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General and Local

Anaesthetics
Anesthesia is a reversible condition of comfort,
quiescence and physiological stability in a patient
before, during and after performance of a procedure.

General anesthesia for Local anesthesia - reversible


surgical procedure to inhibition impulse
render the patient generation and
unaware / unresponsive to propagation in nerves. In
the painful stimuli. sensory nerves, such an
Drugs producing G. effect is desired when
Anaesthesia are called painful procedures must be
general anaesthetics performed, e.g., surgical or
dental operations.
General anaesthetics
INTRODUCTION

General anaesthetics have been used to relieve pain


and suffering in surgical patients for almost 170 years

General anaesthetics (GAs) are drugs which produce


reversible loss of all sensations and consciousness. It
usually involves a loss of memory and awareness with
insensitivity to painful stimuli, during a surgical procedure

Include a reange of structurally diverse molecules that


can be divided into volatile anaesthetics, anaesthetic
gases, alcohols and intravenous anaesthetics
General anesthesia

need for
unconsciousnes need for analgesia need for
s Loss of sensory and muscle
Amnesia- autonomic reflexes relaxation
hypnosis
These general anaesthetics drugs are often
accompained by sedative benzodiazepine: midazolam,
diazepan and lorazepan
At cellular level, anaesthetics alter the behavior of
neurons, by interacting directly with a small number of
ion channels.
Under normal conditions:
These membrane proteins are actived by chemical
signals or change in the membrane environment

Upon activation:
Channels change the electrical excitability of neurons
by controlling the flow of excitatory or inhibitory ions
across the cell membrane via an ion channel that is
integral with the receptor that senses the intial signal.

General anaesthetics act by enhancing


inhibitory signals or by blocking excitatory
signals
MOLECULAR ACTIONS OF GENERAL
ANAESTHETIC
A variety of liganded ion channels, receptors
and signal transduction proteins are modulated
by general anesthetics.

Of these, the strongest evidence for a direct


effect of anesthetics exists for:

GABAA receptors
NMDA receptors
Two-pore K + channels
Ketamine, nitrous oxide

Inhibit ionotropic glutamate receptors.


Their primary action is the blockade of NMDA receptors .
These anesthetics have modest effects on many other
receptor, including GABAaRs, but their primary action is
blockade of NMDA receptor.

Other general anaesthetics and the sedatives

They enhance the function of GABAARs, the most abundant


fast inhibitory neurotransmitter receptor in the CNS.
These general anesthetics also have a strong effects on
other ion channels:
Glycine receptors,
Neuronal nicotin receptors,
5-HT3 receptors,
Gutamate reeptors
Two pore potassium channels.
GABAA and Glycine receptors
Chloride-selective ion channels

Inhibitory neurotransmitter receptors: opening of


chloride channels results in membrane
hyperpolarization

GABA and Glycine are the primary fast inhibitory


neurotransmitters in the CNS: Glycine is abundant in
the spinal cord and GABA is predominant in higher
brain regions
GABAA receptors are sensitive to clinical
concentrations of a wide variety of anesthetics,
including inhalational agents and many intravenous
agents (propofol, barbiturates, etomidate, and
eurosteroids).
GABAA receptor

GABAA receptor is a 4-
transmembrane (4-TM)
ion channel
5 subunits arranged
around a central pore: 2
alpha, 2 beta, 1 gamma
Each subunit has N-terminal extracellular chain
which contains the ligand-binding site.
4 hydrophobic sections cross the membrane 4
times: one extracellular and two intracellular
loops connecting these regions, plus an
extracellular C-terminal chain
NMDA receptors

Ionotropic glutamate receptors

Selective for calcium


Involved in long-term modulation
of synaptic responses (long-term
potentiation) and glutamate-
mediated neurotoxicity.

Ketamine, Nitrous oxide, cyclopropane and xenon


are potent and selective inhibitors of NMDA receptors
What is the clinically relevant
concentration for a general anaesthetic?

