The study of the relationship between a drug's dose, tissue concentration, and elapsed

time is called pharmacokinetics (how a body affects a drug).

The study of drug action, including toxic responses, is called pharmacodynamics (how
a drug affects a body).

course of general anesthesia can be divided into three phases: (1) induction, (2)
maintenance, and (3) emergence.
Inhalation anesthetics are particularly useful in the induction of pediatric patients in
whom it may be difficult to start an intravenous line.
In contrast, adults usually prefer rapid induction with intravenous agents, although
the nonpungency and rapid onset of sevoflurane have made inhalation induction
practical for adults.
Regardless of the patient's age, anesthesia is often maintained with inhalation
agents.
Emergence depends primarily upon the pulmonary elimination of these agents.
Because of their unique route of administration, inhalation anesthetics have useful
pharmacological properties not shared by other anesthetic agents. For instance,
exposure to the pulmonary circulation allows a more rapid appearance
PHARMACOKINETICS OF INHALATION ANESTHETICS
unknown, it is assumed that their ultimate effect depends on attainment of a
therapeutic tissue concentration in the central nervous system

FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI)
mixes with gases in the breathing circuit before being inspired by the patient. Therefore,
the patient is not necessarily receiving the concentration set on the vaporizer
depends mainly on the fresh gas flow rate, the volume of the breathing system, and any
absorption by the machine or breathing circuit

FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA)
1. Uptake
If no uptake of anesthetic agent by the body, the alveolar gas concentration (FA)
would rapidly approach the inspired gas concentration (FI)
Reality alveolar concentrations lag behind inspired concentrations (FA/FI < 1.0).
The greater the uptake, the slower the rate of rise of the alveolar concentration
and the lower the FA:FI ratio
Because the concentration of a gas is directly proportional to its partial pressure,
the alveolar partial pressure will also be slow to rise. The alveolar partial pressure
is important because it determines the partial pressure of anesthetic in the blood
and, ultimately, in the brain. Similarly, the partial pressure of the anesthetic in the
brain is directly proportional to its brain tissue concentration, which determines
clinical effect. Therefore, the greater the uptake of anesthetic agent, the greater
the difference between inspired and alveolar concentrations, and the slower the
rate of induction.
Three factors affect anesthetic uptake:
solubility in the blood,
i. Insoluble agents, such as nitrous oxide, are taken up by the blood less avidly
than soluble agents, such as halothane. As a consequence, the alveolar
concentration of nitrous oxide rises faster than that of halothane, and
induction is faster.
ii. The higher the blood/gas coefficient, the greater the anesthetic's solubility
and the greater its uptake by the pulmonary circulation.
iii. As a consequence of this high solubility, alveolar partial pressure rises more
slowly, and induction is prolonged.
iv. Because fat/blood partition coefficients are greater than 1, it is not
surprising that blood/gas solubility is increased by postprandial lipidemia
and is decreased by anemia.
v. Eg. Blood/gas for NO is 0.47, that means in same 1 ml volume of blood and
alveolar gas, under same partial pressure, theres 0.47 unit of NO in blood, 1
unit of NO in alveolar gas. Things like halothane has much higer solubility,
being 2.4. But why higher solubility takes longer to do induction?
Concentration of gas is directly proportional to its partial pressure. Because
with higher solubility, so achieve the same partial pressure, halothane has to
dissolve 2.4 units in blood!
alveolar blood flow, and
i. cardiac output increases, anesthetic uptake increases, the rise in alveolar
partial pressure slows, and induction is delayed.
ii. Low-output states predispose patients to overdosage with soluble agents, as
the rate of rise in alveolar concentrations will be markedly increased.
the difference in partial pressure between alveolar gas and venous blood.
i. depends on tissue uptake
ii. If anesthetics did not pass into organs such as the brain, venous and alveolar
partial pressures would become identical and there would be no pulmonary
uptake
iii. transfer of anesthetic from blood to tissues is determined by three factors
analogous to systemic uptake: tissue solubility of the agent (tissue/blood
partition coefficient), tissue blood flow, and the difference in partial pressure
between arterial blood and the tissue.
iv. highly perfused vessel-rich group (brain, heart, liver, kidney, and endocrine
organs) is the first to take up appreciable amounts of anesthetic.
v. Anesthetic uptake produces a characteristic curve that relates the rise in
alveolar concentration to time
vi. initial steep rate of uptake is due to unopposed filling of the alveoli by
ventilation. The rate of rise slows as the vessel-rich groupand eventually
the muscle groupreach their capacity
vii.
2. Ventilation
lowering of alveolar partial pressure by uptake can be countered by increasing
alveolar ventilation
constantly replacing anesthetic taken up by the pulmonary bloodstream
results in better maintenance of alveolar concentration.
2 situations
i. The effect of increasing ventilation will be most obvious in raising the
FA/FI for soluble anesthetics, as they are more subject to uptake.
ii. the FA/FI is already high for insoluble agents, increasing ventilation has
minimal effect.
3. Concentration
effects of uptake can also be reduced by increasing the inspired concentration.
Interestingly, increasing the inspired concentration not only increases the
alveolar concentration but also increases its rate of rise (ie, increases FA/FI)
This has been termed the concentration effect
i. The first is confusingly called the concentrating effect. If 50% of an
anesthetic is taken up by the pulmonary circulation, an inspired
concentration of 20% (20 parts of anesthetic per 100 parts of gas) will
result in an alveolar concentration of 11% (10 parts of anesthetic
remaining in a total volume of 90 parts of gas). On the other hand, if the
inspired concentration is raised to 80% (80 parts of anesthetic per 100
parts of gas), the alveolar concentration will be 67% (40 parts of
anesthetic remaining in a total volume of 60 parts of gas.). Thus, even
though 50% of the anesthetic is taken up in both examples, a higher
inspired concentration results in a disproportionately higher alveolar
concentration. In this example, increasing the inspired concentration
4-fold results in a 6-fold increase in alveolar concentration. The extreme
case is an inspired concentration of 100% (100 parts of 100), which,
despite a 50% uptake, will result in an alveolar concentration of 100%
(50 parts of anesthetic remaining in a total volume of 50 parts of gas).
ii. The second phenomenon responsible for the concentration effect is the
augmented inflow effect. Using the example above, the 10 parts of
absorbed gas must be replaced by an equal volume of the 20% mixture
to prevent alveolar collapse. Thus, the alveolar concentration becomes
12% (10 plus 2 parts of anesthetic in a total of 100 parts of gas). In
contrast, after absorption of 50% of the anesthetic in the 80% gas
mixture, 40 parts of 80% gas must be inspired. This further increases the
alveolar concentration from 67% to 72% (40 plus 32 parts of anesthetic
in a volume of 100 parts of gas).
more significant with nitrous oxide than with the volatile anesthetics, as the
former can be used in much higher concentrations. Nonetheless, a high
concentration of nitrous oxide will augment (by the same mechanism) not
only its own uptake but theoretically that of a concurrently administered
volatile anesthetic. The concentration effect of one gas upon another is
called the second gas effect, which is probably insignificant in the clinical
practice of anesthesiology.
FACTORS AFFECTING ARTERIAL CONCENTRATION (FA)
Ventilation/Perfusion Mismatch
Normally, alveolar and arterial anesthetic partial pressures are assumed to
be equal, but in fact the arterial partial pressure is consistently less than
end-expiratory gas would predict. Reasons for this may include venous
admixture, alveolar dead space, and nonuniform alveolar gas distribution.
FACTORS AFFECTING ELIMINATION
Anesthetics can be eliminated by biotransformation, transcutaneous loss, or
exhalation
most important route for elimination of inhalation anesthetics is the alveolus
Many of the factors that speed induction also speed recovery: elimination of
rebreathing, high fresh gas flows, low anesthetic-circuit volume, low
absorption by the anesthetic circuit, decreased solubility, high cerebral blood
flow (CBF), and increased ventilation







