PHARMACOKINETICS AND

PHARMACODYNAMICS INHALATIONAL
DRUGS

Meseret H

Mesi H.
 Objective

At the end of this class; Students should

Understand and practice the concept of pharmacokinetics of

inhalational anesthetics
Understand and practice the concept of pharmacodynamics of

inhalational anesthetics

Mesi H.
 Short history of anaesthesia
 Crawford Long of Jefferson, Georgia,{1842} used diethyl
ether anesthesia
 Horace Wells{1844} had used nitrous oxide in his dental

practice.
 William T. G.Morton, another dentist successfully etherized a

patient at the Massachusetts General Hospital in Boston on

October 16,1846

Mesi H.
 Clinical Signs with Diethyl Ether-Induced
General Anesthesia
1. Stage of Analgesia (voluntary excitation / euphoria)
 Awake to loss of consciousness - normal ocular reflexes,
muscle tone, respiration

2. Stage of Excitation (involuntary excitation)

 Excitement, increased muscle tone just after loss of
consciousness – some blunting of ocular reflexes,
irregular respiration

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 Stages of anesthesia ...contd’s

3. Stage of Surgical Anesthesia light to deep anesthesia

reduced muscle tone, increasing loss of ocular reflexes, no

response to skin incision

4. Stage of Medullary Depression (near death) respiratory /

cardiovascular failure (overdosed).

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 DESIRED COMPONENTS OF GENERAL
ANESTHESIA
I. Unconsciousness

II. Amnesia : temporary memory loss

III. Analgesia : Lack of pain and autonomic stability (generally go hand-

in-hand)
 Intact autonomic responses can indicate pain or discomfort via
changes in heart rate, BP, etc.

IV. Muscle relaxation : Especially important for orthopedic and

abdominal surgery
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Mesi H.
 Pharmacokinetics of inhaled anesthetics

 Absorption (uptake) from alveoli into pulmonary capillary

blood

 Distribution in the body

 Metabolism

 Elimination, principally via the lungs

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Pharmacokinetics of inhaled anesthetics
 A constant and optimal brain partial pressure of the inhaled anesthetic

 The alveolar partial pressure {PA} of inhaled anesthetics mirrors the

brain partial pressure (Pbr).

 So it is can be used as a monitor

 Depth of anesthesia

 Recovery from anesthesia

 Minimum alveolar concentration{MAC}

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Mesi H.
Determinants of Alveolar Partial Pressure
1. Inhaled Partial Pressure (PI)

A high initial input offsets the impact of uptake, thus

accelerating the induction of anesthesia

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 2. Alveolar Ventilation{AV}
 Increased AV, increase in the PA toward the PI and thus the
induction of anesthesia.

 Decreased AV decreases input and thus slows the

establishment of that PA and a Pbr necessary for the
induction of anesthesia.

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 3. Characteristics of anesthetic breathing
system
 Volume of the external breathing system

 Solubility of the inhaled anesthetics in the rubber or

plastic components of the breathing system, and

 Gas inflow from the anesthetic machine

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4. Alveolar-to-Venous Partial Pressure
Differences
Tissues are assigned into four groups based on their
solubility and blood flow:
Vessel-rich group
Brain, heart, liver, kidney, and endocrine organs
Muscle group
Skin and muscle
Fat group
Vessel-poor group
Bone, ligaments, teeth, hair, and cartilage

Mesi H.
 5. Solubility
 The solubility of the inhaled anesthetics in blood and tissues is

denoted by the partition coefficient

 A partition coefficient is a distribution ratio describing how

the inhaled anesthetic distributes itself between two phases at

equilibrium (partial pressures equal in both phases).

