University of Baghdad

Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

Anaesthetics
A- General Anaesthesia
General anaesthesia is a reversible state of central nervous system (CNS) depression,
causing loss of response to and perception of stimuli. For patients undergoing surgical
or medical procedures, anaesthesia provides five important benefits:
a. Sedation and reduced anxiety
b. Lack of awareness and amnesia
c. Skeletal muscle relaxation
d. Suppression of undesirable reflexes
e. Analgesia

❖ Because no single agent provides all desirable properties,

several categories of drugs are combined to produce
optimal anesthesia (Figure1).
❖ Preanesthetics help calm patients, relieve pain, and prevent
side effects of subsequently administered anesthetics or the
procedure itself.
❖ In addition, the neuromuscular blockers facilitate tracheal
intubation and surgery.
❖ Potent general anesthetics usually are delivered via
inhalation and/or intravenous (IV) injection.

Patient factors in selection of anaesthesia

Drugs are chosen to provide safe and efficient anaesthesia
based on the type of procedure and patient characteristics
such as organ function, medical conditions and concurrent
medications.
A. Status of organ systems
1. Cardiovascular system: Anaesthetic agents suppress
cardiovascular function to varying degrees.
So, they should be used with caution in patients with coronary
artery disease, heart failure, dysrhythmias, and other
cardiovascular disorders.
To treat the hypotension, which may develop during anaesthesia
and lead to reduce perfusion pressure and ischemic injury to
tissues, vasoactive agents may be used .
Some anaesthetics, such as halothane, sensitize the heart to Figure 1: Actions of anesthesia
arrhythmogenic effects of sympathomimetic agents. adjunct drugs.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

2. Respiratory system: Respiratory function must be considered for all anesthetics.

Asthma and ventilation or perfusion abnormalities complicate control of inhalation
anesthetics.
Inhaled agents depress respiration but also act as bronchodilators. IV anesthetics and
opioids suppress respiration. These effects may influence the ability to provide
adequate ventilation and oxygenation during and after surgery.

3. Liver and kidney: The liver and kidneys influence long-term distribution and
clearance of drugs and are also target organs for toxic effects.

4. Nervous system: The presence of neurologic disorders (for example, epilepsy,

myasthenia gravis, neuromuscular disease, compromised cerebral circulation)
influences the selection of anesthetic.

5. Pregnancy: Special precautions should be observed when anesthetics and adjunctive

agents are administered during pregnancy.
Effects on fetal organogenesis are a major concern in early pregnancy. Transient use of
nitrous oxide may cause aplastic anemia in the fetus.
Oral clefts have occurred in fetuses when mothers received benzodiazepines in
early pregnancy. Benzodiazepines should not be used during labor because of resultant
temporary hypotonia and altered thermoregulation in the new born.

B- Concomitant use of drugs

1. Multiple adjunct agents:
Premedications play an important role in anesthesia as they can facilitate the smooth
induction of anesthesia and lower required anesthetic doses. However, they can also
enhance undesirable anesthetic effects (hypoventilation) and, when coadministered,
may produce negative effects not observed when given individually.
2. Concomitant use of other drugs:
Patients may take medications for underlying diseases or abuse drugs that alter response
to anesthetics. For example, alcoholics have elevated levels of liver enzymes that
metabolize anesthetics, and drug abusers may be tolerant to opioids.

STAGES AND DEPTH OF ANESTHESIA

General anesthesia has three stages: induction, maintenance, and recovery. Induction
is the time from administration of a potent anesthetic to development of effective
anesthesia. Maintenance provides sustained anesthesia. Recovery is the time from
discontinuation of anesthetic until consciousness and protective reflexes return.
Induction of anesthesia depends on how fast effective concentrations of anesthetic reach
the brain. Recovery is essentially the reverse of induction and depends on how fast the
anesthetic diffuses from the brain. Depth of anesthesia is the degree to which the CNS
is depressed.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

Induction
General anesthesia in adults is normally induced with an IV agent like propofol,
producing unconsciousness in 30 to 40 seconds. Additional inhalation and/or IV drugs
may be given to produce the desired depth of anesthesia. [Note: This often includes an
IV neuromuscular blocker such as rocuronium, vecuronium, or succinylcholine to
facilitate tracheal intubation and muscle relaxation.]

