Local Anaesthetics PDF

.. Chapter 26 Local Anaesthetics Local anaesthetics (LAs) a rc drugs which any structural damage. Thus, not only sensory upon topical ap plication or loca l injectio n but also motor impulses are interr...

.. Chapter 26 Local Anaesthetics Local anaesthetics (LAs) a rc drugs which any structural damage. Thus, not only sensory upon topical ap plication or loca l injectio n but also motor impulses are interrupted when cause reversible loss of sensory perception, a LA is applied to a mixed nerve, resulting especia ll y of pain, in a restricted area of the in muscula r para lysis and loss of autonomic body. They block ge neration and conduction of contro l as well. nerve impulse at any part of the neurone with Im portant differences between genera l and which they come in contact. without causing local anaesthesia are tabulated in Table 26. 1. LOCAL ANAESTHETICS I J~T YJL:; -.... ~. I I --. I I I Low potency, 'Intermediate potency I High potency, I Soluble I insoluble short duration and duration long duration Cocaine Bcnzocaine Proca inr Lidocaine {Lignocaine) Tetracaine Lidocaine Butylamino- Chloroprocaine Prilocaine Bupivacaine Tetracaine benzoa te Ropivacaine Proparacaine Oxethazaine Dibucaine Mep ivacainc. Etidocaine. Artica ine. Dycloninc, arc other arc 1101 used for this purpose because of local irritancy or local anaesthetics, occasionally used in some countries. other prominent systemic activity. Local anaesthesia can Some other drugs, e.g. propranolol, chlorproma7ine, H1 be produced by cooling as wel l, e.g. application o f ice, antih1staminics. quinine have significant LA activity, but CO, snow. ethylchloride spray. Table 26.1: Comparative features of general and local anaesthesia General anaesthesia Local anaesthesia 1. Site of action CNS Peripheral nerves 2. Area of body involved Whole body Restricted area 3. Consciousness Lost Unaltered 4. Care of vital functions Essential Usually not needed 5. Physiological trespass High Low 6. Poor health patient Risky Safer 7. Use in non-cooperative patient Possible Not possible 8. Major surgery Preferred Cannot be used 9. Minor surgery Not preferred Preferred  LOCAL ANAESTHETICS 387 CHEMISTRY +30 T he clinically usefu l LAs are weak bases with amph iphilic property. A hydrophilic secondary b or tertiary amine on one side and a lipophilic 0 aromatic residue on the other arc jo ined by an a lkyl cha in thro ugh an ester or amide linkage. -30 >.s -60 PROCAINE (ester) -90 t ft c::J-CH2-~C2Hs Fig. 26.1: Effect of progressively increasing concen- C2Hs trations (b,c,d) of a local anaesthetic on the generation CH3 of an action potential in a nerve fibre, (a) Untreated nerve LIOOCAINE (amide) fibre Ester-linked LAs Cocaine. procaine, chloro- procaine, tetracaine, benzocaine. The LAs interact with a receptor situated Amide-linked LAs Lidocainc, bupivacaine, within the voltage se nsiti ve a c hannel and dibucaine, prilocaine, ropi vacaine. raise the thres hold of channel opening: Na permeabil ity fai ls to increase in response to Features of amide LAs an impulse or stimulus. Impulse conduction is (compared to ester LAs) interrupted when the I a' c hanne ls over a criti- Produce more intense and longer lasting anaesthesia cal length of the fibre (2- 3 nodes of Ran vier Bind to a, acid glycoprotein in plasma in case of myelinated fibres ) a rc blocked. The Not hydrolysed by plasma esterases details are ex plained in Fig. 26.2. At physio- Rarely cause hypersensitivity reactions: no cross logical pH, the LA molecule is partly ionized. sensitivity with ester LAs The equ ilibrium between the unioniz ed base fom1 (B) and the ionized cati onic form ( BH ' ) Because of their short duration , less intense depends on the pKa of the LA. analgesia and higher risk of hyper ensitivi ly, the Potency of a LA ge nerall y corresponds ester-linked LAs are rarely used for infiltration to the lipid solubility of its base form (B), or nerve block, but are still used topically on because it is this form which penetrates the mucous membranes. axon. Howe ver, the predo minant active s pe- c ies is th e cationic form of the LA w hich is MECHANISM OF ACTION able to approach its receptor easi ly when the The LAs block nerve conduction by decreasing cha nne l is open at the inne r face. and it binds the entry of a ' ions during upstroke of more avidly to the activated a nd inactivated action potential (A P). As the concentration of states of the channel. than to the resting state. the LA is increased, the rate of rise of AP Binding of the LA prolongs the inacti vated and maximum depolarization decreases (Fig. state, so that the c hannel ta kes longer to re- 26. 1) causing slowing of conduction. Finally, cover. Consequently refractory period of the local depolarizat ion fai ls to reach the threshold fibre is increased. A rest ing ne rve is rather potential and conduction block ensues. resista nt to blockade. Blockade develops rapidly 388 DRU GS ACTING ON PERIPHERAL (SOMATIC) NERVO US SYSTE M RESTING ACTIVATED INACTIVATED Axoplasm Fig. 26.2: A model of the axonal Na·channel depicting the site and mechanism of action of local anaesthetics. The Na channel has an activation gate (make or 'm' gate) near its extracellular mouth and an inactivation gate (halt or 'h' gate) at the intracellular mouth. In the resting state the activation gate is closed. Threshold depolarization of the membrane opens the activation gate allowing Na ions to flow in along the concentration gradient depolarizing the membrane. This depolarization inactivates the Na channels within a few msec by closing the inactivation gate; K· channels open quickly-outward flow of K repolarizes the membrane allowing Na channels to recover to the resting state in a time-dependent manner. The local anaesthetic (LA) receptor is located within the channel in its intracellular half. The LA traverses the membrane in its unionized lipophilic form (B), reionizes in the axoplasm and approaches the LA receptor through the intracellular mouth of the channel. It is the cationic form (BH· ) of the LA which primarily binds to the receptor. The receptor has higher affinity, or is more accessible to the LA in the activated as well as inactivated states compared to the resting state. Binding of LA to its receptor stabilizes the channel in the inactivated state and thus reduces the probability of channel opening. The neuronal Na· channel is a 300 KO glycoprotein composed of a large (a) and two small (~,. ~2) subunits. The a subunit encloses the Na selective pore within its 4 homologous domains (I to IV), each domain has 6 membrane spanning helical segments (S 1 to S6) connected alternately by intracellular and extracellular loops. The wall of the pore is formed by all four S5-S6 segments, while the short nonhelical loops connecting SS-S6 on the extracellular surface fold into the pore and serve as the activation gate. Voltage sensors located in the S4 segments move verti· cally on depolarization and open the activation gate by allosteric conformational change. A few msec later, the short intracellular loop connecting domains Ill and IV folds into the inner mouth of the pore inactivating the channel. The LA receptor is located in the S6 segment of domain IV. Channel activation either transforms the LA receptor to a higher affinity conformation or exposes it on the wall of the pore, and this persists during the subsequent inactivation phase. w hen the nerve is stimu lated re peatedly. The acting, beca use 30-40% LA is in the undi sso degree of blockade is frequency depe ndent, i.e. ciated base form at p H 7.4 and it is this form greater blockade occ urs at highe r freq uency w hic h pe ne trates the axon. Procaine, tetracaine, of sti mulat io n. Mo reover, e x posure of the bup ivacaine have higher p Ka (8. 1- 8.9). only fi bre to h igher concentrati o n of Ca2 reduces 15% or less is unionized at pH 7.4; these LAs inacti vati on of a· c hannels and lesse ns the are slow acting. Chloroprocaine is an excep degree of block. Blockade of cond uct io n tion, hav ing rapid onset despite high pKa (9. 