Pharmacological description of Autacoids, CHS Modified.pptx

Autacoids

1. 1 PHARMAOLOGY OF AUTACOIDS

2. 2 Autos; self , akos ; remedy – autacoids (Greek, – self remedy) – considered as local hormones It is a generic name which includes: Variety of substances which occur naturally in the body but have widely different structures, physiological and pharmacological activities They are localized in tissues, usually have short duration and are involved in a response to injury or inflammation They act near their site of synthesis mainly in inflammatory lesions Autacoids include: Amine Autacoids: Histamine, 5-hydroxytryptamine (5-HT) Lipid-derived lipids : Eicosanoids and PAF Peptide autacoids: Kinins , Angiotensin Others ( Subs–P, cytokines, etc…)

3. Histamine and Drugs Targeting Histamine Receptors 3 Histamine (basic amine) is a  - imidazolylethylamine derivative that present in animal tissues as well as a component of venoms, in bacteria, and plants Mast cell is the predominant storage site in most tissues ; in the blood , it is the basophill Conc. of histamine is particularly high in tissues that contain large numbers of mast cells…skin, bronchial mucosa, GIT mucosa Histamine is an important mediator of immediate allergic and inflammatory reactions , role in gastric acid secretion and functions as a neurotransmitter and neuromodulator

4. 4 Synthesis and storage of histamine Histamine is formed by the decarboxylation of the amino acid histidine by the enzyme L- histidine decarboxylase (present in every mammalian tissue that contains histamine) Once formed, it is either stored or rapidly inactivated, very little is excreted unchanged

5. 5 Non-mast cell histamine synthesis, storage and release occurs in: The enterochromaffin -like ( ECL ) cells of the fundus of the stomach – role in acid secretion and In histaminergic neurons in the CNS - where it functions as a neurotransmitter

6. 6 Histamine is released from mast cells by exocytosis during inflammatory or allergic rxns Allergen interaction with IgE antibodies on the mast cell surface …cause release – due to hypersensitivity phenomena: allergy or anaphylaxis Histamine release is also triggered by: Drugs (morphine, tubocurarine , succucinyl choline , amphotericin B, etc), peptides, venoms Agents that ↑ cAMP formation inhibit histamine secretion Cromolyn and nedocromil sodium – drugs that inhibit histamine release

7. 7 Regulation of Mediator Release By a negative FBM mediated by H 2 receptors Hstamine appears to modulate its own release and that of other mediators from sensitized mast cells ( autoinhibition ) and basophills The H 2 receptor causes the activation of adenylate cyclase which increases the amount of cAMP cAMP inhibits the release of histamine Termination of Histamine Action Metabolism ( diamine oxidase and/or by the methylating enzyme imidazole N- methyltransferase ) Cellular uptake Desensitization of cells

8. 8 Table: Histamine Receptors Receptor Signaling Tissue distribution H 1 G q , PLC; ↑IP 3 , DAG Smooth muscle, heart, endothelium, brain H 2 G s , ↑ cAMP production Gastric mucosa, heart muscle, mast cells, CNS H 3 G i , ↓cAMP; decrease Ca2+ influx through G protein-coupled N-type Ca2+ channels Presynaptic : brain, myenteric plexus, other neurons H 4 G i , ↓cAMP Cells of hematopoietic origin

9. 9 Tissue /Organ System Effects of Histamine NERVOUS SYSTEM H 1 Rs in brain densely found in hypothalamus and known to affect wakefulness (many antihistamines cause drowsiness) and cause appetite suppression H 1 /H 2 receptors involve in: thermoregulation, in control of blood pressure, and perception of pain Presynaptic H 3 -R serve as feedback inhibitors of the release of histamine, NE, & other NTs ( Ach , 5-HT , dopamine ) H 1 -Rs on sensory neurons in the epidermis and dermis mediate itch and pain , respectively

10. 10 CARDIOVASCULAR SYSTEM Blood Vessels Histamine dilates blood vessels which involves both H 1 and H 2 receptors Vasodilatation by H 1 Rs is endothelium-NO-dependent; vasodilatation by H 2 receptors is cyclic AMP-PKA pathway mediated Inhibits release of NE (H 3 on sympathetic neurons) Increases capillary permeability (role in edema formation) - due to actions of histamine on postcapillary venules – mediated mainly by H 1 receptors

