Autacoids....with Slide No

AUT ACO ID S Prof. Dr. Shah Murad [email protected]

08/07/09

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 AUTACOIDS 2.Histamine 3.Bradykinin & Kallidin 4.5 Hydroxytryptamine (5HT) 5.Autacoids derived from membrane phospholipid a.Eicosanoids – arachidonic acid  (PG, PGI, TXA2, LT) 08/07/09 b.Modified phospholipids – PAF(platelet activating

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HI STA MI NES Chemistry: imidazole ring + amino group connected by 2 methylene groups

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Syn thesis  Decarboxylation of amino acid L-histidine catalyzed by L-histidine decarboxylase.  Ingested from food or formed by bacteria in the GIT  Storage sites:   

perivascular tissue – mast cell circulation – basophil others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids 08/07/09

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Me taboli sm :  Major pathways  Deamination – small intestine, liver, kidney and monocytes  Methylation – small intestine, liver, skin, kidney, thymus & leukocytes

 N-methylimidazole acetic acid principal urinary metabolite 08/07/09

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Me taboli sm :

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Functions:

1. Role in allergic responses – Ag + IgE (bound to mast cells & basophils)  Preformed mediators  Most important mechanism of release/controlled by H2 esp. in skin & blood  Release of other autacoids  Release by drugs (morphine, urase, amines), peptides, venoms & other agents  Release by urticarias  Gastric secretagogue  Neurotransmitter → increased wakefulness, 08/07/09 thermoregulation

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Sel ected Acti ons of H istami ne in Humans Organ Tissue CARDIOVASCULAR Vascular Facial cutaneous Forearm Gastric mucosa Carotid artery Pulmonary artery Basilar artery Coronary artery Other pre & post cap Arterioles Postcapillary venules Heart

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Action

Receptor

↓ TPR Vasodilatation ↑ Blood flow

H1, H2 H2 H1, H2

↑ Blood flow,relaxation Constriction Relaxation Constriction Constriction Vasodilatation ↑ Permeability ↑ SA rate ↑ Force of contraction Atrial & vent automaticity

H2 (?) H1 H2 H2 H1 H1 H2 H2

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Sel ected Acti ons of H istami ne in Humans Organ Tissue RESPIRATORY Bronchiolar smooth muscle

Action

Receptor

Contraction (more prominent) Relaxation

H1 H2

H2 H1

Gallbladder smooth muscle

Acid and pepsin secretion, If Relaxation & Contraction (more prominent) Relaxation (?)

CUTANEOUS NERVE ENDINGS (Sensory)

Pain & itching (esp to insect bites & needle stings)

H1, H2 (?)

ADRENAL MEDULLA

Epinephrine release

H1

BASOPHILS 08/07/09

Inhibition of IgE – dependent degranulation

H2

GASTROINTESTINAL Oxyntic mucosa GI smooth muscle

H2 (?)

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Sel ected Acti ons of H istami ne 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     

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H1 RE CEPTO R ANT AGO NI STS 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    

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Ad ve rse Ef fects: 1.

3.

5. 6. 7. 8.

CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & convulsions - common in first generation antihistamines GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation - dryness of mouth, throat & airway, urinary retention - first generation Headache, faintness Chest tightness, palpitations, hypotension Visual disturbances Hematological - leukopenia, agranulocytosis 08/07/09

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Th era peutic Use s: 1. 2. 3. 4.

dermatosis allergic rhinitis motion sickness & emesis Parkinson’s disease

Insomnia Adverse reactions 08/07/09

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I.

Hista min e An ts Firsttagonis Generation

Agents

A. Ethanolamines 3. Carbinoxamine maleate 4. Clemastine fumarate 5. Diphenhydramine HCl 6. Dimenhydrinate B. Ethylenediamines 8. Pyrilamine maleate 9. Tripelennemine HCL/citrate C. Alkylamines 12.Chlorpheniramine maleate 13.Brompheniramine maleate 08/07/09

II. Second Generation

Agents

A. Alkylamines  Acrivastine B. Piperazines  Cetirizines HCl C.     

Piperidines Astemizole Levocabastine Loratadine Terfenadine Fexofenadine

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FIRST GENERATION AGENTS D. Piperazines 1. Hydroxyzine HCl/pamoate (long acting) 2. Cyclizine HCl/lactate 3. Meclizine HCl 4. Chlorcyclizine E. Phenothiazines 1. Promethazine HCl 08/07/09

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Structural Class

Prototype

First Gen. Agents: 1. Ethanolamine

Diphenhydramine

Characteristics Significant antimuscarinic activity Sedation, somnolence ↓ Incidence of GI symptoms Effective in emesis & motion sickness

