IV

Notes on General Anesthesia and Sedation:

1. Historical Context:
• Initially, general anesthesia was administered using ether, nitrous
oxide, or chloroform via inhalation.
2. Current Practice:
• Anesthesia and sedation are now induced and maintained using drugs
through various routes: oral, intravenous, intramuscular, or inhalation.
3. Preoperative/Procedural Sedation:
• Typically achieved through oral or intravenous routes.
4. Induction of General Anesthesia:
• Done by inhalation or intravenous drug administration.
• Intramuscular injection of ketamine is an alternative method for
induction and maintenance.
5. Maintenance of General Anesthesia:
• Can be maintained using:
• Total Intravenous Anesthesia (TIVA) technique.
• Inhalation technique.
• A combination of both methods.
6. Injectable Agents for Narcosis:
• Focus on injectable agents used to induce sleep or narcosis:
• Barbiturates
• Benzodiazepines
• Ketamine
• Etomidate
• Propofol
• Dexmedetomidine
---------------------------------------------------------------------------------------------------
Barbiturates in Anesthesia

Historical Use:

• Widespread Use in the Past: Barbiturates were once the primary agents
for inducing general anesthesia in adults.
 • Other Applications: Used for seizure control, anxiolysis, procedural
sedation, and as sleep-inducing agents.
• Current Status: Now much less frequently used in modern anesthesia
practice.

Mechanisms of Action:

• Depression of the Reticular Activating System: Barbiturates act on the

brainstem, affecting consciousness.
• GABA Receptor Binding:
• Barbiturates bind to a distinct site on the GABA-A receptor, different
from the benzodiazepine binding site.
• They potentiate GABA’s action by increasing the duration of chloride ion
channel openings, enhancing inhibitory neurotransmission.
• Inhibition of Kainate and AMPA Receptors: Barbiturates also inhibit
excitatory neurotransmitter receptors, contributing to their sedative
effects.

Structure-Activity Relationships:

• Barbituric Acid Derivatives: Barbiturates are derived from barbituric

acid.
• Substitutions at Carbon C5:
• Determine hypnotic potency and anticonvulsant activity.
• Phenyl group in phenobarbital contributes to its anticonvulsive effects.
• Methyl group in methohexital lacks anticonvulsant properties, making it
suitable for procedures like electroconvulsive therapy (ECT).
• Thiobarbiturates vs. Oxybarbiturates:
• Replacement of oxygen with sulfur at C2 increases lipid solubility,
resulting in greater potency, faster onset, and shorter duration (e.g.,
thiopental and thiamylal compared to pentobarbital).

Stability and Solubility:

 • Water Soluble Sodium Salts: The sodium salts of barbiturates are water
soluble but have certain limitations:
• They are markedly alkaline (e.g., the pH of a 2.5% thiopental solution is
≥ 10), which makes them caustic if extravasated.
• They have limited stability. For instance, a 2.5% thiopental solution has
a shelf life of only about two weeks, making it less convenient for storage
and long-term use.

Summary of Key Barbiturates:

1. Thiopental:
• Higher lipid solubility due to sulfur substitution, leading to faster onset
and shorter duration of action.
• Commonly used for rapid induction but now replaced by newer agents
in many settings.
2. Thiamylal:
• Similar in structure and action to thiopental, with rapid onset and short
duration.
3. Methohexital:
• Useful for electroconvulsive therapy because of its short duration and
lack of anticonvulsant properties.
4. Phenobarbital:
• Primarily used for its anticonvulsant properties rather than for
anesthesia.
--------------------------------------------------------------------------------------------------
Pharmacokinetics of Barbiturates:

A. Absorption:

• Intravenous Administration: Thiopental, thiamylal, and methohexital

were commonly administered IV for induction of general anesthesia
before the use of propofol.
• Rectal Administration: Methohexital has been used rectally for induction
in children.
B. Distribution:

• Redistribution: Determines the duration of action for thiopental,

thiamylal, and methohexital. Not metabolism or elimination.
• Lipid Solubility: Thiopental has high lipid solubility, leading to rapid brain
uptake (within 30 seconds).
• Influencing Factors: Conditions like hypovolemic shock, low serum
albumin, or acidosis increase brain and heart concentrations, lowering
blood pressure more significantly.
• Rapid Redistribution: Plasma and brain concentrations reduce to 10% of
peak levels within 20-30 minutes, with patients typically regaining
consciousness within 20 minutes.
• Dose Considerations: Lower doses are required for elderly patients.
Repetitive doses saturate peripheral compartments, shifting the focus
from redistribution to elimination.

