nonsteroidal anti-inflammatory drugs (nsaids) / orthodontic courses by indian dental academy

Nonsteroidal Anti-Nonsteroidal Anti-inflammatory Drugs (NSAIDs)inflammatory Drugs (NSAIDs)

INDIAN DENTAL ACADEMY

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Synthesis of Prostaglandins

Cell membrane phospholipids #cortisol PLA

Arachidonic acid

#NSAIDs Cyclo-oxygenase

#zileuton (Cox-1 & Cox-2) Lipoxygenase

Endoperoxide

HPETEs

Thromboxane A2, PGs & PGI2 leukotrienes lipoxins#zaferlucast


Classification of NSAIDsClassification of NSAIDs SalicylatesSalicylates: aspirin, Na salicylates & : aspirin, Na salicylates & diflunisal.diflunisal.Propionic acid derivativesPropionic acid derivatives: ibuprofen, : ibuprofen, ketoprofen, naproxen.ketoprofen, naproxen.Aryl acetic acid derivativesAryl acetic acid derivatives: diclofenac, : diclofenac, ketorolacketorolacIndole derivativesIndole derivatives: indomethacin, sulindac: indomethacin, sulindac


AlkanonesAlkanones: Nabumetone.: Nabumetone.OxicamsOxicams: piroxicam, tenoxicam.: piroxicam, tenoxicam.Anthranilic acid derivatives (Anthranilic acid derivatives (fenamatesfenamates): ): mefenamic acid and flufenamic acid.mefenamic acid and flufenamic acid.Pyrazolone derivativesPyrazolone derivatives: phenylbutazone, : phenylbutazone, oxyphenbutazone, azapropazone oxyphenbutazone, azapropazone (apazone) & dipyrone (novalgine).(apazone) & dipyrone (novalgine).Aniline derivatives (analgesic only): Aniline derivatives (analgesic only): phenacetin & paracetamol.phenacetin & paracetamol.


SalicylatesSalicylatesAcetyl salicylic acid (Acetyl salicylic acid (aspirinaspirin).).Sodium salicylates.Sodium salicylates.Diflunisal (dolobid, difluorophenyl salicylate).Diflunisal (dolobid, difluorophenyl salicylate).

Acetyl salicylic acidAcetyl salicylic acid ( (aspirinaspirin).).Kinetics:Kinetics:

Well absorbed from the stomach, but better from the upper small Well absorbed from the stomach, but better from the upper small intestine (large surface area). Distributed allover the body, 50-80% intestine (large surface area). Distributed allover the body, 50-80% bound to plasma protein (albumin).bound to plasma protein (albumin).Metabolized to acetic acid and salicylates (active metabolite). Metabolized to acetic acid and salicylates (active metabolite). Salicylates is conjugated with Salicylates is conjugated with glucuronic acid and glycine.glucuronic acid and glycine.Excreted by the kidney. Excreted by the kidney. Alkalinization of the urine increases the rate of salicylates excretion.Alkalinization of the urine increases the rate of salicylates excretion.


Low dose of aspirin 0.6 gLow dose of aspirin 0.6 g is eliminated by is eliminated by 1st order kinetics1st order kinetics and its t 1/2 is and its t 1/2 is 3-5 h.3-5 h.

while high dose (more than 4 g/day)while high dose (more than 4 g/day) is is eliminated by eliminated by zero-order kineticszero-order kinetics and its t and its t 1/2 may increase up to 1/2 may increase up to 15 h.15 h.

Mechanism of action:Mechanism of action:Aspirin Aspirin irreversibly inhibitsirreversibly inhibits cyclo- cyclo-oxygenase enzyme, so blocks synthesis of oxygenase enzyme, so blocks synthesis of prostaglandins and thromboxane A2.prostaglandins and thromboxane A2.