1). by LA is not due to hyp erpolarizat ion ; in fact, resting membra ne pote ntial is unaltered, LOCAL ACTIONS because K cha nne ls are blocked o nly a t higher The clinica lly used LAs have no/minim al local concentrations of the LA. irrita nt action and block sensory nerve end ings, The onset time of blockade is related primarily nerve trunks, neuromuscul ar j uncti on, ganglio- to the pKa of the LA. Those w ith lower pKa nic synapse an d receptors (no n-selectively), i.e. (7.6- 7.8), e.g. lidocaine, mepivacaine are fast those structures which function thro ugh increased  LOCAL ANAESTHETICS 389 Na permeability. They also reduce re lease of be afTccted. Applied to the tongue, bitter taste acety lcholine from motor nerve endings. Injected is lost Arst followed by sweet and sour, and around a mixed nerve they cause anaesthes ia of salty taste last of all. skin and paralysis of the voluntary muscle sup- In general, fibres that are more susceptible plied by that nerve. to LA arc the first to be blocked and the last Se nso ry and moto r fibres a re inhere ntl y to recover. Also, locati on o f the fibre with in equall y sensi tive, but some LAs do ex hi bi t a nerve trunk detennincs the latency, duration unequa l abi lity to block the m. e.g. e pidu ra l and often the depth of local anaesthesia. e rve bupi vacaine produces sensory block at muc h sheaths restrict diffusion o f the LA into the lower concentration than that needed fo r motor nerve trunk so that fib res in the oute r layers block. The di fTerential se nsory blockade is greatly are blocked ea rl ier than the inner or core fibres. advantageo us for pa in re lief in normal labour by As a result, the more prox imal areas supplied enabling the mother to acti vely push the foetus by a nerve arc a fTected earlier because axons down during uterine contractions. Simi larly, in supply ing them are located more peripherally continuous e pidural ana lgesia for postoperative in the nerve than those suppl ying distal areas. pain relief (e.g. after knee replacement) absence The di fferential arrangement of vari ous types of motor b lock is he lpful in early ambu lation of sensory and motor fibres in a m ixed nerve and performance of exerc ises. may partly account for the di fferentia l bloc kade. The sensi tivity to LA is dete rmin e d by Motor fibres are usually present c ircumferentially. diame ter o f the fibres as well as by fi bre As such, they may be blocked earlier than the ty pe. Diameter re maining the same, mye linated sensory fibres in the core of the nerve. nerves a re blocked earlier than nonmyelinated. The LA often fa ils to afford adequate pain ln genera l, sma ller fibres a re more sensiti ve control in inflamed tissues (like infected tooth). tha n larger fi bres; but th is is not always true. The like ly reasons arc: Fibres difTer in the critical length of the axon a. Infla mmation lowe rs pl! of the tissuc--greater tha t must be exposed to the LA for effecti ve fractio n of the LA is in the ionized form blockade. In myelinated fibres the critical length hindering diffusion into the axolemma. usually covers 2- 3 nodes of Ranvier. Smaller b. Bloo d now to the innamcd area is fibres te nd to have s horter cri t ical le ngths, increased- the LA is removed more rapidly because in them vo ltage c hanges p ropaga te from the site. passively for shorter distances. Further, more c. Effectiveness of Adr injected with the LA slender axons have shorter intemodal d istances, is reduced at the inflamed site. and LAs easily en ter the axon at the nodes of d. Inflammato ry products ma y oppose LA Ranvier. The density of Na channe ls is much action. hi ghe r a t these nodes. Moreove r, frequ e ncy Addition of a vasoconstrictm; e.g. adrenaline dependence of blockade makes sma ller sensory ( I :50,000 to I :200,000): fibres more vulnerable since they generate high Prolo ngs durati o n o f acti o n o f LAs by frequency longer lasting action potentials than decreasing their rate of removal from the the motor fibres. T hus, fibre diameter itself local site in to the c irculation: contact time may not govern sen itivi ty to LA. of the LA with the nerve fibre is prolonged. Autonomic fibres are generally more suscep- Enhances the intensity of nerve block. tible than somatic fibres. Among the somatic Reduces systemic toxic ity of LAs: rate of afferents order o f blockade is: pain- temper- absorpti on is reduced and metabolism keeps ature sense-touch-deep pressure sense. Since the plasma concentration lower. pain is genera lly carried by sma ller diame ter Prov ides a more bloodless field for surgery. fibres tha n those carrying other sensations or Increases the chan ces of subsequent local motor impulses, pain in the first moda lity to tissue edema a nd necrosis as well as delays 390 DRUGS ACTING ON PERIPHERAL (SOMATIC) NERVOUS SYSTE M wound heali ng by red ucing oxygen supply refractory period (E RP). They have a quin idine- and enhanc ing oxygen consumption in the li ke antiarrhythmic action. While procaine is not affected a rea. used c linically as antiarrhythmic because of short May raise BP and promote arrhyth mia in duration of action and propensity to produce susceptible individ ual s. CNS effects, its amide derivative procainamide is a class IA antiarrhythmic (see Ch. 39). SYSTEMIC ACTIONS Electrophysiological prope1ties of heart may be markedly altered at high plasma concentrations Any LA injected or applied locally is ul tim ately of LAs : QTc interva l is prolonged a nd LAs absorbed and ca n produce syste mic effects ca n themselves induce ca rdiac a rrh ythmi as. depending on the concentration attained in the Bupivacaine is relatively more cardiotoxic a nd has plasma and tissues. produced ventricular tachycardia, fibrillation and arrest. Lidocaine has little effect on cono·actility C.N.S. and conductivity; it abbreviates ERP and has All LAs are capable of produci ng a sequence o f minimal proarrhythmic potential. It is used as stimulation fo ll owed by depression. Cocaine is an antia1Thythmic (see C h. 39). a powerful CNS stimu lant causing in sequence Blood vessels LAs tend to produce fall in BP. euphoria---excitemcnt- mental con fusion- rest- This is primarily due to sympathetic blockade, lessness- tremor a nd twitching of muscles- but high concentrati ons, as obtained locally at co nvu Is ions- un conscious ness- respirato ry the site of injection, do cause direct relaxation depression-death, in a dose-dependent manner. of a1teriolar smooth muscle. Bupivacai ne is more The synthetic LAs are much less potent in vasodi la tory than lidocaine, w hile pril ocai ne th is regard. At safe clinical doses, they produce is the least vasodilatory. Toxic doses of LAs litt le apparent CNS effects. H ighcr dose or produce cardiovascular collapse. Cocaine has accidental i.v. injection produces C S stimu- sympathomimetic property; increases sympathetic lation followed by depression. tone, causes local vasocon triction, marked rise The early neurological symptoms of overdose in BP and tachycard ia. w ith lidocaine and other c linically used LAs Procaine and related drugs have weak anticholinergic, are--circumoral num bness, abnormal sensation antihistaminic, ganglion blocking, neuromuscular bloc k- in the tongue, dizz iness, blurred vision, tinnitus ing and smooth muscle relaxant properties, but these are fo llowed by drowsiness, dysphoria and lethargy. cl inically insignificant. Sti ll higher doses produce excitation, restless- nc s, agitation, muscle twitching, seizures and PHARMACOKINETICS finall y un consciousness. Because LAs act near their site of adm in istration, T he basic actio n of all LAs is ne uro na l pharmacok inetic characte ri sti cs are not important inhibition; the apparent st im ulation seen initially determinants of the ir e fficacy, but ma rkedly is due to inhibition of inh ibitory neurones. At inOuencc their systemic effects and toxicity. high doses, all neurones are inhibited and flat- So luble surface anaesthetics (lidocaine, teni ng of waves in the EEG is seen. tetracaine) are rapidly abso rbed from m ucous membranes and abraded areas, but absorption c.v.s. from intact ski n is min ima l. Procaine does not Heart LAs arc cardiac depressants, but no sign ificantly penetrate mucous membranes. Rate significant effects are observed at conventional of absorption depends on the blood flow to the doses. At hi gh doses (2- 3 times the doses area of application or injection, e.g. absorption producing C S effects) or on inadvertent i. v. and blood levels arc higher after interco tal injection, they decrease automaticity, excitability, block than after sciatic block. The absorbed LA contractility, conductivity and prolong effective being lipophilic, is wide ly d istributed; rapidly  LOCAL ANAESTHETICS 391 enters highly perfused brain, heart, li ver, and Hypcrsen itivity reactions li ke rashes, angio- kid ney, fo llowed by muscle and other viscera. edema, dem,atiti s, contact sensitization, asthma Procaine is negligibly bound to plasma pro- and rare ly anaphylaxis occur. A llergic reactions teins, but amide LAs are bound to plasma a 1 are more common with ester-linked LAs, but acid glycoprotein. LAs are rapidly but temporarily rare with lidocaine or its congeners. Cross bound 10 tissues, especially nerves, at the site reactiv ity is freq uent among ester compounds, of injection. Ester-linked LAs (procaine, etc.) but not with ami de-linked LAs. are rapidly hydrolysed by plasma pseudocholin- Often methy lparaben added as preservative esterase and the remaining by este rases in in certain LA solutions is respons ible for the the li ver. Am ide-linked