DA Anesthetics

General Anesthetics

• site of action: CNS

• takes control of whole body

• patient unconscious

• major surgery

• high risks for elderly

Local anesthetics

• site of action: around nerves only

• numb specific area

• patient is fully awake

• minor procedures

• min. side effects

Ideal anesthetic drug

• induce rapid, smooth loss of consciousness

• rapidly reversible upon discontinuation

• wide margin of safety

5 primary effects of general anesthetics

1. Unconsciousness

2. Amnesia

3. Analgesia

4. Inhibition of autonomic reflexes

5. Skeletal muscle relaxation

Can currently available anesthetics agents achieve all 5 desired effects on their own?

• No

• Modern anesthesiology relies on the use of combinations of IV and inhaled drugs

Meyer-Overton Rule

• suggest hydrophobic site of action

• molecules with larger oil/gas partition coefficient are more potent general anesthetics

• tight correlation between lipid solubility and anesthetic potency

• Potency = lambda (oil/gas)/1.3

Lipid Solubility Hypothesis

• hydrophobic site of action of anesthetics is lipid bilayer of cell membrane

• account for Meyer-Overton Rule

Anesthetic Mechanism

• dissolve in a membrane, increase membrane volume and fluidity and affect excitable transmembrane proteins

• molecular targets at multiple levels of the CNS

• inhalation anesthetics bind stereoselectively to hydrophobic regions of neuronal membrane proteins that interface with membrane lipids

• anesthetics disrupt neuronal firing and sensory processing in the thalamus and causes loss of consciousness and analgesia

• inhibit neuronal output from layer V of cortex and reduces motor activity

Anesthetic Targets

• GABA_A Receptor agonists

• NMDA receptor antagonists

• alpha2-adrenergic agonist

GABA_A Receptors

• inhibit brain cell firing

• allows chloride ions to flow into neuron, decreasing voltage (hyperpolarization)

• agonists: Propofol and Sevoflurane, Barbiturates, Etomidate

NMDA receptor

• allows Na+ and Ca2+ ions to flow into cell and let K+ out, increasing the voltage within the cell and increasing probability of neural firing

• Antagonist: Ketamine (blocks receptor, decrease excitatory actions)

  • nitrous oxide

  • xenon

  • cyclopropane

Alpha2-Adrenergic agonist

• negatively affect release of NE, attentuates neurotransduction

• Dexmedetomidine

• opiod receptor

Inhalational Anesthetics

• Gaseous: Nitrous oxide, Xenon

• Volatile (Liquid):

  • alkanes: cyclopropane, halothane (fluothane)

  • ether: enflurane, desflurane (suprane), isoflurane (forane), sevoflurane (ultane)

IV Anesthetics

• single bolus injection OR continuous infusion

• combination of drugs used

Inhalation anesthetics drug targets

• GABA_A receptor

  • halothane, enflurane, desflurane, isoflurane, sevoflurane

• NMDA receptor

  • nitrous oxide

  • xenon

  • cyclopropane

  • halothane, enflurane, desflurane, isoflurane, sevoflurane

Inhalation anesthetic Pharmacokinetics

• taken up through gas exchange in lung alveoli

• uptake from alveoli into blood and distributed and partitioned into effect compartments within body

• to achieve rapid onset (induction) and offset (emergence), effect site concentration within CNS will need to change rapidly

  • controlled by inspired concentration (MAC), ventilation, solubility (blood-gas coefficient)

Inspired concentration

• amount of drug inhaled

• partial pressure

  • fraction of gas mixture that particular component comprises

  • determines maximum partial pressure that can be achieved in alveoli (potency) and rate of rise of partial pressure in alveoli (speed)

• driving force for uptake of an inhaled anesthetic into the body is the ratio between inspired and alveolar concentration

• most important parameter that can be controlled to change alveolar concentration

Partial Pressure

P=CRT

Stages of Anesthesia

1. Analgesia

2. Excitement

3. Surgical Anesthesia

   1. target for surgery

4. Medullar Depression

   1. DANGEROUS

   2. respiratory arrest, cardiac depression/arrest, no eye movement

Isoflurane Dose-Response Curves

• curves depict the percentage of patients exhibiting endpoints of nonresponsiveness to a set of stimuli and of caridac arrest as alveolar partial pressure of isoflurane is increased

• steep

• higher partial pressures required to achieve lack of response to stronger stimuli

Therapeutic Index

• lethal pressure (LP50)/MAC

Inhalational anesthetics potency

MAC

• minimal alveolar concentration

• indicator of potency

• 1.0 MAC as partial pressure of inhalation anesthetic at which 50% of population of remained immobile at surgical skin incision

