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Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy
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Non steroidal anti inflammatory drugs /certified fixed orthodontic courses by Indian dental academy

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The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.

Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078

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  • 1. NON STEROIDAL ANTIINFLAMMATORY DRUGS ( NSAIDs) INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
  • 2. “Pain is perfect misery, the worst of evils, and excessive, overturns all patience”. John Milton (1608- 1674) Paradise Lost. www.indiandentalacademy.com
  • 3. One of the greatest services doctors can do their patients is to acquire skill in the management of pain. Pain management in dental patients is individualized according to the quality of the pain, its severity, cause and chronicity. Pain arises when there is a noxious stimulus to the tissues as the result of destruction or injury. Such trauma can occur by means of a disease process, formation of an abscess, or through surgical intervention or extraction of a tooth. www.indiandentalacademy.com
  • 4. Dental pain is best managed by selecting a pharmacologic agent from one of the three widely used groups. Local anesthetic Peripherally acting analgesics Narcotic and opiates www.indiandentalacademy.com
  • 5. Bark of willow tree was used in folk medicine for years for mild pain and fever. Salicylic acid was obtained by hydrolysis of the bitter glycoside obtained from this plant. The active ingredient of willow bark was salicin which on hydrolysis yields salicylic acid which was later found in other natural sources. Acetylsalicylic acid was synthesized in 1853 1875 sodium salicylate was used in fever and pain. 1899 it was found to be effective in arthritis and www.indiandentalacademy.com was well tolerated.
  • 6. NSAIDs are weak analgesics. They are also called as non narcotic / non opoid analgesics or aspirin type or antipyretic analgesics. They have anti-inflammatory, elevated body antipyretic (reduce temperature). They the have uricosuric properties antiplatelet activity to varying degrees. They do not depress the CNS, do not produce physical dependence and have no abuse liability. These drugs are chemically diverse, but most are organic acids. www.indiandentalacademy.com
  • 7. PROSTAGLANDINS Prostaglandins are naturally occurring substances composed of fatty acids found throughout body tissues. Prostaglandins and Leukotrienes are biologically active derivatives of 20 carbon atom, poly unsaturated essential fatty acids that are released from cell membrane phospholipids. Prostanoic acid www.indiandentalacademy.com
  • 8. IN 1930’S human semen was found to contract isolated uterine and other smooth muscle strips and to cause fall in blood pressure in animals. The active principle was termed prostaglandin thinking it was derived from prostrate. www.indiandentalacademy.com
  • 9. BIOSYNTHESIS OF PROSTAGLANDINS www.indiandentalacademy.com
  • 10. BENEFICIAL ACTION DUE TO PROSTAGLANDIN SYNTHESIS INHIBITION. Analgesia : prevention of pain nerve ending sensitization Antipyresis: reduces the elevated body temperature Anti-inflammatory Anti-thrombotic www.indiandentalacademy.com Closure of ductus arteriosus.
  • 11. SHARED TOXICITIES DUE TO PROSTAGLANDIN SYNTHESIS INHIBITION Gastric mucosal damage Bleeding : inhibition of platelet function Limitation of renal blood flow : Na + and water retention. Delay / prolongation of labor Asthma and anaphylactoid reaction in susceptible individuals www.indiandentalacademy.com
  • 12. PAIN – is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is mainly a protective mechanism for the body ; it occurs whenever any tissue are being damaged , and it causes the individual to react to remove the pain stimulus. www.indiandentalacademy.com
  • 13. Pain has been classified into two major types: fast pain and slow pain. Fast pain is felt within about 0.1 second after a pain stimulus is applied, whereas slow pain begins only after 1 second or more and then increases slowly over many second and sometimes even minutes. The pain receptors in the skin and other tissues are all free nerve endings. www.indiandentalacademy.com
  • 14. They are widespread in the superficial layers of the skin as well as in certain internal tissues, such as the periosteum, the arterial walls, the joint surfaces, and the falx and tentorium of the cranial vault. Most other deep tissues are sparsely supplied; still summate to cause the slow-chronic aching type of pain in these areas are elicited by multiple types of stimuli. They are classified as mechanical, thermal, and chemical pain stimuli. Fast pain is elicited by the mechanical and thermal types of stimuli, whereas slow pain can be www.indiandentalacademy.com elicited by all three types .
  • 15. The fast-sharp pain signals they are transmitted in the penpheral nerves to the spinal cord by small type Aδ fibers at velocities between 6 and 30 m/sec. On the other hand, the slow: chronic type of pain is specially elicited by the chemical type of pain stimuli but also at times by persisting mechanical or thermal stimuli; this slow-chronic pain is transmitted by C fibers at velocities of between 0.5 and 2m/sec. www.indiandentalacademy.com
  • 16. Because of this double system of innervations, a sudden onset of pain painful stimulus often gives a double pain sensation a fast-sharp pain that is transmitted to the brain by the Aδ fiber pathway followed a second or so later by a slow pain that is transmitted by the C fiber pathway. www.indiandentalacademy.com
  • 17. On entering the spinal cord from the dorsal spinal roots, the pain fibers terminate on neurons in the dorsal horns. On entering the spinal cord the pain signals take two pathways to the brain. Through the neospinothalamic tract and through the paleospinothalamic tract. www.indiandentalacademy.com
  • 18. www.indiandentalacademy.com
  • 19. The fast type Aδ pain fibers transmit mainly mechanical and acute thermal pain. They terminate mainly in lamina I (laimina marginalis) of the dorsal horn, and there excite the second order neurons of the neospinothalamic tract these give rise to long fibers that cross immediately to the opposite side of the cord through the anterior commissure and then pass upward to the brain in the anterolateral columns. www.indiandentalacademy.com
  • 20. Few fibers of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass all the way to the thalamus, terminating in the ventrobasal complex. A few also terminate in the posterior nuclear group of the thalamus. From these areas the signals are transmitted to other basal areas of the brain and to the somatic sensory cortex. www.indiandentalacademy.com
  • 21. The paleospinothalamic pathway transmits pain mainly carried in the peripheral slow-chronic type C pain fibers; although it does transmit some signals from type- A δ fibers as well. In this pathway, the peripheral fibers terminate almost entirely in laminas II and III of the dorsal horn which together are called substantia gelatinosa .Most of the signals then pass through one or more additional short fiber neurons within the dorsal horns themselves before entering laminas V through VIII, also in the dorsal horn. www.indiandentalacademy.com
  • 22. Here the last neuron in the series gives rise to long axons that mostly join the fibers from the fast pathway, passing first through the anterior commissure to the opposite side of the cord and then upward to the brain in the same anterolateral pathway. The slow-chronic paleospinothalamic pathway terminates widely in the brainstem. Only one-tenth to one fourth of the fibers passes all the way to the thalamus. www.indiandentalacademy.com
  • 23. Instead, they terminate principally in one of three areas: (1) the reticular nuclei of the medulla, pons, and mesencephalon; (2) the tectal area of the mesencephalon deep to the superior and inferior coliculli; or (3) the periaqueductal gray region surrounding the aqueduct of Sylvius www.indiandentalacademy.com
  • 24. Glutamate, the neurotransmitter of the Type Aδ Fast Pain Fibers. Type C pain fiber terminals entering the spinal cord might secrete both glutamate transmitter and substance P transmitter. The glutamate transmitter acts instantaneously and lasts for only a few milliseconds. On the other hand, substance P is released much more slowly, building up in con-centration over a period of seconds or even minutes www.indiandentalacademy.com
  • 25. Prostaglandins particularly PGE and PGI produce hyperalgesia associated with inflammation. Prostaglandin alone induces pain only in concentration that is unlikely to occur physiologically. However they enhance the potency of algesia (pain inducing) substances by sensitizing the nerve endings of of unmyelinated C fibers and small diameter Aδ fibers endings to other mediators such as bradykinin and histamine Furthermore bradykinin eliminates formation and release of prostaglandins and a positive feed back of www.indiandentalacademy.com sort.
