General and Local Anaesthetics drugs.pptx

General and Local Anesthetics Drugs

1. General and Local Anaesthetics Drugs Presenter :- Dr Arun Singh Senior Resident Department of Pharmacology SMS Medical College,Jaipur

2. Introduction Anaesthesia is two types on the basis of site of administration:- (A)General Anaesthesia (B)Local Anaesthesia

3. What is Anaesthesia ??? Anaesthesia – is a reversible condition of comfort and quiescence for a patient within the physiological limit before, during and after performance of a procedure. General anaesthesia – for surgical procedure to render the patient unaware/unresponsive to the painful stimuli. Drugs producing General Anaesthesia – are called General Anaesthetics. Local anaesthesia - reversible inhibition of impulse generation and propagation in nerves.

4. In sensory nerves, such an effect is desired when painful procedures must be performed, e.g., surgical or dental operations. Drugs producing Local Anaesthesia – are called Local Anaesthetics e.g. Procaine, Lidocaine and Bupivacaine etc.

5. General Anaesthestics

6. What Are General Anaesthetics ? Definition : Anesthesia (an =without, aisthesis = sensation ) The drugs which produce reversible loss of all sensations and consciousness. Generally administered by an anaesthesiologist in order to induce or maintain general anaesthesia to facilitate surgery.

7. The Cardinal Features Of General Anaesthetics

8. Stages Of General Anaesthesia Stage-1 • Analgesia : Start from beginning of anaesthesia administration and last upto loss of consciousness, feels a dream like state, reflexes and respiration remains normal Stage-2 • Stage of delirium : From loss of consciousness to beginning of irregular respiration. Apparent excitement is seen. Muscle tone increases. Jaws are tightly closed. Heart rate and blood pressure may rise.

9. Stages Of General Anaesthesia Stage-3 • Surgical anaesthesia : Extends from onset of irregular respiration to cessation of spontaneous breathing. This has been divided into 4 planes:- • Plane1:This plane ends when eyes become fixed •Plane 2: Loss of corneal and laryngeal reflexes •Plane 3:Pupil start dilating and light reflex •Plane 4: Dilated pupil, decrease muscle tone ,BP • falls Stage-4 • Medullary paralysis : Respiratory and vasomotor control ceases

10. Difference Between General And Local Anaesthetics Description General Local Site of action CNS Peripheral nerves Area Whole body Restricted areas Consciousness Lost Unaltered Preferential use Major surgery Minor surgery Use in non-cooperative patients Possible Not possible Poor health patient Risky Safer Care for vital functions Essential Not needed

11. Mechanisms of GA Mayer and Overton (1901) pointed out a direct parallelism between lipid/water partition coefficient of the GAs and their anaesthetic potency. Minimal alveolar concentration (MAC) is the lowest concentration of the anaesthetic in pulmonary alveoli needed to produce immobility in response to a painful stimulus (surgical incision) in 50% individuals. It is accepted as a valid measure of potency of inhalational GAs, because it remains fairly constant for most young adults. The MAC of all inhalational anaesthetics declines progressively as age advances beyond 50 years.

12. The MAC of a number of GAs shows excellent correlation with their oil/gas partition coefficient. However, this only reflects capacity of the anaesthetic to enter into CNS and attain sufficient concentration in the neuronal membrane, but not the mechanism by which anaesthesia is produced. The principal locus of causation of unconsciousness appears to be in the thalamus or reticular activating system, amnesia may result from action in cerebral cortex and hippocampus, while spinal cord is the likely seat of immobility on surgical stimulation.

13. Recent findings show that ligand gated ion channels (but not voltage sensitive ion channels) are the major targets of anaesthetic action. The GABAA receptor gated Cl¯ channel is the most important of these. Many inhalational anaesthetics, barbiturates, benzodiazepines and propofol potentiate the action of inhibitory transmitter GABA to open Cl¯ channels. Each of the above anaesthetics appears to interact with its own specific binding site on the GABAA receptor, Cl¯ channel complex, but none binds to the GABA binding site as such; though some inhaled anaesthetics and barbiturates (but not benzodiazepines) can directly activate Cl¯ channels.

