1. REVIEW FOR CNS(1) Dr Soe Aung Myint 23-1-2013

2. CLASSIFICATION OF LA

3. 1. AMIDES Lignocaine (Lidocaine), Prilocaine, Dibucaine, Mepivacaine,Bupivacaine, Etidocaine, Ropivacaine, Articaine

4. 2. ESTERS Benzoic acid esters – Cocaine, Piperocaine, Properacaine PABA esters – Procaine, Benzocaine, Chloroprocaine, Tetracaine

5. MOA

6. Prevents the generation & conduction of nerve impulses reversibly by decreasing the permeability of excitable cell membrane to Na + (Direct block of voltage gated Na + channel)

7. LIDOCAINE / LIGNOCAINE LIDOCAINE / LIGNOCAINE (1948) (Xylocaine, Burocaine)

8. most widely used LA, chemically stable, amide type, all purpose agent produces rapid, prompt, intense, long-lasting, extensive LA

9. Pharmacological actions

10. (A) LA effect block action potential generation in peripheral nerve by inhibiting Na + channel

11. (B) Systemic effects - Seen when large amount of LA reaches systemic circulation, not common.

12. CNS - stimulation (restlessness, tremor, disorientation, and convulsion) followed by medullary depression (respiratory failure) Convulsion should be treated with I.V. diazepam.

13. CVS - direct depression of the heart, reduce electrical excitability and conduction rate (anti-arrhythmic effect); reduce force of cardiac contraction; vasodilatation, hypotension, collapse, death

14. Smooth Muscle - depress contraction in GIT, bronchi, & blood vessels NMJ & Ganglion - reduce transmission

15. Uses - LA for minor surgery subcutaneous, submucous infiltration (0.5 – 1%) nerve block, epidural/ caudal block (1 – 2%) surface anaesthesia: topical on mucosa or conjunctiva (2 – 4%)

16. Uses -Treatment and prevention of ventricular ventricular arrhythmia (I.V. bolus followed by infusion)

17. Adverse Effects

18. CNS: stimulation followed by depression, sleepiness, paraesthesia, convulsion CVS: vasodilatation, hypotension, bradycardia, cardiac arrest and ventricular Fibrillation

19. Allergy: not common

20. CONTRAINDICATION Myasthenia Gravis

21. Classify local anaesthetics. Describe the mechanism of action, pharmacological action, therapeutic uses & untoward effect of lignocaine. OLD QUESTIONS

22. Cocaine (1884)

23. first LA to be discovered, ester type rarely used now, controlled drug, can cause addiction, & toxicity

24. rapid penetration of mucous membrane effective surface anaesthetic but never given by injection

25. intense vasoconstriction (prevents reuptake of catecholamines by adrenergic nerve endings) (S.E. = corneal sloughing; Mydriasis)

26. CNS stimulation may lead to convulsion, medullary depression, respiratory failure and death increases heart rate and BP increases body temperature

27. Procaine (Novocain) (1905)

28. PABA – ester type, not absorbed through mucous membrane not useful for surface anaesthesia

29. allergy is common; otherwise, safe and least toxic, standard LA

30. Bupivacaine (Mercaine, Sensorcaine) (1963), Levobupivacaine (Chirocaine) (2000)

31. widely used amide type LA takes 30 min for full effect potent prolonged potent prolonged LA up to 8 hours

32. more sensory than motor block suitable for continuous epidural analgesia during labour & post-op pain used for spinal anaesthesia (UK)

33. Cardiotoxic (ventricular arrhythmia, myocardial depression) Levobupivacaine is less cardiotoxic Contraindicated in I.V. regional anaesthesia (Bier’s block)

35. What is analgesic?  drugs that relieve pain in general (non- specific)

36. Classification Narcotic analgesics (Opioid analgesics) Non narcotic analgesics (Nonsteroidal anti- inflammatory drugs)

38. NARCOTIC ANALGESICS (OPIOID ANALGESICS) Opioid agonist /Partial agonist/antagonist Common Mechanism of Action Act on the opioid receptors: μ, k, δ, σ Act on opioid receptors  inhibit the release of excitatory neurotransmitters  decrease synaptic transmission. μ 1 receptor – analgesia, euphoria, dependence μ 2 receptor – respiratory depression and inhibition of gut motility k receptor – analgesia at spinal cord level and dysphoria δ receptor – role is not clear in humans

39. OPIOIDS 1. Pure agonists (primarily at μ, perhaps at k & δ): morphine, codeine, diamorphine (HEROIN), methadone, pethidine (meperidine), fentanyl, Levorphanol, oxycodone, tramadol 2. Partial agonist and mixed agonist antagonists: butorphanol, pentazocine (agonist at k, antagonist at μ), nalorphine, nalbuphine, buprenorphine (partial μ agonist) 3. Antagonist (all receptors): naloxone, naltrexone

40. Classification of Opioids by Analgesic Efficacy Low efficacy agents for mild to moderate pain codeine, dihydrocodeine, dextropropoxyphene, nalbuphine, pentazocine High efficacy agents for severe pain buprenorphine, diamorphine, meptazinol, methadone, morphine, pethidine, tramadol

41. MORPHINE one of the alkaloids obtained from Papaver somniferum prototype of opioids and high efficacy opioid analgesics.