C. Biotransformation:

• Hepatic Oxidation: Barbiturates are mainly metabolized by the liver into

inactive, water-soluble compounds.
• Methohexital: Cleared more rapidly than thiopental due to greater
hepatic extraction, resulting in quicker recovery of psychomotor function.

D. Excretion:

• Renal Excretion: Limited to water-soluble end products, except for less

protein-bound agents like phenobarbital.
• Methohexital: Excreted in feces.

Effects on Organ Systems:

A. Cardiovascular:

• Varied Effects: Barbiturate effects depend on the rate of administration,

dose, volume status, and preexisting conditions.
 • Hypotension & Tachycardia: Barbiturates decrease blood pressure and
increase heart rate due to vasodilation and reflex responses.
• Cardiac Output: Maintained by increased heart rate, but situations like
hypovolemia or heart failure may cause severe drops in blood pressure
and cardiac output.

B. Respiratory:

• Depression of Respiratory Centers: Barbiturates depress the medullary

ventilatory center, decreasing the response to hypercapnia and hypoxia.
• Airway Reflexes: Barbiturates incompletely suppress airway reflexes,
potentially causing bronchospasm or laryngospasm in susceptible patients
(e.g., asthmatics).

C. Cerebral:

• Cerebral Vasoconstriction: Decreases in cerebral blood flow, cerebral

blood volume, and intracranial pressure.
• Cerebral Oxygen Consumption: Barbiturates reduce cerebral oxygen
consumption by up to 50%, potentially providing protection during
transient ischemia.
• EEG Changes: Barbiturates induce changes in the
electroencephalogram, progressing from fast activity to burst suppression
and electrical silence at higher doses.
• CNS Effects: Dose-dependent CNS depression ranging from mild
sedation to unconsciousness. Barbiturates do not impair pain perception
but may cause excitement or disorientation at low doses.

D. Renal:

• Decreased Renal Function: Barbiturates reduce renal blood flow and

glomerular filtration rate in proportion to the decrease in blood pressure.

E. Hepatic:
 • Reduced Hepatic Blood Flow: Chronic use induces hepatic enzymes,
increasing drug metabolism, but also interferes with the biotransformation
of other drugs (e.g., tricyclic antidepressants).
• Risk of Porphyria: Barbiturates may precipitate porphyria in susceptible
individuals.

F. Immunological:

• Rare Allergic Reactions: Anaphylactic or anaphylactoid reactions are

rare, though thiobarbiturates may release histamine from mast cells.

Drug Interactions with Barbiturates:

1. Protein Binding Displacement:

• Contrast media, sulfonamides, and other drugs that compete for the
same protein-binding sites as thiopental can displace it, leading to
increased levels of free (active) drug. This potentiates the effects of
thiopental at a given dose, increasing its sedative impact.
2. CNS Depressants:
• Ethanol, opioids, antihistamines, and other central nervous system
depressants enhance the sedative and depressant effects of barbiturates.
This can result in deeper sedation or respiratory depression, requiring
careful dose adjustment when these substances are combined.
---------------------------------------------------------------------------------------------------
Benzodiazepines: Key Notes

Mechanisms of Action

• Bind to GABA_A receptors, enhancing GABA’s inhibitory effects by

increasing the frequency of chloride ion channel openings.
• Flumazenil: A specific antagonist that reverses the CNS effects of
benzodiazepines.

Structure-Activity Relationships
• Composed of a benzene ring and a diazepine ring.
• Midazolam has an imidazole ring, making it water-soluble at low pH,
unlike diazepam and lorazepam (which require propylene glycol in
parenteral preparations).

Pharmacokinetics

1. Absorption:
• Administered orally, intravenously, or intramuscularly for sedation or
anxiolysis.
• Midazolam: Widely used intravenously for anxiolysis before anesthesia.
• Pediatric uses include oral and intranasal midazolam for sedation.
2. Distribution:
• Diazepam is lipid-soluble and penetrates the blood-brain barrier rapidly.
• Midazolam becomes lipid-soluble at physiological pH due to its
imidazole ring, while lorazepam has slower uptake due to lower lipid
solubility.
• All benzodiazepines are highly protein-bound (90-98%).
3. Biotransformation:
• Metabolized by the liver to glucuronidated end products.
• Midazolam has the shortest half-life (2 hours), while diazepam has the
longest (30 hours).
4. Excretion:
• Metabolites are excreted primarily through the urine.
• Diazepam shows a secondary plasma peak due to enterohepatic
circulation.

