Prostaglandins & NSAIDS

Pharmacology of prostaglandins & NSAIDS

1. Prostaglandins & Non- steroidal anti inflammatory drugs or NSAIDs Dr. Rupendra K. Bharti MBBS, MD systemic pharmacology

2. History of Prostaglandins In 1930, Kurzrok and Leib demonstrated the activity of human semen on isolated strips of human uterine muscles. This was confirmed by Von Euler (1935) who demonstrated a substance present in the extracts of human seminal fluid, which caused contraction of the isolated intestine and uterine muscles and vasodilation.( Nobel Prize 1970 ) This substance was named prostaglandin because of its probable origin from the prostate. Bergstrom and associates showed that various PG’s are closely related derivatives of the lipid soluble prostanoic Acid. Bergstrom , samuelson and vane independently obtained PgE2 (Nobel Prize 1982 )

3. Prostaglandins and thromboxanes & leukotrienes are collectively known as eicosanoids . Most are produced from arachidonic acid , a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid). INTRODUCTION

4. Synthesis of prostaglandins The PGs are synthesized from cell membrane phospholipids of nearly all body tissues. There are no prostaglandin stores in the body and these are synthesized locally in response to appropriate stimuli (external, internal, mechanical, chemical, etc ). These stimuli activate the Phospholipase-A 2 enzyme, which converts membrane phospholipids to arachidonic acid (AA). Arachidonic acid is converted to different prostaglandins (PGG 2 , PGH 2 ) via cyclooxygenase (COX) pathway.

5. PGG 2 & PGH 2 are unstable compounds and are converted to PGE 2 , PGD 2 and PGF 2α in the tissues where isomerase enzyme is present. PGI 2 in the tissues where prostacyclin synthase is present. TXA 2 in the tissues where thromboxane synthase is present. The Phospholipsae-A 2 inhibitors (glucocorticoids) & COX inhibitors (NSAIDs), inhibits the synthesis of prostaglandins; thereby produce anti-inflammatory actions.

6. Cyclooxygenase Pathway Arachidonic Acid PGG2 PGH2 PGE2 PGD2 PGF2α PGI2 TxA2 TxB2 6-keto-PGIα COX 1 AND COX 2 COX 1 AND COX 2 PGE2 isomerase PGD2 isomerase PGF2α reductase prostacyclin synthase thromboxane synthase (BRAIN AND MAST CELLS) (UTERUS, LUNG) (ENDOTHELIUM) (PLATELETS) (MACROPHAGES, MAST CELLS)

7. There are two type of cyclooxygenase enzymes, namely COX-1 & COX-2 o COX-1 : most normal cells and tissues, while cytokines and inflammatory mediators that accompany inflammation induce COX-2 production (Seibert et al., 1997) and is known as housekeeping enzyme. o COX-2: is expressed in certain areas of kidney and brain (Breder et al., 1995) and is induced in endothelial cells by laminar shear forces (Topper et al., 1996).

8. Importantly, COX-1, but not COX-2, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation. The inhibition of COX-1 can lead to gastric adverse events that complicate therapy with tNSAIDs, thus providing the rationale for the development of NSAIDs specific for inhibition of COX-2 (FitzGerald and Patrono, 2001).

9. o Recently a spliced variant of COX-1 has been identified and named as COX-3 enzyme . It has COX like enzymatic activity and is known to be involved in pain perception and fever but not inflammation. Paracetamol is a selective COX-3 inhibitor.

10. COMPARISON OF CYCLOOXYGENASE (COX-1& COX-2) ENZYMES Properties COX-1 COX-2 Site of action Found in many tissues, important for homeostasis Induced by inflammatory stimuli at the site of inflammation Effects of activation · Converts arachidonic acid to inflammatory prostaglandins · Maintains renal function · Provides integrity to gastric mucosa [cytoprotective]. · Promotes vascular homeostasis · Autocrine effects cause fever · Increases pain, inflammation · Vasodilatory effects · Blocks platelet clumping Effects of blocking · Decreases swelling, pain and inflammation. · Decreases pain and inflammation Effects of blocking for a prolonged period leads to adverse effects like · Damage to renal system (acute tubular necrosis may occur). · Sodium retention, edema, increased blood pressure · Gastrointestinal erosions (ulcer) and bleeding etc. · Decreases fever · Prevents protective vasodilation, allows platelet clumping, which can lead to myocardial infarction, cerebrovascular accidents. (on prolonged use)

11. Products from PGs

12. Prostaglandin receptors: Prostaglandins & related compounds are transported out of the cells that synthesize them. Most affect other cells by interacting with plasma membrane G-protein coupled receptors . Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP , or may activate a phosphatidylinositol signal pathway leading to intracellular Ca ++ release . These are: DP, EP, IP, TP,FP

13. The contractile group (EP1 , FP, TP) couple primarily with Gq protein and activate PLCβ to generate IP3 and DAG. These second messengers release Ca2+ intracellularly resulting in excitatory responses like smooth muscle contraction, platelet aggregation, etc. The relaxant group (DP1 , EP2 , EP4 and IP) couple with Gs protein—activate adenylyl cyclase to generate intracellular second messenger cAMP. Smooth muscle relaxation, inhibition of platelet aggregation, etc. are produced through cAMP dependent protein kinase (PKA ).

