate BBB Skin allergy Allergic rhinitis Skin allergy Allergic rhinitis 3. Piperazine Cetirizine Rhinitis, urticaria (-) pass BBB

H2 RECEPTOR ANTAGONISTS Pharmacodynamics: Inhibit gastric acid secretion (-) effect of gastric motility, emptying time, LES sphincter, pancreatic & mucous secretion

Adverse Effects Cimetidine:  headache, dizziness constipation, diarrhea skin rashes alterations of hepatic function CNS disturbances (elderly & impaired RF) BM depression – rare Serum prolactin elevation Sexual dysfunction & gynecomastia Ranitidine:  Serum prolactin elevation

Drug Interactions:  Cimetidine inhibits cyto p-450 – accumulation of warfarin, phenytoin, theophylline, propanolol, diazepam & phenobarbital  Ranitidine – weak inhibitor  Nizatidine & famotidine – do not inhibit cyto P – 450  Therapeutic Uses:Peptic acid disorders

Vasoactive Peptides Vasoactive Peptides  Vasoconstrictors—angiotensin II,vasopressin, endothelins, neuropeptide Y  Vasodilators—bradykinin, natri-uretic peptides, vasoactive intestinal peptides, substance P, neurotensin and calcitonin gene-related peptide (CGRP) substance P, neurotensin and calcitonin gene-related peptide (CGRP)

BRADYKININ & KALLIDIN  Peptides that act locally to produce pain, vasodilatation,  vascular permeability & PG synthesis Synthesis:  Liver  Percursors: kininogens—SERINE PROTEASES (HMW & LMW)

Pharmacologic Properties  CVS : (+) inotropic & chronotropic effects (+) inotropic & chronotropic effects vasoconstriction vasoconstriction  Smooth Muscle: Bronchoconstriction  GIT: Enhanced motility

Functions  pain – excites primary sensory neurons & provokes release of substance P, neurokinin A & CGRP  inflammation -  permeability in microcirculation  production of IL-1 & TNF -   respiratory disease

Pharmacological Properties 1. CVS – potent vasodilator (10x more than histamine)  Stimulate histamine release 2. Kidney -  RBF 3. Others:  spermatogenesis & promotes sperm motility dilatation of fetal pulmonary artery closure of ductus arteriosusdilatation of fetal pulmonary artery closure of ductus arteriosus constriction of umbilical vessels

5 HYDROXYTRYPTAMINE (5HT)  Found in enterochromaffin cells (90%), platelets and CNS  Sources : tunicates, mollusks, anthropods, colenterates, fruits, nuts, wasps & scorpions

Synthesis: Tryptophan Hydroxytryptophan Hydroxytryptophan 5 hydroxytryptamine 5 hydroxytryptamine (Serotonin) (Serotonin) 5-hydroxyindole acetaldehyde 5-hydroxyindole acetaldehyde 5-hydroxyindole acetic acid acid 5-hydroxytrytophol (principal metabolite) N-acetyl- 5-HT N-acetyl- 5-HT Melatonin Melatonin

Antagonists: 1. Clozapine: Reduce incidence of EPS High affinity for dopamine receptors Reduced negative symptoms of schizophrenia 2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia Low incidence of EPS

1. Clozapine: Reduce incidence of EPS High affinity for dopamine receptors Reduced negative symptoms of schizophrenia 2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia Low incidence of EPS 3. Methysergide: used for diarrhea & malabsorption in patients with carcinoid tumors

Cyproheptadine: H1 blocker Weak anticholinergic and mild CNS depressant Used for skin allergies, cold urticaria Counteract the sexual side effects of SSRI’s

LIPID-DERIVED AUTOCOIDS Eicosanoids  formed from PUFA (AA)  release from cellular stores by PLA2  human platelets – DAG lipase  coupled to G proteins

EFA (diet) Esterified acid Arachidonic acid in cell lipid PLA2 EFA (diet) Esterified acid Arachidonic acid in cell lipid PLA2 Lipoxygenase Cyclooxygenase X ASA, indomethacin Lipoxygenase Cyclooxygenase X ASA, indomethacin 12-HPETE 5-HPETE 12-HPETE 5-HPETE84 12-HETE 5-HETE LTA4 LTC4 LTB4LTD4 LTE4LTF4

Cycloxygenase Cycloxygenase PGG2 PGG2 PGH2 PGH2 PGG2 PGE2 PGF2  PGD2 TXA2 PGG2 PGE2 PGF2  PGD2 TXA2 PGF1  TXB2 PGF1  TXB2

Inhibitors of Biosynthesis 1.drugs that reduce the availability of Ca 2.glucocorticoids – induce lipocortin synthesis which inhibits PLA2 3.ASA & related NSAID

Pharmacological Properties

Therapeutic Uses 1.PGE1 (Misoprostol) – suppress gastric ulceration 2.PGE1 & PGI2 – improve harvest and storage of platelets for therapeutic transfusion - improve blood flow & tissue oxygenation in neonates (ductus arteriosus – vasodilatation) 3. PGE1 – treatment of impotence

PLATELET ACTIVATING FACTOR (PAF) Synthesized by platelets, neutophils,monocytes, mast cells, eosinophils, renal mesangial cells, renal medullary cells & vascular endothelial cells Synthesized by platelets, neutophils,monocytes, mast cells, eosinophils, renal mesangial cells, renal medullary cells & vascular endothelial cells

Pharmacological Properties A. CVS:Potent vasodilator vascular permeability 1000x more than histamine/bradykinin vascular permeability 1000x more than histamine/bradykinin B. Leukocyte:Chemotaxis C. Smooth Muscle:  Contraction  Airway resistance & responsiveness to other bronchoconstrictors D. Stomach  Potent ulcerogen