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1. LOCAL & GENERAL
ANESTHETICS
Presented By:-Janhavi Yashwant Burade
Vidyabharti College of Pharmacy
Amravati
M. Pharm 1st semester

2. Content
 Local anaesthetic
 Introduction
 History
 Drug classification
 Mechanism of action of LA
 Pharmacokinetic of LA
 Recent advances
 General anaesthetic
 Introduction
 Drug classification
 Mechanism of action of GA
 Pharmacokinetics of GA
 Recent advances
 References

3. LOCAL ANAESTHETIC

4. Introduction
 Local anaesthetics (LAs) are drugs which upon topical
application or local injection causes reversible loss of seneory
perception , especially of pain , in a restricted area of the body.
 These drugs act by blocking the conduction of nerve impulses
along the axon.
 The clinically useful local anaesthetics are weak bases with
amphiphillic property. General structure of local anaesthetic
consist three parts 1. Lipophilic aromatic residue, 2 . Ester or
amide linkage ,3. Hydrophilic secondary or tertiary amine group

5. Comparative features of general and
local anaesthesia

6. History of LAs
Time
Cocaine
1884
Procaine
1905
Tetracaine
1933
Chloroprocaine
1955
Dibucaine
1932
Lidocaine
1948
Mepicaine
1956
Prilocaine
1960 Bupivacaine
1963
Etidocaine
1971
Ropivacaine
1997
Levobupivacain
e
1999
Ester linked LAs
Amide linked
LAs

7. Drug classification

8. Drug classification of local anaesthetics
according to their Structure
Ester linked local
anaesthetics
 Cocaine
 Procoaine
 Chloroprocaine
 Tetracaine
 Benzocaine
Amide linked local anaesthetics
 Lidocaine
 Bupivacaine
 Dibucaine
 Prilocaine
 Ropivacaine

9. Mechanism of action of local anaesthetics
 The main site of local anaesthetics is the cell membrane
 The local anaesthetics in unionised form easily penetrate nerve sheat and axon
membrane.
 Within the axoplasm the molecule become ionised and block the voltage gated
Na+ channel .
1. Local anaesthetics are weak base . At tissue pH 7.4 ( alkaline pH ) they partly
unionised and partly ionised
2. The unionised drug penetrate inside the nerve membrane
3. Enter in axon ( axonal pH is low )
4. LAs blocks the voltage gated Na+ channel from inside
5. No entry of Na+ ions into the neuron
6. Depolarisation doesn’t occurs
7. No generation of action potential
8. No generation and conduction of impulses to CNS
9. Reversible loss of seneory perception without loss of consciousness( local
anaesthetic action )

10. Pharmacokinetics of LAs
Absorption
 Systemic absorption of injected local anesthetic from the site of administration is
determined by several factors, including dosage, site of injection, drug-tissue binding,
local blood flow
 Application of a local anesthetic to a highly vascular area such as the tracheal mucosa
or the tissue surrounding intercostal nerves results in more rapid absorption.
Distribution
 The amide local anesthetics are widely distributed after intravenous bolus
administration.
 After an initial rapid distribution phase, which consists of uptake into highly perfused
organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs
with uptake into moderately well-perfused tissues, such as muscle and the
gastrointestinal tract.

11. Metabolism & Excretion
 The local anesthetics are converted in the liver (amide type) or in plasma (ester
type) to more water-soluble metabolites and then excreted in the urine.
 Ester type LA is metabolized by pseudocholinesterase and amide type by hepatic
microsomal enzymes and enzyme amidase.
Side effects of LAs
 Cardiovascular -depression of heart, bradycardia, hypotension, cardiac
arrhythmias etc.
 CNS-rapid absorption produce restlessness, tremor, convulsions.
 Anaphylactic reaction-common with ester type.-causes asthma, dermatitis, skin
rash eetc
 Corneal change-very rarely reversible corneal change may occur.

