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Pharmacology of

General Anesthesia
Factors Influencing Rate of Induction
Anesthetic Potency
Differences between Inhalational Agents
Concentration and Second Gas Effect
Diffusional Hypoxia

Fixed (Intravenous) anesthetics

Rationale for Preanesthetic Medications

Sedative-Hypnotics including anxiolytics


Opioids
Antiemetics
Antipsychotics
Antihisthamine
Anticholinergics
Gastrokinetic Drugs
Inhaled anesthetics
Halothane (Fluothane
Nitrous oxide
Desflurane (Suprane)
Isoflurane (Forane)
Enflurane (Ethrane)
Comparative Pharmacology and Physiology of Anesthetics
Factors Influencing Rate
of Induction
Depth of anesthesia depends on the agent's partial pressure (tension)
in the brain.
The drug's partial pressure is indicative of the drug's concentration at the
target site (the brain).

Anesthetic physico-chemical properties as well as hemodynamic and


pulmonary function are important determinants of both time to onset of the
drug and recovery from the drug.
Four factors determine the partial pressure
in arterial blood and therefore in the brain:
1. Anesthetic concentration in the inspired air

The rate of increase in tension (concentration) of anesthetic in arterial blood is determined in part by the
concentration of the agent in the inspired gas.

This rate of increase in arterial gas tension is not the same anesthetic to anesthetic.
Differences between agents have to do with differing physico-chemical properties which are manifest as
differences in solubility:
The anesthetic molecule interacts with water molecules in the blood and depending on the anesthetic molecular
structure, the drug will be relatively more or less soluble.

Lower anesthetic solubility in blood results in the "blood" compartment becoming saturated with the drug
following fewer gas molecules transferred from the lungs into the blood.

Once the "blood" compartment is saturated with anesthetic, additional anesthetic molecules are readily
transferred to other compartments, the most important one of which is the brain.
Note that for Nitrous Oxide, the arterial gas tension rises rapidly to approximate that of the inspired tension.
By contrast, the arterial gas tension rises much more slowly for Halothane or Ether
These differences are related to differences in anesthetic physical properties.
For example, Nitrous Oxide is relatively insoluble, enabling its tension (partial pressure) to rise very rapidly.
The rate of rise of anesthetic concentration in the brain is influenced by the rate of rise of arterial blood anesthetic
tension.
Differences in the rate of arterial gas tension increase between agents is only part of the story in terms of
anesthesia because different anesthetics have different potencies.
As a result, different anesthetics exhibit different MAC values.
Underlying these differences would be differences at the level of the anesthetic-receptor interaction.
Pulmonary ventilation

The rate of increase in tension (concentration) of


anesthetic in arterial blood is determined in part by
respiratory minute volume.

The higher the minute volume the more gas per unit time
is delivered to the alveoli for transfer to arterial blood.

Accordingly, overventilation during induction can increase


the rate of rise of arterial blood anesthetic gas tension.

By contrast, respiratory depression can delay the


attainment of brain anesthetic concentrations.
Transfer of the gas from the alveoli to the blood: In the
absence of ventilation-perfusion mismatching* three factors
determine how quickly anesthetics pass from the inspired
gas to the blood:

Anesthetic solubility in the blood

Pulmonary blood flow

Partial Pressures in Arterial and Mixed Venous


Blood
Transfer of the gas from the blood to body
tissues (brain)

Solubility of the gas in tissues is an important factor.

For a relatively lipophilic drug and given the brain's


high lipid content, solubility properties favor transfer

Rate of delivery of anesthetic to tissue is clearly an


important aspect since transfer cannot occur unless
the drug is in fact delivered to the target tissue.

Difference in partial pressures (concentration) between


arterial blood and tissue represent the concentration
gradient C1 - C2 which influences the rate of transfer.
Anesthetic Potency
General anesthetics are dangerous with therapeutic
indicies of about 2 - 4, i.e. a dosage only two to four
times above that required to produce anesthesia
can produce circulatory failure.

