ANALGESICS & antiinflammatory.pptx for cos

Orthopaedic

1. ANALGESICS & ANTIINFLAMMATORY

2. Introduction- definition of terms Analgesics- a drug that selectively relieves pain by acting in CNS or on peripheral pain mechanism, without significantly altering consciousness Anaesthesia - means loss of sensation. Anaesthetic agent is one which brings about loss of all modalities of sensation, particularly pain, along with a reversible loss of consciousness Pain ( algesia )- an unpleasant sensory and emotional experience associated with actual or potential tissue damage Pain is a protective mechanism to warn of damage or presence of a disease. On basis of onset and duration, pain can be classified into two: acute: sudden in onset, usually subsides once treated chronic: persistent/ continually; or recurring and often difficult to treat.

3. OPIOID ANALGESICS Were once called narcotic drugs because of their action in the brain and can induce sleep Narcotics/morphine like analgesics are included in this category Narcotics- drugs derived from opium or opium like compounds with potent analgesic effects associated with significant alteration of mood and behavior, with the potential of dependence and tolerance following repeated administration Obtained from ‘poppy’ papaver somniferous capsule called opium Used for either short or long term relief of moderate to severe pain Opioids interact with protein receptors on the membranes of certain cells in CNS, nerve terminals, GIT & other anatomical regions Subclasses: Natural opium alkaloids- morphine, codeine (common, less addictive, similar to morphine except their chemical structure) , methadone, hydromorphone Semi synthetic opioids- diacetylmorphine, oxymorphone , pholcodeine Synthetic opioids- pethidine, methadone, fentanyl, dextropropoxyphene , tramadol, ethoheptazine

4. CLASSIFICATION

5. Opioid receptors Three main types of opioid receptors: mu (occur throughout CNS), delta (fewer), and kappa. Although they’re similar in some ways, they’re distributed differently throughout your body and can produce different effects . The receptors are part of your body’s endogenous opioid system, which deals with pain, reward, and addiction. They’re present on nerve cells, mainly in your central nervous system (CNS) and gut . Both endogenous & exogenous opioids can activate opioid receptors.

6. Mode of action of opioid analgesics Opioid agonists inhibit pain transmission by mimicking the body’s natural pain control mechanisms. Within the dorsal horn of the spinal cord, the peripheral pain neurons meet the central nervous system (CNS) neurons. At the synapse, the pain neurons release substance P (a pain neurotransmitter). This agent helps transfer pain impulses to the CNS neurons that carry those impulses to the brain. In theory, the spinal interneurons respond to stimulation from the descending neurons of the CNS by releasing endogenous opiates. These opiates bind to the peripheral pain neurons to inhibit release of substance P and to slow the transmission of pain impulses . Synthetic opiates supplement this pain blocking effect by binding with free opiate receptors to inhibit the release of substance P. Opiates also alter consciousness of pain, but how this mechanism works remains unknown.

7. Uses of opioid drugs Pain relief- moderate to severe pain eg post operative pain Low doses can be used in relief of respiratory distress esp. with pleural effusion Methadone, a synthetic opioid analgesic is used to moderate effect of withdrawal from heroin addiction Opiates vs. Opioids › Opiates: substances with active ingredients naturally derived from opium - Morphine , codeine, thebaine › Opioids: Synthetically manufactured substances that mimic the effects of opium

8. Commonly used opioids M orphine Naturally occurring opioid derived from the poppy straw of the opiate poppy Prototypical opioid, against which the potency of all other opioids are measured. Administration routes- IV, oral, buccal, sublingual, intranasal, subQ & intramuscular Oral administration: extensive first pass metabolism Primarily metabolized in the liver by glucuronidation Second phase of this metabolism yields two compounds Morphine-3-glucuronide (no analgesic qualities) Morphine-6-glucuronide (active metabolite) Potency 100x parent compound ↓ lipophilicity ; ↓ crossing of blood brain barrier (normal renal function) Decreased renal function at risk for accumulation →respiratory depression, sedation, potential coma Dose- 10-20mg