14. RECEPTORS SIGNIFICANCE DP This receptor has strongest affinity for PGD2 , but PGE2 can also activate it. Two subtypes DP1 and DP2. DP1: vasodilatation, and inhibits platelet aggregation. DP2: Gi protein and inhibits cAMP generation. EP It has highest affinity for PGE2 ; enprostil is a selective agonist. EP1: contracts visceral smooth muscle, but is less abundant in the body. EP2 and EP4: are relaxant in nature, act by increasing cAMP in smooth muscle. While EP2 is present in few organs, EP4 has wide distribution. EP3: decreases cAMP, has antilipolytic action of PGE2 . FP This contractile receptor is highly expressed in the female genital tract, and is present in many other organs. It exhibits strong affinity for PGF2α ; fluprostenol is a selective agonist. TP Characterized by high affinity for TxA2 . Abundantly present in platelets (aggregatory), cardiovascular system, immune cells and many other organs. PGH2 can also activate TP. IP This relaxant receptor is defined by highest affinity for PGI2 & PGE2. Cicaprost is a selective agonist. It is expressed in heart, lungs, kidney, platelet (antiaggregatory), etc., but the highest density is in the vasculature.

15. Prostaglandins Receptors

16. Eicosanoid Major Site(s) of Synthesis Major Biological Activities PGD 2 Mast cells Inhibits Platelet And Leukocyte Aggregation Decreases T-cell Proliferation And Lymphocyte Migration And Secretion Of IL-1 & TNF; And IL-2; Induces Vasodilation And Production Of cAMP PGE 2 Kidney, Spleen, Heart Increases Vasodilation And Camp Production, Enhancement Of The Effects Of Bradykinin And Histamine, Induction Of Uterine Contractions And Of Platelet Aggregation; Decreases T-cell Proliferation And Lymphocyte Migration And Secretion Of IL-1& TNF; And IL-2

17. Eicosanoid Major Site(s) of Synthesis Major Biological Activities PGF2 α Kidney, Spleen, Heart Increases Vasoconstriction, Bronchoconstriction And Smooth Muscle Contraction PGH 2 Many Sites A Short-lived Precursor To Thromboxane A 2 And B 2 , Induction Of Platelet Aggregation And Vasoconstriction PGI 2 Heart, Vascular Endothelial Cells Inhibits Platelet And Leukocyte Aggregation, Decreases T-cell Proliferation And Lymphocyte Migration And Secretion Of IL-1 & TNF; And IL-2; Induces Vasodilation And Production Of Camp TXA 2 Platelets Induces Platelet Aggregation, Vasoconstriction, Lymphocyte Proliferation And Bronchoconstriction TXB 2 Platelets Induces Vasoconstriction

18. Pharmacological Actions

19. Cardiovascular system PGE2 and PGF2α cause vasodilatation In vascular beds. They are more potent vasodilators than ACh or histamine. PGF2α constricts many larger veins including pulmonary vein and artery. Injection of PGE2 caused Hypotension while PGF2α has little effect. PGI2 is potent hypotensive than PGE2. TXA2 is vasoconstrictive in nature PG endoperoxides (G2 and H2 ) are inherently vasoconstrictor, but often produce vasodilatation also. PGE2 and F2α stimulate heart and enhance cardiac output.

20. Platelets TXA2; produced locally by platelets, is a potent inducer of aggregation and release reaction. The endoperoxides PGG2 and PGH2 are also proaggregatory. PGI2 & D2 is antiaggregatory but the PGI2 is more potent than PGD2. Aspirin interferes with haemostasis by inhibiting platelet aggregation through TXA2.

21. Uterus PGE2 and PGF2α uniformly contract human uterus, in vivo, both pregnant as well as nonpregnant. The sensitivity is higher during pregnancy. Uterus is more sensitive to PGs than oxytocin. PGs increase basal tone as well as amplitude of uterine contractions. PGF2α produces contraction while PGE2 relaxes nonpregnant but contracts pregnant human uterus.

22. Foetal tissues produce PGs. At term PGF2α cause initiation and progression of labour, blocked by Aspirin. Semen contains abundant amount of PGs, which coordinates the movement of sperms in the female genital tract and facilitate fertilization. Dysmenorrhoea is due to raised PG synthesis by the endometrium. PGs induces uncoordinated uterine contractions which compress blood vessels → uterine ischaemia→ pain. NSAIDs are highly effective in relieving dysmenorrhoea in most women.

23. Bronchial muscle PGF2α, PGD2 and TXA2 are potent bronchoconstrictors while PGE2 is a powerful bronchodilator. Asthmatics are more sensitive to constrictor as well as dilator effects of PGs. Asthma may be due to an imbalance between constrictor PGs (F2α, PGD2, TXA2) and LTs on one hand and dilator ones (PGE2 , PGI2) on the other. In allergic human asthma, LTs play a more important role. COX inhibitors have no role in allergic asthma.

24. GIT PGE2 lead to contraction of longitudinal muscle of gut and PGF2α causes contraction circular muscle. PGE2 causes increase peristalsis → colic and watery diarrhoea blocked by Aspirin. PGs appear to play a role in the growth of colonic polyps and cancer. NSAIDs afford relief in familial colonic polyposis by reducing polyp formation. PGE2 markedly reduces acid secretion in the stomach, while PGI2 enhance HCO3 level in stomach. NSAIDs especially Aspirin blocked it and lead to newer incidence of peptic ulcer.

