Autacoids

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1. Autacoids & related drugs Dr. Karun Kumar Senior Lecturer Dept. of Pharmacology

2. Autacoids This term is derived from Greek  autos—self, akos —healing substance or remedy These are Diverse substances Produced by a wide variety of cells in the body Have intense biological activity Act locally (e.g. within inflammatory pockets) at the site of synthesis and release

3. They have also been called ‘local hormones’. However, they differ from ‘hormones’ in two important ways H ormones are produced by specific cells Are transported through circulation to act on distant target tissues

4. Types of autacoids Amine autacoids  Histamine, 5-Hydroxytryptamine (Serotonin) Lipid derived autacoids  Prostaglandins, Leukotrienes , Platelet activating factor Peptide autacoids  Plasma kinins ( Bradykinin , Kallidin ), Angiotensin Cytokines (interleukins, TNF α, GM-CSF, etc.) and several peptides like gastrin, somatostatin , vasoactive intestinal peptide

5. Histamine Histamine, meaning ‘tissue amine’ ( histos —tissue) is almost ubiquitously present in animal tissues and in certain plants Histamine is present mostly within storage granules of mast cells Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta Nonmast cell histamine occurs in brain, epidermis, gastric mucosa

6. Histamine is formed when the amino acid histidine is decarboxylated in a reaction catalyzed by the enzyme l–histidine decarboxylase Histamine is stored in granules ( vesicles) in mast cells and basophils until it is released It is released from mast cells when membrane-bound immunoglobulin E ( IgE ) interacts with an IgE antigen to cause mast cell degranulation

7. Pathophysiological roles Gastric secretion  Histamine mediates secretion of HCl in the stomach Allergic phenomena  Released from mast cells following AG : AB reaction As transmitter  Afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings. Inflammation  M ediator of vasodilatation

8. Classification Highly sedative Diphenhydramine Dimenhydrinate Promethazine Moderately sedative Pheniramine Meclozine (Meclizine) Cinnarizine

9. 3. Mild sedative Chlorpheniramine Dexchlorpheniramine Triprolidine 4. Second generation antihistaminics Fexofenadine Loratadine Desloratadine Cetirizine Levocetirizine

10. H 1 antagonists (1 st gen.) Antagonism of histamine  Block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response—especially wheal, flare and itch Antiallergic action  Many manifestations of immediate hypersensitivity (type I reactions) are suppressed. Urticaria, itching and angioedema are well controlled CNS  The older antihistamines produce variable degree of CNS depression

11. 4. Anticholinergic action 5. BP  Most antihistaminics cause a fall in BP on i.v. injection (not evident on oral administration)

12. Uses Allergic disorders  Antihistaminics do not suppress AG: AB reaction, but block the effects of released histamine—are only palliative. They effectively control certain immediate type of allergies, e.g. itching, urticaria, seasonal hay fever, allergic conjunctivitis and angioedema of lips, eyelids, etc. Some skin rashes also respond

13. 2. Other conditions involving histamine  They afford symptomatic relief in insect bite and ivy poisoning Abnormal dermographism is suppressed They have prophylactic value in blood/saline infusion induced rigor. 3. Pruritides  Though relief is often incomplete, older antihistaminics Chlorpheniramine, Diphenhydramine, remain the first choice drugs for itching 4. Common cold  Afford symptomatic relief by anticholinergic (reduce rhinorrhoea ) and sedative actions

14. 5. Motion sickness  Promethazine, Diphenhydramine, Dimenhydrinate and Meclizine have prophylactic value in milder types of motion sickness; should be taken one hour before starting journey Promethazine can also be used in morning sickness, drug induced and postoperative vomiting 6. Vertigo  Cinnarizine inhibits vestibular sensory nuclei in the inner ear, possibly by reducing stimulated influx of Ca 2+ from endolymph into the vestibular sensory cells Dimenhydrinate is also used

15. 7. Preanaesthetic medication  Promethazine has been used for its anticholinergic and sedative properties 8. Cough  Antihistaminics like Chlorpheniramine , diphenhydramine and promethazine are constituents of many popular cough remedies 9. Parkinsonism  Promethazine and some others afford mild symptomatic relief in early cases—based on anticholinergic and sedative property

16. 10. Acute muscle dystonia  Caused by antiemetic-antipsychotic drugs is promptly relieved by parenteral promethazine, diphenhydramine or hydroxyzine 11. As sedative, hypnotic, anxiolytic  Antihistamines with CNS depressant action have been used as sedative and to induce sleep. Promethazine has produced serious respiratory depression in young children; it is contraindicated in children aged 2 years or less

