general and local anesthesia

general and local anesthetics

1. General and local anesthesia Prepared by SONAL VIJAY PANDE MPHARM DEPARTMENT : PHARMACOLOGY

2. What is Anaesthesia ??? Anesthesia – is a reversible condition of comfort and quiescence for a patient within the physiological limit before , during and after performance of a procedure . Types of anesthesia

3. General anesthesia – for surgical procedure to render the patient unaware/unresponsive to the painful stimuli. Drugs producing General Anaesthesia – are called General Anaesthetics Local anesthesia - reversible inhibition of impulse generation and propagation in nerves . 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.

4. DIFFERENCE BETWEEN GENERAL ANAESTHESIA & LOCAL ANAESTHESIA FEATURES Gen.Anaesthsia Local Anaesthsia Site of action CNS Peripheral nerves Area of body involved Whole body Restricted area Consciousness Lost Unaltered Care of vital functions Essential Usually not needed Poor health patients Risky Safer Use in non cooperative patients Possible Not possible Major surgery Preferred Cannot be preferred Minor surgery Not preferred preferred

5. General anesthesia General Anaesthetics are the drugs which produce reversible loss of all modalities of sensation and consciousness, or simply, a drug that brings about a reversible loss of consciousness . General anaesthetics are – mainly inhalation or intravenous . These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.

6. Stages of general anesthesia

7. Stage 1 analgesia Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness Pain is progressively abolished during this stage Patient remains conscious, can hear and see, and feels a dream like state Reflexes and respiration remain normal It is difficult to maintain - use is limited to short procedures only

8. From loss of consciousness to beginning of regular respiration Excitement - patient may shout, struggle and hold his breath Muscle tone increases, jaws are tightly closed. Breathing is jerky; vomiting, involuntary micturition or defecation may occur. Heart rate and BP may rise and pupils dilate due to sympathetic stimulation. No stimulus or operative procedure carried out during this stage. Breatholding are commonly seen. Potentially dangerous responses can occur during this stage including vomiting, laryngospasm and uncontrolled movement. This stage is not found with modern anaesthesia – preanaesthetic medication, rapid induction etc. Stage II: Stage of Delirium and Excitement

9. Extends from onset of regular respiration to cessation of spontaneous breathing . This has been divided into 4 planes: Plane 1 : Roving eye balls. This plane ends when eyes become fixed . Plane 2: Loss of corneal and laryngeal reflexes . Plane 3: Pupil starts dilating and light reflex is lost . Plane 4: Intercostal paralysis, shallow abdominal respiration, dilated pupil . Stage III Stage of Surgical anaesthesia

10. Cessation of breathing failure of circulation death Pupils : widely dilated Muscles are totally flabby Pulse is imperceptible BP is very low. Stage IV Medullary / respiratory paralysis

11. Theories The three main theories of general anaesthseia

12. LIPID THEORY Suggests that the anesthetic acts nonspecifically on the lipid portions of the neuronal membrane to cause a general disturbance that causes the ion channels to change structure thereby changing their function. Interactions here cause a physical change in the membrane

13. MAYER AND OVERTON THEORY Mayer and Overton separate studies identically postulated that anaesthetic potency varies with the lipid solubility. More the lipid soluble a drug is the greater is its anaesthetic potency. This theory does not suggest any particular mechanism but reflects only capacity of anaesthetic agent to enter into CNS and attain sufficient concentration in neuronal membrane. It is now known that all highly lipid soluble substance s are not anaesthetics and some potent anaesthetic are not lipid soluble. Various lipid theory are given below

14. PAULING AND MILLER THEORY/HYDRATE THEORY This theory was given in 1961 . According to this theory simple molecules like water may be linked together by hydrogen bonding to form ice like structures which are occupied by anaesthetic agent to form anaesthetic hydrate crystals . These hydrates could then impede ionic mobility, electrical charge, and chemical and enzymatic activity of the brain to produce depression and unconsciousness. This theory does not explain anaesthesia produce by barbiturate and some other anesthesia

15. MEMBRANE EXPANSION THEORY This theory postulates that anaesthetic molecules penetrate into hydrophobic region of the cell membrane and causes its expansion . The mechanism of membrane expansion has not been fully explained but may be attributable to formation of hydrates.

16. MEMBRANE FLUIDISATION THEORY/ LATERAL PHASE SEPARATION THEORY This theory postulates that anaesthetic agents by dissolving in the membrane lipids cause loosening or fluidisation of lipid bilayer region of the membrane .

