2. Autacoid pharmacolgy
• This term is derived from Greek: autos—self, akos healing
substance or remedy.
• Are diverse substances produced by a wide variety of cells
in the body, having intense biological activity, but
generally act locally (e.g. within inflammatory pockets) at
the site of synthesis and release.
• They have also been called ‘local hormones’.
• However, they differ from ‘hormones’ in two important
ways—hormones are produced by specific cells, and are
transported through circulation to act on distant target
tissues.
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4. The ArachidonicAcid Cascade
• Learning Objectives : After studying this material, the
student should:
1. Know the fatty acid precursor from which the 2 - -series
of PG prostaglandins (PG2 2 ) is made.
2. Know the 4 major enzyme pathways for production of
arachidonic acid metabolites.
3. Understand the actions of the enzymes phospholipase
and cyclooxygenase and how steroids, aspirin and
cyclooxygenase substitutes affect these enzymes.
4. Know the difference between how aspirin and aspirin
substitutes affect cyclooxygenase enzyme activity.
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5. Objectives
5. Understand the difference between cyclooxygenase 1
(COX - 1) and cyclooxygenase 2 (COX - 2).
6. Know the importance of and the point at which oxygen
radicals are formed in the arachidonic acid metabolic
pathway.
7. Know the major cyclooxygenase products and give the
major known biological structures required) activity or
activities of the more important cyclooxygenase activity
products.
8. Be able to describe the major effects of prostaglandins
in the CNS
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6. Introduction
• 1930's Discovered by Kurzok & Lieb
• Characterized and named by Goldblatt & von Euler,
thought substances came from prostate gland, hence the
name prostaglandin ( abbreviated PG)
• 1960 Bergstrom - elucidated chemical structure of PGs
• 1971 Vane - discovered that MOA of aspirin is inhibition of
PG formation
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7. Introduction
• Mid 1970s - 80s Samuelsson - elucidated structure of
thromboxane and lipoxygenase metabolites
• 1982 Bergstrom, Vane & Samuelsson share Nobel Prize for
work in elucidation of the "Arachidonic Acid Cascade"
• 1980’s Epoxygenase pathway elucidated and functions
studied
• 1992 Anandamide ( arachidonyl ethanolamide ) discovered
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8. Function
• Modulation of cell function
• Arachidonic acid metabolites are found in virtually all cells
and tissues.
• Each cell type appears to have a characteristic balance of
metabolites.
• Are synthesized locally , on demand , and are not stored for
future release.
• Act locally in the area in which they are found and in
general do not have distant sites of action, as do many
other types of chemical modulators or hormones.
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9. Substrates
• Formed from polyunsaturated fatty acids (PUFA).
• Phospholipases release the PUFA precursors from
phospholipids.
• These PUFA can then be metabolized by
•Cyclooxygenase
•Lipoxygenase enzymes or
•P450 “ epoxygenase”
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11. Synthesis of ArachidonicAcid
Metabolites
• Four General Pathways of Arachidonic Acid Product
Formation
1. Cyclooxygenase= 2 isoforms , cyclooxygenase 1 (COX-
- 1) and cyclooxygenase 2 (COX- - 2).
• COX- - 1 is normally present in most tissues.
• COX- - 2 is normally present in brain and kidney and is
induced in most tissues during inflammation and injury.
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12. Cyclooxygenase Pathway
• NSAIDs inhibit COX.
• Aspirin - irreversibly acetylates COX-1 and 2
• Most other NSAIDs - reversibly , competitively inhibit COX-
1 and 2
• Selective COX -2 inhibitors – Celecoxib– reversibly,
competitively, inhibit COX -2.
• Relatively little effect on COX-1
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13. Lipoxygenase Pathway
• Drugs like zileuton, a 5 - lipoxygenase enzyme inhibitor,
and zafirlukast and montelukast , competitive leukotriene
receptor blockers .
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14. BiologicalActions of Metabolites of ArachidonicAcid
A. Nervous System
• PGs are thought to be modulators of neuronal activity.
• Increase or decrease release of NTs and cause changes in
behavior.
• Sensitize pain receptors .
• PGs given intraventricularly into the brain can induce fever
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15. B. Smooth Muscle
1. Vascular
• PGI 2 is the predominant PG produced by vascular tissue,
mainly by endothelium.