LAs ( lidocai ne, e tc.) a llergic reaction. are degraded only in the liver microsomes by dca Iky lat ion and hydrolys is. M etabol ism of Precautions and interactions lidocaine is hepatic blood-fl ow dependent. The I. Before injecting the LA, aspi rate lightly to maxi ma l safe dose of LAs is lower in patients avoid intravascular injection. with hepatic disease and in the e lderly who 2. Inject the LA s lowly and take care not lo have decreased li ver function. exceed the maxi mum safe dose, especia ll y in Afte r oral ingestion both procaine a nd children. lidocaine have high first pass metabol ism in 3. Propranolol (probably other p blockers a lso) th e liver. Thus, they are not active oral ly fo r may reduce metabolism of lidocai nc and other anti arrhythm ic purposes. amide LAs by reducing hepatic blood flow. 4. Vasoconstrictor (adrenaline) conta ining LA ADVERSE EFFECTS should be avoided for patients. wi th ischaem ic Systemi c toxicity on rapid i. v. injection is related heart disease, ca rdiac arrhythmia, thyrotoxicosis, to the intrinsic anaesthetic potency of the LA. uncontrolled hype rtension, and those receiving P However, toxicity after topical application or blockers (rise in BP can occur due to unopposed regional injection is influenced by the relati ve a action) or tri cyclic antidepressants (upta ke rates of absorption and metabolism. Those rapidly blockade and potentiation of Adr). absorbed but slowly metabolized are more toxic. CNS effects are light-headedness, dizziness, INDIVIDUAL COMPOUNDS audi tory an d visua l dis turbances, mental Important properties of local a naestheti cs are confusion, disorientation, shivering, twitchings, compared in Table 26.2. invo luntary movements, finally convulsions Cocaine It is a natural a lkaloid from leaves of Erythroxy- a nd respiratory arrest. This can be prevented lon coca, a south American plant growing on the foothills and treated by diazepam/ midazolam. of the Andes. The natives of Peru and Bolivia habitually chew these leaves. Cocaine is a good surface anaesthetic Cardiovascular toxicity of LAs is manifested and is rapidly absorbed from buceal mucous membrane. as bradycardia, hypotension, cardi ac arrhyth- II was first used for ocular anaesthesia in 1884. Cocaine mias, asystole a nd vascu lar collapse. should never be injected; it is a protoplasmic poison and Inj ection of LAs may be painful, but local causes tissue necrosis. Cocaine produces prominent CNS stimulation with marked effect on mood and behaviour. It t iss ue tox ic ity of LAs is low. However, induces a sense of wellbeing, delays fatigue and increases wou nd healing may be sometimes delayed. power of endurance. In susceptible individuals it produces Addition of vasoconstrictors enhances the a state referred 10 as ' high · lead ting to strong psychological local tissue damage; rarely necrosis results. but liule physical dependence. Cocaine is unique among drugs of abuse in not producing signifi cant tolerance on Vasoconstrictors should not be added fo r ring repeated use; sometimes reverse to lerance is seen (beha- block of ha nds, feet, fingers, toes, penis and vioural effects are experienced at lower doses). in pinna. Bupivacaine has the highest local Cocaine also s timulates vagal ccntrc bradycardia; tissue irrilancy. vasomotor centre rise in BP: vomiting centre nausea 392 DRUGS ACTING ON PERIPHERAL (SOMATIC) NERVOUS SYSTE M Table 26.2: Comparative features of commonly used local anaesthetics Drug Surface Nerve block Cardio- anaesthesia toxicity Relative Cone. Max. Onset Duration potency used (%) dose (Min) Lidocaine + 1 0.5-2.0 300mg Fast 60-120 + Bupivacaine - 4-5 0.25---0.5 150 mg lnterm. 120-360 +++ Ropivacaine - 3-4 0.25---0.75 200 mg Slow 120-300 ++ and vomiting; temperature regulating ccntrc pyrexia (also a rrest li ke o ther LAs. Lidoca ine is a popular due to increased heat production as a result of enhanced ant iarrhythmic (see Ch. 39). muscular activity). XYLOCAl'IE, GESICA I -t%, topical solution. 2°0 3clly, In the periphery, it blocks uptake of A and Adr into 2% ,i~cous, 5% ointment. 1 - and 2% injection (with or adrenergic nerve endings, (see Fig. 9.4) resulting in higher without adrenaline), 5% heavy (for spinal anaesthesia): concentration o f the transmiller around the receptors l00 mg/ml spray (IO mg per actuation). sympathom imetic e ffect, potcntiarion of d irectly acting XYLOCA INE 2% with adrenaline 1:80,000 in 1.5 ml sympathomimetics and suppression of indirectly acting cartridge for dental anaesthesia. sympathornirnctics. Local vasoconstriction , tachycard ia, A transdermal patch of lidoeaine has been produced rise in BP and myd riasis arc the manifestations o f its for application over the affected skin for relief of burning sympathomimctic action. pain clue to postherpetic neuralgia. The only indicatio n for cocaine is in ocular anaesthesia. However, it causes constriction of conjunctiva! vessels, Prilocaine It is similar to lidocainc but docs 110 1 cause c louding and rarely sloughing of cornea (due to drying and vasodilatation at the site of infiltration and has lower C S local tissue toxicity). Its use, therefore, is not warranted. toxicity clue 10 larger vo lume o f distribution and faster clearance. One of its metabolites has the potential to cause Procaine It is t he first synt hetic local a naest hetic methacmoglobinaemia. Prilocainc has been used for infiltration. introduced in 1905. Its popularity dec lined after the nerve block, spinal and intravenous regional anaesthesia. introduction of lidocainc, and it is not used no\\. It is not a surface anaesthetic. Eutectic lidocaine/prilocaine Also called Procaine fom1s poorly soluble salt with bcn7yl penicil- eutectic mixture of local anaesthetics (EM LA), lin; procaine pe11icilli11 injected i.m. acts for 24 hours due th is is a un ique preparation which can anaes- 10 slow absorption from the site o f injection. the tise intact skin afte r s urface application. Lidocaine (Lignocaine) Introduced in E11tectic mixture refers to lowering of me lting 1948, it is c urrentl y the most w ide ly used LA. poi nt o f two solids when they are mixed. Th is It is a versatile LA, good both fo r surface happens when lidocai ne and prilocaine are mixed application as well as injection and is ava il- in equal proportion at 25°C. The resulti ng oil able in a variety of form s. Inj ected around is emulsified into water to fo nn a cream that a nerve it blocks condu ction wi thin 3 min, is applied under occlusive dressing for 1 hr w hereas p roca ine ma y ta ke 15 m in ; a ls o before i.v. cannula ti on, s plit skin graft harvest- a naesthes ia is mo re intense and longer last- ing and other superficial procedures. umbness ing. Vasod ila ta tion occurs in the injected area. up to a depth o f 5 mm lasts for 1-2 hr a fter Tt is used for surface applicatio n, infi ltration, removal. It can be used as an altern at ive to ne rve block. epidural, spinal a nd intravenous lidocaine infi ltration. regio nal block anaesthesia. Lidocaine 2% with PRILOX 5% cream. or without adrenaline is the most popular dental Bupivacaine It is a more lipophi li c a nd anaesthe tic. Cross-sensitivi ty with ester LAs is more potent lo ng-actin g a mide -li nked LA, not seen. T he earl y centra l effects of lidocaine whi ch is used for infilt ra ti o n, ner ve b lock. arc depressant, i.e. drowsiness, mental clouding, epidu ral and spinal anaesthesia of long dura- dysphoria, a lte red taste and ti nn itus. Overdose tion. Because of slow onset of action, it is not causes muscle twitching, convuls ions. cardiac preferred for periphe ral nerve block. A 0.25% a rrhythmias, fa ll in BP, coma a nd respiratory solution injected epidurally produces adequate  LOCAL ANAESTHETICS 393 anal gesia without significant motor blockade. As a obtai ned wi th epidural rop ivaca ine. Continuous result, it has become very popular in obstetrics epidura l ropivacaine has become popular for (mother can actively cooperate by ' bea ri ng down' relief of postoperative and labour pain. It can during vaginal de livery) and for postope rative also be employed for nerve blocks. pain relief by continuous epidural infusion. ROPIN 0.2° 0 inJ. Due to high lipid-solubility it distributes more Tetracaine (Amethocaine) A highly lipid-soluble PABA ester, more potent and more toxic due to slow hydrolysis in tissues than in blood after spinal/e pidural by plasma pseudochol inesterasc. It is both surface and injection. T herefore. it is less like ly to reach conduct1011 block anaesthetic, but its use is restrictt:d to the foetus (when used during labour) Lo produce topical application 10 the eye, nose and throat. Though n neonatal depression. is slow acting, absorption from tracheobroncbial spray is Bupivacaine is more prone to prolong QTc , ery fast and blood concentrations approach those attamed aller 1.v. injection. Therefore, its use for bronchoscopy is interval and induce ventricular tachycardia or contraindicated. cause cardiac depression. Epidural anac thesia ANCTI 1/\NE po"der for solution. 