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 Blood:Gas Partition Coefficients
 A blood:gas partition coefficient of 0.5 means that

The concentration of inhaled anesthetic in the blood is half

that present in the alveolar gases

When the partial pressures on the anesthetic in these two

phases is identical

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 Overpressure technique
 The impact of high blood solubility on the rate of PA increase

can be down regulated to some extent by increasing the PI

above that required for the maintenance of anesthesia

 May be used to speed the induction of anesthesia

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When blood solubility is low, minimal amounts of inhaled
anesthetic must be dissolved before equilibration is achieved;

Therefore, the rate of increase of PA and Pa, and thus onset-

of-drug effects, such as the induction of anesthesia, are rapid
Slow rate of increments during inhalational induction

Soluble

Blood: Gas Brain: Blood Muscle: Blood Fat: Blood Oil: Gas
Partition Partition Partition Partition Partition
Coefficient Coefficient Coefficient Coefficient Coefficient
Methoxyflura
ne
12 2 1.3 48.8 977
Mesi H.
PARTITION COEFFICIENTS OF VOLATILE ANESTHETICS
AT 37°C
Intermediat
ely soluble Blood: Gas Brain: Blood Muscle: Blood Fat: Blood Oil: Gas
Partition Partition Partition Partition Partition
Coefficient Coefficient Coefficient Coefficient Coefficient
Halothane 2.5 41.9 3.4 51.1 224
Enflurane 1.90 1.5 1.7 36.2 98
Isoflurane 1.4 61.6 2.9 44.9 98

Poorly Blood: Gas Brain: Blood Muscle: Blood Fat: Blood Oil: Gas
soluble Partition Partition Partition Partition Partition
Coefficient Coefficient Coefficient Coefficient Coefficient

Nitrous oxide 0.46 1.1 1.2 2.3 1.4

Desflurane 0.42 1.3 2.0 27.2 18.7
Sevoflurane 0.69 1.7 3.1 47.5 55
Xexon 0.115
Mesi H.
 Cardiac Output{CO}
 An increased CO results in a more rapid uptake, so the
rate of increase in the PA (and thus the induction of
anesthesia) is slowed

 A low CO, as with shock, could produce an unexpectedly

high PA of a soluble anesthetic

Volatile anesthetics that depress CO can exert a positive

feedback response.

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 Spontaneous Versus Mechanical Ventilation
 Inhaled anesthetics influence their own uptake by their dose-

dependent depressant effects on alveolar ventilation

Negative feedback protective mechanism in spontaneously

ventilating patients
Eg. LMA ventilated patients

This protective mechanism is lost in patients with controlled

ventilation
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 Second-Gas Effect
 When two inhalational anesthetics are given simultaneously,

the uptake of large volumes of one agent may increase the

alveolar tension of the other, thus accelerating the induction
of anaesthesia.

Eg. Nitrous oxide & halothane induction

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 Tissue:Blood Partition Coefficients
 The tissue:blood partition coefficients determine

The uptake of anesthetic into tissues and

The time necessary for equilibration of these tissues with the

Pa.

 For volatile anesthetics, equilibration between the Pa and Pbr

depends on the anesthetic's blood solubility

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 Oil:Gas Partition Coefficients
 Oil:gas partition coefficients parallel anesthetic
requirements

 An estimated MAC can be calculated as 150 divided by

the oil:gas partition coefficient

 More related to potency

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 Impact of a Shunt
When a right-to-left shunt is present,

 There will be diluting effect of the shunted blood on the

partial pressure of anesthetic in blood coming from

ventilated alveoli

This results in a decrease in the Pa and a slowing in the

induction of anesthesia.

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 Recovery From Anesthesia
The recovery from anesthesia depend on the rate of decrease

in the Pbr, as reflected by the PA

The impact of administration duration on time to recovery is

minimal with poorly soluble anesthetics (sevoflurane and

desflurane).

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 Diffusion Hypoxia
 Diffusion hypoxia occurs when the inhalation of nitrous oxide

is discontinued abruptly
Thus leading to a reversal of partial pressure gradients so

that nitrous oxide leaves the blood to enter alveoli

 This initial high-volume outpouring of nitrous oxide from the

blood into the alveoli can so dilute the PAO 2 that the PaO2
decreases
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 Diffusion Hypoxia .... Contd’s
 Outpouring of nitrous oxide into alveoli is greatest during the

first 1 to 5 minutes after its discontinuation during emergency

phase.

