Analgesic.pptx

Analgesic BY DR. SHIVARAJ W

1. ANALGESICS Prof. Dr.Shivaraj.S.Wagdargi . Navodaya Dental College , Raichur Dept of OMFS

2. CONTENTS INTRODUCTION CLASSIFICATION NSAIDS History Mechanism of action Classification OPIOIDS History Introduction Classification Opioid receptor Opioid receptor mechanism REFERENCES

3. INTRODUCTION Greek : Pharmacon -drug , logy –study Drug - french word DROUGE – a dry herb PAIN ( IASP) –”An unpleasant sensory and emotional experience with actual or potential tissue damage or described in terms of such damage” 1964– Harold Merskey & published in IASP in 1979

4. ANALGESIC Narcotic Non – narcotic morphine like Antipyretic Aspirin like NSAIDs OPIOD ANALGESIC NON OPIOID ANALGESIC The word  analgesia   is derived from Greek word analgetos  (an – without ; algesia – pain ) “It is a drug that selectively relieves pain by acting in CNS or on peripheral pain mechanism without significantly altering consciousness” Analgesic relieve pain as a symptom without affecting its cause CLASSIFICATION

5. CLASSIFICATION

6. Non selective COX inhibitors (conventional NSAID’s) Salicylates : Asprin Propionic acid derivatives : Ibuprofen, Naproxen, Ketoprofen , Flurbiprofen Anthranilic acid derivative : Mephenamic acid Aryl-acetic acid derivatives : Diclofenac Oxicam derivatives : Piroxicam , Tenoxicam Pyrrolo-pyrrole derivative : Ketorolac Indole derivative : Indomethacin Pyrazolone derivatives : Phenylbutazone , Oxyphenbutazone

7. Preferential COX-2 inhibitors Nimesulide , Meloxicam , Nabumetone Selective COX-2 inhibitors Celecoxib , Rofecoxib , Valdecoxib , Etoricoxib Analgesics-antipyretics with poor anti inflammatory action Para aminophenol derivative : Parcetamol (Acetaminophen) Pyrazolone derivatives : Metamizol ( Dipyrone ), Propiphenazone Benzoxazocine derivative : Nefopam

8. ACTIONS OF NSAIDs BENEFICIAL ACTIONS ADVERSE EFFECTS Analgesia Anti pyresis Anti inflammatory Anti thrombotic Dysmenorrhoea Ductus arteriosus closure Gastrointestinal 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) CNS Headache, mental confusion, behavioural disturbances, seizure precipitation Haematological Bleeding, thrombocytopenia, hemolytic anaemia, Other s Asthma exacerbation, nasal polypos is, skin rashes, pruriti s, angio ed ema

9. NON SELECTIVE COX INHIBITOR I . SALICYLATES Aspirin is acetylsalicylic acid PHARMACOLOGICAL ACTIONS Analgesic – obtunding of peripheral pain receptors and prevention of PG mediated sensitization of nerves Antipyretic – resets the hypothalamic thermostat and reduces fever Anti inflammation – cox inhibition ASPIRIN

10. Metabollic effects Cellular metaboism is increased –increased heat production –increased utilization of glucose – blood sugar may decrease GIT Causes gastric irritation Blood Irreversibly inhibits TXA2 synthesis and interferes with platelet aggregation CVS Decreases incidence of transient ischemic attacks, coronary artery thrombosis with MI, thrombosis after coronary artery bypass graft

11. PHARMACOKINETICS Aspirin is absorbed -stomach and small intestine Aspirin - deacetylated -gut wall , liver ,plasma and other tissues –salicylic acid – major circulating and active form

12. USES

13. ADVERSE EFFECTS

14. Fatal dose in adults – 15-30 g Serum salicylate >50mg/dl Treatment – Gastric lavage Administration of activated charcoal which adsorbs aspirin in GIT i.v fluids containing dextrose sych as D5W are recommended to keep urinary output between 2&3ml/kg/hour Sodium bicarbonate –enhances elimination of aspirin in urine Hemodialysis –removal of salicylate from blood usually in those who are severely poisoned ACUTE SALICYLATE POISONING

15. Gastritis, peptic ulcer Chronic liver disease Asthma - bronchospasm Diabetes -hypoglycemia Kidney disease, hyperuricemia or gout –inhibits kidneys ability to excrete uric acid Hemophilia or other bleeding tendencies Children suffering from chicken pox or influenza .risk of Reye syndrome (Australian pathologist R.D.K.Reye 1963 & G.M.Johnson in US ) – fever , convulsions,vomitting,disturbed respiratory rhythm,altered muscle tone ,liver damage CONTRAINDICATIONS