11. 11 Heart Increase in force of contraction via H 2 receptors Increase in heart rate (H 2 receptors) EFFECT ON EXTRAVASCULAR SMOOTH MUSCLE Bronchial smooth muscle contraction (mediated by H 1 Rs) Contraction of uterine smooth muscle (may cause abortion in pregnant women suffering from anaphylactic reactions) Contraction of intestinal smooth muscle

12. 12 EFFECT ON SECRETORY TISSUE Stimulant gastric acid secretion (as well as lesser extent gastric pepsin and intrinsic factor production) – mediated by H 2 receptors on gastric parietal cells Stimulate secretions in salivary glands, small & large intestines and production of nasal and bronchial mucus ANAPHYLAXIS Rapid release of mast cell contents, producing a decrease in BP, impaired respiratory function, abdominal cramps, and urticarial rash Extreme and severe anaphylaxis is life threatening and requires prompt medical intervention

13. 13 THE TRIPLE RESPONSE Intradermal injection of histamine causes: At the site of injection, a reddening appears An edematous wheal at the injection site A red irregular flare surrounding the wheal (arteriole dilation ⎼ axon reflex) The main pathophysiological roles of histamine: Stimulant of gastric acid secretion (H 2 Rs) – H 2 antagonists for PUD H 1 Rs mediate many pathological processes: allergic rhinitis, atopic dermatitis, conjunctivitis, urticaria , bronchoconstriction , asthma , and anaphylaxis

14. Histamine Antagonists 14 The effects of histamine in the body can be decreased in different ways: Physiologic antagonism Epinephrine , have smooth muscle actions opposite to those of histamine Release inhibitors: reduce the degranulation of mast cells Cromolyn , nedocromil and also β 2 -AR agonists Histamine receptor antagonists: represent another approach to the reduction of histamine-mediated responses Inhibition of histamine synthesis

15. H 1 Receptor Antagonists (Antihistamines) 15 The H 1 antagonists are divided into first -generation and second -generation agents First-generation drugs (older agents) Still widely used as they are effective and inexpensive Most of these drugs penetrate the CNS…cause sedation They also tend to interact with other receptors, producing a variety of unwanted adverse effects Second-generation agent (newer agents) More specific to H 1 receptors They do not readily penetrate the BBB… less sedation

16. 16 Drugs Sedating activity Anticholinergic Activity Anti-motion Sickness Acitivity First Generation Antihistamines Ethanolamines Carbinoxamine Clemastine Diphenhydramine Dimenhydrinate ++ ++ +++ +++ +++ +++ +++ +++ ++ ++ Ethylenediamines Pyrilamine Tripelennamine ++ ++ + + Alkylamines Chlorpheniramine Brompheniramine + + + + Piperazines   Hydroxyzine Cyclizine Meclizine +++ + + +++ ++ ++ +++ ++ ++

17. 17 Drugs Sedating activity Anticholinergic Activity Anti-motion Sickness Acitivity First Generation Antihistamines   Phenothiazines   Promethazine +++ +++ +++ Piperidines   Cyproheptadine ++ ++ Second-Generation Antihistamines Alkylamines Acrivastine + Piperazines Cetirizine Piperidines   Loratadine Desloratadine Fexofenadine

18. 18 Mechanism of action of histamine Actions due to histamine receptor blockade H 1 -receptor antagonists block the actions of histamine by reversible competitive antagonism at the H 1 receptor Blocks histamine mediated vasodilation , microvascular permeability, & sensory nerve terminal stimulation and bronchiolar or gastrointestinal smooth muscle contraction

19. 19 Effects not mediated by histamine receptor blockade Anti-cholinergic effects: many of the 1 st -generation H 1 antagonists tend to inhibit responses to Ach that are mediated by muscarinic receptors –role in motion sickness ARs-blocking actions:H 1 antagonists, esp. those in the phenothiazine group; cyproheptadine block 5-HT Rs Local anesthetic effect: some H 1 antagonists have local anesthetic activity; diphenhydramine and promethazine are effective LAs : MSM same as LAs

