General Anesthetics

Inhalation Agents (drugs)

(4)

• Nitrous oxide
• Desflurane
• Isoflurane
• Sevoflurane

Genral Anesthetics

Intravenous Agents (drugs)

(7)

• Propofol
• Etomidate
• Sodium Thiopental
• Methohexital
• Ketamine
• Dexmetomidine
• Midazolam

General Anesthetics

Introductions

(6)

• General anesthetics are primarily used for induction and maintenance of general anesthesia 
• They depress the central nervous system to a sufficient degree to permit the performance of surgery or other noxious or unpleasant procedures. 
• Development of general anesthetic agents is aimed at:
•  speeding induction and emergence, 
• improving the margin of safety, 
• and minimizing organ system side effects and toxicity  

Stages of Anesthesia

General intro

(6)

• General anesthesia is an altered physiologic state characterized by; 
• reversible loss of consciousness
• analgesia of the entire body
• amnesia
• and some degree of muscle relaxation. 
• Depth of anesthesia is a continuum that is traditionally divided into four numbered stages of increasing central nervous system depression; in current practice, distinction between these stages may be obscured because of the more rapid pharmacologic profiles of modern agents and the use of combinations of multiple anesthetic agents 

General Anesthesia

(4)

• Loss of consciousness
• Analgesia
• Amnesia
• Muscle Relaxation

Stages of Anesthesia

Overview

(4)

• Stage 1 - Analgesia
• Stage 2 - Excitation
• Stage 3 - Surgical Anesthesia
• Stage 4 - Medullary depression

Stage 1 of Anesthesia

(3)

Analgesia

• Stage I is characterized by a decrease in activity of cells in the substantia gelatinosa in the dorsal horn of the spinal cord
• Analgesia proceeds amnesia; amnesia develops late in stage I 

Stage 2 of Anesthesia

(3)

Excitation

• Although they are amnesic, as patients pass through this stage of anesthesia, the inhalational anesthetics may have a disinhibitory effect. 
• Because patients may struggle and appear delirious with irregular respiration, retching and vomiting, and sometimes incontinence, attempts are made to minimize the duration of this stage. 

Stage 3 of Anesthesia

(4)

Surgical Anesthesia

• This stage is characterized by progressive depression of ascending pathways in the reticular activating system as well as suppression of spinal reflex activity. 
• At this depth of general anesthesia, surgical procedures can be performed without patient response. 
• The respiratory effects of this stage span from recurrence of regular respirations to cessation of spontaneous respiration. 

Stage 4 of Anesthesia

(3)

Medullary Depression

• This stage is characterized by severe depression of the medullary respiratory and vasomotor centers. 
• Without circulatory and respiratory support, death ensues. 

General Anesthesia

Mechanism of Action

(3)

General Anesthesia

Inhalation Anesthetics

Inhalation Anesthetics

Pharmacokinetics

• The clinical effect of inhalational anesthetics depends on the attainment of therapeutic tissue concentration in the central nervous system
• the rate at which effective central nervous system concentration is attained depends on multiple pharmacokinetic factors that influence the transfer of inhaled anesthetics from the breathing system to the lung alveoli, from the alveoli to the arterial blood, and from the blood to the brain and other tissues 

• FgF - Fresh gas flow is determined by the vaporizer and flowmeter settings
• Fi - Inspired gas concentration is determined by
• FgF rate
• Breathng circuit volume
• Circuit absorption
• FA - Alveolar gas concentration is determined by ;
• Uptake
• Ventilation
• Concentration effect and second gas effect
• Concentrating effect
• Augmented inflow effect 
• Fa - Arterial gas concentration is affected by ventilation/perfusion mismatching

Inhaled Anesthetics 

Uptake and Distribution

(5)

• Inspired anesthetic concentration (Fi)
• Solubility
• Pulmonary Ventilation
• Pulmonary Blood Flow
• Arteriovenous Concentration Gradient

Inhaled Anesthetics 

Uptake and Distribution

Inspired Anesthetic Concentration (Fi)

• Increasing the inspired anesthetic concentration increases the alveolar concentration of anesthetic (FA) and speeds induction of anesthesia by increasing the rate of rise anesthetic concentration in arterial blood (Fa) 

Inhaled Anesthetics 

Uptake and Distribution

Solubility

(3)

• The lower the solubility of an anesthetic in blood, 
• the more rapid the rate of rise of anesthetic partial pressure in the blood
•  the faster the rate of rise of anesthetic partial pressure in the brain
• and thus the faster the rate of induction 

Inhaled Anesthetics 

Uptake and Distribution

Pulmonary Ventilation

• Increasing pulmonary ventilation can speed the induction of anesthesia by increasing the arterial partial pressure of anesthetic agents; this effect is more clinically relevant for agents that are more soluble in blood  