25. Peripheral nerves

26. Some important actions of PGs in different body systems Site of action PGE 2 PGF 2α PGI 2 CVS Vasodilatation, and weak inotropic effect Vasodilatation ,larger veins constrict and Weak inotropic effect Vasodilatation is marked and decrease in BP occurs. Platelets - - Anti-aggregatory effect Inflammation and immunity Mediate inflammation and pain - Mediate inflammation and pain Eye Reduce intraocular pressure Reduce intraocular pressure - Female reproductive system Contraction of uterus and softening of cervix Contraction of uterus and softening of cervix - Male reproductive system Facilitate movement of sperm and thereby fertility. - Facilitate movement of sperm and also have a role in penile erection by causing vasodilatation Respiratory system Relaxation of bronchi Constriction of bronchi Relaxation of bronchi Stomach Decreases acid secretion and increases mucous secretion - Decreases acid secretion and increases mucous secretion Intestines Increase peristalsis or spasmogenic effects Increase peristalsis or spasmogenic effect Weak spasmogenic effect Kidneys Vasodilation , diuretic effect and renin release - Vasodilation, diuretic effect and renin release Endocrine Release of ant. pituitary hormones, steroids, insulin; TSH like action Release of gonadotropins and prolactin hormone. -

27. Pharmacokinetics The prostaglandins can be given by oral, intravaginal , intra-amniotic, extraamniotic and intravenous route depending upon the preparation and the indication of use. Most of the prostaglandins have plasma t½ of a few seconds to a few minutes. These are converted to inactive metabolites, which are excreted in urine. PGI 2 is catabolized mainly in the kidneys.

28. Prostaglandin analogues PGs type PG analogue Preparation and route of administration Therapeutic uses PGE1 Misoprostol 200 mcg tablet, 1-3 tablets Medical Abortion PGE1 Gemeprost 1mg vaginal pessary Cervical priming and mid-trimester abortion PGE2 Alprostil 2.5-25 mcg inj. Erectile dysfunction , maintenance of patency of ductus arteriosus PGF2α Dinoprostone 0.5mg vaginal gel , vaginal tab, extra-amniotic solution Induction and facilitation of labour, mid-trimester abortion PGF2α Dinoprost 5mg/ml intraamniotic injection Induction and facilitation of labour, mid-trimester abortion PGF2α Latanoprost, Bimatoprost 0.0005% eye drops Glaucoma treatment PGI2 Epoprostanol 0.5 mg injection For prevention of platelet aggregation in cardiopulmonary bypass, pulmonary hypertension

29. THERAPEUTIC USES

30. Obstetric and gynecological Abortion : PGE 2 and PGF 2α are used in 1 st and 2 nd trimester abortion and ripening of cervix during abortion. Intravaginal PGE 2 pessary minimises trauma to the cervix by reducing resistance to dilatation. A single oral dose of misoprostol 400mcg is given 2 -3 days after mifepristone (antiprogestin) 600mg for medical abortion upto 49 days of pregnancy. Intravaginal misoprostol can also be given as the side effects are less with this route. PGs are also useful in midterm abortion, missed abortion and molar gestation.

31. For facilitation of labour (Induction or augmentation purpose): PGE 2 and PGF 2α can be used in toxemic and renal failure patients in the place of oxytocin as PGs do not cause fluid retention. PGE 2 may also be used by intravaginal route for this purpose. Cervical priming (cervical ripening): PGE 2 in low doses administered intravaginally or in the cervical canal, makes the cervix soft and more compliant for induction of labour.   Postpartum haemorrhage (PPH): PPH due to atony of uterus can be treated by intramuscular Carboprost (15-methyl PGF 2α ) injection in ergometrine and oxytocin resistant patients.

32. Gastrointestinal uses : In the patients of NSAIDs induced peptic ulcers, PGE 1 ( misoprostol ) and PGE 2 ( enprostil ) are helpful in early healing of the ulcers. Eye: In the patients of glaucoma, PGF 2α analogues like latanoprost , travoprost , bimatoprost are used topically. These days, PG analogues are used as the first choice drugs in wide angle glaucoma.

33. Cardiovascular uses: PGE 1 ( Alprostadil ) is used to maintain patency of ductus arteriosus in neonates with congenital heart defects, till surgery is undertaken. PGI 2 ( Epoprostenol ) is used to prevent platelet aggregation and damage during haemodialysis or cardiopulmonary bypass.

34. Erectile dysfunction or impotence: 2.5-5.0 mcg of PGE 1 ( alprostadil ) as uretheral suppository or injection into the penis causes erection lasting 1–2 hours and may be used as an alternative to sildenafil or tadalafil .

35. Pulmonary hypertension : PGI 2 ( epoprostenol ) infusion is also helpful in management of primary pulmonary hypertension. Peripheral vascular diseases: In the patients of Raynaud’s disease and other peripheral vascular diseases, the intravenous infusion of PGI 2 (or PGE 1 ) provides relief from rest pain, intermittent claudications and promote healing of ischemic ulcers due to vasodilatory effects of these PGs.

36. ADR Vomiting Diarrhoea Abdominal cramps Uterine cramps Bronchospasm fever

37. Non- steroidal anti inflammatory drugs or NSAIDs

38. cyclooxygenase inhibitors COX-1 SELECTIVE INHIBITORS - acetylsalicylic acid at low dosage NONSELECTIVE COX INHIBITORS acetylsalicylic acid at high dosage -diclofenac - ibuprofen - ketoprofen - flurbiprofen - indomethacin - piroxicam - naproxen MORE COX-2 SELECTIVE INHIBITORS - Nimesulide - Etodolac - Meloxicam - Nabumetone COX-2 SELECTIVE INHIBITORS - Celecoxib - Etoricoxib - Valdecoxib

39. slides of contents introduction history Mechanism of Action and Therapeutic Effects of NSAIDs INHIBITION OF PROSTAGLANDIN BIOSYNTHESIS BY NSAIDS pharmacokinetics pharmacodynamics classification indication Contraindication adverse effects interactions various drugs

40. INTRODUCTION Nonsteroidal anti-inflammatory drugs (usually abbreviated to NSAIDs), also called non-steroidal anti-inflammatory agents/analgesics (NSAIAs) or nonsteroidal anti-inflammatory medicines (NSAIMs), are a class of drugs that provides analgesic, antipyretic, and in higher doses, anti-inflammatory effects.