For inhaled anaesthetic:


1 minimum alveolar concentration (MAC)

conventionally refers to the concentration of inhaled


anaesthetic that produces immobility in 50% of
animals studied

Volatile anaesthetic potency is usually quantified in


terms of MAC.
The selection of specific drugs and routes
of administration to produce general
anesthesia is based:

Pharmacokinetic properties

Secondary effects of the various drugs, in the


context of the proposed diagnostic or
surgical procedure and with the
consideration of the individual patients age,
associated medical condition, and
Effects of General Anaesthesia
Hemodynamic Effects:
Decrease in systemic arterial blood pressure.

The causes include:

Direct vasodilation, myocardial depression;


A generalized decrease in central sympathetic tone.

espiratory Effects
Reduce or eliminate both ventilatory drive and the
reflexes that maintain airway patency.

Ventilation generally must be assisted or controlled


for at least some period during surgery.
Hypothermia
Patients commonly develop hypothermia (body
temperature < 36C) during surgery.

The reasons for the hypothermia include:


low ambient temperature,
exposed body cavities,
cold intravenous fluids,
altered thermoregulatory control,
reduced metabolic rate.

Modalities to maintain normothermia include:


using warm intravenous fluids,
heat changers in the anesthesia circuit,
forced-warm-air covers.
Nausea and Vomiting

Nausea and vomiting are caused by an action of


anesthetics on the chemoreceptor trigger zone and the
brainstem vomiting center, which are modulated by
serotonin (5-HT), histamine, acetylcholine (ACh), and
dopamine (DA).

The 5-HT3-receptor antagonists, ondansetron and


dolasetron are very effective in suppressing nausea and
vomiting.
Inhalation anaesthetics
Gases and volatile liquids can produce anesthesia

Halothane
Enflurane
Isoflurane
Desflurane
Nitrous oxide

Halogenated
compounds:
Contain
Fluorine
and/or
bromide
Simple,
small
molecules
Pharmacokinetics of inhalation
anaesthetics
General Actions of Inhaled Anesthetics

Respiration
Depressed respiration and response to CO 2

Kidney
Depression of renal blood flow and urine
output

Muscle
High enough concentrations will relax skeletal
muscle
Cardiovascular System
Generalized reduction in arterial
pressure and peripheral vascular
resistance. Isoflurane maintains CO and
coronary function better than other
agents

Central Nervous System


Increased cerebral blood flow and
decreased cerebral metabolism
Elimination of inhalation
anesthetics
Redistribution from brain to blood to air

Anesthetics that are relatively insoluble in blood


and brain are eliminated faster

For agents with low blood and tissue


solubility
recovery from anesthesia should mirror
anesthetic induction, regardless of the
duration of anesthetic administration.

For inhalational agents with high blood


and tissue solubility
recovery will be a function of the duration
Halothane
Halothane is a volatile liquid at room temperature

Potent anaesthetic, 2-4% for induction and 0.5-1%


for maintenance.

Approximately 60 to 80% of halothane is eliminated


unchanged. 20% retained in body for 24 hours and
metabolized.

The major metabolite of halothane is trifluoroacetic


acid, which is formed by removal of bromine and
chlorine ions. Trifluoroacetic acid, bromine, and
chlorine all can be detected in the urine.
Advantages:

Potent anesthetic, rapid induction & recovery

Neither flammable nor explosive, sweet smell,


non irritant

Does not augment bronchial and salivary


secretions.

Low incidence of post operative nausea and


vomiting.

Relaxes both skeletal and uterine muscle, and


can be used in obstetrics when uterine
relaxation is indicated.

Not hepatotoxic in pediatric patient, and


Disadvantages:

Cardiovascular System
Is the
dose-dependent reduction in arterial blood pressure result of
direct myocardial
depression leading
to reduced cardiac
output
Halothane does not cause a significant change in systemic
vascular resistance but it does alter the resistance and
autoregulation of specific vascular beds, leading to
redistribution of blood flow
Halothane also has significant effects on cardiac rhythm.
Sinus bradycardia and atrioventricular rhythms occur
frequently during halothane anesthesia but usually are
benign
Respiratory System
Spontaneous respiration is rapid and shallow during
halothane anesthesia
Halothane also inhibits peripheral chemoceptor responses to
arterial hypoxemia
Halothane also is an effective bronchodilator and has been
effectively used as a treatment of last resort in patients with
Nervous System

