Diclofenac

NSAID
DRUGS

1. DICLOFENAC Dr.ZIKRULLAH

2. Diclofenac is non- steriodal anti-inflammatory drug (NSAID). It is an over the counter available drug, prescribed for its anti- inflammtory and analgesic properties.

3. HISTORY Diclofenac was first synthesized by the pharmaceutical company called NOVARTIS in 1973. For clinical use it was first launched in United Kingdom in the year 1979.

4. CHEMICAL STRUCTURE Its chemical name is 2-(2,6-dichloranilino) phenylacetic acid. It is either supplied as a Sodium or Potassium salt. Molecular mass – 296.198g/mol

5. C 14 H 11 CL 2 NO 2

6. PHARMACOKINETICS Protein binding - around 99% Half life - 1.2-2 hrs (around 35% of the drug enter the entero -hepatic circulation). Metabolism - chiefly hepatic, no active metabolites are formed. Excretion - Biliary . Only 1% is excreted in the urine.

7. MECHANISM OF ACTION Inhibition of prostaglandin synthesis by the inhibition of Cyclooxegenase enzyme. (COX). Diclofenac had low to moderate preference to block the COX2 isoenzyme .

8. Other proposed mechanism Bacteriostatic activity by inhibition of DNA sunthesis . Inhibiton of the Lipoxygenase pathway and phospholipase A2 thus reducing the formation of pro-inflammatory autocoids called Leucotrienes . Blockade of voltage gate gated Sodium channels.

9. Blockade of Acid sensing ion channels (ASIC’s) Positive allosteric modulation of KCNQ and BK potassium channels.

10. The action of one single dose is much longer (6 to 8 hours) than the very short half-life that the drug indicates.This could be partly because it persists for over 11 hours in synovial fluids .

11. formulations Diclofenac is available in following preparations: Oral Intravenous and Intramuscular Transdermal Rectal Topical

12. Diclofenac is available in stomach acid resistant formulations (25 and 50 mg), fast-disintegrating oral formulations (25 and 50 mg), Powder for oral solution (50 mg), Slow- and controlled-release forms (75, 100 or 150 mg).

13. Injectable forms (50 and 75 mg). to given deep intramuscularly in the gluteal region, or as intravenous infusion. Topical lotion formulation of 1.5- 3 % w/w diclofenac sodium. Rectal suppositories (50 and 100 mg).

14. Commonly available trade names - VOVERAN DICLAC DYNAPAR DYFENE OFLAM ORTOFEN NU PATCH

15. DOSES For pain due to musculoskeletal disorders - 50 mg 2-3 times a day orally or 75 km twice a day orally. Adult dose for post operative and post traumatic pain relief – initial 100 mg orally once a day followed by 50 mg once daily. Adult Parenteral dose – 1-1.5 mg/kg

16. Pediatric doses 2-3mg/kg/day orally divided in 2-4 doses over 24 hrs . Maximum dose not to exceed 200mg. Pediatric parenteral dose - 0.3-0.5 mg/kg

17. Clinical uses Inflammatory disorders:- Musculoskeletal complaints arthritis , rheumatoid arthritis , polymyositis , dermatomyositis , osteoarthritis , dental pain, TMJ , spondylarthritis , ankylosing spondylitis , gout attacks. Pain management in cases of kidney stones and gallstones .

18. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, in particular when inflammation is also present, and is effective against menstrual pain and endometriosis .

19. An external, gel-based formulation containing 3% of diclofenac is available for the treatment of facial A ctinic keratosis caused by over-exposure to sunlight. Diclofenac Eye-drops to treat acute and chronic non-bacterial inflammations of the anterior part of the eyes.

