General Anaesthetics

An ideal anaesthetic drug would induce a smooth and rapid loss of consciousness,
while allowing for a prompt recovery after its administration is discontinued. The
drug would also possess a wide margin of safety and be devoid of adverse effects.
The physiologic state induced by general anaesthetics typically includes
 Analgesia
 Amnesia(temporary memory loss)
 Loss of consciousness
 Inhibition of sensory and autonomic reflexes
 Skeletal muscle relaxation.
Types of General Anesthesia
General anaesthetics are typically of two types
1. Intravenous anaesthetics
2. Inhalation anaesthetics
Intravenous Anesthetics
Several different classes of intravenous drugs are used, alone or in combination
with other anaesthetic and analgesic drugs, to achieve the desired anaesthetic
state.
These drugs include the following:
 Barbiturates (e.g., thiopental, methohexital)
 Benzodiazepines (e.g., midazolam, diazepam)
 Propofol
 Ketamine
 Opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil)
 Miscellaneous sedative-hypnotics (e.g., etomidate, dexmedetomidine).
Inhalation anaesthetics
The most commonly used inhaled anaesthetics are
 Halothane
 Enflurane
 Methoxyflurane
 Isoflurane
 Desflurane
 Sevoflurane.
The above compounds are volatile liquids that are aerosolized in specialized
vaporizer delivery systems.
Nitrous oxide, a gas at ambient temperature and pressure, continues to be an
important adjuvant to the volatile agents.
Balanced Anesthesia
Modern anaesthesia typically involves a combination of intravenous (e.g., for
induction of anaesthesia) and inhaled (e.g., for maintenance of anaesthesia)
drugs.
However, volatile anaesthetics (e.g., sevoflurane) can also be used for induction
of anaesthesia, and intravenous anaesthetics (e.g., propofol) can be infused for
maintenance of anaesthesia.

Stages of Anesthesia
The traditional description of the various stages of anaesthesia (the so-called
Guedel's signs) were derived from observations of the effects of inhaled diethyl
ether, which has a slow onset of central action owing to its high solubility in
blood. Using these signs, anaesthetic effects on the brain can be divided into four
stages of increasing depth of central nervous system (CNS) depression.
 Stage of analgesia: The patient initially experiences analgesia without
amnesia. Later in stage I, both analgesia and amnesia are produced.
  Stage of excitement: During this stage, the patient often appears to be
delirious(euphoric), excited and may vocalize but is definitely amnesic.
Respiration is irregular both in volume and rate and retching (gag, make a
sound or movement of vomit) and vomiting may occur if the patient is
stimulated. For these reasons, efforts are made to limit the duration and
severity of this light stage of anaesthesia by rapidly increasing the
concentration of the agent. This stage ends with the reestablishment of
regular breathing.
 Stage of surgical anaesthesia: This stage begins with the recurrence of
regular respiration and extends to complete cessation of spontaneous
respiration (apnea). Four planes of stage III have been described in terms of
changes in ocular movements, eye reflexes, and pupil size, which may
represent signs of increasing depth of anaesthesia.
This stage is divided into four planes
Plane 1: the eyeballs rotate ventrally, swallowing reflexes are depressed,
respiration is normal
Plane 2: pupils are slightly dilated, respiration is regular but shallow, heart rate
and B.P mildly decreased, suitable for most surgery
Plane 3: Deeply anesthetized, pulpils dilated, light reflex weak or absent,
respiratory rate less than 12 breaths/ min.
Plane 4: pupil is severely dilated with absent light reflex, loss muscle tone, severe
drops in heart rate and blood pressure.
 Stage of medullary depression: This deep stage of anaesthesia includes
severe depression of the CNS, including the vasomotor centre in the
medulla, as well as the respiratory centre in the brain stem. Without
circulatory and respiratory support, death rapidly ensues.