  • 26. FEVER which means a body temperature above the usual range of normal can be caused by abnormalities in the brain itself or by toxic substances that affect the temperature regulatory centers. Body temperature between 99ºF (37.22ºC ) and 105ºF(40.57ºC) and onwards is called PYREXIA. Rise of body temperature above 107ºF (41.66ºC) www.indiandentalacademy.com is called HYPERPYREXIA.
  • 27. Regulation of body temperature require a delicate balance between production of heat and loss of heat and the hypothalamus regulates the set point at which body temperature is maintained. www.indiandentalacademy.com
  • 28. FEVER PRODUCTION www.indiandentalacademy.com
  • 29. Many proteins, breakdown products of proteins and certain other substances esp. lipopolysaccharide toxins released from bacterial cell membrane cause the set point of the hypothalamic thermostat to rise. Substances that cause this effect are called pyrogens. The pyrogens can act directly on the hypothalamic temperature regulating centre to increase its set point. It can act indirectly and may require several hours of latency before causing their effect. www.indiandentalacademy.com
  • 30. When bacteria or breakdown products of bacteria are present in the tissues or the blood, they are phagocytized by the blood leukocytes, tissue macrophages and large granular killer lymphocytes. All these cells in turn digest the bacterial products and then release into the body fluids the substance interleukin1(cytokines) formation of which prostaglandin induces in the vascular organs in the preoptic hypothalamic area. Prostaglandin (PGE 2 ) produced acts on the www.indiandentalacademy.com hypothalamus to elicit fever reaction.
  • 31. When the set temperature point of regulating the hypothalamic centre becomes increased to a higher level than normal all the mechanisms for raising the body temperature are brought into play, including heat conservation . The temperature is increased to the new set point (higher level) and the body temperature also approaches this level. www.indiandentalacademy.com
  • 32. Anti-pyretic action of NSAIDs is central. In fever the temperature regulating system maintains temperature at a higher level than normal. The stimulus for the shift to a higher level is the action of endogenous pyrogens such as interleukin 1 on neurons of the thermoregulatory system in the preoptic hypothalamus. NSAIDs it reduces the effect of pyrogen. www.indiandentalacademy.com
  • 33. NSAIDs reduces elevated temperature by increased dissipation of heat caused by vasodilatation of superficial blood vessels. The antipyresis may be accompanied by profuse sweating. NSAIDs block both the pyrogen induced production of prostaglandin and the central nervous system response to interleukin 1 and so may reset the “temperature control” in the hypothalamus thereby facilitating heat dissipation. www.indiandentalacademy.com
  • 34. Therapeutic doses of aspirin affect neither normal body temperature nor an elevated temperature associated with exercise, drugs or hypothalamic lesions as there is no pyrogen and no production of interleukin 1. www.indiandentalacademy.com
  • 35. INFLAMMATION Inflammation is defined as the local response of living mammalian tissue to injury due to any agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent. The word inflammation means burning. www.indiandentalacademy.com
  • 36. Signs of inflammation— Roman writer Celsus in 1st century AD named the famous four cardinal signs of inflammation. Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Fifth sign function laesa (loss of function) was later added by Virchow. www.indiandentalacademy.com
  • 37. Types of inflammation Acute and Chronic Inflammation. Changes in acute inflammation— Vascular changes Cellular events 1.Haemodynamic changes 1. Exudation of leucocytes 2.Vascular Permeability 2. Phagoctosis www.indiandentalacademy.com
  • 38. www.indiandentalacademy.com
  • 39. Chemical mediators of inflammation also called as permeability endogenous mediators factors of or increased vascular permeability .These are a large and increasing compounds number which can of endogenous enhance vascular permeability. The substance acting as a chemical mediator of inflammation may be released from the cells , the plasma or www.indiandentalacademy.com damaged tissue itself. They are broadly
  • 40. Mediators released by cells 1. Vasoactive amines (histamine, 5hydroxytryptamine) 2. Arachidonic acid metabolite a. Metabolite via cyclo-oxygenase pathway Prostaglandin, ThromboxaneA2, Prostcyclin b. Metabolite via lipo-oxygenase pathway 5HETE, Leukotrienes c.Metabolite via non-enzymatic pathway Chemotatic lipid 3. Lysosomal components 4. Platelet activating factor. 5. Cytokines (interleukin I, tumor necrosis factor) Mediators originating from plasma The The The The kinin system clotting system fibrinolytic system www.indiandentalacademy.com complement system.