20. INVESTGATIONAL USES Diclofenac is often used to treat chronic pain associated with cancer , in particular if inflammation is also present (Step I of the World Health Organization (WHO) Scheme for treatment of chronic pain). Combinations with psychoactive drugs such as chlorprothixene and/or amitriptyline have also been investigated and found useful in a number of cancer patients

21. Fever due to malignant lymphogranulomatosis ( Hodgkin's lymphoma ) often responds to diclofenac . Diclofenac has been found to be effective against all strains of multi drug resistant E. coli, with a MIC of 25 micrograms/ mL. Therefore, it may be suggested that diclofenac has the capacity to treat uncomplicated urinary tract infections (UTI) caused by E. coli

22. ADVERSE EFFECTS Diclofenac is among the better tolerated NSAIDs. Though 20% of patients on long-term treatment experience side-effects. 2% have to discontinue the drug, mostly due to gastrointestinal complaints.

23. Increased risk of cardiovascular morbidity and mortality due to increased incidence of myocardial infarction. Gastritis, gastric ulceration , and GI haemorrhage . Hepatotoxicity and hepatitis. Nephrotoxicity

24. Bone marrow depression is noted infrequently ( leukopenia , agranulocytosis , thrombopenia with/without purpura , aplastic anemia ). These conditions may be life-threatening and/or irreversible, if detected too late. All patients should be monitored closely. Diclofenac is a weak and reversible inhibitor of thrombocytic aggregation needed for normal coagulation.

25. Induces warm antibody hemolytic anemia by inducing antibodies to Rh antigens, ibuprofen also does this. Diclofenac may disrupt the normal menstrual cycle.

26. CONTRAINDICATIONS Hypersensitivity against diclofenac History of allergic reactions ( bronchospasm , shock , rhinitis , urticaria ) following the use of aspirin or another NSAID Third-trimester pregnancy Active stomach and/or duodenal ulceration or gastrointestinal bleeding Inflammatory intestinal disorders such as Crohn's disease or ulcerative colitis .

27. Severe insufficiency of the heart (NYHA III/IV) Recently, a warning has been issued by the FDA not to use for the treatment of patients recovering from heart surgery Severe liver insufficiency (Child-Pugh Class C) Severe renal insufficiency ( creatinine clearance <30 ml/min)

28. Caution in patients with preexisting hepatic porphyria , as diclofenac may trigger attacks Caution in patients with severe, active bleeding such as cerebral hemorrhage. NSAIDs in general should be avoided during dengue fever , as it induces (often severe) capillary leakage and subsequent heart failure.

29. PREGNANCY AND LACTATION Diclefenac is a category C drug in the first and second trimester and a category D drug in the third trimester. Diclofenac is secreted in human milk, however its effect on new born babies has not been studied.

30. DRUG INTERACTIONS Diclofenac , like other NSAIDs is associated with several suspected or probable interactions that affect the action of other drugs Diclofenac may increase the blood levels of lithium by reducing the excretion of lithium by the kidneys. Increased levels of lithium may lead to lithium toxicity.

31. When diclofenac is used in combination with aminoglycoside antibiotics for example, gentamicin the blood levels of the aminoglycoside may increase, presumably because the elimination of aminoglycosides from the body is reduced. This may lead to more aminoglycoside -related side effects like nephrotoxicity and deafness.

32. Individuals taking oral blood thinners or anticoagulants eg , warfarin should avoid diclofenac as it may predispose to excessive bleeding. Diclofenac decrease the excretion of Methotrexate from the body and may precipitate methotrexate toxicity.

33. Diclofenac may reduce the blood pressure lowering effects of blood pressure medications. This may occur because prostaglandins play a role in the regulation of blood pressure.

34. ECOLOGICAL EFFECTS Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent. The mechanism is, it is presumed, renal failure , a known side-effect of diclofenac . Vultures eat the carcasses of livestock that have been administered veterinary diclofenac , and are poisoned by the accumulated chemical. At a meeting of the National Wildlife Board in March 2005, the Government of India announced that it intended to phase out the veterinary use of diclofenac .

35. THANKS.