41. The term nonsteroidal distinguishes these drugs from steroids, which, among a broad range of other effects, have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic and thus are used as a non-addictive alternative to narcotics. The most prominent members of this group of drugs, Aspirin, ibuprofen and naproxen, are all available over the counter in most countries.

42. Paracetamol (acetaminophen) is generally not considered an NSAID because it has only little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body. Most NSAIDs inhibit the activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and thereby, the synthesis of prostaglandins and thromboxanes.

43. It is thought that inhibiting COX-2 leads to the anti-inflammatory, analgesic and antipyretic effects and that those NSAIDs also inhibiting COX-1, particularly aspirin, may cause gastrointestinal bleeding and ulcers.

44. history Hippocrates and Celsus, who used willow bark as anti inflammatory agents. In 1763, Edward Stone wrote to the Royal Society, describing his observations on the use of willow bark-based medicines in febrile patients. The active ingredient of willow bark, a glycoside called salicin, was first isolated by Johann Andreas Buchner in 1827.

45. By hydrolysis, salicin releases glucose and salicylic alcohol which can be converted into salicylic acid, both in vivo and through chemical methods. The acid is more effective than salicin and, in addition to its antipyretic, anti-inflammatory and analgesic properties.

46. In 1869, Hermann Kolbe synthesised salicylate, although it was too acidic for the gastric mucosa. The reaction used to synthesise aromatic acid from a phenol in the presence of CO2 is known as the Kolbe-Schmitt reaction. By 1897 the German chemist Felix Hoffmann converted salicylic acid into acetylsalicylic acid—named aspirin by Heinrich Dreser.

47. During 1899 first time this drug was tested on animals, followed by human and the marketing of aspirin was begin.

48. Mechanism of Action and Therapeutic Effects of NSAIDs The mechanism of action of aspirin (and the tNSAIDs) was elucidated only in 1971, when John Vane and his associates demonstrated that low concentrations of aspirin and indomethacin inhibited the enzymatic production of prostaglandins, for which he received a Nobel Prize.

49. PGs have two major actions: o They are mediators of inflammation, stimulate sensory nerve endings and cause pain. o They also allow the movement of other inflammatory mediators like histamine and bradykinins the site of inflammation and aggravate the pain.

50. • The main mechanism involved in providing pain relief requires inhibition of formation of PGs and other inflammatory mediators, which can be achieved by inhibiting the different enzymes involved in their synthesis. • Therefore, it can be achieved by inhibition of Phospholipase A, COX enzyme and LOX enzyme, which arrests the further pathway of events.

51. • Phospholipase-A is inhibited by Steroids . • COX enzymes(COX-1 and COX-2) are inhibited by different NSAIDs . • LOX enzyme is inhibited by Zileuton . • COX and LOX both are inhibited by Licofelone .

52. There are two type of cyclooxygenase enzymes, namely COX-1 & COX-2 o COX-1 : most normal cells and tissues, while cytokines and inflammatory mediators that accompany inflammation induce COX-2 production (Seibert et al., 1997) and is known as housekeeping enzyme. o COX-2: is expressed in certain areas of kidney and brain (Breder et al., 1995) and is induced in endothelial cells by laminar shear forces (Topper et al., 1996).

53. Importantly, COX-1, but not COX-2, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation. The inhibition of COX-1 can lead to gastric adverse events that complicate therapy with tNSAIDs, thus providing the rationale for the development of NSAIDs specific for inhibition of COX-2 (FitzGerald and Patrono, 2001).

54. o Recently a spliced variant of COX-1 has been identified and named as COX-3 enzyme . It has COX like enzymatic activity and is known to be involved in pain perception and fever but not inflammation. Paracetamol is a selective COX-3 inhibitor.

55. Aspirin and NSAIDs inhibit the COX enzymes and prostaglandin production; they do not inhibit the lipoxygenase pathways of AA metabolism and hence do not suppress LT formation. Glucocorticoids suppress the induced expression of COX-2, and thus COX-2 mediated prostaglandin production. They also inhibit the action of phospholipase A 2 , which releases AA from the cell membrane.

56. COMPARISON OF CYCLOOXYGENASE (COX-1& COX-2) ENZYMES Properties COX-1 COX-2 Site of action Found in many tissues, important for homeostasis Induced by inflammatory stimuli at the site of inflammation Effects of activation · Converts arachidonic acid to inflammatory prostaglandins · Maintains renal function · Provides integrity to gastric mucosa [cytoprotective]. · Promotes vascular homeostasis · Autocrine effects cause fever · Increases pain, inflammation · Vasodilatory effects · Blocks platelet clumping Effects of blocking · Decreases swelling, pain and inflammation. · Decreases pain and inflammation Effects of blocking for a prolonged period leads to adverse effects like · Damage to renal system (acute tubular necrosis may occur). · Sodium retention, edema, increased blood pressure · Gastrointestinal erosions (ulcer) and bleeding etc. · Decreases fever · Prevents protective vasodilation, allows platelet clumping, which can lead to myocardial infarction, cerebrovascular accidents. (on prolonged use)

57. At higher concentrations, NSAIDs also are known to reduce production of superoxide radicals , induce apoptosis, inhibit the expression of adhesion molecules, decrease nitric oxide synthase, decrease proinflammatory cytokines ( e.g., TNF, interleukin-1), modify lymphocyte activity, and alter cellular membrane functions.