17. Side effects Most common  Sedation, diminished alertness and concentration, light headedness, motor incoordination, fatigue and tendency to fall asleep are the most common, impairment of psychomotor performance Patients should be cautioned not to operate motor vehicles or machinery requiring constant attention 2. Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision  anticholinergic property 3. Epigastric distress and headache may be felt Local application can cause contact dermatitis

18. Second generation antihistaminics Absence of CNS depressant property. Higher H 1 selectivitiy : no anticholinergic side effects. Additional antiallergic mechanisms apart from histamine blockade They have poor antipruritic, antiemetic and antitussive actions

19. Indications Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing, runny but not blocked nose, and red, watering, itchy eyes Urticaria, dermographism, atopic eczema Acute allergic reactions to drugs and foods

20. 5-Hydroxytryptamine Serotonin was the name given to the vasoconstrictor substance which appeared in the serum when blood clotted and was shown to be 5-hydroxytryptamine ( 5-HT ) About 90% of body’s content of 5-HT is localized in the intestines; most of the rest is in platelets and brain

21. Actions Constriction of larger arteries and veins but dilatation of arterioles Enhanced peristalsis and secretion in gut causing diarrhoea Inhibition of gastric acid and pepsin secretion (ulceroprotective) Proaggregatory action on platelets Activation of afferent nerve endings  Tingling/Pricking sensation, pain

22. Pathophysiological roles Neurotransmitter in brain; involved in sleep, temperature regulation, cognitive function, behaviour and mood, vomiting and pain perception Regulation of gut peristalsis Precursor of melatonin in pineal gland (Regulation of biological clock) Control of anterior pituitary hormones function by hypothalamus Nausea and vomiting (Cancer chemo/radiotherapy)

23. 6. Migraine  Involved in initiating constriction of cranial vessels 7. Haemostasis  By promoting platelet aggregation and blood vessel retraction 8. Vasospastic disorders like Raynaud’s phenomenon and variant angina 9. Carcinoid syndrome  5-HT mediated bowel hypermotility and bronchoconstriction

24. Lipid derived autacoids Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids that are released from cell membrane phospholipids (Eicosanoids)

25. Cyclooxygenase (COX) - 1 Constitutive enzyme in most cells “House keeping” enzyme Secretion of mucus for protection of gastric mucosa Haemostasis Maintenance of renal function

26. Cyclooxygenase (COX) - 2 “Inducible” by Cytokines, Growth factors, and Other stimuli during inflammatory response Participates in inflammation Constitutively present in kidney and brain

27. Lipoxygenase (LOX) Pathway operates in L ung L eucocytes (WBCs) B lood (Platelets)

28. Biosynthesis of PGs and LTs Annexins

29. Inhibition of synthesis Synthesis of COX products can be inhibited by nonsteroidal anti inflammatory drugs (NSAIDs ) Aspirin acetylates COX and causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors Most NSAIDs are nonselective COX-1 and COX-2 inhibitors , but some later ones like Celecoxib, E toricoxib are selective for COX-2

30. Degradation Biotransformation of arachidonates occurs rapidly in most tissues (fastest in the lungs) Most PGs, TXA 2 and prostacyclin have plasma t½ of a few seconds to a few minutes A specific carrier mediated uptake into cells occurs , side chains are oxidized & double bonds are reduced in a stepwise manner to yield inactive metabolites Metabolites are excreted in urine PGI2 is catabolized mainly in the kidney

31. Pathophysiological roles PGI 2  Regulation of local vascular tone (dilator) PGE 2  Continuously produced in the ductus arteriosus during fetal life (keeps it patent). At birth, their synthesis stops and closure occurs. Aspirin and indomethacin have been found to induce closure PGs along with LTs and other autacoids may mediate vasodilatation and exudation at the site of inflammation TXA 2 and PGI 2 constitute a mutually antag . system

32. Importance of PGs & LTs PGE 2

33. Aspirin NSAID with analgesic , antipyretic, & anti-inflammatory effects Inhibits platelet aggregation & used to prevent and treat arterial thromboembolic disorders Prostacyclin (PGI 2 )  Vasc . Endoth . & inh . P.a. TXA 2  P latelets & promotes platelet aggreg . Low doses of aspirin  S el. Inh . TXA 2 synth. Higher doses  I nhibit the synthesis of both

34. Aspirin TXA 2 produced by platelet COX-1 amplifies platelet aggregation Aspirin is an irreversible inhibitor of COX and decreases the synthesis of both TXA 2 and PGI 2 After some time, endothelial cells produce new COX enzyme (contains nucleus) whereas platelets due to lack of nucleus cannot produce TXA 2  Net effect is platelet anti aggregatory activity Aspirin is only NSAID in MI prophylaxis

35. Why low dose Aspirin ? At low dose, Aspirin selectively inhibits COX-1 in platelets in the portal circulation (by acetylation) The compound which leaves the portal circulation is salicylic acid which is unable to inhibit COX enzyme in endothelium If a high dose is given, the compound leaving the portal circulation may contain active acetyl salicylic acid which can interfere with anti-platelet action by inhibiting PGI 2 synthesis in endothelium