Although the brain is the site of action, anesthetic


potency is measured on the basis of an alveolar
gas concentration that produce immobility in 50% of
patients exposed to painful stimuli. Classically, the
painful stimulus is defined as associated with an
abdominal incision.
Anesthetic Potency
Therefore, the minimum alveolar concentration (MAC) is the
alveolar anesthetic concentration at one atmosphere (760 mm
Hg) preventing movement in 50% of patients exposed to noxious
stimuli.

The 95% confidence ranges for MAC correspond to about the


MAC value +/- 25%, which provides a rationale for the clinical
dose of about 1.2-1.3 MAC which would be expected to prevent
overt patient reaction during surgical stimulation.

A central question is whether or not the patient during


anesthesia might be aware of the procedure or might recall it.
Probably such awareness or recall is highly unlikely if the
anesthetic is administered in the 1.2-1.3 MAC range.
Anesthetic Potency
MAC values associated with loss of recall or self-
awareness would be about 0.4-0.5 MAC.

An example would be the use of nitrous oxide in the


context of a dental procedure.

In this case patients receiving 50% nitrous oxide,


which corresponds to about 0.45 MAC, do not recall
the procedure.

EEG changes appear to correlate with loss of self-


awareness.
Anesthetic Potency
Waking up: The MAC value range at which a patient will open eyes upon
command is about 0.15-0.5 MAC

Suppression of autonomic adrenergic responses to painful stimulation:

At certain times during the surgical procedure it is likely that an increase in


painful stimulation will occur -- most apparently at the time of initial incision but
also during subsequent manipulations.

MAC values which are sufficient to ensure patient non-overt responsiveness to


pain are not sufficient to prevent adrenergic responses to pain. These
responses are manifested as increasing blood pressure and heart rate.

To suppress these responses requires an increase in MAC by about 50%.


Therefore, an anesthesia provider, anticipating a noxious stimulation, such as
the initial incision, can largely prevent or certainly reduce the hemodynamic
response by increasing temporarily the delivered anesthetic concentration.
MINIMUM ALVEOLAR
CONCENTRATION
Anesthetic MAC values change with the age of the patient.

The general rule is that, with aging, MAC values decrease and that the rate of change (rate of decrease) does not
appear dependent on which agent is considered.

The rule of thumb is that the MAC value decreases by about 6% per 10 years (22% decline in MAC from age 40
to age 80; 27% decline in MAC from age 1 to 40)

MAC values typically used refer to 40 year-old individual

Halothane (Fluothane): 0.75%

Isoflurane (Forane): 1.17%

Enflurane (Ethrane): 1.63%

Sevoflurane (Sevorane, Ultane): 1.8%

Desflurane (Suprane): 6.6%

Nitrous oxide: 104%

An equation which allows estimation of the change in MAC as a function of difference in age in years from 40:
MAC =a(10bx) where a is the MAC value at age 40 for the particular anesthetic, x is the difference in cage of the
patient from 40 and b = -0.00269.
MINIMUM ALVEOLAR
CONCENTRATION
Rationale for using alveolar concentrations rather
than brain levels

Alveolar concentrations are easy to measure


accurately.

At equilibrium the partial pressure of the gas in the


lung is about the same as in the brain.

Blood and brain anesthetic concentrations rapidly


equilibrate.
More about MAC
MAC values are not dependent on the nature of the noxious (painful) stimulus.

MAC values are relatively insensitive to sex, height, weight, and duration of anesthesia,
although age and temperature do affect MAC.

On the other hand, there are factors that increase the apparent MAC value for an
anesthetic. These factors include:

Hypernatremia

Hyperthermia

Chronic ethanol abuse

Increased central neurotransmitter level which might be associated with monoamine


oxidase inhibition, L-DOPA administration (presumably given to manage Parkinsonism),
acute d- amphetamine administration,ephedrine administration or cocaine use.

