Anesthetics

Local
General
 General Anesthetics
General anesthetics are drugs which produce reversible loss of all sensations
and consciousness.

The features of general anesthetics are:

Los of sensation, especially of pain.

Sleep (unconsciousness) & amnesia (loss of memory).

Immobility & muscle relaxation.

Abolition of reflexes such as muscular movement & cardiovascular stimulation

No single drug is capable of achieving these effects rapidly and safely

So combination of drugs should be used to achieve these modalities

 General Anesthetics
An ideal anesthetic should:
Have anxiolytic effect---- calm the patient
Have sedative property
Have analgesic activity
Not bring about emesis
Cause muscle relaxation
Possess rapid induction and recovery
Be chemically stable, non-flammable, non toxic & easy to administer.
Be inexpensive.
How ever, no currently available anesthetic agent possesses all these
properties at tolerable doses
 General Anesthetics cont
Hence, the need for pre-anesthetic medication arises to produce a
balanced anesthesia.
Barbiturates
Benzodiazepines
Opioid analgesics
Anti-emetics
Anticholinergics
Muscle relaxant drugs
Antihistamines
Multiple adjunct agents & their functions to anesthesia
Benzodiazepines, such as midazolam or diazepam, to allay anxiety and
facilitate amnesia;
To induce sedation by making use of sedatives such as Barbiturates &
Benzodiazepines.
Antihistamines, such as diphenhydramine, for prevention of allergic
reactions,
Antiemetics, such as ondansetron, to prevent the possible aspiration of
stomach contents;
Opioids, such as fentanyl, for analgesia;
Anticholinergics, such as scopolamine and atropine, to prevent bradycardia
and secretion of fluids into the respiratory tract.
To induce muscle relaxation by making use of muscle relaxant drugs

These agents facilitate smooth induction of anesthesia,

they also lower the dose of anesthetic required to maintain surgical (Stage
III) anesthesia.
 General Anesthetics cont
Classification of general anesthetics
Based on the route of administration
Inhalation anesthetics
Gaseous anesthetics: Nitrous oxide, Cyclopropane
Volatile liquids: Diethyl ether, Enflurane, Halothane, Desflurane,
Isoflurane, sevoflurane
Intravenous anesthetics
Ultrashort acting barbiturates
Neuroleptic analgesics
Benzodiazepines
Dissociative anesthetics (ketamine)
Propofol
Etomidate
 Except nitrous oxide, modern
Drugs
inhaled anesthetics are all
volatile, halogenated
hydrocarbons
Induction, Maintenance, and Recovery from Anesthesia
Anesthesia can be divided into three stages:
Induction:
Period of time from the onset of administration of the
anesthetic to the development of effective surgical anesthesia
Maintenance:
Period during which the patient is surgically anesthetized
Recovery:
Time from discontinuation of administration of the anesthesia
until consciousness and protective physiologic reflexes are
regained
Induction, Maintenance, and Recovery from Anesthesia
Induction:
Depends on how fast effective concentrations of the anesthetic drug reach
the brain
Dangerous excitatory phase (Stage II delirium)-- some earlier anesthetics
IV anesthetic like thiopental, which produces unconsciousness within 25
seconds
Combination may be given, then, to produce the desired depth of surgical
(Stage III) anesthesia
often includes coadministration of an IV skeletal muscle relaxant to facilitate intubation
and relaxation.
Currently used muscle relaxants include pancuronium, vecuronium, atracurium,
succinylcholine etc.
Induction, Maintenance, and Recovery from Anesthesia

Maintenance:
Provides a sustained surgical anesthesia

Anesthesiologist monitors the patient's vital signs and response to various

stimuli
To balance the amount of drug inhaled and/or infused with the depth of anesthesia

Volatile anesthetics are employed,

because these agents offer good minute-to-minute control over the depth of anesthesia

Opioids, such as fentanyl, are often used for pain along with inhalation agents
Induction, Maintenance, and Recovery from Anesthesia

Recovery:
Postoperatively, the anesthesiologist withdraws the anesthetic
mixture and monitors the return of the patient to consciousness.
Depends on how fast the anesthetic drug diffuses from the brain
For most anesthetic agents, recovery is the reverse of induction;
that is:
Redistribution from the site of action (rather than metabolism of the
anesthetic) underlies recovery
 Depth of anesthesia
Four sequential stages--- stage I, stage II, stage III, stage IV

Each stage is characterized by increased CNS depression

Which is caused by accumulation of the anesthetic drug in the brain

These stages were defined with ether, which produces a slow onset of
anesthesia.