58. pharmacokinetics Most nonsteroidal anti-inflammatory drugs are weak acids, except, nabumetone, which is a prodrug, which is metabolized through acidic medium. They are highly protein-bound in plasma (typically >95%), usually to albumin. Most NSAIDs are metabolised in the liver by oxidation and conjugation.

59. Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. Almost all NSAID is metabolised by CYP3A or CYP2C families of P450 enzymes in the liver .

60. Renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal (GI) tract irritation correlates with the amount of enterohepatic circulation.

61. All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives.

62. Pharmacodynamics NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis. some another mechanisms of action of NSAIDs inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, interference with calcium-mediated intracellular events.

63. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while the non-COX-selective NSAIDs are reversible inhibitors. Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized.

64. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing, using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved.

65. On the other hand, selective COX-2 inhibitors may increase the incidence of oedema and hypertension. Rofecoxib and valdecoxib , a selective COX-2 inhibitors, were withdrawn from the market because of their association with increased cardiovascular thrombotic events. In 2011, celecoxib and the less selective meloxicam were the only COX-2 inhibitors, which is available in market.

66. All NSAIDs are gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin. NSAIDs is also associated with nephrotoxicity, which is due to the interference with the auto regulation of renal blood flow, which is modulated by prostaglandins.

67. Hepatotoxicity can also occur with any NSAID. Although these drugs effectively inhibit inflammation. Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically. Several large epidemiologic studies have shown a 50% reduction in relative risk when the drugs are taken for 5 years or longer.

68. The NSAIDs have a number of commonalities. various indication of NSAIDs by FDA rheumatoid arthritis, seronegative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout).

69. cyclooxygenase inhibitors COX-1 SELECTIVE INHIBITORS - acetylsalicylic acid at low dosage NONSELECTIVE COX INHIBITORS acetylsalicylic acid at high dosage -diclofenac - ibuprofen - ketoprofen - flurbiprofen - indomethacin - piroxicam - naproxen MORE COX-2 SELECTIVE INHIBITORS - Nimesulide - Etodolac - Meloxicam - Nabumetone COX-2 SELECTIVE INHIBITORS - Celecoxib - Etoricoxib - Valdecoxib

70. Effects of nsaids in various systems

71. ANALGESIC EFFECTS NSAIDs usually are classified as mild to moderate analgesics. NSAIDs are particularly effective when inflammation has caused sensitization of pain receptors to normally painless mechanical or chemical stimuli. Pain that accompanies inflammation and tissue injury probably results from local stimulation of pain fibers and enhanced pain sensitivity (hyperalgesia), in part a consequence of increased excitability of central neurons in the spinal cord.

72. Bradykinin, released from plasma kininogen, and cytokines, such as TNF ∝ , IL-1, and IL-8, appear to be particularly important in eliciting the pain of inflammation. These agents liberate prostaglandins and other mediators that promote hyperalgesia. Neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), also may be involved in eliciting pain.

73. Prostaglandins also can cause headache and vascular pain when infused intravenously. The capacity of prostaglandins to sensitize pain receptors to mechanical and chemical stimulation apparently results from a lowering of the threshold of the polymodal nociceptors of C fibers.

74. Fever may reflect infection or result from tissue damage, inflammation, graft rejection, or malignancy. These conditions all enhance formation of cytokines such as IL-1ℬ, IL-6, interferons, and TNF -alfa . The cytokines increase synthesis of PGE 2 in circumventricular organs in and adjacent to the preoptic hypothalamic area; PGE 2 , in turn, increases cyclic AMP and triggers the hypothalamus to elevate body temperature by promoting an increase in heat generation and a decrease in heat loss. ANTIPYRETIC EFFECT

75. Aspirin and NSAIDs suppress this response by inhibiting PGE 2 synthesis. Prostaglandins, especially PGE 2 , acting via its EP3 receptor, can produce fever when infused into the cerebral ventricles or when injected into the hypothalamus. As with pain, NSAIDs do not inhibit the fever caused by directly administered prostaglandins; rather they inhibit fever caused by agents that enhance the synthesis of IL-1 and other cytokines, which presumably cause fever, at least in part, by inducing the endogenous synthesis of prostaglandins.

76. RESPIRATORY SYSTEM Salicylates increase oxygen consumption and CO 2 production (especially in skeletal muscle) at full therapeutic doses; these effects are a result of uncoupling oxidative phosphorylation. The increased production of CO 2 stimulates respiration. The increased alveolar ventilation balances the increased CO 2 production, and thus plasma CO 2 tension (PCO 2 ) does not change or may decrease slightly.

77. ACID BASE AND ELECTROLYTE BALANCE Therapeutic doses of salicylate produce definite changes in the acid base balance and electrolyte pattern. At low dose it causes stimulation of respiratory center and lead to respiratory alkalosis. At moderate high dose: Metabolic acidosis. At high dose: it depresses the respiratory center and lead to accumulation of Co2 and causes Respiratory acidosis .

78. CARDIOVASCULAR EFFECTS Low doses of aspirin (<100 mg daily) are used widely for their cardioprotective effects. At high therapeutic doses (>3 g daily), as might be given for acute rheumatic fever, salt and water retention can lead to an increase (up to 20%) in circulating plasma volume and decreased hematocrit.

79. There is a tendency for the peripheral vessels to dilate salicylate having direct effect on vascular smooth muscle. Cardiac output and work are increased. High doses of salicylates can produce noncardiogenic pulmonary edema, particularly in older patients who ingest salicylates regularly over a prolonged period.

