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ANALGESICS

ANALGESICS. TYPES OF PAIN. PAIN CLASIFICATION. TREATMENT OF PAIN. Local anesthetics Infiltration Intravenous Epidural Intrarahidian General anesthetics : Inhalatory Intravenous Intrarectal Epidural. TREATMENT OF PAIN. Analgesics Opioids Natural Semisynthetics synthetics

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ANALGESICS

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  1. ANALGESICS

  2. TYPES OF PAIN

  3. PAIN CLASIFICATION

  4. TREATMENT OF PAIN • Local anesthetics • Infiltration • Intravenous • Epidural • Intrarahidian • General anesthetics : • Inhalatory • Intravenous • Intrarectal • Epidural

  5. TREATMENT OF PAIN • Analgesics • Opioids • Natural • Semisynthetics • synthetics • Non-opioids • Inhibitors of COX1,2,3 • Alfa 2 agonists • 5HT agonists • NMDA antagonists

  6. TREATMENT OF PAIN

  7. CHRONOLOGICAL MARKERS

  8. Non-opioid analgesics Opioid analgesics Drugs for neuropathic and functional pain Antimigraine drugs

  9. Acetaminophen (paracetamol) NSAIDs – non selective - Selective Cox 2 inhibitors NONOPIOID ANALGESICS

  10. ANALGESICS-ANTIPIRETICS-NONSTEROIDALANTIINFLAMMATORY AGENTS • Non selective inhibitors of COX • Organic acids • Salicitats – acetic acid, sodium salicilate, diflunisal, sulfasalazine, olsalasine • Heteroaril acetic acid deriv – indometacin, sulindac • Aril propionic deriv – tolmetin, diclofenac, ketorolac • Arilpropionic deriv – ibuprofen, naproxen, flurbiprofen • Antranilic deriv (fenamats) – mefenamic acid, meclofenamic acid • Enolic acid deriv – piroxicam, meloxicam • Non acidic compounds • Pirazolone deriv – metamizol (dipyrone) • Para-amino-fenol deriv – acetaminofem, fenacetine • Fenazone deriv – fenazone, propifenazone

  11. ANALGESICS-ANTIPIRETICS-NONSTEROIDALANTIINFLAMMATORY AGENTS • Selective inhibitors of COX2 • Sulfonanilide – nimesulide • Coxibi (furanone/pirazolone diaril-substitute) – rofecoxib, celecoxib • Indol-acetic acids - etodolac

  12. NSAIDs Classifications Mild to moderate anti-inflammatory action - propionic acid derivatives ibuprofen, naproxen - fenamic acids mefanamic acid Marked anti-inflammatory action - salicylic acids aspirin - pyrazolone derivatives azapropazone, phenylbutazone - acetic acid derivatives diclofenac, indomethacin - oxicam derivatives piroxicam Selective COX2 inhibitors celecoxib, rofecoxib

  13. Aspirin (acetyl salicylate) Actions Analgesic - central and peripheral action Antipyretic - act in hypothalamus to lower the set point of temperaturecontrol elevated by fever, also causes sweating anti-inflammatory - inhibition of peripheral prostaglandin synthesis respiratory stimulation - direct action on respiratory centre, indirectly by ↑ CO2 production

  14. Aspirin (acetyl salicylate) Metabolic effects ↑peripheral O2 consumption (uncoupled oxidative phosphorylation) hence ↑CO2 production with ↑ respiration, and direct analeptic action - respiratory alkalosis renal loss of bicarbonate with sodium, potassium and water Dehydration metabolic acidosis - effects on Krebs cycle, ↑ ketone body, salicylic acid in blood, renal insufficiency due to vascular collapse, dehydration hypoglycaemia or even hyperglycaemia can occur

  15. Aspirin (acetyl salicylate) Uricosuric effects reduces renal tubular reabsorption of urate but treatment of gout requires 5-8g/d, < 2g/d may cause retention of urate antagonises the uricosuric action of other drugs Reduced platelet adhesion – irreversible inhibition of COX by acetylation, prolongs bleeding time, useful in arterial disease Note: low doses are adequate for this purpose since the platelet has no biosynthetic capacity and can not regenerate the enzyme Hypothrombinaemia : occurs with large doses ie >5g/day