  • 41. NSAIDs reduce the synthesis of eicosonoid mediators of inflammation; it also interferes with chemical mediators of kallikerin system. As a result inhibits granulocyte adherence to damage vasculature, stabilizes lysosmes and inhibits the migration of ploymorphonuclear leukocytes and macrophages into the site of inflammation. www.indiandentalacademy.com
  • 42. CLASSIFICATION OF NSAIDs A. Analgesic and anti-inflammatory 1 Salicylates 2 Pyrazolone derivative 3 Indole derivatives 4 B. Analgesic but poor anti-inflammatory Propionic acid derivatives 1 2 5 Anthranilic acid derivative 6 Aryl-acetic acid derivatives 7 3 Benzoxazocine derivative Pyrrolo-pyrrole derivative 9 Pyrazolone derivatives Oxicam derivatives 8 Paraaminophenol derivative Sulfonanilide derivative 10 Alkanones www.indiandentalacademy.com
  • 43. SALICYLATES --- (Aspirin- protype) (Aspirin, Salicylamide, Benorylate, Diflunisal) The name aspirin was coined from German word for the compound acetylspirsaure (spirea, the genus of plants from which it was obtained and saure, the German word for acid) www.indiandentalacademy.com
  • 44. Apirin is acetylsalicylic acid . It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. It is one of the oldest analgesics – anti-inflammatory drugs and still is widely used. Sodium salicylate Aspirin www.indiandentalacademy.com Methyl salicylate
  • 45. PHARMACOLOGICAL ACTIONS -Analgesic, antipyretic, anti-inflammatory actions Aspirin is a weaker analgesic than morphine type drugs: aspirin 600 mg ~ codeine 60 mg. It relieves inflammatory, tissue injury related, connective tissue and integumental pain but is relatively ineffective in severe visceral and ischemic pain. 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 contributes, but the morphine like action on psychic processing or reaction component of the pain is missing. No sedation, subjective effects, tolerance or www.indiandentalacademy.com physical dependence is produced.
  • 46. 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 (36 g/day or 100 mg/kg/day). Signs of inflammation like pain, tenderness, swelling, and vasodilatation and leukocyte infiltration are suppressed. However, the progression of the underlying disease in rheumatoid arthritis, rheumatic fever and osteoarthritis etc. is not affected. www.indiandentalacademy.com
  • 47. 2. Metabolic effects- These are significant only at anti-inflammatory doses. Cellular metabolism is increased, specially in skeletal muscles, due to uncoupling of oxidative phosphorylation by salicylates leads to conversion of a large part of energy derived from oxidation into heat production. Large doses of salicylates may lead to hyperpyrexia. Increased protein catabolism leading www.indiandentalacademy.com to aminoaciduria and a negative nitrogen balance.
  • 48. Large doses of salicylates produce hyperglycemia and gylcosuria in normal individuals this is due to central sympathetic stimulus- release of adrenaline and gluccocorticoids. www.indiandentalacademy.com
  • 49. 3. Respiration Salicylates stimulate respiration as a result of direct and indirect action. As a result of their action on the mitochondria, at anti-inflammatory doses of salicylate increase the consumption of oxygen primarily by the skeletal muscles. This results in increased production of CO2. Increased production of CO2 production leads to a direct stimulation of the respiratory centre producing an increase in depth and to some extent in the rate of respiration. With the entry of salicylates into the brain, the medullary respiratory centre is stimulated directly. In addition, it also stimulates the www.indiandentalacademy.com chemoreceptors.
  • 50. This produces an increase in the rate as well as the depth of respiration leading to hyperventilation. Hyperventilation is prominent in salicylate poisoning. Further rise in salicylate level causes respiratory depression; death is due to respiratory failure www.indiandentalacademy.com
  • 51. 4. Acid-base and electrolyte balance The respiratory alkalosis produced by the anti-inflammatory doses is countered by the excretion of alkaline urine containing bicarbonate along with sodium and potassium. This is termed the stage of compensatory respiratory alkalosis. Reduction in the bicarbonate and potassium levels reduces the buffering capacity of the extracellular fluids and a patient on aspirin therapy is prone to develop acid-base imbalance . www.indiandentalacademy.com
  • 52. Hypokalemia as a result of urinary loss of potassium is accompanied by water loss through lungs due to hyperventilation through the skin via augmented sweating and through urine as a result of alkalosis .This may lead to dehydration and hypernatremia. With acute doses of salicylates hypokalemia is aggravated, the respiratory centre is depressed. With CO2 retention and excess CO2 production continues leads to respiratory acidosis . www.indiandentalacademy.com
  • 53. To this are added dissociated salicylic acid as well as metabolic acids (lactic, pyruvic, acetoacetic) which are produced in excess and metabolically derived sulfuric and phosphoric acid which are retained due to depression of renal function. These entire combine to cause uncompensated metabolic acidosis since plasma HCO3- is already low. Dehydration occurs in poisoning due to increased water loss in urine (to accompany Na +, K+ and HC03-) increased sweating and hyperventilation. www.indiandentalacademy.com
  • 54. 6. Gastrointestinal tract the ingestion of salicylates may produce dyspepsia, nausea, vomiting as a result of gastric irritation by the released salicylic acid. www.indiandentalacademy.com
  • 55. Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This 'ion trapping' in the gastric mucosal cell enhances gastric toxicity. Further local absorption into the mucous cell causes inhibition of prostaglandin synthesis , thus causing a loss of protective effect on the stomach. Salicylates also reduce the motility of the stomach and increases the gastric emptying time. These effects increase the period of contact of salicylates www.indiandentalacademy.com with the gastric mucosa.
