4-4 General & Local Anesthetics DSA

Question 1

What are the stages of anesthesia?

Answer 1

1. Four stages of increasing depth of CNS depression:
   
   1. Stage I Analgesia
      
      1. Patient initially experiences analgesia without amnesia; later in Stage I, both analgesia and amnesia produced.
   2. Stage II Excitement
      
      1. Patient appears delirious, may vocalize but is completely amnesiac; respirations rapid, heart rate and blood pressure increase.
   3. Stage III Surgical Anesthesia
      
      1. Begin with slowing respiratory rate and heart rate; extends to complete cessation of spontaneous respiration (apnea).
      2. Four planes described based on changes of ocular movements, eye reflexes, and pupil sizes indicating increasing depth of anesthesia
2. Stage IV Medullary Depression
   
   1. Severe CNS depression, including vasomotor center in medulla & respiratory center in brainstem. Without circulatory or respiratory support, death would rapidly ensue.

Question 2

Discuss the factors in pharmacokinetic properties of inhaled anesthetics.

Answer 2

Factors affecting uptake include:

volatile versus gaseous forms

alveolar concentration of gas

Blood:gas partition coefficient

Brain:blood partition coefficient

Cardiac output

Alveolar-Venous partial pressure differences

Question 3

What are the volatile inhaled anesthetics?

Answer 3

halothane, enflurane, isoflurane, desflurane, sevoflurane

Question 4

What are the physical characteristics of volatile inhaled anesthetics?

Answer 4

liquids at room temp:

1. Low vapor pressures, high boiling points, liquids at room temperature (20˚C).
2. Special characteristics of volatile anesthetics make it necessary to administer using vaporizer.

Question 5

What are the gaseous inhaled anesthetics?

Answer 5

Nitrous oxide

Question 6

What are the physical characteristics of nitrous oxide?

Answer 6

1. High vapor pressure, low boiling point, gas at room temperature.

Question 7

How are inhaled anesthetics taken up into the body? What is important in the kinetics?

Answer 7

1. volatile and gaseous inhaled anesthetics are taken up through gas exchange in the alveoli.
   
   1. Uptake from the alveoli into the blood as well as distribution/partitioning into the effect compartments are important determinates of the kinetics of these agents.
   2. An ideal anesthetic would have rapid onset (induction) and termination of effect; thus, the effect site concentration in the CNS (brain, spinal cord) must change rapidly.

*

Question 8

What is the driving force for uptake of an inhaled anesthetic?

Answer 8

alveolar concentration

Question 9

What factors determine alveolar concentration changes of inhaled anesthetics?

Answer 9

The two factors that determine how quickly the alveolar concentration changes (can be controlled by anesthesiologist) are (1) inspired concentration or partial pressure and (2) alveolar ventilation.

Increases in either the inspired partial pressure or in ventilation will increase the rate of rise in the alveoli and will accelerate induction.

Partial pressure in ­­the alveoli is expressed as a ratio of alveolar concentration (F_A) over inspired concentration (F_I); the faster F_A/F_I approaches 1 (representing inspired-to-alveolar equilibrium), the faster anesthesia will occur during an inhaled induction.

Question 10

Explain how the blood:gas partition coefficient, and how it affects uptake/Pk of inhaled anesthetic.

Answer 10

useful index of solubility and defines the relative affinity of an anesthetic for blood compared to inspired gas.

There is an inverse relationship between the blood:gas partition coefficient value and rate of anesthesia onset

Agents with low blood solubility (nitrous oxide, desflurane) reach high arterial pressure rapidly, which in turn results in rapid equilibrium with the brain and fast onset of action.

Agents with high blood solubility (halothane) reach high arterial pressure slowly, which in turn results in slow equilibration with the brain and a slow onset of action.

In other words, if the blood compartment can be ‘saturated’ to its max carrying capacity with a smaller amount of anesthesia, the anesthetic will start working more quickly. Any ‘extra’ anesthesia in the blood over that small amount will be dumped across the BBB into the brain. Poor solubility also makes for a lower partition coefficient.

Question 11

What is the brain:blood partition coefficient similar to? What does it indicate?

Answer 11

similar to blood:gas partition coefficient

indicates all agents are more soluble in the brain than in the blood.

Question 12

How does cardiac output and alveolar-venous partial pressure affect inhaled anesthetic uptake?

Answer 12

Increased pulmonary blood flow (increased cardiac output), increases uptake of anesthetic, thereby decreasing rate by which F_A/ F_I rises, which will decrease the rate of induction of anesthesia.