2.Ethylenediamine/ Ethylamine 3. Alkylamine

Pyrilamine Mepyramine Pyranesamine

Most specific H1 antagonist ↓ Anticholinergic activity Feeble CNS effects

Chlorpheniramine Pheniramine

Most potent Not so prone to develop drowsiness More suitable for older patients

Chlorphenamine 4. Piperazine 08/07/09

Chlorcyclizine

Somnolence GI s/s common

Sedation/CNS stimulation

Oldest member More prolonged action ↓ Incidence of drowsiness 16

Structural Class

Prototype Hydroxyzine

08/07/09

Characteristics Long acting Widely used for skin allergies CNS depressant More prominent antipruritic action

Cyclizine

Counters motion sickness (primarily)

Meclizine/Meclozine

Counters motion sickness & emesis

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Structural Class 5. Phenothiazine

Prototype Promethazine

Second Gen.Agents Terfenadine 1. Piperidine

2. Alkylamine

Acrivastine

Characteristics Anticholinergic Prominent sedation Counters motion sickness primarily antiemetic

Highly selective for H1 receptor Non-sedating (-) anticholonergic action (-) pass BBB ↓ incidence of S/E Rapid onset of action (30 mins) (-) anticholinergic effects Reduce both wheal & flare response ↓ Potential to penetrate BBB Skin allergy

3. Piperazine 08/07/09

Cetirizine

Allergic rhinitis

Rhinitis, urticaria (-) pass BBB

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

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Adverse Effects Cimetidine: • headache, dizziness • constipation, diarrhea •skin rashes •alterations of hepatic function •CNS disturbances (elderly & impaired RF) •depression – rare •Serum prolactin elevation •Sexual dysfunction & gynecomastia Ranitidine: • Serum prolactin elevation 08/07/09

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Dr ug I nteractions: 

  

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

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Vaso active Peptides  Vasoconstrictors—angiotensin II,vasopressin, endothelins, neuropeptide Y

 Vasodilators—bradykinin, natri-uretic peptides, vasoactive intestinal peptides, substance P, neurotensin and calcitonin 08/07/09 22 gene-related peptide (CGRP)

BRAD YKI NIN & KAL LIDI N  Peptides that act locally to produce pain, vasodilatation, ↑ vascular permeability & PG synthesis Synthesis:  Liver  Precursurs: kininogens—SERINE PROTEASES (HMW & LMW) 08/07/09

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Ph arm acolo gic Pr opert ie s CVS : (+) inotropic & chronotropic effects vasoconstriction  Smooth Muscle: Bronchoconstriction  GIT: Enhanced motility 

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Functions 

 

pain – excites primary sensory neurons & provokes release of substance P, neurokinin A inflammation - ↑ permeability in microcirculation respiratory disease

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Ph arm acolo gical Pr opert ie s 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 arteriosus constriction of umbilical vessels 08/07/09

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 

5 HYD ROXY TRYP TAMI NE (5HT )

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

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Synthesis:

Tryptophan Hydroxytryptophan 5 hydroxytryptamine (Serotonin) 5-hydroxyindole acetaldehyde

5-hydroxyindole acetic acid (principal metabolite) 08/07/09

acid 5-hydroxytrytophol N-acetyl5-HT 28 Melatonin

Antagonists: 1. Clozapine: High affinity for dopamine receptors Reduced negative symptoms of schizophrenia

2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia 08/07/09

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1. Clozapine: • • High affinity for dopamine receptors • Reduced negative symptoms of schizophrenia 2. Risperidone: • D2 receptor blocker • Reduced negative symptoms of schizophrenia 3. Methysergide:

used for diarrhea & malabsorption in patients with carcinoid tumors 08/07/09

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

• • •

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LIPI D-DERI VED AUT OCO ID S Eicosanoids    

formed from PUFA release from cellular stores by PLA2 human platelets – DAG lipase coupled to G proteins 08/07/09

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EFA (diet)

Lipoxygenase 12-HPETE 12-HETE

Esterified acid in cell lipid

Arachidonic acid PLA2

Cyclooxygenase

X ASA, indomethacin

5-HPETE 5-HETE

84 LTA4 LTC4 LTB4

LTD4 LTE4

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LTF4

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Cycloxygenase PGG2 PGH2

PGG2

PGE2 PGF2α PGD2

PGF1α

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TXA2 TXB2

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Inhib itors o f Bio syn thesis   

drugs that reduce the availability of Ca glucocorticoids – induce lipocortin synthesis which inhibits PLA2 ASA & related NSAID

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Pharmacological Properties

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Th era peutic Use s 1. 2.

3.

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

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

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Ph arm acolo gical Pr opert ie s A. CVS: Potent vasodilator vascular permeability 1000x more than histamine/bradykinin B. Leukocyte: Chemotaxis C. Smooth Muscle:  Contraction  Airway resistance & responsiveness to other bronchoconstrictors D. Stomach 08/07/09 39  Potent ulcerogen