2. AUTACOIDS (LOCAL HORMONES) HORMONES) AND THEIR PHARMACOLO- GICAL MODULATION summary

3. endogenious compounds; play an important role in the physiological and pathological processes; have very short t 1/2 ; have local action. Autacoids

4. Histamine is presented in high concentration in the skin, and in the mucous layer of the lung and GIT as an autacoid. At cellular level, it is found largely in mast cells and basophiles. Non-mast-cell histamine occurs as a neurotransmitter in CNS.

5. In mast cells and basophiles histamine is located in intra cellular granules together with heparin.

6. Histamine is released from mast cells by a secretory process during inflammatory or allergic reactions (Ag-Ab reactions). The secretory process is initiated by a raise in intracellular Ca 2+. Histamine is released from mast cells during burns too.

7. Some drugs (mainly alkaloids atropine, morphine, reserpine, tubocurarine in high doses ) release histamine by non-receptor action and can cause bronchoconstriction, arterial hypotension, and other unwanted effects.

8. Histamine produces effects by acting on H 1, H 2, H 3, H 4, and H 5 -receptors. Histamine’s receptors are G-protein coupled.

9. Stimulation of H 1 -receptors contraction of endothelium, increasing of vascular permeability and producing type I hypersensitivity reactions (urticaria and hay fever); contraction of smooth muscle of bronchi, GIT, uterus; excitement of CNS.

10. H 1 -blockers Used mainly for the treatment of urticaria and hay fever. Some of them (embramine, promethazine) have antiemetic effect too.

11. Didimetindene Embramine Chlorpyramine Promethazine Cyproheptadine (H 1 &5-HT 2 ) H 1 -blockers from 1 st generation (with sedative and M-cholinolytic effects) Clemastine (weak sedation)

12. Astemizole Cetirizine Loratadine Terfenadine H 1 -blockers from 2 nd generation (without sedative and M-cholinolytic effects) prolongation of QT interval and hypokalemia

13. H 1 -blockers from 3 …rd… 3 …rd… generation Desloratadine (Aerius ® – film-tab. 5 mg; t 1/2 27 h) Levocitirizine

14. cardiac stimulation stimulation of gastric acid secretion Activation of H 2 -receptors:

15. Cimetidine (? …) Famotidine Nizatidine Ranitidine Roxatidine Antagonist of H 2 -receptors (H 2 -blockers) – for the treatment of peptic ulcer:

16. Cromoglycate – per inh. (Cromolyn – USAN) Ketotifen (p.o.) Nedocromil – per inh. Mast cell stabilizers They prevent degranulation and release of histamine and other autacoids from mast cells. They also inhibit leukocyte activation and chemotaxis. Indications: prophylactic treatment of asthma.

17.  b) Serotonin (5-Hydroxytryptamine: 5-HT) Indol derivative Rang et al. Pharmacology – 5 st Ed. (2003) Rang et al. Pharmacology – 5 st Ed. (2003)

18. Structures rich in 5-HT GIT (chromaffin cells and enteric neurons) platelets CNS

19. Important actions of 5-HT increased GI motility increased platelet aggregation increased microvascular permeability stimulation of nociceptive nerve endings control of appetite, sleep, mood, hallucinations, stereotyped behavior, pain perception, and vomiting

20. Clinical conditions in which 5-HT plays a role include: migraine mood disorders (depressive illnesses) anxiety vomiting carcinoid syndrome carcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)

21. 5-HT 1 -receptors: 5-HT 1A  5-HT 1F All subtypes occur in CNS and cause neural inhibition Act by inhibiting adenylate cyclase

22. Buspirone anxiolytic agent partial agonist of the 5-HT 1A -receptors used in anxiety

23. 5-HT 1D -receptors are found in some blood vessels (a. carotis externa et interna, meningeal vessels). They produce vasoconstriction. pathophysiology of migraine

24. The agonist of 5-HT 1D -receptors are highly effective, but expensive, in acute attacks of migraine: Naratriptan Rizatriptan Sumatriptan Zolmitriptan

25. Antagonists of 5-HT 2 -receptors are used: for prophylaxis of migraine - cyproheptadine - iprazochrome - methysergide - pizotifen as a peripheral vasodilator - Naftidrofuryl (Dusodril ® )

26. Adverse effects of methysergide: retroperitoneal fibrosis renal failure

27. SSRIs (selective serotonin reuptake inhibitors): Fluvoxamine, Citalopram, Fluoxetine, Paroxetine,Sertraline are used in humans to treat: chronic anxiety chronic anxiety Depression, bulimia Depression, bulimia

28. 5-HT 3 -receptors Located in enteric neurons and in CNS. Effects are excitatory, causing GI motility and vomiting.