An increase in cardiac output and pulmonary blood flow will increase uptake of anesthetic into the blood, but the anesthetic taken up will be distributed in all tissues, not just the CNS; increased cardiac output will increase delivery of anesthetic to other tissues and not the brain (cerebral blood flow well regulated).

Anesthetic partial pressure differences between alveolar and mixed venous blood is dependent mainly on uptake of anesthetic by tissues, including nonneural tissues.

Depending on rate and extent of tissue uptake, venous blood returning to lungs may contain significantly less anesthetic than arterial blood. The greater this difference, the more time necessary to achieve equilibrium.

Question 13

What factors affect elimination of anesthestics?

Answer 13

Time to recovery from anesthesia depends on rate of elimination from brain.

Two parameters manipulated by anesthesiologist useful in controlling speed of induction and recovery: concentration of anesthetic in inspired air and alveolar ventilation.

Concentration in inspired air cannot be < 0, hyperventilation only way to speed recovery.

Duration of exposure may have a significant impact on recovery.

Accumulation in muscle, skin, and fat increases with prolonged exposure (especially in obese) and blood tension may decline slowly during recovery as anesthetics are slowly eliminated from these tissues.

Clearance of inhaled anesthetics via the lungs is the major route of elimination from the body, although some agents are metabolized by the liver to varying degrees.

Question 14

What is MAC?

Answer 14

Anesthetic potency currently described by the minimum alveolar concentration (MAC) required to prevent a response to surgical incision.

1.0 MAC = partial pressure of inhaled anesthetic in alveoli at which 50% of population remained immobile at time of skin incision

Question 15

How are the values of MAC expressed?

Answer 15

Values are expressed as a volume %, the percentage of atmosphere that is anesthetic at the MAC. Example: 1 MAC of isoflurane is 1.4 volume % while 1 MAC of halothane is 0.75 volume %.

Question 16

How many MACs are needed for anesthesia?

Answer 16

Patients may need 0.5-2 MAC for successful anesthesia (> 90% of patients will become anesthetized at 1.3 MAC).

MAC is additive: 0.5 MAC of an agent added to 0.5 MAC of another = 1 MAC.

Question 17

What does a MAC value >100% mean?

Answer 17

MAC values greater than 100% indicate that even if 100% of the inspired air at barometric pressure is anesthetic, the MAC value would still be less than 1 and other agents must be supplemented to achieve full surgical anesthesia (e.g., nitrous oxide).

Question 18

What is a general contraindication with inhaled anesthetics?

Answer 18

Inhaled anesthetics decrease the metabolic activity of the brain which generally results in reduction of blood flow;

however,

volatile anesthetics may also cause cerebral vasodilation (undesirable in patients with increased intracranial pressure).

Question 19

What are the CV effects of inhaled anesthetic?

Answer 19

Halothane, enflurane, isoflurane, desflurane, sevoflurane all depress normal cardiac contractility (halothane and enflurane more so than others).

Tend to decrease mean arterial pressure in direct proportion to alveolar concentration.

A decrease in arterial blood pressure leads to activation of autonomic nervous system reflexes which may trigger an increase in HR (significant with desflurane and isoflurane, others attenuate baroreceptor response).

Question 20

What are the respiratory effects of inhaled anesthetics?

Answer 20

All volatile anesthetics are respiratory depressants. They cause dose-dependent decrease in tidal volume with increase in respiratory rate which results in rapid, shallow breathing.

Respiratory depressant effects overcome by assisting (controlling) ventilation mechanically.

During prolong exposure, mucus pooling and plugging may result in atelectasis and the development of postoperative respiratory complications (including hypoxemia and respiratory infections).

Question 21

What are some common ADRs associated with inhaled anesthetics?

Answer 21

Common side effects include nausea and vomiting.

Halothane may cause hepatitis after a previous first-time exposure (1:20,000-35,000).

Agents metabolized to products including fluoride ions may cause renal toxicity (e.g., enflurane).

Inhaled volatile anesthetics may cause malignant hyperthermia, which consists of rapid onset tachycardia and hypercapnia, severe muscle rigidity, hyperthermia, hyperkalemia, and metabolic acidosis (treatment: dantrolene).

Question 22

What are IV anesthetics used for?

Answer 22

Replaced inhalation as preferred method of anesthesia induction in most settings (exception: pediatrics). Also used commonly to provide sedation during monitored anesthesia care and for patients in the intensive-care unit (ICU) setting

Question 23

Why is balanced anesthesia important with IV anesthetics?

Answer 23

Do not produce all five desired effects (unconsciousness, amnesia, analgesia, inhibition of autonomic reflexes, skeletal muscle relaxation);

therefore,

balanced anesthesia employing multiple drugs (inhaled anesthetics, sedative-hypnotics, opioids, neuromuscular blocking drugs) is used.