20. 20 Pharmacokinetics Well absorbed from the GI tract following oral administration Widely distributed throughout the body, and the first-generation drugs enter the CNS readily All first-generation H 1 antihistamines and some second-generation, such as desloratadine and loratadine , are metabolized by the hepatic CYP450 Cetirizine and fexofenadine undergo little hepatic metabolism Cetrizine elimination mainly as unchanged in the urine; fexofenadine via feces Many H 1 antagonists have active metabolites The active metabolites (also available as drug) of hydroxyzine … cetirizine ; terfenadine … fexofenadine ; loratadine … desloratadine

21. 21 Therapeutic Uses Allergic reactions To prevent/treat the symptoms of allergic reactions as in allergic rhinitis and urticaria , conjunctivitis and atopic dermatitis 1st & 2nd generation drug have about equal efficacy but vary in their tendency to cause sedation Motion sickness and vestibular disturbances Scopolamine and certain 1 st H 1 antagonists are the most effective agents available for the prevention of motion sickness Among H 1 antagonists: diphenhydramine , promethazine , dimenhydrinate , and the piperazines ( cyclizine and meclizine )

22. 22 Nausea and vomiting Promethazine may be used in treating the nausea and vomiting due to chemotherapy or radiation therapy for cancer Useful in treating nausea and vomiting of pregnancy… Promethazine doxylamine are useful Somnifacients Though not DOC of choice for insomnia, 1 st G antihistamines may be useful for wakeful children and treatment of mild insomnia …e.g. dyphenhydramine , doxylamine , hydroxzine , promethazine Others Diphenhydramine may partially be effective to reverse the EPS caused by certain anti-psychotic drugs

23. 23 Adverse Effects Sedation, antimuscarinic action (dry mouth, urine retention, etc) – first generation H 1 -R antagonists Second generation one causes: Doses above the usual therapeutic level can cause sleepiness in certain individuals Cardiotoxicity (arrhythmias) – esp. with terfenadine or astemizole

24. 24 Antihistamine: Warning Second-generations are recommended for elderly patients (>65 years of age) First-generation antihistamines are not recommended for use in children; the second-generations loratadine , desloratadine , fexofenadine , cetirizine , levocetirizine , and azelastine (intranasal) have been approved by the FDA for use in children CYP450 inhibitors, such as erythromycin or ketoconazole ..may ↑H 1 antihistamine levels Caution in pregnant or lactating women Cetirizine and loratadine are preferred; but if they are not effective, diphenhydramine can be used safely in pregnant (but not in breast-feeding) women

25. Serotonin (5-Hydroxytryptamine) 25 Serotonin is widely distributed in nature, being found in plant (e.g. banana, pineapple) and animal tissues, venoms, and stings Regulator of smooth muscle in the CVS and the GIT, an important NT in CNS, and a component of the platelet clotting process Plays role in various disorders: psychotic behaviors, depression and obsessive-compulsive disorder, migraine, anxiety disorders and drug abuse, vomiting It is also one of the mediators of the signs and symptoms of carcinoid syndrome

26. 26 Synthesis and Metabolism

27. 27 Distribution of 5-hydroxytryptamine Gastrointestinal Tract Over 90% of the body's total 5-HT is found in the GIT in the enterochromaffin cells It is also made in nerves ( serotonergic nerves) which make up a minor component of the myenteric plexus (enteric nervous system) - functions as an excitatory NT Blood Platelets take up (don’t synthesize) serotonin very efficiently - via a Na + dependent carrier mediated uptake It is bound tightly to granules found in the platelets

28. 28 Central Nervous System Serotonin is synthesized, stored, and released as a neurotransmitter by tryptaminergic neurons found in the brain Brain serotonergic neurons are involved in different functions such as mood, sleep, appetite, and temperature regulation, as well as the perception of pain, the regulation of blood pressure, and vomiting

29. 29 Storage and Release of 5- HT 5-HT is stored in secretory granules by a vesicular transporter Released by exocytosis from serotonergic neurons Its action is terminated by neuronal uptake mediated by a specific transporter in the membrane of serotonergic axon terminals and metabolism by MAO 5-HT Receptors Currently, there are 14 known receptor subtypes They are divided into seven classes (5-HT 1-7 ), with further subtypes of 5-HT 1 (A-F) and 5-HT 2 (A-C) 5-HT 3 is a ligand-gated ion channel and the remainder six are G-protein-coupled receptors