Anaesthetic adjuncts/ Preanesthetic medication

A general anaesthetic is rarely given as the sole agent. Anaesthetic adjuncts
usually are used to augment specific components of anaesthesia, permitting
lower doses of general anaesthetics with fewer side effects.
 (1) Benzodiazepines
While benzodiazepines can produce anaesthesia similar to that of barbiturates,
they are more commonly used for sedation rather than general anaesthesia
because prolonged amnesia and sedation may result from anesthetizing doses. As
adjuncts, benzodiazepines are used for anxiolysis, amnesia, and sedation prior to
induction of anaesthesia or for sedation during procedures not requiring general
anaesthesia.
The benzodiazepine most frequently used in the perioperative period is
MIDAZOLAM followed distantly by diazepam (VALIUM, others), and lorazepam
(ATIVAN, others).
Benzodiazepines modestly decrease blood pressure and respiratory drive,
occasionally resulting in apnea. Thus, blood pressure and respiratory rate should
be monitored in patients sedated with intravenous benzodiazepines.
MIDAZOLAM is water soluble and typically is administered intravenously but also
can be given orally, intramuscularly, or rectally; oral midazolam is particularly
useful for sedation of young children.
Midazolam produces minimal venous irritation as opposed to diazepam and
lorazepam. These drugs also sometime cause thrombophlebitis.
Midazolam has more rapid onset and shorter in duration of effect.
(2) α2 Adrenergic Agonists
Dexmedetomidine (PRECEDEX) is an imidazole derivative that is a highly selective
α 2 adrenergic receptor agonist.
Dexmedetomidine is a sedative-hypnotic that provides analgesia with little
respiratory depression and, in most patients, a tolerable decrease in blood
pressure and heart rate. The drug is likely to be increasingly used for sedation and
as an anaesthetic adjunct.
It is particularly valuable in sedation of patients who are not endotracheally
intubated and mechanically ventilated. The sedation produced resembles more to
natural sleep, making patient to easily arouse.
The most common side effects of dexmedetomidine include hypotension and
bradycardia, both of which are attributed to decreased catecholamine release by
activation peripherally and in the CNS of the alpha 2A receptor.
(3) Analgesics
With the exception of ketamine, neither parenteral nor currently available
inhalational anesthetics are effective analgesics. Thus, analgesics typically are
administered with general anesthetics to reduce anesthetic requirement and
minimize hemodynamic changes produced by painful stimuli.
During the perioperative period, opioids often are given at induction to prevent
responses to predictable painful stimuli (e.g., endotracheal intubation and
surgical incision).
Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, and acetaminophen
sometimes provide adequate analgesia for minor surgical procedures. However,
opioids are the primary analgesics used during the perioperative period because
of the rapid and profound analgesia they produce.
Fentanyl, sufentanil, alfentanil, remifentanil, meperidine, and morphine are the
major parenteral opioids used in the perioperative period. The primary analgesic
activity of each of these drugs is produced by agonist activity at mu opioid
receptors.
Marked decreases in respiratory rate and heart rate with much smaller reductions
in blood pressure are seen to varying degrees with all opioids.
Muscle rigidity that can impair ventilation sometimes accompanies larger doses of
opioids.
The incidence of sphincter of Oddi spasm is increased with all opioids, although
morphine appears to be more potent in this regard.
The frequency and severity of nausea, vomiting, and pruritus after emergence
from anesthesia are increased by all opioids to about the same degree.
A useful side effect of meperidine is its capacity to reduce shivering, a common
problem during emergence from anesthesia other opioids are not as efficacious
against shivering, perhaps due to less kappa receptor agonism.
Opioids often are administered intrathecally and epidurally for management of
acute and chronic pain.
(4) Neuromuscular Blocking Agents
Depolarizing (e.g., succinylcholine) and non-depolarizing muscle relaxants (e.g.,
vecuronium) often are administered during the induction of anesthesia to relax
muscles of the jaw, neck, and airway and thereby facilitate laryngoscopy and
endotracheal intubation.
Barbiturates will precipitate when mixed with muscle relaxants and should be
allowed to clear from the intravenous line prior to injection of a muscle
relaxant.
Muscle relaxants are not by themselves anesthetics and should not be used for
the purpose of adequate anesthetic depth.
The action of non-depolarizing muscle relaxants usually is antagonized, once
muscle paralysis is no longer desired, with an acetylcholinesterase inhibitor such
as neostigmine or edrophonium combined with a muscarinic receptor antagonist
(e.g., glycopyrrolate or atropine) to offset the muscarinic activation resulting from
esterase inhibition.
Muscle relaxants used in anesthesia have few side effects. However,
succinylcholine has multiple serious side effects (bradycardia, hyperkalemia, and
severe myalgia) including induction of malignant hyperthermia in susceptible
individuals.
(5) Oxygen
Since oxygen delivery is the product of blood flow and oxygen content, hypoxia
may result from alterations in tissue perfusion, decreased oxygen tension in the
blood, or decreased oxygen-carrying capacity
Under ideal conditions, when ventilation and perfusion are well matched, the
alveolar PO2 will be ~14.6 kPa . The corresponding alveolar partial pressures of
water and CO2 are 6.2 kPa and 5.3 kPa , respectively. Under normal conditions,
there is complete equilibration of alveolar gas and capillary blood, and the PO2 in
end-capillary blood is typically within a fraction of a kPa of that in the alveoli.
 (6) Anticholinergic drugs (e.g., atropine and glycopyrrolate) may be used to
decrease oral and airway secretions and to treat bradycardia; however, they can
also dilate the pupils.
(7) Although vital sign monitoring remains the most common method of
assessing depth of anesthesia during surgery, newer techniques often involve
computer-assisted monitoring of cerebral function using indices of EEG activity.
These automated cerebral monitoring techniques use indices derived from EEG
signals.