• PGI 2 and PGE 2 –relax muscle, vasodilation.
• Thromboxane A 2 (TxA2) and LTC4- contracts muscle,
vasoconstriction
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16. 2. Bronchial and Tracheal
• LTC4 and LTD4 are very potent contractors of airway
smooth muscle.
• Released by compounds by leukocytes, resident
macrophages or mast cells (asthma and immediate
hypersensitivity reactions).
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17. 3. GI
• Generally PGs increase contraction and motility .
• PGE2 and PGI2 inhibit gastric acid secretion induced by
feeding, histamine or gastrin.
• Also increase GI mucous secretion.
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18. 4. Uterine
• PGs cause contraction of uterine smooth muscle.
• Normal uterine production of PGs is thought to contribute
menstrual cramping.
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19. C. Hemostasis
• Blood platelets are prolific metabolizers of AA.
• PGG2 , PGH2 and TxA2 are produced by platelets and these
compounds induce platelets to adhere to one another, thus
inducing platelet aggregation.
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20. 2. Vasculature
• PGI2 is a very potent inhibitor of platelet aggregation
induced by ADP, collagen or epinephrine
• There is evidence that very low doses of oral aspirin (1/8 -
1/4 tablet) may achieve a semi- selective inhibition of platelet
but not arterial COX.
• This would maximize the anti-thrombotic effect of aspirin
since PGI2 inhibits platelet aggregation.
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21. D. Kidney Function
• The kidney papilla is rich in AA.
• PGI2 and PGE2 given into the renal artery produce diuresis
and increase Na + and K+ excretion.
• The mechanisms by which PGs alter renal function are not
certain but likely , involve redistribution of intrarenal blood
flow and a change in blood flow and a change in tubular
transport
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22. F. Endocrine System
• Exogenous PGs can stimulate the release of several
hormones.
• However the exact role of PGs in endocrine function has
not been adequately explored.
• PGs are known, however, to stimulate calcium
metabolism and bone resorption.
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23. G. Inflammation
• There is little doubt that arachidonic acid metabolites are
important in inflammation.
• Evidence supporting this conclusion includes that:
exogenous PGs and LTs can promote inflammation.
• PGs and LTs are found in inflammatory exudates .
• Drugs which inhibit cyclooxygenase, reduce inflammation.
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24. Arachidonic acid metabolites contribute to
inflammation by:
1. Increasing capillary permeability
2. Inducing local vasodilation and thus redness
3. Promoting infiltration of inflammatory cells
4. Production of tissue injuring oxygen free radicals during
the synthesis of PGs and LTs
5. Producing inflammation -associated hyperalgesia
(increased pain)
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26. Aloprostadil (PGE1)
• Can be used in infants with congenital heart defects in order
to increase pulmonary blood flow until definitive surgery can
be performed.
• Also treat penile erectile dysfunction of neurogenic,
vasculogenic or psychogenic origin.
• It causes erection by causing arterial dilation and occlusion of
venous outflow
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27. 2. Carboprost
• 15- methyl PGF2a
• Induces second trimester abortion.
• It is a more powerful uterine contractor than oxytocin.
• The methyl group is present to prevent oxidation
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28. 3. Dinoprost (PGF2A)-tromethamine
• Is used intra-amniotically to induce abortion, usually in
pregnancy longer than 15 weeks.
4. Dinoprostone (PGE2)
• Is used in suppository form to induce abortion in
pregnancies of less than 28 weeks.
• It is also used to induce full term labor
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30. PGE1
• Used for the t/t of GI ulceration by virtue of their
cytoprotective effects on the gastric mucosa.
• Rapidly absorbed and metabolized in the liver and excreted in
the urine.
• T1/2 <30 min.
• When administered chronically, can prevent gastric ulceration
caused by NSAIDS.
• Causes bleeding in 40% of women and, in a lower
percentage, partial or complete expulsion of the products of
conception
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31. 7. Latanoprost
• Used for treatment of glaucoma
• Acts by decreasing production of intraocular fluid.
• Works as timolol , but has side effect of turning blue eyes
brown
• Effectiveness and side effects of long term use is less
certain.
