3. General anesthesia
General anesthesia is a reversible state of CNS depression, causing loss of
response to a perception of stimuli.
For patients undergoing surgical or medical procedures, anesthesia
provides five important benefits:
• Sedation and reduced 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 (I.V and inhaled
anesthesia and preanesthetic medications) to produce optimal anesthesia
known as a Balancedanesthesia
4. Preanesthetic medications:
It is the term applied to the administration of drugs prior to general
anesthesia so as to make anesthesia safer for the patient”
Ensures comfort to the patient & to minimize adverse effects of
anesthesia
Preanesthetic medications serve to
calm the patient, relieve pain, protect against undesirable effects of
the subsequently administered anesthetics or the surgicalprocedure.
facilitate smooth induction of anesthesia, lowered the required dose
ofanesthetic
5. Preanesthetic medications:
Anti-anxiety drugs:
Provide relief from apprehension & anxiety
Post-operative amnesia
e.g. Diazepam (5-10mg oral), Lorazepam (2mg i.m.) (avoided co-
administration with morphine, pethidine due to the antagonism)
Opioid analgesics:
Morphine (8-12mg i.m.) or Pethidine (50- 100mg i.m.) used one hour
before surgery Provide sedation, pre-& post-operative analgesia,
reduction in anesthetic dose.
Fentanyl (50-100μg i.m. or i.v.) preferred nowadays (just before
induction of anesthesia)
6. Preanesthetic medications:
Anticholinergics
• Atropine (0.5mg i.m.) or Hyoscine (0.5mg i.m.) or Glycopyrrolate (0.1-
0.3mg i.m.) one hour before surgery.
• Reduces salivary & bronchial secretions, vagal bradycardia,
hypotension.
• Glycopyrrolate(selective peripheral action) acts rapidly, longer acting,
potent antisecretory agent, prevents vagal bradycardia effectively
Antiemetics
Metoclopramide (10mg i.m.) used as antiemetic & as prokinetic gastric
emptying agent prior to emergency surgery
Domperidone (10mg oral) more preferred (does not produce
extrapyramidal side effects)
Ondansetron (4-8mg i.v.), a 5HT3 receptor antagonist, found effective
in preventing post-anaesthetic nausea & vomiting.
7. Preanesthetic medications:
Drugs reducing acid secretion
Ranitidine (150-300mg oral) or Famotidine (20-40mg oral) given
night before & in morning along with Metoclopramide reduces risk of
gastric regurgitation & aspiration pneumonia
Proton pump inhibitors like Omeprazole (20mg) with Domperidone
(10mg) is preferred nowadays.
8. Depth of Anesthesia
(GUEDEL’SSigns)
Guedel (1920) described four sequential stages with ether anaesthesia,
dividing the stage 3 into 4 planes. The order of depression in the CNS is,
Cortical Centre &
Spinal Cord
Basal ganglia &
Medulla
9. Stages of Anesthesia
Stage of Analgesia
Analgesia and amnesia, the patient is conscious and conversational.
Starts from beginning of anesthetic inhalation and lasts up to the loss
of consciousness.
Pain is progressively abolished
Reflexes and respiration remain normal
Stage of delirium
From loss of consciousness to beginning of regular respiration
Patient may shout, struggle and hold his breath; muscle tone
increases, jaws are tightly closed, breathing is jerky; vomiting,
involuntary micturition or defecation may occur
Heart rate and BP may rise and pupils dilate due to sympathetic
stimulation
No operative procedure carried out
Can be cut short by rapid induction, premedication
10. Cont..
Stage of Surgical Anesthesia
Extends from onset of regular respiration to cessation of spontaneous
breathing. This has been divided into 4 planes which may be
distinguished as:
Plane 1 roving eye balls. This plane ends when eyes become fixed.
Plane 2 loss of corneal and laryngeal reflexes, surgical procedures
performed in this plane
Plane 3 pupil starts dilating and light reflex is lost.
Plane 4 Intercostal paralysis, shallow abdominal respiration, dilated pupil.