  • 56. To avoid gastric irritation salicylate may be administered - with plenty of water after food - With milk - With an alkali such as sodium bicarbonate - As a soluble buffered aspirin - With a prostaglandin analogue Alkali induces the ionization of salicylates thereby reducing their gastric absorption and local irritant effect. As the ionized salicylate is more water soluble, it tends to pass more quickly into the intestine and does not adhere to the mucous membrane of the stomach. www.indiandentalacademy.com
  • 57. 7. Blood- Aspirin, even in small doses irreversibly inhibits TXA2 synthesis by platelets. Thus it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelets). Long term use of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding. www.indiandentalacademy.com
  • 58. This can be detrimental in patients scheduled for surgery. Bleeding time can be prolonged for a week. Thus aspirin should not be used in presurgical dosing for its analgesic effect. Recent evidence shows that a dose of one aspirin daily can prevent myocardial infarction and or cerebrovascular accident due to clots initiated by the same mechanism. www.indiandentalacademy.com
  • 59. 8. Uricosuric effects- Urate present in the glomerular infiltrate is reabsorbed by the proximal tubules of the kidney and the main excretion of urate in urine occur due to its secretion by the distal tubule. Salicylates exhibit biphasic action on the excretion of urate. In small doses (1-2g per day) salicylate interferes with urate secretion by the distal tubule, thereby elevating the plasma urate level. The high doses of salicylates (over 5g per day) inhibit the reabsorption of urate by proximal tubule which can cause uricosuria. www.indiandentalacademy.com
  • 60. 6. CVS -Aspirin has no deleterious effect in therapeutic doses. Larger doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation. Toxic doses depress vasomotor centre: BP may fall. Because of increased cardiac work and Na + water retention, CHF may be precipitated in patients with low cardiac reserve. www.indiandentalacademy.com
  • 61. Pharmacokinetics- Salicylates are absorbed from the stomach and largely from the upper part of the small intestine. www.indiandentalacademy.com
  • 62. On oral therapeutic administration dose, concentrations are of a appreciable found single plasma within 30 minutes, peak plasma level is achieved within 2 hrs and approximately 50% of the dose is eliminated in urine within 24hrs. The plasma half-life ranges from 2-8 hrs. Factors such as particle size, pH of the GIT, solubility of the salicylate preparation, www.indiandentalacademy.com presence of food in the stomach modify the
  • 63. Both salicylate and salicylic acid are absorbed from intact skin, esp. when applied with alcohol, petrolatum, lard or lanolin base and systemic poisoning in children has been reported following such local application. Aspirin is rapidly deacetylated in the gut wall, liver plasma and other tissues to release salicylic acid which is a major circulating and active form. www.indiandentalacademy.com
  • 64. After absorption, salicylate mainly is approx. bound albumin. It to is 80% plasma rapidly of the proteins distributed through most of the tissues and achieves a significant concentration in the saliva, milk, spinal, sensorial and peritoneal fluids and in the erythrocytes. www.indiandentalacademy.com
  • 65. Salicylates are mainly metabolized in the liver and excreted in the urine in the form of conjugate with glycine and glucuronic acid. A small portion is oxidized to gentisic acid and excreted in the urine. High salicylate concentrations are observed in the liver, heart and muscle while brain contains relatively smaller amounts. www.indiandentalacademy.com
  • 66. Adverse Effects— Side effects that occur at analgesic dose (0.3-1.5 g/day) are nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important adverse effect of aspirin is gastric mucosal damage and peptic ulceration. www.indiandentalacademy.com
  • 67. Hypersensitivity and idiosyncrasy though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. Salicylates induced angioedema and anaphylaxis like reaction respond to adrenaline .Aspirin can induce idiosyncratic mild haemolysis in individuals with glucose 6 phosphate dehydorgenase deficiency (G6PD). www.indiandentalacademy.com
  • 68. GIT – the commonest side effects of salicylates and other NSAIDs are dyspepsia, nausea, vomiting and heartburn. Therapeutic doses of aspirin may irritate gastric mucosa and increases the blood loss in majority of persons without obvious symptoms. A nonacetylated salicylate may be less irritating, should be avoided in patients with a history of ulcers and should not be used with alcohol or other agents that promote ulcer formation. Risk is greater in elderly and debilitated patients, esophageal injury may also www.indiandentalacademy.com occur.
  • 69. Haemopoietic system -salicylates in large doses reduce the plasma prothrombin level by interfering with the action of vitamin k in the liver. Kidney- in normal people, aspirin has little effect on the kidney. However if there is an underlying circulatory problem such as congestive heart failure, aspirin decreases renal blood flow. This can precipitate acute renal failure. Aspirin also enhances sodium and water retention which can increase edema www.indiandentalacademy.com formation in some patients.
  • 70. Reyes syndrome- This serious and often fatal complication occur a few days after viral infection, especially influenza and varicella, in children below12 years. There occur anicteric liver dysfunction due to hepatic mitochondrial injury and a consequent metabolic encephalopathy. Therefore aspirin should be avoided in children under the age of 12 years. www.indiandentalacademy.com
  • 71. Pregnancy and infants- When taken during term, aspirin by inhibiting prostaglandin synthesis in the uterus may delay the onset of labor and may cause greater blood loss at delivery. They cause premature closure of the ductus arteriosus with resultant serious pulmonary hypertension in the newborn. Salicylate readily crosses the placental barrier and may prove toxic to the newborn as the ability of the newborn to detoxify and excrete salicylate is poor. www.indiandentalacademy.com
  • 72. Anti-inflammatory doses (3-6 g/day) produce the syndrome called salicylism diziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. www.indiandentalacademy.com
  • 73. Salicylism- prolonged administration of salicylates may produce a condition of mild salicylate intoxication termed salicylism. The syndrome usually develops when the plasma salicylate level exceed 25mg% and characterized by headache, dizziness, vertigo, tinnitus, difficulty in hearing, and dizziness of vision, drowsiness ,lethargy, mental confusion, nausea and vomiting. The signs and symptoms of salicylism are reversible on cessation of therapy. www.indiandentalacademy.com
  • 74. Acute salicylate poisoning – may be due to overzealous therapy in infants or an accidental ingestion by children and adults. A serum salicylate level of 50 mg% indicates mild toxicity, level above 75mg%, are potentially fatal. www.indiandentalacademy.com
