ANESTHETICS

Edited BY:
Dr. MAG
Assistant Professor (Lahore-UBAS)
 1. To explain the concept of Anesthesia
and General Anesthetics and the stages
of anesthesia.

2. To explain the concept of depth of

anesthetic.
LEARNING
OBJECTIVES 3. General Anesthetic classification.

[Link] of action, pharmacological

uses, pharmacokinetics, adverse effects,
and drug interactions of different
classes of General Anesthetics.
5. Local Anesthetics
WHAT IS AN ANESTHESIA ???
A Reversible condition of comfort, Quiescence, and
Physiological stability in a patient before, during, and after
the performance of a surgical procedure.

There are 2 types of anesthesia.

1. General Anesthesia
2. Local Anesthesia
 GENERAL “General anesthesia is a
reversible state of the central
ANESTHESIA nervous system (CNS)
depression, causing loss of
response to and perception of
painful stimuli”.
 The neurophysiologic state produced by general anesthetics
is characterized by five primary effects:
1. Unconsciousness

2. Amnesia

3. Analgesia

4. Inhibition of autonomic reflexes

5. Skeletal muscle relaxation

DESCRIPTION
❑ None of the currently available anesthetic agents when
used alone can achieve all five of these desired effects.

❑ The modern practice of anesthesiology relies on the use of

combinations of intravenous and inhaled drugs ( balanced
anesthesia techniques) to take advantage of the favorable
properties of each agent while minimizing their adverse
effects.
Characteristics of an Ideal Anesthetic Agent

Induce rapid and smooth loss of

consciousness

Be rapidly reversible upon

discontinuation

Possess a wide margin of safety

PATIENT FACTORS IN SELECTION OF
ANESTHESIA
❑ Drugs are chosen to provide safe and efficient anesthesia
based on;
✓The type of procedure and patient characteristics

✓Organ function (CVS, Liver, Kidney, and Respiratory

system)

✓Medical conditions (Hypertensive, Asthma etc.)

✓Concurrent medications
STAGES OF GENERAL ANESTHESIA
General anesthesia has three stages:
1. Induction

2. Maintenance

3. Recovery
1-INDUCTION
“Induction is the time from administration of a potent
anesthetic to development of effective anesthesia/state
of unconsciousness”

✓In adults, induction is done with an IV agent, producing

unconsciousness in 30 to 40 seconds.
✓Additional inhalation and/or IV drugs may be given to
produce the desired depth of anesthesia.
✓In children, without IV access, non-pungent agents, such as
sevoflurane, are inhaled for induction.
2-MAINTENANCE
“Maintenance provides sustained anesthesia during the
course of procedure”
✓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.
✓It is commonly provided with volatile anesthetics.
✓IV infusions of various drugs may also be used during the
maintenance phase.
3-RECOVERY
“Recovery is the time from discontinuation of anesthetic
until regaining consciousness and protective and return
of normal reflexes”

✓Postoperatively, the anesthetic admixture is withdrawn, and

the patient is monitored for return of consciousness.
✓The patient is monitored to ensure full recovery, with normal
physiologic functions such as……
▪ (Spontaneous respiration, acceptable blood pressure, and
heart rate, intact reflexes, and no delayed reactions such as
respiratory depression).
DEPTH OF ANESTHESIA
“Depth of anesthesia is the degree to which the CNS is
depressed”
✓The depth of anesthesia has four sequential stages.
➢1. Analgesia
➢2. Excitement
➢3. Surgical Anesthesia and
➢4. Medullary paralysis
▪ Characterized by increasing CNS depression as the anesthetic accumulates in the brain.
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.
STAGE II—EXCITEMENT
✓The patient displays delirium (Delirium is a mental state in which you are
confused, disoriented, and not able to think or remember clearly) and possibly
combative behavior.
✓A rise and irregularity in blood pressure and respiration
occur, as well as a risk of laryngospasm (a condition in which your vocal
cords suddenly spasm)

✓To shorten or eliminate this stage, rapid-acting IV agents

are given before inhalation anesthesia is administered.
STAGE III—SURGICAL ANESTHESIA
✓There is a gradual loss of muscle tone and reflexes as the
CNS is further depressed.
✓Regular respiration and relaxation of skeletal muscles with
eventual loss of spontaneous movement occur.
✓This is the ideal stage for surgery.
✓Careful monitoring is needed to prevent undesired
progression to stage IV.
STAGE IV—MEDULLARY PARALYSIS
✓Severe depression of the respiratory and vasomotor
centers occurs.
✓Ventilation and/or circulation must be supported to
prevent death.
 Anesthetic agents affect neurons at
various levels, but the primary focus
has been on the synapse.
MECHANISM OF
✓A presynaptic action may alter
ACTION (GENERAL the release of neurotransmitter

