Inhalation Anesthetics

• Anesthesia :defined as the abolition of sensation

• characterized by:

• 1 reversible loss of consciousness

• 2 analgesia of the entire body

• 3 amnesia

• 4 some degree of muscle relaxation .

Stages of Anesthesia

• Stage I (analgesia stage) – Conscious, Perception of pain is diminished ( Mild CNS depression)

• Stage II (delirium stage) – Unconscious – Body responds reflexively– Breath holding, pupils dilated – Muscle tone intact (An excited state resulting from cortical motor depression), can be avoided with rapidly acting, potent anesthetics

• Stage III (surgical anesthesia) – Increasing degrees of muscular relaxation – (disappearance of muscle tone)

• IV (medullary depression) – Depression of cardiovascular and respiratory centers

The course of a general anesthetic can be divided into three phases: (1) induction (2) maintenance (3) emergence

• Inhalation anesthetics , are useful in the induction in patients whom it may be difficult to start an intravenous line

• Regardless of the patient’s age, anesthesia is often maintained with inhalation agents

Inhalational Anesthetic Agents

• Inhalational anesthesia, refers to the delivery of gases or vapors from the respiratory system to induct or maintain anesthesia

• Exposure to the pulmonary circulation allows a more rapid appearance in arterial blood than IV administration

• Advantages:

• 1. Completely painless induction

• 2.No IV (intravenous) access needed

• 3. Rapid appearance of drug in arterial blood

• 4.Safe.

Dose • While intravenous agents are given in mg (or mcg)/kg doses , the inhaled agents are

given in volume percent concentrations

• This brings us to the concept of Minimum Alveolar Concentration (MAC).

• The concentration of a gas in the alveoli creates an alveolar partial pressure of gas which in turn reflects its partial pressure in the active site (brain).

• MAC refers to the concentration of the inhaled agent in alveolar gas necessary to prevent movement of 50% of patients when a standard incision is made.

• The rationale for this measure of anaesthetic potency is: a. alveolar concentration can be easily measured b. near equilibrium, alveolar and brain tensions are virtually equal c. the high cerebral blood flow produces rapid equilibration b. individual variability is small c. sex, height, weight & anaesthetic duration do not alter MAC

MAC is a useful measure because: 1. it mirrors brain partial pressure 2. allows comparisons of potency between agents 3. provides a standard for experimental evaluations

• Many factors influence MAC, and therefore influence the concentrations required to maintain anesthesia.

FACTORS AFFECTING INSPIRATORY CONCENTRATION (FI)

• 1.the fresh gas flow rate • 2 the volume of the breathing system, • 3 any absorption by the machine or breathing circuit • The fresh gas leaving the anesthesia machine mixe 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

• The greater the fresh gas flow rate , the smaller the breathing system volume, and the lower the circuit absorption, the closer the inspired gas concentration will be to the fresh gas concentration

FACTORS AFFECTING ALVEOLAR CONCENTRATION (FA)

• 1.The uptake • If there were no uptake of anesthetic agent by the

body, the alveolar gas concentration (FA) would rapidly approach the inspired gas concentration (FI)

• The greater the uptake, the slower the rate of rise of the alveolar concentration and the lower the FA:FI ratio.

• So initially, FA:FI=O CUZ there is no agent in the lung yet

• EQ when , FA:FI=1

• Fast induction is defined as FA:FI=1 quickly

• FA is proportional to PA=Pblood=Pcns

• Therefore, the greater the uptake of anesthetic agent, the greater the difference between inspired and alveolar concentrations, and the slower the rate of induction

factors affect anesthetic uptake( Factors determining how quickly the

inhalational agent reaches the brain from

the alveoli ) • solubility in the blood

• alveolar blood flow

• the difference in partial pressure between alveolar gas and venous blood

solubility in the blood

• the blood/gas partition coefficient (λb/g) • A higher solubility (λb/g)>1… more agent in blood than in gas so need to dissolve more

gas to get certain partial pressure • A lower solubility (λb/g)<1… more agent in gas than in blood so need to dissolve less gas

to get certain partial pressure • The higher the blood/gas coefficient, the greater the

anesthetic’s solubility and the greater its uptake by the pulmonary circulation

• As consequence of this increased solubility, alveolar partial pressure rises to a steady state more slowly

