【Pharmacology】General and local anesthetics

Anesthesia 

A reversible condition induced by anesthetic drugs that cause reduction or complete loss of response to pain or another sensation such as consciousness and muscle movements during surgery or other invasive procedures that can be painful.

Two main types of anesthesia:

• General anesthesia: makes the whole body lose feeling movement and consciousness drugs
• Local anesthesia: numbs only a specific targeted area of the body drugs

 

Content:

1. Anesthesia stage
2. Mechanism of action
3. General anesthetics
    i. 1st group (Intravenous agents)
    ii. 2nd agent (Intravenous & Inhalation agent)
    iii. 3rd agent (halogenated volatile anesthetics)
4. Dexmedetomidine
5. Local anesthetics
6. Reference

1. Anesthesia stage

Anesthesia performed with general anesthetics occurs in four stages:

Stage 1: Induction
a period during which the patient goes from state of consciousness to a state of unconsciousness

Stage 2: Excitement

depression of inhibitory neurons in the CNS leads to increased excitement involuntary muscle movement, increased heart rate blood pressure and respiration

Stage 3: Surgical anesthesia
a gradual loss of muscle tone and reflexes.

patient is fully unconscious unresponsive to surgery and has regular breathing

this is the ideal stage for surgery

Stage 4: Medullary paralysis

Stage 3 without careful monitoring or overdose

Respiratory and cardiovascular failure occurs which lead to death if the patient cannot be revived quickly

2. Mechanism of action

Not entirely clear

At the macroscopic level, the action of general anesthetics on thalamus and reticular activating system, leads to reversible loss of consciousness the action on the hippocampus amygdala and prefrontal cortex, causes amnesia.

Action on the spinal cord is responsible for immobility and analgesia.

3. General anesthetics

At the molecular level, divide general anesthetics into three groups:

i. 1st group (Intravenous agents)

• Drug:
• Etomidate
• Propofol
• Barbiturates
• more potent at producing unconsciousness rather than immobility or analgesia
• commonly used in the induction phase 
• effects appear to be mediated by a subset of gamma-Aminobutyric acid type A receptors (GABA-A)
• GABA-A receptors 
• located both postsynaptically and extrasynaptically on the majority of neurons in the central nervous system 
• composed of pentameric arrangements of subunits around a central ion channel pore

When endogenous GABA binds to receptor, 

• it causes a conformational change which opens central pore allowing chloride ions to pass down electrochemical gradient
• leads to stabilization or hyperpolarization of the resting potential 
• making it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential

When Etomidate, Propofol and Barbiturates bind to specific sites on the GABA-A receptor

• prolong opening of the channel suppress neuronal excitability
• promote unconsciousness

Side effects

Etomidate 

• adrenal suppression
• transient skeletal muscle movements including myoclonus

Propofol 

• respiratory depression 
• hypotension

Barbiturates

• apnea cough 
• bronchospasms

ii. 2nd agent (Intravenous & Inhalation agent)

Intravenous agent: Ketamine

Inhalation agents: Nitrous Oxide, Xenon, Cyclopropane

• produce significant analgesia (in contrast to group 1 and group 3 agents)
• their ability to produce unconsciousness and immobility is relatively weak
• these drugs are typically used in the maintenance phase of anesthesia
• little to no effect on GABA-A receptors
• effects appear to be mediated primarily by N-methyl-D-aspartate receptors (NMDA) 
• NMDA receptors
• located in a spinal cord
• crucial in pain modulation and processing

When neurotransmitter glutamate binds to NMDA receptor

• causes inflow of extracellular calcium into the postsynaptic neuron
• activates a series of signaling molecules causing the pain signal to increase and fire more frequently

Ketamine, Nitrous Oxide, Xenon and Cyclopropane

• selectively inhibit NMDA receptors
• prevents or decreases neurotransmission of pain
• affect members of the 2-pore-domain potassium channel family
• regulate the resting membrane potential of neurons, specifically promote the opening of these channels 
• leading to increased potassium efflux
• producing a reduction in neuronal excitability
• contributes to their sedative effects

Side effect

Ketamine

• hypertension 
• tachycardia 
• hypersalivation
• emergence phenomena ranging from vivid dreams to hallucinations and delirium
• may continue for 24 hours after treatment 

Nitrous Oxide and Cyclopropane

• dizziness 
• nausea 
• vomiting 

Xenon

• has virtually no significant side effects

iii. 3rd agent (halogenated volatile anesthetics)

• Drug:
• Halothane 
• Enflurane 
• Isoflurane 
• Sevoflurane
• Desflurane
• more diverse mechanism of action and are more potent at producing immobility 
• produce unconsciousness via different GABA-A receptor subunits
• many 2-pore-domain potassium channels that are activated by group 3 anesthetics appear to highly affect immobility
• also inhibit NMDA receptors a wide variety of other ion channels
• also sensitive to volatile anesthetics including
• neuronal nicotinic acetylcholine receptors
• serotonin type 3 receptors 
• sodium channels 
• mitochondrial ATP-sensitive potassium channels
• hyperpolarization-activated cyclic nucleotide-gated channels

Side effects 

All: produce a dose-dependent reduction in blood pressure and cardiac output

Halothane

• cardiac arrhythmias
• hepatotoxicity 

Sevoflurane

• renal toxicity

4. Dexmedetomidine

• doesn't belong to any of the three groups
• has a unique ability to produce sedation and analgesia without the risk of respiratory depression
• result from its binding to the presynaptic alpha-2 adrenergic receptors of the subtype 2A
• located in a brain and spinal cord
• inhibits the release of norepinephrine
• terminating the propagation of pain signals
• inducing light sedation

Side effects of Dexmedetomidine

bradycardia

hypotension

transient hypertension due to weak peripheral alpha-1 receptor agonist activity

5. Local anesthetics

produce transient loss of sensory perception especially of pain in a localized area of the body without producing unconsciousness

Local anesthetics

• able to pass through the neuronal membrane 
• bind to a specific receptor at the opening of the voltage-gated sodium channel
• preventing sodium influx
• prevents the initiation and conduction of action potentials
• loss of sensation in the area supplied by the nerve

Drug:

• Bupivacaine 
• Lidocaine 
• Mepivacaine 
• Procaine 
• Ropivacaine
• Tetracaine

Side effect

• generally very safe
• When systemic toxicity occurs, may experience symptoms ranging from blurry vision and lightheadedness to seizures and cardiac arrhythmias

【Pharmacology】Pharmacology Hack 16. Lidocaine toxicity

6. Reference

https://youtu.be/wx3dZmv5pM0

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