Inhalation anaesthetics
It is essential to understand that inhalational anaesthetics distribute between
tissues (or between blood and gas) such that equilibrium is achieved when the
partial pressure of anaesthetic gas is equal in the two tissues.
Pharmacokinetics
Uptake & Distribution of Inhaled Anesthetics
The concentration of an inhaled anesthetic in a mixture of gases is proportional to
its partial pressure (or tension).
Achievement of a brain concentration of an inhaled anesthetic necessary to
provide an adequate depth of anesthesia requires transfer of the anesthetic from
the alveolar air to the blood and from the blood to the brain.
The rate at which a therapeutic concentration of the anaesthetic is achieved in
the brain depends primarily on
1. Solubility of anaesthetic
2. Concentration of anaesthetic in the inspired air
3. Volume of pulmonary ventilation
4. Pulmonary blood flow
5. Partial pressure gradient between arterial and mixed venous blood
anaesthetic concentrations.
 I. Solubility
The blood: gas partition coefficient is a useful index of solubility and defines the
relative affinity of anaesthetics for the blood compared with that of inspired gas.
The partition coefficients for desflurane and nitrous oxide, which are relatively
insoluble in blood, are extremely low. When an anaesthetic with low blood
solubility diffuses from the lung into the arterial blood, relatively few molecules
are required to raise its partial pressure, and therefore the arterial tension rises
rapidly.
Anesthetics with moderate-to-high solubility (e.g., halothane, isoflurane), more
molecules dissolve before partial pressure changes significantly, and arterial
tension of the gas increases less rapidly.
For example, for a given concentration or partial pressure of the two anesthetic
gases in the inspired air, it will take much longer for the blood partial pressure of
the more soluble gas (halothane) to rise to the same partial pressure as in the
alveoli. Since the concentration of the anesthetic agent in the brain can rise no
faster than the concentration in the blood, the onset of anesthesia will be slower
with halothane than with nitrous oxide.
 II. Anesthetic Concentration in the Inspired Air
Increase in the inspired anesthetic concentration increase the rate of induction of
anesthesia by increasing the rate of transfer into the blood according to Fick's law
(Rate of diffusion is directly proportional to conc gradient)
Advantage is taken of this effect in anesthetic practice with inhaled anesthetics
that possess moderate blood solubility (e.g., enflurane, isoflurane, and
halothane). For example, a 1.5% concentration of isoflurane may be administered
initially to increase the rate of rise in the brain concentration; the inspired
concentration is subsequently reduced to 0.75–1% when an adequate depth of
anesthesia is achieved.
In addition, these moderately soluble anesthetics are often administered in
combination with a less soluble agent (e.g., nitrous oxide) to reduce the time
required for loss of consciousness and achievement of a surgical depth of
anesthesia. ( Concentration effect & second gas effect)
III. Pulmonary Ventilation
The rate of rise of anesthetic gas tension in arterial blood is directly dependent on
both the rate and depth of ventilation.
For example, a fourfold increase in ventilation rate almost doubles the arterial
tension of halothane during the first 10 minutes of administration but increases
the arterial tension of nitrous oxide by only 15%. Therefore, hyperventilation
increases the speed of induction of anesthesia with inhaled anesthetics that
would normally have a slow onset. Depression of respiration by opioid analgesics
slows the onset of anesthesia of inhaled anesthetics unless ventilation is manually
or mechanically assisted.(spontaneous breathing system)
IV. Pulmonary Blood Flow
An increase in pulmonary blood flow (i.e., increased cardiac output) slows the
rate of rise in arterial tension, particularly for those anesthetics with moderate-to-
high blood solubility. Increased pulmonary blood flow exposes a larger volume of
blood to the anesthetic agent in the alveoli, thereby increasing the blood carrying
capacity and decreasing the rate of rise in the anesthetic tension in the blood (and
brain).( decrease the time of uptake of drug)
In patients with circulatory shock, the combined effects of decreased cardiac
output (resulting in decreased pulmonary flow) and increased ventilation will
accelerate induction of anesthesia with halothane and isoflurane. However, this
effect is much less important with the less soluble agent’s sevoflurane, nitrous
oxide, and desflurane.
V. Arteriovenous Concentration Gradient
The anesthetic concentration gradient between arterial and mixed venous blood
is dependent mainly on uptake of the anesthetic by the tissues, including
nonneural tissues. Depending on the rate and extent of tissue uptake, venous
blood returning to the lungs may contain significantly less anesthetic than arterial
blood. The greater this difference in anesthetic gas tensions, the more time it
will take to achieve equilibrium with brain tissue.
During the induction phase of anesthesia (and the initial phase of the