• A higher solubility =more uptake =more time for induction(slow induction)

alveolar blood flow

• essentially equal to cardiac output

• As cardiac output increases, anesthetic uptake increases, the rise in alveolar partial pressure slows, and induction is delayed

2.ventilaion

• The 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

• So increasing the ventilation will increase the absorption of agent into the lung so accelerating the EQ and faster induction

3.Concentration • two phenomena:

• 1.Concentrating effect 2.augmented gas inflow

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 • 1 venous admixture • 2 alveolar dead space • 3. nonuniform alveolar gas distribution

the existence of ventilation/perfusion mismatching will increase the alveolar–arterial difference

• Mismatch acts as a restriction to flow: It raises the pressure in front of the restriction, lowers the pressure beyond the restriction, and reduces the flow through the restriction

• The overall effect is an increase in the alveolar partial pressure (particularly for highly soluble agents) and adecrease in the arterial partial pressure (particularly for poorly soluble agents).

Nitrous Oxide Physical Properties :

-Non explosive , Nonflammable gas. -Colorless , tasteless and essentially odorless gas at room temperature. -The only inorganic anesthetic gas in clinical use. -Weak Anesthetic good analgesic agent?? -Nitrous oxide, even at 80% concentration, doesn’t produce surgical level anaesthesia in most persons, so it must be used as an adjunct anaesthetic, along with other agents. -Low blood solubility “0.47” blood/gas partition coefficient value. -MAC value is 104% in adults. -Excreted via lungs.

• Cardiovascular : - Depress myocardial contractility - Arterial BP, CO, HR: unchanged or slightly↑ due to stimulation of catecholamines - Constriction of pulmonary vascular smooth muscle increase pulmonary vascular resistance - Higher incidence of epinephrine-induced arrhythmia why? - Because it has a tendency to stimulate the sympathetic nervous system • Respiratory - Respiratory rate: ↑ - Tidal volume: ↓ - Minute ventilation, resting arterial CO2: minimal change • Cerebral : – CBF, cerebral blood volume, ICP: ↑ – Cerebral oxygen consumption (CMRO2): ↑

Nitrous Oxide Systemic Effects

• Neuromuscular - Not provide significant muscle relaxation - At high concentration it can cause skeletal Muscle rigidity - Not a triggering agent of malignant hyperthermia • Renal - Increase renal vascular resistance - Renal blood flow, glomerular filtration rate, U/O: ↓ • Hepatic - Hepatic blood flow: ↓ • Gastrointestinal : - Postoperative nausea and vomiting

• NOTE…..

• Prolonged exposure to anesthetic concentrations of nitrous oxide can result in bone marrow depression (megaloblastic anemia) and even neurological deficiencies (peripheral neuropathies).

Nitrous Oxide (N2O) SECOND GAS EFFECT

Second gas effect: The ability of the large volume uptake of

one gas (first gas) to accelerate the rate of rise of the

alveolar partial pressure of a concurrently administered

companion gas (second gas) is known as the second gas

effect.

Nitrous Oxide (N2O) DIFFUSION HYPOXIA

What is diffusion hypoxia?

Diffusion hypoxia is a decrease in PO2 usually observed as the patient

is emerging from an inhalational anesthetic where nitrous oxide

(N2O) was a component. The rapid outpouring of insoluble N2O can

displace alveolar oxygen, resulting in hypoxia. All patients should

receive supplemental O2 at the end of an anesthetic and during the

immediate recovery period.