12. Cocaine
 First local anaesthetic obtained from leaves of plant Erythroxylon Coca.
 It is no more in use nowadays because of its corneal toxicity, addicting nature etc.
Procaine
 First synthetic local anaesthetic . Used as a small area infiltration and spinal anaesthetic.
 It is poorly absorbed from mucous membraneso no topical use.
 2% injection is the usual preparation.
Lignocaine
 Most commonly used LA
 In ophthalmology 4% [topical] and 2% [infiltration] solutions are commonly used.
 It has quick onset of action and high degree of penetration
 The drug is recommended for topical, nerve block, infiltration and epidural injection and
for dental analgesia.
 It may cause drowsiness.

13. Benzocaine
 It is an ester of amino-benzoic acid that lacks a cationic
amino terminus which makes benzocaine poorly soluble
in water and a poor candidate for parentral use. It is
available in the forms of Spray, gel, gel-patch, ointment or
solution as 6-20% and in different flavours also.
 Brand names available : Orajel, Hurricaine
 Combinations of benzocaine :
1. Orabase- combination of benzocaine,gelatin, pectin &
sodium carboxymethylcellulose
2. Cetacine: It contains 14% benzocaine, 2% butamen, 2%
tetracaine Hcl

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

15. Recent advances in LAs
 Newer LA agents
 LA delivery system
1. Computer controlled local anaesthetic delivery system ( CCLAD)
2. Jet injection
3. Safety dental syringes
4. Devices for intraosseous LAs
 Latest Trends :- Nasal spray, liposomal delivery system, syringe merovibrator ,
Dentipatch , TENS( Transcutaneous electrical nerve stimulator )
 Future of LA :- Nanoanesthesia

16. 1.Newer LA Agents
 Two relatively new drugs that have proved to be equally or more efficient to
lignocaine are :-
A. Articaine
B. Centbucridine

17. Articaine
 It belongs to the amide group of local anaesthetics
 It consists of a thiophene ring instead of a benzene ring as in an ester
group
 Metabolism is mainly in the liver and plasma by unspecified plasma
esterases Elimination of articaine is exponential with a half life of about 20
min.

18. Articaine V/S Lignocaine
 Articaine has a faster onset of action
 Articaine has a longer duration of action
 Articaine has higher success rate
 Articaine has a greater potency ( 1.5 times more potent )
 Systemic intoxication of articaine is lower
 Articaine is a very safe drug

19. Centbucridine
It is anaesthetic molecule synthesized at the centre for Drug
Research of India at Lucknow , India in the year 1983
 It is a quinolone derivative with local anaesthetic action
 It has intrinsic vasoconstricting and anti histaminic properties
 Centbucridine in a concentration of 0.5 % can be used
effectively for infiltration , nerve blocks and spinal
anaesthesia with an anesthetic potency 4-5 times greater
than that of 2% lignocaine

20. Hurripak
 Hurripak which contains 20% benzocaine is anaesthetic
liquid which is one of the recent development topical
anaesthetics for periodontal procedures.
 It is available as a needle –free periodontal anaesthetic
kit.
 It consists of 3ml plastic syringe and disposable plastic
tips which are inserted deep within the gingival sulcus.
 The onset of action is 30 seconds and the duration of
action is 15 minutes.
 Sometimes it won’t provide adequate anaesthesia for a
routine dental visit on adult patients, so multiple
administration is recommended

21. Precooling (Cryo Anaesthesia)
 It is the application of cold to a localised part of body in order to block the local
nerve conduction of painful impulses. The local application of ice before and
sometimes after painful procedures has been practiced for thousands of years and
was one of the first source of local anaesthesia and analgesia.Topical cold
application stimulates myelinated A fibers, activating inhibitory pain pathways
which in turn raises pain threshold. Iqra et al 2015 in her article concluded that,
cooling will slow down or eliminate transmission of pain signals. It is available in
ice (crushed ice or cubed ice), refrigerant spray forms The trade names of
refrigerant spray are Gebauer’s pain ease, Pharma ethyl
Advantages of precooling:
 1. It produces immediate anaesthesia as it suppresses both pain and pressure
 2. It is an easy, reliable, and effective technique.
 3. It is comfortable, safe and physiologically active.
 4. Cost effective.