ANESTHETIC) ✓A postsynaptic effect may

change the frequency or
amplitude of impulses exiting
the synapse
NEUROTRANSMITTER TYPES
Excitatory Glutamate (Glu)
neurotransmitters Acetylcholine (ACh)
Histamine
Dopamine (DA)
Norepinephrine (NE); also known as noradrenaline (NAd)
Epinephrine (Epi); also known as adrenaline (Ad)

Inhibitory Gamma-aminobutyric acid (GABA)

neurotransmitters Serotonin (5-HT)
Dopamine (DA)
Glycine
Primary inhibitory ion channels

✓Chloride channels
(γ-aminobutyric acid-A [GABA-A] and
glycine receptors)

✓Potassium channels (K ATPase channels)

Excitatory ion channel
The targets include those activated;
✓By acetylcholine (nicotinic and muscarinic
receptors),
✓By excitatory amino acids

(Amino-3-hydroxy-5-methyl4-isoxazole-
propionic acid [AMPA],
✓By Kainate or kainic acid receptor, which
responds to excitatory glutamate and
✓N-methyl D aspartate [NMDA] receptors).
Mechanism of Action:

• General anesthetics increase the sensitivity of the γ-

aminobutyric acid (GABA-A) receptors to the inhibitory
neurotransmitter GABA.
• This increases chloride ion influx and hyperpolarization of
neurons as a result postsynaptic neuronal excitability and,
thus, CNS activity are diminished.
• Nitrous oxide and ketamine do not have actions on GABA-A
receptors rather their effects are likely mediated via inhibition of
the N-methyl-d-aspartate (NMDA) receptors.
• Additionally, inhalation anesthetics block excitatory postsynaptic
currents of nicotinic receptors as well.
 Classification of GENERAL ANESTHETICS

INHALED INTRAVENOUS

Gas Volatile Barbiturates Dissociative

Nitrous liquid Thiopental Ketamine
oxide Halothane Opioids
Benzodiazepines
Isoflurane Midazolam Fentanyl
Desflurane
Sevoflurane Miscellaneous
Etomidate Propofol
INHALATION ANESTHETICS
INHALATION ANESTHETICS
❑ Primarily used for maintenance of anesthesia after
administration of an IV agent.
❑ Depth of anesthesia can be rapidly altered by changing
the inhaled concentration.
❑ Inhalational agents have very steep dose–response
curves and very narrow therapeutic indices, so the
difference in concentrations causing surgical anesthesia
and severe cardiac and respiratory depression is small.
Common features of inhalation anesthetics:
✓ Nonflammable, and nonexplosive agents.

✓Decrease cerebrovascular resistance, resulting in

increased brain perfusion.

✓Cause bronchodilation.

✓Solubility: The 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.
PHARMACOKINETICS
✓Inhaled anesthetics, volatile as well as gaseous, are taken
up through gas exchange in the alveoli.

✓Uptake from the alveoli into the blood and distribution and
partitioning into the different compartments are important
determinants of the kinetics of these agents.
Factors Controlling Uptake:

1. Solubility

2. Cardiac output

3. Alveolar-venous partial pressure difference

HALOTHANE
Characteristics:
✓Prototype inhalation anesthetics.
✓Anesthetic of choice (Rapid induction and quick recovery).
✓Due to adverse effects and the availability of other more
suitable anesthetics with fewer complications, halothane has
been largely replaced in most countries.
Uses:

✓ It is usually co-administered with nitrous oxide, opioids, or local

anesthetics in the maintenance phase.
✓Relaxes both skeletal and uterine muscles and can be used in
obstetrics (the branch of medicine and surgery ) when
concerned with childbirth and midwifery

uterine relaxation is indicated.

