C8 Inhalation Anesthetics

Introduction

The most widely used inhalational anesthetics are:

Nitrous oxide
Desflurane
Sevoflurane
Isoflurane
Enflurane (no longer marketed in the US)
Halothane (no longer marketed in the US)

Pharmacokinetics and pharmacodynamics

Inhaled air ? lung ? blood ? brain
??? ???? brain?? ?? ? ? ??? ????.

Solubility to tissue

?Tissue solubility ? ?arteriovenous concentration gradient ? saturation of the blood requires further absorption of anesthetic ? slower onsets of action

?Tissue solubility ? ?arteriovenous concentration gradient ? less anesthetic is required ? concentrations in the brain to equilibrate faster ? faster onsets of action

Solubility to blood – blood/gas partition coefficient

?� Solubility in blood = rapid induction and recovery times. Desflurane? ??. ?? ??? ?

Agents with a low blood:gas partition coefficient reach FA/FI equilibrium more rapidly. The blood:gas coefficient is affected by:

Temperature
- Blood:gas partition coefficients decrease as temperature increases.
Haematocrit
- Variable effect, which depends on the particular agents affinity for red cells or plasma (and serum constituents, e.g. albumin).
- An agent that is less soluble in red cells (e.g. isoflurane) will have a decreased blood-gas partition coefficient in anaemia.
Fat
- Blood:gas partition coefficient increases following fat ingestion.

Arterial tension curve

The steepness depends on the solubility of the anesthetic in the blood.
Less soluble – partial pressure in the blood ?rapidly – steeper curve.

??? FA? FI?? ????? ??? ???? – hysteresis

? Solubility in lipids = ? potency = 1/MAC

? Blood and lipid solubility
- e.g., NO
- Fast induction and low potency.
? Blood and lipid solubility
- e.g., Halothane, propofol, thiopental
- High potency and slow induction

Concentration effect

??? ??? ?? ?? ?? ?? ?, ????? ?
Second gas effect
???? N2O? ?? ??
?? ??? CO ??? ? , Ventilation??? ?

MAC

Concentration of the vapour in the lungs that is needed to prevent movement(motor reponse) in 50% of subjects in response to surgical(pain) stimulus

0.3 MAC	50%? ????
1.3 MAC	95%? ???? ??
1.5 MAC	Reflex?? ??

??? ?? ? MAC ?? ??
??? ???? MAC? ???

	Brain-blood partition coefficient	Brain-blood partition coefficient	Minimal alveolar concentration (MAC)
Nitrous oxide	0.47	1.1	> 104%
Desflurane	0.42	1.3	6�7%
Sevoflurane	0.69	1.7	2%
Isoflurane	1.40	2.6	1.4%
Enflurane	1.80	1.4	1.7%
Halothane	2.30	2.9	0.75%

Pharmacologic effects

Cardiovascular effects

BP?, HR?, Cardiac index?, SVR?, hypotension
?atrial & ventricular pressure

Respiratory effects

Except NO, all are depressants.
?TV, ?RR, ?minute ventilation ? hypercapnia
Suppresion of mucociliary function ? post-op. atelectasis
Halothane, sevoflurane has bronchodilator effect: prefered in asthma.

CNS effects

?Vascular resistance ? ?CBF ? IICP (undesirable effect)
?? O2 ?? ?, ICP? ??? ??
??? ?? ??? ?? ???.

Musculoskeletal effects

Muscle relaxant? ??? ??.

Other effects

?Vascular resistance in kidney and liver
? ?Renal & hepatic blood flow, ?GFR
N2O? MAC 1? ??? ???? ?????? ?? ? 0.5MAC?? cover

Side effects

General side effects
- Postoperative nausea and vomiting
- Risk of malignant hyperthermia
- Postoperative shivering
Side effects of specific substances
- Nitrous oxide
  - Can diffuse into gas-filled body compartments and cause expansion of the gas present there ? potential damage to organs/tissues ? should not be used in patients with conditions such as pneumothorax
  - Causes mild myocardial depression and increases pulmonary vessel resistance ? should not be used in patients with conditions such as pulmonary hypertension
- Desflurane: sympatho-adrenergic reaction ? ? blood pressure and ? heart rate
- Sevoflurane: interacts with soda lime ? nephrotoxic breakdown products (known as compounds A�E)
- Methoxyflurane: nephrotoxic
- Enflurane: proconvulsive
- Halothane: hepatotoxic ? halothane hepatitis
  - Pathophysiology
    - Underlying mechanism not fully understood
    - An immunoreaction to hepatic halothane metabolites is suspected.
  - Clinical features
    - Occurs 2 days to 3 weeks after halothane exposure
    - Signs of acute hepatitis
    - Rash, arthralgias
  - Diagnostics: diagnosis of exclusion
    - Possible laboratory findings: ? eosinophils, ? serum transaminases , ? bilirubin, ? alkaline phosphatase
    - Biopsy shows massive centrilobular hepatic necrosis
  - Treatment: depending on the severity of liver damage, ranges from supportive treatment to liver transplantation ^[6]

Hepatotoxicity
- Most are halogenated which metabolized by the hepatic CYP450 -> reactive intermediates -> halothane hepatitis (centrilobular necrosis) – free radical injury?
- Other halogenated anesthetics, such as enflurane, isoflurane, desflurane, and sevoflurane are much safer, but there have been reports of associated hepatotoxicity.
- Mild asymptomatic AST/ALT elevation ~ fulminant hepatitis with a 50% fatality rate.
- Liver atrophy and appear shrunken on autopsy.

Typically presents 2 days to 3 weeks after medication exposure with fever, nausea, jaundice.

Hepatotoxicity: Halothane

Nephrotoxicity: Methoxyflurane

Epileptogenic: Enfluarane

Expansion of trapped gas in a body cavity: N2O

Malignant hyperthermia

Rare, life-threatening condition – fever and severe muscle contractions.

Susceptibility is often inherited as autosomal dominant with variable penetrance.
Mutations in voltage-sensitive ryanodine receptor (RYR1 gene)
?Ca2+ release from SR
- Tachycardia, hypertension
- Stimulates its ATP-dependent reuptake by
- Rhabdomyolysis: hyperkalemia, myoglobinemia, ?Cr

Tachycardia, tachypnea, myoglobinuria, and masseter/generalized muscle rigidity following exposure to succinylcholine or a volatile anesthetic.

Most cases arise during or shortly after induction, but symptoms are sometimes delayed until just after anesthesia cessation.

Treatment: dantrolene (ryanodine receptor antagonist)

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