Anesthetics- Part 1

Dr. Dalia Abd Al- Kader

PhD Pharmacology
General anesthesia 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, 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, several categories of drugs are combined
to produce optimal anesthesia.
-Preanesthetics help calm patients, relieve pain, and
prevent side effects of subsequently administered
anesthetics or the procedure itself.
Neuromuscular blockers facilitate tracheal intubation
and surgery.
Potent general anesthetics are delivered via inhalation
and/or (IV) injection. Except for nitrous oxide, inhaled
anesthetics are volatile, halogenated hydrocarbons.
IV anesthetics consist of several chemically unrelated
drug types commonly used to rapidly induce
anesthesia.
PATIENT FACTORS IN SELECTION OF ANESTHESIA
Drugs are chosen to provide safe and efficient
anesthesia 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:
-Anesthetic agents suppress cardiovascular function
to varying degrees. This is an important
consideration in patients with coronary artery
disease, heart failure, dysrhythmias, valvular
disease, and other cardiovascular disorders.
-Hypotension may develop during anesthesia,
resulting in reduced perfusion pressure and
ischemic injury to tissues. Treatment with
vasoactive agents may be necessary.
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. Release of fluoride,
bromide, and other metabolites of halogenated
hydrocarbons can affect these organs, especially if
they accumulate with frequently repeated
administration of anesthetics.
4. Nervous system: The presence of neurologic disorders (for
example, epilepsy, 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 newborn.
B. Concomitant use of drugs
1. Multiple adjunct agents:
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.
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. It depends on how fast effective
concentrations of anesthetic reach the brain.
Maintenance provides sustained anesthesia.
Recovery is the time from discontinuation of
anesthetic until consciousness and protective
reflexes return. It depends on how fast the
anesthetic diffuses from the brain.
Depth of anesthesia
1. Stage I—Analgesia: Loss of pain sensation
results from interference with sensory
transmission.
2. Stage II—Excitement: The patient displays
delirium. 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.
4. Stage IV—Medullary paralysis: Severe
depression of the respiratory and vasomotor
centers occurs. Ventilation and/or circulation
must be supported to prevent death.
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.
Common features of inhalation anesthetics
Modern inhalation anesthetics are nonflammable,
nonexplosive agents, including nitrous oxide and
volatile, halogenated hydrocarbons.
Uptake and distribution of inhalation anesthetics
The alveoli are the “windows to the brain” for
inhaled anesthetics.
-Because gases move from one body compartment
to another according to partial pressure gradients,
steady state is achieved when the partial pressure
in each of these compartments is equivalent to
that in the inspired mixture.
Mechanism of action
• At clinically effective concentrations, general anesthetics
increase the sensitivity of the GABAA receptors to the
inhibitory neurotransmitter GABA. This increases chloride ion
influx and hyperpolarization of neurons.
• 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.]
• Other receptors are also affected by volatile anesthetics.
For example, the activity of the inhibitory glycine receptors in
the spinal motor neurons is increased.
• inhalation anesthetics block excitatory postsynaptic currents
of nicotinic receptors.
Halothane
• is the prototype to which newer inhalation
anesthetics are compared. Its rapid induction and
quick recovery made it an anesthetic of choice.
But 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.
- it is usually coadministered with nitrous oxide,
opioids, or local anesthetics.
-It is a potent bronchodilator. 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.
Pharmacokinetics: Halothane is oxidatively metabolized in the
body to tissue-toxic hydrocarbons (for example, trifluoroethanol)
and bromide ion. These substances may be responsible for toxic
reactions that some adults (especially females) develop after
halothane anesthesia. This begins as a fever, followed by
anorexia,
nausea, and vomiting, and possibly signs of hepatitis. Although
the incidence is low (approximately 1 in 10,000), half of affected
patients may die of hepatic necrosis. To avoid this condition,
halothane is not administered at intervals of less than 2 to 3
weeks.
All halogenated inhalation anesthetics have been associated with
hepatitis, but at a much lower incidence than with halothane.
Adverse effects:
a. Cardiac effects:
- may cause atropine-sensitive bradycardia.
- Cardiac arrhythmias.
- concentration-dependent hypotension. This
is best treated with a direct-acting vasoconstrictor,
such as phenylephrine.
b. Malignant hyperthermia: In a very small
percentage of susceptible patients, exposure to
halogenated hydrocarbon anesthetics or the
neuromuscular blocker succinylcholine may induce
malignant hyperthermia (MH), a rare life-
threatening condition, leading to circulatory
collapse and death if not treated immediately.
Strong evidence indicates that MH is due to an
excitation–contraction coupling defect. Burn
victims and individuals with muscular
dystrophy, myopathy, myotonia, and
osteogenesis imperfecta are susceptible to MH.
Susceptibility to MH is often inherited.
Dantrolene blocks release of Ca2+ from the
sarcoplasmic reticulum of muscle cells,
reducing heat production and relaxing muscle
tone.
The patient must be monitored and supported for
respiratory, circulatory, and renal problems.
Use of dantrolene and avoidance of triggering
agents such as halogenated anesthetics
in susceptible individuals have markedly reduced
mortality from MH.
Isoflurane
-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 produces 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
-provides very rapid onset and recovery.
-However, it has a low volatility, requiring
administration via a special heated vaporizer.
-Because it stimulates respiratory reflexes,
desflurane is not used for inhalation induction.
-It is relatively expensive and thus rarely used for
maintenance during extended anesthesia.
-Its degradation is minimal and tissue toxicity is
rare.
Sevoflurane
- has low pungency, allowing rapid
induction without irritating the airways.
- suitable for inhalation induction in pediatric
patients.
- It has a rapid onset and recovery
- is metabolized by the liver, and compounds
formed in the anesthesia circuit may be
nephrotoxic.
Nitrous oxide (“laughing gas”)
-is a nonirritating potent analgesic but a weak general anesthetic.
--Nitrous oxide alone cannot produce surgical anesthesia, but it is
commonly combined with other more potent agents.
-Nitrous oxide is poorly soluble in blood and other tissues,
allowing it to move very rapidly in and out of the body.
- Nitrous oxide 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,
- it is the least hepatotoxic of the inhalation agents.
- it is probably the safest of these anesthetics, provided that
sufficient oxygen is administered at same time.