Not surprisingly there are many factors which decrease the apparent MAC value for an
anesthetic. These factors include:
Factors
Factors that may Decrease the Apparent MAC Value for an Anesthetic

Increasing age

Induced hypotension (MAP < 50 mm Hg)

Lithium

Acute ethanol use

Ketamine (Ketalar)

Pancuronium (Pavulon)

Physostigmine (Antilirium) (at 10 times clinical dose)

Hydroxyzine (Atarax,Vistaril)

Metabolic acidosis

Decreased central neurotransmitter concentration*

Hypo-osmolality

Pregnancy
Factors that may Decrease the
Apparent MAC Value for an Anesthetic
Metabolic acidosis

Decreased central neurotransmitter concentration*

Hypo-osmolality

Pregnancy

Neostigmine (Prostigmin) (at 10 times clinical dose)

Diazepam (Valium)

Verapamil (Isoptin, Calan)


Factors that may Decrease the
Apparent MAC Value for an Anesthetic
Hypoxia (PaO2, 38 mm Hg)

2 adrenergic receptor agonists

Hypothermia

Hyponatremia

Lidocaine (Xylocaine)

Opioids

Barbiturates

Chlorpromazine (Thorazine)

Anemia (< 4.3 ml/O2/dl-1 blood


Pharmacological and clinical differences among the
inhalational anesthetics
Differences between Inhalational Agents
Halothane (Flurothane)

Isoflurane (Forane)

Enflurane (Ethrane)

Desflurane (Suprane)

Sevoflurane

Nitrous Oxide
Halothane: (Flurothane)

Overview

Halothane causes unconsciousness; however, does not provide adequate analgesia.

Halothane (FluOverview:

Halothane causes unconsciousness; however, does not provide adequate analgesia.

Halothane (Fluothane) may not adequately suppress visceral reflexes or provide adequate muscle relaxation for surgery

Halothane (Fluothane) is associated with reversible reduction in glomerular filtration rates (GFR)

Halothane Advantages:

Halothane (Fluothane) is relatively potent and is nonflammable.

This drug's low blood:gas partition coefficient explains both relatively rapid anesthesia induction and recovery from
anesthesia

Halothane (Fluothane) can be used to provide controlled hypotension to reduce/manage bleeding

Halothane Disadvantages

Halothane (Fluothane) is associated with unpredictable hepatitis occurrences

Significant myocardial depression is observed with halothane (Fluothane)


Enflurane (Ethrane)
Enflurane anesthesia: provides unconsciousness

Slight stimulation of salivation and tracheobronchial secretions

Enflurane is typically avoided in epileptic patients because of a CNS excitatory property


occasionally seen.

May provide adequate muscle relaxation greater than seen with halothane; perhaps adequate for
abdominal procedures

Reversible reduction of GRF

Fluoride (a metabolite of enflurane) usually does not reach levels required for kidney toxicity

Enflurane Advantages

Rapid, smooth adjustment of depth of anesthesia with limited effects on pulse or respiration.

Compared to halothane: less arrhythmias, nausea, post-operative shivering and vomiting

Relaxation of skeletal muscles may be adequate for surgery

Enflurane Disadvantages:

possible concern about its use in patients with seizure disorders

Enflurane Status: Enflurane is used as an inhalational agent for adults; but is not widely used for
pediatric cases.
Isoflurane
Isoflurane anesthesia: provides unconsciousness

By contrast to enflurane or halothane, cardiac output is well maintained with


isoflurane.

Initially, until deeper levels of anesthesia are reached, isoflurane stimulates airway
reflexes with attendant increases in secretions, coughing and laryngospasm.
(greater with isofluorane than enflurane or halothane)

May provide adequate muscle relaxation greater than seen with halothane which
may be adequate for abdominal procedures.

As with enflurane, isoflurane relaxation of uterine muscle is not desirable if uterine


contraction is required to limit blood loss.