maintenance period), the tissues that exert greatest influence on the
arteriovenous anesthetic concentration gradient are those that are highly
perfused (e.g., brain, heart, liver, kidneys, and splanchnic bed). These tissues
receive over 75% of the resting cardiac output. In the case of volatile anesthetics
with relatively high solubility in highly perfused tissues, venous blood
concentration will initially be very low, and equilibrium with the arterial blood is
achieved slowly.
Muscle and skin constitute 50% of the total body mass, anesthetics accumulate
more slowly in these tissues than in highly perfused tissues (e.g., brain) because
they receive only one-fifth of the resting cardiac output. Although most anesthetic
agents are highly soluble in adipose (fatty) tissues, the relatively low blood
perfusion to these tissues delays accumulation, and equilibrium is unlikely to
occur with most anesthetics during a typical 1- to 3-hour operation.
Measurement of Anesthetic Potency
The potency of general anesthetic agents usually is measured by determining the
concentration of general anesthetic that prevents movement in response to
surgical stimulation. For inhalational anesthetics, anesthetic potency is measured
in MAC units, with 1 MAC defined as the minimum alveolar concentration that
prevents movement in response to surgical stimulation in 50% of subjects.
Elimination
The time to recovery from inhalation anesthesia depends on the rate of
elimination of the anesthetic from the brain.
One of the most important factors governing rate of recovery is the blood: gas
partition coefficient of the anesthetic agent.
Other factors controlling rate of recovery include the pulmonary blood flow, the
magnitude of ventilation, and the tissue solubility of the anesthetic.
Inhaled anesthetics that are relatively insoluble in blood (i.e., possess low blood:
gas partition coefficients) and brain are eliminated at faster rates than the more
soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane
occurs at a rapid rate, leading to a more rapid recovery from their anesthetic
effects compared with halothane and isoflurane.
Halothane is approximately twice as soluble in brain tissue and five times more
soluble in blood than nitrous oxide and desflurane; its elimination therefore takes
place more slowly, and recovery from halothane- and isoflurane-based anesthesia
is predictably less rapid.
Clearance of inhaled anesthetics via the lungs is the major route of elimination
from the body. However, hepatic metabolism may also contribute to the
elimination of some volatile anesthetics.
Oxidative metabolism of halothane results in the formation of trifluoroacetic acid
and release of bromide and chloride ions. Under conditions of low oxygen
tension, halothane is metabolized to the chlorotrifluoroethyl free radical, which is
capable of reacting with hepatic membrane components and on rare occasion has
resulted in halothane-induced hepatitis.
Pharmacodynamics
The inhalational anesthetics inhibit excitatory synapses and enhance inhibitory
synapses in various preparations
1) Chloride channels gated by the inhibitory GABAA receptors are sensitive to
clinical concentrations of a wide variety of anesthetics, including the
halogenated inhalational agents.
2) Clinical concentrations of inhalational anesthetics enhance the capacity of
glycine to activate glycine-gated chloride channels (glycine receptors),
which play an important role in inhibitory neurotransmission in the spinal
cord and brainstem.
3) Nitrous oxide, cyclopropane and xenon are potent and selective inhibitors
of NMDA-activated currents, suggesting that these agents also may
produce unconsciousness by means of actions on NMDA receptors. NMDA
receptors are glutamate-gated cation channels that are somewhat selective
for calcium and are involved in long-term modulation of synaptic responses
(long-term potentiation) and glutamate-mediated neurotoxicity.
 4) Halogenated inhalational anesthetics activate some members of a class of
K+ channels known as two-pore domain channels. These channels are
located in both pre-synaptic and post-synaptic sites. The post-synaptic
channels are important in setting the resting membrane potential of
neurons. Activation of pre-synaptic channels can lead to hyperpolarization
of the pre-synaptic terminal, thereby reducing neurotransmitter release.
In principle, general anesthetics could interrupt nervous system function,
including peripheral sensory neurons, the spinal cord, the brainstem, and the
cerebral cortex.
Organ System Effects of Inhaled Anaesthetics
Effects on the Cardiovascular System
Bradycardia with halothane because of direct vagal stimulation. In contrast,
enflurane, and sevoflurane have little effect, and both desflurane and isoflurane
increase heart rate. In the case of desflurane, transient sympathetic activation
with elevations in catecholamine levels can lead to marked increases in heart rate
and blood pressure when high inspired gas concentrations are administered.
The bronchodilating action of halothane and sevoflurane makes them the
induction agents of choice in patients with underlying airway problems (e.g.,
asthma, bronchitis, chronic obstructive pulmonary disease). Airway irritation,