80. GASTROINTESTINAL EFFECTS The ingestion of salicylates may result in epigastric distress, nausea, and vomiting. Salicylates also may cause gastric ulceration, exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive gastritis.

81. These effects occur primarily with acetylated salicylates ( i.e.,  aspirin). Because nonacetylated salicylates lack the ability to acetylate cyclooxygenase and thereby irreversibly inhibit its activity, they are weaker inhibitors than aspirin. Aspirin-induced gastric bleeding sometimes is painless, and if unrecognized may lead to iron-deficiency anemia. The daily ingestion of antiinflammatory doses of aspirin (4 or 5 g) results in an average fecal blood loss of between 3 and 8 ml per day, as compared with approximately 0.6 ml per day in untreated subjects.

82. HEPATIC EFFECTS Salicylates can cause hepatic injury, usually in patients treated with high doses of salicylates that result in plasma concentrations of more than 150 micro gm/ml. The use of salicylates is contraindicated in patients with chronic liver disease. The use of salicylates as an important factor in the severe hepatic injury and encephalopathy observed in Reye's syndrome.

83. URICOSURIC EFFECTS The effects of salicylates on uric acid excretion are markedly dependent on dose. Low doses (1 or 2 g per day) may decrease urate excretion and elevate plasma urate concentrations. intermediate doses (2 or 3 g per day) usually do not alter urate excretion. large doses (more than 5 g per day) induce uricosuria and lower plasma urate levels.

84. EFFECTS ON THE BLOOD Ingestion of aspirin by healthy individuals prolongs the bleeding time . For example, a single 325-mg dose of aspirin approximately doubles the mean bleeding time of normal persons for a period of 4 to 7 days. This effect is due to irreversible acetylation of platelet cyclooxygenase and the consequent reduced formation of TXA 2 until sufficient numbers of new, unmodified platelets are produced from megakaryocyte precursors.

85. Patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia should avoid aspirin because the inhibition of platelet hemostasis can result in hemorrhage. Salicylates do not ordinarily alter the leukocyte or platelet count, the hematocrit, or the haemoglobin content. However, doses of 3 to 4 g per day markedly decrease plasma iron concentration and shorten erythrocyte survival time.

86. Aspirin can cause a mild degree of hemolysis in individuals with a deficiency of glucose-6-phosphate dehydrogenase.

87. other uses

88. 1. Systemic Mastocytosis Systemic mastocytosis is a condition in which there are excessive mast cells in the bone marrow, reticuloendothelial system, gastrointestinal system, bones, and skin. In patients with systemic mastocytosis, prostaglandin D 2 , released from mast cells in large amounts, has been found to be the major mediator of severe episodes of vasodilation and hypotension; this PGD 2 effect is resistant to antihistamines.

89. The addition of aspirin or ketoprofen has provided relief (Worobec, 2000). However, aspirin and tNSAIDs can cause degranulation of mast cells, so blockade with H 1 and H 2 histamine receptor antagonists should be established before NSAIDs are initiated.

90. 2. Bartter’s Syndrome Bartter's syndrome includes a series of rare disorders (1-0.1/100,000) characterized by hypokalemic, hypochloremic metabolic alkalosis with normal blood pressure and hyperplasia of the juxtaglomerular apparatus. Fatigue, muscle weakness, diarrhoea, and dehydration are the main symptoms. Distinct variants are caused by mutations in a Na + :K + :2Cl cotransporter , an apical ATP-regulated K + channel, a basolateral Cl channel, a protein (barttin) involved in cotransporter trafficking, and the extracellular calcium-sensing receptor. Renal COX-2 is induced and biosynthesis of PGE 2 is increased.

91. Treatment with indomethacin , combined with potassium repletion and spironolactone , is associated with improvement in the biochemical derangements and symptoms. Selective COX-2 inhibitors also have been used (Guay-Woodford, 1998).

92. 3.Cancer Chemoprevention Many evidence suggested that the intrinsic apoptotic pathway appears to be activated by selective COX 2 inhibitors (celecoxib) includes the observations that expression of the antiapoptotic proteins Bcl-2, Bcl-xL, Mcl-1, and surviving decreases after treatment of cancer cells with celecoxib , whereas expression of the proapoptotic protein Bad increases and rapid release of cytochrome c from mitochondria and the activation of Apaf-1 and caspases 3, 8, and 9 are observed.

93. In addition NSAIDs might influence apoptosis through different pathways, including: an increase in ceramide and subsequent release of proapoptotic proteins from the mitochondria via the formation of ceramide channels; inhibition of the activity of Ca2+ ATPase, so that the reuptake of Ca2+ from the cytosol is prevented, which elevates the free intracellular concentration of Ca2+; induction of 15-lipoxygenase 1 and increased production of proapoptotic molecules, such as 13-S-hydroxyoctadecadienoic acid (13-S-HODE); or changes in gene expression, as in the case of the NSAID activated gene-1 (NAG-1), a member of the TGF superfamily, which is involved in tumor progression and development.

94. 4. Niacin Tolerability Large doses of niacin (nicotinic acid) effectively lower serum cholesterol levels, reduce LDL, and raise HDL. However, niacin is tolerated poorly because it induces intense flushing . This flushing is mediated by a release of prostaglandin D 2 from the skin, which can be inhibited by treatment with aspirin (Jungnickel et al., 1997) and would be susceptible to inhibition of PGD synthesis or antagonism of its DP receptors.