16. Pregnancy – premature closure of ductus arteriosus Glucose -6-phosphate dehydrogenase deficiency – hemolytic anemia ASPIRIN – 350 mg tab BABY ASPIRIN -81 mg COLSPRIN – 100, 325 , 650 mg tab DISPRIN – 350 mg tab ECOSPRIN - 75 , 150 ,325 mg tab LOPRIN – 75, 162.5 mg tab Minor dentoalveolar surgical procedures can be carried out safely without interrupting antithrombotic therapy if dosage is <325mg INR <3.5 . Although aspirin may increase bleeding risk which can be controlled by local hemostasis , pressure , suturing The risk of fatal outcome is generally higher if treatment is stopped

17. II. PROPIONIC ACID DERIVATIVES Stewart Sanders Adams(1923-2019) –British chemist -1961 & initially marketed as Brufen Isobutylphenylpropionic acid IBUPROFEN BIOAVAILABILITY 80-1005%(mouth ) 87% (rectal) HALF LIFE 2-4 hours METABOLISM Liver METABOLITES Ibuprofen glucuronide , 2-hydroxyibuprofen EXCRETION Urine (95% )

18. USES ADVERSE EFFECTS Analgesic , antipyretic RA , OA ,Musculoskeletal disorders Dental pain ,headaches , Pain from kidney stones Soft tissue injuries,fractures Closure of ductus arteriosus Nausea ,diarrhea , constipation ,gastric discomfort , CNS – dizziness, tinnitus CVS – risk of hypertension and MI ,heart failure Increases-risk-kidney &liver failure Can worsen asthma- bronchospasm Alcohol -stomach bleeding Interfere with antiplatelet effect of low dose aspirin –less effective Drug t1/2 Dosage Preparations Ibuprofen 2hr 400-600mg (5-10mg/kg) TDS BRUFEN,EMFLAM-200,400,600 mg tab Naproxen 12-16hr 250 mg BD NAPROSYN,NAXID – 250 mg tab Ketoprofen 2-3hr 50-100mg BD-TDS KETOFEN 50,100 mg tab OSTOFEN -50 mg cap

19. III . ANTHRANILIC ACID DERIVATIVE (FENAMATE) Claude Winder -1960s Di me thyl phe nyl am inobenzo ic acid MEFENAMIC ACID PHARMACOKINETICS Bioavailability – 90% Protein binding – 90% Metabolism – hepatic Half life -2 hours Excretion –urine (66%) faeces (20%) USES Analgesic Antipyretic Dysmenorrhoea Muscle, join and soft tissue pain Migraine ADVERSE EFFECTS Diarrhoea Epigastric ditress Hemolytic anemia Nausea , hematemesis Hematuria Rash,itching Associated –liver damage DOSE – 250 -500 mg TDS MEDOL -250 ,500 mg cap ; MEFTAL – 250,500 mg tab

20. IV . ARYL –ACETIC ACID DERIVATIVE Pharmacokinetics analog Well absorbed orally similar properties Metabolism –liver Half life -1.2 – 2hr (35% - enterohepatic recirculation) Excreted urine -60%and bile -40% Uses Toothache Post operative and post traumatic inflammatory conditions Rheumatoid arthritis and osteoarthrit is Contraindications Hypersenstivity,git bleeding,3 rd trimester pregnancy DICLOFENAC SODIUM DOSE -50 mg TID -VOVERAN ,DICLONAC ; movonac-25mg/ml in 3ml amp. i.m . DICLOMAX- 25, 50 mg tab , 75 mg /3ml inj ; VOVERAN –1% topical gel ACECLOFEANC DOSE – 100 mg BD ACECLO, ZERODOL- 100-200 mg sr tab

21. V . OXICAM DERIVATIVES PIROXICAM PHARMACOKINETICS Completely absorbed Metabolised in liver Excreted in urine ,bile Palsmat1/2 – nearly 2 days (50 hours ) USES Analgesic Long term antiinflammatory in RA ,OA Acute gout Ankylosing spondylitis ADVERSE EFFECTS Nausea, vomiting Dizziness , tinnitus Insomnia , high BP Rarely kidney failure pancreatitis ,liver damage Oedema , DOSE – 20 mg BD for 2 days followed by 20mg OD DOLONEX,PIROX -10 , 20mg cap,20 mg dispersible tab ,20 mg/ml inj in 1 ml amps