B. Maintenance of anesthesia
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 of anesthesia. 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.

C. Recovery
Postoperatively, the anesthetic admixture is withdrawn, and the patient is monitored for
return of consciousness. For most anesthetic agents, recovery is the reverse of
induction. Redistribution from the site of action (rather than metabolism of the drug)
underlies recovery.
If neuromuscular blockers have not been fully metabolised, reversal agents may be
used. 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 respiratory depression).

THE DEPTH OF ANESTHESIA

The depth of anesthesia has four sequential stages characterized by increasing CNS
depression as the anesthetic accumulates in the brain. [Note: These stages were defined
for the original anesthetic ether, which produces a slow onset of anesthesia. With
modern anesthetics, the stages merge because of the rapid onset of stage III.]
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: The patient displays delirium and possibly combative

behavior. A rise and irregularity in blood pressure and respiration occur, as well as a
risk of laryngospasm. To shorten or eliminate this stage, rapid-acting IV agents are
given before inhalation anesthesia is administered.

3. Stage III—Surgical anesthesia: There is 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.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

4. Stage IV—Medullary paralysis: Severe depression of the respiratory and

vasomotor centers occurs. Ventilation and/or circulation must be supported to prevent
death.

A brief summary about depth of anaesthesia and its stages are illustrated in Figure 2.

Figure 2: Stages of anesthesia.

There are 3 different routes of administration of the

anaesthetics, which are:
A- INHALATION ANESTHETICS
• Inhaled gases are used primarily for maintenance of anesthesia after
administration of an IV agent.
• Depth of anesthesia can be rapidly altered by changing the inhaled
concentration. The inhaled anaesthetics are summarised in Figure 3.

Figure 3: Inhaled anaesthetics

Common features of inhalation anesthetics

• Modern inhalation anesthetics are non-flammable, nonexplosive agents.
• They include nitrous oxide and volatile, halogenated hydrocarbons.
• 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.
✓ The above- mentioned factors play a role in induction and recovery.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

Mechanism of action of inhaled anesthetics

❖ Generally, no specific receptor has been identified as the locus of general
anesthetic action. The fact that chemically unrelated compounds produce
anesthesia argues against the existence of a single receptor.

❖ At clinically effective concentrations, general anesthetics increase the

sensitivity of the γ-aminobutyric acid (GABAA) receptors to the inhibitory
neurotransmitter GABA. This increases chloride ion influx and
hyperpolarization of neurons. Postsynaptic neuronal excitability and, thus, CNS
activity are diminished.

❖ Unlike other anesthetics, nitrous oxide and ketamine do not have actions on
GABAA receptors. Their effects are likely mediated via inhibition of the N-
methyl-d-aspartate (NMDA) receptors. [Note: The NMDA receptor is a
glutamate receptor. Glutamate is the body’s main excitatory neurotransmitter.]

Halothane
❖ Halothane is the prototype to which newer inhalation anesthetics are compared.
When halothane was introduced, its rapid induction and quick recovery made it
an anesthetic of choice. Due to adverse effects and the availability of other
anesthetics with fewer complications, halothane has been replaced in most
countries.
❖ Therapeutic uses
✓ Halothane is a potent anesthetic but a relatively weak analgesic. Thus,
it is usually coadministered with nitrous oxide, opioids, or local
anesthetics.
✓ Halothane relaxes both skeletal and uterine muscles and can be used in
obstetrics when uterine relaxation is indicated.
✓ Halothane is not hepatotoxic in children (unlike its potential effect on
adults).
✓ Combined with its pleasant odor, it is suitable in pediatrics for inhalation
induction, although sevoflurane is now the agent of choice.
✓ Adverse effects such as cardiac arrhythmias and produce
concentration-dependent hypotension, which can be best treated with a
direct-acting vasoconstrictor, such as phenylephrine. Moreover, it can
cause Malignant hyperthermia (MH).

