General Anesthetics
Prepared by:
Ms. Sushma kaphle
Lecturer,
Department of clinical pharmacology
General anesthesia(GA) is the state produced when a
patient receives medication for amnesia, analgesia,
muscle relaxants and sedation.
General anesthetics depress the CNS to a sufficient
degree to permit the performance of surgery and other
noxious or unpleasant procedures.
GA uses intravenous and inhaled agents to allow
adequate surgical access to the operative site. A point
worth noting is that general anesthesia may not always
be the best choice; depending on a patient’s clinical
presentation, local or regional anesthesia may be more
appropriate.
General anaesthetics (GAs) are drugs which produce
reversible loss of all sensation and consciousness.
For patients undergoing surgical and other medical
procedures, anesthesia provides these five important
benefits:
Sedation and reduction of anxiety
Lack of awareness and amnesia
Skeletal muscle relaxation
Suppression of undesirable reflexes
Analgesia
Because no single agent provides all desirable
properties both rapidly and safely, several categories of
drugs are combined (IV and inhaled anesthesia and
pre-anesthetic medications) to produce optimal
anesthesia known as a Balanced anesthesia.
STAGES OF ANESTHESIA
Induction:
The period of time from the onset of administration of
anesthetics to the development of effective surgical
anesthesia in the patient, it depends on how fast effective
concentration of anesthetic drug reach the brain.
Thus GA is normally induced with an I.V thiopental
(within 25s) or propofol (30-40s).
At that time, additional inhalation or I.V drugs may be
given to produce the desired depth of surgical stage III
anesthesia. Muscle relaxants
(vecuronium/succinylcholine) can be used to facilitate
tracheal intubation and muscle relaxation.
Maintenance:
After administering the anesthetic, vital signs and
response to stimuli are monitored continously to
balance the amount of drug inhaled and/or infused with
the depth of anesthesia.
Maintenance is commonly provided with volatile
anesthetics, which offer good control over the depth of
anesthesia.
Opioids such as fentanyl are used for analgesia along
with inhalation agents.
Recovery:
The time from discontinuation of the administration of
the anesthesia until consciousness and protective
physiologic reflexes are regained, it depends on how fast
the anesthetics drug diffuses from the brain.
The patient is monitored to assure full recovery, with
normal physiological functions (spontaneous
respiration, acceptable blood pressure and heart rate,
intact reflexes, and no delayed reactions such as
respiration depression).
DEPTH OF ANAESTHESIA
(GUEDEL’S signs)
(These clear-cut stages are not seen now-a-days
with the use of faster acting GAs, premedication
and employment of many drugs together.)
1. Stage I – Analgesia
Loss of pain sensation results from interference
with sensory transmission in the spinothalamic tract.
The patient progresses from conscious and
conversational to drowsy.
Amnesia and reduced awareness of pain occur
as Stage II is approached.
2. Stage II – Excitement (stage of delirium)
The patient experiences delirium and possibly
combative behavior.
HR and BP may rise and pupil dilate due to
sympathetic stimulation
To shorten or eliminate this stage of anesthesia, a rapid
acting agent, such as propofol, is given intravenously
before inhalation anesthesia is administered.
No operative procedure is carried out.
3. Stage III – Surgical anesthesia
This has been divided into 4 planes which may be
distinguished as:
Plane 1: Roving eyeballs. This plane ends when eyes
become fixed.
Plane 2: Loss of corneal and laryngeal reflexes
Plane 3: Pupil starts dilating and light reflex is lost.
Plane 4: lntercostal paralysis, shallow abdominal
respiration, dilated pupil.
4. Stage IV – Medullary Paralysis
Severe depression of the respiratory and vasomotor
centers occur during this stage.
Death can rapidly occur unless measures are taken to
maintain circulation and respiration.
Patient factor in selection of anesthesia
Drugs are chosen to provide safe and efficient
anesthesia based on:
1. The type of surgical and diagnostic procedure
2. Patient characteristics such as organ function,
medical conditions and concurrent medications eg:
HTN, bronchial asthma.
Effect on organ systems
Respiratory system
All inhaled anesthetics depress the respiratory system.
They are bronchodilators.
Liver and Kidney
The release of fluoride, bromide and other metabolite
of the halogenated hydrocarbons can affect these
organs, especially with repeated anesthetic
administration over a short period of time.
Pregnancy
Effects on fetal organogenesis are a major concern in
early pregnancy.
• Nitrous oxide can cause aplastic anemia in the unborn
child.
• Oral cleft have been occurred in the fetuses of women
who have received benzodiazepines.