which may provoke coughing or breath-holding, is rarely a problem with
halothane and sevoflurane. However, the pungency of desflurane makes this
agent less suitable for induction of anesthesia despite its low blood: gas partition
coefficient.
Effects on the Brain
Inhaled anesthetics decrease the metabolic rate of the brain. the more soluble
volatile agents increase cerebral blood flow because they decrease cerebral
vascular resistance. The increase in cerebral blood flow is clinically undesirable in
patients who have increased intracranial pressure because of a brain tumor or
head injury. Volatile anesthetic-induced increases in cerebral blood flow increase
cerebral blood volume and further increase intracranial pressure. Of the inhaled
anesthetics, nitrous oxide is the least likely to increase cerebral blood flow.
Effects on the Kidney
Depending on the concentration, volatile anesthetics decrease the glomerular
filtration rate and renal blood flow and increase the filtration fraction.
Effects on the Liver
Volatile anesthetics cause a concentration-dependent decrease in hepatic blood
flow.
Effects on Uterine Smooth Muscle
Nitrous oxide appears to have little effect on uterine musculature. However, the
halogenated anesthetics are potent uterine muscle relaxants and produce this
effect in a concentration-dependent fashion.
Toxicity
Hepatotoxicity
Serum from patients with halothane hepatitis contains a variety of autoantibodies
against hepatic proteins. Trifluoroacetylated (TFA) proteins in the liver could be
formed in the hepatocyte during the biotransformation of halothane by liver
drug-metabolizing enzymes.
Nephrotoxicity
Metabolism of methoxyflurane, enflurane, and sevoflurane leads to the formation
of fluoride ions. Changes in renal concentrating ability have been observed with
prolonged exposure to both methoxyflurane and enflurane but not sevoflurane.
Malignant Hyperthermia
Malignant hyperthermia is an autosomal dominant genetic disorder of skeletal
muscle that occurs in susceptible individuals undergoing general anesthesia with
volatile agents and muscle relaxants (e.g., succinylcholine). The malignant
hyperthermia syndrome consists of the rapid onset of tachycardia and
hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base
imbalance with acidosis that follows exposure to one or more of the triggering
agents.
Treatment includes administration of dantrolene (to reduce calcium release from
the sarcoplasmic reticulum) and appropriate measures to reduce body
temperature and restore electrolyte and acid-base balance.
Chronic Toxicity
Under normal conditions, inhaled anesthetics (including nitrous oxide) are neither
mutagens nor carcinogens in patients.
Prolonged exposure to nitrous oxide decreases methionine synthase activity and
theoretically can cause megaloblastic anemia, a potential occupational hazard for
staff working in inadequately ventilated dental operating suites.
Individual anaesthetics agents
Halothane:
o no longer widely used
o potent, non-irritant
o blood: gas partition coefficient is 2.4 and oil: gas coefficient is 220
o Minimum alveolar concentration is 0.8 % v/v
o may cause hypotension and dysrhythmias; about 30% metabolised.
o can be useful when slow recovery is desirable but otherwise the 'hangover'
due to high lipid solubility is unwanted
o because of its potential for inducing hepatotoxicity, halothane has largely
been replaced by newer volatile anaesthetics.
Enflurane:
o halogenated anaesthetic similar to halothane
o less metabolism than halothane, therefore less risk of toxicity
o faster induction and recovery than halothane (less accumulation in fat)
o risk of epilepsy-like seizures.
o blood: gas partition coefficient is 1.9 and oil: gas coefficient is 98
o Minimum alveolar concentration is 0.7 % v/v
Isoflurane:
o similar to enflurane but lacks epileptogenic property
o may precipitate myocardial ischemia in patients with coronary disease
 o irritant to respiratory tract.
o It is typically used for maintenance of anesthesia after induction with other
agents because of its pungent odor, but induction of anesthesia can be
achieved in < 10 minutes with an inhaled concentration of 3% isoflurane in
O2,
o blood: gas partition coefficient is 1.4 and oil: gas coefficient is 91
o Minimum alveolar concentration is 1.2 % v/v
Sevoflurane:
o Sevoflurane is widely used, particularly for outpatient anesthesia, because
of its rapid recovery profile
o similar to desflurane, with lack of respiratory irritation.
o Well suited for inhalation induction especially in children
o Hepatic metabolism of sevoflurane also produces inorganic fluoride. Serum
fluoride concentrations peak shortly after surgery and decline rapidly.
o blood: gas partition coefficient is 0.6 and oil: gas coefficient is 53
o Minimum alveolar concentration is 2.1 % v/v
Nitrous oxide:
o low potency, therefore, must be combined with other agents
o It is combined with oxygen to avoid hypoxia
o rapid induction and recovery
o good analgesic properties
o risk of bone marrow depression with prolonged administration
o accumulates in gaseous cavities.
o N2O is frequently used in concentrations of about 50% to provide analgesia
and mild sedation in outpatient dentistry.