PHARMACODYNAMICS OF INHALATION
ANESTHETICS

multitude of substances capable of producing general anesthesia is remarkable:
inert elements (xenon), simple inorganic compounds (nitrous oxide),
halogenated hydrocarbons (halothane), and complex organic structures
(barbiturates)
various agents probably produce anesthesia by different methods
(agent-specific theory)
The unitary hypothesis proposes that all inhalation agents share a common
mechanism of action at the molecular level. This is supported by the
observation that the anesthetic potency of inhalation agents correlates directly
with their lipid solubility (MeyerOverton rule). The implication is that
anesthesia results from molecules dissolving at specific lipophilic sites.
Neuronal membranes contain a multitude of hydrophobic sites in their
phospholipid bilayer. Anesthetic binding to these sites could expand the bilayer
beyond a critical amount, altering membrane function (critical volume
hypothesis)
Anesthetic binding might significantly modify membrane structure. Two
theories suggest disturbances in membrane form (the fluidization theory of
anesthesia and the lateral phase separation theory)
General anesthetic action could be due to alterations in any one of several
cellular systems including ligand-gated ion channels, second messenger
functions, or neurotransmitter receptors. For example, many anesthetics
enhance -aminobutyric acid (GABA) inhibition
MINIMUM ALVEOLAR CONCENTRATION
is the alveolar concentration that prevents movement in 50% of patients in
response to a standardized stimulus (eg, surgical incision)
a useful measure because it mirrors brain partial pressure, allows comparisons of
potency between agents, and provides a standard for experimental evaluations
MAC values for different anesthetics are roughly additive
Factors which Increase Anesthetic Requirements Factors which Decrease Anesthetic Requirements
Chronic ETOH
Infant (highest MAC at 6 mo.)
Red hair
Hypernatremia
Hyperthermia
Acute ETOH
Elderly Patients
Hyponatremia
Hypothermia
Anemia (Hgb < 5 g/dL)
Hypercarbia
Hypoxia
Pregnancy
One of the most striking is the 6% decrease in MAC per decade of age,
regardless of volatile anesthetic. MAC is relatively unaffected by species, sex,
or duration of anesthesia