✓Suitable in pediatrics for inhalation induction, because of its
pleasant odor.
Adverse effects:
✓Bradycardia and Concentration-dependent hypotension

✓Cardiac arrhythmias

✓Malignant hyperthermia characterized by

• Severe muscle rigidity or spasms.
• Rapid, shallow breathing and problems with low oxygen and high carbon
dioxide.
• Rapid heart rate.
• Irregular heart rhythm.
• Dangerously high body temperature.
• Excessive sweating.
• Patchy, irregular skin color (mottled skin)
ISOFLURANE
Characteristics:
✓This agent undergoes little metabolism and is, therefore,
not toxic to the liver or kidney.
✓Does not induce cardiac arrhythmias or sensitize the
heart to catecholamines.
✓It does produce dose-dependent hypotension.
✓It has a pungent odor and stimulates respiratory reflexes
(for example, breath holding, salivation, coughing,
laryngospasm) and is therefore not used for inhalation
induction.
DESFLURANE
Characteristics:
✓Very rapid onset and recovery.
✓Stimulates respiratory reflexes, therefore desflurane is not
used for inhalation induction.
✓It is relatively expensive and thus rarely used for
maintenance during extended anesthesia.
✓Degradation is minimal and tissue toxicity is rare.
SEVOFLURANE
Characteristics:
✓ Has low pungency, allowing rapid induction without
irritating the airways.
✓ Therefore, it is suitable for inhalation induction in
pediatrics.
✓ It has a rapid onset and quick recovery.
✓ Metabolized by the liver, and compounds formed in the
anesthesia circuit may be nephrotoxic.
NITROUS OXIDE
Characteristics:
✓Nonirritating potent analgesic but a weak general
anesthetic.
Therapeutic Concentration:
✓Used at concentrations of 30 to 50% in combination with
oxygen for analgesia, particularly in dentistry.
Pharmacological Effects:

✓Alone cannot produce surgical anesthesia.

✓When co-administered with other anesthetics, it has moderate
to no effect on the cardiovascular system or on increasing
cerebral blood flow, and it is the least hepatotoxic of the
inhalation agents.
✓Therefore, the safest anesthetics (Inhalational), provided
that sufficient oxygen is administered simultaneously.
INTRAVENOUS ANESTHETICS
 ❑Primarily used to facilitate
rapid induction of
anesthesia.

INTRAVENOUS ❑These are lipophilic and

preferentially partitioned into
ANESTHETICS highly perfused lipophilic
tissues (brain, spinal cord),
which accounts for their rapid
onset of action.
 PROPOFOL
Characteristics:
❑Propofol is an IV sedative/hypnotic used for
induction of anesthesia.
Replaced thiopental as the first choice for
induction of general anesthesia and sedation.
❑ Poorly water-soluble, therefore, supplied as an
emulsion containing soybean oil and egg
phospholipid, giving it a milk-like appearance.
Pharmacokinetics:
❑ Induction Dose: 1–2.5 (mg/kg IV)
❑ Induction is smooth and occurs 30 to 40 seconds after
administration.
❑ Duration of Action : 3–8 (min)
❑ Recovery usually occurs within 8–10 minutes.
❑ Rapidly metabolized in the liver; the resulting water-soluble
compounds are presumed to be inactive and are excreted
through the kidneys.
❑ The recovery from propofol is more complete, with less
“hangover” than that observed with thiopental, likely due to the
high plasma clearance.
Mechanism of action:

The presumed mechanism of action of propofol is

through potentiation of the chloride current
mediated through the GABA-A receptor complex.
Pharmacological Effects:
A. CNS Effects:
✓Acts as hypnotic without analgesic properties.
✓Excitatory effects: such as twitching or spontaneous movement are
occasionally observed during induction of anesthesia at therapeutic
concentrations.
B. Cardiovascular Effects:
✓Decrease in systemic blood pressure (vasodilation) reductions
in preload and afterload.
✓Hypotensive effects
(Inhibition of the normal baroreflex response)
✓Bradycardia and asystole, despite prophylactic anticholinergic
drugs.
C. Respiratory Effects:

✓Act as a potent respiratory depressant (apnea)

✓A maintenance infusion reduces minute ventilation through
reductions in tidal volume and respiratory rate.
Side effects:

✓Tachycardia.
✓Pain on injection is a common complaint.
✓Additionally it causes Antiemetic activity. (Desirable)
BARBITURATES
❑ Thiopental and methohexital were used for induction of
general anesthesia.
 However, these barbiturate hypnotics have been largely
replaced as induction agents by propofol.
Mechanism of action:

❑ The anesthetic effect of barbiturates presumably involves

a combination of enhancement of inhibitory and inhibition
of excitatory neurotransmission.