17. PROTEIN THEORY This theory suggests that the anaesthetic must act specifically with hydrophobic pockets on certain membrane proteins to produce the effect Lock and Key Problem : Too many keys that would have to all fit the same lock

18. BIOCHEMICAL THEORY A number of biochemical theories have also been postulated and reviewed . These include- inhibition of glucose metabolism in brain cells, interference in production of ATP. Interference in oxygen utilization and cellular respiration.

19. Classification of General anesthesia Inhalation: Gas: Nitrous Oxide Volatile liquids: Ether Halothane Enflurane Isoflurane Desflurane Sevoflurane Intravenous : Inducing agents:  Thiopentone , Methohexitone sodium, propofol and etomidate Benzodiazepines (slower acting): Diazepam, Lorazepam, Midazolam Dissociative anaesthesia: Ketamine Neurolept analgesia: Fentany

20. Mechanism For inhalation anesthetics Minimum Alveolar Concentration (MAC) – 1 (one) MAC is defined as the minimum alveolar concentration that prevents movement in response to surgical stimulation in 50% of subjects. Correlates with oil/gas partition coefficient Practically – Alveolar concentrations can be monitored continuously by measuring end-tidal anesthetic concentration using spectrometry End point (immobilization) – can me measured . Other end points – Verbal commands or memory etc.

21. For Intravenous agents Potency of IV agent is defined as the free plasma concentration (at equilibrium) that produces loss of response to surgical incision in 50% of subjects . Difficult to measure : no available method to measure blood or plasma concentration continuously Free concentration at site of action cannot be determined (MAC explains only capacity of anaesthetics to enter in CNS and attain sufficient concentration, but not actual MOA)

22. Properties of G eneral anesthesia For Patient: - Pleasant , non-irritating and should not cause nausea or vomiting – Induction and recovery should be fast  For Surgeon: - analgesia, immobility and muscle relaxation - nonexplosive and noninflammable For the anaesthetist : 1 . Margin of safety: No fall in BP 2 . Heart, liver and other organs: No affect 3 . Potent 4 . Cheap, stable and easily stored 5. Should not react with rubber tubing or soda lime 6. Rapid adjustment of depth of anaesthesia should be possible

23. 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 Ether – contd.  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

24. Nitrous oxide/laughing gas (N2O )  NH4NO3 (s) → 2 H2O (g) + N2O (g)  Colourless, odourless inorganic gas with sweet taste  Noninflammable and nonirritating , 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 Advantages: - Non-inflammable and nonirritant – 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

25. 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

26. Halothane  Fluorinated volatile liquid with sweet odour, nonirritant 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 Advantages: - Non-inflammable and nonirritant – Abolition of Pharyngeal and laryngeal reflexes bronchodilatation – preferred in asthmatics Potent and speedy induction & recovery Controlled hypotension

27. 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 Inhibits intestinal and uterine contractions – external or internal version - Popular anaesthetic in developig countries - can be used in children for induction and maintenance and adult maintenance

28. 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

29. 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

30. LOCAL ANESTHESIA DEFINITION: They are drugs which, when applied directly to peripheral nervous tissue, block the nerve conduction and abolish all sensations in the part supplied by the nerve without loss of consciousness. All local anesthetics are weak bases, they have amphiphilic properties

31. FEATURES OF LOCAL ANAESTHETICS Should have quick onset of action Should have low Systemic toxicity Duration of action must be long enough to allow d esi red surgery to be completed Should be effective on both injection & local application

32. INJECTABL ANAESTHETIC

33. Surface anesthesia

34. MECHANISM 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 1. Voltage gated Ca2+ channels 2. K+ channels

35. 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- lipophilics taken up by highly perfused organs-then moderately perfused Ester type- short plasma half life Metabolism and excretion  Esters are hydrolyzed by plasma and liver esterases . Longer-acting esters are often metabolized more slowly.. Patients with altered pseudo-cholinesterase activity may be highly sensitive to these drugs.  Amides are metabolized in the liver by cyp450.-Ndealkylation then hydrolysis except prilocainehydrolysis first-o toludine -can cause methhamoglobinemia

36. Techniques of Local Anaesthesia 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.

37. 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

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

39. 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 , appendicectomy , 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, ulner 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.

40. Epidural Anaesthesia. S pinal 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 obstretric . Divided into 3 categories depending on site of action: Thoracic: Lumbar: Caudal:

41. 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.

42. 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 C omplication of spinal anaesthesia:  Respiratory paralysis  Hypotension  Headache  Cauda equina syndrome  Septic meningitis Contraindications:  Hypotension & hypovolemia  Infant & childrens - control of level is difficult  Vertebral abnormalities - kyphosis

43. 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

44. Should not cause any permanent damage on any tissue. Should be relatively free from producing allergic reaction.  Should be stable in solution and readily undergo biotransformation.