30. 30 Effects of Serotonin NERVOUS SYSTEM 5-HT 3 Rs in the GIT and in the vomiting center of the medulla participate in the vomiting reflex Serotonin is a potent stimulant of pain and itch sensory nerve endings Serotonin (at 5-HT 3 -R) directly stimulates vagal nerve endings to the heart marked bradycardia and hypotension 5-HT in brain involve in sleep, cognition, sensory perception, motor activity, temperature regulation, nociception , mood , appetite, sexual behavior

31. 31 CARDIOVASCULAR SYSTEM 5-HT directly causes the contraction of vascular smooth muscle mainly through 5-HT 2 receptors; powerful vasoconstrictor except in skeletal muscle and heart ( dilation ) A triphasic blood pressure response Initially, there is ↓HR, CO , BP (caused by the chemoreceptor response) Then ↑BP (due vasoconstriction) The third phase is again ↓BP attributed to vasodilation in vessels supplying skeletal muscle

32. 32 PLATELETS 5-HT causes platelet aggregation by acting on 5-HT 2A receptors GASTROINTESTINAL TRACT Stimulant of GI smooth muscle Due to direct action of 5-HT on 5-HT 2 smooth muscle receptors and 5-HT 4 Rs on ganglion cells located in the ENS – activation 5-HT 4 Rs of in the ENS cause to ↑Ach release and thereby mediates a motility -enhancing or prokinetic effect 5-HT acting on 5HT 3 Rs on afferent nerves (sensory nerves from the gut) may stimulate emesis

33. Drugs Acting on 5-HT Receptors 33 Serotonin Agonists Buspirone , gepirone , and ipsapirone a 5-HT 1A partial agonists, are useful as an effective non-benzodiazepine anxiolytic Sumatriptan & its congeners are selective agonists for 5-HT 1B/1D Rs (vasoconstriction in cerebral and meningeal vessels) Effective in the treatment of acute migraine Include: sumatriptan , zolmitriptan , naratriptan , rizatriptan , frovatriptan , almotriptan and eletriptan

34. 34 Serotonin Antagonists Cyproheptadine Potent H 1 -Rs-blocking as well as 5-HT 2 (5-HT 2A ) blocking actions It prevents the smooth muscle effects of both amines It also has significant anti- muscarinic effects and causes sedation Used in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria

35. 35 Ketanserin Potently blocks 5-HT 2A receptors, less potently blocks 5-HT 2C receptors Potently blocks vascular  1 - ARs Inhibits 5-HT-induced platelet aggregation (5-HT 2 mediated) Value for the treatment of hypertension and vasospastic conditions Ritanserin Another 5-HT 2 antagonist, has little or no  1 - blocking action Ondansetron , granisetron , tropisetron , dolasetron … 5-HT 3 antagonists Used in prevention of nausea and vomiting associated with surgery and cancer chemotherapy

36. Kallikrein–Kininogen–Kinin System 36 Three kinins have been identified in mammals: each contains bradykinin Bradykinin Lysylbradykinin (or kallidin ), and Methionyllysylbradykinin A number of factors, such as tissue damage , allergic reactions , infections , etc activate a series of proteolytic reactions that generate bradykinin and kallidin in the tissues These peptides contribute to inflammatory responses : produce pain , vasodilation , and increased vascular permeability but can also have beneficial effects, for example in the heart, kidney, and circulation Much of their activity is due to stimulation of the release of potent mediators such as prostaglandins , NO , or endothelium-derived hyperpolarizing factor ( EDHF )

37. 37 Figure: Synthesis and receptor interactions of active peptides generated by the kallikrein-kinin and renin-angiotensin systems

38. 38 Bradykinin Receptors Two types of kinin receptors, B 1 and B 2 - are G-protein-coupled receptors B 2 -Rs are constitutively present in many normal cells (affinity BK > Kallidin > Met-Lys- bradykinin )... mediates majority of effects of kinins B 1 - Rs are inducible; absent or expressed at low levels in most tissues Expression up-regulated by inflammatory mediators in inflammatory conditions…cytokines, endotoxins , and growth factors