  • 75. Manifestations areVomiting, dehydration electrolyte imbalance, acidotic breathing, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory failure cardiovascular collapse. Treatment is symptomatic and supportive. Most important is external cooling and iv fluid with Na+, K+, HCO3-] 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. www.indiandentalacademy.com
  • 76. Precaution and contraindication-Aspirin is contraindicated in patients who are sensitive to it and in peptic ulcer, bleeding tendencies, in children suffering from chicken pox or influenza. Due to risk of Reye’s syndrome pediatric formulations of aspirin are prohibited. - In chronic liver disease: cases of hepatic necrosis. - It should be avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis. www.indiandentalacademy.com
  • 77. -Aspirin should be stopped 1 week before elective surgery. - Given during pregnancy it may be responsible for low birth weight babies. Delayed or prolonged labor, greater postpartum blood loss and premature closure of ductus arteriosus are possible if aspirin is taken at or near term. -It should be avoided by breast feeding mothers. -Avoid high doses in G-6-PD deficient individuals-haemolysis can occur. www.indiandentalacademy.com
  • 78. Uses-As analgesic -As antipyretic -Acute rheumatic fever -Rheumatoid arthritis -Osteoarthritis -Postmyocardial infarction and post stroke patients www.indiandentalacademy.com
  • 79. PYRAZOLONES – These are-Aminopyrine and antipyrine -Phenylbutazone and Oxyphenbutazone -Other drugs like Phenyldimethyl pyrazolone (analgin) www.indiandentalacademy.com
  • 80. Antipyrine (phenazone) and amidopyrine (aminopyrine) were introduced in 1884 as antipyretics and analgesics. Their use was associated with high incidence of agranulocytosis: are banned in many countries. Phenylbutazone was introduced in 1949 and soon its active metabolite oxyphenbutazone was also marketed. These two are potent antiinflammatory drugs. Two other pyrazolones available in India metamizol and propiphenazone are primarily used as analgesic and antipyretic. www.indiandentalacademy.com
  • 81. Phenylbutazone It inhibits COX and is more potent anti-inflammatory than the usually tolerated doses of aspirin; somewhat comparable to corticosteroids. The analgesic and antipyretic action is poorer and slower in onset. It is uricosuric by virtue of a metabolite which inhibits renal tubular reabsorption of uric acid. Phenylbutazone causes definite retention of Na + and water by direct action on renal tubules, edema, and expansion of plasma volume occur after 1-2 weeks of use: CHF may be precipitated. www.indiandentalacademy.com
  • 82. Pharmacokinetics Phenylbutazone is completely absorbed orally. Absorption from i.m. sites is slower and it causes local tissue damage: this route is not recommended. It is 98% bound to plasma: proteins: completely metabolized in liver by hydroxylation and glucuronidation. The plasma t1/2 is 60 hours; even then divided daily doses are given to minimize gastric irritation. www.indiandentalacademy.com
  • 83. Adverse effects- More toxic than aspirin. Nausea, vomiting, epigastric distress and peptic ulceration are common. Diarrhea and a variety of CNS side effects are reported. Edema is the major limitation of use for more than 1-2 weeks. Hypersensitivity: rashes, serum sickness, hepatitis and stomatits. . Bone marrow depression, agranulocytosis and Stevens-Johnson syndrome are serious dangers. Goiter and hypothyroidism have occurred on long term use. www.indiandentalacademy.com
  • 84. Uses -Because of risk of fatal agranulocytosis and other serious reactions, phenyl-butazone and oxyphenbutazone have-been banned in some countries. With the availability of safer NSAIDs, these drugs should be used only in severe cases not responding to other drugs. Rheumatoid arthritis and ankylosing spondylitis: for short period (1-2 weeks) during an acute exacerbation. Rheumatic fever: cases not responding to aspirin. Acute gout: to suppress the attack. It is nearly as effective as colchicines and better tolerated. Though uricosuric, it is not recommended for long term therapy of chronic gout. www.indiandentalacademy.com
  • 85. INDOLE DERIVATIVES (Indomethacin, Sulindac ) Indomethacin it is a potent anti-inflammatory drug, comparable to phenylbutazone. In addition, it is a potent and promptly acting antipyretic. Analgesic action is better than phenylbutazone, but it relieves only inflammatory or tissue injury related pain. It is a highly potent inhibitor of PG synthesis and suppresses neutrophil motility. In toxic doses it uncouples oxidative phosphorylation (like aspirin). www.indiandentalacademy.com
  • 86. Pharmacokinetics Indomethacin is well absorbed orally; rectal absorption is slow but dependable. It is 90% bound to plasma proteins partly metabolized in liver to inactive products and excreted by kidney. Plasma t1/2 is 2-5 hours. www.indiandentalacademy.com
  • 87. Adverse effects - A high incidence (upto, 50%) of gastrointestinal and CNS side effects are produced. Marked gastric irritation, nausea, anorexia, gastric bleeding and diarrhea. Frontal headache (very common), dizziness, ataxia, mental confusion, hallucination. Depression and psychosis. Leukopenia, rashes and other hypersensitivity reactions are also reported. Increased risk of bleeding due to decreased platelet agreeability. It is contraindicated in machinery operators, drivers, psychiatric patients, epileptics, kidney www.indiandentalacademy.com disease. pregnant women and in children.
  • 88. Uses - it is indicated in rheumatoid arthritis not controlled by aspirin. It is particularly efficacious in ankylosing spondylitis, acute exacerbations of destructive arthropathies and psoriatic arthritis. It acts rapidly in acute gout. Malignancy associated fever refractory to other antipyretics may respond to indomethacin. It has been the most common drug used for medical closure of patent ductus arteriosus three 12 hourly doses of 0.1-0.2 mg/kg achieves closure in majority of www.indiandentalacademy.com cases.
  • 89. PROPIONIC ACID DERIVATIVES ( Ibuprofen, Naproxen, Ketoprofen, Fenoprofen, Flurbiprofen ) Ibuprofen was the first member of this class to be introduced in 1969 as a better tolerated alternative to aspirin. The analgesic, antipyretic and antiinflammatory efficacy is rated somewhat lower than high dose of aspirin. All inhibit PG synthesis, naproxen being most potent; but their in vitro potency for this action does not closely parallel in vivo anti-inflammatory potency. They inhibit platelet aggregation and prolong bleeding time. www.indiandentalacademy.com
  • 90. Pharmacokinetics - All are well absorbed orally, highly bound to plasma proteins (90-99%), but displacement interactions are not clinically significant dose of oral anticoagulants and oral hypoglycemic need not be altered. Because they inhibit platelet function, use with anticoagulants should, nevertheless, be avoided. All propionic acid derivatives enter brain, synovial fluid and cross placenta. They are largely metabolized in liver by hydroxylation and glucuronide www.indiandentalacademy.com conjugation and excreted in urine as well as bile.