Nitrous oxide (NO)

• NO (“laughing gas”) is a non-irritating potent analgesic but a weak general
anesthetic. It is frequently used at concentrations of 30 to 50% in combination
with oxygen for analgesia, particularly in dentistry.
• NO alone cannot produce surgical anesthesia, but it is commonly combined with
other more potent agents.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

• NO is poorly soluble in blood and other tissues, allowing it to move very rapidly
in and out of the body.
• Within closed body compartments, nitrous oxide can increase the volume (for
example, causing a pneumothorax) or pressure (for example, in the sinuses),
because it replaces nitrogen in various air spaces faster than the nitrogen leaves.
Its speed of movement allows nitrous oxide to retard oxygen uptake during
recovery, thereby causing “diffusion hypoxia,” which can be overcome by
significant concentrations of inspired oxygen during recovery.
• NO does not depress respiration and does not produce muscle relaxation.
• When coadministered 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, it is probably the safest of these anesthetics, provided that sufficient
oxygen is administered simultaneously.
INTRAVENOUS ANESTHETICS
• IV anesthetics cause rapid induction often occurring within one “arm– brain
circulation time,” or the time it takes 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 inhalation agent.
• IV anesthetics may be used as sole agents for short procedures or administered
as infusions to help maintain anesthesia during longer cases.
• In lower doses, they may be used for sedation.
Propofol
• Propofol is an IV sedative/hypnotic used for induction and/or maintenance of
anesthesia.
• It is widely used and has replaced thiopental as the first choice for induction of
general anesthesia and sedation.
• Because propofol is poorly water soluble, it is supplied as an emulsion
containing soybean oil and egg phospholipid, giving it a milk-like appearance.
• Induction is smooth and occurs 30 to 40 seconds after administration.
• Propofol is commonly infused in lower doses to provide sedation.
• The incidence of postoperative nausea and vomiting is very low, as this agent
has some antiemetic effects.
Barbiturates
• Thiopental is an ultra–short-acting barbiturate with high lipid solubility. It is a
potent anesthetic but a weak analgesic.
• Barbiturates require supplementary analgesic administration during anesthesia.
• When given IV, agents such as thiopental and methohexital quickly enter the
CNS and depress function, often in less than 1 minute.
• These drugs may remain in the body for relatively long periods, because only
about 15% of a dose entering the circulation is metabolized by the liver per hour.
• Thiopental has minor effects on the normal cardiovascular system but may
contribute to severe hypotension in patients with hypovolemia or shock.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

Benzodiazepines
• The benzodiazepines are used in conjunction with anesthetics for sedation.
• The most commonly used is midazolam.
• Diazepam and lorazepam are alternatives. All three facilitate amnesia while
causing sedation, enhancing the inhibitory effects of various neurotransmitters,
particularly GABA.
• Benzodiazepines can induce a temporary form of anterograde amnesia in which
the patient retains memory of past events, but new information is not transferred
into long-term memory. Therefore, important treatment information should be
repeated to the patient after the effects of the drug have worn off.
Opioids
• Because of their analgesic property, opioids are commonly combined with other
anesthetics. The choice of opioid is based primarily on the duration of action
needed. The most commonly used opioids are fentanyl and sufentanil and
remifentanil, because they induce analgesia more rapidly than morphine.
• They may be administered intravenously, epidurally, or intrathecally (into the
cerebrospinal fluid).
• Opioids are not good amnesics, and they can all cause hypotension, respiratory
depression, and muscle rigidity, as well as postanesthetic nausea and vomiting.
• Opioid effects can be antagonized by naloxone.
• In addition to the above-mentioned drugs, there are Etomidate, Ketamine,
Neuromuscular blockers and Dexmedetomidine. Their important properties are
summarised in figure 4.

Figure 4: Therapeutic disadvantages and advantages of some anesthetic agents.

(MEMORISABLE)

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

LOCAL ANESTHETICS
• Local anesthetics block nerve conduction of sensory impulses and, in higher
concentrations, motor impulses from the periphery to the CNS.
• 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.
• Different delivery techniques can be used such as topical administration,
infiltration, peripheral nerve blocks.
• Structurally, local anesthetics all include a lipophilic group joined by an amide
or ester linkage to a carbon chain, which, in turn, is joined to a hydrophilic group
(Figure 5).
• The most widely used local anesthetics are bupivacaine, lidocaine,
mepivacaine, procaine, ropivacaine, and tetracaine. Bupivacaine is noted for
cardiotoxicity if inadvertently injected IV.
• Bupivacaine liposome injectable suspension may provide postsurgical analgesia
lasting 24 hours or longer after injection into the surgical site.
• Non-bupivacaine local anesthetics may cause an immediate release of
bupivacaine from the liposomal suspension if administered together locally.
• Mepivacaine should not be used in obstetric anesthesia due to its increased
toxicity to the neonate.