Medullary Paralysis
Cessation of breathing to failure of circulation and death.
Pupil is widely dilated, muscles are totally flabby, pulse is thready or
imperceptible and BP is very low
11. Phases of general anesthesia
Induction
The period of time from the onset of administration of the anesthetic to
the development of effective surgical anesthesia in the patient. It depends
on how fast effective concentrations of the anesthetic drug reach the
brain.
Thus GA is normally induced with an I.V thiopental, which produces
unconsciousness within 25 seconds or propofol producing
unconsciousness in 30 to 40 seconds after injection. At that time,
additional inhalation or IV drugs may be given to produce the desired
depth of surgical stage IIIanesthesia.
This often includes an IV neuromuscular blocker such as rocuronium,
vecuronium, or succinylcholine to facilitate tracheal intubation and
muscle relaxation.
12. Maintenance:
After administering the anesthetic, vital signs and response to stimuli
are monitored continuously 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 ofanesthesia.
Opioids such as fentanyl are used for analgesia along with
inhalation agents, because the latter are not good analgesics. IV
infusions of various drugs may be used during the maintenance
phase.
Usually: N2O +volatile agent (halothane, isoflurane) Less often N2O +I.V
Opioid analgesic (fentanyl, morphine, pethidine +N.Mblocking agents)
13. Recovery:
The time from discontinuation of administration of the anesthesia until
consciousness and protective physiologic reflexes are regained. It
depends on how fast the anesthetic drug diffuses from thebrain.
For most anesthetic agents, recovery is the reverse of induction.
Redistribution from the site of action (rather than metabolism of the
drug) underliesrecovery.
If neuromuscular blockers have not been fully metabolized, reversal
agents may beused.
The patient is monitored to assure full recovery, with normal
physiologic functions (spontaneous respiration, acceptable blood
pressure and heart rate, intact reflexes, and no delayed reactions such
as respiratorydepression).
14. CHARACTERISTICS OF AN
IDEAL ANESTHETIC
Rapid and pleasant induction
Rapid changes in the depth of anesthesia
Adequate muscle relaxation
Wide margin of safety
Absence of toxic/adverse effects
? But Unfortunately No single agent yet identified is an ideal
anesthetic
16. Inhalation Anesthetics
Inhaled gases are used primarily for maintenance of anesthesia.
Depth of anesthesia can be rapidly altered by changing the inhaled
concentration, very narrow therapeutic index, No antagonists exist.
Common features of inhaled anesthetics
Modern inhalation anesthetics are nonflammable, non explosive
agents.
Decrease cerebrovascular resistance, resulting in increased perfusion
of the brain
Cause broncho dilation, and decrease both spontaneous ventilation
and hypoxic pulmonary vasoconstriction (increased pulmonary
vascular resistance in poorly aerated regions of the lungs, redirecting
blood flow to more oxygenated regions).
Movement of these agents from the lungs to various body
compartments depends upon their solubility in blood and tissues, as
well as on blood flow. These factors play a role in induction and
recovery.
17. Pharmacokinetics
MAC Concept:
The minimum alveolar concentration (MAC) of volatile agents is a term
used to describe the potency of anesthetic vapors.
It is defined as the concentration that prevents movement in response
to skin incision in 50% of unpremedicated subjects studied at sea level
(1 atmosphere), in 100% oxygen.
Hence, it is inversely related to potency and the more potent the agent,
the lower the MAC value.
18. Pharmacokinetics
The principal objective of inhalation anesthesia is a constant and
optimal brain partial pressure (Pbr) of inhaled anesthetic (partial
pressure equilibrium between alveoli [Palv] and brain [Pbr]).
Thus, the alveoli are the “windows to the brain” for inhaled anesthetics.
The partial pressure of an anesthetic gas at the origin of the respiratory
pathway is the driving force moving the anesthetic into the alveolar
space and, thence, into the blood (Pa), which delivers the drug to the
brain and other body compartments.
Because gases move from one compartment to another within the body
according to partial pressure gradients, a steady state (SS) is achieved
when the partial pressure in each of these compartments is equivalent
to that in the inspired mixture.