  • 91. Adverse effects- Ibuprofen and all its congeners are better tolerated than aspirin. Side effects are milder and their incidence is lower. Gastric discomfort, nausea and vomiting, though less than aspirin or indomethacin, are still the most common side effects. However, even some peptic ulcer patients are able to tolerate these drugs. Gastric erosion and occult blood loss are rare. www.indiandentalacademy.com
  • 92. CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression. Rashes, itching and other hypersensitivity phenomena are infrequent. However, these drugs also precipitate aspirin induced asthma. Fluid retention is less marked than that with phenylbutazone. They are not to be prescribed to pregnant women and should be avoided in peptic ulcer patient. www.indiandentalacademy.com
  • 93. Uses Ibuprofen is used as a simple analgesic and antipyretic in the same way as low dose of aspirin. It is particularly effective in dysmenorrhoea in which the action is clearly due to PG synthesis inhibition. Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, specially where pain is more prominent than inflammation. They are indicated in soft tissue injuries, fractures, vasectomy, tooth extraction, postpartum and postoperatively: suppress swelling and www.indiandentalacademy.com inflammation.
  • 94. ANTHRANILIC ACID DERIVATIVE (Mephenamic acid) Mephenamic acid an analgesic, antipyretic and anti-inflammatory drug, known from 1950s, but has not gained popularity because of lower efficacy. It inhibits PG synthesis and antagonizes certain actions of PGs as well. Mephenamic acid exerts peripheral as well as www.indiandentalacademy.com central analgesic action.
  • 95. Pharmacokinetics- Oral absorption is slow but almost complete. It is highly bound to plasma proteins displacement interactions can occur; partly metabolized and excreted in urine as well as bile. Plasma tl/2 is 2-4 hours. www.indiandentalacademy.com
  • 96. Adverse effects- Diarrhea is the most important dose related side effect. Epigastric distress is complained, but gut bleeding is not significant. Skin rashes, manifestations dizziness have and occurred. other Hemolytic anemia is rare but serious complication. www.indiandentalacademy.com CNS
  • 97. Uses Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is not needed. It is quite effective in dysmenorrhoea. It may be useful in some cases of rheumatoid and osteoarthritis but has no distinct advantage www.indiandentalacademy.com
  • 98. ARYL-ACETIC ACID DERIVATIVES (DiclofenacE, Tolmetin ) Diclofenac sodium a newer analgesic- antipyretic-anti-inflammatory drug, similar in efficacy to naproxen. It inhibits PG synthesis and has short lasting anti platelet action; Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced. www.indiandentalacademy.com
  • 99. Pharmacokinetics It is well absorbed orally, 99% protein bound, metabolized and excreted both in urine and bile. The plasma t1/2 is 2 hours. However, it has good tissue penetrability and concentration in synovial fluid is maintained for 3 times longer period than in plasma, exerting extended therapeutic action in joints. www.indiandentalacademy.com
  • 100. Adverse effects - are generally mild: epigastric pain, nausea, headache, dizziness, and rashes. Gastric ulceration and bleeding are less common. Reversible elevation of serum aminotransferases can occur; kidney damage is rare. www.indiandentalacademy.com
  • 101. Uses - Its indications are similar to those of ibuprofen - rheumatoid and osteoarthritis, bursitis, ankylosing dysmenorrhoea, postoperative spondylitis, post-traumatic inflammatory and conditions affords quick relief of pain and wound edema. www.indiandentalacademy.com -
  • 102. OXICAM DERIVATIVES (Piroxicam, Tenoxicam, Meloxicam ) Piroxicam It is a novel long acting potent NSAID with anti-inflammatory potency similar to indomethacin and good analgesic-antipyretic action. It is a reversible inhibitor of cyclooxygenase; lowers PG, concentration in synovial fluid and inhibits platelet aggregationprolonging bleeding time. In addition, it decreases the production of IgM rheumatoid factor. Chemotaxis of leukocytes and ratio of Thelper to T-suppressor lymphocytes are reduced. Thus, it can inhibit inflammation in diverse ways. www.indiandentalacademy.com
  • 103. Pharmacokinetics it completely absorbed: bound; largely is rapidly and 99% plasma protein metabolized in liver by hydroxylation and glucuronide conjugation; excreted in urine and bile; enterohepatic cycling occurs. Plasma t1/2 is long-nearly 2 days. Steady state concentrations are achieved in a week. Single daily administration is sufficient. www.indiandentalacademy.com
  • 104. Adverse effects Common side effects are heart burn, nausea and anorexia, but it is better tolerated and less ulcerogenic than indomethacin or phenylbutazone; causes less faecal blood loss than aspirin. Rashes and pruritus are seen in < 1% patients. Edema and reversible azotemia have been observed. www.indiandentalacademy.com
  • 105. Uses It is suitable for use as short term analgesic as well as long term anti- inflammatory drug - rheumatoid and osteoarthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries, dentistry, episiotomy, dysmenorrhoea etc. Its efficacy is comparable indomethacin. to high dose www.indiandentalacademy.com aspirin or
  • 106. PYRROLO-PYRROLE DERIVATIVE (Ketorolac) Ketorolac A novel NSAID with potent analgesic and modest anti-inflammatory activity. In postoperative pain it has equaled the efficacy of morphine, but does not interact with opioid receptors and is free of respiratory depressant, dependence producing, hypotensive and constipating side effects. It inhibits PG synthesis and is believed to relieve pain by a peripheral mechanism. In short lasting pain, it has compared favorably with aspirin. Platelet www.indiandentalacademy.com aggregation is inhibited for short periods.