9. Fentanyl Most widely used synthetic opioid; potency 100x that of morphine Highly lipophilic & high membrane permeability → rapid onset/offset Routes: IV, epidural, intrathecal, transdermal, intranasal, other transmucosal Highly alpha-1-glycoprotein bound Increasingly common substance of abuse Unreliable purity and potency: analogues with up to 10,000x that of morphine Dose- 20 to 50 mcg/kg/dose IV Combined with heroin, other substances of abuse; frequently sold as oxycodone

10. Hydromorphone Hydrophilic, semi-synthetic (from morphine), hydrogenated ketone Potency approximately 5x greater than that of morphine Low oral bioavailability; Converting from IV to PO, dosage increased by approximately 4x Peak effect at 15-30 minutes when given intravenous; duration 2-3 hours Hepatic metabolism by phase 2 glucuronidation Dose- 2-4 mg q4-6hr PRN Accumulation associated with neuroexcitatory effects – Allodynia – Agitation, confusion, hallucination – Myoclonus, ataxia, tonic- clonic seizures

11. Oxycodone Semisynthetic opiate derived from the alkaloid compound thebaine Full μ receptor agonism ; partial κ and δ agonism 1.5x potency of morphine Oral solution, immediate release tablet, extended release tablet Frequently combined with acetaminophen Onset of action (IR formulation) 10-30 min; peak plasma at 30-60 min Oxymorphone ▪ Active metabolite ▪ Responsible for 10-15% of drug action In renal or hepatic dysfunction, may accumulate and cause a pronounced level of respiratory depression and sedation dose- 0.05 to 0.15 mg/kg q 4hrs

12. Codeine Opioid agonism primarily via active metabolite, morphine Convert codeine to morphine more rapidly and completely adverse effects- Somnolence , decreased arousability , disorientation, confusion, apnea , hypoxia Discouraged use in pediatrics by multiple organizations Dose- 15-60 mg PO q4-6hr PRN Dehydrocodeine - semi-synthetic opioid, similar to codeine in both its structure and its analgesic effect

13. Methadone Synthetic opioid first tested as a treatment for heroin addiction in 1964. also used for acute & chronic pain. Opioid weaning dependence , thought to mitigate hyperalgesia Mechanism-Full μ opioid agonism Highly lipophilic Excretion- Fecal excretion primarily (some renal) › Analgesic effect of 12-36 hours after single dose Steady state maximal effect ~ 5 days Oral bioavailability 65-95 % QTc prolongation → Torsades de Pointe › Monitor EKG › Treatment magnesium

14. Tramadol Atypical opioid of the benzoid class [Bozkurt] that is structurally related to codeine and morphine. Potency 10% that of morphine Multiple means of action Opioid agonism (primarily μ) Inhibition of serotonin and norepinephrine reuptake Serotonin 5-HT2C antagonism- mood Caries the risk of decreased seizure threshold , serotonin syndrome, dose related overdose and respiratory depression • Monoamine oxidase inhibitors and tricyclic antidepressants Oral dose- 100mg 20% protein binding Undergoes extensive first pass hepatic metabolism; explains the low bioavailability 75% Metabolized in the liver & excreted in urine and feaces Side effects- dizziness, somnolence, nausea, constipation, sweating and pruritus contraindicated in patients under 12 years old as “Serious risks, including slowed or difficulty breathing and death appear to be a greater risk in children younger than 12yrs

15. Opioid antagonist Commonly used naloxone and its longer acting orally active version, naltrexone, are used primarily to reverse the effects of morphine overdose and to reverse the chemical stupor of a wider variety of chemical causes eg alcohol intoxication & anaesthesia Naloxone is a fast-acting medication that reverses the effects of an opioid overdose inn emergency situation. Prevents binding at the opioid receptors. Dose- 4-8mg Naltrexone doesn't work in overdose situations. It's a once daily or once monthly medication that can treat alcohol use disorder or opioid use disorder . Dose- 25- 50mg per day