Effects on Organ Systems

1. Cardiovascular:
• Minimal effects unless combined with opioids, which can lead to
myocardial depression and hypotension.
• Benzodiazepines alone slightly lower blood pressure and peripheral
vascular resistance.
2. Respiratory:
• Depress the ventilatory response to CO₂, potentially leading to apnea,
especially when administered intravenously.
• Must be titrated carefully to avoid overdose, and ventilation must be
monitored.
3. Cerebral:
• Reduce cerebral oxygen consumption, blood flow, and intracranial
pressure.
• Effective for controlling grand mal seizures and often produce
anterograde amnesia.
• Lack analgesic properties but provide sedation and muscle relaxation.

Drug Interactions

• Cimetidine reduces the metabolism of diazepam.

• Erythromycin prolongs and intensifies the effects of midazolam.
• Opioids combined with benzodiazepines increase the risk of
hypotension and myocardial depression.
• Benzodiazepines lower the required dose of volatile anesthetics (up to
30%).
• Ethanol, barbiturates, and other CNS depressants potentiate their
sedative effects.
---------------------------------------------------------------------------------------------------
Ketamine: Key Notes

Mechanisms of Action

• Ketamine primarily inhibits N-methyl-D-aspartate (NMDA) receptors,

dissociating sensory inputs from the limbic cortex, leading to a dissociative
anesthesia state.
• The patient may appear conscious but is unable to process sensory
input.
• Ketamine is used in treatment-resistant depression and to reduce opioid
requirements during and after surgery.
• Recognized as an essential medicine by the WHO.
Structure-Activity Relationships

• Structurally related to phencyclidine (PCP), ketamine is one-tenth as

potent but retains psychotomimetic effects.
• Often used for intravenous induction of anesthesia, especially in trauma
and hypovolemia where sympathetic stimulation is advantageous.
• The racemic mixture of ketamine contains two enantiomers: S(+) (more
potent, fewer side effects) and R(-). The S(+) enantiomer is not available in
the U.S.

Pharmacokinetics

1. Absorption:
• Administered intravenously or intramuscularly (can also be given orally,
nasally, rectally, etc.).
• Peak plasma levels occur 10-15 minutes after intramuscular injection.
2. Distribution:
• Highly lipid-soluble, with rapid brain uptake due to increased cerebral
blood flow and cardiac output.
• Awakening occurs via redistribution from the brain to peripheral
compartments.
3. Biotransformation:
• Metabolized in the liver to active metabolites, including norketamine.
• Tolerance can develop with repeated dosing.
4. Excretion:
• Metabolites are excreted via the kidneys.

Effects on Organ Systems

1. Cardiovascular:
• Increases blood pressure, heart rate, and cardiac output by stimulating
the sympathetic nervous system.
• Can increase pulmonary artery pressure and myocardial workload.
• Should be used cautiously in patients with coronary artery disease,
hypertension, or heart failure.
 2. Respiratory:
• Minimal impact on ventilatory drive, but may cause apnea when
combined with opioids.
• Effective bronchodilator, making it ideal for induction in asthmatic
patients.
• Increases salivation, which can be reduced with glycopyrrolate.
3. Cerebral:
• Increases cerebral blood flow, oxygen consumption, and intracranial
pressure (controversial in head trauma).
• Psychotomimetic effects (hallucinations, delirium) are common but can
be mitigated with benzodiazepines or combined with propofol.

Drug Interactions

• Synergistic with volatile anesthetics, additive with propofol,

benzodiazepines, and other GABAergic agents.
• Diazepam prolongs ketamine’s elimination half-life and attenuates its
cardiovascular effects.
• Propofol combined with ketamine is popular for procedural sedation
and anesthesia due to complementary effects.
---------------------------------------------------------------------------------------------------
Etomidate: Key Notes

Mechanisms of Action

• Etomidate works by depressing the reticular activating system and

enhancing GABA receptor activity, increasing the receptor’s affinity for
GABA.
• The drug often causes myoclonus (30-60% of cases) due to disinhibition
of motor activity centers in the nervous system.