 Thus, it is common practice to fill the lungs with oxygen at

the end of anesthesia to ensure that arterial hypoxemia will

not occur as a result of PAO2 dilution by nitrous oxide
Pre-oxygenation before extubation
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PHARMACODYNAMICS OF INHALED
ANESTHETICS

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 Minimal Alveolar Concentration (MAC)

 The MAC of an inhaled anesthetic is defined as that

concentration at 1 atm that prevents skeletal muscle

movement in response to a supramaximal painful stimulus
(surgical skin incision) in 50% of patients

 A unique feature of MAC is its consistent measure of potency

and varying only 10% to 15% among individuals

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 MAC ....contd’s
 The immobility produced by inhaled A. is mediated
principally by the effects of these drugs on the
Spinal cord, and
Only a minor component of immobility results from
cerebral effects

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 Factors That Alter MAC
 MAC values for inhaled anesthetics are additive.

 For example, 0.5 MAC of nitrous oxide plus 0.5 MAC isoflurane

has the same effect at the brain as does a 1-MAC concentration of

either anesthetic alone

 A 1-MAC dose prevents skeletal muscle movement in response to a

painful stimulus in 50% of patients,

 Whereas a modest increase to about 1.3 MAC prevents movement in

at least 95% of patients

Mesi H.
Comparative minimum alveolar
concentration (Mac) of inhaled anesthetics
MAC (%, 30 to 55 Years Old at 37°C, PB 760
mm oxide
Nitrous Hg) 104

Halothane 0.75

Enflurane 1.63

Isoflurane 1.17

Desflurane 6.6

Sevoflurane 1.80

Xenon 63-71

Mesi H.
 Impact of physiologic and pharmacologic factors on
Mac
Increases in MAC Decreases in MAC No change in MAC
Hyperthermia Hypothermia Anesthetic metabolism
Drug-induced increases in central Increasing age Chronic alcohol abuse
nervous system catecholamine
levels

Hypernatremia Preoperative medication Gender

Drug-induced decreases in Duration of anesthesia (?)
central nervous system
catecholamine levels
α-2 Agonists PaCO2 15 to 95 mm Hg
Acute alcohol ingestion PaO2 >38 mm Hg
Pregnancy Blood pressure >40 mm Hg
Postpartum (returns to Hyperkalemia or
normal in 24 to 72 hours) hypokalemia
Lithium Thyroid gland dysfunction
Lidocaine
PaO2 <38 mm Hg
Mesi H.
 Mechanism of Anesthesia-Induced
Unconsciousness
 Two separate phenomena

1. General anesthesia is a process requiring a state of

unconsciousness of the brain – the mechanism is still not known

2. Immobility in response to a noxious stimulus - These effects are

mediated by the action of volatile anesthetics on the spinal cord

Mesi H.
 Meyer and Overton theory
 According to these concepts, phospholipids were considered to

be the primary targets of anaesthetic action

 Modification of their physical properties then produced

secondary effects on enzymes, receptors and ion channels.

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Inhalational anesthetics were believed to initially dissolve in

membrane phospholipids and change their physical properties

 Fluidity, volume,

 Surface tension or lateral surface pressure, and

 Thus modify the degree of order or disorder within the

membrane

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 Alterations in the physical properties of boundary lipids

were considered to have secondary effects on membrane

proteins, resulting in conformational changes, which
modified their activity.

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 Protein theories of anaesthesia
 Recent evidence suggests that inhalational agents may
primarily interact with receptor proteins, producing
conformational changes in their molecular structure, which
affect the function of ion channels or enzymes.

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 Ionotropic and Metabotropic Receptors
 Neurotransmitters signal through two families of receptors,

designated as ionotropic and metabotropic receptors.

 Ionotropic receptors are also known as ligand-gated ion

channels because the neurotransmitter GABA binds directly to

ion channel proteins

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 This interaction causes the opening (gating) of the ion

channels, thus allowing the transmission of specific ions

(chloride ions), with resulting changes in membrane potentials

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 Inhibitory ligand-gated and voltage gated channels (Glycine
and GABA receptors)

Glycine receptors are major mediators of inhibitory

neurotransmission in the spinal cord and mediate part of the
immobility produced by inhaled anesthetics.

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 Glutamate (NMDA, AMPA, and Kainate
Receptors)

 Glutamate receptors include G-protein-coupled receptors and

the ligand-gated receptors (NMDA, AMPA, and Kainate)

 NMDA receptors likely are important mediators of the

immobilizing effects of inhaled anesthetics.

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 AMPA receptors mediate the initial (fast) component of

excitatory postsynaptic transmission and are likely targets for

volatile anesthetic-induced immobility

Sodium Channels
 Inhaled anesthetics can inhibit the presynaptic terminal release

of neurotransmitters, particularly glutamate.