22. VI . PYRROLO –PYRROLE DERIVATIVE KETOROLAC Bioavailability -100% Metabolism – liver Half life – 3- 9 hours Excretion – 91% kidney ,bile – 6% USES Short term pain management , ADVERSE EFFECTS Not -5days-kidney damage Paresthesia ,dry mouth abnormal taste ,hypersensitivity ,stroke DOSE – 10 -20 mg orally 6 hrly 15-30 mg i.m – i.v 4-6 hrly

23. VII. INDOLE DERIVATIVE INDOMETHACIN Bioavailability – 100% oral ,80-90% rectal Metabolism – hepatic Half life –-11.2 hrs Excretion – renal -60%,fecal 33% USE S –RA , OA ,reduce amniotic fluid in polyhydraminosis ,headaches ADVERSE EFFECTS Edema , hyperkalemia,hypertension DOSE – 25 -50 mg BID- QID INDOFLAM – 25,75 mg caps ,1% eye drop

24. VIII . PYRAZOLONES METAMIZOLE Bioavailability – 100% Protein binding – 48-58% Metabolism – liver Half life -2-4 hrs Excretion –urine 96%,. USES – Perioperative pain , acute injury ,high fever ADVERSE EFFECTS Agranulocytosis , hypersensitivity Less kidney ,cardiovascular , git toicity DOSE 0.5-1.5 g oral / i.m / i.v Analgin – 0.5 g tab , ultragin – 0.5 g/ml inj 30 ml vial

25. PREFERENTIAL COX-2 INHIBITORS Inhibition –COX 2 -5-50 fold selectivity NIMESULIDE 100% absorbed, ,hepatic metabolism T1/2- 2-4hrs Renal(50%)fecal(29%) USES –short lasting pain,dysmmenorhea , patient with history of asthma and anaphylactic reactions to other NSAIDs. CONTRAINDICATION Liver problems, pregnancy, flu like symptoms,long -tem –arthritis-liver toxixity ADVERSE EFFECTS - GIT, rash,pruritis,dizziness DOSE -100mg BD NIMULID,NIMEGESIC- 100 mg tab

26. SELECTIVE COX 2 INHIBITORS >50 fold selectivity of COX2 inhibition Advantage – withou affecting COX1 –decrease gastric muosal damage DISADVANTAGE – COX2 inhibitors reduce PGI2 production ( vasodilators,anti -platelet) without affecting platelet TXA2 synthesis- excert prothrombotic influence & enhance cardiovascular risk Used – high risk of peptic ulcer ,perforation or bleeds,lowest dose for shortest period of time Contraidicated – pts with history of ischaemic heart disease/hypertension/cardiac failure

27. CELECOXIB Slowly absorbed, metabolised in liver ,t1/2- 9-11 hrs ,excreted in faeces (57%) ,urine (27%) USES – OA, RA, ADVERSE EFFECTS – mild diarrhoea , dyspepesia , rashes ,edema ,small rise in BP DOSE – 100-200 mg BD CELACT ,COLIBRA – 100,200 mg caps ETORICOXIB Highest COX 2 selectivity 100% bioavailability , metabolism is hepatic , t1/2 – 22 hours , excreted through renal (70%) Fecal (20%) USES – OA, RA, acute gouty arthritis , acute pain ADVERSE EFFECTS – dry mouth , aphthous ulcer , taste disturbances DOSE – 60-120 mg OD ETODY , ETOXIB – 60 , 90 , 120 mg tabs

28. WEAK INHIBITORS OF BOTH ISOFORMS PARA AMINO PHENOL DERIVATIVES Phenacetin -1887 –analgesic-antipyretic-banned –analgesic abused nephropathy Acetaminophen , de-ethylated active metabolite of phenacetin –common use in 1950s Well absorbed orally ,1/4 th is protein bound Metabolised in liver and rapidly excreted in urine Plasma t1/2 - 2-3 hours ,effects after an oral dose lasts for 3-5 hours PARACETAMOL

29. ACTIONS – Analgesic ,poor antiinflamatory , no increase in cellular mmetabolism , gastric irriation is insignificant ,not affect platelet function or clotting factor USES Headache , muskuloskeletal pain ,toothache , Used in all age groups ,pregnant/lactating women DOSE Adults – 0.5-1g TDS Infants – 50mg Children – 80-160 mg ,1-3 years 240-320 mg , 4-8 years 300 – 600 mg , 9-12 years Crocin –0.5 ,1g tab , metacin , paracin – 125 mg /5ml syrup Fevastin -300mg /2 ml inj .