Reversible reduction of GRF;

Unlike enflurane, convulsive activity has not been seen with isoflurane.
Isoflurane
Isoflurane Advantages:

Rapid, smooth adjustment of depth of anesthesia with limited effects on pulse or respiration.

Depth of anesthesia is easily controlled.

No hepatic and renal toxicity

Cerebral blood flow and intracranial pressure are readily controlled.

Relaxation of skeletal muscles may be adequate for surgery

Arrhythmias are uncommon.

Isoflurane Disadvantages:

As with halothane and enflurane, isoflurane may cause malignant hyperthermia

Isoflurane Status:

Isoflurane may be the most widely used inhalational agent.


Sevoflurane (Sevorane,
Ultane)
Overview:

Low blood solubility; high potency allow excellent anesthesia


control.

Pharmacological properties resemble desflurane

Very commonly used.

Increase fluoride levels rarely associated with kidney or renal


damage.

Compared to desflurane, sevoflurane is more extensively


metabolized, releasing more fluoride.
Nitrous Oxide
With a MAC value of 105%, nitrous oxide, by itself is not suitable or safe as a sole anesthetic agent.

Nitrous oxide is an effective analgesic.

Effective: Nitrous oxide in combination with:

Thiopental for induction

A skeletal muscle relaxant

and hyperventilation to reduce CO2

Despite the relative insolubility of nitrous oxide, large quantities of gas are rapidly absorbed due to its high inhaled
concentration. This concentration effect speeds induction as fresh gas is literally drawn into the lung from the breathing
circuit.

Since nitrous oxide is often administered with a second gas, the second gas effect also enhances the rate of induction.

If administration of nitrous oxide is abruptly discontinued, rapid transfer of NO from blood and tissues to the alveoli decreases
arterial tension of oxygen. This process is diffusional hypoxia.

Nitrous oxide should NOT be used if pockets of trapped air are suspected in the patient (e.g. following a
pneuomoencephalogram) or in an occluded middle ear, because of exchange of NO with nitrogen with attendant gas
expansion.

Nitrous oxide has minimal effects on the circulation compared to the other inhalational agents with which it is co-
administered.
Nitrous Oxide
Nitrous Oxide Advantages:

Excellent analgesia

Nonflammable

Very rapid onset and recovery

Little or no toxicity

Use as an adjunct to other inhalational agents allows reduction in their dosage

Nitrous Oxide Disadvantages:

No skeletal muscle relaxation

Weak anesthetic

Air pockets in closed spaces expand

Post-anesthesia hypoxia (diffusion hypoxia)

Not suitable as a sole anesthetic agent


Concentration and Second Gas Effect

If the concentration of an anesthetic gas is high, the rate of increase of


gas tension in arterial blood is high.

For example, if 75% nitrous oxide and 25% oxygen were administered,
the rate of uptake of gas may be 1 liter/min.

As this volume of gas is removed from the lung, fresh gas is pulled into
the lung from the breathing circuit of the anesthetic delivery equipment.

This effect further increases the delivery of gas mixture and therefore
the rate of rise of arterial tension for nitrous oxide is increased.

Speed of induction is therefore increased since the faster the arterial


tension rises, the faster the rate of rise of gas tension in the brain.

This effect is dependent on the high concentration of inhaled gas.


Second Gas Effect:
If the above condition is present, but a second
anesthetic gas is present, the rate of rise of arterial
tension of the second gas is enhanced also.

If the first gas is nitrous oxide and the second


enflurane, the concentration effect due to NO
which pull more gas from the breathing circuit into
the lung, pulls both fresh NO and fresh enflurane.

Thus the rate of rise of arterial tension of enflurane


is faster as well.
Diffusional Hypoxia

Reverse of the concentration effect: high rate of


transfer of anesthetic from the blood and tissues
to the alveoli.

This additional gas dilutes alveolar oxygen and


can result in postoperative hypoxia.

This process is referred to as "diffusion hypoxia"

Lessened by administration of supplemental


oxygen.