General and Local Anesthetics Drugs

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

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

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

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

5. General Anaesthestics

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

7. The Cardinal
Features Of
General
Anaesthetics
Loss of all sensation, especially pain
Sleep (unconsciousness) and amnesia
Abolition of somatic and autonomic
reflexes
Immobility and muscle relaxation

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

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

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

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

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

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

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

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

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

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

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

20. 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

36. Local Anaesthestics

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

38. Features Of
Local
Anaesthetics
Should have quick onset of action
Should not be irritating to skin & mucous
membranes
Duration of action must be long enough to
allow desired surgery to be completed
Should be effective on both injection & local
application
Should have low Systemic toxicity

39. Should not cause any permanent damage on any
tissue.
Should be relatively free from producing allergic
reaction.
Should be stable in solution and readily undergo
biotransformation.
No LA in use today satisfy all of these criteria
, however all anesthetics do meet a
majority of them.

40. Chemistry
All local anesthetics are weak bases,they have
amphiphilic property
Consist of hydrophilic secondary or tertiary amine on
one side
Lipophilic aromatic residue on other side
ØTwo are joined by an alkyl chain through an ester
or amide linkage

41. Based on linkage they can be classified as-

42. Advantage of Amide LAs over Ester LAs
• Produce more intense and longer lasting anaesthesia .
• Bind to α1acid glycoprotein in plasma.
• Not hydrolyzed by plasma esterase's.
• Rarely causes hypersensitivity reaction.

43. Classification
1.InjectableAnaesthetic
(a)Low Potency, Short Duration
ex. Procaine, Chloroprocaine
(b)Intermediate potency and
duration
ex. Lidocaine, Prilocaine
(c)High potency and long duration
ex. Tetracaine, Bupivacaine,
Ropivacaine, Dibucaine
2.SurfaceAnaesthetic:
(a)Soluble
ex. Cocaine, Lidocaine, Tetracaine
(b)Insoluble
ex. Benzocaine, Butyl-amino-
benzoate, Oxethazaine benoxinate

44. Mechanism of action of LAs

45. Mechanism of action of LAs
 LA blocks the nerve conduction by reducing entry of Na+
through the voltage gated channels
 Due to this, they block the initiation & propagation of nerve
impulse.
 At higher doses it also blocks
-Voltage gated Ca2+ channels
-K+channels

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

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

48. PK properties of amide LAs:

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

50. Techniques of Local
Anaesthesia

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

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

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

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

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

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

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

58. • Complication of spinal anaesthesia:
Respiratory paralysis Hypotension Headache
Cauda equina syndrome Septic meningitis
• Contraindications:
Hypotension & hypovolemia
Infant & children's - control of level is difficult Vertebral abnormalities -
kyphosis

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

60. • 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.

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

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

63. 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.

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

65. 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.

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