95. 5. Rheumatoid arthritis 6. Alzheimer disease 7. Dysmenorrhoea 8. osteoarthritis 9. acute gout 10. inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis) 11. Tennis elbow 12.They are also given to neonate whose ductus arteriosus is not closed within 24 hours of birth

96. ADVERSE EFFECTS OF NSAIDs Gastrointestinal effects: abdominal pain, gastric and duodenal ulcer, diarrhoea, pancreatitis gastrointestinal hemorrhage, hepatotoxicity Renal effects - disturbances of renal function with water and sodium retention Inhibition of platelet aggregation CNS : headache, decreased hearing, tinnitus, dizziness, confusion, depression Allergic reactions : asthma, rashes, photosensitivity Reye’s syndrome

97. PHARMACODYNAMIC INTERACTION NSAIDs WITH OTHER DRUGS NSAIDs + hypotensive drugs ( β-blockers, ACE-inhibitors, diuretics ) = ↓ hypotensive effect NSAIDs + ethanol = ↑risk of GI bleeding NSAIDs + ticlopidine/clopidogrel = ↑risk of bleeding NSAIDs + lithium = ↑lithium toxicity NSAIDs + cyclosporine/tacrolimus= ↑nephrotoxicity of drugs NSAIDs + fluoroquinolone = ↑ toxic action of fluoroquinolone on CNS NSAIDs + OHA =↑ risk of hypoglycaemia

98. NSAIDs + corticosteroids = ↑ risk gastropathy & GI Bleed NSAIDs + aminoglycosides = ↑ ototoxicity and nephrotoxicity NSAIDs + methotrexate or digoxin = ↑ toxicity methotrexate or digoxin NSAIDs + tricycles anti-depressive/ neuroleptic/ SSRI = ↑ action of drugs

99. Acetaminophen/ Paracetamol poisoning Acetaminophen overdose constitutes a medical emergency. Severe liver damage occurs in 90% of patients with plasma concentrations of acetaminophen greater than 300 g/ml at 4 hours or 45 g/ml at 15 hours after the ingestion of the drug. Minimal hepatic damage can be anticipated when the drug concentration is less than 120 g/ml at 4 hours or 30 g/ml at 12 hours after ingestion.

100. N-acetylcysteine (NAC) is indicated for those at risk of hepatic injury. NAC therapy should be instituted in suspected cases of acetaminophen poisoning before blood levels become available, with treatment terminated if assay results subsequently indicate that the risk of hepatotoxicity is low.

101. An oral loading dose of 140 mg/kg is given, followed by the administration of 70 mg/kg every 4 hours for 17 doses. Where available, the intravenous loading dose is 150 mg/kg by intravenous infusion in 100 ml of 5% dextrose over 15 minutes (for those weighing less than 20 kg), followed by 50 mg/kg by intravenous infusion in 250 ml of 5% dextrose over 4 hours, then 100 mg/kg by intravenous infusion in 500 ml of 5% dextrose over 16 hours.

102. EFFECTS OF NSAIDs BENEFICIAL EFFECTS TOXIC EFFECTS • Anti-inflammatory
• Antipyretic
• Analgesic effects
• Antithrombotic
• Closure of ductus arteriosus in newborn • GI ulcer
• Asthma precipitation
• Anaphylactic reaction in susceptible individuals
• Rash & pruritus
• Sodium and water retention, hyperkalemia, and proteinuria.
• Delay/prolongation of labour
• Bleeding [Prolong bleeding time]
• Abnormal liver function tests

103. NONSELECTIVE COX INHIBITORS (TRADITIONAL NSAIDs) Groups Drug name t ½ [hours] Dose Salicylates Aspirin 0.25-5 [dose dependent] • As Antiplatelet: 40-80 mg/day
• In Pain/fever: 325-650 mg QID
• In Rheumatic fever: 1 g every QID
• In Rheumatoid arthritis: 3-5 gm, OD
• As Antiinflammatory: 1.2-1.5 gm, TDS
• Children: 10 mg/kg every QID
• All above doses are oral. Propionic acid derivatives Ibuprofen 2-4 400-600 mg TDS, oral Naproxen 14 250mg BD/TDS, oral Ketoprofen 1.8 50-100 mg BD/TDS, oral Flurbiprofen 6 50 mg BD/QID, oral Fenamate Mephenamic acid 2-3 250-500 mg TDS, oral Enolic acid derivatives Piroxicam 57 20 mg OD/BD, oral, 20mg/1 ml, i.m. Acetic acid derivatives Ketorolac 4-6 10-20 mg QID, oral 30mg/1ml i.v./i.m. Indomethacin 2.5 25-50 mg BD/QID, oral Nabumetone 24 500 mg OD, oral Sulindac 7 150-200 mg BD, Oral Pyrazolone derivatives Phenylbutazone, propiphenazone ,Oxyphenbutazone, Metamezol etc.

104. PREFERENTIAL COX-2 INHIBITORS Drug name t ½ [hours] Dose Nimesulide 2-5 100 mg BD, oral Diclofenac 1-2 50 BD/TDS, oral
75 mg i.v./i.m., 1% topical gel Aceclofenac - 100 mg BD, oral Meloxicam 15-20 7.5-15 mg OD, oral Piroxicam 45-50 20 mg/day OD, oral Etodolac 7 200-400 mg BD/TDS, oral

105. SELECTIVE COX-2 INHIBITORS Drug name t ½ [hours] Dose Celecoxib 6-12 100-200 mg BD, oral Etoricoxib 24 60-120 mg OD, oral Parecoxib - 40 mg BD-QID, i.v.,i.m., oral ANALGESIC-ANTIPYRETICS WITH POOR ANTIINFLAMMATORY ACTION Groups Drug name t ½ [hours] Dose Paraaminophenol derivative Paracetamol (Acetaminophen) 2 500 mg QID, oral.
300mg/2ml i.m. Pyrazolone derivatives Metamizol - 0.5–1.5 g oral/i.m./i.v. Propiphenazone - 300–600 mg TDS. Benzoxazocine derivative Nefopam 20-60 mg TDS
20mg i.m. QID