1° o omtmcnt with 0. 75% bupivacaine during labour has caused Proparacaine (proxymetacai ne) This few fatalities due to cardiac arrest. As such, newer surface anaesthetic is the most commonly use of this concentration is contraindicated. used ophthalmic anaesthetic now. It is a meta- Cardiac toxicity is a maj or concern which amino ben zoic acid derivative which is equally limits the total dose of bapivacaine. Recently, effective but faster acting than tetracaine. i.v. infusion of lipid emulsion has been found Tonometry can be performed 30 sec. after to reverse bupivacaine cardiotoxicity, probably instilling one drop 0.5% proparacaine in the by extracting lipophil ic bupivacaine from plasma eye. Corneal anaesthesia lasts for I 0-20 min. and cardiac tissues. Deeper anaesthesia needed for cataract extraction The strength of bupivacaine solution for can be obtai ned by applying 1- 2 drops eve1y different types of blocks is: 5- 10 min. for a maximum of 5 applications, Peripheral ner,e block: 0.25 0.5% Spinal anaesthesia: 0.5% (hyperbaric) whi le for foreign body/suture removal 2- 3 Epidural anaesthesia: 0.25 0.5% applications may be enough. Proparacaine causes Continuous epidural analgesia: 0. 125%. minimal ocular irritation. A llergic reactions are \1ARCAI 0.50., inj. for ncnc block, o.5% hyperban c infreq uent compared to tetracaine. However, ror spinal anae,thcsia. SENSORCA INE 0.25%, 0.5% inj, 0.5% heavy inj. severe immediate corneal reac tion may occu r Levobupivacalne The S(-) cnamiomcr ofbupivacai ne is rarely. equally potent but less cardiotoxic and less prone to cause PARACAl'\E. PROPCA I E 0.5°0 eye drops. 5 ml bottle. sci7ures (after inadvertent intra vascular injection) than racemic Dlbucaine (Cinchocaine) It is the most potent, most bupivacaine. It is being used in some countries as a single toxic and longest acting LA. It is used as a surface anaes- enantiomer preparation. thetic on less delicate mucous membranes (anal canal). Use Ropivacaine A newer bupivacaine congener, for spinal anaesthesia of long duration has been abandoned. NUPERCA l"IA L 1% ointment, in OTOG ESIC I% ear drops. nearly as long act ing but less card iotox ic. Benzocaine and Butylaminobenzoate (Butam- It blocks A8 and C fibres ( involved in pain ben) Because of very low aqueous solubility, these LAs transmission) more completely than AP fib res are not significantly absorbed from mucous membranes or wh ic h control motor fu nction. Lower lipid abraded skin. They produce long-lasting numbness without solubility of ropivacaine makes it less like ly systemic tox icity. When absorbed. benzocaine can cause methaemoglobinemia. These LAs arc used as lozenges for to penetrate large myelinated motor fibres than stomatitis, sore throat; as dusting powder/ointment on wounds/ the sensory fibres. The same may account for ulcerated surfaces and as suppository for anorcctal lesions. its lower C S and cardiac toxicity. Used as Both arc PABA derivative, therefore can antagonize sulfona- the S(- ) e nantiomer, equieffective concentra- mides locally. PROCTOSEDYL- M: Butylammobcn,wate I% oint "ith tions of ropivacaine are higher tha n those of fram)Ct:t in and hydrocon isonc acetate: for piles. bupivacaine, but a greater degree of separation PROCTOQUINOL 5% ointment of bcn7ocamc. ZOKE:-. between sensory and motor block has been 20°0 gd. 394 DRUGS ACTING ON PER IPHE RAL (SOMATIC) NERVO US SYSTEM Oxethazaine A potent topical anaesthetic, unique in ion prolong topical anaesthesia. Absorption of soluble izing lo a very small extent even at low pH values. ll is, LAs from mucous membranes is rapid; blood therefore, able to anaesthetise gastric mucosa despite acidity concentrations of tetracaine sprayed in throat/ of the medium. Swallowed along with antacids it affords symptomatic relief in gastritis, drug induced gastric irritation, tracheobronchial tree approach those attai ned gastroesophageal reflux and heartburn of pregnancy. Doses o n i. v. injec tion- toxicity can occur. Except exceeding I 00 mg/day may produce di.a.iness and drowsiness. for eutectic lidocaine/prilocaine, no other LA is MUCAINE Oxetha?ainc 0.2% in alumina gel + magnesium capable of anaesthetizing intact skin. The sites hydroxide suspension; 5 IO ml orally. TRICAINE-M PS: OxethaMtine 10 mg with methyl poly- and purposes fo r which surface anaesthes ia is s il oxane 125 mg, alum. hydroxide gel 300 mg, mag. used a re given in Table 26.3. hydroxide 150 mg per 5 ml gel. 2. Infiltration anaesthesia Dilute solution of LA is infiltrated under the skin in the area USES ANO TECHNIQUES OF LOCAL of operation so that sensory nerve endings are ANAESTHESIA blocked. O nset of act ion is almost immediate and 1. Surface anaesthesia This is produced durati on is shorter than that afte r nerve block, by topical application of a surface anaesthetic e.g. lidocaine 30-60 min, bupi vacaine 90-1 80 to mucous membranes or abraded skin. Only min. Infiltration is used for minor operations. the superficial layer is anaesthetised and there is e.g. incis ions, excisions, hydrocele, hernior- no loss of motor function. Onset and duration rha phy, etc. when the area to be anaesthetised depends on the site, the drug, its concentration is small. Relatively larger amount of LA is and form, e.g. lidocaine ( 10%) sprayed in the required compared to the area a naesthetised, throat acts in 2- 5 min and produces anaesthesia but motor function is not affected. for 30-45 m in. Addition of Adr does not affect 3. Conduction block The LA is inj ected duration of topical anaesthesia, but phenyleph- aro und nerve trunks so that the area d istal to rine can cause mucosal vasoconstr iction and injection is anaesthetised and paralysed. Choice of Table 26.3: Sites and uses of surface anaesthesia Site Drugs Form Purpose 1. Eye Proparacaine 0.5% drops tonometry, cataract and other Tetracaine 1-2% ointment, drops ocular surgery 2. Nose, ear Lidocaine 2--4% drops painful lesions, polyps Tetracaine 1-2% 3. Mouth, throat Benzocaine lozenges stomatitis, sore throat Lidocaine 2% rinse solution painful ulcers 4. Pharynx, larynx, trachea, Lidocaine 4- 10% spray tonsillectomy, endotracheal bronchi 2% jelly intubation, endoscopies 5. Esophagus, stomach Oxethazaine 0.2% suspension gastritis, esophagitis, heartburn 6. Abraded skin Tetracaine 1% cream, ointment, ulcers, bums, itching Benzocaine 1- 2% dusting powder dermatoses Butamben 1-2% 7. Intact skin Eutectic 5% cream under i.v. cannulation, skin surgery lidocaine/ occlusion prilocaine 8. Urethra Lidocaine 2% jelly for dilatation, catheterisation 9. Anal canal, rectum Lidocaine 2--4% ointment, cream, fissure, painful piles, surgery, Dibucaine 1% suppository proctoscopy Benzocaine 5%  LOCAL ANAESTHETICS 395 the LA and its concentrarion is mainly dic tated gravity of drug solution a nd posture of the by the required duration of action; lidocaine patient. The drug solution could be hyperbaric ( 1- 2%) wi th shorter duration of action is most (in 10% glucose) or isobaric with CS F. commonly used. but for longe r lasting anaes- The nerve roots rapidly take up and retain thesia bupivacaine may be se lected. the LA, therefore, its concentration in CSF falls (a) Field block l t is produced by injecting the quick ly after injection. T he level of anaesthesia LA subcutaneously in a manner that a l I nerves does not change with change o f posture (becomes comi ng to a partic ula r field a re blocked-as fixed) after IO min. Also, h ighe r segments a re is don e for he rni orrhaphy, appe ndi cectomy, exposed to progressively lower concentrations dental procedures, scalp stitching, operations of the LA. ince autonomic preganglionic fibres on forearms and legs. etc. Larger area begin- are more sensitive and somatic motor fibres less ning 2- 3 cm distal to the line of inj ection can sensitive than somatic sensory fibres, the level of be anaestheti sed with lesser drug compared to sympathetic block is about 2 segments higher and infi ltraiion. The same concentrat ion o f LA as the level o f motor para lysis about 2 segments for infi ltration is used for field block. lower than the level of cutaneous ana lgesia. The duration of spina l a naesthesia depends (b) Nerve block It is produced by injecting on the drug used and its concentration (Table the LA around the appropriate nerve trunks or 26.4). Addit ion o f 0.2-0.4 mg of adrenaline to plexuses. T he area of resulting anaesthes ia is the LA prolongs spinal anaesthesia by about larger compared to the amount of drug used. I/3rd when measured by the time taken for the Muscles suppl ied by the injected nerve/plexus level of ensory block to recede to LI. Ad r are paralysed. The latency of anaesthesia depends may be enhancing spinal anaesthesia by reduci ng on the drug a nd the area to be cove red by spina l cord blood flow or by its own analgesic diffusion , e.g. lidocaine anaesthetises intercostal effect exerted through spina l a , adrenocepto rs nerves within 3 min, but brachia! plexus block (intrathccal clonidine, an a , agonist, produces may take 15 min. For plexus block a ' flood- spinal ana lgesia by itself). ing' technique is used and larger volumes are Women during late pregnancy req ui re less needed. erve block lasts longer than field block drug for spinal anaesthesia, because inferior vena or infiltration anaesthesia. Frequently performed cava compression by the e nlarged uterus leads nerve blocks are-lingual, intercosta l, ulnar, sci- to engorgement of the vettebral system and a atic. femoral, brachia! plexus, trigeminal, facial, decrease in the capacity of suba rac hnoid space. phrenic, etc.