in this lecture we are going to cover pharmacology of general and local
anesthetics but first things first what is anesthesia so anesthesia is 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 there are two main types of anesthesia first is general anesthesia
which makes the whole body lose feeling movement and consciousness drugs that
are used to induce this type of anesthesia are called general
anesthetics the second type is local anesthesia which numbs only a specific
targeted area of the body drugs that are used to induce local anesthesia are
called local anesthetics now anesthesia performed with general anesthetics
occurs in four stages that were first introduced and described back in 1930s
these four stages remained essentially the same over time however updated delivery
methods and modern anesthetics have improved the speed of onset safety and
recovery so the first stage is known as induction it is simply a period during
which the patient goes from state of consciousness to a state of
unconsciousness next we have the second stage known as excitement at this stage
depression of inhibitory neurons in the CNS leads to increased excitement
involuntary muscle movement increased heart rate blood pressure and
respiration next we progress to the third stage known as surgical
anesthesia at this stage there is 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 and careful monitoring is
necessary to prevent further progression to stage four known as medullary
paralysis or overdose at this stage respiratory and cardiovascular failure
occurs which lead to death if the patient cannot be revived quickly now
let's move on to discussing how general anesthetics work so the mechanism of
action of general anesthetics is not entirely clear although early theories
focused on a single common path of action for all anesthetics over time it has
become increasingly apparent that multiple sites and different mechanisms
are most likely responsible for the effects of general anesthetics so 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 and finally the
action on the spinal cord is responsible for immobility and analgesia now at the
molecular level things get a little bit more complicated so to make it simple we
can divide general anesthetics into three groups based on their relative
abilities to produce unconsciousness immobility and analgesia but before we
proceed in order to gain a better understanding of mechanism of action of
anesthetics I think it's important to know how nerve impulses are generated
therefore for those who need a refresher I would highly recommend to first watch my
video about neuronal action potential now going back to our grouping of
general anesthetics the first group consists of intravenous agents Etomidate
Propofol and Barbiturates these drugs are much more potent at producing
unconsciousness rather than immobility or analgesia and they are commonly used
in the induction phase their effects appear to be mediated by a subset of
gamma-Aminobutyric acid type A receptors GABA-A for short
so GABA-A receptors are located both postsynaptically and extrasynaptically
on the majority of neurons in the central nervous system they are composed of
pentameric arrangements of subunits around a central ion channel pore when
endogenous GABA binds to this receptor it causes a conformational change which
opens central pore allowing chloride ions to pass down electrochemical
gradient this in turn 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 so when Etomidate Propofol and Barbiturates bind to specific sites on
the GABA-A receptor they prolong opening of the channel suppress neuronal
excitability and thus promote unconsciousness now when it comes to
side effects Etomidate can cause adrenal suppression and transient skeletal
muscle movements including myoclonus Propofol is known to cause respiratory
depression and hypotension lastly Barbiturates can cause apnea cough
bronchospasms and just like Propofol respiratory depression now let's move on
to the second group of general anesthetics which consists of
intravenous agent Ketamine and inhalation agents Nitrous Oxide Xenon
and Cyclopropane in contrast to group 1 and group 3 agents these drugs produce
significant analgesia however their ability to produce unconsciousness and
immobility is relatively weak because of that these drugs are typically used in
the maintenance phase of anesthesia unlike the drugs in group 1 the group 2
drugs have little to no effect on GABA-A receptors and instead their effects
appear to be mediated primarily by N-methyl-D-aspartate receptors NMDA for
short NMDA receptors are located in a spinal cord and are crucial in pain
modulation and processing when neurotransmitter glutamate binds to NMDA
receptor it causes inflow of extracellular calcium into the
postsynaptic neuron which then activates a series of signaling molecules causing
the pain signal to increase and fire more frequently now Ketamine Nitrous Oxide
Xenon and Cyclopropane selectively inhibit NMDA receptors which ultimately
prevents or decreases neurotransmission of pain group 2 general anesthetics also
affect members of the 2-pore-domain potassium channel family which regulate
the resting membrane potential of neurons specifically they promote the
opening of these channels leading to increased potassium efflux producing a
reduction in neuronal excitability that contributes to their sedative effects
now when it comes to adverse effects Ketamine can cause
hypertension tachycardia and hypersalivation
as well as emergence phenomena ranging from vivid dreams to hallucinations
and delirium that may continue for 24 hours after treatment next Nitrous Oxide
and Cyclopropane are known to cause dizziness nausea and vomiting lastly we
have Xenon which has many characteristics of the ideal anesthetic
and has virtually no significant side effects
now let's move on to the third group of general anesthetics which consists of
halogenated volatile anesthetics Halothane Enflurane Isoflurane
Sevoflurane and Desflurane in contrast to group 1 and 2 drugs
group 3 drugs have more diverse mechanism of action and are more potent
at producing immobility studies suggest that volatile anesthetics produce
unconsciousness via different GABA-A receptor subunits than those targeted by
the group 1 drugs also many 2-pore-domain potassium channels that are
activated by group 3 anesthetics appear to highly affect immobility rather than
anesthesia just like group 2 drugs volatile
anesthetics also inhibit NMDA receptors a wide variety of other ion channels
are also sensitive to volatile anesthetics including neuronal nicotinic acetylcholine receptors
serotonin type 3 receptors sodium channels mitochondrial ATP-sensitive potassium channels
and hyperpolarization-activated cyclic nucleotide-gated channels
now when it comes to side effects all of the agents in
this group produce a dose-dependent reduction in blood pressure and cardiac
output additionally Halothane in particular may
cause cardiac arrhythmias and hepatotoxicity while Sevoflurane
may cause renal toxicity now before we move on there is one more agent that's
worth mentioning here which doesn't belong to any of the three groups that
we discussed so far and that is Dexmedetomidine
unlike the other commonly used general anesthetics
Dexmedetomidine has a unique ability to produce sedation
and analgesia without the risk of respiratory depression these effects
result from its binding to the presynaptic alpha-2 adrenergic receptors
of the subtype 2A which are located in a brain and spinal cord the action on
these receptors inhibits the release of norepinephrine terminating the
propagation of pain signals and inducing light sedation when it comes to
side effects of Dexmedetomidine the most common ones are bradycardia and
hypotension as well as transient hypertension due to weak peripheral
alpha-1 receptor agonist activity now let's switch gears and let's move on to
brief discussion of the pharmacology of local anesthetics unlike general
anesthetics local anesthetics produce transient loss of sensory perception
especially of pain in a localized area of the body without producing
unconsciousness so how do these drugs work due to their distinct chemical
properties local anesthetics are able to pass through the neuronal membrane and
bind to a specific receptor at the opening of the voltage-gated sodium
channel thus preventing sodium influx this in turn prevents the initiation and
conduction of action potentials which ultimately leads to loss of sensation in
the area supplied by the nerve examples of the most widely used local
anesthetics are Bupivacaine Lidocaine Mepivacaine Procaine Ropivacaine
and Tetracaine when used properly local anesthetics are generally very safe
and serious reactions are rare however when systemic toxicity occurs
patients may experience symptoms ranging from blurry vision and lightheadedness
to seizures and cardiac arrhythmias and with that I wanted to thank you for
watching I hope you enjoyed this video and as always stay tuned for more