Palv = Pa = Pb
19. Elimination
Elimination of inhalational anesthetics is largely a reversal of uptake.
For inhalational agents with high blood and tissue solubility, recovery
will be slow. This occurs because the accumulated amounts of
anesthetic in the fat reservoir will prevent blood (and therefore
alveolar) partial pressures from falling rapidly.
20. Mechanism
Most intravenous general anesthetics act predominantly through
GABAA receptors and perhaps through some interactions with other
ligand gated ion channels such as NMDA receptors and two-pore K+
channels.
Chloride channels gated by the inhibitory GABAA receptors are
sensitive to a wide variety of anesthetics, including the halogenated
inhalational agents, many intravenous agents (propofol,
barbiturates, and etomidate), and neurosteroids.
At clinical concentrations, general anesthetics increase the sensitivity
of the GABAA receptor to GABA, thereby enhancing inhibitory
neurotransmission and depressing nervous system activity.
21. Cont…
The action of anesthetics on the GABAA receptor probably is mediated
by binding of the anesthetics to specific sites on the GABAA receptor
protein (but they do not compete with GABA for its binding site).
The capacity of propofol and Etomidate to inhibit the response to
noxious stimuli is mediated by a specific site on the β3 subunit of the
GABAA receptor, whereas the sedative effects of these anesthetics are
mediated by on the β2 subunit.
25. Volatile
Liquids
Isoflurane
Isoflurane is a volatile liquid at room temperature and is neither
flammable nor explosive in mixtures of air or O2.
Isoflurane is a commonly used inhalational anesthetic worldwide.
Clinical Use and ADME.
Isoflurane is typically used for maintenance of anesthesia after
induction with other agents because of its pungent odor.
Induction of anesthesia can be achieved in less than 10 min with an
inhaled concentration of 1.5%–3% isoflurane in O2; this concentration
is reduced to 1%–2% (~1–2 MAC) for maintenance of anesthesia.
26. Cont…
The use of adjunct agents such as opioids or nitrous oxide reduces the
concentration of isoflurane required for surgical anesthesia.
Isoflurane has a blood:gas partition coefficient substantially lower
than that of enflurane. Consequently, induction with isoflurane and
recovery from isoflurane are relatively faster.
More than 99% of inhaled isoflurane is excreted unchanged by the
lungs.
27. Sevoflurane
Sevoflurane is a clear, colorless, volatile liquid at room temperature and
must be stored in a sealed bottle. It is nonflammable and nonexplosive
in mixtures of air or O2.
However, sevoflurane can undergo an exothermic reaction with
desiccated CO2 absorbent to produce airway burns or spontaneous
ignition, explosion, and fire.
Sevoflurane must not be used with an anesthesia machine in which the
CO2 absorbent has been dried by prolonged gas flow through the
absorbent.
The reaction of sevoflurane with desiccated CO2 absorbent also can
produce CO, which can result in serious patient injury.
28. Clinical use
Sevoflurane is widely used for outpatient anesthesia because of its
rapid recovery profile and because it is not irritating to the airway.
Induction of anesthesia is rapidly achieved using inhaled
concentrations of 2%–4% sevoflurane.
Sevoflurane has properties that make it an ideal induction agent:
pleasant smell, rapid onset, and lack of irritation to the airway. Thus, it
has largely replaced halothane as the preferred agent for anesthetic
induction in adult and pediatric patients.
The low solubility of sevoflurane in blood and other tissues provides
for rapid induction of anesthesia and rapid changes in anesthetic depth
following changes in delivered concentration.
29. Desflurane
Desflurane is a highly volatile liquid at room temperature (vapor
pressure =669 mm Hg) and must be stored in tightly sealed bottles.
Delivery of a precise concentration of desflurane requires the use of a
specially heated vaporizer that delivers pure vapor that then is diluted
appropriately with other gases (O2, air, or N2O).
Desflurane is nonflammable and nonexplosive in mixtures of air or O2.