14. Action of glycine (another inhibitory transmitter which also activates Cl¯ channels) in the spinal cord and medulla is augmented by barbiturates, propofol and many inhalational anaesthetics. This action may block responsiveness to painful stimuli resulting in immobility of the anaesthetic state. Certain fluorinated anaesthetics and barbiturates, in addition, inhibit the neuronal cation channel gated by nicotinic cholinergic receptor which may mediate analgesia and amnesia. On the other hand, N2O and ketamine do not affect GABA or glycine gated Cl¯ channels. Rather they selectively inhibit the excitatory NMDA type of glutamate receptor.

15. This receptor gates mainly Ca2+ selective cation channels in the neurones, inhibition of which appears to be the primary mechanism of anaesthetic action of ketamine as well as N2O. The volatile anaesthetics have little action on this receptor. Neuronal hyperpolarization caused by GAs has been ascribed to activation of a specific type of K+ channels called ‘two-pore domain’ channels. This may cause inhibition of presynaptic transmitter release as well as postsynaptic activation.

16. Inhibition of transmitter release from presynaptic neurones has also been related to interaction with certain critical synaptic proteins. Thus, different facets of anaesthetic action may have distinct neuronal basis, as opposed to the earlier belief of a global neuronal depression. Unlike local anaesthetics which act primarily by blocking axonal conduction, the GAs appear to act by depressing synaptic transmission.

17. Classification Of General Anaesthetics Inhalation: 1.Gas: Nitrous Oxide 2.Volatile liquids: Ether, Halothane, Enflurane, Isoflurane ,Desflurane, Sevoflurane Intravenous: 1. Inducing agents: Thiopentone, Methohexitone sodium, propofol and etomidate 2. Benzodiazepines (slower acting): Diazepam, Lorazepam, Midazolam 3.Dissociative anaesthesia: Ketamine 4.Neurolept analgesia: Fentanyl

18. Inhalational Anaesthetics Inhalational anaesthesia refers to the delivery of gases or vapours to the respiratory system to produce anaesthesia.

19. Diethyl ether (C2H5 – O – C2H5) Colourless, highly volatile liquid with a pungent odour. Boiling point = 35ºC Produces irritating vapours and are inflammable and explosive. Pharmacokinetics: - 85 to 90 percent is eliminated through lung and remainder through skin, urine, milk and sweat Can cross the placental barrier.

20. Advantages – -Can be used without complicated apparatus -Potent anaesthetic and good analgesic -Muscle relaxation -Wide safety of margin -Respiratory stimulation and bronchodilatation -Does not sensitize the heart to adrenaline -No cardiac arrythmias -Can be used in delivery -Less likely hepato or nephrotoxicity Disadvantages -Inflammable and explosive -Slow induction and unpleasant -Struggling, breath holding, salivation and secretions (drowning) -Atropine -Slow recovery -Nausea & vomiting - Cardiac arrest - Convulsion in children - Cross tolerance – ethyl alcohol

21. Nitrous oxide/laughing gas (N2O) NH4NO3 (s) → 2 H2O (g) + N2O (g) Colourless, odourless inorganic gas with sweet taste Non-inflammable and non-irritating, but of low potency Very potent analgesic, but not potent anaesthetic Carrier and adjuvant to other anaesthetics – 70% + 25-30% + 0.2-2% As a single agent used wit O2 in dental extraction and in obstetrics

22. Advantages : -Non-inflammable and non-irritant -Rapid induction and recovery -Very potent analgesic (low concentration) -No effect on heart rate and respiration – mixture advantage -No nausea and vomiting -Post anaesthetic not marked -Nontoxic to liver, kidney and brain Disadvantages : -Not potent alone (supplementation) -Not good muscle relaxant, not -Hypoxia, unconsciousness cannot be produced without hypoxia -Inhibits methionine synthetase (precursor to DNA synthesis) -Inhibits vitamin B-12 metabolism -Dentists, OR personnel, abusers at risk -Gas filled spaces expansion (pneumothorax) - dangerous