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32. PLATELETACTIVATING FACTOR (PAF)
• Like eicosanoids, platelet activating factor (PAF) is a cell
membrane derived polar lipid with intense biological
activity
• Discovered in 1970s and now recognized to be an
important signal molecule.
• PAF is acetyl-glyceryl ether-phosphoryl choline.
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33. • Synthesis and degradation PAF= is synthesized from
precursor phospholipids present in cell membrane by the
following reactions:
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34. Pathophysiological roles of PAF
• Inflammation
• Bronchial asthma
• Anaphylactic and other shock conditions
• Hemostasis and thrombosis
• Rupture of mature graafian follicle and implantation
• Ischaemic states of brain, heart
• G.I. ulceration.
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35. PAF antagonists
• Ginkgolide B (from a Chinese plant), and some structural
analogues of PAF.
• Have many fold therapeutic potentials like t/t of stroke,
intermittent claudication, sepsis, MI, shock, G.I.
ulceration, asthma and as contraceptive.
• Alprazolam and triazolam antagonize some actions of PAF.
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38. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
1. Non selective drugs
Salicylates e.g. Aspirin is the prototype drug
Mechanisms of action
1- Antiinflammatory
A) Inhibit prostaglandines synthesis through irreversible
inhibition of cyclo-oxygenase enzymes ( Cox-1 & Cox-2).
B) Interferes with the chemical mediators of the kallikrein
system.
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41. Pharmacokinetics of salicylates
• After p.o. are absorbed rapidly, the nonionized salicylates are
passively absorbed from the stomach and the small intestine.
• Appreciable conc are found in plasma in less than 30 min
• Peak value is reached in about 2 hours
• Rectal absorption is slower than after p. o. and is incomplete
and unreliable
• SA is rapidly absorbed from the intact skin, especially when
applied in oily liniments or ointments.
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42. Pharmacokinetics (cont.)
• Distribution - distributed throughout most body tissues and
most transcellular fluids, primarily by pH- dependent passive
processes, readily crosses the placental barrier and BBB
• The VD 13L;. at high doses, increases to about 35L
• 80% to 90% of the salicylate is bound to PP.
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43. Elimination
• The biotransformation takes place in many tissues, but particularly in
the liver.
• Are excreted in the urine as free salicylic acid (10%), salicyluric acid
(75%), salicylic phenolic (10%) and acyl (5%) glucuronides, and
gentisic acid (<1%).
• Half-life for aspirin is 15 minutes; that for salicylates is 2 to 3 hours
in low doses and about 12 hours at usual antiinflammatory doses
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45. Clinical uses
A) Analgesic
B) Antipyretic
C) Anti-inflammatory
D) Antithrombotic( cardioprotective):- Low doses of aspirin
are used prophylactically to decrease the incidence of
transient ischemic attack and unstable angina in men as well
as that of coronary artery thrombosis.
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46. Clinical uses
E) Chronic gouty arthritis
F) Cancer pain in combination with opioid drugs
G) Aspirin also facilitates closure of the patent ductus
arteriosus (PGE2 is responsible for keeping the ductus
arteriosus open).
H) Colon cancer: Chronic use of aspirin may reduce the
incidence of colorectal cancer.
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47. Adverse effects
At therapeutic doses
A) Gastric upset ( intolerance) & gastric or duodenal
ulceration
B) Gouty arthritis
C) Asthma, rashes
D) Hepatotoxicity & renal toxicity are less frequent.
E) Reye syndrome
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48. High doses or Prolonged use of aspirin
A) Salicylism( tinnitus, vertigo, decreased hearing).
B) Hyperapnea
C) Respiratory alkalosis
D) Metabolic acidoses
E) Hyperthermia
F) Gastric & doudenal ulcer & bleeding
H) Glucose intolerance
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50. Drug-Drug interactions
• Potentiates the gastric irritant effect of alcohol
• Potentiates the hypoglycaemic effects of oral
hypoglycaemic drugs
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51. PARACETAMOL
• Is effective only as analgesic & antipyretic.
• Has no anti-inflammatory effect.
• Has no antiplatelet effect or the excretion of uric acid .
• Can be used in patients with haemophilia or peptic ulcer or
allergic to aspirin.
• Can be used during pregnancy and in children with viral
infections.