Structure-Activity Relationships

• Etomidate is a carboxylated imidazole that is water-soluble in acidic

solutions and lipid-soluble at physiological pH.
• It is dissolved in propylene glycol for injection, which can cause pain
upon injection, often reduced with lidocaine.

Pharmacokinetics

1. Absorption:
• Etomidate is available only for intravenous use and is primarily used for
induction of general anesthesia.
2. Distribution:
• Highly protein-bound with a rapid onset due to high lipid solubility and
non-ionized fraction at physiological pH.
• Redistribution leads to awakening, with a two-compartment
pharmacokinetic model.
3. Biotransformation:
• Hepatic microsomal enzymes and plasma esterases metabolize
etomidate into inactive compounds.
4. Excretion:
• Metabolites are primarily excreted in the urine.

Effects on Organ Systems

1. Cardiovascular:
• Etomidate does not affect sympathetic tone or myocardial function,
though it may cause a slight decrease in peripheral vascular resistance
leading to lowered blood pressure.
• Myocardial contractility and cardiac output are typically unchanged.
• It provides light anesthesia for intubation, and may cause increased
heart rate and blood pressure during laryngoscopy if no other agents are
used.
2. Respiratory:
• Etomidate affects ventilation less than other agents (e.g., barbiturates,
benzodiazepines), and apnea is rare unless combined with opioids.
3. Cerebral:
• Reduces cerebral metabolic rate, cerebral blood flow, and intracranial
pressure.
 • Etomidate increases the amplitude of somatosensory evoked potentials
and affects auditory evoked potentials by increasing latency and
decreasing amplitude.
• Higher incidence of postoperative nausea and vomiting compared to
other anesthetics like propofol.
4. Endocrine:
• Etomidate inhibits adrenocortical function, particularly enzymes
CYP11B1 and CYP11B2, which suppress cortisol and aldosterone
production.
• Continuous infusions in ICU patients are associated with adrenal
suppression and increased mortality, particularly in septic patients.

Drug Interactions

• Fentanyl increases etomidate plasma levels and prolongs its elimination

half-life.
• Opioids reduce the incidence of etomidate-induced myoclonus.
---------------------------------------------------------------------------------------------------
Propofol: Key Notes

Mechanisms of Action

• Propofol works primarily by facilitating GABA-mediated inhibition in the

central nervous system, increasing GABA binding affinity to its receptor.
This enhances the opening of chloride channels, causing neuronal
hyperpolarization.
• Propofol also binds to multiple ion channels, although its actions are not
reversed by flumazenil, a GABA antagonist used for benzodiazepines.

Structure-Activity Relationships

• Structurally, propofol consists of a phenol ring with two isopropyl

groups.
• It is not water-soluble and is available as a 1% aqueous emulsion with
soybean oil, glycerol, and egg lecithin for intravenous administration.
 • The formulation can cause pain during injection, which can be mitigated
with lidocaine.
• It supports bacterial growth, so sterile technique is critical, and the
solution must be used within 6 hours of opening.

Pharmacokinetics

1. Absorption:
• Propofol is available only for intravenous administration and is
commonly used for induction of general anesthesia or moderate to deep
sedation.
2. Distribution:
• Propofol has a rapid onset with a short distribution half-life (2-8
minutes), which results in rapid awakening after a single bolus.
• Recovery is quicker and less associated with hangover effects compared
to other anesthetics like methohexital or ketamine.
• Propofol is widely used in ambulatory surgery due to its rapid recovery
profile.
3. Biotransformation:
• Propofol is cleared faster than hepatic blood flow suggests, implying
extrahepatic metabolism.
• It undergoes hepatic conjugation and is excreted as inactive metabolites
via renal clearance.
• The pharmacokinetics are not significantly affected by obesity, cirrhosis,
or kidney failure.
4. Excretion:
• Urinary excretion is the primary route for propofol metabolites, but
end-stage kidney disease does not alter its clearance.