• Nitrous Oxide (N2O) Effect on closed gas spaces

• Nitrous oxide can diffuse( 20-30) times faster into

closed spaces than it can be removed, resulting in

expansion of pneumothorax, bowel gas, or air embolism

or in an increase in pressure within noncompliant

cavities such as the cranium or middle ear.

• Contraindications ??????

-Venous or arterial air embolism

-Pneumothorax

-Acute intestinal obstruction with bowel distention

-Pulmonary air cysts

Halothane Physical Properties:

- Halogen substituted ethane

- Non pungent Volatile liquid easily vaporized, stable, and nonflammable.

- Most potent inhalational anesthetic, but not a good analgesic and it’s muscle relaxation effect is moderate.

- Efficacious in depressing consciousness.

- Very soluble in blood and adipose “2.4” blood/gas partition coeffecient.

- MAC of 0.75%

- The induction dose varies from patient to patient 0.5-3% .The maintenance dose varies from 0.5 to 1.5%.

- Halothane may be administered with either oxygen or a mixture of oxygen and nitrous oxide.

Halothane Systemic Effects:

• Cardiovascular : - Direct myocardial depression--> dose-dependent reduction of arterial BP

- Coronary artery vasodilator, but coronary blood flow↓ due to systemic BP↓

- Hypotension inhibits baroreceptors in aortic arch and carotid bifurcation -> vagal stimulation↓ ->compensatory rise in HR (Halothane blunt this reflex result in bradycardia).

- Sensitizes the heart to the arrhythmogenic effects of epinephrine, so doses of epinephrine above 1.5 mcg/kg should be avoided.

- Systemic vascular resistance: unchanged.

• Respiratory : - Rapid, shallow breathing

- Alveolar ventilation: ↓”because the ↑RR isn’t enough to counter the ↓tidal volume”

- Resting PaCO2: ↑ “Apneic Threshold” the highest PaCO2 at which a patient remains apneic.

- Hypoxic drive: severely depressed even by low concentration of Halothane.

- A potent bronchodilator, reverses asthma-induced bronchospasm.

- Depress clearance of mucus promoting postoperative hypoxia and atelectasis.

• Cerebral :

- Dilating cerebral vessels -> cerebral vascular resistance↓ -> CBF ↑

- Blunt auto regulation (the maintenance of constant CBF during changes in arterial BP).

- ICP: ↑ prevented by hyperventilation prior to administration of halothane.

- Cerebral activity↓: leading to ↓Metabolic oxygen requirement.

• Neuromuscular :

- Relaxes skeletal muscle.

- A triggering agent of malignant hyperthermia

1/60.000 cases (autosomal dominant inheritance )

Classic : rapid rise in body temperature, muscle rigidity, tachycardia, rhabdomyolysis, acidosis, hyperkalemia, DIC

Diagnosis -- previous symptoms, increase CO2, rise in CPK levels, myoglobinuria Treatment -- early detection, hyperventilate, IV dantrolene (2.5 mg/kg), ice packs/cooling blankets, Lasix/mannitol/ fluids.

ICU monitoring

Halothane Systemic Effects:

• Renal : - Renal blood flow, GFR, U/O: ↓

- Because the reduction in renal blood flow is greater than the reduction in glomerular filtration rate, the filtration fraction is increased. Preoperative hydration limits these changes.

• Hepatic : - Hepatic blood flow: ↓

- ” Halothane Hepatitis” -- 1/35,000 cases (rare)

Patients exposed to multiple halothane anesthetics at short intervals, middle-aged obese women, and persons with a familial predisposition to halothane toxicity or a personal history of toxicity are considered to be at increased risk.

Present with fever, jaundice, increased ALT AST, hepatic necrosis.

• Biotransformation & toxicity : - Oxidized in liver by cytochrome P-450 to trifluroacetic acid.

• Contraindications: - Unexplained liver dysfunction following previous exposure.