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 1,1,1,-tri fluro-2-bromo-2chlorethane

Mesi H.
 Halothane was not chemically inert and prolonged usage of

this agent damage metal rubber and some plastic component

of the anesthetic circuit.

 Halothane is susceptible to spontaneous oxidation and

photochemical decomposition
Requiring storage in tinted glass bottle (amber glass bottle)

containing 0.01% thymol ( it renders its stability)

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 Colorless liquid, relatively pleasant smell, non irritant ,

decomposed by light in to hydrochloric acid (HCL),

hydrobromic acid (Hbr), chloride (CL-), bromide (Br-).

 Potent with a MAC of 0.75%.

 Non-explosive, non inflamable

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 Induction
 The potency and relative lack of irritation favor the use of

halothane for rapid smooth inhalation induction of anesthesia.

 Especially when it is administered together with 60-70%
N₂O.

Mesi H.
 Halotane... contd’s
 Halothane has a relatively low blood gas solubility
coefficient of 2.5 and thus

 Induction of anesthesia is relatively fast in pediatrics

However it may take at least 30min. For the alveolar

concentration to reach 50% of the inspired conc

This is slower than for Enflurane or Sevoflurane

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 As with all volatile anesthetics it is customary to use the

techniques of administration of a higher partial pressure of

anesthetic (PI) than the alveolar concentration (PA) (over
pressurization)

 Induce halothane anesthesia with concentration 2-3× higher

than the MAC value

 The inspired value can be reduced when a stable level of

anesthesia has been achieved.

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 For halothane MAC is almost
-1.1% in neonate.
-0.9% in infants.
-0.9% at 1-2 years.
-0.75% at 4-5 years.
-0.65% at 80 yrs.

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 Recovery from halothane is slower compared to newer

drugs( induction is also slower) because of its higher tissue

gas coefficient

 -During awakening after halothane anesthesia patient remain

drowsy for several hours.

 Because of the reactive metabolite bromide

 This is due to higher solubility in brain, muscle and fat

when compared to other volatile agents.

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 The greater solubility of halothane in those tissues increase the

amount of halothane that accumulate during anesthesia and

increase the time it takes to clear halothane from those
compartments after administration is discontinued.
Re-Distribution

Delayed awakening

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 Cardiovascular effects
 Potent direct myocardial depressant effect

 The most prominent circulatory effect of halothane is dose

dependent arterial hypotension

 Decreased HR and coronary blood flow

 Slow conduction to AV node lead to Bradycardia

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Heart rate and IAA

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 Systemic vascular resistance
 ABP is decreased due to myocardial depressant not in
decreasing SVR for halothane

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 Halotane CVS effect .. contd’s
 During controlled ventilation halothane is associated with dose

dependent depression of COP by decreasing myocardial

contractility thus there is reduction of ABP.

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 The hypotensive effect of halothane is augmented by
reduction in HR
Antagonism of bradycardia with atropine usually leads to
increased arterial BP.

 The reduction in myocardial contractility and low HR leads to

reduction in myocardial oxygen demand and coronary blood
flow
So halothane is advantageous in patients with coronary
artery disease.
Because of reduced oxygen demand caused by low HR and
decreased contractility.

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 The depressant effect of halothane on COP is aggravated in the

presence of β-blocker

 Inadequate anesthesia or exogenous administration of CA’s

increases myocardial sensitization leading to myocardial

dysarrythmia and also cardiac arrest.

 During local infiltration with adrenaline containing local

anesthetic, caution should be taken.

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 Guidelines
Avoid hypoxemia and hypercapnia

Avoid concentration of adrenaline greater than 1:100,000

Avoid a dosage in adults exceeding 10ml of 1:100,000

adrenaline in 10 min. or 30ml/hr.

 Over dosage of halothane causes bradycardia and

hypotension ,so treat with atropine and discontinue halothane.

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 Respiratory Effects
 Alveolar hypoventilation (hypoxia) and arterial hypercapnia

occurs in a dose dependent manner during halothane

anesthesia in a spontaneously breathing patient so patient
breathing should be assisted or controlled.

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 Non irritant, pleasant to breath during induction of anesthesia

 The respiratory pattern associated with halothane anesthesia is

characterized by rapid shallow respiration.