16. Side effects of opioid analgesics Chest pain Euphoria Vomiting Hypotension Hypothermia Somnolence- Sleep/ drowsiness Constipation Respiratory depression Abnormal heart beat Cardiac arrest Death

17. Opioid use in renal failure Typically Avoided: Codeine, Morphine and morphine-6-glucuronide active metabolites 1. Morphine- Metabolized to morphine-3-clucuronide (55%) and morphine-6-glucuronide (10%) and renally excreted M6G accumulation leads to respiratory depression, hypotension, narcolepsy 2. Hydrocodone- Metabolized to hydromorphone-3-glucuronide : potential for neuroexcitatory effects 3. Meperidine- Normeperidine active metabolite; accumulation decreased seizure threshold Used with Caution Oxycodone- Active metabolite oxymorphone ; plasma levels typically negligible Hydromorphone Typically Used › Fentanyl: metabolized by liver; lacks active metabolites › Sufentanil : metabolized by liver; lacks active metabolites. Decreased context sensitive half time. › Alfentanil : metabolized by liver; lacks active metabolites Methadone- Fecal and urinary excretion without active metabolite. Typically considered safe in renal disease

18. Opioids and substance abuse Potential for tolerance, acute desensitization, dependence and addiction Up to 25% of patients receiving opioid for non cancer pain experience struggle with addiction Approximately 75% of new heroin users misused prescription opioids prior to using heroin Preventive strategies: D ecreased opioid administration, give adjunctive medications for pain eg muscle relaxants for muscle spasm (baclofen), acetaminophen, NSAIDS Medication administration- decrease dose and frequency interval Patient education

19. NON- OPIOID ANALGESICS Are: NSAIDS (Non- Steroidal Anti-inflammatory Drugs) Non- NSAIDS eg paracetamol Non- opioid analgesics which alleviate pain by reducing local inflammatory responses. Are used for short term pain relief and for modest pain eg headache, bruising, muscle strain or arthritis

20. NON- OPIOID ANALGESICS (anti-inflammatory analgesics) Chemically diverse, but most are organic acids Have common analgesic, anti-inflammatory and antipyretic effects. Weaker analgesic than morphine (except inflammatory pain) Do not depress CNS, no physical dependence or abuse liability Primarily act on peripheral pain mechanism, also in CNS (raise pain threshold) Most common anti-inflammatory analgesics are derived from: Salicylic acid- aspirin Pyrazolone - no longer used due to its adverse effects (leukopenia) Phenacetin- acetaminophen

21. CLASSIFICATION OF NON- OPIOID ANALGESICS- NSAIDS Salicylates- salicylamide , aspirin, benorylate , diflunisal Pyrazolone derivatives- phenyl butazone , oxyphenyl - butazone Propionyl acid derivatives- ibuprofen, ketoprofen , naproxen, fenoprofen , oxaprozin , flurbiprofen Indole derivatives- indomethacin, sulindac Anthranilic acid derivatives- mephenamic acid Arryl - acetic acid derivatives- diclofenac, aceclofenac Pyrrolo - pyrrole derivative- ketorolac Pyrazolone derivative- phenylbutazone , oxyphenybutazone Oxicam derivatives- piroxicam , tenoxicam , lornoxicam 1. Non selective COX 1 & COX-2 inhibitors

22. Classification contd.. 2. preferential COX- 2 inhibitors: Nibesulide Meloxicam Nabumetone 3. Selective COX- 2 inhibitors Valdecoxib Celecoxib Rofecoxib Etoricoxib 3. A nalgesics with poor anti-inflammatory action: paraminophenol derivative- paracetamol (acetaminophen) Pyrazolone derivative- metamizol , propiphenazone Benzoxazocine derivatives- nefopam