- uscd for tooth extracti on, operations Spina l anaesthesia is used fo r operations on on eye, limbs, abdominal wall, fracture setting, the lower limbs. pelvis, lower abdomen, e.g. trauma to ribs, neuralgias, persistent hiccup, etc. The primary purpose of nerve block anaesthesia is 10 abolish prostatectomy, fracrure setti ng, obstetric proce- pain and other sensations. The accompanying motor paralys is dures, caesarean section. etc. Choice of the LA may be advantageo us by providing muscle relaxation during fo r spinal anaesthesia primarily depends on the surgery, as well as disadvantageous ifit interferes with breath- nature and duration of the operative procedure. ing, ability 10 walk afte r the operation. or pa11ic ipation of the patient in labour or produci;,s postural hypote nsion. The LAs employed with their doses and dura- 4. Spinal anaesthesia The LA is injected tion of a naesthesia are given in Table 26.4. in the subarac hno id space between L2- 3 or Advantages of spinal anaesthesia over general L3--4, i.e. below the lower end of spi nal cord. anaesthesia are: The primary site of action is the nerve roots It is safer. in the cauda equina rather than the spi nal cord. Produces good analgesia and muscle relaxa- Lower abdomen and hind limbs are anaesthetised ti on without loss o f consciousness. and paralysed. The level of anaesthesia depends Cardiac, pulmonary. renal disease and diabetes on the volu me and speed of injection, spec ific pose less problem. 396 DRUGS ACTING ON PER IPHERAL (SOMATIC) NERVOUS SYSTE M Table 26.4: Local anaesthetics used for spinal and epidural anaesthesia and continuous epidural analgesia Drug Spinal Epidural (lumbar) Cont. epidural Concn. Tota/dose Duration Concn. Tota/dose Concn. (max. dose) Lidocaine 1.5-5% 25-75 mg 60-90 min 1- 2% 200-300 mg (Heavy) Bupivacaine 0.5% 10-20 mg 90-150 min 0.25-0.5% 75-150 mg 0.125% (400 mg/day) (Heavy) Ropivacaine 0.75% 25mg 90-120 min 0.75% 100-200 mg 0.2% (12-24 mg/hour) Complications of spinal anaesthesia 5. Cauda equina syndrome It is a very rare neurological complicati on resulting in 1. Respiratmy para(vsis With proper care, this pro longed loss of control over b ladder and is rare. Even when intercostal musc les a re bowel sph incters. T he cause is uncertain, but paralysed, the diaphragm (supplied by phrenic may be due to traumatic damage to nerve nerve) mainta ins breathing. Hypotension and roots or chron ic a rach n oid itis caused by ischaemi a o r respiratory centre is more fre- inadvertent introduction of the antiseptic in quently the cause of respiratory fai lure than the su barachnoid space. eurotoxicity of the diffusion or the anaesthetic to higher centres. LA has also been blamed, especially when Due to paralysis of external abdominal and high/ repeated doses are given. intercostal muscles, coughing and expectora- tion becomes less effective. This may lead to 6. Nausea and vomiting This is more com- pulmonary compli cations. mon after abdom inal operations, and is due 2. llypotension It is due to blockade of to refl exes triggered by traction on abdominal sy mpatheti c vasocons tri c tor o utfl ow to the v iscera. Premedica tion with ondansetron or blood vessels; venous pooling and decreased metoclopramide prevents it. return to the heart contributes more to the fall 5. Epidural anaesthesia The spinal dural in BP than arteriolar dilatation. Paralysis of space is filled with semiliquid fat through which skeletal muscles of lower limb is another factor ne rve roots travel. The LA injected in this reducing venous return. Decreased sympathetic space-acts primarily on the nerve roots (in flow to heart and low venous return produce the epidural as well as subarachnoid spaces to bradycardia. Rais ing the foot end overcomes whi ch it diffuses) and small amount permeates the hypotension by pro moting venous d rain- through intervertebral foramina to produce mul- age. Sympathomimetics. especial ly those with tiple paravertebral blocks. Epidural anaesthesia prominent constrictor effect on veins (ephed- can be di vided into 3 categori es depending on rine, mephcntcrmine) effectively prevent and the site of injection. counteract the hypotension. (i) Thoracic The LA is injected in the midtho- 3. Neurologicul ~ymptoms Pain an d/ or par- rac ic region. The epidural space in thi s region aeslhesias in the back and lower limbs lasting is relative ly narrow; therefore smaller vol ume of short periods are fe lt by some patients after the drug is needed and a wide segme ntal band recovery from spina l anaesthesia, especially of analgesia involving the midd le and lower when lidocai ne is used. This is infrequent w ith thoracic derrnatomes is produced. It is used bupivacai ne. However, no neurological deficit generally for pain relief following thoracic/upper attends the symptoms. abdominal surgery. Specially des igned catheters 4. Headache It may occur due to seepage of are avai lable which can be placed for repeated CSF, which can be minim ised by us ing smaller injections or continuous infusion of the LA to bore needle. achieve epidural analgesia lasting few days.  LO CAL ANAESTHETICS 397 Contraindications to spinal anaesthesia periods. Spread of the LA in the epidural s pace is governed by the vo lume injected: larger vol- Hypotension and hypovolemia. ume anaesthetizes mo re exte nsive area. Zone of Uncooperative or mentally ill patients. d ifferentia l sympathetic blockade is no t evident Infants and children-control of level is difficult. after epidura l injecti on but motor para lysis is Bleeding diathesis. 4- 5 segme nts c auda l, especia lly w ith lower Raised intracranial pressure. concentrati ons of the LA. Greatest sepa ratio n Vertebral abnormalities e.g. kyphosis, lordosis, etc. between sensory and mo to r b lock is o bta ined Sepsis at injection site. by use of 0.25% bupivacaine and ropi vaca ine. (ii) Lumbar Relatively large volume of drug T his is especiall y valuable for obstetric purposes is needed because epid ura l space is wide. It (mother can partici pate in labo ur w ithout fee ling produces anaesthesia of lower abdo men, pelvis pain) a nd for postoperative pa in re lief. and hind limbs. Use of lumbar epidural anaes- 6. Intravenous regional anaesthesia (lntravascular infiltration anaesthesia, or Bier's block) It con- thesia is similar to that of spina l anaesthesia. sists o r inject ion of the LA solution in a large vein of (iii ) Caudal Inj ection is g iven in the sacral a tourn iquet occluded lim b such that the drug diffuses cana l through the sacra l hiatus. T his produces retrograde from the peripheral vascu lar bed to nonvascular anaesthesia of pel vic and perinea[ region. 