ANALGESICS

1. ANALGESICS

2. CONTENTS • Introduction • Classification of Analgesics • NSAID • History • Classification • Pharmacodynamics • Therapeutic Effects • Adverse Effects • Contraindications • Drug Interaction with NSAIDS

3. Salicylates • Propionic Acid Derivatives • Anthranilic Acid Derivatives • Aryl-Acetic Acid Derivatives • Oxicam Derivatives • Pyrrolo-Pyrrole Derivatives • Indole Derivative • Pyrazolones • Preferential Cox-2 Inhibitors • Selective Cox-2 Inhibitors • Paraaminophenol Derivative • Guidelines in Using Nsaids

4. Opioid Analgesics • Introduction • Classification • Pharmacological Actions • Pharmacokinetics • Therapeutic Indications • Contraindications • Adverse Effects • Contraindications • Drug Interactions

5. Codeine • Pholcodeine • Heroin: • Pethidine • Fentanyl • Methadone • Tramadol • Conclusion

6. PAIN

7. ANALGESIC • Is a drug that selectively relieves pain by acting in the CNS or on peripheral pain mechanism , without significantly altering consciousness. Relieves pain as a symptom without affecting its cause

8. The management of pain is a critical and challenging component in dentistry. Pain is a major postoperative symptom in many dental surgical procedures. There are a variety of analgesics and techniques to treat dental pain. Knowing how well an analgesic and technique works and its associated adverse effects is fundamental to clinical decision-making.

9. ANALGESICS DIVIDED INTO 2 GROUPS • Opioid /narcotic/morphine like analgesics • Nonopioid /non-narcotic /aspirin like analgesics or non steroidal antiinflammatory drugs (NSAIDs).

10. NSAID

11. Most widely used analgesics - millions of users per day over the counter drugs. More commonly employed for dental pain because tissue injury and inflammation due to tooth abscess , caries ,tooth extraction , etc. In addition they have anti-inflammatory , antipyretic and uricosuric property- without addiction liability

12. HISTORY • 1875 – Sodium salicylate was first used for treatment of fever and pain • Willow bark –active ingredient (salicin) • 1899 – Deser introduced Acetylsalicylic acid (Aspirin) • 1949 – Devolopment of Penylbutazone(comparable to corticosteroid )

13. CLASSIFICATION • A. non selective COX inhibitors • Salicylic acid derivatives: aspirin, sodium salicylate, diflunisal, salicylsalicylic acid, • Propionic acid derivatives: ibuprofen, naproxen, fenoprofen, ketoprofen. • Anthranilic acids: mefenamic acid, meclofenamic acid • Aryl-acetic acid derivatives: diclofenac, aceclofenac. • Oxycam derivatives: Piroxicam, Tenoxicam. • Pyralo-Pyrroleacetic acid derivatives:ketorolac • Indole derivatives: indomethacin. • Pyrazolone derivatives: phenylbutazone, oxyphenylbutazone

14. B.Preferential COX-2 inhibitors Nimusulide,Meloxicam , Nabumetone C.Selective COX-2 inhibitors Celecoxib, rofecoxib, valdecoxib, etoricoxib D. Analgesic antipyretics with poor anti-inflammatory action • Para-aminophenol derivatives:Paracetamol (acetaminophen) • Benzoxazocine derivative: Nefopam

15. Phospholipids Corticosteroids Phospholipase • (Lipocortin) • Lipoxygenase inhibitors Arachidonic acid Cyclo-oxygenase • NSAIDs Lipoxygenase Prostagladins Leucotrienes Prostacyclin Throboxane A2 NSAIDs

16. PHARMACODYNAMICS • NSAIDs block the • Cyclooxygenase enzymes, which exist in 2 forms known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) • COX-1 is responsible for the synthesis of several mediators, including the prostaglandins that protect the gastric mucosa and that regulate renal blood flow, and the thromboxanes that initiate platelet aggregation • Traditional NSAIDs block both COX-1 and COX-2, but in recent years, new NSAIDs have been developed that are much more selective for COX-2. • These selective COX-2 inhibitors were developed to be less damaging to the gastric mucosa

17. Tissue damage such asperiodontitis or pulpitis , or tissue damage resulting from surgery, will induce the production of COX-2, which, in turn, leads to the synthesis of the prostaglandins that sensitize pain fibers and promote inflammation. • Prostaglandins sensitize peripheral nociceptors (C fibers) and potentiate algesic action of bradykinin, histamine and substance P, which are released during inflammation. As a consequence, a hyperalgesic state is produced in which the perception of painful stimuli is intensified in the face of mechanical, thermal or chemical stimuli

18. Therapeutic effects • Analgesia NSAIDs are effective against pain of mild to moderate intensity . . Do not affect the tenderness induced by direct application of PGs but block pain sensitizing mech induced by bradykinin, etc. so effective against inflammation associated pain

19. Anti-inflammatory action Useful in treatment of musculoskeletal disorders . NSAIDs provide only symptomatic relief from the pain and inflammation associated with the disease and do not arrest the progression of pathological injury to tissue.