39. 39 Effects of Kinins CARDIOVASCULAR SYSTEM Produce marked vasodilatation in several vascular beds The kallikrein–kinin system is cardioprotective Studies showed that many of the beneficial effects of ACEIs on heart function are attributable to enhancement of BK effects, such as their anti-proliferative activity or ability to increase glucose uptake in tissue BK contributes to the beneficial effect to protect the heart against ischemia BK also stimulates tissue plasminogen activator ( tpa ) … may contribute to the endogenous defense against some cardiovascular events, such as MI and stroke

40. 40 ROLE IN INFLAMMATION Play an important role in the inflammatory process Produce redness , local heat , swelling , and pain RESPIRATORY SYSTEM The kinins have been implicated in the pathophysiology of allergic airway disorders such as asthma and rhinitis

41. Drugs Affecting the kallikrein-Kinin System 41 B 1 receptor antagonists [Leu8-des-Arg9] bradykinin and Lys[Leu8-des-Arg9] bradykinin Nonpeptide antagonists are not yet available B 2 receptor antagonists First-generation are peptide derivatives of bradykinin Short half-life , and almost inactive on the human B 2 receptor (extensively used in animal studies )

42. 42 Icatibant A peptide-based, second-generation B 2 receptor antagonist It is orally active, potent, and selective, has a long duration of action (> 60 minutes), and displays high B 2 -receptor affinity Extensively used in human studies to evaluate the role of kinins in pain, hyperalgesia , and inflammation Has been approved in the EU for treatment of acute episodes of swelling in patients with hereditary angioedema

43. Eicosanoids 43 The principal eicosanoids are the prostaglandins , the thromboxanes and the leukotrienes They are membrane lipid derived autacoids…g enerated from membrane phospholipids – from esterified fatty acids Eicosa = 20 ; tetraenoic = 4 db’s Precursor essential FAs contain 20 carbons and three, four, or five double bonds: 8,11,14-eicosatrienoic acid 5,8,11,14-eicosatetraenoic acid [ arachidonic acid (AA)], and 5,8,11,14,17-eicosapentaenoic acid

44. 44 The main eicosanoid precursor is arachidonic acid (5,8,11,14-eicosatetraenoic acid), is either derived from dietary linoleic acid (9,12-octadecadienoic acid) or ingested directly as a dietary constituent Unlike histamine and serotonin, eicosanoids are not preformed in cells but are generated on demand

45. 45 Biosynthesis The biosynthesis depends on the availability of free AA Diverse physiological and pathological stimuli, such as growth factors, hormones or cytokines…stimulate tissues to release AA from membrane PLs by the action of PLA 2 enzymes…converted into different eicosanoids AA can be enzymatically metabolized by three main pathways: Cyclooxygenase ( COX ) Lipoxygenase ( LOXs ) Cytochrome P450 epoxygenase Other minor pathway also exist: Isoprostane pathways…generate isoprostanes via non-enzymatic free radical attack

46. 46 Figure: Eicosanoids biosynthesis from AA

47. 47 Cyclooxygenase (COX) Pathway Responsible for production of prostanoids ( PGs, PGI 2 , thromboxane ) Are the end products of the successive metabolism of AA by COX , PG synthases , and TX synthase Synthases include: PGD synthase , PGE synthase , PGF synthase , PGI synthase , and TXA synthase , which form PGD 2 , PGE 2 , PGF 2α , PGI 2 ( prostacyclin ) and TXA 2 , respectively Prostanoids …role in modulating biological processes such as smooth muscle tone , vascular permeability , hyperalgesia , fever and platelet aggregation

48. 48 There are two distinct COX isoforms , COX-1 and COX-2 COX-1 Constitutive enzyme (always present and active) in most cells Responsible for basal production of eicosanoids Subserve “ housekeeping ” functions such as cytoprotection of the gastric epithelium Act as homeostatic regulators (e.g. modulating vascular responses)

49. 49 COX-2 COX-2 is not normally active; it is inducible Inducible by cytokines, growth factors, or other inflammatory stimuli COX-2 isoform is responsible for the production of the prostanoid mediators of inflammation Renal COX-2-derived prostanoids are important for normal renal development and maintenance of function Endothelial COX-2 is the primary source of vascular prostacyclin ( PGI 2 )