30. ADVERS EFFECTS Nausea,rashes occasionally occur ACUTE PARACETAMOL POISONING Larger dose >150mg/kg or >10g in aduts Fatal - > 250 mg/kg

31. N- acetylcysteine infused i.v is specific antidote .it replenishes hepatic glutathione & prevents binding of toxic metabolite .it is given as a continuous infusion over 20 hours for a total dose 300mg/kg Infusion of 150mg/kg over 15-60 min , - 50mg/kg -4 hours , last 100mg/kg -16 hours < 1 hour 1-8 hours >8 hours Gastric lavage Activated charcoal Measure serum paracetamol levels <30 mg/l Commence NAC Infusion

32. HISTORY Galen -2 nd –tincture of opium 16 th –manuscripts can be found describing drug abuse in egypt ,Germany & England 1806-Serturner isolated active ingredient in opium MORPHINE- god of dreams morpheus 1850s – minor surgical procedure,chronic pain & adjunct to GA 1898- Heroin was synthesized 1939-meperidine ,first opiate with structure diff from that of morphine 1942 – Weijlard & Erikson produced nalorphine ,first opiate antagonist which led to discovery of nalaxone 1973 – Pert & Synder ,Simon et al& Terenius succeded almost simultaneously in showing that there are opiate binding sites in CNS OPIOID ANALGESICS

33. INTRODUCTION OPIOD ANALGESICS are derived from OPIUM OPIUM : dark brown resinous material obtained from poppy ( Papaver Somniferum )capsule CLASSIFICATION NATURAL OPIUM ALKALOIDS SEMI -SYNTHETIC OPIATES SYNTHETIC OPIOIDS Morphine Codeine Diacetylmorphine(heroin) Pholcodeine Pethidine ( meperidine ) Fentanyl Methadone tramadol

34. I . NATURAL OPIUM ALKALOIDS Pharmacological actions CNS Analgesia- Strong analgesic Nociceptive pain arising from peripheral pain receptor is inhibited Intrathecal injection cause segmental analgesia by acting on substantia gelatinosa of dorsal horn to inhibit release of neurotransmitters. Sedation Drowsiness and indifference to surroundings as well as to own body , ataxia and apparent excitement also occur Higher doses produce sleep and coma Mood and subjective changes Calming effect , Euphoria Loss of apprehension, feeling of detachment, mental clouding and inability to concentrate MORPHINE

35. Respiratory and cough centres Depresses Respiration and Cough centre Temperature regulating Depressed Edinger westphal nucleus IIInerve - miosis GIT Constipation is a prominent feature Neuro -endocrine Causes sympathetic stimulation – mild hyperglycemia Chronic abusers - infertility CVS Causes vasodilation Cardiac work is consistently reduced due to decrease in peripheral resistance

36. PHARMACOKINETICS USES ADVERSE EFFECTS Bioavailability 20-40% -mouth 70%-rectally , 100% i.v,i.m 30% -plasma protein bound Small fraction-brain-slowly ; crosses placenta Metabolized – liver 90 Morphine-6-glucuronide Plasma t1/2- 2-3 hours Effect – 4-6 hours Excretion – renal 90%, biliary 10% Pain due to MI , labour Cancer pain ,beneficial in reducing the symptom of shortness of breath due to both cancer & non cancer 9663 Itch , nausea,vomiting Constipation ,drowsiness ,dry mouth , dizzinness Loss of appetite Depression Slow breathing Sedation Mental clouding Lethargy Opioid dependence DOSE – 10-50mg oral 10-15 mg i.m . 2-6 mg i.v . Children – 0.1-0.2mg/kg

37. Tolerance and dependence Partly pharmacokinetic (enhanced rate of metabolism) but mainly pharmacodynamic (cellular tolerance) Treated by substitution with oral methadone Precautions and contraindications Infants and elderly-more susceptible to respiratory depression Bronchial asthma-morphine can precipitate attack by hitamine release Head injury-intracranial tension - retention of CO2 Hpothyroidism,liver and kidney dseases patients are mor sensitive to morphine ACUTE MORPHINE POISONING Human lethal dose is 250mg . Death is due to respiratory failure Treatment : respiratory support and maintain BP Gastric lavage with KMnO4- to remove unabsorbed drug ANTIDOTE – NALOXONE 0.4-0.8mg i.v repeated every 2-3 mins till respiration picks up

38. PHARMACOKINETICS USES ADVERSE EFFECTS Bioavailability –oral -90% Metabolism – liver Metabolites – morphine norcodeine T1/2 - 2.5- 3 hrs Duration of action 4-6 hrs Mild to moderate pain Relieve coughing Diarrhea Drowsiness ,constipation , itching ,nausea , vomitting ,dry mouth ,urinary retention , respiratory depression CODEINE DOSE: 30-60mg tab Codein QID