23. Mechanism of action of NSAIDS Anti-inflammatory effect Inhibition of synthesis of prostaglandins (natural products of inflamed white blood cells) that induce the responses in local tissue that include pain and inflammation. Role of prostaglandins in inflammation: Promote & modulate development and regulate inflammatory cell function Can induce pain, edema, redness & vasodilation when they are induced by other mediators PGs also inhibit lysosomal enzyme release during phagocytosis, enhances chemotaxis & chemokinesis These agents are further divided into selective and non selective COX inhibitors COX (cyclooxygenase) – an enzyme responsible for the synthesis of prostaglandins and related compounds Has two forms: - COX-1- found in most normal tissues & acts in physiological processes. - COX-2- induced in the presence of inflammation by pathological stimulus not normally expressed in the stomach therefore use of these agents( celecoxib, refecoxib ) seem to result in less gastric ulceration than with other NSAIDS. However, COX-2 inhibitors do not reduce the ability to form clots, a benefit with aspirin and other non selective cox inhibitors Aspirin irreversibly inactivate COX-1 and COX-2 by acetylation which distinguishes from other NSAIDS which reversibly inhibit COX-1 and COX-2

24. Analgesic effect Thought to be related to peripheral inhibition of prostaglandin production Inhibition of pain stimuli at subcortical site NSAIDS also prevent the potentiating actions of prostaglandins on endogenous mediators of peripheral nerve stimulation ( eg bradykinin) Antipyretic effect Believed to be related to inhibition of production of prostaglandins induced by interleukin-1 & 6 in the hypothalamus and resetting the thermo-regulatory system thereby leading to vasodilation and increased heat loss

25. FUNCTIONS OF NSAIDS Analgesia- they do so by affecting the transducing properties of free nerve endings Antipyresis - fever reduction by blocking the action of pyrogens Antiinflamatory - due to inhibition of prostaglandin synthesis at the site of injury. They also act by inhibiting integrin, selectins, growth factor like GM- CSF, IL-6 & lymphocyte transformation factor Antiplatelet aggregation- by inhibiting synthesis of prostanoids Ductus arteriosus closure- when administered in late trimester of pregnancy has been found to cause premature closure of ductus arteriosus Delaying labor- by inhibition of prostaglandin synthesis

26. THERAPEUTIC USES Mainly in acute or chronic conditions where pain and inflammation are present Examples of orthopedic conditions include: Rheumatoid arthritis Osteoarthritis Inflammatory arthropathies (ankylosing spondylitis) Acute gout Mild to moderate pain due to inflammation and tissue injury Others: Dysmenorrhea Headache and migraine Post operative pain Renal colic Pyrexia

27. ADVERSE EFFECTS Analgesics doses are generally well tolerated but anti-inflammatory doses are associated with adverse effects when u sed for prolonged periods 1. GIT- epigastric pain, nausea, vomiting, gastric or peptic ulcer, occult blood in stool Allergic reactions Gastric mucosal damage is due to inhibition of COX-1 mediated gastro-protective prostaglandins synthesis. This causes reduction in mucus, bicarbonate (HCO3), and tends to enhance acid secretion and may promote mucosal ischemia therefore enhance aggressive factors over defensive factors. PCM is relatively a weak COX inhibitor so practically free of gastric toxicity and selective COX2 inhibitors are safer 2. Allergic reactions- may be manifested as rashes, photosensitivity, anaphylaxis. Thought to be due to accumulation of prostaglandins after the pathway that breakdown prostaglandins are blocked 3. H emolysis 4. Nephrotoxicity- by inhibition of PGs – impairment of renal blood flow, Na+ & water retention, papillary necrosis with prolonged use 5. Reyes syndrome- rare & serious illness affecting brain and liver part. With aspirin

28. Role of NSAIDS in bone resorption - By facilitating release of osteoclasts activating factor from lymphocytes Inhibit bone collagen formation which results in inhibition of the repair of resorbed bone - Also, studies have highlighted that NSAIDs could exert a negative effect on bone healing process possibly by down-regulating chondrogenesis and endochondral ossification

29. General contraindications Ulcer & GI bleeding Asthma Hypo coagulation state Chronic allergic disorder Chronic liver disease Renal disorder Gout Salicylate allergy Pregnancy and lactation Thrombosis- increases risk esp. in pts with history KEY POINTS : - Never take two NSAIDS simultaneously - Use lowest dose for shortest time possible