Xenon:
o Xenon is an inert gas that first was identified as an anaesthetic agent in
1951. It is unlikely to enjoy widespread use because it is a rare gas that
cannot be manufactured and must be extracted from air. This limits the
quantities of available xenon gas and renders xenon very expensive.
 o Xenon exerts its analgesic and anaesthetic effects at a number of receptor
systems in the CNS.
o Xenon is extremely insoluble in blood and other tissues, providing for rapid
induction and emergence from anaesthesia.
o It is sufficiently potent to produce surgical anaesthesia when administered
with 30% oxygen.

Neuroleptanalgesia
The combined use of a sedative (e.g. the dopamine antagonist droperidol) related
to antipsychotic drugs and an opiate analgesic such as fentanyl can produce a
state of deep sedation and analgesia (known as neuroleptanalgesia) in which the
patient remains responsive to simple commands and questions, but does not
respond to painful stimuli or retain any memory of the procedure. This can be
used for minor procedures such as endoscopy but is less used since the advent of
midazolam which has a shorter duration of action. Use of neuroleptanalgesics is
more common in veterinary medicine.

LOCAL ANESTHETICS
“Local anesthetics are drugs which upon topical application or local injection
cause reversible loss of sensory perception, especially of pain in a localized area of
the body”.
LAs, do not cause the loss of consciousness when administered correctly.