• lower MAC = more potent agent

• alveolar concentration is used for definition bc conc in lung easily and accurately measured

• brain is not easy to measure but directly correlates to alveolar levels

• Low potency: Nitrous oxide (>1)

  • must combine with other drugs

• Middle potency: Deslurane, Sevoflurane (0.2-0.6)

• High potency: Enflurane, Isoflurane, Halothane (<0.02)

Gas Partition Coefficient (lambda)

• solubility of an inhalation anesthetic in blood relative to air

• anesthetic conc in blood: concnetration in gas [jase

• high for soluble agents, low for insoluble

• defines rate of induction and recovery of anesthesia

• more soluble = high coef = slower onset

  • dissolve slowly in blood and takes longer for partial pressure to rise

  • Enflurane, Isoflurane, Halothane

• less soluble = low coef = faster onset

  • saturate blood quickly

  • NO, Desflurane, Sevoflurane

• the more soluble an anesthetic is in blood, the more of it must be dissolved in blood to raise its partial pressure in blood

Ventilation

• increase tidal volume and respiratory rate to deliver larger amounts of anesthetic agent faster

Inhalational Anesthetics Elimination

• eliminated by lungs

• lower blood-gas partition coef, faster effect ceases

  • rate of recovery inversely proportional

• rate of recovery proportional to duration of anesthesia

Intravenous anesthetics

• facilitate rapid induction of anesthesia

• good option for maintenance of anesthesia

• like inhaled agents, not ideal anesthetic drugs in sense of producing all and only the 5 desired effects

• balanced anesthesia employs multile drugs

Pharmacokinetics: single bolus injection

termination of effect determined by redistribution of drug into less perfused and inactive tissues such as skeletal muscle and fat (go to more hydrophobic areas)

short-lived because of re-distribution

Pharmacokinetics: continuous infusion

• context-sensitive half-time: elimination half-time after discontinuation of a continuous infusion as function of duration

• assess suitability of drug for use as maintenance anesthetic

• high context-sensitive half-time = longer recovery

  • thiopental

• small context-sensitive half time desired (propofol)

  • etomidate and ketamine also, but have other effects that limit use

Chemical structure of IV anesthetics

• lipophilic

• preferentially partition into highly perfused lipophilic tissues

Propofol

• unconsiousness, sedation

• GABA_A agonist: potentiate chloride current

• most common anesthetic drug

• good for maintenance of anesthesia bc of pharmacokinetics

  • alternative for inhaled anesthetics

• poorly soluble in water

• milky white, slightly viscous solution

  • lipid emulsion formulation

Fospropofol

• water-soluble prodrug of propofol

  • rapidly metabolized by alkaline phosphatase to produce propofol, phosphate, and formaldehyde

• sterile, aqeous, colorless, clear soln in single-dose vial

• brand name: Lusedra

• combat severe injection pain during propofol admin and disadvantages of lipid emulsion

• more complex pharmacokinetics than propofol

• onset and recovery are prolonged vs. propofol

Barbiturates

• thiopental and methohexital

• used for induction of anesthesia (unconsciousness), usually takes less than 30 seconds

• bind GABA_A receptors

• thiopental recovery after single bolus injection is comparable to methohexital and propofol because if depends on redistribution, not metabolism

  • CANNOT use continuously, will have prolonged recovery

• rapid co-injection of thiopental sodium (high pH) with muscle relaxants (low pH) may cause precipitation

  • important in rapid sequence inductions

Benzodiazepines

• commonly used in pre-operative period

• midazolam, lorazepan, diazepam

• readily terminated by admin of selective antagonist, flumazenil

• effects: anxiolysis and anterograde amnesia, sedative effects

• rapid onset of action followed by redistribution

• midazolam: shortest context-sensitive half time

  • only benzo suitable for continuous infusion

• lorazepam: slow onset and prolonged duration

Etomidate

• GABA_A agonist

• hyponotic (unconsciousness) but not analgesic effects

• minimal hemodynamic effects and short context-sensitive half-time

  • can be used in larger doses and repeated boluses

• propofol alterative

• endocrine side-effects limit use

Ketamine

• produces significant analgesia

• NMDA receptor antagonist

• highly lipid soluble → rapid onset

• small bolus doses useful when additional analgesia needed

• provides effective analgesia without compromise of airway

• use limited by unpleasant psychotomimetic side effects

  • dissociative drugs, cause person to feel detached from reality

Dexmedetomidine

• highly selective Alpha2-adrenergic agonist

• sedative, analgesic without respiratory depression

• significant increase in context-sensitive half-time after longer infusion

• used in short-term sedation