23. Halothane Fluorinated volatile liquid with sweet odour, non-irritant non-inflammable and supplied in amber coloured bottle Potent anaesthetic (if precise control), 2-4% for induction and 0.5-1% for maintenance Boiling point - 50ºC Pharmacokinetics: 60 to 80% eliminated unchanged. 20% retained in body for 24 hours and metabolized Delivered by the use of a special vapourizer Not good analgesic or relaxants Potentiates NM blockers

24. Advantages : -Non-inflammable and nonirritant -Abolition of Pharyngeal and laryngeal reflexes -Bronchodilatation – preferred in asthmatics Potent and speedy induction & recovery Controlled hypotension Inhibits intestinal and uterine contractions – external or internal version - Popular anaesthetic in developing countries - can be used in children for induction and maintenance and adult maintenance Disadvantages : Special apparatus Vapourizer Poor analgesic and muscle relaxation Myocardial depression – direct depression of Ca++ and also failure of sympathetic activity – reduced cardiac output (more and more) - Hypotension – as depth increases and dilatation of vascular beds Heart rate – reduced due to vagal stimulation, direct depression of SA node and lack of Baroreceptor stimulation - Arrythmia Sensitize heart to Adrenaline Respiratory depression – shallow breathing (PP of CO2 rises) assisted ventilation Decreased urine formation – due to decreased GFR - Hepatitis: 1 in 10,000 Malignant hyperthermia: Abnormal Ryanodine receptor - Prolong labour

25. Enflurane Non-inflammable, with mild sweet odour and boils at 57ºC Similar to halothane in action, except better muscular relaxation Depresses myocardial force of contraction and sensitize heart to adrenaline Induces seizure in deep anaesthesia and therefore not used now - Epileptiform EEG Metabolism one-tenth that of halothane-- does not release quantity of hepatotoxic metabolites Metabolism releases fluoride ion-- renal toxicity

26. Isoflurane Isomer of enflurane and have similar properties but slightly more potent Induction dose is 1.5 – 3% and maintenance dose is 1 – 2% Rapid induction (7-10 min) and recovery By special vapourizer

27. Advantages : Rapid induction and recovery - Good muscle relaxation Good coronary vasodilatation CO maintained, HR increased – beta receptor stimulation Less Myocardial depression than no myocardial sensitization to adrenaline - No renal or hepatotoxicity Low nausea and vomiting No dilatation of pupil and no loss of light reflex in deep anaesthesia No seizure and preferred in neurosurgery - Uterine muscle relaxation Disadvantages : Pungent and respiratory irritant Special apparatus required Respiratory depression-- prominent Maintenance only, no induction - Hypotension - ß adrenergic receptor stimulation - Costly (Desflurane and Sevoflurane ----- read yourself)

28. Intravenous Anaesthetics For induction only Rapid induction (one arm brain circulation time) For maintenance not used Alone – supplemented with analgesic and muscle relaxants .

29. Inducing agents: Thiopentone, Methohexitone sodium, propofol and etomidate Benzodiazepines (slower acting): Diazepam, Lorazepam, Midazolam Dissociative anaesthesia: Ketamine Neurolept analgesia: Fentanyl

30. Thiopentone sodium : Barbiturate: Ultra short acting ---Water soluble Alkaline Dose-dependent suppression of CNS activity Dose: 3-5mg/kg iv (2.5%) solution – 15 to 20 seconds Pharmacokinetics : -Redistribution -Hepatic metabolism (elimination half-life 7-12 hrs) -CNS depression persists for long (>12 hr)

31. Disadvantages : - Depth of anaesthesia difficult to judge - Pharyngeal and laryngeal reflexes persists - Apnoea – controlled ventilation Respiratory depression Hypotension (rapid) – shock and hypovolemia – CVS collapse Poor analgesic and muscle relaxant Gangrene and necrosis - Shivering and delirium Advantages : Rapid induction Does not sensitize myocardium to adrenaline No nausea and vomiting Non-explosive and non-irritant Short operations (alone) Other uses: convulsion, psychiatric patients and narcoanalysis of criminals – by knocking off guarding

32. Propofol Rapid onset and have a short duration of action Highly protein bound in vivo and is metabolized by conjugation in the liver Very good anesthetic for induction and maintaince of anesthesia with no accumulation effect Side-effects are pain on injection, hypotension and transient apnea following induction Used for the induction, maintenance of GA and sedation Useful for day-case surgery