Inhaled Anesthetics 

Uptake and Distribution

Pulmonary Blood Flow

• Slowing pulmonary blood flow can increase the contact time of pulmonary blood with anesthetic agents in the alveoli and thus increase the rate of rise of arterial anesthetic partial pressure; again the effect is more relevant for more soluble agents  

Inhaled Anesthetics 

Uptake and Distribution

Arteriovenous Concentration Gradient

• The solubility of anesthetic agents in other tissues (e.g. muscle, adipose) decreases venous anesthetic partial pressure and thus slows achievement of equilibrium 

Inhaled Anesthetics 

Elimination

• Currently used inhalational anesthetics undergo minimal metabolism; they are primarily eliminated by exhalation through the alveoli. 
• High fresh gas flow rates, high ventilation rate, and low blood solubility all speed emergence from inhalational anesthesia 

Inhaled Anesthetics

Pharmacodynamics

• Dose response characteristics
• Organ system effects

Inhaled Anesthetics

Pharmacodynamics

Dose Response Characteristics

(4)

• The dose of anesthetic gas that is administered can be stated in multiples of Minimum Alveolar Concentration (MAC). 
• MAC is the alveolar concentration of an inhaled anesthetic that prevents movement in 50% of patients in response to a standardized stimulus (e.g. surgical incision); roughly 1.3 MAC prevents movement in about 95% of patients. 
• The MAC values for different anesthetics are roughly additive such that a mixture of 0.4 MAC of Agent A and 0.5 MAC of Agent B provides a total of 0.9 MAC anesthesia  
• MAC is analogous to ED50 in a conventional quantal dose-response curve. 

Inhaled Anesthetics

Pharmacodynamics

Organ System Effects
(6) 

• In General the inhalational anesthetics depress organ system function.
• Have effects on;
•  Cerebral
• Cardiovascular
• Renal/hepatic
• Respiratory
• Metabolic

Inhaled Anesthetics

Pharmacodynamics

Organ System Effects

Cardiovascular

(2)

• Nitrous oxide has minimal cardiovascular effects. 
• Isoflurane, desflurane, and sevoflurane all decrease blood pressure primarily by causing systemic vasodilation. 

Inhaled Anesthetics

Pharmacodynamics

Organ System Effects

Respiratory

(5)

• The volatile agents depress the respiratory system by;
• decreasing tidal volume, 
• increasing respiratory rate, 
• and decreasing carbon dioxide responsiveness. 
• Nitrous oxide also decreases tidal volume and increases respiratory rate, but minute ventilation is generally preserved. 

Inhaled Anesthetics

Pharmacodynamics

Organ System Effects

Cerebral

(3)

• Inhalational agents increase cerebral blood flow. 
• Nitrous oxide increases cerebral metabolic rate
• The other agents decrease cerebral metabolic rate. 

Inhaled Anesthetics

Pharmacodynamics

Organ System Effects

Renal/Hepatic

• The inhalational agents decrease renal and hepatic blood flow.    

Inhaled Anesthetics

Pharmacodynamics

Organ System Effects

Metabolic

• All of the inhalational anesthetics except nitrous oxide are triggering agents for malignant hyperthermia in susceptible patients. 

Malignant Hyperthermia

(3)

• Malignant Hyperthermia (MH) is an acute hypermetabolic state within muscle tissue that may be triggered by halogenated volatile anesthetics or succinylcholine when administered to genetically susceptible patients. 
• MH treatment includes cessation of triggering agents, administration of dantrolene, and supportive care. 
• Except for nitrous oxide and xenon, all of the inhalational agents are Malignant Hyperthermia triggers. 

• Intravenous anesthetics are primarily used for induction of general anesthesia; propofol can also be used for sedation or maintenance of anesthesia in selected patients 

Intravenous Anesthetics

Pharmacokinetics

(3)

• The intravenous general anesthetics are small, hydrophobic, substituted aromatic or heterocyclic compounds that preferentially partition into lipophilic tissues of the central nervous system after a single intravenous bolus; 
• they are able to produce general anesthesia within a single circulation time [1]. 
• Termination of anesthesia after a single bolus dose of an intravenous anesthetic primarily reflects redistribution out of the central nervous system rather than metabolism 

Intravenous Anesthetics

Pharmacokinetics

Context-Sensitive Half-Time

(7)

• The time for plasma concentration of a drug to decrease by 50% after an intravenous infusion has stopped. 
• With prolonged infusions the half-lives and durations of action of the intravenous anesthetics are dependent on complex interactions between; R
• edistribution rates 
• Fat accumulation 
• and metabolism; 
• This phenomenon is termed context-sensitive half-time [1].
• The context-sensitive half-times vary greatly among intravenous general anesthetics  

Intravenous Anasthetics

Organ System Efeects

• Organ system effects vary among the intravenous anesthetics; these effects are summarized in Figure 4. 
• With the exceptions noted for etomidate and ketamine, intravenous general anesthetics have depressing effects on cerebral, cardiac, and pulmonary function.