30. Comparison Preference in COX selectivity and additional molecular action may explain the difference in therapeutic effects between NSAIDS and acetaminophen Example: NSAIDS is effective analgesics, anti-inflammatory, antipyretic while acetaminophen are potent antipyretic, analgesics. Acetaminophen has inferior anti-inflammatory activity compared to NSAIDS thus it is relatively ineffective in treating inflammatory conditions such as rheumatoid arthritis. On the other hand, acetaminophen has no gastrointestinal effects so its safe for patients with known gastric ulcer Combinations: Aspirin+ paracetamol, diclofenac +paracetamol, paracetamol+ ibuprofen- supra-additive effect

31. NON- SELECTIVE COX INHIBITORS S alycylates - Aspirin Aspirin is acetylsalicylic acid, the prototype, converted to salicylic acid Oldest analgesic with natural sources- fruits, vegetables, herbs MOA- Irreversibly inhibit COX- 1 & COX-2 activity- prevention of PG- mediated sensitization of nerve endings, raise CNS pain threshold, resetting hypothalamic thermostat- fever reduction Has more anti-inflammatory action than analgesic when compared to morphine Pharmacokinetics- absorbed in the stomach and small intestines, metabolized by liver & excreted via kidney Poor water soluble; 80-85% bound to plasma protein Can cross placenta & CSF Therapeutic uses- analgesia, fever of any origin, RA,OA, post myocardial infarction, post stroke ADRs- GI irritation, hypersensitivity, hepatic & renal toxicity, prolonged bleeding time , salicylism Drug interaction- antagonize the effect of probenecid rendering it ineffective for gout, increases tendency for bleeding when used with oral anticoagulants warfarin, cause fluid retention blunting effects of furosemide and decrease antihypertensive effects

32. Propionic acid derivatives- ibuprofen Their efficacy is somewhat rated lower than high dose of aspirin Inhibit PG synthesis Naproxen- most potent Ibuprofen is available in lower analgesic dose- 400mg. Well absorbed orally; highly bound to plasma protein They enter brain, placenta and synovial fluid Largely metabolized by the liver by hydroxylation and glucuronide conjugation and excreted via kidney, bile Used as simple analgesic, antipyretic and for inflammatory conditions eg rheumatoid arthritis

33. Anthranilic acid derivatives- M efenamic acid Has analgesic, antipyretic and weaker anti-inflammatory effect with peripheral and central action COX inhibitor Oral absorption is slow but almost complete. Highly bound to plasma protein Plasma Half life- 2-4hrs Partly metabolized and excreted in urine and bile Uses- indicated primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is not needed Adverse effects- gastric irritation, diarrhea, skin rashes, dizziness

34. Arryl - acetic acid derivatives Diclofenac- among the extensively used analgesic, anti-inflammatory employed in rheumatoid arthritis, AS, OA, bursitis Efficacy is similar to naproxen MOA- inhibit PG synthesis somewhat COX 2 selective Adverse effects- mild GI irritation, headache, dizziness, rashes Aceclofenac - similar properties to diclofenac. Its role in enhancing glycosaminoglycan synthesis confer its chondroprotective property

35. Oxicam derivatives Piroxicam Long acting potent NSAID, reversible COX inhibitor; lowers PG concentration in synovial fluid. Also decreases I gM rheumatoid factor and leucocyte chemotaxis Rapidly and completely absorbed; 99% protein bound Largely metabolized in the liver by glucuronide conjugation and hydroxylation and excreted in urine and bile Has longer half life- upto 2days Adverse effects- GI irritation, rashes, azotemia

36. Pyrrolo - pyrrole derivative Ketorolac- novel NSAID with potent analgesic and modest anti-inflammatory effect Used mainly in post operative pain, dental or acute musculoskeletal pain, has equal efficacy to morphine but does not interact with opioid receptors so its free of opioid side effects Inhibits PG synthesis relieves pain by a peripheral mechanism Rapidly absorbed via oral or IM administration Highly plasma protein bound 60% Excreted unchanged in urine Plasma half life- 5-7 hours Dose- 15-30mg q 4-6hrs Continuous use for more than 5/7 not recommended Adverse effects- nausea, abdominal pain, dyspepsia, ulceration, pruritus, pain at injection site, fluid retention