33. Ketamine Dissociative anaesthetic NMDA Receptor Antagonist Cardiovascular stimulant Catatonia, analgesia, and amnesia without loss of consciousness Useful for anesthetizing patients at risk for hypotension and bronchospasm and for certain paediatric procedures

34. Etomidate Rapid induction Minimal change in cardiac function and respiratory rate Not analgesic Cause pain on injection and nausea postoperatively Prolonged administration may cause adrenal suppression

35. Local Anaesthestics

36. Introduction Local anaesthetics (LAs) are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain, in a restricted area of the body. They block generation and conduction of nerve impulse at any part of the neuron with which they come in contact, without causing any structural damage. Thus, not only sensory but also motor impulses are interrupted when a LA is applied to a mixed nerve, resulting in muscular paralysis and loss of autonomic control as well.

37. Features Of Local Anaesthetics

38. C h em i stry

39. Based on linkage they can be classified as-

40. Advantage of Amide LAs over Ester LAs Produce more intense and longer lasting anaesthesia . Bind to α 1 acid glycoprotein in plasma. Not hydrolyzed by plasma esterase's. Rarely causes hypersensitivity reaction.

41. Classification 1.Injectable Anaesthetic (a)Low Potency, Short Duration ex. Procaine, C h l or o p r o c a i n e (b)Intermediate potency and duration ex. Lidocaine, Pri l o c a i n e (c)High potency and long duration ex. Tetracaine, B upi v a c ai ne, R opivacaine, Dibucaine 2. Surface Anaesthetic: (a)Soluble ex. Cocaine, Lidocaine, Tetracaine (b)Insoluble ex. Benzocaine, B u ty l- a mi n o- ben z o a te, Oxethazaine b e n o x i n a te

42. Mechanis m of action of LAs

43. M echanism of action of LAs LA blocks the nerve conduction by reducing entry of Na+ through the voltage gated channels Due to this, they block the initiation & propagation of nerve impulse. At higher doses it also blocks -Voltage gated Ca 2+ channels -K + channels

44. Pharmacokinetics Absorption :- Local anesthetics are absorbed when ingested. Some local anesthetics may be absorbed in toxic amounts after topical use. Absorption after an injection depends on drug solubility in lipid and in water, tissue vascularity and local anesthetic and vasoconstrictor effects on local circulation. Distribution :- Amides-wide distribution –I.V.-lipophilic taken up by highly perfused organs-then moderately perfused. Ester type- short plasma half life

45. Metabolism and excretion :- Esters are hydrolyzed by plasma and liver esterases. Longer-acting esters are often metabolized more slo wly. Patients with altered pseudo-cholinesterase activity may be highly sensitive to these drugs. Amides are metabolized in the liver by cyp450.-N-dealkylation then hydrolysis except prilocaine- hydrolysis first-o toludine-can cause methemoglobinemia. Patients with severe hepatic damage or advanced congestive heart failure may be unusually sensitive to these drugs. Some amides are partially excreted unchanged in the urine. Acidification can enhance excretion.

46. PK properties of amide LAs :

47. Precautions and interactions:- Aspirate lightly to avoid intravascular injection. Inject the LA slowly &take care not to exceed the maximum safe dose, especially in children. Propranolol may reduce metabolism of lidocaine and other amide LAs by reducing hepatic blood flow. Vasoconstrictor (Adr) containing LA should be avoided for patients with ischemic heart disease, cardiac arrhythmia, uncontrolled hypertension those receiving β-blockers or tricyclic antidepressants .

48. Techniques of Local Anaesthesia

49. Surface Anaesthesia Application of a local anesthetic to nose, mouth, throat, tracheobronchial tree, esophagus. Onset & duration depends on the site, the drug, its concentration and form. Absorption of soluble LAs from mucous membrane is rapid.

50. Infiltration Anaesthesia Injection of LA directly into tissue under the skin. Used primarily for surgical procedures. LAs most frequently used are lidocaine (1%), bupivacaine (0.25%), etidocaine(0.5-1%), ropivacaine(0.5-1%), mepivacaine(1-3%) and prilocaine(1-4%). Mix with adrenaline (1:20000) to prolong the action

51. Conduction block Injected around nerve trunks so that area distal to injection is anaesthetised and paralyzed Choice of LA and concentration is mainly determined by the required duration of action. Lidocaine for intermediate duration of action. Longer lasting anesthesia bupivacaine may be selected.