Halothane dilates the cerebral vasculature, increasing


cerebral blood flow and cerebral blood volume

alothane attenuates autoregulation of cerebral blood flow in


a dose-dependent manner

Muscle

Halothane causes some relaxation of skeletal muscle by its


central depressant effects

Halothane can trigger malignant hyperthermia, a syndrome


characterized by severe muscle contraction, rapid
development of hyperthermia, and a massive increase in
metabolic rate in genetically susceptible patients
Isoflurane

It is a volatile liquid at room temperature

This small amount of isoflurane degradation


products produced is insufficient to produce any
renal, hepatic, or other organ toxicity. Isoflurane
does not appear to be a mutagen, teratogen, or
carcinogen.
Advantages:

A very stable molecule that undergoes little


metabolism

Does not induce cardiac arrhythmias

Does not sensitize the heart to the action of


catecholamines

It also dilates the coronary vasculature,


increasing coronary blood flow and oxygen
consumption by the myocardium, this property
may make it beneficial in patients with IHD.
Disadvantages:

Cardiovascular System
Isoflurane produces vasodilation in most vascular beds, with
particularly pronounced effects in skin and muscle.

Isoflurane is a potent coronary vasodilator, simultaneously producing


increased coronary blood flow and decreased myocardial O2
consumption.

Isoflurane significantly attenuates baroreceptor function.

Patients anesthetized with isoflurane generally have mildly elevated


heart rates as a compensatory response to reduced blood pressure.
Respiratory System
Isoflurane produces concentration-dependent depression of
ventilation.

Isoflurane is particularly effective at depressing the ventilatory


response to hypercapnia and hypoxia.

While isoflurane is an effective bronchodilator, it also is an airway


irritant and can stimulate airway reflexes during induction of
Nervous System
Isoflurane dilates the cerebral vasculature, producing increased
cerebral blood flow; this vasodilating activity is less than that of
either halothane or enflurane .

Isoflurane reduces cerebral metabolic O2 consumption in a dose


dependent manner.

The modest effects of isoflurane on cerebral blood flow can be


reversed readily by hyperventilation.
Muscle
Isoflurane produces some relaxation of skeletal muscle by its central
effects. It also enhances the effects of both depolarizing and non-
depolarizing muscle relaxants.

Isoflurane is more potent than halothane in its potentiation of


neuromuscular blocking agents.
Enflurane
Advantages:
Less potent than halothane, but produces rapid
induction and recovery
Has some analgesic activity
Differences from halothane: Fewer arrhythmias,
less sensitization of the heart to catecholamines,
and greater potentiation of muscle relaxant due
to more potent curare-like effect.

Disadvantages:
Can induce seizure
Nitrous Oxide
Nitrous oxide is a colorless, odorless gas at room temperature

Nitrous oxide is very insoluble in blood and other tissues

Nitrous oxide is almost completely eliminated by the lungs, with


some minimal diffusion through the skin.

Nitrous oxide is not biotransformed by enzymatic action in


human tissue, and 99.9% of absorbed nitrous oxide is eliminated
unchanged.

Noncompetitive antagonist activity at the NMDA receptor


contributes to its anesthetic mechanism.
Disadvantages:

Cardiovascular System
The cardiovascular effects of nitrous oxide also are heavily
influenced by the concomitant administration of other anesthetic
agents. When nitrous oxide is co-administered with halogenated
inhalational anesthetics, it generally produces an increase in
heart rate, arterial blood pressure, and cardiac output. In
contrast, when nitrous oxide is co-administered with an opioid, it
generally decreases arterial blood pressure and cardiac output.

Respiratory System
Causes modest increases in respiratory rate and decreases in tidal
volume in spontaneously breathing patients.