Pharmacological effects of aspirin:Pharmacological effects of aspirin:Anti-infammatory effects:Anti-infammatory effects:

Inhibits Inhibits prostaglandin prostaglandin synthesis.synthesis.Blocks action of Blocks action of kinins kinins which are mediated which are mediated through prostaglandin synthesis.through prostaglandin synthesis.Inhibits Inhibits granulocytegranulocyte adherence to damaged adherence to damaged vasculature.vasculature.Stabilizes Stabilizes lysosomes.lysosomes.Inhibits migration of Inhibits migration of PMN leukocytesPMN leukocytes & & macrophages into the site of inflammation.macrophages into the site of inflammation.


Analgesic effects:Analgesic effects:CentrallyCentrally:: it inhibits prostaglandin synthesis, so it inhibits prostaglandin synthesis, so

increasing increasing pain thresholdpain threshold in the thalamus. in the thalamus.PeripherallyPeripherally:: inhibits prostaglandin synthesis, so inhibits prostaglandin synthesis, so

inhibiting inhibiting inflammationinflammation and diminishes activation and diminishes activation of peripheral pain sensors.of peripheral pain sensors.Aspirin alleviates Aspirin alleviates mild to moderate painmild to moderate pain of of muscular and dental origin, postpartum states, muscular and dental origin, postpartum states, arthritis & bursitis.arthritis & bursitis.


Antipyretic effect:Antipyretic effect:It inhibits prostaglandin synthesis in the CNS It inhibits prostaglandin synthesis in the CNS Resetting of temperature control in the Resetting of temperature control in the hypothalamus.hypothalamus.VD of the superficial BV, so increasing heat VD of the superficial BV, so increasing heat dissipation & sweating.dissipation & sweating.

NBNB: aspirin lowers elevated temperature while : aspirin lowers elevated temperature while normal body temperature is only slightly normal body temperature is only slightly affectedaffected..


Platelet effect:Platelet effect:Aspirin in small dose (75-100 mg /day) Aspirin in small dose (75-100 mg /day) irreversibly inhibits thromboxane A2 synthesisirreversibly inhibits thromboxane A2 synthesis in in the platelets the platelets without affecting prostacyclinwithout affecting prostacyclin synthesis in the vascular endothelium. synthesis in the vascular endothelium.

Aspirin must be stopped one week prior to Aspirin must be stopped one week prior to surgery if potential bleeding complications are a surgery if potential bleeding complications are a concern.concern.

Aspirin hasAspirin has longer duration longer duration as antiplatelet thanas antiplatelet than ticlopidine, dipyridamole and phenylbutazone.ticlopidine, dipyridamole and phenylbutazone.


Uses:Uses:Antipyretic (0.5-2 g / day).Antipyretic (0.5-2 g / day).Analgesic for mild to moderate superficial pain Analgesic for mild to moderate superficial pain (headache, arthritis, toothache, myalgia) 0.5-2 g/day.(headache, arthritis, toothache, myalgia) 0.5-2 g/day.Acute rheumatic fever (6-12 g/ day).Acute rheumatic fever (6-12 g/ day).Rheumatoid arthritis (6-8 g / day).Rheumatoid arthritis (6-8 g / day).Prophylaxis in thromboembolic diseases e.g. transient Prophylaxis in thromboembolic diseases e.g. transient ischemic attack, unstable angina, & MI (75-100 mg / ischemic attack, unstable angina, & MI (75-100 mg / day).day).Other uses under investigation e.g. aspirin may reduce Other uses under investigation e.g. aspirin may reduce cataract formation and the incidence of cancer colon.cataract formation and the incidence of cancer colon.