- No evidence associating halothane with worsening of preexisting liver disease

- Intracranial mass lesions because of the possibility of intracranial hypertension secondary to increased cerebral blood volume and blood flow.

- Hypovolemic patients & patients with severe LT ventricular dysfunction may not tolerate halothane’s negative inotropic effects.

• Drug interactions: - Myocardial depression is exacerbation by β-blockers and CCB

- With aminophylline serious ventricular arrhythmia.

Halogenated Organic Compounds

• Isoflurane and sevoflurane ,are the most commonly used agents in this class

– Others include??

– Desflurane, Halothane, and Enflurane, but these are not commonly used

• Pungent & Liquid at room temperature

• Stored in a vaporizer on an anesthetic machine

• Vaporized in oxygen that flows through the vaporizer

Isoflurane

• Physical properties:

- Nonflammable

- MAC of 1.15 %

- Haloginated methyl ethyl ether

- A chemical isomer of enflurane

- Often another medication is used to start anesthesia due to airway irritation with isoflurane.

• Mechanism of action: Isoflurane likely binds to GABA, glutamate and glycine receptors, but has different effects on each receptor.

Isoflurane acts as a positive allosteric modulator of the GABAA receptor

It potentiates glycine receptor activity, which decreases motor function.

It inhibits receptor activity in the NMDA glutamate receptor subtypes.

• Isoflurane Systemic Effects : • Cardiovascular

- Minimal cardiac depression

- HR: ↑ due to partial preservation of carotid baro reflex so maintain CO

- Systemic vascular resistance↓: ↓BP

- Dilates coronary arteries

- Sensitizes myocardium to catecholamine -- less than halothane or enflurane

• Respiratory

- Respiratory depression & decreased minute ventilation

but tachypnea less pronunced.

- Blunt the normal ventilatory response to hypoxia and hypercapnia

- Irritate upper airway reflex.

- A good bronchodilator not potent as halothane.

• Neuromuscular :

- Isoflurane relaxes skeletal muscle.

• Renal :

- Isoflurane decreases renal blood flow, glomerular filtration rate, and urinary output.

• Hepatic :

- Total hepatic blood flow: ↓

- Liver function tests are usually not affected.

• Contraindications :

Isoflurane presents no unique contraindications. Patients with severe hypovolemia may not tolerate its vasodilating effects. It can trigger malignant hyperthermia.

• Drug Interactions : Epinephrine can be safely administered in doses up to 4.5 mcg/kg.

Non depolarizing NMBAs are potentiated by Isoflurane.

Sevoflurane Physical Properties:

-Halogenated ether

-Non flammable.

-Non irritant & has sweet odor even at high concentrations, making this the

agent of choice for inhalational induction.

-Low blood solubility “0.65” blood/gas partition coefficient (fast in

induction & recovery)

-fastest for induction, inhalation induction with 4-8% Sevoflurane in a 50%

mixture of nitrous oxide and oxygen can be achieved within 1 min

-MAC 2%.

Sevoflorane Systemic effects

• Cardiovascular - Mildly depress myocardial contractility - Systemic vascular resistance, arterial BP: ↓ - CO: not maintained well due to little rise in HR - Prolong QT interval • Respiratory - Depress respiration - Reverse bronchospasm • Hepatic - Portal vein blood flow: ↓ - Hepatic artery blood flow: ↑

• Cerebral

- CBF, ICP: slight ↑

- Cerebral metabolic oxygen requirement: ↓

• Neuromuscular

- Adequate muscle relaxation for intubation of children

• Renal

- Renal blood flow: slightly ↓

- Associated with impaired renal tubule function

• Contraindications

- Severe hypovolemia

- Susceptibility to malignant hyperthermia & intracranial hypertension

• Drug interactions

- Potentiate NMBAs

- Not sensitize the heart to catecholamine-induced arrhythmias

Desflurane

MAC =6 %

Enflurane

MAC =1.68%

Potent cardiovascular depressant