Question 24

Generally speaking, IV anesthetics are lipophilic. Why?

Answer 24

Intravenous agents used for induction of general anesthesia are lipophilic and preferentially partition into highly perfused lipophilic tissues (brain, spinal cord) which accounts for rapid onset of action.

Question 25

What is the MOA for propofol?

Answer 25

Most frequently administered drug for anesthesia induction in most countries **MOA:** presumed potentiation of Cl^- current mediated through GABA_A receptor complex.

Question 26

Explain the Pk with propofol.

Answer 26

PK: poorly soluble in water; formulated as a lipid emulsion. Emulsion contains: 10% soybean oil, 2.25% glycerol, 1.2% lecithin, major component of egg yolk phosphatide fraction (hence susceptible patients may experience allergic reactions). Rapidly metabolized in the liver; water soluble metabolites excreted through kidneys. Extraheptatic metabolism also contributes (occurs in lungs). Fast onset, fast plasma clearance, recovery more complete (awakening after induction dose within 8-10 minutes), less “hangover” effect. Brief context-sensitive half-time (even after a prolonged infusion) and recovery remains relatively prompt.

Question 27

What is context-sensitive half-time?

Answer 27

elimination half-time after discontinuation of a continuous infusion as a function of the duration of infusion Relatively short for propofol, etolamide and ketamine Considerably long for thiopental, less so for midazolam

Question 28

What are the CNS effects of propofol?

Answer 28

General suppression of CNS activity, even though excitatory effects such as twitching or spontaneous movements are occasionally observed during induction. No analgesic properties. Decreases cerebral blood flow and the cerebral metabolic rate for oxygen (CMRO₂), which decreases intracranial pressure (ICP) and intraocular pressure. Produces burst suppression in the EEG when administered in large doses, which conveys a neuroprotective effect during neurosurgical procedures (as does decreased CMRO₂).

Question 29

What are the CV effects of propofol?

Answer 29

Compared with other induction agents, produces the most pronounced decrease in systemic blood pressure due to profound vasodilation in both arterial and venous circulation leading to reductions in preload and afterload. Hypotensive effects are augmented by inhibition of the normal baroreflex response.

Question 30

What are the respiratory effects of propofol?

Answer 30

Potent respiratory depressant; generally produces apnea after an induction dose. Causes a greater reduction in upper airway reflexes than thiopental does, which makes it well suited for instrumentation of the airway, such as placement of a laryngeal mask airway. Pain on injection is a common (premedicate with opioid or co-administer lidocaine)

Question 31

What are the therapeutic uses of propofol?

Answer 31

anesthesia induction, continuous infusions, maintenance of anesthesia, sedation in ICU, conscious sedation, and short duration general anesthesia in locations outside the operating room (e.g., interventional radiology suites, emergency department)

Question 32

What is the MOA and Pk for fospropofol?

Answer 32

**MOA:** effect profile similar to propofol; but onset/recovery is prolonged compared with propofol. **PK:** water soluble prodrug, rapidly metabolized by alkaline phosphatase; produces propofol, phosphate, and formaldehyde; formaldehyde metabolized by aldehyde dehydrogenase in liver and erythrocytes

Question 33

What are the therapeutic uses for fospropofol?

Answer 33

sedation during monitored anesthesia care

Question 34

What are the ADRs for fospropofol?

Answer 34

less pain on administration than propofol; common ADR is the experience of paresthesia, often in perianal region, which occurs in up to 74% of patients (mechanism unknown).

Question 35

What are some common barbiturates that are used for IV anesthetic?

Answer 35

**Barbiturates** **Agents:** thiopental (not currently available in the U.S.), methohexital

Question 36

What is the MOA for barbiturates?

Answer 36

act on GABAA receptor (distinct site from benzodiazepines) to increase duration of channel opening. Presumed to also inhibit excitatory neurotransmission

Question 37

What are the CNS effects of barbiturates?

Answer 37

_CNS effects_ Dose-dependent CNS depression ranging from sedation to general anesthesia when given as bolus injections. Do not produce analgesia. Except for methohexital (activated epileptic foci) barbiturates decrease electrical activity on EEG and can be used as anticonvulsants.

Question 38

What are the respiratory effects of barbiturates?

Answer 38

Respiratory depressants; induction doses typically produce transient apnea

Question 39

What is the MOA for benzodiazepines?

Answer 39

acts on the GABAA receptor to increase receptor sensitivity to GABA (agonist) and enhances inhibitory neurotransmission. Unique among IV anesthetics as effect can be terminated by administration of selective antagonist, **flumazenil**

Question 40

What is the Pk for benzodiazepines?