20. Antipyretic action Reduce the body temperature in febrile states. Cytokines produced at the site of inflammation stimulates prostagladin synthesis in the hypothalamus ,this is blocked by NSAIDs • Antiplatelet aggregation Platelet function is reduced because formation of thromboxane is prevented This action is used to protect against vascular occlusion

21. Prolongation of gestation and labour Sudden spurt of prostagladin synthesis by uterus Probably triggers labour and facilitates its progression NSAIDs inhibits prostagladin synthesis so it has been used to prevent premature labour Ductusarteriosus closure Patency of ductusarteriosus is maintained by prostagladin , unknown mechanisms switch off this synthesis at birth and the ductus get closed . When this fails to occur a small amount of indomethacin or asprin brings about the closure .

22. Treatment of Primary dysemenorrhoea levels of PGs in menstrual flow of dysmenorrhic women is high. NSAIDs reduce uterine PG levels, excellent relief in 60-70% women.headache, muscle ache nausea are relieved. Excess flow will be normalised. • Treatment of cancer Prostagladin E2 also been implicated in humoral hypercalcemia associated with some neoplasms , and treatment with NSAIDs can be effectively suppress serum calcium levels in some patients . An important area where the use of NSAIDs is emerging is in the prevention of colon cancer

23. ADVERSE EFFECTS OF NSAIDs • GIT - Gastric irritation, erosions, peptic ulceration, gastric bleeding/perforation, esophagitis. • Renal - Sodium and water retention, chronic renal failure, interstitial nephritis, papillary necrosis (rare). • Hepatic - Raised transaminases, hepatic failure (rare).

24. CNS - Headache, mental confusion, behavioural disturbances, seizure precipitation. • Haematological - Bleeding, thrombocytopenia, haemolytic anemia, agranulocytosis. • Others - Asthma exacerbation, nasal polyposis, skin rashes, pruritis, angioedema.

25. Hypersensitivityto NSAIDs. • Urticaria and angioedema.Thereare two different types of hypersensitivity to NSAIDs. The most common form observed is chronic urticaria. • The other type of hypersensitivity is bronchospasm.

26. Contraindications • Gastric ulcers or gastrointestinal inflammatory diseases • Who are sensitive to it. • Chronic liver disease • Bleeding concerns • Third-trimester pregnancy • Significant renal disease

27. Drug interaction with NSAIDs • Diuretics – decreases diuresis • Beta blockers – decreases antihypertensive effect • ACE inhibitors – decreases antihypertensive effect • Sulfonylureas – enhance the action • Anticoagulant – increase risk of GI bleeding • Alcohol - increase risk of GI bleeding • Corticosteroid - increase risk of GI bleeding

28. SALICYLATES • Aspirin (prototype) • Aspirin is acetylsalicylic acid. • It is one of the oldest analgesic anti-inflammatory drugs and is still widely used. • It is rapidly converted in the body to salicylic acid which is responsible for most of the actions.

29. PHARMACOLOGICAL ACTIONS • Analgesic, antipyretic, anti-inflammatory action • The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG-mediated sensitization of nerve endings. • A central sub cortical action raising threshold to pain perception also adds up.

30. Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but does not decrease heat production. • Anti-inflammatory action is exerted at high doses (3-5g/day or 100 mg/kg/ day). Signs of inflammation like pain, tenderness, swelling, vasodilatation and leukocyte infiltration are suppressed.

31. Metabolic effect • Cellular metabolism is increased • There is increased utilization of glucose blood sugar may decreased • Toxic dose Hyperglycemia is often seen this is due to central sympathetic stimulation Respiration • Hyperventilation salicylate poisoning • Further rise in salicylate respiratory depression

32. CVS No direct effect in theraputic dose Large dose increase cardiac out put and cause direct vasodilatation Toxic dose depress vasomotor center fall in BP • GIT Irritates gastric mucosa epigastric distress, nausea, vomiting . • BLOOD Even in small dose irreversibly inhibits TXA2 synthesis by platelet interferes with platelet aggregation prolong bleeding time

33. PHARMACOKINETICS • Absorbed from the stomach and small intestines. • Poor water solubility is the limiting factor in absorption. • Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. • ~80% bound to plasma proteins. • Slowly enters brain but freely crosses placenta.