1t is tissues incl uding nerve endings. The limb is fi rst elevated to ensure venous drainage by gravity and the n tightly used mostly fo r vagina l de livery, ano recta l and wrapped in an elastic bandage for max imal exsanguinat ion. genito urinary o peratio ns. Tourniquet is then applied proximally and inflated to above Lidocaine ( 1- 2%) and bup ivacaine (0.25- arterial BP. Elastic bandage is now removed and 20-40 ml 0.5%) are popular drugs for epidural anaesthesia. o f 0.5% lidocaine is injected i.v. under pressure dista l to the tourniquet. Regional ana lgesia is produced within 2- 5 Onset is slower a nd duration of anaesthesia is min and lasts ti ll 5-10 min after deflating the tourniquet longer w ith bupivacaine and actio n of bo th the which is kept inflated for not more than 15-60 min to d rugs is prolo nged by addition of adrena line. avoid ischaemic injury. Deflation in < 15 min may allow Technica lly epidura l a naesthesia is more difficult toxic amounts of the LA to enter systemic circulation. than s pi nal ana esthesia and re latively larger The safety of the procedure depends on the rapid uptake of LA by peripheral tissues; only 1/4 of the injected drug vo lumes of drug are needed. Consequ ently, enters systemic circulation when the tourniquet is released. blood co ncentrat ions o f the L A are hig he r. Bradycard ia can occur. Ca rd iovascul ar co mp lication s a re s im ila r to It is mainly used for the upper limb and for orthopaed ic th ose after s pina l anaesthe sia , but headac he procedures. Obstruct ing the blood supply o f lower limb is more difficult and larger volume of the anaesthetic is and neurological c omplications are less Iike ly, needed. Therefore, it is rarely used for lower limb. except because intrathecal space is not entered and the the foot. Bupivacaine should not be employed because of LA is not restri cted to a small area for lo ng its higher cardiotoxicity. er PROBLEM DIRECTED STUDY 26.1 A healthy full-term primigravida aged 26 ye ars w ho has gone into la bour presents for del ivery. There is no ce phalopelvic dis pro portion o r a ny oth e r cont ra ind icatio n t o no rm a l vagina l delive ry. However, she de mands rel ief of pain associated with la bo ur and de live ry. (a ) Can some form of regional anaesthesia be use d t o re lieve he r pa in? If so, w hich type of regiona l a naesthe sia with whi ch drug wo uld be most s uita ble fo r he r? (see Appe ndix-1 for so lution)  DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Chapter 27 General Anaesthetics General a naesthetics (GAs) are drugs w hi ch MECHANISM OF GENERAL produce reversib le loss of all sensation and ANAESTHESIA consciousness. The cardinal features of general The mechanism of ac tion of GAs is not precisely anaesthesia are: known. A wide variety of chemical agents pro- Loss of all sensation, espec ially pain duce genera l anaesthesia. Therefore, GA actio n Sleep (unconsciousness) and amnes ia had been related to so me common physicoc he- Immobility and muscle relaxatio n mi cal property of the drugs. Mayer and Overton Abolition of somatic and autonomic reflexes. (190 1) pointed out a direct parallelism between In the modem practice of balanced anaesthesia, lipid/water partition coefficient of the GAs and these modalities are achieved by us ing combi- their anaesthetic potency. nation of inhaled and i. v. drugs, each drug for Minimal alveolar concentration (MAC) It a s pecific purpose. Anaesthesia has developed is the lowe t concentrat ion o f the anaesthetic as a hig hly specialized science in itself. in the pulmonary alveoli needed to produce History Before the middle of I 9th century a number of agents like alcohol, opium, cannabis, or even concus- immobil ity in response to a painful stimulus sion and asphyxia were used to obtund surgical pain, but (surgical inc is io n) in 50% individuals. It is operat ions were horrible ordeals. Horace Wells, a dentist, accepted as a valid meas ure of potency of picked up the idea of using 11itrot1l' oxide (N,O) from a demonstration of laughing gas in 1844. 1lowever, he often inhalational GAs, because it remains fairly con- fai led to relieve dental pain completely and the use of stant for most young adults. The MAC of a ll N,O had to wait till other advances were made. Morton. a inhalational anaesthetics declines progressively dentist and medical student at Boston, after experimenting as age advances beyond 50 years. on animals. gave a demonstration of ether anaesthesia in 1846, and it soon became very popular. Chloroform was The MAC of a number of GAs shows used by Simpson in Britain for obstetrical purpose in 1847. excellent correlation wi th their oil/gas partition and despite its toxic potential. it became a , ery popular coefficient. However, th is only reflects capac- surgical anaesthetic. Cyclopropane was introduced in 1929, ity of the anaesthe tic to e nter into C S and but the new generation of anaesthetics was heralded by ha/01ha11e in 1956. The first i.v. anaesthetic thiopentone attain sufficient concentrati on in the neurona l was introduced in 1935. membrane, but no t the mechanism by which 400 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM anaesthesia is produced. The 'unita,y hypothesis' On the other hand, pa nd ketamine do not that some single common molecular mechanism affect GA BA or g lycine gated C f channels. Rather (like membrane expansion or membrane perturba- they selectively inhibit the excitatory MDA type tion or membrane fluid ization) is responsible of glutamate receptor. This receptor gates mainly for the actio n of all inha lational anaesthetics Ca2 selective cation channels in the neurones, has now been replaced by the 'agent specific inhibition of which appears to be the primary theory' according to which different GAs produce mechanism of anaesthetic action of keta mine as anaesthesia by dilTerent mechanisms. well as N 20. The volatile anaesthetics have little Recent evidence favours a di rect interaction acti on on this receptor. of the GA mo lec ules with the hydrophobi c Neuronal hyperpolarization caused by GAs has do mains of me mbra ne prote ins or the lipid- been ascribed to activation of a specific type of protein interface. K+ cha nne ls called ' two-pore domain' cha nnels. ot only different anaesthetics appear to act This may cause inhibition of presynaptic trans- by different mo lecular mec hanisms, they also mitter release as well as postsynaptic activation. may exhibit stereospecific effects, and that various Inhibition of transmitter re lease from presynaptic components of the anaesthetic state may involve neurones has also been related to interaction with action at discrete loci in the cerebrospinal axis. The certain critical synaptic proteins. Thus, dilTerent principal locus of causation o f unconsciousness facets of anaesthetic action may have distinct appears to be in the thalamus or reticular activating neuronal basis, as opposed to the earlier belief system, amnesia may result from action in cerebral of a g lobal neuronal depression. cortex and hippocampus, while spinal cord is the Unl ike local anaesthetics which act primarily likely seat of immobility on surgical stimulation. by blocking axonal conduction, the GAs appear Recent findings show that ligand gated ion to act by depressing synaptic transmission. channels (but not voltage sensiti ve ion channels) are the major targets of a naesthetic action. The STAGES OF ANAESTHESIA GABAA receptor gated er c hannel is the most important of these. Many inhalational a naes- GAs cause an irregularly descending depression thetics, barbiturates, benzodiazepines and propo- of the CNS, i.e. the higher functions are lost first and progressively lower areas of the brain fol potentiate the action of inhibitory transmitter are in volved , but in the spinal cord lower GABA to open C l- channe ls. Each of the above segments are a ffected some what earli er than a naesthetics appears to interact with its own the higher segments. The vital ce ntres located specific binding site o n the GABAA receptor-C l in the medu lla are paralysed the last as the channe l complex, but none binds to the GABA depth of anaesthesia increases. binding site as such; though some inhaled anaes- Guedel ( 1920) described four stages with ether anaesthesia, di viding the 111 stage into 4 planes. These clear-cut stages thetics and barbiturates (but not benzodiazepines) are not seen now-a-days with the use of faster acting GAs, can d irectly activate Cl channels. Action of premedicatio n and employment o f many drugs together. glycine (another inhibitory transmitter which also The prec ise sequence of even ts d iffers somewhat with activates Cf channels) in the spinal cord and anaesthetics other than ether. However, description of medulla is augmented by barbiturates, propofol these stages still serves to define the effects of light and and many inhalational anaesthetics. This action deep anaesthesia. Important features of different stages arc depicted in Fig. 27.1. may block responsiveness to painfu l stimuli resulting in immobility of the anaestheti c state. I. Stage of analgesia Stans from beginning of anaes- thetic inhalation and lasts upto the loss of consciousness. Certain fluorinated anaesthetics and barbiturates, Pain is progressively abolished. Patient remains conscious, in addition, inhibit the neuronal cation channel can hear and see, and feels a dream like state; amnesia gated by nicotinic cholinergic receptor which develops by the end of thi s stage. Reflexes and respira- may mediate anal gesia and amnesia. tion remain nonnal.  GENERAL ANAESTHETICS 401 Ocular Pupil SK.mus. STAGE Respiration movem. size Reflexes tone B. P. H. R. USES Thor. Abd..J Labour, I 0 J w ,(..I I- Incisions and ANALGESIA w z w I " w 0: n:z JC, Minor ops. II ,(0 NIL DELIRIUM J: CJ 0.. 2 MAC. of induction is greatest in the case of agents Decrease in cerebral metabolic rate which which have high blood solubility because their indirectly reduces cerebral blood flow (CBF). PP in blood takes a long time to approach the However, at higher concentrations, their PP in alveoli. However, it does not affect the direct vasodilatory action predominates and terminal depth of anaesthesia attained at any CBF may actually increase. These higher given concentration of a GA. concentrations should be avoided in patients w ith raised intracranial pressure. 