52. Field block : Produced by injecting the LA subcutaneously in the surrounding area of nerve so that all nerves coming to particular field are blocked. Herniorrhaphy, Appendicectom y,dental procedures, scalp stitching, operations on forearms and legs etc. Larger area can be anaesthetized with lesser drug compared to infiltration. Nerve Block: local anesthetic is injected around a nerve that leads to the operative site. Usually more concentrated forms of local anesthetic solutions are used. eg. radial nerve block, ulnar nerve block so on. Nerve block lasts than field block or infiltration anaesthesia. Lidocaine (1.5%), mepivacaine(1.5%), bupivacaine (0.25- 0.35%) can be used.

53. Epidural Anaesthesia Spinal dural space is filled with semi liquid fat through which nerve root travel Injected in this space- acts primarily on nerve roots and small amounts permeates through intravertebral foramina to produce multiple paravertebral blocks. Used to produce analgesia or anaesthesia in surgical and obstetric. Divided into 3 categories depending on site of action: 1.Thoracic: 2.Lumbar: 3.Caudal:

54. Spinal Anaesthesia Injected into the subarachnoid space between L2-3 or L3-4 of the spinal cord . Suitable LA like lidocaine (3-5%), bupivacaine (0.5- 0.8%), tetracaine(0.3-0.5%). Primary site of action is cauda equina rather than spinal cord. Used to anaesthetize lower abdomen and hind limbs.

55. Use of hyperbaric(in7.5-10% glucose) or hypobaric (in distilled water) solution of LA . Proper positioning of the patient is also limiting the block to the desired level. Advantages over general anaesthesia are : Safer Produces good analgesia and muscle relaxation without loss of consciousness Cardiac, pulmonary, renal disease and diabetic pose less problem.

56. Complication of spinal anaesthesia: Respiratory paralysis Hypotension Headache Cauda equina syndrome Septic meningitis Co n t r ai n dicati o n s: Hypotension & hypovolemia Infant & children's - control of level is difficult Vertebral abnormalities - kyphosis

57. Intravenous regional anaesthesia: Also referred as Bier’s block & used for upper limb and orthopedic procedures. Regional analgesia produced within 2-5min and last till 5- 10min. Only ¼ of the injected drug enters systemic circulation when tourniquet is removed. Bradycardia can occur and bupivacaine should not be used because of higher cardio toxicity.

58. Commonly used drug with LA Adrenaline –to prolong the effect of LA and to reduce the toxicity by reducing absorption from local area. Hyaluronidase-enzyme which cause depolymerization of hyaluronic acid and increase the permeability of injected fluid.

59. Tetracaine [Amethocaine] Topical anaesthetic [0.5%] in ophthalmic practice. Onset of action is 30 minutes. Side effects-stinging sensation, punctate ,drug allergy.

60. Proparacaine Topical anaesthetic. [0.75%] Onset of action-30 sec

61. Cocaine First local anaesthetic obtained from leaves of plant Erythroxylon Coca. It is no more in use nowadays because of its corneal toxicity, addicting nature etc.

62. Procaine First synthetic local anaesthetic • Used as a small area infiltration and spinal anaesthetic. • It is poorly absorbed from mucous membrane so no topical use. • 2% injection is the usual preparation.

63. Lignocaine Most commonly used LA In ophthalmology 4% [topical] and 2% [infiltration] solutions are commonly used. It has quick onset of action and high degree of penetration. The drug is recommended for topical, nerve block, infiltration and epidural injection and for dental analgesia. It may cause drowsiness.

64. Bupivacaine Onset of action is slow • A 0.75% solution produce anaesthesia and akinesia for 8-12 hours. • In ophthalmic practice, usually a combination of 2% lignocaine,0.75% bupivacaine and 7.5 TRU of hyaluronidase is used for periocular injection, and surgery of any kind may be performed on such type of anaesthetized eye.