Nervous System
When administered alone, nitrous oxide can significantly increase
cerebral blood flow and intracranial pressure.
The combination of N2O and inhaled agents results in greater
vasodilation than the administration of the inhaled agent alone at
equivalent anesthetic depth.
Intravenous anesthetics
They are used to facilitate rapid induction of anesthesia

Intravenous agents are also used to provide sedation during monitored


anesthesia care and for patients in intensive care (ICU) settings

The intravenous anesthetics used for induction of general anesthesia are


lipophilic and preferentially partition into highly perfused lipophilic tissues
(brain, spinal cord), which accounts for their rapid onset of action.

All drugs used for induction of anesthesia have a similar duration of action
when administered as a single bolus dose despite significant differences in
their metabolism.

Most exert their actions by potentiating GABA-A


receptor
GABAergic actions may be similar to those of volatile
INTRAVENOUS AGENTS

Used in combination with Inhaled anesthetics to:


Supplement general anesthesia
Maintain general anesthesia
Provide sedation
Control blood pressure
Protect the brain (decrease cerebral
metabolism and intracranial pressure)
INTRAVENOUS AGENTS
Primary role as induction agents
Maintenance with total intravenous
anesthesia
Rapid redistribution
Shorter half lives
Rapid distribution to vessel rich tissues
High lipid solubility allows for rapid induction
When redistributed out of the brain, effect
decreases
Advantages
Rapid and complete induction
Less CV depression
Propofol
propofol is also used during maintenance of anesthesia and is a
common choice for sedation in the setting of monitored anesthesia
care.
The presumed mechanism of action of propofol is through potentiation
of the chloride current mediated through the GABA A receptor complex.

Propofol is rapidly metabolized in the liver

Organ System Effects


CNS Effects
Anticonvulsant effect of propofol, and the drug may be safely
administered to patients with seizure disorders.

Propofol decreases cerebral blood flow and the cerebral metabolic rate
for oxygen (CMRO 2 ), which decreases intracranial pressure (ICP) and
intraocular pressure; the magnitude of these changes is comparable to
that of thiopental.
ardiovascular Effects
Produces the most pronounced decrease in systemic blood pressure

This effect on systemic blood pressure is more pronounced with increased


age, in patients with reduced intravascular fluid volume, and with rapid
injection.

Respiratory Effects
Propofol is a potent respiratory depressant and generally produces apnea
after an induction dose
Barbiturates
Thiopental and Methohexital

The effects on inhibitory transmission probably result from activation of


the GABA A
receptor complex, the effects on excitatory transmission are less well
understood.

Methohexital has a shorter elimination half-time than thiopental due to


its larger plasma clearance ( Table 252 ), leading to a faster and more
complete recovery after bolus injection.

CNS Effects
Barbiturates produce dose-dependent CNS depression ranging from
sedation to general anesthesia when administered as bolus injections.

Barbiturates are potent cerebral vasoconstrictors and produce


predictable decreases in cerebral blood flow, cerebral blood volume, and
ICP.
Cardiovascular Effects
Decrease in systemic blood pressure
The depressant effects on systemic blood pressure are increased in
patients with hypovolemia, cardiac tamponade, cardiomyopathy,
coronary artery disease, or cardiac valvular disease because such
patients are less able to compensate for the effects of peripheral
vasodilation.
Respiratory Effects

Barbiturates are respiratory depressants and produces


transient apnea
Barbiturates lead to decreased minute ventilation through reduced tidal
volumes and respiratory rate and also decrease the ventilatory
responses to hypoxia.

The principal clinical uses of thiopental (35 mg/kg IV) or methohexital


11.5 mg/kg IV) is for induction of anesthesia (unconsciousness), which
usually occurs in less than 30 seconds.
Benzodiazepines
Benzodiazepines commonly used in the perioperative period include
midazolam, lorazepam, and less frequently, diazepam.

Benzodiazepines are unique among the group of intravenous anesthetics


because their action can readily be terminated by administration of their
selective antagonist, flumazenil.