• General anesthetics are used primarily for the induction and maintenance of general anesthesia for surgical or other noxious procedures. 
• Some of the general anesthetic agents are also used for procedures requiring sedation but not general anesthesia. 
• Because no single currently available anesthetic agent is capable of achieving all of the desired effects without some disadvantages, most anesthetics employ a combination of intravenous and inhaled agents and adjuncts to take advantage of the agents’ favorable properties and minimize their adverse effects [4]. 

General Anesthetic Adjuncts

(4)

• Benzodiazepines
• Analgesics
• Alpha-2 adrenergic antagonists
• Neuromuscular blocking agents

General Anesthetic Adjuncts

Benzodiazepines

(3)

• Although benzodiazepines can produce anesthesia similar to that of barbiturates, the large doses required for induction or maintenance of anesthesia can cause undesirably prolonged amnesia and sedation.
• The benzodiazepines are more often used for pre-operative anxiolysis and sedation; 
• midazolam is commonly chosen for its rapid onset (peak effect within two minutes) and relatively short duration of action (approximately 30 minutes)  

General Anesthetic Adjuncts

Analgesics

(3)

• Except for ketamine and nitrous oxide, the general anesthetics do not provide effective analgesia. 
• For this reason, analgesics are administered to reduce anesthetic requirements and minimize the hemodynamic changes caused bypainful stimuli. 
• NSAIDS, acetaminophen, and especially opioids are all employed in the perioperative period to provide analgesia.

General Anesthetic Adjuncts

Alpha-2 Adrenrecptor Agonists

• Dexmedetomidine is a centrally acting alpha-2A receptor agonist that produces sedation and analgesia but is not capable of providing general anesthesia. 
• It is often used for sedation in intensive care units and may also be used as an adjunct to surgical anesthesia and sedation. 

Gneral Anesthetic Adjuncts

Neuromuscular Blocking Agents

• Neuromuscular blocking agents do not have anesthetic properties, but they are often used to facilitate tracheal intubation during general anesthesia and to improve surgical exposure and provide assurance of immobility 

• The only inorganic anesthetic gas in clinical use; it is colorless and odorless; it is a gas at room temperature. 
• Because its MAC is 105%, nitrous oxide cannot be used as the sole agent for general anesthetic maintenance. 
• Inhalation

• Desflurane is notable for its low solubility, rapid onset and emergence, and high volatility (i.e. it boils at room temperature in Salt Lake City). 
• Inhalation

• Isoflurane is a potent inhalational agent with a pungent odor and moderate blood solubility. 
• Inhalation

• A non-pungent inhalational agent suitable for inhalational inductions; associated with a higher incidence of emergence delirium in some pediatric populations  
• Inhalation

• Nitrous Oxide
• Desflurane
• Isofluarne
• Sevoflurane

Intravenous Agents

(5)

• Barbiturates
• Dexmedetomidine
• Etomidate
• Ketamine
• Propofol

Barbiturates

(3)

• Sodium thiopental and methohexital are the most commonly used barbiturates for induction of general anesthesia.
• These agents are highly protein bound; termination of their clinical effects is caused by redistribution. 
• They undergo hepatic metabolism with inactive metabolites excreted renally. 

Dexmedetomidine

(4)

• Dexmedetomidine is a centrally acting alpha-2A receptor agonist that produces sedation and analgesia without respiratory depression.
• Even at maximal dosage is not capable of producing general anesthesia, and dexmedetomidine does not provide reliable amnesia.
• It is often used for sedation in intensive care units and may be used as an adjunct to surgical anesthesia and sedation
• Side effects of hypotension and bradycardia are attributed to decreased catecholamine release. 

Etomidate

(4)

• Etomidate is notable for its cardiovascular stability with little or no decrease in blood pressure or cardiac output. 
• Adrenocortical suppression precludes its utility for maintenance of general anesthesia. 
• Etomidate is associated with pain on injection and myoclonic movements. 
• Termination of effect after a single dose is by redistribution; etomidate is hepatically metabolized with renal and biliary elimination 

• Ketamine is an NMDA receptor inhibitor that is a congener of phencyclidine; it causes dissociative anesthesia characterized by profound analgesia and amnesia often with;
•  spontaneous breathing 
• open eyes
• and involuntary limb movement. 
• Unlike other intravenous agents, ketamine is notable for producing profound analgesia. 
• Ketamine is also notable for causing; 
• increased cerebral blood flow, 
• potent bronchodilation, 
• indirect sympathomimetic action that causes
•  increased blood pressure,
•  heart rate, 
• and cardiac output. 
• Ketamine is hepatically metabolized to norketamine which has reduced CNS activity; norketamine is further metabolized and excreted in urine and bile. 
• Ketamine’s rapid clearance makes it suitable for continuous infusion