30. Clinical Use
Desflurane is for outpatient surgery because of its rapid onset of action
and rapid recovery time. The drug irritates the tracheobronchial tree and
can provoke coughing, salivation, and bronchospasm.
Anesthesia therefore usually is induced with an intravenous agent, with
Desflurane subsequently administered for maintenance of anesthesia.
Maintenance of anesthesia usually requires inhaled concentrations of
6%–8% (∼1 MAC).
Lower concentrations of Desflurane are required if it is coadministered
with nitrous oxide or opioids.
31. Halothane
Halothane is a volatile liquid at room temperature and must be
stored in a sealed container. Because halothane is a light-sensitive
compound, it is marketed in amber bottles with thymol added as a
preservative. Mixtures of halothane with O2 or air are neither
flammable nor explosive.
32. Clinical use
Halothane has been used for maintenance of anesthesia Concerns over
hepatic toxicity have limited its use in developed countries. Halothane
can produce fulminant hepatic necrosis (halothane hepatitis) in ∼1 in
10,000 patients receiving halothane and “is referred to as halothane
hepatitis”.
This syndrome (with a 50% fatality rate) is characterized by fever,
anorexia, nausea, and vomiting, developing several days after
anesthesia, and can be accompanied by a rash and peripheral
eosinophilia.
Halothane hepatitis may be the result of an immune response to
hepatic proteins that become trifluoroacetylated as a consequence of
halothane metabolism. Halothane has a low cost and is still widely used
in developing countries.
33. Enflurane
Enflurane is a clear, colorless liquid at room temperature and has a
mild, sweet odor. Like other inhalational anesthetics, it is volatile and
must be stored in a sealed bottle. It is nonflammable and nonexplosive
in mixtures of air or oxygen.
Clinical Use
Enflurane is primarily utilized for maintenance rather than induction of
anesthesia.
Surgical anesthesia can be induced with enflurane in less than 10 min
with an inhaled concentration of 2%–4.5% in oxygen and maintained
with concentrations from 0.5% to 3%.
Enflurane concentrations required to produce anesthesia are reduced
when it is coadministered with nitrous oxide or opioids.
Concerns over enflurane’s ability to decrease seizure threshold and
potentially produce nephrotoxicity have limited its clinical utility in
developed countries.
34. GASES
Nitrous Oxide
Nitrous oxide is a colorless, odorless gas at room temperature. N2O is
sold in steel cylinders and must be delivered through calibrated
flowmeters provided on all anesthesia machines.
N2O is neither flammable nor explosive, but it does support
combustion as actively as oxygen does when it is present in proper
concentration with a flammable anesthetic or material.
35. Clinical Use
N2O is a weak anesthetic agent that has significant analgesic effects.
Surgical anesthetic depth is only achieved under hyperbaric conditions.
By contrast, analgesia is produced at concentrations as low as 20%.
The analgesic property of N2O is a function of the activation of opioid
neurons in the periaqueductal gray matter and the adrenergic neurons
in the locus ceruleus.
N2O is frequently used in concentrations of ∼50% to provide analgesia
and mild sedation in outpatient dentistry. N2O cannot be used at
concentrations above 80% because this limits the delivery of adequate
O2.
Because of this limitation, N2O is used primarily as an adjunct to other
inhalational or intravenous anesthetics.
36. Xenon
Xenon, an inert gaseous element, is not approved for use in the U.S. and
is unlikely to enjoy widespread use because it is a rare gas that cannot
be manufactured and must be extracted from air; thus, xenon is
expensive and available in limited quantities. Xenon, unlike other
anesthetic agents,has minimal cardiorespiratory and other side effects.
37. Xenon exerts its analgesic and anesthetic effects at a number of
receptor systems in the CNS. Of these, noncompetitive antagonism of
the NMDA receptor and agonism at the TREK channel (a member of the
two-pore K+ channel family) are thought to be the central mechanisms
of xenon action.
Xenon is extremely insoluble in blood and other tissues, providing for
rapid induction and emergence from anesthesia.
It is sufficiently potent to produce surgical anesthesia when
administered with 30% oxygen. However, supplementation with an
intravenous agent such as propofol appears to be required for clinical
anesthesia.