However, with halothane and other commonly used anesthetics, the

stages are difficult to characterize clearly because of the rapid onset
of anesthesia.
 Depth of anesthesia

Stage I (Analgesia):
Loss of pain sensation results from
interference with sensory transmission in the
spinothalamic tract.
The patient is conscious and conversational.
 Depth of anesthesia
Stage II (Excitement):
The patient experiences delirium and possibly
violent, combative behavior.
There is a rise and irregularity in blood pressure.
The respiratory rate may increase.
To avoid this stage of anesthesia, a short-acting
barbiturate, such as thiopental, is given
intravenously before inhalation anesthesia is
administered.
 Depth of anesthesia
Stage III (Surgical anesthesia):

Regular respiration and relaxation of the

skeletal muscles occur in this stage.

Eye reflexes decrease progressively, until

the eye movements cease and the pupil is
fixed.

Surgery may proceed during this stage

 Depth of anesthesia

Stage IV (Medullary paralysis):

Severe depression of the respiratory and vasomotor centers occur.

Death can rapidly ensue unless measures are taken to maintain

circulation and respiration.
 Inhalation Anesthetics
Used for maintenance of anesthesia after
administration of an intravenous agent.
Advantage over IV anesthetics?
Depth of anesthesia can be rapidly altered
Inhalation anesthetics are also reversible, because
most are rapidly eliminated from the body by
exhalation
Includes nitrous oxide (N2O) and a number of
volatile, halogenated hydrocarbons

Chemical structures of inhaled anesthetics

 Inhalation Anesthetics
Potency
The potency of inhaled anesthetics is defined quantitatively as the median
alveolar concentration (MAC).
MAC is the end-tidal concentration of anesthetic gas needed to eliminate
movement among 50 percent of patients challenged by a standardized skin
incision.
[Note: MAC is the median effective dose (ED50) of the anesthetic.]
MAC is usually expressed as the percentage of gas in a mixture required to
achieve the effect.
MAC is an index of potency; an anesthetic with low MAC is said to be
potent
 Inhalation Anesthetics
The more lipid soluble an
anesthetic, the higher the
potency of the anesthetic

MAC for anesthetic gases

Uptake and distribution of inhalation anesthetics

Anesthetic uptake is the product of:

Gas solubility in the blood,
Cardiac output, and
Alveolar and venous partial pressure gradients of the anesthetic
Uptake and distribution of
inhalation anesthetics
1. Solubility in the blood:
Drugs with low versus high
solubility in blood differ in
their speed of induction of
anesthesia
 Why induction of anesthesia is slower with more soluble anesthetic gases. In this schematic
diagram, solubility in blood is represented by the relative size of the blood compartment (the
more soluble, the larger the compartment).
Relative partial pressures of the agents in the compartments are indicated by the degree of filling
of each compartment. 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.
Uptake and distribution of inhalation anesthetics