50. 50

51. 51 Lipoxygenase (LOXs) Pathway AA is also metabolised by LOX enzymes, found as 5- , 12- , or 15-LOX in leukocytes, platelets and endothelial cells, respectively LOXs enzymes generates hydroperoxyeicosatetraenoic acids (HPETEs), which is rapidly converted to hydroxy derivatives (HETEs) and leukotrienes (LTs)

52. 52 The 5-lipoxygenase present in inflammatory cells (PMNs, basophils , mast cells, eosinophils , macrophages)…this pathway is responsible in: The synthesis of the LTs, which play a major role in the development and persistence of the inflammatory response 5-LOX…produces first the unstable compound LTA 4 …then will be converted enzymatically to LTB 4 and LTA 4 is also the precursor of the cysteinyl -containing LTs…LTC 4 , LTD 4 , LTE 4 (also referred to as cysLTs or the sulfidopeptide leukotrienes Associated with asthma , anaphylactic shock , and cardiovascular disease

53. 53

54. 54 Table: Eicosanoid Receptors Receptor 1 Endogenous Ligands Signal Transduction Mechanism DP 1 PGD 2 ↑ cAMP (G s ) DP 2 / CRHT2 PGD 2 ↓ cAMP , ↑Ca 2+ i ( G i ) EP 1 PGE 2 ↑Ca 2+ i ( G q ) EP 2 PGE 2 ↑ cAMP (G s ) EP 3 (I-VI, e, f) PGE 2 ↓cAMP, ↑Ca 2+ i (G i ); ↑cAMP (G s ); ↑PLC, Ca 2+ i (G q )   EP 4 PGE 2 ↑ cAMP (G s ) FP A , B PGF 2  ↑PLC, ↑Ca 2+ i (G q ) IP PGI 2 ↑ cAMP (G s ) TP α,β TxA 2 ↑ PLC, ↑ Ca 2+ i ( G q , G i , G 12/13 , G 16 ); Rho activation BLT 1 LTB 4 ↑ Ca 2+ i , ↓ cAMP (G 16, G i ) BLT 2 LTB 4 ↑ Ca 2+ i ( G q -like, G i -like, G z -like) CysLT 1 LTD 4 ↑ PLC, ↑ Ca 2+ i ( G q ) CysLT 2 LTC 4 /LTD 4 ↑ PLC, ↑ Ca 2+ i ( G q )

55. 55 Effects of Prostanoids Platelets TxA 2 is the major product of COX-1 (the only COX isoform expressed in mature platelets ) Platelets release TxA 2 during activation and aggregation It is a potent platelet aggregator Platelet function is also affected by other PGs: PGI 2 , PGD 2 , PGE 2 PGI 2 inhibits platelet aggregation, PGD 2 (on DP 1 R) as well Low conc. of PGE 2 ……enhance platelet aggregation Higher conc. of PGE 2 ……inhibit platelet aggregation

56. 56 VASCULAR SMOOTH MUSCLE TXA 2 is a potent vasoconstrictor and smooth muscle cell mitogen In most vascular beds, PGE 2 , PGI 2 , and PGD 2 elicit vasodilation and a drop in blood pressure PGE 2 can cause vasoconstriction PGF 2  … is a potent constrictor of both pulmonary arteries and veins in humans

57. 57 EXTRAVASCULAR SMOOTH MUSCLE PGs also contract/or relax smooth muscles in tissues outside the vasculature Bronchial and Tracheal Muscle PGE 2 and PGI 2 relax whereas TxA 2 , PGF 2  , and PGD 2 contract , bronchial and tracheal muscle PGD 2 is the primary bronchoconstrictor PGI 2 causes bronchodilation in most species (particularly human bronchial tissue which is more sensitive)

58. 58 Uterus PGF 2  and TxA 2 cause contraction of non-pregnant human uterus , but PGEs result in relaxation Uterus of pregnant women is contracted by PGF 2  and low concentrations of PGE 2 PGE 2 , together with oxytocin , is essential for the onset of parturition PGI 2 and high concentrations of PGE 2 produce relaxation I.V. infusion of PGE 2 and/or PGF 2  to pregnant women produces a dose-dependent ↑in uterine tone, frequency and intensity of rhythmic uterine contractions PGEs and PGFs are used to terminate pregnancy