Xenon is well tolerated in patients of advanced age. No long-term side
effects from xenon anesthesia have been reported.
38. Side Effects
Cardiovascular System.
It produces a concentration-dependent decrease in arterial blood
pressure; cardiac output is well maintained; hypotension is the result of
decreased systemic vascular resistance.
Respiratory System.
Produces concentration-dependent depression of ventilation. These
drugs are particularly effective at depressing the ventilatory response to
hypercapnia(Hypercarbia) and hypoxia.
Muscle.
Produces some relaxation of skeletal muscle by its central effects. They
also enhances the effects of both depolarizing and nondepolarizing
muscle relaxants.
Halogenated inhalational anesthetics and isoflurane relaxes uterine
smooth muscle and is not recommended for analgesia or anesthesia for
labor and vaginal delivery.
39. Parenteral
Parenteral anesthetics are the most common drugs used for anesthetic
induction of adults.
Their lipophilicity, coupled with the relatively high
perfusion of the brain and spinal cord, results in rapid onset and short
duration after a single bolus dose.
Hydrophobicity is the key factor governing their pharmacokinetics.
After a single intravenous bolus, these drugs preferentially partition
into the highly perfused and lipophilic tissues of the brain and spinal
cord, where they produce anesthesia within a single circulation time.
40. Subsequently, blood levels fall rapidly, resulting in drug redistribution
out of the CNS back into the blood. The anesthetic then diffuses into
less-perfused tissues, such as muscle and viscera, and at a slower rate
into the poorly perfused but very hydrophobic adipose tissue.
Termination of anesthesia after single boluses of parenteral anesthetics
primarily reflects redistribution out of the CNS rather than metabolism.
42. Propofol
Fospropofol is a prodrug form that is converted to propofol in vivo.
Fospropofol, which itself is inactive, is a phosphate ester prodrug of
propofol that is hydrolyzed by endothelial alkaline phosphatases to
yield propofol, phosphate, and formaldehyde. The formaldehyde is
rapidly converted to formic acid, which then is metabolized by
tetrahydrofolate dehydrogenase to CO2 and water.
43. Clinical Use.
The induction dose of propofol in a healthy
adult is 2–2.5 mg/kg. Dosages should be reduced in the elderly and in
the presence of other sedatives and increased in young children.
Because of its reasonably short elimination t1/2, propofol often is used
for maintenance of anesthesia as well as for induction.
For short procedures, small boluses (10%–50% of the induction dose)
every 5 min or as needed are effective.
An infusion of propofol produces a more stable drug level (100–300
μg/kg/min) and is better suited for longer-term anesthetic
maintenance. Sedating doses of propofol are 20%–50% of those
required for general anesthesia
44. Etomidate
Etomidate is a substituted imidazole that is supplied as the active d-
isomer.
Etomidate is poorly soluble in water and is formulated as a 2-mg/mL
solution in 35% propylene glycol. Unlike thiopental, etomidate does
not induce precipitation of neuromuscular blockers or other drugs
frequently given during anesthetic induction .
45. Clinical Use
Etomidate is primarily used for anesthetic induction of patients at risk
for hypotension. Induction doses of Etomidate are accompanied by a
high incidence of pain on injection. Lidocaine effectively reduces the
pain of injection.
Etomidate is pharmacokinetically suitable for infusion for anesthetic
maintenance (10 μg/kg/min) or sedation (5 μg/kg/min); however,
long-term infusions are not recommended because of side effects.
An induction dose of etomidate has a rapid onset; redistribution limits
the duration of action. Metabolism occurs in the liver, primarily to
inactive compounds.
Elimination is both renal (78%) and biliary (22%). Compared to
thiopental, the duration of action of etomidate increases less with
repeated doses .
46. Ketamine
Ketamine is an arylcyclohexylamine and congener of
phencyclidine. Ketamine is supplied as a mixture of the R+
and S- isomers even though the S- isomers is more potent
and has fewer side effects. Although more lipophilic than
thiopental, ketamine is water soluble.