Example of inhalation anasesthetics

Inorganic VS organic

1. NITROUS OXIDE
N
2
O; laughing gas is the only inorganic anesthetic gas in clinical use
colorless and essentially odorless
gas at room temperature and ambient pressure
relatively inexpensive anesthetic, however, concerns regarding its safety
have led to continued interest in alternatives such as xenon
Effects on organs
CVS: stimulate the sympathetic nervous system
Resp: increases respiratory rate (tachypnea) and decreases tidal volume
as a result of central nervous system stimulation and, perhaps, activation
of pulmonary stretch receptors
Brain: By increasing CBF and cerebral blood volume, nitrous oxide
produces a mild elevation of intracranial pressure
MSK: In contrast to other inhalation agents, nitrous oxide does not
provide significant muscle relaxation.
Problems
Although nitrous oxide is insoluble in comparison with other inhalation
agents, it is 35 times more soluble than nitrogen in blood. Thus, it tends
to diffuse into air-containing cavities more rapidly than nitrogen is
absorbed by the bloodstream.
Examples of conditions in which nitrous oxide might be
hazardous include air embolism, pneumothorax, acute
intestinal obstruction, intracranial air (tension
pneumocephalus following dural closure or
pneumoencephalography), pulmonary air cysts, intraocular
air bubbles, and tympanic membrane grafting.
Because the relatively high MAC of nitrous oxide prevents its use as a
complete general anesthetic
2. HALOTHANE
halogenated alkane
Halothane is the least expensive volatile anesthetic, and because of its safety
profile (see below), continues to be used worldwide
Effects on organs
CVS: dose-dependent reduction of arterial blood pressure is due to
direct myocardial depression; 2.0 MAC of halothane results in a 50%
decrease in blood pressure and cardiac output
Resp: causes rapid, shallow breathing
MSK: relaxes skeletal muscle and potentiates nondepolarizing
neuromuscular-blocking agents (NMBA)
Problems
Halothane hepatitis is extremely rare (1 per 35,000 cases)
Contraindicated in patients with unexplained liver dysfunction following
previous exposure
halothane hepatitis appears to affect primarily adults and children past
puberty, some anesthesiologists choose other volatile anesthetics in
these patients
3. ISOFLURANE
nonflammable volatile anesthetic with a pungent ethereal odor
4. DESFLURANE
NON-FLMAMMABLE FLUORINATED METHYL ETHYL ETHER
5. SEVOFLURANE
Like desflurane, sevoflurane is halogenated with fluorine














NONVOLATILE ANESTHETIC AGENTS: INTRODUCTION
Nothing much to say. Divide into groups like opioid, non-opioid.

Neuromuscular Blocking Agents
KEY CONCEPTS
It is important to realize that muscle relaxation does not ensure unconsciousness,
amnesia, or analgesia.
Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists, whereas
nondepolarizing muscle relaxants function as competitive antagonists.
Because depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they
diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by
another enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or
butyrylcholinesterase).
With the exception of mivacurium, nondepolarizing agents are not significantly
metabolized by either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade
depends on redistribution, gradual metabolism, and excretion of the relaxant by the body, or
administration of specific reversal agents (eg, cholinesterase inhibitors) that inhibit
acetylcholinesterase enzyme activity.
Muscle relaxants owe their paralytic properties to mimicry of ACh. For
example, succinylcholine consists of two joined ACh molecules.
Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom
blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a
very long blockade (eg, 46 h) following succinylcholine administration.
Succinylcholine is considered contraindicated in the routine management of children and
adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children
with undiagnosed myopathies.
Normal muscle releases enough potassium during succinylcholine-induced depolarization
to raise serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with
normal baseline potassium levels, a life-threatening potassium elevation is possible in patients
with burn injury, massive trauma, neurological disorders, and several other conditions.
As a general rule, the more potent the nondepolarizing muscle relaxant the longer its
speed of onset.
Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the
kidneys, and their action is prolonged in patients with renal failure.
Cirrhotic liver disease and chronic renal failure often result in an increased volume of
distribution and a lower plasma concentration for a given dose of water-soluble drugs, such as
muscle relaxants. On the other hand, drugs dependent on hepatic or renal excretion may
demonstrate prolonged clearance. Thus, depending on the drug, a greater initial dosebut
smaller maintenance dosesmight be required in these diseases.
Atracurium and cisatracurium undergo degradation in plasma at physiological pH and
temperature by organ-independent Hofmann elimination. The resulting metabolites (a
monoquaternary acrylate and laudanosine) have no intrinsic neuromuscular blocking effects.
Mivacurium, like succinylcholine, is metabolized by pseudocholinesterase. It is only
minimally metabolized by true cholinesterase.
Hypertension and tachycardia may occur in patients given pancuronium. These
cardiovascular effects are caused by the combination of vagal blockade and catecholamine
release from adrenergic nerve endings.
Long-term administration of vecuronium to patients in intensive care units has resulted in
prolonged neuromuscular blockade (up to several days), possibly from accumulation of its
active 3-hydroxy metabolite, changing drug clearance, or the development of a
polyneuropathy.
Rocuronium (0.91.2 mg/kg) has an onset of action that approaches succinylcholine
(6090 s), making it a suitable alternative for rapid-sequence inductions, but at the cost of a
much longer duration of action.