3. Alveolar exchange T he GAs diffuse freely A ll fluorinated anaesthetics depress card iac across a lveoli, but if a lveolar ventilation and contractility a nd lower BP. pe rfusion are mismatched (as occurs in emphy- Respiratory depression, bronchodilatation and sema a nd other lung diseases) the attainment reduced airway mucociliary function occurs; of equilibrium between alveoli and blood is so that prolonged anaesthesia predisposes to delayed: we ll perfused alveol i may not be respiratory complications. well ventilated- blood draining these alveoli Limited and reversible lowering of GFR carries less anaesthetic a nd di lutes the blood and urine fl ow. coming from well ventilated alveoli. Induction Reduced gastrointestinal motility. and recovery both are slowed.  GENERAL ANAESTHETICS 403 4. Solubility of anaesthetic in blood This prolonged anaesthesia, especially in case of more is the most important property determining lipid-soluble anaesthetics (halothane, isoflurane), induction and recovery. Large amou nt of an because large quantities of the anaesthetic have anaesthetic that is high ly soluble in blood entered the muscle and fat, from which it is (ether) must dis olve before its PP is raised. released slowly into blood. The rise as well as fall of PP in blood and Second gas effect and diffusion hypoxia consequently induction as well as recovery are In the initial part of induction, diffusion gradient slow. Drugs with low blood solubility, e.g. Np, from alveoli to blood is high and larger quantity sevoflurane, desfl urane induce quickly. of anaesthetic is entering blood. If the inhaled Blood: gas partition coefficient p,.) given by concentration of anaesthetic is high, substantial the ratio of the concentration of the anaesthetic loss of alveolar gas volume will occur and the in blood to that in the gas phase at equi librium gas mixture will be sucked in, independent of is the index of solubility of the GA in blood. ventilatory exchange- gas Row will be higher 5. Solubility of anaesthetic in tissues Rela- than tidal volume. This is significant only with tive solubili ty of the anaesthetic in blood and Np, since it is given at 70- 80% concentration. a tissue determines its concentration in that Though it has low solubility in blood, about tissue at equil ibrium. Most of the GAs are I litre/ min of ,0 enters blood in the first equally soluble in lean tissues as in blood, but few minutes. As such, gas flow is I litre/min more soluble in fauy tissue. Anaesthetics with higher than minute volume. If another potent higher lipid solubility (halothane) continue to anaesthetic, e.g. halothane ( 1- 2%) is being given enter adipose tissue for hours and also leave at the same time, it will also be delivered to it slowly. The concentration of these agents is blood at a rate I litre/min higher than minute much higher in white matter than in grey matter. volume and induction will be faster. Th is is called 'second gas effect '. 6. Cerebral blood flow Brain is a highly per- The reverse occurs when 20 is discontinued fused organ; as such GAs are quickly delivered after prolonged anaesthesia: ,0 having low to it. This can be hastened by CO2 inhalation blood solubility rapidly diffuses into alveoli and which causes cerebral vasodilatation- induction dilutes the alveolar air, and PP of oxygen in and recovery are accelerated. Carbon dioxide alveoli is reduced. The resulting hypoxia, called stimulates respiration and this also speeds up diffusion hypoxia, is not of much consequence if the transport. cardiopulmonary reserve is normal. but may be Elimination When inhalation of the anaes- dangerous if it is low. Diffusion hypoxia can be thetic is discon tinued, gradients are reversed prevented by continuing I00% 0 2 inhalation for and the channel of absorption (p ulmonary a few minutes after discontinuing 20 , instead epithelium) becomes the channel of elimination. of straight away switching over to air. Di ffusion All inhaled anaesthetics are eliminated mainly hypoxia is not significant with other anaesthetics, through lungs. The same factors which govern because they are administered at low concentra- induction also govern recovery. Anaesthetics, in tions (0.2-4%) and cannot dilute alveolar air by general, continue to enter and persist for long more than 1- 2% in any case. periods in adipose tissue because of their high lipid solubility and low blood flow to fatty TECHNIQUES OF INHALATION OF ANAESTHETICS tissues. Muscles occupy an intermediate posi- tion between brain and adipose tissue. Most Diffore111 1echniques are used according to facility available, GAs are eliminated unchanged. Metabolism is agen 1 used. condilion of 1hc patient, type and dura1ion of operation. significant only for halothane which is >20% 1. Open drop method Liquid anaesthetic is poured over metabolized in liver. Others are practically not a mask "ith gauze and its Yapour is inhaled with air. A lot metabolized. Recovery may be delayed after of anaeslhelic , apour escapes in the surroundings and the 404 DRUGS ACTI NG ON CENTRAL NE RVOUS SYSTEM concentration of anaesthetic breathed by the patient cannot Properties of an ideal anaesthetic be determined. IL is wastefiil-can be used only for a cheap anaesthetic. I lowever. it is simple and requires no special A. For the patient lt should be pleasant, non- apparatus. Use now is limited to peripheral areas. Ether is the irritating, should not cause nausea or vomiting. only agent administered by this method. especially in children. Induction and recovery should be fast with 2. Through anaesthetic machines Use is made no after elTects. of gas cylinders. spec ialized graduated vaporizers, flow meters, unidirectional valves, corrugated rubber tubing 8. For the surgeon It should provide adequate and reservoir bag. analgesia, immobility and muscle relaxation. The gases are delivered to the patient through a tightly It should be non inflammable and nonexplosive fitting face mask or endotracheal tube. Administration of the so that cautery may be used. anaesthetic can be more precisely controlled and in many situations its concentration estimated. Respiration can be C. For the anaesthetist Its admi nistration controlled and assisted by the anaesthetist. should be easy, controllable and versatile. (a) Open system The exhaled gases are allowed to escape Margin of safety should be wid no fall in BP. through a valve and fresh anaesthet ic mixture is drawn Heart, li ver and other organs should not in each time. No rcbreathing is allow.:d now rates are be affected. high- more drug is consumed. However, prcdctcrmined 0 2 and anaesthetic concentration can be accurately delivered. It should be potent so that low concentrations (b) Closed system The patient rebreaths the exhaled are needed and oxygenation of the patient gas mixture after it has c ircu lated through sodalime does not suffer. which absorbs CO,. Only as much O, and anaesthetic Rapid adj ustments in depth of anaesthesia as have been taken up by the patient are added to the should be possible. circuit. Flow rates are low. This is especially useful for It should be cheap, stable and easily stored. expensive and explosive agents (litt le anaesthetic escapes in the s urrounding air). Halothane, isonurane, desfluranc It should not react with rubber tubing or can be used through closed system. However, control of soda lime. inhaled anaesthetic concentration is imprecise. The important physical and anaesthetic proper- (c) Semiclosed system Partial rcbrcathing is allowed ties of inhalational anaesthetics are presented through a partially closed valve. Cond itions are intennediate with moderate flow rates. in Table 27.1. GENERAL ANAESTHETICS Gas Fast acting drugs Slower acting drugs Nitrous oxide Ether Thiopentonc sod. Halothanc Methohexitone sod. Isoflurane Propofol Desflurane Etomidate Benzodlazepines Opioid analgesic Sevoflurane Diazepam Fentanyl Lorazcpam Remifentanil Midazolam Dissociative anaesthetic Kctamine Cyclopropane, trichloroethylene, methoxyflurane and enflurane are no longer used.  GENERAL ANAESTHETICS 405 Table 27.1 : Physical and anaesthetic properties of inhalat1onal anaesthetics Anaesthetic Botling lnflamma lrritancy Oil: Gas Blood: MAC Induction Muscle point (°C) bility (odour) partition Gas parti- (%) relaxation coefficient· lion coef- ficient· 1. Ether 35 Intl.+ +++ 65 12.1 1.9 Slow V. good Explo. (Pungent) 2. Halothane 50 Noninfl. 224 2.3 0.75 lnterm. Fair (Pleasant) 3. lsoflurane 48 Noninfl. ± 99 1.4 1.2 lnterm. Good (Unpleasant) 4. Desflurane 24 Noninfl. + 19 0.42 6.0 Fast Good (Unpleasant) 5. Sevoflurane 59 Noninfl. 