22. Iontophoresis
Iontophoresis is a method of enhancing the transport of topically applied
drugs using a mild electric current to increase the permeability of charged
drugs through the skin.
Mechanism of action: The drug which can exists in positively charged state
like lignocaine and adrenaline can be encouraged to penetrate the tissue
under the influence of electrical charge. The apparatus consists of two
electrodes and a circuit. The electrode has to be placed over the tooth to
be treated and the other one is applied to the skin over the surface of the
wrist, with the help of iontophoretic apparatus and a low votage direct
current (0-3ma) is applied, which travels through the skin reaches
underlying connective tissue goes back the same path and is
collected by a return electrode. The ions of the drug traverse through the
same path as the current. This procedure will enhance the penetration of
the drug by 20–60-fold when compared with topical application

23. Advantages
1. Patient acceptance is very high.
2. Provide rapid and effective anaesthesia compared to topical anaesthesia alone.
Disadvantages
1. At higher current densities or upon longer application, it can cause skin irritation.
2. Sometimes mild electrical sensation can be uncomfortable for some patients.
3. Equipment is expensive and bulky
4. Cannot be used over large surface areas of the body.

24. Computer controlled local anaesthetic
delivery system (CCLAD)
 In 1997 the first computer controlled local anaesthetic delivery system was
introduced into dentistry

25. Advantages
Disadvantages
Results in a controlled, highly effective and comfortable injection
even in resilient tissue
It’s very expensive
Required additional armamentarium

26. Jet Injection Based on the principle of using a
mechanical energy source to
create a release of pressure
sufficient to push a dose of liquid
medication through a very small
orifice, creating a thin column of
fluid with enough force that it can
penetrate soft tissue into the
subcutaneous tissue without a
needle .

27. Liposomal drug delivery system

28. TENS ( Transcutaneous electrical nerve
stimulator )
 It is non invasive , safe and
can be used to achieve
anesthesia in needle-phobic
patients.
 Patient are able to self
administer TENS treatment
and learn to titrate dosages
accordingly to manage their
painful condition. This results
in positive acceptance by
the patients .

29. Nanoanesthesia
 Nanotechnology uses millions of active
analgesic micrometer sized dental
nanorobots in a colloidal suspension for
local anesthesia.
 On reaching the dentin , the nanorobots,
within 100 sec , are said to enter dentinal
tubular holes that are 1-4um in diameter
and proceed toward the pulp , guided by a
combination of chemical gradients ,
temperature differential and even position
of navigation , all under the control of the
onboard nanoconputer as directed by
dentist.

30. GENERAL ANAESTHETIC

31. Introduction
 General anesthesia is a reversible state of CNS depression, causing loss of
response to and perception of stimuli. For patients undergoing surgical
or medical procedures,
 Anesthesia provides five important benefits:
Sedation and reduced anxiety
Lack of awareness and amnesia
Skeletal muscle relaxation
Suppression of undesirable reflexes
Analgesia
 Because no single agent provides all desirable properties both rapidly
and safely, several categories of drugs are combined (I.V
and inhaled anesthesia and preanesthetic medications) to
produce optimal anesthesia known as a Balanced anesthesia.6

32. Drug classification of GAs

33. Mechanism of action of GAs
 No specific receptor has been identified. The fact that chemically unrelated
compounds produce anesthesia argues against the existence of a single receptor.
 The focus is NOW on proteins comprising ion channels:
GABAA receptors, Glycine receptors,
NMDA glutamate receptors (nitrous oxide and ketamine )
Nicotinic receptors: Blocks the excitatory postsynaptic current of the nicotinic
receptors.
 Currently, there are 5inhalational and 5 intravenous anesthetics used to induce or
maintain
 general anesthesia: Inhalational:Nitrous Oxide, Isoflurane, Sevoflurane,
etomidate and Xenon.
Intravenous: Propofol, Etomidate, Ketamine, Methohexita
and Thiopental.
 These 10 general anesthetic drugs are often accompanied by sedative
benzodiazepines: midazolam, diazepam and lorazepam.