HISTORY OF LOCAL ANESTHETICS

Albert Niemann (1860) isolated crystals from the coca shrub – and called it
“COCAINE”, he found that it reversibly numbed his tongue.
German chemist Alfred Einhorn (1905) produced the first synthetic ester type
local anesthetic Novocaine (procaine) which retained the nerve blocking
properties but lacked the powerful CNS actions of cocaine.
Swedish chemist Nils Löfgren (1943) synthesized the first amide-type local
anesthetic - marketed under the name of Xylocaine (Lidocaine).
CHEMISTRY OF LOCAL ANESTHETICS

Three major parts of any Local Anesthetics:

1. Aromatic Ring (Lipophilic Moiety).
2. Intermediate Chain is of Amide or Ester, basis of classification.
3. Amine Group (Hydrophilic Group).
4. Potency = Lipid Solubility
Higher solubility = Can use a lower concentration and reduce potential for
toxicity.

Classification of Local Anesthetics on basis of Duration of action

Short Acting (20-25 Min.):

 Procaine
 Chloroprocaine.
Intermediate Acting (45-60 Min.):
  Lidocaine (Lignocaine)
 Prilocaine
 Lignocaine
 Cocaine
Long Acting (2-3 Hours):
 Bupivacaine
 Etidocaine
 Ropivacaine
 Tetracaine

Classification on basis of Chemical Nature:

Esters:
 Cocaine
 Procaine
 Tetracaine
 Benzocaine
Amides:
 Lidocaine
 Mepivacaine
 Bupivacaine
 Etidocaine
AMIDE LAs
 Produce more intense & longer lasting anesthesia.
 Not hydrolyzed by plasma esterases.
 Rarely cause hypersensitivity reactions( donot produce PABA upon
hydrolysis).
ESTERS LAs
 Short duration of action and less analgesia.
 Hydrolyzed by plasma esterases.
 High risk of hypersensitivity(produce PABA upon hydrolysis)

Properties of ideal Local Anesthetics

o Reversible in action
o Nonirritant
o No allergic reaction
o No systemic toxicity
o Rapid onset of action
o Sufficient duration of action
o Potent
o Stable in solution
o No interference with healing of tissues
o Should have vaso-constrictive action
o Not expensive.

Mechanism of Action of Local Anesthetics

o The primary target of the LA, Voltage Activated Sodium Channels (VASC) is
one the numerous membrane proteins which reside in phospholipids
bilayer encapsulating the neurons.
o LAs block VASC → Reduce Na+ influx → No depolarization → No Conduction
of Active Potential (PA).
o Local anesthetics gain access to the inner axonal membrane by:
 Traversing sodium channels while they are more often in an open
configuration.
 Pass directly through the plasma membrane.
o More lipid soluble (Unionized/Uncharged) form → More effective
intracellular conc.
o Inside the neuron → Ionized form is more effective blocking entity.
 o Both ionized & unionized forms play significant role in
 First in reaching the receptor site.
 Second in causing the effect.