59. 59 Gastrointestinal Muscle PGEs and PGFs stimulate contraction of the longitudinal muscle from stomach to colon; circular muscle is contracted strongly by PGF 2α and weakly by PGI 2 , and is relaxed by PGE 2 TxA 2 and PGI 2 also produce contraction but are less active

60. 60 GASTRIC AND INTESTINAL SECRETIONS In the stomach, PGE 2 and PGI 2 ↑mucus secretion…role in cytoprotection , ↓ acid secretion, and reduced pepsin content PGE 2 and its analogs…also inhibit gastric damage caused by various ulcerogenic agents and promote healing from duodenal and gastric ulcers

61. 61 KIDNEY The major renal prostanoids PGE 2 and PGI 2 play a role in kidney function; PGF 2α and TxA 2 also have some role Synthesized in both the renal medulla (more synthesis here) and cortex COX-2 derived PGE 2 and PGI 2 ↑ medullary blood flow and inhibit tubular sodium reabsorption; COX-1-derived products promote salt excretion in the CTs Cortical COX-2 derived PGE 2 and PGI 2 ↑RBF and ↑GFR …crucial in maintaining renal function in poorly functioning kidneys and volume-contracted states Normal kidney generates low levels of TxA 2 , which has potent vasoconstrictor effects that reduce RBF and GFR

62. 62 EYE PGF 2α induces constriction of the iris sphincter muscle…but overall effect is to ↓IOP by increasing the aqueous humor outflow of the eye probably via the uveoscleral pathway PGE derivatives may also lower IOP

63. CENTRAL NERVOUS SYSTEM 63 PGE2 increases body temperature and exogenous PGF2α and PGI2 induce fever Endogenous pyrogens release interleukin-1 , which in turn promotes the synthesis and release of PGE2 . This synthesis is blocked by aspirin, other antipyretic NSAIDs, and acetaminophen.

64. 64 PAIN Inflammatory mediators such as LTs and PGs …↑the sensitivity of nociceptors and potentiate pain perception PGE 2 and PGI 2 …↓reduce the threshold to stimulation of nociceptors , causing sensitisation of peripheral nociceptive nerve terminals Centrally in spinal cord, PGE 2 , and perhaps also PGD 2 , PGI 2 , and PGF 2α , ↑excitability in pain transmission neuronal pathways Release of PGs and also LTs (e.g. LTB 4 ) during inflammation…serve potentiation of the pain mechanism

65. 65 BONE PGs are strong modulators of bone metabolism PGE 2 stimulates bone formation by increasing osteoblastogenesis ; bone resorption also is mediated via PGE 2 , through activation of osteoclasts

66. 66 INFLAMMATION AND IMMUNITY Eicosanoids play significant role in the inflammatory and immune responses LTs generally are pro-inflammatory, lipoxins anti-inflammatory; prostanoids , however can exert both kinds of activity PGE 2 and PGI 2 are the predominant pro-inflammatory prostanoids PGs generally inhibit lymphocyte function and proliferation, suppressing the immune response

67. 67 Effects of Leukotrienes INFLAMMATION LTB 4 is a potent activator and chemotactic agent for: neutrophils, T lymphocytes, eosinophils , monocytes, and possibly also mast cells CysLTs are chemotaxins for eosinophils and monocytes Also induce distinct set of cytokine generation through activation of mast cell CysLT 1 and CysLT 2 LTs, at higher conc. also promote eosinophil adherence, degranulation, cytokine or chemokine release, and oxygen radical formation LTB 4 is an important mediator in all types of inflammation

68. 68 Moreover, CysLTs contribute to inflammation by increasing endothelial permeability…which promote migration of inflammatory cells to the site of inflammation LTs have been strongly implicated in the pathogenesis of inflammation , especially in chronic diseases such as asthma and inflammatory bowel disease

69. 69 CVS LTC 4 and LTD 4 reduce myocardial contractility and coronary blood flow ( have little effect on most large arteries or veins) …leading to cardiac depression AIRWAYS CysLTs are potent bronchoconstrictors … 1000 times more potent than histamine both in vitro and in vivo They also increase microvascular permeability, stimulate bronchial mucus secretion and cause mucosal edema The cysLTs are of particular importance in asthma