A/E:A/E:GIT upsetGIT upset: nausea, vomiting, gastritis, ulceration & : nausea, vomiting, gastritis, ulceration & bleeding (prevented by misoprostol).bleeding (prevented by misoprostol).HypersensitivityHypersensitivity:: bronchial asthma, angioedema & bronchial asthma, angioedema & rashes.rashes.IdiosyncracyIdiosyncracy:: aspirin causes hemolytic anemia in aspirin causes hemolytic anemia in patient with G-6-PD deficiency.patient with G-6-PD deficiency.HypoprothrombinemiaHypoprothrombinemia and bleeding tendency as and bleeding tendency as aspirin competes with vitamin K, so decreasing aspirin competes with vitamin K, so decreasing prothrombin synthesis.prothrombin synthesis.Salicylism:Salicylism: aspirin in large doses for long time therapy aspirin in large doses for long time therapy causes headache, tinnitus, hearing difficulty, blurring of causes headache, tinnitus, hearing difficulty, blurring of vision, GIT upset, irritability & hyperventilation (these vision, GIT upset, irritability & hyperventilation (these symptoms disappear on stopping aspirin).symptoms disappear on stopping aspirin).


At low toxic doseAt low toxic dose: aspirin produces : aspirin produces respiratory alkalosis followed by acidosis respiratory alkalosis followed by acidosis TeratogenicityTeratogenicity Nephropathy.Nephropathy.Reye's syndromeReye's syndrome : aspirin in children with : aspirin in children with viral infection may cause viral infection may cause liver injury and liver injury and encephalopathy.encephalopathy.


Acute aspirin poisoning:Acute aspirin poisoning:Restlessness, tremors, convulsion, vomiting, Restlessness, tremors, convulsion, vomiting, dehydration, hypotension, hyperventilation, dehydration, hypotension, hyperventilation, hyperreflexia, hyperpyrexia & coma.hyperreflexia, hyperpyrexia & coma.

Treatment:Treatment:Activated charcoalActivated charcoal 50g p.o to adsorb salicylates and 50g p.o to adsorb salicylates and prevents its absorption. prevents its absorption. Alkalinization of urineAlkalinization of urine (to enhance excretion) by i.v Na (to enhance excretion) by i.v Na HCO3 which also corrects acidosis.HCO3 which also corrects acidosis.AnticonvulsantAnticonvulsant e.g. i.v diazepam. e.g. i.v diazepam.Cold fomentationCold fomentation and ice bags. and ice bags.Correct dehydration by i.v Correct dehydration by i.v fluids (5% dextrose).fluids (5% dextrose).Correct Correct acid / base balanceacid / base balance (alkalosis or mixed (alkalosis or mixed alkalosis/acidosis need no specific treatment).alkalosis/acidosis need no specific treatment).Correct hypoprothrombinemia by i.v Correct hypoprothrombinemia by i.v vitamin K.vitamin K.HemodialysisHemodialysis may be needed. may be needed.www.indiandentalacademy.comwww.indiandentalacademy.com

Contraindications:Contraindications:Peptic ulcer, esophageal varices, Peptic ulcer, esophageal varices, bronchial asthma, idiosyncrasy, allergy, bronchial asthma, idiosyncrasy, allergy, viral infection in children, bleeding viral infection in children, bleeding tendency and small dose in gout tendency and small dose in gout (competes with uric acid excretion).(competes with uric acid excretion).


Interactions:Interactions:Alcohol increases aspirin-induced GIT bleeding.Alcohol increases aspirin-induced GIT bleeding.

Aspirin displaces oral anticoagulants and oral Aspirin displaces oral anticoagulants and oral hypoglycemics from their plasma protein binding sites, hypoglycemics from their plasma protein binding sites, so increasing their activities and may lead to toxicity.so increasing their activities and may lead to toxicity.

Aspirin inhibits the uricosuric effects of Aspirin inhibits the uricosuric effects of sulphinpyrazone sulphinpyrazone and probenecid.and probenecid.

BarbituratesBarbiturates increase the analgesic effect of aspirin. increase the analgesic effect of aspirin.

NBNB: : DiflunisalDiflunisal (difluorophenyl salicylate): it has analgesic (difluorophenyl salicylate): it has analgesic and anti-inflammatory effects like aspirin, but has and anti-inflammatory effects like aspirin, but has no no antipyretic action.antipyretic action.