Pharmacokinetics of Local Anesthetics

1. ABSORPTION:
Factors affecting the Absorption of Local Anesthetics:
1. Site of Injection (Intrapleural > Intercostal > Lumbar Epidural > Brachial
Plexus > Sciatic > Femoral).
2. Dose
3. Physicochemical Properties (Lipid Solubility & Protein Binding).
 4. Addition of Epinephrine.
2. DISTRIBUTION:
Tissue distribution of LA is proportional to:
 Lipid solubility of drug
 Blood supply to that tissue
LA drugs are distributed rapidly in:
 Brain, Heart, Liver, Lung.
But more slowly distributed…. which have lower blood supply:
 Muscles & Adipose Tissues.
Patient age, cardio-vascular status and hepatic function influence the tissue blood
flow.
3. METABOLISM:
Amide:
 Metabolism is dependent on hepatic blood flow.
 Toxicity of amides is more likely with:
 Prolonged infusions in sick, elderly patients.
Esters:
 Hydrolyzed rapidly in plasma by pseudo cholinesterase to the
metabolite
 Para-aminobenzoic acid (PABA), which can generate an allergic
reaction.
4. EXCRETION:
 Kidneys are primary excretory organs of LA drugs & their
metabolites.
 Esters appears in very small conc. of parent compound in urine.
 Metabolism is fastest in the rank order:
 Prilocaine > Lidocaine > Bupivacaine.
 Most of the LA drugs cross the placenta.

LIDOCAINE

 Concentration 2%
 Potency is 2X than Procaine
 Toxicity is 2X than Procaine
 Metabolized in Liver
 Excreted via Kidney
 Time to onset: 2-3 min.
 Half-life: 90 min.

MEPIVACAINE
 Concentration - 2% or 3%
 Potency is 2X than Procaine
 Toxicity is 1.5-2X than Procaine
 Metabolized in Liver
 Excreted via Kidney
 Time of onset of action: 1.5-2 min.
 Half-life: 1.9 Hours
 Max. safe dose: 3% without Vasoconstrictor & 2% with Vasoconstrictor.

BUPIVACAINE
 Concentration: 0.5%
 Potency: 8X Procaine (4X Lidocaine)
 Toxicity:8X Procaine (4X Lidocaine)
  Metabolized: Liver
 Excreted: Kidney
 Onset of action: 5-10 min.
 Half-life: 2.7 Hours
 Max. Recorded Dose: 1.3 mg/Kg
 Max. Safe Dose: 90 mg

PROCAINE
 Concentration - 2-4%
 Potency - 1
 Toxicity - 1
 Metabolized: Hydrolyzed in plasma by pseudo-cholinesterase to PABA
 Excreted: Kidney
 Onset of action: 6-10 min.
 Duration of action: 2-3 hours in tissues.
 Max. Recorded Dose: 6.6 mg/Kg
 Max. Safe Dose: 400 mg
 Strong vasodilatation.
 Very short duration of anesthesia.
 High incidence of allergic reactions.
 Drug of choice for Tx of inadvertent intra-arterial injection (relieves pain
and spasm).
 Consider for Amide allergic patient.

IMPORTANCE OF ADDING VASOCONSTRICTOR IN Las

 Vasoconstrictors Constrict blood vessels
  Decrease blood flow
 Decrease the blood level of the drug
 Increase the concentration of drug at the site
 Decrease bleeding at site
 Increase the duration of drug.
Toxicity
CNS effects
Light headedness or sedation, restlessness, nystagmus
Cardiovascular effects
 Heart block and disturbance in cardiac electrical event
 Bupivacaine ( racemic mixture) cause arrhythmias , and hypotension
 Cocaine ( hypertension, cerebral hemorrhage, cardiac arrhythmias & MI)
Other toxicities
 Prilocaine produce o-toluidine that can cause methemoglobinemia
 Ester type drugs can cause allergic rxn