34. Continue…
 Of these 10 general anesthetics ketamine , nitrous oxide and xenon
inhibit ionotropic glutamate receptors, with the strongest effects being
seen on the NMDA receptor subtype. These anesthetics also have
modest effects on many other receptors, including GABAARs, but their
primary action is the blockade of NMDA receptors.
 The other 7 general anesthetics and 3 sedatives share a common target
and mechanism of action, they all enhance the function of GABAARs, the
most abundant fast inhibitory neurotransmitter receptor in the CNS.
These 7 general anesthetics also have a spectrum of modest to strong
effects on other ion channels, including glycine receptors, neuronal
nicotinic receptors, 5-HT3 receptors, glutamate receptors and the
potassiu channels.Mechanisms underlying the anesthetic effect are not
properly known yet.

35. Minimum alveolar concentration (MAC)
 It is the Minimum alveolar concentration, the
endtidal Concentration Of inhaled anesthetic
Needed to eliminat Movemen in 50 % of
Patients stimulated by a standardized incisi.
MAC is the ED50 of the anesthetic.
the inverse of MAC is an index of potency of
the anesthetic.
 MAC expressed as the percentage of gas in a
mixture required to achieve the effect.
 Numerically, MAC is small for potent
anesthetics such as sevoflurane and large for
less potent agents such as nitrous oxide.

36. Pre anesthetic medication
Preanesthetic medications serve to
 calm the patient, relieve pain
 protect against undesirable effects of the subsequentlyadministered anesthetics or the surgical
procedure.
 facilitate smooth induction of anesthesia, lowered the required dose of anesthetic
Preanesthetic Medicine:
 Benzodiazepines; midazolam or diazepam: - Anxiolysis & amnesia.
 Diphenhydramine:- Prevention of allergic reactions: - antihistamines
 H2 receptor blocker- famotidine, ranitidine: Reduce gastric acidity.
 Antiemetics- ondansetron: Prevents aspiration of stomach contents and post surgical vomiting
 Acetaminophen or opioids (fentanyl) for analgesia
 Anticholinergics: (glycopyrrolate, scopolamine):
 Reduce bronchial and salivary secretion: irritant inhaled anesthetic cause excessive salivation and
secretion.

37. Stages of GAs
Stage I :- Analgesia
 analgesia and amnesia, the patient is conscious and
conversational. Starts from beginning of anaesthetic inhalation
and lasts upto the loss of consciousness
 Pain is progressively abolished
 Reflexes and respiration remain normal
 Use is limited to short procedures

38. Stage II :- Delirium
 From loss of consciousness to beginning of regular
respiration
 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 operative procedure carried out
 Can be cut short by rapid induction, premedication

39. Stage III:- Surgical Anasthesia
 Extends from onset of regular respiration to cessation of
spontaneous breathing. This has been divided into 4 planes
which may be distinguished as:
 Plane 1 moving 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.

40. Stage IV :- Medullary paralysis
 Cessation of breathing – failure of circulation – death
 Pupils: widely dilated
 Muscles are totally flabby
 Pulse is imperceptible
 BP is very low.