❑Inhibitory transmission results from activation of the

GABA-A receptor complex, however, the effects on
excitatory transmission are less well understood.
Pharmacokinetics:
Induction Dose: Methohexital 1–1.5 (mg/kg IV)
Thiopental 3–5 (mg/kg IV)
Duration of Action (min): Methohexital 4–7
Thiopental 5–10
❑ Thiopental and methohexital undergo hepatic metabolism,
mostly by oxidation but also by N-dealkylation, desulfuration,
and destruction of the barbituric acid ring structure.
❑ Methohexital has a shorter elimination half-time than
thiopental due to its larger plasma clearance, leading to a
faster and more complete recovery after bolus injection.
Organ System Effects:
A. CNS Effects

✓Dose-dependent CNS depression

✓They do not produce analgesia; instead, some evidence
suggests they may reduce the pain threshold causing
hyperalgesia.
✓Potent cerebral vasoconstrictors and produce
predictable decreases in cerebral blood flow, cerebral
blood volume, and ICP.
B. Cardiovascular Effects:

✓Decrease in systemic blood pressure (vasodilation)

✓Direct negative inotropic effects on the heart

✓Inhibition of the baroreceptor reflex thus,

compensatory increases in heart rate limit the decrease in
blood pressure and make it transient.
C. Respiratory Effects:

✓Respiratory depressants and a usual induction dose of

thiopental or methohexital typically produce transient
apnea, which will be more pronounced if other
respiratory depressants are also administered.

✓Barbiturates lead to decreased minute ventilation

through reduced tidal volumes and respiratory rate and
also decrease the ventilatory responses to hypercapnia
and hypoxia.
BENZODIAZEPINES
❑ Benzodiazepines commonly used in the perioperative
period include midazolam, lorazepam, and less frequently,
diazepam.
❑Action can be terminated by administration of their selective
antagonist, flumazenil.
❑ Their most desired effects are anxiolytis and anterograde
amnesia, which are extremely useful for premedication.
Pharmacokinetics:
Induction Dose: Midazolam 0.1–0.3 (mg/kg IV)
Lorazepam 0.03–0.1 (mg/kg IV)
Diazepam 0.3–0.6 (mg/kg IV)

Duration of Action (min): Midazolam 15–20

Lorazepam 60–120
Diazepam 15–30
❑ The highly lipid-soluble benzodiazepines rapidly enter the CNS

❑Rapid onset of action

Organ System Effects:

A. CNS Effects:

✓Decrease cerebral metabolic rate of oxygen (CMR)O2

and cerebral blood flow but to a smaller extent.
(Cerebral O2 consumption in normal, conscious, young men is approximately 3.5
ml/100 g brain/min)
✓The CNS effects of benzodiazepines can be promptly
terminated by administration of the selective benzodiazepine
antagonist flumazenil, which improves their safety profile.
B. Cardiovascular Effects:
✓ Midazolam produces a greater decrease in systemic blood

pressure than comparable doses of diazepam.

C. Respiratory Effects:
✓Benzodiazepines produce minimal depression of
ventilation, although transient apnea may follow rapid
intravenous administration of midazolam, especially in the
presence of opioid premedication.
D. Other Effects:
Pain during intravenous and intramuscular injection and
Thrombophlebitis is most pronounced with diazepam.
ETOMIDATE
❑ Etomidate is an intravenous I.V. anesthetic with hypnotic
properties without analgesic effects.
❑ It is a carboxylated imidazole derivative that is poorly
soluble in water.
❑Endocrine side effects limit its use for continuous
infusions.
Pharmacokinetics:

Induction Dose: 0.2–0.3 (mg/kg IV)

Duration of Action (min): 3–8

❑ Metabolism is primarily by ester hydrolysis to inactive

metabolites, which are then excreted in urine (78%) and
bile (22%).
❑ Poses minimal effects on hemodynamics
Mechanism of action:

▪ Etomidate appears to have GABA-like effects and seems to act

primarily through the potentiation of GABA-A-mediated
chloride currents, like most other intravenous anesthetics.
Organ System Effects:

A. CNS Effects:
✓Etomidate is a potent cerebral vasoconstrictor, as reflected
by cerebral blood flow and ICP decreases.

B. Cardiovascular Effects:
✓Etomidate produces minimal changes in heart rate and
cardiac output.
✓Its depressant effects on myocardial contractility are
minimal at concentrations used for induction of anesthesia.
C. Respiratory Effects
✓ Depressed ventilation and apnea may occasionally follow
rapid intravenous injection of the drug.
✓Depression of ventilation may be exaggerated when
etomidate is combined with inhaled anesthetics or opioids.
D. Endocrine Effects
✓Causes adrenocortical suppression by producing a dose-
dependent inhibition of 11β-hydroxylase, (an enzyme
necessary for the conversion of cholesterol to cortisol).
✓Because of its endocrine effects, etomidate is not used as a
continuous infusion.
 KETAMINE
Characteristics:
✓Partially water-soluble and highly lipid-soluble
phencyclidine derivative with significant analgesic
characteristics.
✓Designated as a “dissociative anesthesia,”
✓A condition wherein the patient’s eyes remain open with a
slow nystagmus gaze.
Mechanism of action:

Ketamine’s mechanism of action is complex, but the major

effect is probably produced through inhibition of the
NMDA receptor complex.
Pharmacokinetics:

Induction Dose: 1–2 (mg/kg IV)

Duration of Action (min): 5–10

❑ Metabolism occurs primarily in the liver and involves N-

demethylation by the cytochrome P450 system.
Pharmacological Effects:

❑ Induce amnesia,
❑ Respiratory reflexes are often preserved,
❑ The eyes remain open and the pupils are moderately
dilated with a nystagmus gaze.
❑ Lacrimation and salivation are increased and
premedication with an anticholinergic drug may be
indicated to limit this effect.
A. CNS Effects :

✓Cerebral vasodilation that increases cerebral blood

flow, as well as (CMR)O2.
✓Unpleasant emergence reactions. e.g. vivid colorful
dreams, hallucinations, out-of-body experiences, and
increased and distorted visual, tactile (designed to be
perceived by touch), and auditory sensitivity.
✓Fear and confusion,
✓Euphoric state
B. Cardiovascular Effects :

✓Significant increases in systemic blood pressure, heart

rate, and cardiac output. (Sympathetic outflow)
C. Respiratory Effects:

✓Transient hypoventilation and, in rare cases, a short

period of apnea can follow rapid administration of a
large intravenous dose for induction of anesthesia.
OPIOID ANALGESICS
❑ Opioidsare strong analgesic agents distinct
from general anesthetics and hypnotics.
❑Used to achieve postoperative analgesia
and Intraoperative procedures e.g. fentanyl,
Epidural
sufentanil, and remifentanil.
❑Administered intravenously, epidurally, or
intrathecally (into the cerebrospinal fluid).
Pharmacological Effects
❑Hypotension,
❑Respiratory depression,
❑Muscle rigidity,
❑Postanesthetic nausea and vomiting.

❑ Actions can be antagonized by naloxone.

LOCAL ANESTHETICS

Local anesthetics block nerve conduction of sensory

impulses and, in higher concentrations, motor impulses from
the periphery to the CNS.
CLASSIFICATION
➢ Bupivacaine,
➢ Lidocaine,
➢ Mepivacaine,
➢ Procaine,
➢ Ropivacaine, and
➢ Tetracaine
DELIVERY/ADMINISTRATION TECHNIQUES

• Topical administration,
• Infiltration, (Intra-dermal, Sub-mucosal, Sub-cutaneous)
• Peripheral nerve blocks, and
• Neuraxial (spinal, epidural, or caudal) blocks.
MECHANISM OF ACTION:
• Na+ ion channels are blocked to prevent the transient
increase in permeability of the nerve membrane to Na+
that is required for an action potential.

• When propagation of action potentials is prevented,

sensation cannot be transmitted from the source of
stimulation to the brain
Mechanism of Action:
REFERENCE BOOKS
✓ Katzung, B.G., 2011. Basic and Clinical Pharmacology.
12th Ed., McGraw-Hill Medical Publishers, New York,
USA.

✓ Richard, F., M. Clark and L. Cubbedu, 2011. Lippincott’s

Illustrated Reviews, Pharmacology. 6
✓ th Ed., Lippincott William & Wilkins, USA.

✓ Rang, H.P., Dale, M.M., 2011. Rang and Dale’s

Pharmacology. 7th Ed. Elseivier, Churchill Living
Stone, London, UK