39. II . SEMI SYNTHETIC OPIATES PHOLCODEINE Codeine like properties Used mainly as antitussive,less constipating HEROIN 3 times more potent than morphine Considered to be more euphorient & highly addicting Enters brain more rapidly Banned in most of the countries

40. III . SYNTHETIC OPIOIDS PETHIDINE METHADONE Bioavailability –oral (50-80%) Protein binding – 65-75% Metabolism – liver T1/2- 2.5-4 hrs Liver disease -7-11 hours Excretion – renal Bioavailability – 15-20% s.c 41-99% mouth Protein binding – 85-90% Metabolised – liver T1/2 -15 -55 hrs Excretion – renal ,fecal USES – Diverticulitis as it decreases intraluminal pressure , Cause less histamine release & safe in asthamatics NO miosis USES – Substitution therapy of opioid dependence – 1mg oral methadone can be substituted for 4mg morphine , 20mg pethidine ADVERSE EFFECTS – dizziness ,vomiting ,overdose – respiratory depression , ADVERSE EFFECTS – constricted pupil ,dry mouth , nausea ,vomiting DOSE – 50-100 mg PETHIDINE HCL -50,100 mg tab 100mg/2ml inj DOSE – 2.5 mg oral / i.m PHYSEPTONE 10mg inj

41. Bioavailability – 92% transdermal 89% intranasal 50% buccal 33% ingestion 100% intramuscular Protein binding – 80-85% Metabolism – liver Onset of action – 5 minutes Elimination half life – i.v . -1hr-16hr transdermal – 20-27 hr buccal/sublingual -2.6-13hrs Excretion – urine FENTANYL ADVERSE EFFECTS Diarrhea, nausea,constipation ,dry mouth , Shortness of breath Patches –delayed respiratory depression Overdose leading to death Lethal dose for a avr person is estimated to be 2mg

42. USES Along with hypnotic to produce sedation during procedures like endoscopy,oral surgery Given intrathecally as a part of spinal anesthesia Widely used in obstetrical anesthesia because of its short time to action peak Fentanyl transdermal patches are used in chronic pain management which work slowly releasing fentanyl through skin into bloodstream over 48-72 hrs People with moderate to severe kidney failure In children intranasal fentanyl is useful for the treatment of moderate and severe pain & is well tolerated Fentanyl lozenges are a solid formulation of fentanyl citrate on a stick in a form of lolipop that dissolves slowly in mouth for transmucosal absorption

43. PHARMACOKINETIC USES ADVERSE EFFECTS Bioavailability 70-75%oral Metabolised in liver T1/2 – 6-7hrs Excretion urine Onset of action -1hr Mild to severe pain 1/10 th potency of morphine Injected i.v . 100mg tramadol is equianalgesic to 10mg i.m .morphine Nausea,dizziness , constipation,respiratory depression TRAMADOL DOSE 50-100 mg oral/ i.m ./ i.v Children 1-2mg /kg 4-6 hourly CONTRAMAL,DOMADL, 50 mg cap, 100 mg SR tab 50mg /ml inj in 1 & 2 ml amps.

44. Opioids interact with specific receptors present on neurons in the CNS and peripheral tissues Radioligand binding studies divide receptors into mu, kappa and delta Pattern of effect of particular agent depends on the nature of its interaction with different opioid receptors and also its relative affinity to these receptors OPIOID RECEPTORS

45. OPIOID RECEPTOR MECHANISM

46. Complex action opioids and opioid antagonists Agonist- antagonist Nalorphine Pentazocaine Butorphanol Partial /weak agonist Buprenorphine Pure antagonist Naloxone , naltrexone

47. Pentazocaine Indicated in post operative and moderately severe pain in trauma, cancer and burns, Mu agonist is weak while k agonist is marked 50-100mg oral dose , 30-60 mg i.m , s.c plasma t2/2 -3-4 hrs ,duration of action 4-6 hrs , Naloxone Competitive antagonist for all opioid receptors It blocks mu receptors at much lower doses Injected i.v (0.4- 0.8mg) it antagonizes all actions of morphine Drug of choice in morphine poisoning

48. REFERENCES Basic and clinical pharmacology -11 th edition –Lange Essentials of medical pharmacology – 7 th edition K.D. Tripathi Essentials of pharmacology for dentistry -2 nd edition K.D.Tripathi

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