• Diazepam should not be used routinely during labor ,
because it results in temporary hypotonia and altered
thermoregulation in the newborn.
Nervous system
The existence of neurological disorders (eg. Epilepsy or
Myasthenia gravis) influence the selection of
Anesthetics.
Malignant hyperthermia (an autosomal dominant
genetic disorder of skeletal muscle)
Pre-anesthetic Medications
Pre-anesthetic medications serve to:
Calm the patient and relieve the pain.
Protect against undesirable effects of the subsequently
administered anesthetics or surgical procedure.
Facilitate smooth induction of anesthesia.
Lowered the required dose of anesthetics.
Medicines
Benzodiazepines (midazolam or diazepam):
Anxiolysis and amnesia
Diphenhydramine: prevention of allergic reactions
Famotidine/ranitidine: reduces gastric acidity
Antiemetics (ondansetron): prevents aspiration of
stomach contents and post surgical vomiting.
Acetamenophen/opioids(fentanyl): Analgesics
Anticholinergics (glycopyrrolate/scopolamine):
reduces bronchial and salivary secretion, irritant
inhaled anesthetic cause excessive salivation and
secretion.
Concomitant use of other drugs may alter the response
of anesthetics:
Medications for underlying diseases
Drug abuser
Alcoholics
Inhalation anesthetics
Inhaled gases are used primarily for maintenance of
anesthesia . Depth of anesthesia can be rapidly altered
by changing the inhaled concentration.
Common features of inhaled anesthetics
Modern inhalation anesthetics are nonflammable, non-
explosive agents.
Decrease cerebrovascular resistance, resulting in
increased perfusion of the brain.
These factors play a role in induction and recovery.
Mechanism of action
No specific receptor has been identified as the site of general
anesthetic action.
Indeed, the fact that chemically unrelated compounds produce
the anesthetic state argues against the existence of such a
receptor.
The focus is now on interactions of the inhaled anesthetics with
proteins comprising ion channels.
For example, the general anesthetics increase the sensitivity
of the γ-aminobutyric acid (GABA) receptors to the
neurotransmitter, GABA, at clinically effective concentrations
of the drug.
This causes a prolongation of the inhibitory chloride ion current
after a pulse of GABA release.
Halothane
This agent is the prototype to which newer inhalation
anesthetics have been compared.
When halothane was introduced, its ability to induce
the anesthetic state rapidly and to allow quick recovery
(and the fact that it was nonexplosive) made it an
anesthetic of choice.
Therapeutic uses:
Halothane is a potent anesthetic but a relatively weak
analgesic.
Thus, halothane is usually coadministered with nitrous oxide,
opioids, or local anesthetics. It is a potent bronchodilator.
Halothane relaxes both skeletal and uterine muscle, and it
can be used in obstetrics when uterine relaxation is indicated.
Halothane is not hepatotoxic in pediatric patients (unlike its
potential effect on adults), and combined with its pleasant odor,
this makes it suitable in children for inhalation induction,
although sevoflurane is now the agent of choice for inhalation
induction if cost is not a factor.
Pharmacokinetics:
Halothane is oxidatively metabolized in the body to tissue-toxic
hydrocarbons (for example, trifluoroethanol) and bromide ion.
These substances may be responsible for the toxic reaction that
some patients (especially females) develop after halothane
anesthesia. This reaction begins as a fever, followed by
anorexia, nausea, and vomiting, and patients may exhibit
signs of hepatitis. [Note: Although the incidence of this
reaction is low (approximately 1 in 10,000 individuals) 50
percent of affected patients may die of hepatic necrosis.
To avoid this condition, halothane anesthesia is not repeated at
intervals of less than 2 to 3 weeks.
All halogenated inhalation anesthetics have been reported to
cause hepatitis, but at a much lower incidence than with
halothane. For example, isoflurane does so in 1 in 500,000
Adverse effects:
a. Cardiac effects:
a. Vagomimetic and causes atropine-sensitive
bradycardia.
b. Cardiac arrhythmias.
c. Concentration dependent hypotension (a direct-
acting vasoconstrictor, such as phenylephrine, be
given)
b. Malignant hyperthermia (MH)
Isoflurane
This halogenated anesthetic has been widely used in the
United States. It is a very stable molecule that undergoes
little metabolism and is not, therefore, toxic to the liver or
kidney.
Isoflurane does not induce cardiac arrhythmias and
does not sensitize the heart to the action of
catecholamines.
Like the other halogenated gases, it produces dose-
dependent hypotension due to peripheral vasodilation.
It has a pungent odor and stimulates respiratory
reflexes (for example, breath-holding, salivation,
coughing, and laryngospasm) and is, therefore, not used for
inhalation induction.