41. 1. 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
Advantages-
1. Can be used without complicated apparatus
2. Potent anaesthetic and good analgesic
3. Muscle relaxatio
4. Wide safety of margin
5. Respiratory stimulation and bronchodilatation
6. Does not sensitize the heart to adrenaline- No cardiac arrythmias
7. Less likely hepato or nephrotoxicity
Disadvantages- Inflammable and explosive- Slow induction and unpleasant –
atrethy- Slow recovery – nausea & vomitin- Cardiac arres- Convulsion in children -
Cross tolerance – ethyl alcohol

42. 2. Nitrous oxide/laughing gas (N2O)
 Colourless, odourless inorganic gas with sweet taste
 Noninflammable and nonirritating, but of low potency
 Very potent analgesic
 As a single agent used with O2 in dental extraction and in obstetrics
3. Halothane
 Fluorinated volatile liquid with sweet odour, non-irritant non-inflammable and
supplied in amber coloured bottle
 Potent anaesthetic, 2-4% for induction and 0.5-1% for maintenance
 Pharmacokinetics: 60 to 80% eliminated unchanged. 20% retained in body for 24
hour and metabolized

43. Recent advances in GAs
 New inhalational anaesthetics allow rapid, pleasant gaseous induction of
anaesthesia and rapid recovery with a minimal “hangover” effect
 Target controlled infusion techniques have improved the accuracy of total
intravenous anaesthesia and pave the way for “closed loop” automatic
anaesthesia
 A unique opioid, remifentanil, allows fine control of intraoperative
analgesia but its effects wear off within minutes of stopping infusion
 Separation of stereoisomers has allowed the development of improved
safer local anaesthetics
 Mobile epidurals are rapidly gaining popularity in labour wards because
they allow normal mobility with high quality pain relief
 Neurokinin type 1 receptor antagonists promise to further improve
management of postoperative nausea and vomiting
 Recent developments in equipment have helped to minimise the
problems of anaesthetising patients with “difficult” airways

44. Bisprctral Index
 The newer technologies
include the bisprctral
Index (BIS)which purport
to monitor the depth of
anesthetic agents to a
specific bisprctral index
during general
anaesthesia allows the
anaesthetist to adjust
the amount of
anaesthetic agents to
needs of the patient.

45. Target controlled infusion
 Target controlled infusion systems allow the anaesthetist to set a desired plasma concentration,
which the software inside the pump produces rapidly but safely by controlling the infusion rate
according to complex but standard pharmacokinetic equations.
 12,13 Changes may still be required according to clinical signs, but the technique enables
changes in rate to reflect factors such as patient characteristics, previous administration of
propofol, and duration of infusion
 If a reliable monitor of anaesthetic depth becomes available it will be possible to “close the loop”
and provide virtually automatic anaesthesia by feedback control of a target controlled infusion
system.
 Much research has focused on this, with the aim of producing a machine that will reliably indicate
whether a paralysed patient is anaesthetised.
 Unfortunately, autonomic clinical signs do not always detect an aware patient especially in the
presence of drugs that affect these signs, such as β blockers.
 Recent work has concentrated on measurements derived from an electroencephalogram, but
most of these are unreliable or too complex for practical use.
 The auditory evoked potential index—a single numerical variable derived from the auditory
evoked potential—was found to show consistent changes that may reliably detect awareness.
 15,16 Prototype closed loop systems, using the auditory evoked potential index to control
propofol given by target controlled infusion, have been described.

46. Remifentanil
 Remifentanil is a new potent synthetic opioid ideally suited for infusion
(often with a target controlled infusion system) during anaesthesia.
 Unlike other opioids, remifentanil contains a methyl ester in its structure,
which allows rapid extrahepatic non-saturable metabolism by non-
specific esterases in blood and tissues.
 The terminal half life of remifentanil is less than 10 minutes and, unlike all
other opioids, this is not affected by duration of iinfusion.
 Remifentanil’s place in anaesthesia has yet to be fully determined. Critics
point out the lack of postoperative analgesia with remifentanil, but it is
already widely used during neuroanaesthesia and is likely to represent a
significant advance in several other areas such as cardiac and
cardiovascular anaesthesia.

47. References
 Essential of medical pharmacology – K.D. Tripathi 7th edition
 Lippincott – Modern Pharmacology With Clinical Applications 6E
 International Journal of Advanced Research ( IJAR) -Dr.Hridya M. Menon , Dr.
Shilpa Jaidka , Dr. Rani Soman

48. Thank You !