70. 70 GIT LTs have potent contractile effects CysLTs …may contribute to the gastric damage through constricting gastric blood vessels and enhancing production of pro-inflammatory cytokines

71. Drugs Targeting the Eicosanoid System 71 Corticosteroids/ Glucocorticoids Block all the known pathways of eicosanoid synthesis Inhibit PLA 2 …indirectly by inducing the synthesis of a group of several inhibitory proteins called annexins (formerly lipocortins ) that modulate PLA 2 activity …preventing arachidonic acid release Also Inhibit the generation of inflammatory prostanoids by suppression of gene expression of COX-2 enzyme

72. 72 Non-Steroidal Anti-inflammatory Drugs (NSAIDs ) Block both PG and TXs formation by inhibiting COX activity Many of the traditional NSAIDs are non-selective inhibitors of COX-1/2; there are also selective COX-2 inhibitors These drugs do not inhibit LOXs…may ⇑formation of LTs by shunting of substrate to the LOX pathway Dual COX/5-LOX Inhibitors : Licofelone … under investigation Retain the activity of classical NSAIDs while avoiding undesirable adverse effects due to accumulation of LTs 5-lipoxygenase Inhibitor: Zileuton Block leukotriene synthesis Value for mild to moderate asthma treatment

73. 73 Selective CysLT Receptor Antagonists : zafirlukast , pranlukast , and montelukast Orally active selective cys-LT 1 receptor antagonists of CysLTs Have efficacy in the treatment of mild to moderate asthma

74. Therapeutic Uses of Prostaglandins 74 Therapeutic Abortion PGEs , PGFs , and their analogs…capacity to terminate pregnancy at any stage through promoting uterine contractions Dinoprostone (a synthetic preparation of PGE 2 ) is approved for inducing abortion in the second trimester of pregnancy, and for cervical ripening prior to induction of labor Systemic or intravaginal administration of the PGE 1 analog misoprostol in combination with mifepristone or methotrexate is highly effective in the termination of early pregnancy

75. 75 Carboprost tromethamine , analog of PGF 2α , is used to induce second-trimester abortions and to control postpartum hemorrhage…resistant cases PGE 2 /PGF 2α can induce labor at term…but provide more value in facilitation of labor by promoting ripening and dilation of the cervix Gastric Cytoprotection Several PG analogs suppress gastric ulceration Misoprostol , a PGE 1 analog, is approved for prevention of NSAID -induced gastric ulcers It is about as effective as the proton pump inhibitor, omeprazole

76. 76 Impotence PGE 1 ( alprostadil ), intracavernous injection or urethral suppository is a second-line treatment of erectile dysfunction ... erection lasts for 1-3 hours When given by injection, alprostadil may be used as monotherapy or in combination with either papaverine or phentolamine PGE 1 has been superseded largely by the use of PDE5 inhibitors, such as sildenafil , tadalafil , and vardenafil

77. 77 Cardiovascular Role Maintenance of Patent Ductus Arteriosus COX-2-derived PGE 2 maintains the ductus arteriosus patent until birth When reduced PGE 2 levels (a consequence of increased PGE 2 metabolism) permit closure Ductus arteriosus in neonates is highly sensitive to vasodilation by PGE 1 Maintenance of a patent ductus may be important hemodynamically in some neonates with congenital heart disease PGE 1 ( alprostadil ) is highly effective for palliative therapy to maintain temporary patency until surgery can be performed

78. 78 Pulmonary Hypertension Primary pulmonary hypertension is a rare idiopathic disease that mainly affects young adults…leads to right-sided heart failure and frequently is fatal Long-term therapy with PGI 2 ( prostacyclin ; epoprostenol ), via continuous intravenous infusion (has very short t 1/2 , 3–5 minutes), improves symptoms and can delay or reduce the need for lung/heart-lung transplantation in a number of patients Several PGI 2 analogs with longer t 1/2 have been developed and used clinically Inhalation and IV administration of Iloprost (t 1/2 30 minutes) Treprostinil (t 1/2 4hrs) may be delivered by continuous s.c . or i.v . infusion

79. 79 Glaucoma Latanoprost (a stable, long-acting PGF 2α analog)..the first prostanoid used for open-angle glaucoma Other congeners: bimatoprost , travoprost , unoprostone They are administered as ophthalmic drops

80. 80 THANKYOU….