Lithium

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Introduction0:00–0:25

Lithium is mainly used for the treatment of bipolar disorder, which is a mental health condition characterized by periods of lowered mood and depression, as well as periods of heightened mood and mania.
Although the mechanism of action is not well understood, lithium acts as a mood stabilizer that can smooth out the highs and lows they experience.

Pathophysiology0:25–2:15

All right. Almost everyone has ups and downs throughout their life.
They can feel happy on a sunny day or a bit down when it's raining outside. They might also have some extreme highs like when they meet the love of their life, and they might even have some pretty serious lows after losing a job or a person they were close to.
However, in bipolar disorder, which used to be called manic depression, the individual has dramatic shifts in emotions, mood, and energy levels involving extreme lows and extreme highs.
These shifts usually happen over several days or weeks. The low moods are identical to those in major depressive disorder, also known as unipolar depression.
Individuals with this feel hopeless and discouraged, have a lack of energy and mental focus, and have physical symptoms like eating and sleeping too much or too little.
But along with these lows, they have periods of high moods as well, which are called manic episodes or hypomanic episodes, depending on their level of severity.
In a manic state, people feel energetic, overly happy and optimistic, or even euphoric with really high self-esteem. And on the surface, these might seem like very positive characteristics, but when an individual is in a full manic episode, these symptoms can reach a dangerous extreme.
Patients experiencing mania can behave recklessly, they can have pressured speech, where they talk constantly at a rapid-fire pace, or they might have racing thoughts and feel as if they don't need sleep.
Manic episodes also include delusions of grandeur, for example, they might believe that they are on a personal mission from God, or that they have supernatural powers.

Mechanism of Action2:15–4:41

Now, the exact underlying cause of bipolar disorder isn't known, but it's thought that both genetic and environmental factors play a part.
Even though there's no cure for bipolar disorder, identifying and treating individuals is really important, since there's a real danger that the person could harm themselves or die by suicide.
One of the oldest treatments for bipolar disorder is also one of the most effective treatments, and that's lithium. It can be used as maintenance therapy to decrease the frequency and the magnitude of the ups and downs.
Lithium can also be used in the treatment of acute manic episodes, although the treatment of choice is antipsychotics. Apart from the treatment of bipolar disorder, lithium is also indicated for unipolar depression that doesn't respond to antidepressants.
OK, but the exact mechanism by which lithium acts still remains a mystery. It's thought that lithium regulates the release of neurotransmitters, which are signaling molecules in the brain like serotonin, that regulate a lot of brain functions like a person's mood.
Neurotransmitters are released by one neuron, the pre-synaptic neuron, and received by receptors on the post-synaptic neuron.
OK, let's zoom into a pre-synaptic neuron. Inositol is a cyclic sugar alcohol that is abundant in neurons and is the structural basis of some super important molecules.
Inositol is first phosphorylated to phosphatidylinositol or PI, which is then phosphorylated again to phosphatidylinositol 4 phosphate or PIP, and a third time to form phosphatidylinositol 45 bisphosphate or PIP2.
Next, a membrane-bound enzyme called phospholibase C or PLC splits PIP2 into inositol triphosphate or IP3, and dacyl glycerol or DAG.
IP3 is soluble and diffuses freely through the cytoplasm and into the endoplasmic reticulum, where it opens up calcium channels to release stored calcium into the cytoplasm.

Metabolism4:41–5:18

This increase in free intracellular calcium concentration helps to trigger the release of the neurotransmitters into the synaptic cleft.
All right, but we need to recycle the IP3 back to a nose atoll before it can be used again. So, IP3 isd phosphorylated to IP2, and then inositol polyphosphate phosphatase, or IPPasedhosphorylates IP2 to IP1, and inositol monophosphatase or IMPase dhosphorylates IP1 to inositol.