  16. Aspirin (acetyl salicylate) OVERDOSAGE Ingestion of > 10 g can cause moderate/severe poisoning in an adult Clinical features - ‘salicylism’ Tremor Tinnitus Hyperventilation Nausea Vomiting sweating Management- mainly supportive

  17. PARACETAMOL(acetaminophen) equivalent analgesic efficacy to aspirin no useful anti-inflammatory action used for mild to moderate pain, but aspirin is preferred if due to inflammatory process

  18. PARACETAMOL(acetaminophen) Metabolism is conjugated in the liver as the inactive glucuronide and sulphate a number of minor oxidation products N-acetylbenzoquinoneimine (NABQI) are also formed NABQI is highly chemically reactive and is usually inactivated by conjugation with SH (thiol) groups of glutathione Supply of glutathione is limited and exhausted in overdose NABQI then reacts with cellular macromolecules and causes cell death

  19. PARACETAMOL(acetaminophen) Adverse effects rare in therapeutic usage occasional skin rash and allergy overdose can result in fulminant hepatic necrosis and liver failure

  20. PARACETAMOL(acetaminophen) Paracetamol overdose Ingestion of >10g of paracetamol may be fatal may be lower in chronic alcoholics or subjects with underlying liver disease. Clinical features In severe poisoning up to 24 hours – none/nausea and vomiting > 24 hours nausea and vomiting Right upper quadrant pain jaundice encephalopathy

  21. PARACETAMOL(acetaminophen) Management Blood for paracetamol at 4 hours post ingestion Check treatment curve for N-acetylcysteine infusion ( if in doubt of severe poisoning, don’t delay) Check prothrombin time and plasma creatinine, pH acute renal (due to acute tubular necrosis) and hepatic failure and occur at 36-72 hours after ingestion Indications for referral to liver unit are - rapid development of Grade 2 encephalopathy - PTT >45 secs at 48 hours or >50 secs at 72 hours - rising plasma creatinine - Arterial pH <7.3 more than 24 hours after ingestion

  22. NSAIDs Mechanism of action inhibits cyclo-oxygenase (prostaglandin synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxides 2 isoforms of enzyme - COX-1constitutive, present in platelets, stomach and kidney - COX-2inducible by cytokines & endotoxins at sites of inflammation e.g., joints

  23. NSAIDs Main actions 1.) Analgesic -effective against mild to moderate pain, do not cause dependence 2.) Anti-inflammatory 3.) Anti-pyretic 4.)Anti-platelet- prevent thromboxane production, derived from prostaglandins and cause platelet aggregation Others 5.) Useful in treatment of dysmenorrhea, associated with increased prostaglandin synthesis and increased uterine contractility 6.) Used to close the patent ductus arteriosus

  24. NSAIDs Adverse effects 1.) Gastric or intestinal mucosal damage - mucosal prostaglandins inhibit acid secretion, promote mucus secretion, prevent back diffusion of acid into the gastric submucosa - Inhibition thus results in erosions, ulceration, bleeding, perforation 2.) Disturbances of fluid and electrolyte balance - inhibition of renal prostaglandin production results in sodium retention and oedema, possible hyponatraemia, hyperkalaemia, antagonism of anti-hypertensive agents

  25. NSAIDs Adverse effects 3.) Analgesic nephropathy - due to long term ingestion of mixtures of agents - chronic interstitial nephritis, renal papillary necrosis, acute renal failure

  26. NSAIDs Non selective Vs selective COX2 inhibitors ↑ risk of cardiovascular adverse events with COX 2 inhibitors Rofecoxib was withdrawn from the market Higher BP, incidence of myocardial infarction, stroke Mechanism _ ? Unopposed effect of cox 1 action - ? Block protective effect of COX2 on ishaemic myocardium or atherogenesis

  27. OPIOID ANALGESICS

  28. SOURCE Opium is obtained from the opium poppy by incision of the seed pod after the petals of the flower have dropped. The white latex that oozes out turns brown and hardens on standing. This sticky brown gum is opium. It contains about 20 alkaloids, including morphine, codeine etc. The principal alkaloid in opium is morphine, present in a concentration of about 10%. OPIOID ANALGESICS