Answer 40

highly lipid soluble, enters CNS rapidly, rapid onset of action. Midazolam has shortest context-sensitive half-time, only benzodiazepine suitable for continuous infusion

Question 41

What are the effects that benzodiazepines have on the CNS and resp systems?

Answer 41

_CNS effects_ Potent anticonvulsants used in status epilepticus, alcohol withdrawal, and local-anesthetic induced seizures. _Respiratory effects_ Severe respiratory depression may occur when administered together with opioids

Question 42

What is the therapeutic use of benzodiazepines in anesthesia?

Answer 42

produces anxiolysis and anterograde amnesia, extremely useful as premedication. Also used for IV sedation and suppression of seizure activity

Question 43

What is the MOA for etomidate?

Answer 43

: GABA like effects, acts primarily through potentiation of GABAA mediated Cl- currents

Question 44

What is the effect of etomidate on the CNS, CV, and endocrine systems?

Answer 44

_CNS effects_ Potent cerebral vasoconstrictor; decreases cerebral blood flow and intracranial pressure. _Cardiovascular effects_ Minimal hemodynamic effects. _Endocrine effects_ Adrenocortical suppression, producing dose dependent inhibition of 11B-hydroxylase, an enzyme necessary for conversion of cholesterol to cortisol.

Question 45

What are the therapeutic uses of etomidate?

Answer 45

alternative to propofol or barbiturates for rapid IV induction of anesthesia, especially in those with compromised cardiac contractility. Does not provide analgesia, and postoperative nausea and vomiting may be more common than after administration of thiopental or propofol.

Question 46

What is the MOA and Pk for ketamine?

Answer 46

1. **MOA:** complex; major effect is probably produced through inhibition of NMDA receptor complex. 2. **PK:** high lipid solubility = rapid onset of action. Also particularly water soluble. Similar in structure to phencyclidine (PCP). Hepatic metabolism, *N*-demethylation CYP450 to less potent metabolite norketamine

Question 47

What are the effects of ketamine in the CNS?

Answer 47

In contrast to other anesthetics, ketamine considered a cerebral vasodilator and increases cerebral blood flow, as well as cerebral metabolic rate. Not recommended for use in patients with intracranial pathology, especially increased ICP. Emergence reactions: vivid colorful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity. Reactions associated with fear/confusion but euphoric state may also be induced (explains potential for abuse). Children may have lower incidence of and less severe emergence reactions. “Dissociative anesthesia” wherein patients eyes remain open with slow nystagmic gaze.

Question 48

What are the cardiovascular effects of ketamine?

Answer 48

Can increase systemic blood pressure, heart rate, and cardiac output; presumably by centrally mediated sympathetic stimulation. Ketamine is considered to be a direct myocardial depressant, a property masked by stimulation of the sympathetic nervous system (the depressant actions of ketamine may be more apparent in critically ill patients with limited ability to increase their sympathetic nervous system activity).

Question 49

What is the therapeutic use of ketamine?

Answer 49

**Therapeutic Use:** *profound analgesia*, sympathetic nervous system stimulation, bronchodilation, and minimal respiratory depression make ketamine an important alternative to other anesthetics. Lacrimation and salivation are increased upon administration, and premedication with an anticholinergic may be indicated

Question 50

What is the MOA for dexmedetomidine?

Answer 50

highly selective α2-adrenergic agonist; effects may be antagonized by α2-antagonists

Question 51

What is the Pk for dexmedetomidine?

Answer 51

water soluble, available IV. Rapid hepatic elimination, *N*-methylation and hydroxylation followed by conjugation; metabolites excreted in urine and bile High clearance, short half-time. Significant increase in context-sensitive half-time from 4 minutes after 10 minute infusion to 250 minutes after an 8 hour infusion

Question 52

What are the CNS effects of dexmedetomidine?

Answer 52

_CNS effects_ Activates CNS α₂-receptors, hypnosis presumably from stimulation of α₂-receptors in locus caeruleus, and analgesia at level of spinal cord. Sedative effect resembles physiologic sleep state (endogenous sleep pathway activation)

Question 53

What are the CV effects of dexmedetomidine?

Answer 53

Moderate decrease in heart rate and systemic vascular resistance, consequently in systemic blood pressure. Bradycardia may require treatment

Question 54

What are the therapeutic uses of dexmedetomidine?

Answer 54

short-term sedation of intubated and ventilated patients in the ICU setting; in operating room, may be used as adjunct to general anesthesia or provide sedation; awakening and the transition to postoperative setting may benefit from dexmedetomidine produced sedative and analgesic effects without respiratory depression