106. Propionic acid derivates Drugs Indications Special Feature Ibuprofen Fever, Pain, dysmenorrhoea, rheumatoid arthritis, osteoarthritis, musculoskeletal disorders, fractures and tooth extraction related pain. It available as OTC drug. Naproxen Rheumatoid arthritis, ankylosing spondylitis & migraine It has longer t ½ than other propionic acid derivatives.
It has less renal side effects.
Antiinflammatory effects appear after 2-4 weeks. Ketoprofen Same as above Additional action to stabilize lysosomes and LOX inhibition. Flurbiprofen Same as above and inflammatory eye conditions It is also available in 0.03% in ophthalmic solution.

107. ACETIC ACID DERIVATIVES (Ketorolac, Indomethacin, Nabumetone, Sulindac) Ketorolac Indomethacin It is a potent analgesic. It is indicated in: Postoperative pain (as its efficacy equals morphine): 15-30 mg i.m ./i.v. QID (max. 90 mg/ day). Renal colic, migraine, pain due to bony metastasis, dental pain and musculoskeletal pain. Non-infective ocular inflammatory conditions: 0.5% eye drops; 1–2 drops BD-QID. It should not be used for more than five days as side effects start appearing. It has potent anti-inflammatory and antipyretic action. It is highly effective in pain induced by inflammation or tissue injury. It is most common used drug for medical closure of patent ductus arteriosus given in a dose of 0.1-0.2 mg/kg i.v. BD. Other: inflammations associated with psoriatic arthritis, ankylosing spondylitis, acute gout or rheumatoid arthritis, which are non-responsive to other NSAIDs. It may also cause headache, confusion, hallucinations and depression, hence, contraindicated in pregnant women, children, machinery operators and patient with epilepsy & psychiatric illness.

108. PREFERENTIAL COX-2 INHIBITORS Drugs MOA Indications Special features Nimesulide Inhibits COX-2 selectively, PAF and TNF-α. Short lasting painful inflammatory conditions such as dental pain, dysmenorrhoea, ENT disorders, bursitis. Pediatric used is banned in India and many countries due to fulminant liver disease. No cross reactivity with other NSAIDs; so, can be given to asthma patients also. Diclofenac COX-2 selective inhibition. Reduction of inflammatory mediators locally. Rheumatoid, osteoarthritis, bursitis, ankylosing spondylitis, toothache, dysmenorrhoea, renal colic, posttraumatic and postoperative inflammatory conditions. It has good tissue penetrability. It remains in synovial fluid in 3 times higher concentration than plasma; hence effective in joints inflammation.   Aceclofenac Moderately COX-2 inhibitor. Same as above Chondroprotective in nature. Etodolac Moderately COX-2 inhibitor Used as Postoperative analgesic. Rheumatoid arthritis, osteoarthritis & musculoskeletal pain. It is better tolerated at low doses than other NSAIDs. Relatively safer in renal patients.

109. SELECTIVE COX-2 INHIBITORS Drug name MOA Indications Special feature Celecoxib Modest COX-2 selective inhibition. Rheumatoid, osteoarthritis and inflammatory condition in GI ulcer patients. It does not interfere in platelets aggregation.   Etoricoxib Highest COX-2 selective inhibition. Rheumatoid arthritis, gout, ankylosing spondylitis, dysmenorrhoea and osteoarthritis It does not affect the gastric mucosa and platelets function.   Parecoxib Modest COX-2 selective inhibition. (Prodrug of valdecoxib) Short-term use for postoperative pain It is available in injectable form.  

110. Difference between nonselective COX and selective COX-2 inhibitors Pharmacological feature Non-selective COX Selective COX-2 Antipyretic effects Yes Yes Analgesic effects Yes Yes Anti inflammatory effects Yes Yes Effect on gastric mucosa Yes No For closure of ductus arteriosus Yes No Precipitation of Asthma Yes No Risk of bleeding Yes No CVS toxicity Less More Hepatotoxicity Less More Renal toxicity More Less Licofelone is a dual inhibitors of the COX and 5-LOX pathways.

111. ACUTE SALICYLATE POISONING Cause: Over dosing of salicylates. In adults the fatal dose is 15-30 gm and less in children (but the poisoning is common in children). Seen only when the plasma level of salicylate exceeds ≥ 50 mg/dL. Clinical features: Vomiting, hyperpyrexia, electrolyte imbalance, dehydration, hyper/hypoglycaemia, delirium, convulsions, coma, cardiovascular collapse and death due to respiratory failure.

112. Management : There is no specific antidote available to manage acute salicylate poisoning. The management is as follows: a) Hospitalization b)IV fluid administration for correction of dehydration & electrolyte imbalance. c) External cooling in the form of cold sponging. d)Gastric lavage to remove the unabsorbed drug. e)Intravenous infusion of sodium bicarbonate for metabolic acidosis. f)Haemodialysis in severe cases & administration of vitamin-K in case of bleeding.

113. Further study : 1. GOODMAN & GILMAN'S PHARMACOLOGY  12TH EDITION (2013) 2. BASIC AND CLINICAL PHARMACOLOGY KATZUNG 1 4 TH EDITION (201 7 ) 3 . RANG AND DALE’S PHARMACOLOGY 7TH EDITION (2012) . 4. ESSENTIAL OF MEDICAL PHARMACOLOGY, 7TH EDITION, K.D. TRIPATHY (2013)

114. thank’s