An(a)esthetics

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

© Assoc. Prof. Iv. Lambev

General anesthetics (GAs)

General anesthesia was introduced into clinical practice in the 19th centurywith the use of volatile liquids asdiethyl ether and chloroform.

Cardiac and hepatic toxicity limitedthe usefulness of chloroform (out of date!).

History

William Morton (Boston, 1846) used

ether successfully to extract a tooth. Pirogoff (Russia, 1847)Simpson (Glasgow, 1847) used chloroform in obstetrics.Queen Victoria gave birth to her children under chloroform anesthesia.

4W. Morton (1846)

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General anesthesia causes:•loss of consciousness•analgesia•amnesia•muscle relaxation (expressed in different extent)•loss of homeostatic control of respiration and cardiovascular function

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Goals of surgical anesthesiaLüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

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The mode of action of GAs is still debated. •All GAs act on the mid-brain reticular activating system and cerebral cortex to produce complete but reversible loss of consciousness. •The principle site of their action is probably the neuronal lipid membrane or hydrophobic domains of membrane proteins.

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According to the new

polysynaptolytic theory general anesthetics

inhibit reversible neurotransmission

in many synapses of CNS.

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GAs depress the CNSin the following order:

1st – cerebral cortex 2nd – subcortex3rd – spinal cord4th – medulla oblongata

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10Principles of Medical Pharmacology – 6th Ed (1998) Principles of Medical Pharmacology – 6th Ed (1998)

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Traditional monoanesthesia vs. modern balanced anesthesia

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

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Regimen for balanced anesthesia

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

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Pharmacokinetic aspectsFor practical purposes GAs can beregarded physicochemicaly as idealgases: their solubility in differentmedia can be expressed as partitioncoefficients (PC), defined as the ratio of the concentration of the agent in two phases at equilibrium.

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•The minimum alveolar concentration (MAC)

indicates the minimum concentration of an anesthetic

required to prevent reflex response to surgical

stimulation.

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DesfluraneIsoflurane EnfluraneHalothaneSevoflurane

halogenated anesthetics

GENERAL ANAESTHETICS

1. Inhalational GAs•Volatile liquids

Diethyl ether (Aether anaestheticus – out of date)•Gases

Nitrous oxide

Structures of inhalational general anesthetics

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Drug Blood/gas Oil/gas Induction PC PC time (min) N2O 0.5 1.4 2 - 3 Isoflurane 1.4 91 - Enflurane 1.9 96 - Halothane 2.3 224 4 - 5 Ether 12.1 65 10 - 20

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Drug MAC Metabo- Flame- (%) lism (%) аbility

N2O >100 0 -Isoflurane 1.2 0.2 -Enflurane 1.7 2-10 -Halothane 0.8 -Ether 2 5-10 ++

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Elimination routes of different volatile anesthetics

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

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Isoflurane is a less soluble isomerof enflurane, and is widely use. Itpotentiates the action of neuromuscularblockers. It produces dose-dependentperipheral vasodilatation and hypoten-sion but with less myocardial depres-sion than enflurane and halothane.

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•Cerebral blood flow is little affected by isoflurane which makes it an agent of choice during neurosurgery.•Uterine tone is well maintained compared with halothane or enflurane and thereby isoflurane reduces postpartum hemorrhage.

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Particular aspects of the use of

Halothane relate to the following:•Moderate muscular relaxation is produced, but is rarely sufficient for major abdominal surgery. It poten- tiates the action of neuromuscular blockers. •Heat loss is accelerated.•It is useful in bronchitic and asthma- tic patients.

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Adverse effects of halothane• Increased myocardial excitability (ventricular exstrasystoles, tachycardia and fibrillation). Extrasystoles can be controlled by beta-blockers. • Blood pressure usually falls, due to central vasomotor depression and myocardial depression.• Cerebral blood flow is increased which is an contraindication for use in head injury and intracranial tumors.

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• Halothane is not good analgesic and also may lead to convulsions. • It can produce massive hepatic necrosis or subclinical hepatitis following anesthesia. The liver damage appears to be a hypersensitivity type of hepatitis which is independent of dose.• Halothane can cause malignant hyperthermia (which need treatment with Dantrolene i.v.) uterine atony and postpartum hemorrhage. It has a teratogenic activity.

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•N2O uses to reduce pain

during childbirth. •Concomitant administration of N2O with one of the volatile GAs reduces the MAC value of the volatile drug by up to 75%.•Risk of bone marrow depression occurs with prolonged administ- ration of N2O.

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2. Parenteral GAsBarbiturates and thiobarbiturates

•Methohexital i.v.•Thiopental (Thiopenthone) i.v.

Other preparations•Ketamine i.v./i.m.•Propofol i.v.•Etomidate i.v.

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Structures of parenteral general anesthetics

Thiopental(thiopentone)-redistri- bution in muscle and fat (long post- narcotic sleep)

Principlesof Medical

Pharmacology(1994)

Principlesof Medical

Pharmacology(1994)

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Thiopental use i.v. for induc-tion of anesthesia, which is main-tained with an inhalation agents.

