General anesthetics

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Introduction0:00–0:41

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.

Pathophysiology0:41–2:02

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 Anesthetics2:02–3:07

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.

Thiopental3:07–3:35

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.

Midazolam3:35–3:58

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.

Propofol3:58–4:54

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.

Ketamine4:54–5:49

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 Anesthetics5:49–6:39

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.

Nitrous Oxide6:39–8:01

It has a very low solubility in blood and lipids, so induction and recovery from anesthesia is rapid, but its effects are weaker.
So in order to achieve anesthesia on its own, the patient needs to inhale pure nitrous oxide, which is unsafe, since it means they are not getting any oxygen.
However, at lower concentrations, nitrous oxide has an analgesic effect, so it’s used in dentistry. Now, nitrous oxide also has a “second gas effect”, which means when combined with other anesthetics, it lowers the therapeutic dose required for the other agents.
It’s important to keep in mind that the respiratory system normally responds to hypoxia by increasing the respiratory rate, but nitrous oxide diminishes this response.
As a result, it’s hard to notice hypoxia, because we don’t have signs like tachypnea. That’s why it’s important to monitor arterial oxygen saturation at all times.
In addition, nitrous oxide can cause expansion of trapped gases in closed body cavities, so its use is contraindicated for people with pneumothorax and bowel obstructions.
But the silver lining is nitrous oxide is the only inhaled anesthetic that doesn’t cause malignant hyperthermia, which is an important side effect we’ll talk about later.
Next, we have the halogenated inhalational anesthetics and their suffix is “-ane.” Common medications in this class include halothane, enflurane, methoxyflurane, and desflurane.

Halogenated Anesthetics8:01–10:05

These act as NMDA receptor antagonists, but also as GABA receptor agonists. Induction and recovery from anesthesia can vary, since these medications have different blood solubility, but they are more tissue-soluble than nitrous oxide, so they are more potent, and can induce anesthesia.
These medications all cause vasodilation, cardiovascular depression, and respiratory depression. Just like nitrous oxide, they blunt the sympathetic response to hypoxia, so it’s important to monitor arterial oxygen saturation.
Finally, these medications increase the blood flow to the brain, which can lead to increased intracranial pressure. Okay, let’s go over each medication!
Halothane dilates the airways, so it can be used in asthmatics. However, halothane is no longer used in developed countries like the U.S.
due to its severe, and sometimes fatal, hepatotoxicity. Methoxyflurane is also not widely used anymore since it causes nephrotoxicity.
Desflurane has a pungent, musty smell, and can cause airway irritation, leading to coughing, so it’s not used as an induction agent.
Enflurane on the other hand, lowers the seizure threshold, so it’s contraindicated in people with epilepsy. Okay, one last side effect shared by all halogenated anesthetics is that they can cause a life-threatening condition called malignant hyperthermia, where the anesthetic agents cause increased release of calcium stored in muscle cells, causing them to contract without resting and generate heat.
This is especially true in people with a mutation in the RYR1 gene that makes them more susceptible. Symptoms include muscle rigidity, rhabdomyolysis, hyperthermia, metabolic acidosis, and tachycardia.
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts! Let’s start with a river stream, where we’ll put the parenteral anesthetics that go into the blood, and a field of fragrant flowers where we’ll put the inhaled anesthetics.

Memory palace10:05–14:27

So by the river, there’s a dazzling maiden for midazolam, and she’s throwing flower petals into the river for thiopental.
She has many suiter and one of them is a folk singer who’s proposing to her through song, which represents propofol. Next, there is a young man named Tom, who’s holding up a sign that says “will you go on a date with me?” He represents Etomidate.
Let’s have the lady stand on a pile of garbage so you know this group of medications all work on GABA receptors. Standing farther away there’s a man who’s ignoring her so he can focus on training his karate moves, and he represents ketamine.
He’s got a bindle since he’s a nomad to help you remember the fact that ketamine works on the NMDA receptor. Okay, for side effects and contraindications, let’s put the maiden’s heart in a big block of ice, so this way you know that she and the drugs around her, like thiopental, propofol, and etomidate cause cardiovascular depression, which can lead to hypotension.
Etomidate is further away from her so it has less cardiovascular depression compared to the others, and ketamine isn’t interested in her, so it doesn’t have this side effect at all.
Now there’s an asthma inhaler in the river with the flower petals to help you remember thiopental can trigger asthma attacks.
The maiden has a breathing mask for postoperative respiratory depression, and she’s got a question mark above her head since she tends to forget her suiter’s names, which represents amnesia.
For propofol, let’s have a giant liver with a piece of butter on it to help remind you of propofol infusion syndrome, which decreases fatty acid metabolism and leads to a fatty enlarged liver.
Next, Ketamine causes delusions and hallucinations, so let’s have the karate man train against an imaginary opponent. Okay, let’s move to the field of flowers for the inhaled anesthetics.
There’s a big block of ice in the middle of the field and there’s a pair of lungs and a heart inside to help you remember that all the inhaled anesthetics cause cardiovascular and respiratory depression.
For the specific drugs, let’s start with a dentist with a tank of nitrous oxide, and he’s working on a nomad with a bindle since this drug works by inhibiting NMDA receptors.
The tank has a tube that connects to another gas tank with the number “2” on it, to help you remember it can be mixed with other inhaled anesthetics for the “second gas effect.” Next, another tube from the tank is connected to a balloon, and this balloon popped, which represents the expansion of trapped gases and its contraindication in people with pneumothorax.
Okay moving on to the halogenated anesthetics. So let’s have an angel with a halo for halothane, and she’s holding a rotting liver to represent the hepatotoxicity.
She’s riding on a meaty looking ox for methoxyflurane, and this ox is chewing on a rotting kidney for renal toxicity. Now, she’s riding on an ox because her car had engine failure for enflurane, and it’s shaking violently to help you remember enflurane can lower the seizure threshold.
The car broke down in a patch of sand that looks a little like a desert for desflurane. There’s an animal skull in the sand that’s giving off an awful smell to represent the pungent odor, and there’s a coughing vulture next to it which represents airway irritation.
Both factors make desflurane unsuitable for initiating anesthesia. Okay, behind these four drugs, let’s put a pile of garbage with a bindle sticking out from the top, since halogenated anesthetics work on both GABA and NMDA receptors.
Next, let’s set the entire pile on fire to help you remember they also cause malignant hyperthermia. The dentist has a fire extinguisher next to him since nitrous oxide is the only inhaled anesthetic that doesn’t have this side effect.
All right, as a quick recap… General anesthetics are medications used to produce induction or maintenance of the anesthetic state.

Review14:27–15:06

The role of general anesthetics is to depress the central nervous system by depressing excitatory synapses or stimulating inhibitory synapses.
Depending on how anesthetics are administered, there are two classes of general anesthetics: parenteral anesthetics, which include thiopental, propofol, etomidate, and ketamine; and inhalational anesthetics, which include nitrous oxide and different halogenated compounds like halothane, isoflurane, sevoflurane, and desflurane.
But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.

Mind map15:06–15:33

Stay tuned for the answers at the end.