  • 107. Pharmacokinetics Ketorolac is rapidly absorbed after oral and i.m. administration. It is highly plasma protein bound and 60% excreted unchanged in urine. Major metabolic pathway is glucuronidation; plasma t1/2 is 5-7 hours. www.indiandentalacademy.com
  • 108. Adverse effects Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in serumtransaminase and fluid retention have been noted. . No significant drug interactions have been reported and it has been used concurrently with morphine. However, it should not be given to patients on anticoagulants. Its safety in ulcer patients, in cardiac, renal and hepatic disease, children, elderly and pregnant women has not been established. www.indiandentalacademy.com
  • 109. Uses Ketorolac is frequently used in postoperative and acute musculoskeletal pain: 15-30 mg i.m. every 4-6 hours (max. 120 mg/day). It may also be used for renal colic, migraine and pain due to bony metastasis. Orally it is used in a dose of 10-20 mg 6 hourly for short term management of moderate pain. Continuous use for more than 5 days is not at present recommended. It should not be used for preanaesthetic analgesia medication or www.indiandentalacademy.com for obstetric
  • 110. SULFONANILIDE DERIVATIVE (Nimesulide ) Nimesulide- this newer NSAID is a relatively weak inhibitor of PG synthesis (may be somewhat selective for COX-2); appears to exert its effects by other mechanisms like reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and TNFα release, free radical scavanging, inhibition of metalloproteinase activity in cartilage. www.indiandentalacademy.com
  • 111. The analgesic, antipyretic and anti- inflammatory activity of nimesulide has been rated comparable to other NSAIDs. It has been used primarily for short lasting painful inflammatory conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, dysmenorrhoea; bursitis, low postoperative osteoarthritis. www.indiandentalacademy.com backache, pain and
  • 112. Pharmacokinetics Nimesulide is almost completely absorbed orally, 99% plasma protein bound, extensively metabolized and excreted mainly in urine with a t1/2 of 2-5 hours. www.indiandentalacademy.com
  • 113. Adverse effects of nimesulide are gastrointestinal (epigastralgia, heart burn, nausea, loose motions), dermatological (rash, pruritus) and central (dizziness). Claims of better gastric tolerability than other NSAIDs have not been substantiated. There is also no proof that renal complications associated with NSAID use are missing with nimesulide. However, most asthmatics and those who develop bronchospasm or intolerance to aspirin and other NSAIDs do not cross react with nimesulide. Its specific usefulness appears to be only in such patients. www.indiandentalacademy.com
  • 114. PARA-AMINO PHENOL DERIVATIVES (Paracetamol ) Phenacetin was introduced in 1887. It was extensively used but is now banned in many countries, including India, because it was implicated in analgesic abuse nephropathy. Paracetamol (acetaminophen) the deethylated active metabolite of phenacetin, was also introduced in the last century but has come into common use only since 1950. The central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold, but has www.indiandentalacademy.com weak peripheral
  • 115. Anti-inflammatory component. Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and promptly acting antipyretic. Paracetamol has negligible anti-inflammatory action. It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in brain. One explanation offered for the discrepancy between its analgesic-antipyretic and anti-inflammatory actions is its poor ability to inhibit COX in the presence of peroxides www.indiandentalacademy.com which are generated at sites of inflammation.
  • 116. Subjective effects: Phenacetin probably produces a sense of relaxation and well being in some people. In the early part of present century it was widely abused by factory workers in the industrializing Europe. It was claimed to reduce tension, fatigue and to increase work capacity: was considered habit forming, but dependence not though producing physical discontinuation did produce mild symptoms. Paracetamol has not www.indiandentalacademy.com shown such a pattern of abuse.
  • 117. In contrast to aspirin, paracetamol does not stimulate respiration or affect acid-base, nor increase cellular metabolism. It has no effect on CVS. Gastric irritation is insignificant -mucosal erosion and bleeding occur rarely only in overdose. It. does not affect function or clotting factors and is not uricosuric. www.indiandentalacademy.com
  • 118. Pharmacokinetics Paracetamol is well absorbed orally, only about 1/3 is protein bound in plasma and uniformly distributed in the body. It is conjugated with glucuronic acid and is excreted rapidly in urine. Plasma tl/2 is 2-3 hours. Effects after an oral dose last 35hrs. www.indiandentalacademy.com
  • 119. Adverse effects in isolated antipyretic doses paracetamol are safe and well tolerated. Nausea and rashes occur occasionally. Analgesic nephropathy occurs after years of heavy ingestion of analgesics; such individuals have some personality defect. It manifests as papillary necrosis, tubular atrophy followed by renal fibrosis. Urine concentrating ability is lost and the kidneys shrink. Because phenacetin was commonly abused, it was primarily implicated and has gone into disrepute, though other analgesics www.indiandentalacademy.com are also liable to produce similar effects.
  • 120. Paracetamol poisoning it occurs specially in small children who have low glucuronide conjugating ability. If a large dose (> 150 mg/kg or> 10 g in an adult) is taken serious toxicity can occur. Fatality is common with> 250 mg/kg. Early manifestations are just nausea, vomiting, abdominal pain and liver tenderness impairment of consciousness. After 12-18 hours centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycemia that may progress to coma. Jaundice starts after 2 days. Further course www.indiandentalacademy.com depends on the dose taken.
  • 121. Fulminating hepatic failure and death are likely if the plasma levels are above the line joining 200 µg/ml at 4 hours and 30 µg/ml at 15 hours. If the levels are lower-recovery with supportive treatment is the rule. www.indiandentalacademy.com
  • 122. Mechanism of toxicity N-acetyl-benzoquinoneimine is a highly reactive arylating minor metabolite of paracetamol which is detoxified by conjugation with glutathione. When a very large dose of paracetamol is taken, glucuronidation capacity is saturated, more of minor metabolite is formed- hepatic glutathione is depleted and this metabolite binds to proteins in liver cells (and renal tubules) causing necrosis. Toxicity thus shows a threshold effect manifesting only when glutathione is depleted to a critical point. In chronic alcoholics even 5-6 g/day taken for a few days can result in hepatotoxicity. www.indiandentalacademy.com
  • 123. Paracetamol is not recommended in premature infants (2 kg) for fear of hepatotoxicity. Treatment-If the patient is brought early, vomiting should be induced or gastric lavage done. Activated charcoal is given orally or through the tube to prevent further absorption. Other supportive measures, as needed, should be taken. www.indiandentalacademy.com
  • 124. N-acetylcysteine 150 mg/kg should be infused i.v. over 15 min, followed by the same dose i.v. over the next 20 hours. Alternatively, 75 mg/kg may be given orally every 4-6 hours for 2-3 days. It replenishes the glutathione stores of liver and prevents binding of the toxic metabolite to other cellular constituents. Ingestion-treatment interval is critical; earlier the better. It is practically ineffective if started 16 hours or more after paracetamol ingestion. www.indiandentalacademy.com
  • 125. Uses Paracetamol is one of the most commonly used over the counter' analgesic for headache, musculoskeletal pain, dysmenorrhoea etc. where anti-inflammatory action is not required. It is one of the best drugs to be used as antipyretic. Dose to dose it is equally efficacious as aspirin for noninflammatory conditions, It is much safer than aspirin in terms of gastric irritation, ulceration and bleeding (can be given to ulcer patients), does not prolong bleeding time. Hypersensitivity reactions are rare; no metabolic effects or acid-base disturbances; can be used in patients in whom aspirin is contraindicated. It does not have significant drug interactions. Thus, it may be www.indiandentalacademy.com preferred over aspirin for most minor conditions.