Skeletal muscle relaxation can be produced by deep inhalational anesthesia,
regional nerve block, or neuromuscular blocking agents (commonly
called muscle relaxants)
neuromuscular junction blocking agents produce paralysis, not anesthesia. In
other words, muscle relaxation does not ensure unconsciousness, amnesia, or
analgesia
NEUROMUSCULAR TRANSMISSION
As a nerve's action potential depolarizes its terminal, an influx of
calcium ions through voltage-gated calcium channels into the nerve
cytoplasm allows storage vesicles to fuse with the terminal
membrane and release their contents of acetylcholine (ACh)
structure of ACh receptors varies in different tissues and at different
times in development. Each ACh receptor in the neuromuscular
junction normally consists of five protein subunits, two subunits
and single , , and subunits. Only the two identical subunits
are capable of binding ACh molecules
Cations flow through the open ACh receptor channel (sodium and
calcium in; potassium out), generating an end-plate potential.
contents of a single vesicle, a quantum of ACh (10
4
molecules per
quantum), produce a miniature end-plate potential
ACh is rapidly hydrolyzed into acetate and choline by the
substrate-specific enzyme acetylcholinesterase. This enzyme
(also called specific cholinesterase or true cholinesterase) is
embedded into the motor end-plate membrane immediately adjacent
to the ACh receptors

Table 91. Depolarizing and Nondepolarizing Muscle Relaxants.

Depolarizing Nondepolarizing
Short-acting Short-acting
Succinylcholine Mivacurium
Intermediate-acting
Atracurium
Cisatracurium
Vecuronium
Rocuronium
Long-acting
Doxacurium
Pancuronium
Pipecuronium

Similar to ACh, all neuromuscular blocking agents are quaternary
ammonium compounds whose positively charged nitrogen imparts an
affinity to nicotinic ACh receptors
Depolarizing muscle relaxants
very closely resemble ACh and therefore readily bind to ACh
receptors, generating a muscle action potential. Unlike ACh,
however, these drugs are not metabolized by
acetylcholinesterase, and their concentration in the synaptic
cleft does not fall as rapidly, resulting in a prolonged
depolarization of the muscle end-plate Continuous end-plate
depolarization causes muscle relaxation because opening of the
lower gate in the perijunctional sodium channels is time limited
After the initial excitation and opening, these sodium channels
close and cannot reopen until the end-plate repolarizes.
The end-plate cannot repolarize as long as the depolarizing
muscle relaxant continues to bind to ACh receptors; this is called
a phase I block. After a period of time, prolonged end-plate
depolarization can cause ionic and conformational changes in
the ACh receptor that result in a phase II block, which clinically
resembles that of nondepolarizing muscle relaxants.
Nondepolarizing muscle relaxants
bind ACh receptors but are incapable of inducing the
conformational change necessary for ion channel opening.
Because ACh is prevented from binding to its receptors, no
end-plate potential develops. Neuromuscular blockade occurs
even if only one subunit is blocked
use of peripheral nerve stimulators to monitor neuromuscular
function
Four patterns of electrical stimulation with supramaximal
square-wave pulses are considered:
1. Tetany: A sustained stimulus of 50100 Hz, usually lasting
5 s.
2. Twitch: A single pulse 0.2 ms in duration.
3. Train-of-four: A series of four twitches in 2 s (2-Hz
frequency), each 0.2 ms long.
4. Double-burst stimulation (DBS): Three short (0.2 ms)
high-frequency stimulations separated by a 20-ms interval
(50 Hz) and followed 750 ms later by two (DBS
3,2
) or three
(DBS
3,3
) additional impulses