2. Cardiac output:
It is obvious that cardiac output affects the delivery of anesthetic to
tissues.
Low cardiac output will result in slow delivery of the anesthetic.
3. Alveolar to venous partial pressure gradient of the anesthetic:
more gas moves into the blood from the lung according to the partial
pressure difference.
Over time, the partial pressure in the venous blood closely
approximates the partial pressure in the inspired mixture; that is,
no further net anesthetic uptake from the lung occurs.
 Mechanism of action
No specific receptor has been identified
The focus is now on interactions of the inhaled anesthetics with proteins
comprising ion channels.
Anesthetic drugs may increase inhibitory synaptic activity or diminish
excitatory activity.
Chloride channels (GABAA and glycine receptors) and potassium channels
remain the primary inhibitory ion channels
Excitatory ion channel targets include:
those activated by acetylcholine (nicotinic and muscarinic receptors),
those activated by excitatory amino acids (amino-3-hydroxy-5-methyl-4-isoxazol-
propionic acid [AMPA], kainate, and N-methyl-Daspartate [NMDA] receptors), or by
serotonin (5-HT2 and 5-HT3
receptors).
The mechanism by which the anesthetics perform these modulatory roles
is not understood.
MOA
MOA
 Halothane:
This agent is the prototype to which newer inhalation anesthetics have been compared
Has very pleasant smell, there fore is accepted by many patients
Enflurane
Isoflurane
Desflurane
Sevoflurane:
is an inhalation anesthetic with low pungency
Does not irritate the airway, therefore, less likely to cause laryngo-spasm
Nitrous oxide:
Nitrous oxide (laughing gas) is a potent analgesic but a weak general anesthetic
 Intravenous Anesthetics
IV anesthetics are used for rapid induction of anesthesia,
which is then maintained with appropriate inhalation agent.
The rapid cessation of action is attributed to redistribution
The effect subsides before the agent leaves the body.
High lipid solibility
Thiopental
Ketamine
Propofol
Fentanyl
Barbiturates
Theopental:
Produce sedation, sleepiness or anesthesia
potent anesthetic but a weak analgesic
require supplementary analgesic administration to avoid changes in blood
pressure and autonomic function
Ultrashort-acting and has a high lipid solubility.
On intravenous injection, it causes unconsciousness with in
20 seconds and this lasts for 5-10 minutes.
Benzodiazepines
BDZs are used in conjunction with anesthetics to
sedate the patient.
The most commonly employed is midazolam.
Diazepam and lorazepam are alternatives.
All three facilitate amnesia while causing
sedation.
Opioids
For their analgesic property, opioids are used together with
anesthetics;
for example, the combination of morphine and nitrous oxide provides good
anesthesia for cardiac surgery.
Choice is primarily based on the duration of action needed.
The most frequently employed opioids are fentanyl and its congeners,
sufentanil or remifentanil,
because they induce analgesia more rapidly than morphine does.
Opioids are not good amnesics, and they can all cause hypotension,
respiratory depression, and postanesthetic nausea and vomiting.
Opioid effects can be antagonized by naloxone
Etomidate
used to induce anesthesia
It is a hypnotic agent but lacks analgesic activity
Its water solubility is poor, so etomidate is formulated in a propylene
glycol solution
No effect on the heart and circulation, but
Decrease plasma cortisol and aldosterone levels
Ketamine
Dissociative anesthesia
Is a dissociative anesthetic agent --- the patient is not in a full conscious state
and does not feel pain but appears to be awake
It is lipophylic and enters the brain very quickly
It produces profound analgesia, immobility, amnesia with light sleep.
On regaining consciousness, the patient may experience a
disconnection between out side reality and inner mental state.
Frequently there is memory loss for the duration of the recovery period.
Stimulates the central sympathetic outflow,
stimulation of the heart and increased blood pressure and cardiac output
beneficial in patients with either hypovolemic or cardiogenic shock
Disadvantage in hypertensive or stroke patients
Propofol
IV sedative/hypnotic used in the induction or maintenance of
anesthesia.
Onset is smooth and occurs within about 40 seconds of
administration.
Supplementation with narcotics for analgesia is required.
Propofol is widely used and has replaced thiopental as the first choice
for anesthesia induction and sedation,
because it produces euphoric feeling in the patient and
does not cause postanesthetic nausea and vomiting
 Local Anesthetics (LA)
Are generally applied locally and block nerve conduction of
sensory impulses from the periphery to the CNS

LA abolish sensation (and, in higher concentrations, motor

activity) in a limited area of the body without producing
unconsciousness (for example, during spinal anesthesia)

The small, unmyelinated nerve fibers that conduct impulses for

pain, temperature, and autonomic activity are most sensitive to
actions of local anesthetics

The most widely used of these compounds are:

bupivacaine, lidocaine, procaine, and tetracaine
 Local Anesthetics (LA)
At physiologic pH, these compounds are charged;

It is this ionized form that interacts with the protein receptor of the Na+
channel to inhibit its function and, thereby, achieve local anesthesia

The LA differ pharmacokinetically as to onset and duration of action

By adding the vasoconstrictor epinephrine to the local anesthetic, the rate of

anesthetic absorption is decreased.
This both minimizes systemic toxicity and increases the duration of action

Seizures and cardiovascular collapse are the most significant of these systemic
adverse effects
 Local Anesthetics (LA)
Most LA agents consist of a lipophilic group (eg, an aromatic ring) connected by an
intermediate chain via an ester or amide to an ionizable group (eg, a tertiary amine)
Because ester links are more prone to hydrolysis than amide links, esters usually have a
shorter duration of action
Local anesthetics are weak bases and are usually made available clinically as salts to increase
solubility and stability.
In the body, they exist either as the uncharged base or as a cation
The relative proportions of these two forms are governed by their pKa and the pH of the
body fluids according to the Henderson-Hasselbalch equation
This issue of ionization is of critical importance because the cationic form is the most active at
the receptor site
the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the
charged form of the anesthetic penetrates biologic membranes poorly.
Thus, the uncharged form is important for cell penetration.
After penetration into the cytoplasm, equilibration leads to formation and binding of the
charged cation at the sodium channel, and hence the production of a clinical effect
 SAR

The smaller and more highly lipophilic local anesthetics have a faster
rate of interaction with the sodium channel receptor.
As previously noted, potency is also positively correlated with lipid
solubility.
Lidocaine, procaine, and mepivacaine are more water soluble than
tetracaine, bupivacaine, and ropivacaine.

The latter agents are more potent and have longer durations of local
anesthetic action
Difference between General & Local anesthetics
GA LA
Site of action CNS Peripheral nerves
Consciousness Lost Unaltered
Area of body involved Whole body Restricted area
Preferential use Major surgery Minor surgery