Propofol. The onset of itsaction begins after 30 s. Aftera single dose patient recoversafter 5 min with a clear headand no hangover.

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Propofol is a donor of NOwith amnesic and antiemetic action. Indications:

•i.v. induction (2–2.5 mg/kg)•maintenance of anaesthesia in doses of 6–12 mg/kg •sedation (2–3 mg/kg) in intensive care or during intensive procedures.

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Ketamine is an antagonist of NMDA-receptor. •It produces dissosiative anaesthesia (seda- tion, amnesia, dissosiation, analgesia). •Ketamine can cause hallucinations and unp- leasant, brightly coloured dreams in 15% of patients during recovery, which are very often accompanied by delirium. •Its use widespread in countries where there are few skilled specialists.•Usually it applied mainly for minor procedures in children (10 mg/kg i.m.).

Ketamine•Calypsol amp. 500 mg/10 ml

Children:10 mg/kg i.m.

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Local anesthetics (LAs)

•LAs are drugs which reversibly pre- vent the transmission of pain stimuli locally at their site of administration. •The clinical uses and responses of LAs depend both on the drug selected and the site of administration.

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LAs are weak bases (pKb 7–8). They exist as an equilibrium between io-nized (LAH+) and unionized (LA) forms.The unionized forms are lipid solubleand cross the axonal membranes. Afterthat the part of the unionized forms protonates intracellulary into the ionized forms. The ionized forms bindto the intracellular receptors, obstruct,and block Na+ channel (see figure).

ExInLAH+ (localanaes-thetics)blockNa+

channels.

Principlesof Medical

Pharmacology(1994)

Principlesof Medical

Pharmacology(1994)

CH3

CH3

NH CH2 CH2N

CH2 CH3

CH2 CH3

NH2

O

O CH2 CH2 N

CH2

CH2

CH3

CH3Procaine

Lidocaine

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Anesthetic potency

LidocaineBupivacaineProcaineArticaine

416 1 4

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LAs from the group of ester (procaine,tetracaine, benzocaine) in plasma andliver hydrolyze to the para-amino-benzoic acid, which is a competitiveantagonist of the sulfonamides. Thus,the co-administration of esters andsulfonamides is not rational.

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Unwanted effectsLocal effects at the site of administra-tion: irritation and inflammation;local hypoxia (if co-administered withvasoconstrictor); tissue damage (some-times necrosis) following inappropri-ate administration (e.g accidentalintra-arterial administration or spinaladministration of an epidural dose).

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Systemic effects. High systemic dosesmay affect other excitable membranessuch as the heart (e.g. lidocaine cancause AV block and cardiovascularcollapse; bupivacaine can cause seriousarrhythmias) or the CNS (tetracainecan cause convulsions and eyesdisturbances; cocaine – euphoria, hallucinations and drug abuse).

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Procaine sometimes causes urticaria.Some systemic unwanted effects

due to the vasoconstrictors - NA or adrenaline. They includehypertension and tachycardia.

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Clinical usesThe extent of local anesthesia dependslargely on technique of administrations:

Surface administration (anesthesia)- high concentrations (2–5%) of theLAs can slowly penetrate the skin andmucous membranes to give a smalllocalized anesthesia.

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Benzocaine and tetracaine are sui-table for these purposes. They produce useful anesthesia of mucous membranesof the throat. Cocaine and tetracaine are used befo-re painful ophthalmological procedures.Propipocaine widely use in dentistry,dermatology, and obstetrics to producesurface anesthesia.

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Infiltration anesthesia can produce with 0.25–0.5%

aqueous solution oflidocaine or procaine

(usually withco-administration

of adrenaline).

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The other main types of local anesthesia are:•nerve trunk block anesthesia;•epidural anesthesia (injection the LAs to the spinal column but outside the dura mater), used in obstetrics; •spinal anesthesia (injection the LAs into the lumbar subarachnoid space, usually between the 3rd and 4th lumbar vertebrae).

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1. Esters1.1. Esters of benzoic acid

•Cocaine (out of date)1.2. Ester of para-aminobenzoic acid

•Benzocaine (... Almagel A®)•Procaine

•Oxybuprocaine•Proxymetacaine•Tetracine (Dicain®)

Erythroxyloncoca

2. Amides•Lidocaine (PRC B) •Bupivacaine•Cinchocaine•Mepivacaine•Prilocaine•Propipocaine

•Articaine (Ultracain)•Xylodren

•Emla(lidocaine +prilocaine)cream5% 5 g

•Emla Patch

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Lidocaine (Lignocaine)has also antiarrhythmic action. It is an antidysrrhythmic agent from class IB, used for treatmentof ventricular tachyarrhythmiafrom myocardial infarction, ventricular tachycardia andventricular fibrillation.

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ARs: Bradycardia, AV block, () inotropiceffect, disturbances of GIT, rashes

Class IB: Decreases the duration of AP

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Ventricular fibrillation, characterized by irregular undulations without clear ventricular complexes

Ventricular flutter

Dorland’s Illustrated Medical Dictionary (2003/2004)Dorland’s Illustrated Medical Dictionary (2003/2004)