AUTACOIDS

1.

2.

Histamine Bradykinin & Kallidin 3.

5 Hydroxytryptamine (5HT) 4.

a.

b.

Autacoids derived from membrane phospholipid  Eicosanoids – arachidonic acid (PG, PGI, TXA2, LT) 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.

2.

3.

4.

5.

6.

Role in allergic responses – Ag + IgE (bound to mast cells & basophils) 1.

2.

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, thermoregulation

Selected Actions of Histamine 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 Action



TPR



Vasodilatation Blood flow



Blood flow,relaxation Constriction Relaxation Constriction Constriction Vasodilatation



Permeability



SA rate



Force of contraction Atrial & vent automaticity Receptor H1, H2 H2 H1, H2 H2 (?) H1 H2 H2 H1 H1 H2 H2

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

Selected Actions of Histamine in Humans

      

H1, H2 H3

- located in post synaptic membrane – 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.

2.

3.

4.

5.

6.

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, HA

Therapeutic Uses:

1.

2.

3.

4.

5.

6.

7.

dermatosis allergic rhinitis motion sickness & emesis Parkinson’s disease EPS Insomnia Adverse reactions

Histamine Antagonists

I.

First Generation Agents

A.

Ethanolamines

1.

2.

3.

Carbinoxamine maleate Clemastine fumarate Diphenhydramine HCl 4.

Dimenhydrinate B.

Ethylenediamines

1.

2.

3.

Pyrilamine maleate Tripelennemine HCL/citrate PPA 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) 2. Cyclizine HCl/lactate 3. Meclizine HCl 4. Chlorcyclizine E. Phenothiazines 1. Promethazine HCl

Structural Class

First Gen. Agents: 1. Ethanolamine

Prototype

Diphenhydramine 2.Ethylenediamine/ Ethylamine 3. Alkylamine 4. Piperazine Pyrilamine Mepyramine Pyranesamine Chlorpheniramine Pheniramine Chlorphenamine Chlorcyclizine

Characteristics Significant antimuscarinic activity Sedation, somnolence



Incidence of GI symptoms Effective in emesis & motion sickness Most specific H1 antagonist



Anticholinergic activity Feeble CNS effects Somnolence GI s/s common Most potent Not so prone to develop drowsiness More suitable for older patients Sedation/CNS stimulation Oldest member More prolonged action



Incidence of drowsiness

Structural Class Prototype

Hydroxyzine Cyclizine

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

Counters motion sickness (primarily) Meclizine/Meclozine

Counters motion sickness & emesis

Structural Class

5. Phenothiazine

Prototype

Promethazine

Characteristics Anticholinergic Prominent sedation Counters motion sickness primarily antiemetic

Second Gen.Agents

1. Piperidine Terfenadine 2. Alkylamine 3. Piperazine Acrivastine Cetirizine

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 Allergic rhinitis 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 Ranitidine: RF) •BM depression – rare •Serum prolactin elevation •Sexual dysfunction & gynecomastia  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



Vasoconstrictors

—angiotensin II,vasopressin, endothelins, neuropeptide Y 

Vasodilators

—bradykinin, natri-uretic peptides, vasoactive intestinal peptides, 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



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 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 5 hydroxytryptamine (Serotonin ) 5-hydroxyindole acetaldehyde 5-hydroxyindole acetic acid (principal metabolite) acid 5-hydroxytrytophol N-acetyl 5-HT 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 in cell lipid Arachidonic acid PLA2 Lipoxygenase 12-HPETE 12-HETE Cyclooxygenase X ASA, indomethacin 5-HPETE 5-HETE 84 LTA4 LTC4 LTB4 LTD4 LTE4 LTF4

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

Inhibitors of Biosynthesis

1.

2.

3.

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

Pharmacological Properties

Therapeutic Uses

1.

2.

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) 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

Pharmacological Properties

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



Potent ulcerogen