Benzodiazepines are most commonly used for preoperative medication,


intravenous sedation, and suppression of seizure activity

CNS
Effects
benzodiazepines decrease cerebral blood flow.
These drugs are potent anticonvulsants used in the treatment of status
epilepticus, alcohol withdrawal, and local anesthetic-induced seizures
Cardiovascular Effects
Midazolam produces a greater decrease in systemic blood pressure
than comparable doses of Diazepam

Respiratory Effects
Benzodiazepines produce minimal depression of ventilation

Benzodiazepines decrease the ventilatory response to carbon dioxide,


but this effect is not usually significant if they are administered alone.
Ketamine
Ketamine is a partially water-soluble and highly lipidsoluble
phencyclidine derivative differing from most other intravenous
anesthetics in that it produces significant analgesia.
Ketamines mechanism of action is complex, but the major effect is
probably produced through inhibition of the NMDA receptor complex.

If ketamine is administered as the sole anesthetic

ketamine can be administered by multiple routes (intravenous,


intramuscular, oral, rectal, epidural)

CNS Effects
ketamine is considered to be a cerebral vasodilator that increases
cerebral blood flow
ketamine is considered an anticonvulsant and may be recommended for
treatment
of status epilepticus when more conventional drugs are ineffective.
Cardiovascular Effects
Ketamine can produce transient but significant increases in systemic blood
pressure, heart rate, and cardiac output, presumably by centrally mediated
sympathetic stimulation
increased cardiac workload and myocardial oxygen consumption, are not
always desirable and can be blunted by coadministration of
benzodiazepines, opioids, or inhaled anesthetics.

Respiratory Effects
Ketamine is not thought to produce significant respiratory depression
LOCAL ANESTETHICS
Loss of sensation in a limited region of the body.

Loss of sensory perceptions by


reversibly inhibiting the propagation
of signals along nerve pathways in a
specific area of the body.

LAs block generation and conduction


of impulse at all parts of neurons
where they come in contact.
Prosperities of ideal LA
Reversible action.
Non-irritant.
No allergic reaction.
No systemic toxicity.
Rapid onset of action.
Sufficient duration of action.
Potent.
Stable in solutions.
Not interfere with healing of tissue.
Have a vasoconstrictor action or compatible with VC.
Not expensive
The molecular structure of all local anesthetics consists
of 3 componets:

Each of these components contributes


distinct clinical properties to the molecule.
Types of Local Anaesthetics
Esters Amides

Cocaine Lignocaine
Procaine Mepivicaine
Tetracaine Prilocaine
Chlorprocaine Bupivacaine
More intense and
Benzocaine longer lasting
Less intense analgesia anaesthesia
Esters vs Amides
The ester linkage is more easily broken so the
ester drugs are less stable in solution and
cannot be stored for as long as amides.
Amide anaesthetics are also heat-stable.
The metabolism of most esters results in the
production of para-aminobenzoate (PABA)
which is associated with allergic reaction.
Amides, in contrast, very rarely cause allergic
phenomena. For these reasons amides are
now more commonly used than esters.
Absorption
Determined by several factors:
Dosage, site of injection, drug-tissue binding, local tissue blood
flow, use of a vasoconstrictor (eg, epinephrine), and the
physicochemical properties of the drug itself.
Anesthetics that are more lipid soluble are generally more potent
and have a longer duration of action

Distribution
1. Localized As local anesthetic is usually injected directly at the
site of the target organ, distribution within this compartment plays
an essential role with respect to achievement of clinical effect.
2. Systemic The peak blood levels achieved during major
conduction anesthesia will be minimally affected by the
concentration of anesthetic or the speed of injection.

etabolism and Excretion


The amide local anesthetics are converted to more water-soluble
metabolites in the liver (amide type) or in plasma (ester type), which are
excreted in the urine.
Mechanism of action

Local anesthetics have greater affinity


for receptors within sodium channels
during their activated and inactivated
states than when they are in their
resting states
Inhibits sodium influx through sodium-specific ion
channels in the nerve cytoplasm
Sodium ions cannot flow in, so potassium ions
cannot flow out, thereby preventing the
depolarization of the nerve
Depolarisation decreases with increase in
concentration of LAs

To do this the
anaesthetic
molecules must
actually enter
through the cell
membrane of the
nerve.
Small nerve fibres are more sensitive than
large nerve fibres

Myelinated fibres are blocked before non-


myelinated fibres of the same diameter.