47. Clinical Use
• Ketamine is useful for anesthetizing patients at risk for hypotension
and bronchospasm and for certain pediatric procedures.
• Ketamine rapidly produces a hypnotic state quite distinct from that of
other anesthetics. Patients have profound analgesia, unresponsiveness
to commands, and amnesia but may have their eyes open, move their
limbs involuntarily, And breathe spontaneously. This cataleptic state
has been termed dissociative anesthesia.
• Ketamine typically is administered intravenously but also is effective
by intramuscular, oral, and rectal routes. Ketamine does not elicit pain
on injection.
49. Skeletal Muscle Relaxants
Skeletal muscle relaxants are drugs that block the neuromuscular
junction (NMJ) by binding to acetylcholine receptors located on it.
This process leads to paralysis of all skeletal muscles, starting with the
small muscles of the face and paralyzing the diaphragm last.
succinylcholine, the only depolarizing NMJ-blocking drug, binds to Ach
Receptors and causes a prolonged depolarization of the motor end
plate, resulting in flaccid paralysis.
Nondepolarizing NMJ-blocking drugs bind to the Ach Receptors and
prevent depolarization of the motor end plate (depolarization block).
52. Introduction
Local anesthetics bind reversibly to a specific receptor site within the
pore of the Na+ channels in nerves and block ion movement through
this pore.
When applied locally to nerve tissue in appropriate concentrations,
local anesthetics can act on any part of the nervous system and on
every type of nerve fiber, reversibly blocking the action potentials
responsible for nerve conduction.
Thus, a local anesthetic in contact with a nerve trunk can cause both
sensory and motor paralysis in the area innervated. These effects of
clinically relevant concentrations of local anesthetics are reversible
with recovery of nerve function and no evidence of damage to nerve
fibers or cells in most clinical applications
53. MECHANISM OF ACTION
The LAs block nerve conduction by decreasing the entry of Na+ ions
during upstroke of action potential (AP). As the concentration of the LA
is increased, the rate of rise of AP and maximum depolarization
decreases causing slowing of conduction.
Finally, local depolarization fails to reach the threshold potential and
conduction block ensues.
The LAs interact with a receptor situated within the voltage sensitive
Na+ channel and raise the threshold of channel opening: Na+
permeability fails to increase in response to an impulse or stimulus.
54. Cont…
• Impulse conduction is interrupted when the Na+ channels over a
critical length of the fibre (2–3 nodes of Ranvier in case of myelinated
fibres) are blocked.
• At physiological pH, the LA molecule is partly ionized. The equilibrium
between the unionized base form (B) and the ionized cationic form
(BH+) depends on the pKa of the LA. Potency of a LA generally
corresponds to the lipid solubility of its base form (B), because it is this
form which penetrates the axon.
57. ADR
CNS effects are light-headedness, dizziness, auditory and visual
disturbances, mental confusion, disorientation, shivering, twitchings,
involuntary movements, finally convulsions and respiratory arrest.
This can be prevented and treated by diazepam.
Cardiovascular toxicity of LAs is manifested as bradycardia,
hypotension, cardiac arrhythmias and vascular collapse.
Injection of LAs may be painful, but local tissue toxicity of LAs is low.
However, wound healing may be sometimes delayed.
Hypersensitivity reactions like rashes, angioedema, dermatitis,
contact sensitization, asthma and rarely anaphylaxis occur. These are
more common with ester-linked LAs, but rare with lidocaine or its
congeners. Cross reactivity is frequent among ester compounds, but
not with amide-linked Las.
58. Reference
Goodman, Gilman, L.Bruton: The Pharmacological Basis
of THERAPEUTICS; 12th Edition. New York: McGraw Hill
Medical; 2011.
H.P Rang, J.M. Ritter, R.J. Flower, G.Henderson: RANG &
DALE’S Pharmacology; 8th Edition. China: Elsevier; 2016.
K.D Tripathi: Essentials of Medical Pharmacology; 7th
Edition. New Delhi: Jaypee Brothers; 2013.