  29. OPIOID AGONISTS Morphine (strong mu receptor agonist) Codeine Heroin Meperidine (pethidine) Fentanyl Loperamide (over the counter for diarrhea) Diphenoxylate Dextromethorphan

  30. OPIOID AGONIST-ANTAGONIST/PARTIAL AGONIST • Nalbuphine • Pentazocine

  31. OPIOID ANTAGONISTS Nalorphine Naloxone Naltrexone

  32. Routes of administration Oral Parenteral Suppositories Transdermal- Patch s/c Syringe driver OPIATE ANALGESICS

  33. Pethidine/meperidine and fentanyl are the most widely used agents in this family of synthetic opioids The principal effects of pethidine with affinity for mu receptors are on the central nervous system. Opioid Analgesics-Pethidine Pharmacological Effects • the pharmacological effects of Pethidineis similar to morphine, primarily at the mu receptor • it has less potent analgesics than morphine and has a shorter duration of action • Pethidine dosn`t delay delivery

  34. The Opioid Antagonists The opioid antagonist drugs naloxone and naltrexone are morphine derivatives. When given in the absence of an agonist drug these antagonists are almost inert at doses that produce marked antagonism of agonist effects. When given intravenously to a morphine-treated subject, the antagonist will completely and dramatically reverse the opioid effects within 1-3 min.

  35. Mechanism of action Opioid agonists produce analgesia by binding to specific receptors, located primarily in brain and spinal cord regions involved in the transmission and modulation of pain.

  36. Mechanism of action Receptor types: The major classes of receptors are µ (mu for morphine) delta (δ) Kappa (κ) All are members of the G-protein-coupled family of receptors.

  37. Mechanism of action Analgesia, as well as the euphoriant,respiratory depressant, and physiologic dependence properties of morphine result principally from actions at mu receptors. Most of the currently available opioid analgesics act primarily at the mu receptor.

  38. OPIOID RECEPTORS • Certain opioid receptors are located: • on primary afferent and spinal cord pain transmission neurons(ascending pathways) • in the midbrain and medulla (descending pathways) that function in pain modulation • All 3 receptors appear to be involved in anti nociceptive and analgesics mechanisms

  39. OPIOID RECEPTORS • Presynaptically: • Opioid receptor activation can close voltage –gated calcium ion channels to inhibit neurotransmitter release (serotonin, glutamate and substance P)

  40. OPIOID RECEPTORS • Postsynaptically: • Activation of these receptors can open potassium ion channels to cause membrane hyperpolarization (inhibitory post synaptic potential). • Direct inhibition of neurons in ascending pathways

  41. PHARMACOLOGICAL EFFECTS CNS: • Analgesia: most powerful drug available for relief of pain • Euphoria: addict experiences a pleasant floating sensation and freedom from anxiety and distress. • Sedation • Respiratory depression: main cause of death from opioid overdose due to reduced responsiveness of respiratory centre in brainstem to blood levels of CO2

  42. PHARMACOLOGICAL EFFECTS • Increase arterial CO2 retention causes cerebral vasodilation resulting in increase intracranial pressure • Cough suppression: suppression of cough centre in nucleus of tractus solitarius • Miosis: results from stimulation of Edinger- Westphalnucleus causing pin-point pupilsexcept meperidine. • Emesis: due to stimulation of brainstem chemoreceptor trigger zone results in nause and vomiting

  43. MIOSIS

  44. PHARMACOLOGICAL EFFECTS • CVS: No significant direct effect on CVS • Hypotension may occur if CVS is already stressed. Due to the peripheral arterial and venous dilation resulting from histamine release. • GIT:Decrease intestinal propulsive peristalsis and stomach motility leads to constipation • Biliary tract: Constriction of biliary smooth muscles leads to biliary colic except meperidine • Constriction of sphincter of oddi leads to increase biliary pressure, reflux of biliary and pancreatic secretions and elevated plasma and lipase levels

  45. PHARMACOLOGICAL EFFECTS • Renal functions: depressed due to decrease renal plasma flow. • Also has antidiuretic effect. Mechanism involve both CNS and peripheral site • Ureteral and bladdertone is increased • Increased sphincter tone….urinary retention • Occasionally, ureteral colic caused by renal calculus is made worse by opioid induced increase in ureteral tone

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