Locally acting salicylatesLocally acting salicylatesSalicylic acidSalicylic acid: keratolytic, antiseptic & fungistatic.: keratolytic, antiseptic & fungistatic.Methyl salicylateMethyl salicylate (wintergreen oil): used as (wintergreen oil): used as counterirritant for muscle and joint pain. counterirritant for muscle and joint pain. SulfasalazineSulfasalazine : it is a combination of : it is a combination of sulfapyridine and 5-aminosalicylic acid (5-ASA). sulfapyridine and 5-aminosalicylic acid (5-ASA). Sulfasalazine liberates Sulfasalazine liberates 5-ASA5-ASA in the colon where in the colon where it it blocks the synthesis of leukotriene B4 locally blocks the synthesis of leukotriene B4 locally and used in ulcerative colitis. and used in ulcerative colitis.


Nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (NSAIDs(NSAIDs))

DrugDrugCommon Common UsesUses

A/EA/EContraindicContraindicationsations

PhenylbutazonePhenylbutazoneIbuprofenIbuprofenNaproxen Naproxen KetoprofenKetoprofenIndomethacinIndomethacinSulindacSulindacMefenamic acidMefenamic acidDiclofenacDiclofenacPiroxicamPiroxicamMeloxicamMeloxicam

Acute gout Acute gout DysmenorrheDysmenorrhe

a a AntirheumaticAntirheumaticOsteoarthritisOsteoarthritisRheumatoid Rheumatoid

arthritisarthritis

GastritisGastritisNephropathyNephropathySalt &water Salt &water

retentionretentionHypertensionHypertensionBronchospasmBronchospasmBleedingBleeding

Peptic ulcerPeptic ulcerPregnancyPregnancyRenal & Renal &

liver failureliver failure


Non-acidic NSAIDsNon-acidic NSAIDsSelective COX-2 inhibitors.Selective COX-2 inhibitors. are not concentrated in the gastric mucosa.are not concentrated in the gastric mucosa. and are less likely to produce peptic ulcersand are less likely to produce peptic ulcers

Examples:Examples:NabumetoneNabumetone: it is a pro-drug, changed in the body to its : it is a pro-drug, changed in the body to its active metabolite. It is relatively selective active metabolite. It is relatively selective COX-2 COX-2 inhibitor.inhibitor.Meloxicam, rofecoxib & celecoxibMeloxicam, rofecoxib & celecoxib are selective COX-2 are selective COX-2 inhibitors.inhibitors.Rofecoxib and celecoxib may cause Rofecoxib and celecoxib may cause cardiac toxicity cardiac toxicity (myocarditis). (myocarditis).


Acetaminophen (paracetamol)Acetaminophen (paracetamol)..

It is only analgesic and antipyretic,It is only analgesic and antipyretic, it has no anti-inflammatory effect as it acts it has no anti-inflammatory effect as it acts centrally only.centrally only.It doesn’t cause gastritis.It doesn’t cause gastritis.It doesn’t cause bronchial asthma.It doesn’t cause bronchial asthma.


KineticsKinetics: : Well absorbed orally and rectally, Well absorbed orally and rectally, Conjugated with glucuronic acid and Conjugated with glucuronic acid and sulforic acid sulforic acid Excreted in urine. Excreted in urine.


DynamicsDynamics: inhibits PG synthesis in the CNS : inhibits PG synthesis in the CNS only.only.

UsesUses: analgesic, antipyretic especially in : analgesic, antipyretic especially in children and those who cannot tolerate children and those who cannot tolerate aspirin e.g. patients with bronchial asthma, aspirin e.g. patients with bronchial asthma, peptic ulcer or gout.peptic ulcer or gout.

A/E:A/E: Rashes, blood dyscrasias Rashes, blood dyscrasias


Toxicity of paracetamolToxicity of paracetamol

Large toxic dose causes liver cell Large toxic dose causes liver cell necrosis. necrosis.

Treated by: Treated by: N-acetylcysteine and methioneine which N-acetylcysteine and methioneine which supply the supply the S-H S-H group necessary to group necessary to detoxify the toxic metabolites.detoxify the toxic metabolites.


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