37. Indole derivative Indomethacin- a potent anti-inflammatory NSAID with prompt antipyretic effect Highly potent PG inhibitor and suppresses neutrophil motility Well absorbed orally; 90% bound to plasma protein Partly metabolized in the liver and excreted via kidney Plasma half- life – 2-5hrs Dose- Adverse effects- high incidence of GI & CNS side effects

38. PREFERENTIAL COX-2 INHIBITORS Nimesulide - Weak inhibitor of PG synthesis and cox- 2 selective Anti-inflammatory activity may be exerted by other mechanisms as well eg reduced neutrophil-generation of superoxide etc Has been used for short term pain relief eg sport injuries Completely absorbed orally; 99% protein bound Extensively metabolized and excreted in urine Half- life 2-5hrs Adverse effect- GI disturbance, skin irritation, somnolence, dizziness

39. PREFERENTIAL COX-2 INHIBITORS CONTD.. Meloxicam- Has a longer half-life than most other NSAIDS, it is a favorable option for those who require once-daily dosing. Meloxicam is available in oral, transdermal, and intravenous formulations. It is a preferential COX-2 inhibitor, purportedly reducing the risk of adverse gastrointestinal tract effects. Studies also have demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP As with other NSAIDS, prolonged use of meloxicam can result in renal or cardiovascular impairment or thrombotic cardiovascular events The half-life of meloxicam is longer approximately 20 hours Meloxicam is almost completely metabolized in the liver by CYP2C9 enzyme and excreted via renal and feacal elimination Possible interactions- abacavir , alcohol,

40. SELECTIVE COX-2 INHIBITORS Cause little gastric mucosal damage do not inhibit platelet aggregation or prolong bleeding time bit inhibit PGI2 production by vascular endothelium Should only be used in patients with high risk of PUD, at lowest dose for short duration Avoided in patients with history of cardiovascular issues who are redisposed to cardiovascular events eg MI eg Celecoxib - has low ulcerogenic potential, effective as naproxen, diclofenac without affecting COX-1 activity at gastrointestinal mucosa although some patients experience abdominal pain, dyspepsia, rash as side effects Metabolized in the liver. Half life- 10hrs Dose- 100mg-200mg

41. Etoricoxib - - Newest, with highest COX-2 selectivity - Suitable for once a day dose. Has no effect on platelet function or on gastric mucosa - T1/2- 24hrs - Side effects- dry mouth, taste disturbances, apthous ulcers, paresthesia Parecoxib - prodrug of valdecoxib suitable for injection mostly used for post operative pain with efficacy similar to ketorolac

42. Commonly used acetaminophen Paracetamol (N-acetyl-P- Amino- Phenol) IUPAC name- N-(4-hydroxyphenyl) acetamide An analgesic and antipyretic drug. Most commonly used over the counter medication for mild to moderate pain It treats pain mainly by blocking COX-2 in CNS thereby reducing pain and increases pain threshold Safe- less GI effects, no prolonged bleeding time, no reye’s syndrome, no significant interaction, can be given in all groups- pregnancy Administration- oral, IM,IV. Has maximal effect between 2-4hrs Well distributed throughout the body and excreted vial liver Toxicity-safe and well tolerated. Overdose leads to renal and liver damage Acute hepatic failure: severe, acute liver injury with encephalopathy & impaired synthetic function (INR of ≥1.5) in a patient without cirrhosis or preexisting liver disease

43. Mode of action of paracetamol

44. Paracetamol Unlike NSAIDS, acetaminophen/ paracetamol weakly inhibit COX enzyme that produce prostaglandins therefore not suitable for chronic inflammatory conditions eg rheumatoid arthritis Therapeutic uses- reduction of mild to moderate pain- headache, migraine, muscle pain Fever control Osteoarthritis Was most preferred during pandemic more than NSAIDS due to their lesser side effect

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