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52. Paracetamol
• Is only a weak inhibitor of COX.
• Is rapidly and completely absorbed from the GI tract.
• Peak concentration in plasma in 30 to 60 minutes, and the
half-life in plasma is about 2 hours
• After large doses of paracetamol, the metabolite (n-acetyl-
benzoquinoneimine) is formed -and hepatic necrosis can
result.
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53. ADVERSE EFFECTS
• Mainly on liver due to its active metabolite ( N-acetyl-p-
benzoquinone).
• At therapeutic doses increases hepatic enzymes.
• In therapeutic dosage is usually well tolerated.
• Acute overdosage ( 2-3 g) is a dose-dependent, potentially
fatal hepatic necrosis.
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54. ADVERSE EFFECTS
• Renal tubular necrosis and hypoglycemic coma also may
occur.
• Toxicity is potentiated by ethanol
• Antidote - N-acetylcysteine.
• At high doses causes hepatic necrosis & renal necrosis.
• Treatment of paracetamol toxicity with N-acetylcystine
(SH donor ) as life saving
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55. 2-Propionic acid derivatives
1. Ibuprofen
• The same mechanism & pharmacological actions of
aspirin
• Except that it is reversible inhibitor for COX
enzymes
• More potent as anti-inflammatory than aspirin
Pharmacokinetics
Rapidly absorbed after oral ingestion.
Half-life 1-2 hours
Highly bound to PP (99%)
Excreted through kidney as metabolites.
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56. Clinical uses
A) Analgesic
B) Antipyretic
C) Anti-inflammatory
D)Acute gouty arthritis
E) Patent ductus arteriosus
F) RA, OA, dysmenorrhea
Preparations of Ibuprofen
• Oral preparations.
• Topical cream for osteoarthritis.
• A liquid gel for rapid relief of postsurgical dental pain.
• Intravenous route as in patent ductus arteriosus
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57. Adverse effects
1. Gastric upset ( less frequent than aspirin ).
2. Fluid retention
3. Hypersensetivity reactions
4. Ocular disturbances
5. Rare hematologic effects (agranulocytosis & aplastic
anaemia).
Contraindications
1. Peptic ulcer
2. Allergic patients to aspirin 3. Kidney impairment
4.Liver diseases 5.Pregnancy 6.Haemophilic patients
The concomitant administration of ibuprofen antagonizes the
irrevesible platelet inhibition of aspirin( limit cardioprotective
effect of aspirin ).
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58. Oxicam derivatives
• Piroxicam
• Tenoxicam
• Meloxicam
Mechanism of actions
A) Non-selective inhibitors to Cox1 & Cox2
B) Traps free radicals
C) Inhibits polymorphonuclear leukocytes migration
D) Inhibits lymphocyte function.
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59. Pharmacokinetics
• Well absorbed orally
• Half- Life 45 hours
• Given once daily
Adverse effects
• Less frequent gastric upset (20%) .
• Dizziness
• Tinnitus
• Headache
• Allergy
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60. Acetic acid derivatives
1. Diclofenac
Mechanism of action
As aspirin ,but non-selective inhibitor to cox1 & Cox2.
More potent as anti-inflammatory than analgesic and
antipyretics
Accumulates in synovial fluid
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61. Clinical uses
A) Any inflammatory conditions
B) Musculoskeletal pain
C) Dysmenorrhea
D) Acute gouty arthritis
E) Fever
F) Locally to prevent or treat post ophthalmic inflammation
G) A topical gel for solar keratosis
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62. Adverse effects
• Gastric upset
• Renal impairment
• Elevation of serum aminotransferase
• Salt & water retention
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63. Preparations of Diclofenac
• With misoprostol decreases upper gastrointestinal ulceration
,but result in diarrhea.
• Diclofenac with omeprazole to prevent recurrent bleeding.
• 0.1% ophthalmic preparation for postoperative ophthalmic
inflammation.
• A topical gel 3% for solar keratosis.
• Rectal suppository as analgesic or for postoperative nausea.
• Oral mouth wash.
• IM/IV preparations.
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64. Indomethacin: Indole derivative
• More potent than ASA but inferior at doses tolerated by
rheumatoid arthritis patients.