42. Pharmacological Action 1. CNS: it both stimulates and depresses the CNS. CNS depression analgesia  eliminates both acute and chronic pain by raising pain threshold and also allow subject to tolerate pain by reducing the distress (emotional reaction to pain) (μ 1 ) respiratory depression : occurs with analgesic dose, dose-related effect on respiratory center, cause of death in acute opioid poisoning (μ 1 ) By reducing sensitivity of respiratory center to raised blood PaCO 2 sedation (μ 1 & k)

43. cough suppression (central action by depressing cough reflex) mental clouding, impair reasoning ability mood changes: euphoria (occurs in patients with pain or in addicts) (μ 1 ) Dysphoria (occurs in normal persons) (k, σ) Dependence

44. CNS excitation leading to Vomiting - by stimulating the CTZ, disappear with repeated injection. Ambulation ↑ the incidence of vomiting Miosis - due to excitatory action on parasympathetic nerve innervating the pupil (overdose and addiction) Convulsion - rare Peripheral nervous system – analgesia

45. 2. Smooth muscle GIT - ↑ segmental contraction of the circular muscle and ↓ the propulsive movement of GIT  constipation Biliary tract - sphincter of Oddi spasm  ↑ intrabiliary pressure (μ) Urinary tract - retention of urine due to spasm of the bladder sphincter and sedation Uterus - ↓ the uterine tone Bronchial smooth muscle  bronchoconstriction partly due to histamine release

46. 3. CVS: by central action  impairs sympathetic vascular reflexes causing venous and arteriolar dilatation induces histamine release reducing mental distress by tranquilizing All these effects are beneficial in acute left ventricular failure. It also stimulates vagal center (bradycardia)

47. 4. Antidiuresis by releasing ADH 5. Loss of appetite 6. Others: sweating, histamine release, pruritus and piloerection.

48. Therapeutic Uses 1. to relieve moderate to severe pain of any origin, eg. fracture, postoperative pain, acute myocardial infarction, renal colic, obstetric pain 2. to produce euphoria and pain relieve in dying patients 3. to relieve anxiety in serious and frightening disease with pain e.g. trauma, severe haemorrhage, shock

49. 4. to relieve dyspnoea in acute left ventricular failure and in terminal cancer 5. Preanaesthetic medication 6. suppressing cough (codeine) 7. symptomatic control of diarrhoea (diphenoxylate, loperamide) 8. application in anaesthesia

50. Adverse Effects tolerance (within l2-24 hrs), physical and psychological dependence (after repeated use), addiction respiratory depression, drowsiness, mental clouding, impaired reasoning ability nausea, vomiting, constipation, biliary colic, urinary retention, bronchospasm, viscid bronchial secretion itching, hypotension (due to histamine release) cerebral vasodilatation - increased intracranial pressure due to respiratory depression and CO 2 retention overdose - coma, pinpoint pupil (miosis), respiratory depression (Treatment: opioid antagonist-naloxone)

51. Contraindications respiratory insufficieny undiagnosed abdominal pain BPH head injury ↑ ICP

52. HEROIN Is semisynthetic diacetylmorphine and converted to morphine in the body 2.5 times more potent than morphine and is more euphoric  high abuse potential

53. CODEINE is natural alkaloid, methylmorphine converted in the body to morphine reliably absorbed from the GIT  can be given orally. used as anticough and antidiarrhoeal agent used in mild to moderate pain less addictive potential than morphine Respiratory depression is the same degree with morphine

54. PETHIDINE synthetic substance, bind to μ & k receptor. lower analgesic action, shorter duration of action, less spasmogenic effect on smooth muscles than morphine. anticholinergic action (dry mouth, blurred vision, sometime mydriasis, though usually miosis). possible CNS excitation action

55. Pethidine differs from morphine in that does not suppress cough usefully does not constipate; but its effect in the small intestine is similar to morphine and there is spasm of the sphincter of Oddi is less likely to cause urinary retention and to prolong childbirth has little hypnotic effect has shorter duration of analgesia (2-3 hr)

56. opioid with additional actions analgesic effects appears to derive from a combination of weak μ agonist action, neuronal inhibition of uptake of NA and serotonin rapidly absorbed from the GIT, 20% of an oral dose undergoes first-pass metabolism and <30% dose is excreted unchanged in the urine TRAMADOL

57. NALOXONE pure competitive antagonist at all opioid receptors In the absence of agonist it produce no effect In the presence of agonist, it can reverse the effect of agonist within 1 - 2 minutes In chronic narcotic users, it can precipitate withdrawal syndrome. Uses: in the treatment of acute opiate overdose, diagnosis for addicts and shock caused by anaphylaxis, endotoxins, hypovolemia and spinal cord injury. No side effects - occur but can produce drowsiness, and cardiac arrhythmias with overdose. Must be given parenterally because of high first-pass effect (IV). Dose - 0.8-2 mg IV 2-3 hourly (maximum- 10 mg)

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