36. 5. PGs produced by fetal tissues at term mediate initiation and progression of labour. Aspirin has been found to delay the initiation of labour. 6. Dysmenorrhoea in many women is due to uterine cramps and ischemia induced by ↑ PG synthesis in endometrium (NSAIDs help in relieving it) 7. PGs may be involved in mediating toxin induced ↑ fluid movement in secretory diarrhoeas. PGs appear to play a role in growth of colonic polyps and cancer. Regular intake of low dose Aspirin lowers incidence of colon cancer.

37. 8. PGs (esp. PGI 2 ) may be functioning as natural ulcer protectives by enhancing gastric mucus and bicarbonate production as well as by improving mucosal circulation. The ulcerogenic action of NSAIDs may be due to loss of this protective influence. 9. NSAIDs tend to retain salt and water (Blunt action of Furosemide) 10. PGE 2 mediate bacterial or other pyrogen induced fever. Aspirin and other NSAIDs (antipyretic)

38. 11. PGs (esp. PGE 2 and PGI 2 ) sensitize afferent nerve endings to pain inducing chemical and mechanical stimuli 12. PGF 2 α lowers i.o.t. by enhancing uveoscleral and trabecular outflow of aqueous humor . Latanoprost is 1 st line drug for open angle glaucoma

39. Leukotrienes LTB 4  neutrophils; LTC 4 and LTD 4  macrophages CVS and blood  LTC 4 and LTD 4 injected i.v . evoke a brief ↑ in BP followed by ↓ LTB 4  C hemotactic for T-lymphocytes, neutrophils & monocytes LTC 4 and LTD 4  C hemotactic for eosinophils Role  Mediators of inflammation, greater role in chronic inflammatory states

40. 2. Visceral smooth muscle  LTC 4 & D 4 contract most smooth muscles Bronchoconstrictors & induce spastic contraction of g.i.t. at low conc. ↑ mucus secretion in airways Role  The cysteinyl LTs ( C 4 and D 4 ) are the most important mediators of human allergic asthma LTs Also responsible for abdominal colics during systemic anaphylaxis

41. 3. Afferent nerves  Like PGE 2 and I 2 , LTB 4 also sensitizes afferents carrying pain impulses ↓ Pain and tenderness of inflammation

42. Prostanoid receptors 5 prostanoid receptors have been designated, each after the natural PG for which it has the greatest affinity DP (for PGD2), EP (for PGE2) FP (for PGF2 α), IP ( for prostacyclin or PGI2) and TP (for TXA2 ) All prostanoid receptors are GPCRs which utilize the IP3/DAG or cAMP transducer mechanisms .

43. ‘ Excitatory’ group (EP1, FP, TP )  S mooth muscle contraction, platelet aggregation, etc ‘Relaxant’ group (DP1, EP2, EP4, IP )  Smooth muscle relaxation, inhibition of platelet aggregation ‘Inhibitory’ group (EP3)  Inhibits lipolysis

44. 3 i

45. LEUKOTRIENE RECEPTORS Function through the IP3/DAG transducer mechanism The cys LT1 receptor is expressed in bronchial and intestinal muscle cys LT1 receptor antagonists ( Montelukast , Zafirlukast )  B ronchial asthma

46. LTR antagonists

47. Classification of PGs Natural 1. Dinoprostone (PGE 2 ) 2. Gemeprost 3. Dinoprost (PGF 2 α ) 4. Alprostadil (PGE 1 ) 5. Prostacyclin (PGI 2 ) PG analogues Carboprost Misoprostol Latanoprost Bimatoprost

48. Uses of PGs Abortion  Single oral dose of Misoprostol after 2 days of Mifepristone (antiprogestin) priming is used to terminate pregnancy of upto 7 weeks duration. Extra or intra amniotic injection of PGE 2 or PGF 2 α can be used for 2 nd trimester abortion Induction/augmentation of labour  Intravaginal PGE 2 or PGF 2 α are alternatives to i.v. Oxytocin but less reliable

49. 3. Cervical priming (ripening)  Low doses of PGE 2 applied in cervical canal/vagina make the cervix soft and more compliant for delivery/abortion 4 . Postpartum haemorrhage (PPH )  Carboprost (15-methyl PGF 2 α ) i.v. is an alternative drug to Ergometrine or Oxytocin 5. Peptic ulcer  Misoprostol (PGE 1 analogue) can be used for healing NSAID associated peptic ulcer 6 . Glaucoma  Topical PGF 2 α analogues like Latanoprost , Travoprost , Bimatoprost are the first choice drugs in wide angle glaucoma