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 In awake individual hypercapnia does not occur because even

small increase in arterial CO₂ stimulates the respiratory drive

to increase minute ventilation.

 Halothane and other volatile anesthetics abolish physiologic

mechanism that protect against hypercapnia

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 Rapid loss of pharyngeal and laryngeal reflexes might lead

to risk of aspiration.

 Inhibition of salivary and bronchial secretion.

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 PaCO₂ increases as the depth of anesthesia increases and

patient becomes hypoxic(PaCO2 increase PaO₂ decrease)

 Decrease in mucociliary function which may persist several

hours after halothane anesthesia.

This may contribute to post op. hypoxia and atelectasis

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 CNS
 Cerebral vasodilatation

 Increase CBF

 Increase ICP

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 Other systems
 Potentiate action of NDMR by direct relaxation of skeletal

muscle.
 Trigger malignant hyperthermia.

 Post op. shivering is common in old age (this increase O ₂

requirement ⇒300% and result in hypoxemia unless O ₂ is

administered)

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 GI motility is inhibited – paralytic illus

 PONV are seldom severe.

 Decrease HBF this is proportional to COP.

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 Biotransformation
 Major route of elimination is lung 80%

 10-20% is bio-transformed in the liver

 Small amount diffuse out through skin

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 Hepatic biotransformation occurs through the cytochrome

P450 system resulting in the release of bromide and chloride

ion and the formation of fluorine containing compounds mostly
trifluoroacetic acid

 Many believe that the hepatic complication of halothane results

from its biotransformation

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 Emergence
 Awakening is prompt but may take several hours because of

higher solubility of halothane in brain, muscle, fat increase

accumulation

 Clearing time is increased after discontinuation

 PONV

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 Halothane hepatitis
 Defined as the appearance of liver damage within 28 days of

halothane exposure in a person in whom other known causes

of liver disease have been excluded

 Approximately 20% of halothane is metabolized in liver by the

oxidative pathway, the end product excreted in urine.

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 The major metabolites are bromine, chlorine, trifluoroacetic

acid and trifluoroacetyl-ethanol amide

 A small proportion of halothane may undergo reductive

metabolism, particularly in the presence of hypoxemia and

when the hepatic microsomal enzymes has been stimulated by
enzyme inducing agents such as phenobarbitone

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 Reductive metabolism may result in the formation of reactive metabolite

 Chlorine when absorbed or contact with dry soda lime and will get

broken down to BCDFE (2-bromo-2-chloro-1,1-difluoroethene) which

has organ toxicity in animal models

 Halothane hepatitis

 In mild cases halothane increase enzyme of liver, but in severe cases

halothane hepatitis and liver necrosis

 Incidence is 1:35,000
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 This is supported by the fact that the risk of post operative

liver dysfunction is increased in the presence of

Obesity which increase hypoxia and greater storage of
halothane
Hypoxemia

A short interval b/n administrations of

the drug
Enzyme induction produced by drugs e.g.-
phenobarbitone, phenytoin
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 The incidence of hepatic toxicity is high in obese middle age

women but less in pediatric (halothane is the drug of choice in

pediatrics)

 As a result of this concern the committee on safety of medicine

has made the following recommendations in respect halothane.

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1. A careful anesthetic history should be taken to determine previous
exposure and any previous reaction to halothane.

2. Repeated exposure to halothane with in a period of three months

should be avoided unless there are over riding clinical conditions.

3. A history of jaundice or pyrexia after previous exposure to

halothane is an absolute C/I to its future use in that patient.

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 Precaution
 Pheochromocytoma

 MHT

 History of PPH,APH, hypovolaemic

 Unexplained liver dysfunction

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 Indication
 Induction of anesthesia in children

 Maintenance of anesthesia

 In air way obstructions

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Advantage Disadvantage

-rapid and smooth induction -poor analgesia

-effective in low conc. -CA’s induced arrhythmia

-Minimal stimulation of salivary -post op. shivering

and bronchial secretions

-bronchodilation -liver toxicity

-Muscle relaxation -slow recovery

- cheap -Halothane hepatitis

-less stable
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 Dose – induction-2-3% in adult
-1-2% child

- maintenance-0.8%-1.5%

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Mesi H.