Thus the loss of nerve function proceeds as


loss of pain, temperature, touch,
proprioception, and then skeletal muscle
tone. This is why people may still feel touch
but not pain when using local anaesthesia.
FACTORS THAT AFFECT ACTION OF
LOCAL ANESTHETICS
pH
Cationic form binds to receptor site. The uncharged
form penetrates membrane. Efficacy of drug can be
changed by altering extracellular or intracellular pH

Lipid solubility and potency


Lipophilicity
Main determinant of anesthetic Drug Relative Lipid
potency solubility
potency.
Compounds with high lipophilicity Procaine =1 100
Prilocaine 1.8 129
penetrate the nerve membrane easily. Lignocaine 2 366
Bupivicaine 8 3420
TOXICITY

Blockage of voltage-gated Na channel affects


action potential propagation throughout the
body

Potential is present for systemic toxicity


Excitation anxiety, agitation, restlessness
Convulsions
Reduced myocardial contractility
Vasodilatation
Progression of local
anesthesia
Loss of:
1. Pain
2. Cold
3. Warmth
4. Touch
5. Deep pressure
6. Motor function
PHARMACOLOGICAL ACTIONS
CNS :
All can produce CNS stimulation followed by
depression.
Cocaine:
Euphoria-excitement-mental Confusion-
tremors-muscle Twitching-convulsions-
Unconciousness -resp. Depression.
Procaine, Lignocaine: safe at clinical doses
CVS :
Cardiac depressant at iv doses
Antiarrhythmic action (procainamide)
Techniques of
administration
Topical Anesthesia
Infiltration
Conduction block
Field block
Nerve block
Peridural
Spinal anesthesia
Topical Anesthesia

Done by the administering the


anesthetic to mucous membranes or
skin. Relieves itching, burning and
surface pain, i.e. sunburns.
Infiltration

Occurs by directly injecting a local


anesthetic to block the nerve
endings under the skin or in the
subcutaneous tissue. Used mainly for
surgeries, i.e. cavities being filled.
TRONCULAR BLOCK ANESTHESIA

Inject a drug around


the nerve
Let the drug diffusing
toward the fibers
Anesthetise a region
Epidural Anesthesia
This is accomplished
by injecting a local
anesthetic into the
peridural space, a
covering of the
spinal cord

EPIDURAL (infusion)
Sympathetic nerve block
hypotension
Spinal anesthesia
Here, the local
anesthetic is
injected into the
subarachnoid
space of the spinal
cord
SPINAL (one-shot)
No sympathetic nerve
block
No hypotension
ARTICAINE
Approved for use in the USA as a dental anesthetic in 2000, articaine is
unique among the amino-amide anesthetics in having a thiophene,
rather than a benzene ring, as well as an
additional ester group that is subject to metabolism by plasma
esterases .

The modification of the ring serves to enhance lipophilicity, and thus


improve tissue penetration, while inclusion of the ester leads to a shorter
plasma half-life (approximately
20 minutes) potentially imparting a better therapeutic index with respect
to systemic toxicity.

These characteristics have led to widespread popularity in dental


anesthesia, where it is generally considered to be more effective, and
possibly
BENZOCAINEsafer, than lidocaine, the prior standard.
As previously noted, benzocaines pronounced lipophilicity has relegated
its application to topical anesthesia.

Elevated levels can be due to inborn errors, or can occur with exposure
to an oxidizing agent, and such is the case with significant exposure to
benzocaine.
COCAINE
Current clinical use of cocaine is largely restricted to topical anesthesia
for ear, nose, and throat procedures, where its intense vasoconstriction
can serve to reduce bleeding.

Even here, use has diminished in favor of other anesthetics combined


with vasoconstrictors
because of concerns about systemic toxicity, as well as the inconvenience
of dispensing and handling this controlled substance.
LIDOCAINE
Aside from the issue of a high incidence of TNS with spinal administration,
lidocaine has had an excellent record as an intermediate duration
anesthetic, and remains the reference standard against which most
anesthetics are compared.