29. Dolasetron Granisetron Ondansetron Tropisetron Antagonists of 5-HT 3 - receptors are very powerful antiemetics:

30. 2. EICOSANOIDS (20 carbon atoms!) 2. EICOSANOIDS (20 carbon atoms!) prostanoids  prostaglandins (PGs)  thromboxanes (Txs) leucotrienes (LTs) lipoxins (eicosi = 20)

31. The eicоsanoids are important mediators of inflammation and allergy. The main source of eicosanoids is arachidonic acid. It is a 20-carbon unsaturated fatty acid.

32. Phospholipase A 2 Phospholipids Arachidonic acid 5-lipoxygenase Leucotrienes Cyclooxygenase (Cox) Endoperoxides PGs TxA 2 15-lipoxygenase Lipoxins Inflammatory stimulus

33. PGI 2 (prostacyclin) is located predominantly in vascular endothelium. Main effects: vasodilatation inhibition of platelet aggregation TxA 2 is found in the platelets. Main effects: platelet aggregation vasoconstriction PROSTANOIDS (PGs & Txs)

34. PGE 1 alprostadil (prodrug – used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects, and for treatment of erectile dysfunction by injection misoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs); gemeprost used for termination of pregnancy.

35. Cyclooxygenase (COX) Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. COX exists in 3 isoforms: COX-1 COX-1 (constitutive) acts in physiological conditions. COX-2 COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. COX-3 COX-3 (in brain)

37. This has relevance for the mechanism of action of NSAIDs. Most of them inhibit mainly COX-1 and can cause peptic ulcer, GI bleeding, bronchial asthma, and nephrotoxicity.

38. COX-2inhibitors Selective (coxibs) Selective (coxibs) Preferential Preferential SelectiveCOX-3inhibitors Antipyretic Antipyretic analgesics analgesics NonselectiveCOX-1/COX-2inhibitors IL ® NSAIDs COX INHIBITORS

39. Coxibs are selective COX-2 inhibitors. They exert anti-inflammatory, analgesic and antipyretic action with low ulcerogenic potential. Coxibs can cause infertility. They have prothrombotic cardiovascular risk.

40. INFLAMMATION alteration exudationexudation proliferationproliferation NSAIDs ()() Gluco- Gluco-corticoids ()() ()()

41. 4. Peptides Endothelins: ET-1, ET-2, RT-3

42. soluble proteins and glycoproteins that interact with specific cellular receptors. Cytokines are involved in inflammatory and immune response. 5. Cytokines –

43. Cytokines act together (“as a team”) on: endothelium, leucocytes, mastocytes, fibroblasts, stem cells and osteoclasts. Cytokines control their proliferation, differentiation and/or activation by receptor mechanism.

44. IL-1 IL-1 participates in the pathogenesis of rheumatoid arthritis. Glucocorticosteroids and glucosamine depress the synthesis of IL–1. INTERLEUKINES (ILs)

45. Interferon alpha-2bInterferon alpha-2b (Intron © ): - in chronic hepatitis B and C - lymphomas, melanomas, etc. Interferon beta-1bInterferon beta-1b (Betaferon © ) s.c. in multiple sclerosis. Interferon gammaInterferon gamma – in the regulation of the immune system. INTERFERONS (INFs)

46. Colony-stimulating factors Colony-stimulating factors [ recombinant human colony stimulating [ recombinant human colony stimulatingFactors]: - Filgrastim, Molgramustim, Lenograstim - Filgrastim, Molgramustim, Lenograstim Used in cancer chemotherapy