• Quite toxic
• PDA
Pharmacological properties
• Has prominent ant inflammatory and analgesic-antipyretic
properties, is more potent than aspirin.
• Effects are evident in patients with rheumatoid and other
types of arthritis, including acute gout.
• Is evidence for both a central and a peripheral action, also
is an antipyretic.
• Is also inhibitor of polymorphonuclear leukocytes.
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65. Pharmacokinetic
• After Oral ingestion the peak concentration within 2 hours.
• Its concentration in synovial fluid is equal to that in plasma
within 5 hours.
• Converted primarily to inactive metabolites, including those
formed by O-demethylation (about 50%), conjugation with
glucuronic acid (about 10%), and N-deacylation.
• 10% - 20% of the drug is excreted unchanged in the urine,
in part by tubular secretion.
• The half-life averages about 3 hours.
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66. Therapeutic uses
Analgesic-antipyretics
Treatment of ankylosing spondylitis and osteoarthrosis,
treatment of acute gout
In obstetrics and neonatal medicine. - As a tocolytic agent to
suppress uterine contractions.
Cardiac failure in neonates caused by a patent ductus
arteriosus
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67. Side effects
• About 20% must discontinue its use. Most adverse effects
are dose-related.
• GIT
• Some fatal cases of hepatitis and jaundice have been
reported.
• Most frequent is severe frontal headache.
• Hematopoietic reactions include neutropenia,
thrombocytopenia, and, rarely, aplastic anemia.
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68. Others
Sulindac:
-inactive pro-drug closely related to indomethacin
-must be metabolized by hepatic microsomal enzymes to
active form
-long duration of action (half-life = 8h)
-adverse effects less severe than other NSAIDS (ex. GI and
renal)
Ketoprofen:
-inhibits both cyclooxygenase and lipoxygenase (decreases
PGs, TXs, and LTs)
*recall LTs: bronchospam, bronchoconstriction
-may be desirable for asthmatics or inflammation plus
allergic response
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69. Phenylbutazone:
PYRAZOLONE DERIVATIVE
• An older effective anti- inflammatory agent (available
since 1949)
• Was once widely used to treat inflammation associated
with rheumatoid arthritis
-powerful anti-inflammatory drug
-usefulness is limited by its toxicity
-chiefly short-term therapy
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70. Phenylbutazone
• Long- term use is limited due to significant side effects such
as: gastric distress, allergies, skin rashes, ulcer formation,
liver and renal dysfunction, and severe abnormalities in
various types of blood cells
• Half - life is quite long (~ 2 days)
• Rarely used in USA, more use in veterinary medicine (horses)
and in Europe
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72. Selective Cox2 inhibitors--Advantages :
1. Highly selective inhibitors to cox2 enzyme.
2. Potent anti-inflammatory.
3. Have analgesic& antipyretic
4. Highly bound to plasma proteins.
5. Lower incidence of gastric upset
6. No effect on platelet aggregation (cox1 )
7. Renal toxicities ( they are not recommended for patients
with severe renal insufficiency)
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73. Selective Cox2 inhibitors
8. High incidence of cardiovascular thrombotic events with
some of them as rofecoxib.
9- They are recommended in postoperative patients
undergoing bone repair.
10- Also, indicated in primary familial adenomatous
polyposis, dysmenorrhea, Acute gouty arthritis, acute
musculoskeletal pain , ankylosing spondylitis.
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74. Celecoxib
• Absorption is decreased by food.
• Half-life 11hours
• Highly bound to plasma proteins
• No effect on platelet aggregation
• Metabolized in liver by CYP2C9 to in active metabolite.
• Its clearance is decreased in liver impairment.
• Given twice daily.
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76. Drug interactions
• With warfarrin potentiate its,through interfering with its
metabolism actions
Meloxicam
• Relatively selective Cox2 inhibitors.
• Safer than piroxicam.
• Given orally ,rectally, I.M.,I.V.
• Metabolized in liver to inactive metabolites.
• Excreted in urine 50% and in feces 50%.
• Half-life 20 hours and given once daily.
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77. Clinical uses
• Analgesic
• Rheumatoid arthritis
• Osteoarthritis.
Adverse effects
• Gastric upset
• Skin rash
• Headache
Drug interactions
• Cholestyramine increases the clearance of the drug .
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