Side Effects5:18–7:17

Both of these enzymes need the cion magnesium as a cofactor in order to function. And the theory is that lithium inhibits these enzymes by displacing the magnesium.
This way, IP3 doesn't get recycled back into a nose at all, and we end up with decreased neurotransmitter release. OK, now lithium is taken orally, and it's absorbed rapidly from the gut.
It doesn't get metabolized by the liver, and it's almost exclusively excreted by the kidneys. It's important to note that lithium has a narrow therapeutic window, which means that there is a thin line between the safe dose and the toxic dose.
So lithium requires close monitoring of serum levels. For example, in patients with impaired renal function, or who take medications that reduce GFR like thiazides, NSAIDs, loop diuretics, and ACE inhibitors, lithium is not eliminated efficiently, and it's very easy to overdose.
All right, moving on to side effects. Common side effects of lithium are gastrointestinal symptoms like nausea, vomiting, diarrhea, and a mild tremor.
Lithium can also block two super important hormones in our body. In the kidneys, lithium blocks the effects of anti-diuretic hormone, or ADH.
ADH normally concentrates urine, so with lithium, the kidneys reabsorb too little water from the lumen of the renal tubules, causing the body to produce unusually large quantities of urine, which is called polyuria.
Since there's less water in the blood, plasma osmolarity increases, and that triggers thirst and causes an individual to drink a lot, which is called polydipsia.

Memory Palace7:17–8:34

This condition is called nephrogenic diabetes insipiditus. Now, in the thyroid gland, lithium blocks the effects of thyroid stimulating hormone or TSH.
TSH normally stimulates the thyroid gland to release the thyroid hormones. So when TSH is blocked, there's hypothyroidism, which presents with things like weight gain, cold sensitivity, slower heart rate, mental slowness, and constipation.
Surprisingly, hypothyroidism can also present with a goiter. This is due to reactive hypertrophy and hyperplasia of the thyroid gland, in an effort to compensate for the decrease in thyroid hormones.
Lithium also causes leukocytosis, or an increase in the white blood cell count, but there's no clear mechanism. Note that lithium is not safe to use during pregnancy, because it increases the risk of congenital heart defects like Epstein anomaly, which means that the leaflets of the tricuspid valve are abnormally located lower than normal into the right ventricle.
Finally, if the levels of lithium increase to toxic levels, they can cause acute renal failure, severe neurological symptoms like ataxia or poor coordination of muscle movements, confusion, dysarthria, or an inability to speak clearly, coma, and eventually death.

Review8:34–9:11

Now let's make a simple and fun mnemonic that will help you efficiently memorize these pharmacology facts. First, let's have a large lithium battery trying to break into a house.
He's stuck in the window, which represents this medication's narrow therapeutic window. For indications, a two-headed polar bear representing bipolar disorder is investigating this strange object.

Mind Map9:11–11:30

Ignoring the battery is a sad, crying man with a force field bouncing medications away for medication resistant major depressive disorder.
For the major side effects, let's have Einstein for Epstein anomaly. He's holding a baby wearing a heart t-shirt, to help you remember it's a congenital heart defect.
There are 3 leaves on Einstein's right pant cuff. To help you remember, the leaflets of the tricuspid valves are displaced downwards.
Next to them, we have a giant sippy cup for the baby, which represents diabetes insipidus. The cup is wearing a frozen bow tie for hypothyroidism.
A bunch of little white blood cells are trying to climb this side of the bottle to represent leukocytosis. Finally, for the dangerous side effects of an overdose, let's have a taxi that's driven by a brain crash through the wall by the window, which represents CNS toxicity and ataxia.
It hit and killed a kidney, since it can also cause acute renal failure. All right, as a quick recap.
Lithium is primarily used as a mood stabilizer for people with bipolar disorder. Lithium has a narrow therapeutic window, and requires close monitoring of blood levels.
Common side effects of lithium include GI symptoms, tremor, nephrogenic diabetes insipiditus, hypothyroidism, and leukocytosis.
Lithium also has teratogenic effects, and can cause congenital heart anomalies like Epstein anomaly. Lithium toxicity can lead to acute renal failure and severe CNS symptoms.
But wait, there's more. Here's a mind map with all of the mnemonics.
Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.