Figure 5: Representative structures of ester and amide anesthetics.

Metabolism
• Biotransformation of amides occurs primarily in the liver. Prilocaine, a dental
anesthetic, is also metabolized in the plasma and kidney, and one of its
metabolites may lead to methemoglobinemia.
• Esters are biotransformed by plasma cholinesterase (pseudocholinesterase).
Patients with pseudocholinesterase deficiency may metabolize ester local
anesthetics more slowly. At normal doses, this has little clinical effect.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

Onset and duration of action

The onset and duration of action of local anesthetics are influenced by several factors
including tissue pH, nerve morphology, concentration, pKa, and lipid solubility of the
drug. Of these, the pH of the tissue and pKa are the most important.
At physiologic pH, these compounds are charged. The ionized form interacts with the
protein receptor of the Na+ channel to inhibit its function and achieve local anesthesia.
The pH may drop in infected sites, causing onset to be delayed or even prevented.
Within limits, higher concentration and greater lipid solubility improve onset
somewhat. Duration of action depends on the length of time the drug can stay near the
nerve to block sodium channels.

Actions
• Local anesthetics cause vasodilation, leading to rapid diffusion away from the
site of action and shorter duration when these drugs are administered alone. By
adding the vasoconstrictor epinephrine, the rate of local anesthetic absorption
and diffusion is decreased. This minimizes systemic toxicity and increases the
duration of action.
• Hepatic function does not affect the duration of action of local anesthesia, which
is determined by redistribution and not biotransformation.
• Some local anesthetics have other therapeutic uses (for example, lidocaine is an
IV antiarrhythmic).

Allergic reactions
• Patient reports of allergic reactions to local anesthetics are fairly common, but
often times reported “allergies” are actually side effects from epinephrine added
to the local anesthetic. Psychogenic reactions to injections may be misdiagnosed
as allergic reactions and may also mimic them with signs such as urticaria,
edema, and bronchospasm. True allergy to an amide local anesthetic is
exceedingly rare, whereas the ester procaine is somewhat more allergenic.
Allergy to one ester rules out use of another ester, because the allergenic
component is the metabolite para-aminobenzoic acid, produced by all esters.
• In contrast, allergy to one amide does not rule out the use of another amide. A
patient may be allergic to other compounds in the local anesthetic, such as
preservatives in multidose vials.

Administration to children and the elderly

• Before administering local anesthetic to a child, the maximum dose based on
weight should be calculated to prevent accidental overdose.
• There are no significant differences in response to local anesthetics between
younger and older adults.
• It is prudent to stay well below maximum recommended doses in elderly
patients who often have some compromise in liver function.

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 University of Baghdad
Lecture 14 (Grade-3)
Dr Noor Al-Hasani Pharmacology College of dentistry

• Because some degree of cardiovascular compromise may be expected in elderly

patients, reducing the dose of epinephrine may be prudent.
• Local anesthetics are safe for patients who are susceptible to malignant
hyperthermia.

Systemic local anesthetic toxicity

• Toxic blood levels of the drug may be due to repeated injections or could result
from a single inadvertent IV injection.
• Aspiration before every injection is imperative. The signs, symptoms, and
timing of local anesthetic systemic toxicity are unpredictable. One must
consider the diagnosis in any patient with altered mental status or cardiovascular
instability following injection of local anesthetic. CNS symptoms may be
apparent but may also be nonspecific or absent.
• Treatment for systemic local anesthetic toxicity includes airway management,
support of breathing and circulation, seizure suppression and, if needed,
cardiopulmonary resuscitation. Administering a 20% lipid emulsion infusion
(lipid rescue therapy) is a valuable asset.

Figure 6 summarizes pharmacologic properties of some local anesthetics.

Figure 6: Summary of pharmacologic properties of some local anesthetics. PABA = para-

aminobenzoic acid. (MEMORISABLE)

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