Effects on Organ Systems

1. Cardiovascular:
• Propofol induces a reduction in arterial blood pressure by decreasing
systemic vascular resistance, cardiac preload, and contractility.
 • It can cause hypotension, especially in high doses or in the elderly, but
this is often reversed during laryngoscopy and intubation.
• Occasionally, reflex bradycardia may occur due to the Bezold-Jarisch
reflex, which can lead to marked drops in heart rate.
• It can impair normal baroreflexes and may cause myocardial oxygen
supply-demand imbalance in some patients.
2. Respiratory:
• Propofol is a potent respiratory depressant, often causing apnea after
induction.
• It decreases the hypoxic ventilatory drive and response to hypercarbia,
making its administration limited to trained personnel.
• Propofol depresses upper airway reflexes, allowing procedures like
intubation or laryngeal mask placement without neuromuscular blockade.
3. Cerebral:
• Propofol decreases cerebral blood flow, intracranial pressure, and
cerebral blood volume, making it suitable for patients with elevated
intracranial pressure.
• It offers cerebral protection in cases of ischemia, reduces intraocular
pressure, and has antipruritic and antiemetic properties.
• It has anticonvulsant properties, useful in managing status epilepticus.
• Propofol is generally not associated with tolerance or physical
dependence, though misuse for sleep induction has resulted in fatal
consequences in non-surgical contexts.

Drug Interactions

• Midazolam can reduce the propofol dose needed by more than 10%,
commonly administered in small amounts before propofol induction.
• Propofol is often combined with remifentanil, dexmedetomidine, or
ketamine in total intravenous anesthesia (TIVA).

Conclusion

Propofol’s quick action, minimal “hangover” effect, and versatility in

inducing sedation and anesthesia have made it a preferred drug for
various procedures, particularly in outpatient settings. However, its
cardiovascular, respiratory, and cerebral effects require careful
management and monitoring.
--------------------------------------------------------------------------------------------------
Fospropofol

Mechanisms of Action:

• Fospropofol is a water-soluble prodrug of propofol, meaning that it is

metabolized into propofol in the body. It also produces phosphate and
formaldehyde as byproducts.
• Fospropofol was introduced due to its ability to produce better
conscious sedation and more complete amnesia compared to midazolam
plus fentanyl during procedures like endoscopy.
• Its slower onset and recovery compared to propofol makes it less
favored by anesthesiologists.

Pharmacokinetics:

• Onset/Recovery: Slower onset and recovery compared to propofol.

Place in Clinical Use:

• It has limited favor over propofol and its exact role in clinical practice
remains to be fully established.

Dexmedetomidine

Mechanisms of Action:

• Dexmedetomidine is a selective α2-adrenergic agonist, similar to

clonidine.
• It provides anxiolysis, sedation, and analgesia but is not a true
anesthetic in humans.
 • Commonly used in combination with other anesthetic agents for a range
of sedation needs including procedural sedation, ICU sedation, and
supplemental anesthesia to reduce intraoperative opioid use and
postoperative delirium.
• It is favored for procedures like awake craniotomies and fiberoptic
intubation and can be used in treating alcohol withdrawal and cocaine
intoxication side effects.

Pharmacokinetics:

1. Absorption:
• Approved for intravenous injection. Typical doses include an initial
loading dose (1 mcg/kg over 5-10 minutes) followed by a maintenance
infusion (0.2-1.4 mcg/kg/h).
• Can also be used nasally or orally in pediatric patients for
premedication.
2. Distribution:
• Rapid redistribution, short elimination half-life (under 3 hours).
3. Biotransformation:
• Metabolized primarily in the liver via the CYP450 system and
glucuronidation.
• Caution in patients with severe liver disease.
4. Excretion:
• Mostly excreted in the urine.

Effects on Organ Systems:

1. Cardiovascular:
• Dexmedetomidine can cause sympatholysis, leading to reduced heart
rate and mean arterial pressure.
• Hypertension, hypotension, and bradycardia can occur depending on
the dosing regimen. Avoiding rapid boluses minimizes these side effects.
2. Respiratory:
• It produces no respiratory depression, making it ideal for patients being
weaned off mechanical ventilation or undergoing awake intubations.
3. Cerebral:
• Provides sedation in a dose-dependent manner, and is an opioid-sparing
agent.
• Commonly used for patients undergoing awake craniotomy.

Drug Interactions:

• Dexmedetomidine may cause exaggerated bradycardia when used with

beta-blockers.
• It has additive effects when combined with other sedative-hypnotic
agents.
Order
Etomidate> Propofol> Barbiturates> Ketamine> Dexmedetomidine>
Benzodiazepines> Fospropofol