General anesthetics

General anesthetics are medications used to induce an anesthetic state in patients who are about to go under surgery.

The anesthetic state refers to a number of conditions that make surgery tolerable for the patient and more manageable for the surgeon.

The conditions include: unconsciousness, where the person isn’t aware of themselves or their environment; sedation, so they don’t move in response to painful stimulation; analgesia, so they don’t feel pain; and amnesia, so they don’t remember the procedure.

Local anesthetics are different in the fact that they only block pain sensation in a specific part of the body, and don’t affect consciousness.

Okay, to achieve the anesthetic state, general anesthetics depress the central nervous system. In other words, they diminish the total amount of action potentials that are constantly firing in the brain. The generation of these action potentials depends on excitatory and inhibitory synapses.

Excitatory, means that the neurotransmitters released into the synaptic space stimulate the postsynaptic neuron to start an action potential.

The main neurotransmitter involved is glutamate, which binds to postsynaptic NMDA receptors, so some general anesthetics work by blocking these receptors.

Inhibitory synapses, on the other side, do the opposite; they release the inhibitory neurotransmitter called GABA, which binds to the postsynaptic neuron and keep it from firing.

So certain anesthetics work by stimulating these GABA receptors or by increasing their sensitivity to GABA.

Moving on, there are two main phases in anesthesia: induction, which is when the patient enters the anesthetic state; and maintenance, when the anesthetic state is prolonged for as long as required.

Some anesthetics are better for induction, while others are better for maintenance.

Now, depending on how they’re administered, there are two classes of general anesthetics: parenteral and inhalational anesthetics.

Parenteral anesthetics are given by injection into a vein. They’re highly lipophilic agents that are commonly used for anesthetic induction in a single intravenous injection, although some of them, in special situations, can be used for maintenance by continuous intravenous infusion.

Once in the bloodstream, these medications travel through the body to highly lipophilic tissues that receive a lot of blood, like the brain and spinal cord. There, they can induce the anesthetic state.

After this, the medications diffuse back into the bloodstream, get metabolized by the liver, and then excreted by the kidneys.

Common parenteral anesthetics like thiopental, midazolam, propofol, and etomidate have similar properties as well as mechanisms of action, mainly stimulating GABA receptors or increasing their sensitivity to GABA.

They all have rapid onset, which means they start working within 20-30 seconds, but tend to have a shorter duration. So, they’re commonly used for induction of anesthesia and maintenance in short procedures like tracheal intubation.

Thiopental is a barbiturate and it causes cardiovascular depression, which can lead to hypotension and respiratory depression. It also decreases intracranial pressure so it can be used in people with traumatic brain injury.

Thiopental causes mast cells in the airways to release histamine, which causes bronchoconstriction; making it unsuitable for asthmatics.

It diffuses quickly into other tissues so the duration is very short.

Midazolam is a benzodiazepine and it has a slower onset than the other medications in this group, but a longer duration.

It causes less respiratory and cardiovascular depression than thiopental, but it can cause cognitive dysfunctions like amnesia; and postoperative respiratory depression, which can be reversed with flumazenil, a GABA antagonist.

Next, we have propofol which has a short duration, so recovery is faster, making it a good choice for outpatient surgery.

It’s preferred over thiopental since it doesn’t cause bronchoconstriction, but it does cause vasodilation and cardiovascular depression, which leads to hypotension.

However in rare cases, it can also inhibit mitochondrial fatty acid metabolism and cause propofol infusion syndrome, where the person experiences bradycardia, heart failure, metabolic acidosis, rhabdomyolysis, and enlarged or fatty liver.

Finally, etomidate is a medication that causes less cardiovascular depression, so it’s preferred for patients with coronary artery disease, cardiomyopathy, cerebral vascular disease, or hypovolemia; who are at greater risk for hypotension.

The downside is that it causes adrenal suppression.

Ketamine is quite different from other parenteral anesthetics.

First off, its main mechanism of action is blocking NMDA receptors.

It has a rapid onset but a longer duration than other parenteral anesthetics.

Ketamine increases cerebral blood flow and increases intracranial pressure.

It stimulates the sympathetic nervous system, which results in increased blood pressure and cardiac output, as well as dilation of the bronchi. So ketamine is suitable for patients at risk of hypotension and for asthmatics.

Ketamine causes a state called dissociative anesthesia, where the patient is not completely unconscious, they can breathe, open their eyes, swallow, and move involuntarily. Thankfully, they don’t remember the procedure or feel pain.

A disadvantage is that when the patient wakes up, they can have hallucinations or delusions for a short while.

Okay, now let’s switch gears and look at inhaled anesthetics.

Unlike parenteral agents, inhaled agents have a small therapeutic window, so the dose needed to produce the desired effect and the toxic dose are very close.

Inhaled anesthetics are gases or volatile liquids given through a mask or a tracheal tube for the patient to inhale. The anesthetic then goes from the alveoli of the lungs into the blood, and finally to different parts of the body.

When the anesthetic agent has a high lipid solubility, it accumulates over time in the body fat, increasing its potency.

On the other hand, inhaled anesthetics with high blood solubility will bind to blood proteins and tend to have slower onset and recovery.

Each one of the inhaled anesthetics is better suited for specific patients according to their side effects.

Let’s start with nitrous oxide, which acts as an NMDA receptor antagonist. It has a very low solubility in blood and lipids, so induction and recovery from anesthesia is rapid, but its effects are weaker.