50 0.68 2.0 Fast Good (Pleasant) 6. Nitrous oxide Gas Noninll. 1.4 0.47 105 Fast Poor At 37°C; Oil: gas and blood: gas partition coefficients are measures of solubility of the anaesthetic in lipid and blood respectively. MAC-Minimal alveolar concentration ; lnfl. -lnflammable; Explo.- Explosive; lnterm.-lntermediate INHALATIONAL ANAESTHETICS of 70% p + 2S- 30% 0 2 + 0.2- 2% another potent anaesthetic is employed for most surgi- 1. Nitrous oxide (N2O) It is a colourless, cal procedures. In this way concentration of the odourless, heavier than a ir, noninftammable gas other anaesthetic can be reduced to 1/3 for the supplied under pressure in steel cylinders. It same level of anaesthesia. Becau e Np has little is nonirritating, but low potency anaesthetic; effect on respiration, heart and BP: breathi ng and unconsciousness can not be produced in all circulation are better maintained with the mixture individuals without concomitant hypoxia; MAC than with the potent anaesthetic given alone in full is I OS% imply ing that even pure p cannot doses. However, N,O can expand pneumothorax produce adeq uate anaesthesia at I atmosphere and other abnom1a-l air pockets in the body. It pressure. Patients maintai ned on 70% 2 0 + increases cerebral blood flow and tends to e levate 30% 0 2 a long with muscle re laxa nts often intracranial pressure. Thus, N2O a lone is not suit- reca ll the events during anaesthesia, but some able for patients with raised intracranial pressure. lose awareness completely. As the sole agent, Np (50%) has been used itrous oxide is a good analgesic; even 20% with 0 , for dental and obstetric analgesia. It is produces analgesia equivalent to that produced nontoxic to liver, kidney and brain. However, by convent ional doses of morphine. Muscle prolonged panaesthes ia has th e potential relaxation is min ima l. euromuscular blockers to depress bone marrow and cause peripheral a re mostly requi red. Onset of 20 action is neuropathy, probably by depressing methionin e quick and smooth (but thiopentone is o ften used synthase acti vity. Metabolism of Np does not for induc tion), and recovery is rapid, because occ ur; it is qu ickly removed from the body by of its low blood solubility. Second gas effect lungs. It is cheap and commonly used. and diffus ion hypoxia occur with p only. 2. Ether (Diethyl ether) ll is a highly , olati le liquid, Post-anaesthetic nausea is not marked. It tends produces irritating vapours which arc innammable and explosive. to increase sympathetic tone which inc reases (C2H 5 - 0 - C,H ,) cerebral blood flow and counteracts the weak Ether is a potent anaeslhelic, produces good analgesia and direct de pressant action on heart and circulation. marked muscle relaxation by reducing ACh oulpuL from motor itrous oxide is generally used as a carrier nerve endings. The dose o f compelilive neuromuscular blockers and adjuvant to other anaesthetics. A mixture should be reduced to about 1/3. 406 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM II is highly soluble in blood. Induction is prolonged Halothane causes relatively greate r dep ression and unpleasant with struggling, breath-holding. sali, at ion of respiration; breath ing is shal low and rapid- PP and marked respiratory secretions (atropine must be given as premedica1ion to prevent the patient from drowning in of CO2 in blood rises if respiratio n is not assisted. his own secretions). Recovery is slow: post-anaesthetic Ce rebral blood flow increases. Ventilatory sup- nausea, vomiting and retching are marked. port w ith added oxygen is freque ntly required. Respiration a nd BP are generally \\ ell maintained It tends to accentuate perfusion-ventilation mis- because o f reflex stimulation and high sympathetic tone. It does not sensitize the hcan to Adr, and is not hcpatotoxie. match in the lungs by causing vasodi latation in Ether is not used now. except in periphe ral and hypoxic alveoli. resource-poor areas, because of its unpleasant and inflam- Pharyngea l and laryngeal reflexes are aboli- mable properties. However. ii is cheap, can be given by shed ea rly and cough ing is s uppressed w hile open drop method ( though congestion of eye. soreness of trachea and ether b ums o n face can occur) without the bronchi dilate. As such, ha lothane is the preferred need for any equipment, and is relatively safe even in anaesthetic for asthmatics. It inhibits intestinal inexperienced hands. and uterine contractions. This property is util ized 3. Halothane (FLUOTHANE) It is a vo lat ile for faci litating external or internal version during liquid with sweet odour, nonirritant and nonin- la te pregnancy. However, its use during labour flam mable. Solubility in blood is modera te- can prolong de li very and inc rease postparta l induction is reasonably qu ick and pleasant. blood loss. Urine formation is decreased during ha lothane F'-... / H anaesthesia- primarily due to low g.f.r. as a F-C-C- Br result of fall in BP. F/ "-c1 Hepati ti s occurs in rare susceptible ind ividuals HALOTHANE ( I in 35000 to I in I0,000) especially a fter repea- ted use and in those w ith fami lial predi sposition. A Ha lothane is a pote nt anaesthetic; therefore metaboliteofhalothane is probably involved which precise control of admin istered concentration is believed to cause chemical or immunological is essential. For induction 2-4% and for main- tenance 0.5- 1% is delivered by the use of a injury. Halothane toxicity is less frequent in children. special vapourizer. It is not a good analgesic or A genetically determi ned reaction malignant muscle relaxant, but it po tentiates competitive hyperthermia occu rs rare ly. Many s usce pti ble neuromuscular blockers. s ubjec ts have a n a b normal Ry RI ( Rya nodine Halothane cau es direct depression of myo- receptor) calcium channel at th e sa rcoplasmic cardial contractility by reducing intracellular reticulum of skeletal muscles. This c hannel is Ca1 concentration. Moreover, sympathetic activ- triggered by halothane to release massive amounts ity fails to increase reflexly. Cardiac o utput is of Ca2 intracell ularly causing persistent muscle reduced with deepening anaesthesia. BP starts contraction and increased heat production. Suc- fa lli ng early a nd parallels the depth. A 20-30 c iny lcho li ne accentuates the condition (see Ch. mm Hg drop in BP is common. Many vascular 25). Ra pid external cooling, bicarbonate infusion, beds dilate but total peripheral resistance is 100% 0 2 inhalation and i.v. dantrolene (seep. 382) not significantly reduced. Heart rate is reduced are used to treat maligna nt hyperthermia. by vagal stimulation, direct depression of SA About 20% of halothane that enters blood is noda l automatici ty and absence of barorecep- metabo li zed in the liver, the rest is exhaled out. tor activation even w hen BP fa lls. It te nds to El iminati on may continue for 24-48 hours after sensitize the heart to the aIThythmogenic action prolonged adm inistration d ue to accum ulation in of Adr. The electrophysiological efTects are con- fauy and other tissues. Recovery from halothane ducive to reentry-tachyarrhythmias occur occa- anaesthesia is smooth and reasonably quick; sionally, particularly if sympathetic stimulation shivering may occur but nausea and vomiti ng occurs d ue to inadequate anaesthesia. are rare. Psychomotor performa nce and mental  GENERAL ANAESTHETICS 407 ability remai n depressed for everal hours after Uterine and skeletal musc le re laxation is regaining consciousness. similar to that with halothane, but potentiation Halothane is a frequently used anaesthetic of neuromuscular blockers is greater. in developing countries, because it is relatively Pupils do noLdilate and light reflex is not lost cheap and nonin-itanl, noninflammable, pleasant even at deeper levels. with relatively rapid action. It is particularly Metabolism of isofl urane is negligible. Renal suita ble for use in children, both fo r induction as and hepatic toxiciLy has not been encountered. well as maintenance. In adul ts, it is mainly used Postanaesthetic nausea and vomiting is mild. as a maintenance anaesthetic a fter i.v. induction. Though mildly pungent, isoflurane has many However, in affluent countries it has been largely advantages, i.e. better adj ustment of depth of replaced by the newer agents which are costlier. Its anaesthesia and low toxicity. It is a good mainte- deficiencies in terms of poor analgesia and muscle nance anaestheLic, but not preferred for induction relaxation are compensated by concomitant use because of ether-like odour which is not liked by of p or opioids and neuromuscular blockers. conscious patients, especially children. In contTast 4. lsoflurane (SOFANE, FORANE, ISORANE) This to enflurane, it does not provoke seizures and is fl uorinated anaesthetic introduced in 198 1 is particularly