  • 126. BENZOXAZOCINE DERIVATIVE (Nefopam) Nefopam It is a recently introduced nonopioid analgesic which does, not inhibit PG synthesis. In traumatic and postoperative pain, it acts rapidly with an efficacy approaching morphine, yet has no opioid actions. Favorable results have been obtained in short lasting musculoskeletal pain not responding to other nonopioid analgesics. Nefopam produces anticholinergic (dry mouth, urinary retention, blurred vision and sympathomimetic (tachycardia, nervousness) side effects, and nausea is often dose www.indiandentalacademy.com Limiting. It is contraindicated in epileptics
  • 127. Celecoxib This selective COX-2 inhibitor has become available in India in 2000. It exerts potent antiinflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac, without affecting COX-I activity in gastroduodenal mucosa even at maximal therapeutic dose. Platelet aggregation in response to collagen exposure remained intact in www.indiandentalacademy.com celecoxib recipients.
  • 128. Though tolerability of celecoxib is better than older NSAIDs, still abdominal pain, dyspepsia and mild diarrhea are the most common side effects. Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized primarily by CYP 2C9 with mean t1/2 of 11 hrs. It is approved for use in osteo- and rheumatoid arthritis in a dose of 100-200 mg B D. www.indiandentalacademy.com
  • 129. Rofecoxib It is a COX-2 selective inhibitor. Rofecoxib has been found to be as effective as other NSAIDs in osteoarthritis, rheumatoid arthritis as well as in dysmenorrhoea, dental, postoperative and acute musculoskeletal pain at a dose of 12.5-25 mg once daily. Occurrence of peptic ulcer is rare and incidence of ulcer bleeds over 1 year of use has been found to be significantly lower than with other NSAIDs .Rofecoxib has no effect on TXA2 production by platelets. Side effects are www.indiandentalacademy.com mild g.i. complaints, headache and dizziness.
  • 130. Pedal edema and rise in BP occurs occasionally. Rofecoxib is well absorbed orally, 87% plasma protein bound, extensively metabolized and has an average t1/2 of 17 hours. It should be avoided in presence of severe hepatic/renal disease and in those receiving rifampin, warfarin, methotrexate. www.indiandentalacademy.com
  • 131. Valdecoxib Recently marketed selective COX-2 inhibitor having similar efficacy and tolerability profile as Rofecoxib. The plasma t1/2 is 8-11 hours. In osteoarthritis and rheumatoid arthritis it is recommended in a dose of 10 mg once daily, while for primary dysmenorrhoea or postoperative pain upto 20 mg twIce daily may be used. www.indiandentalacademy.com
  • 132. Name Available as Dose / Frequency Salicylates (Aspirin) 300, 350 mg tab 300-350 mg t.i.d Ibuprofen (Brufen) 200, 400mg tab 400-600mg t.i.d Naproxen (Naprosyn) 250mg tab 250-500mg b.i.d Diclofenac (voveran) 50mg tab 50mg b.i.d Piroxicam (pirox) 10-20mg capsules 10-20mg o.d Paracetamol (Crocin) 300, 500mg 300-500mg t.i.d Indomethacin (Indocid) 25mg 25-50mg t.id www.indiandentalacademy.com
  • 133. Choice of Nonsteroidal anti-inflammatory drug NSAIDs have their own spectrum of adverse effects. They differ quantitatively among themselves in producing different side effects and there are large inter-individual differences. At present NSAIDs is a bewildering array of strongly promoted drugs. No single drug is superior to all others for every patient. Choice of drug is www.indiandentalacademy.com inescapably empirical. .
  • 134. The nature of problem (acute/chronic; pain: inflammation ratio, severity) along with consideration of risk factors in an individual patient directs the initial selection. 1. Mild to moderate pain with little inflammation paracetamol or low dose ibuprofen. 2. Acute musculoskeletal, osteoarthritis, injury associated inflammation - a propionicacid derivative, diclofenac or piroxicam. 3. Postoperative or other acute but short lasting painful conditions with minimal inflammation www.indiandentalacademy.com ketorolac, nefopam.
  • 135. 4. Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheu-matic fever - high dose aspirin, indomethacin, naproxen, piroxicam. 5. Patients anaphylactoid with history reactions of to asthma or aspirin/other NSAIDs-nimesulide. 6. Combination of two or more NSAIDs is not superior to single agents. If at all used, combination therapy should be limited to short periods. www.indiandentalacademy.com
  • 136. The Propionic acid derivatives and other newer drugs - diclofenac, piroxicam are, in general, better tolerated. Due to risk of Reye's syndrome, aspirin should not be used in children without medical advice. During pregnancy lower dose of aspirin is probably the safest but it should be discontinued near term. The possibility of drug interactions should be considered in patients receiving prolonged therapy with other drugs (e.g. hypertensives, diabetics, ischemic heart disease patients etc . www.indiandentalacademy.com
  • 137. References – 1. Manual of dental therapeutics Raymond F. Zambite ,James J Sciubber (1993) 2.Medical Pharmacology Clark, Barter, John (1992) 3.Essentials of medical pharmacology K D Tripathi (1999) 4.Concise medical pharmacology Chaudhuri 5.Medical physiology Guyton Hall www.indiandentalacademy.com
  • 138. 6. Essential pathology for dental students Harsh Mohan 7.Pharmacology and pharmacotherapeutics R. S. Satoskar 8. Textbook of dental pharmacology and therapeutics John G Walton, John W. Thompson www.indiandentalacademy.com
  • 139. www.indiandentalacademy.com

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