Nitrous oxide (N2O)
Nitrous oxide (N2O) It is a colourless, odourless, non-
inflammable gas supplied under pressure in steel
cylinders.
Nitrous oxide (“laughing gas”), is non-irritating and a
potent analgesic but a weak general anesthetic;
unconsciousness can not be produced in all
individuals.
For example, nitrous oxide is frequently employed at
concentrations of 30–50 percent in combination with
oxygen for analgesia, particularly in dental surgery.
Properties of an ideal anaesthetic
1. For the patient:
It should be pleasant, non-irritating, should not cause
nausea or vomiting. Induction and recovery should be
fast with no after effects.
2. For the surgeon:
It should provide adequate analgesia, immobility and
muscle relaxation. It should be non inflammable and
nonexplosive so that cautery may be used.
3. For the anaesthetist:
Its administration should be easy, controllable and versatile.
• Margin of safety should be wide - no fall in BP.
• Heart, liver and other organs should not be affected.
• It should be potent so that low concentrations are needed
and oxygenation of the patient does not suffer.
• Rapid adjustments in depth of anaesthesia should be
possible.
• It should be cheap, stable and easily stored.
• It should not react with rubber tubing or soda lime
INTRAVENOUS ANESTHETICS
IV anesthetics cause the rapid induction of anesthesia.
This is often described as occurring within one "arm-
brain circulation time,” or the time it takes the drug to
travel from the site of injection (usually the arm) to the
brain, where it has its effect.
Anesthesia may then be maintained with an appropriate
inhalation agent.
IV anesthetics may be used as the sole agents for short
procedures or administered as infusions to help
maintain anesthesia during longer procedures.
In lower doses, they may be used to provide sedation.
A. Induction:
After entering the blood stream, a percentage of the
drug binds to the plasma proteins, and the rest
remains unbound or “free.” The degree of protein
binding depends upon the physical characteristics of
the particular drug, such as degree of ionization and
lipid solubility.
Drug is carried by venous blood to the right side of the
heart, through the pulmonary circulation, and via the
left side of the heart into the systemic circulation.
Unbound, lipid-soluble, non-ionized molecules cross
the blood-brain barrier most quickly.
Once the drug has penetrated the CNS tissue, it exerts
its effects. Like the inhalation anesthetics, the exact
mode of action of the IV anesthetic drugs is unknown.
B. Recovery
Recovery from IV anesthetics is due to redistribution
from sites in the CNS.
Following the initial flooding of the CNS and other
vessel-rich tissues with non-ionized molecules, the drug
starts to diffuse into other tissues with a lesser blood
supply.
The plasma concentration of the drug falls, allowing it to
diffuse out of the CNS.
This initial redistribution of drug into other tissues leads
to the rapid recovery seen after a single dose of an
induction drug.
Repeat doses or infusions, equilibration with fat tissue
forms a drug reservoir, often leading to delayed recovery
Propofol
Propofol is an IV sedative/hypnotic used in the
induction or maintenance of anesthesia.
Propofol is widely used and has replaced thiopental as
the first choice for anesthesia induction and sedation,
because it produces a euphoric feeling in the patient
and does not cause postanesthetic nausea and
vomiting.
1. Onset:
The induction of anesthesia is smooth and occurs
within about 30–40 seconds of administration.
Following an IV bolus, there is rapid equilibration
between the plasma and the highly perfused tissue of
the brain
Plasma levels decline rapidly as a result of
redistribution, followed by a more prolonged period of
hepatic metabolism and renal clearance.
The initial redistribution half-life is between 2 and 4
minutes.
The pharmacokinetics of propofol are not altered by
moderate hepatic or renal failure.
2. Actions:
Supplementation with narcotics for analgesia is
required. Whereas propofol facilitates depression in
the CNS, it is occasionally accompanied by excitatory
phenomena, such as muscle twitching, spontaneous
movement, and hiccups.
Propofol decreases blood pressure without depressing
the myocardium. It also reduces intracranial pressure,
mainly due to systemic vasodilation.
The incidence of postoperative nausea and vomiting
is very low with the use of propofol.
Fospropofol
Fospropofol is a new, water-soluble drug approved only
for sedation.
Fospropofol is metabolized to propofol in the body, and
the pharmacological effects of fospropofol are attributed
to propofol (thus, fospropofol is a “prodrug” of
propofol).
Because fospropofol is water soluble, the problems
associated with lipid-formulated propofol (such as pain
at the IV injection site and increased chance for
bacterial contamination) are expected to be less
frequent.
Fig: Therapeutic disadvantages and advantages of some anesthetic
agents.