34. The plasma t1/2 of aspirin as such is 15-20 min, but taken together with that of released salicylic acid, it is 3-5 hours. • The metabolic processes gets saturated over the therapeutic range; t1/2 of anti-inflammatory doses may be 8-12 hours while that during poisoning may be up to 30 hours.

35. ADVERSE EFFECTS • Side effects at analgesic dose (0.3-1.5 g/day) include nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important being the gastric mucosal damage and peptic ulceration. • Hypersensitivity and idiosyncrasy Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactic reaction. Profuse gastric bleeding occurs in rare instances.

36. Anti-inflammatory doses (3-5 g/day) produce the syndrome called salicylism—dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance.

37. Acute salicylate poisoning - common in children. Fatal dose in adults is estimated to be 15-30 g • Serious toxicity is seen at serum salicylate levels > 50 mg/dl. • Manifestations are: Vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycaemia, petechial hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory failure + cardiovascular collapse.

38. Treatmentis symptomatic and supportive. • Recommended external cooling and i.v. fluid with Na+, K+, HCO; and glucose according to need determined by repeated monitoring. • Gastric lavage to remove unabsorbed drug • Forced alkaline diuresis or haemodialysis to remove absorbed drug is indicated in severe cases. • Blood transfusion and Vit K should be given if bleeding occurs.

39. When not give aspirin? • Patients who are sensitive to aspirin • Peptic ulcer, bleeding tendencies • In children suffering from chicken pox or influenza. • Chronic liver disease • avoided in diabetics and in juvenile rheumatoid arthritis.

40. Aspirin should be stopped 1 week before elective surgery. • Given during pregnancy it may lead to low birth weight babies. Delayed or prolonged labour, greater postpartum blood loss and premature closure of ductusarteriosus are possible if aspirin is taken at or near term. • Avoided in breastfeeding mothers. • Avoid high doses in G-6-PD deficient individuals—haemolysis can occur.

41. USES • As analgesic: For headache (including mild migraine), backache, myalgia, joint pain, pulled muscle, toothache, neuralgias and dysmenorrhoea (0.3-0.6g 6-8hourly) • As antipyretic: It is effective in fever of any origin (not useful in fever due to heat stroke); only external cooling lowers body temperature.

42. Acute rheumatic fever - Aspirin is the drug of choice here (4-5g). • Rheumatoid arthritis- Aspirin in a dose of 3-5 g/day is effective. • Osteoarthritis • Postmyocardial infarction and poststroke patients- Aspirin acts by inhibiting platelet aggregation. Large studies have demonstrated that aspirin 60-100 mg/day reduces the incidence of myocardial infarction (MI).

43. PROPIONIC ACID DERIVATIVES • Ibuprofen was the first member of this class to be introduced in 1969 as a better tolerated alternative to aspirin.

44. PHARMACOKINETICS AND INTERACTIONS • Well absorbed orally • Highly bound to plasma proteins (90-99%) • Enters brain, synovial fluid and crosses placenta. • Largely metabolized in liver. • Excreted in urine as well as bile.

45. USES • Analgesic and antipyretic • Particularly effective in dysmenorrhoea in which the action is clearly due to PG synthesis inhibition. • Widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, especially where pain is more prominent than inflammation.

46. Indicated in soft tissue injuries, fractures, vasectomy, tooth extraction, postpartum and postoperatively: suppress swelling and inflammation.

47. ADVERSE EFFECTS • Side effects are milder and their incidence is lower. • Gastric discomfort, nausea and vomiting are still the most common side effects. • Gastric erosion and occult blood loss are rare. • CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression. • Not advocated in pregnant women and in peptic ulcer patient.

48. contraindication • Bronchial asthma • pregnant women • peptic ulcer patient.

49. IBUPROFEN • Rated as the safest conventional NSAID by the spontaneous adverse drug reaction reporting system in U.K. • Ibuprofen (400 mg) has been found equally or more efficacious than a combination of aspirin (650 mg) + codeine (60 mg) in relieving dental surgery pain. • Plasma t1/2- 2hrs • dosage – adult - 400-600 mg tid • children – 7.5 – 10mg/kg tid

50. Naproxen • Particularly potent in inhibiting leucocyte migration. • More valuable in acute gout: dose 750 mg stat followed by 250 mg 8 hourly till attack subsides. • Recommended for ankylosing spondylitis. • Dose should be reduced in the elderly. • Plasma t1/2 – 12-16 hrs dosage - 250mg bd– tds; Maximum daily dose- 1.5g