Antimetabolites: Sulfonamides and trimethoprim

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Introduction0:00–1:05

Antimetabolites are medications that interfere with the synthesis of DNA. Some antimetabolites are used in chemotherapy to kill cancer cells, while others are used as antibiotics since they inhibit bacterial folate synthesis.
Folate, or folic acid, also known as vitamin B9, is necessary for the synthesis of nucleic acids, which are the building blocks of DNA and RNA.
Simply put, a lack of folate results in a lack of nucleic acids, which then results in decreased DNA and RNA synthesis, leading to hindered cell division and function.
Now, a key difference between our cells and bacterial cells is that we get all of our folate through our diet, while bacteria can make their own folate from scratch.
Because of this, we can target the bacterial folate synthesis pathway to minimize the damage done to our cells. So in order to synthesize folate, the bacteria will first use the host’s para-aminobenzoic acid, or pABA, and convert it to dihydropteroic acid via the enzyme dihydropteroate synthetase, or DHPS.

Pathophysiology1:05–1:59

In the second step, dihydropteroic acid is converted into dihydrofolic acid by dihydrofolate synthetase. The third step is the conversion of dihydrofolic acid into tetrahydrofolic acid via dihydrofolate reductase.
Tetrahydrofolic acid is a folic acid derivative and can be used to synthesize purines like adenine and guanine, which are used to build DNA and RNA, as well as thymidine, which is only used in DNA.
Now, the first group of antimetabolite antibiotics are the sulfonamides, which include sulfamethoxazole, or SMX, sulfisoxazole, and sulfadiazine.

Sulfonamides1:59–2:43

These medications bind to dihydropteroate synthetase, or DHPS, in the first step of folate synthesis and prevents the bacteria from making dihydropteroic acid.
These medications can be given peroral or injected into a vein, but they need to be metabolized by the liver in order to work.
Now, they are broad spectrum and can treat a variety of gram positive and gram negative bacteria, as well as chlamydia and nocardia species.

Trimethoprim2:43–4:34

Next we have trimethoprim, which inhibits the 3rd step of folate synthesis by inhibiting dihydrofolate reductase, or DHFR, preventing the formation of tetrahydrofolic acid.
Now humans also have dihydrofolate reductase, but the bacterial version of this enzyme is 4-5 times more sensitive to this medication.
Trimethoprim is also broad spectrum and is effective against both gram positive and gram negative bacteria. Now, it’s mainly used in combination with sulfamethoxazole.
The combination of these medications is called TMP/SMX. These medications are used together because they are synergistic and can block folate synthesis at two key steps.
When used alone, both medications are bacteriostatic, meaning they can stop the bacteria from reproducing. But when combined, they are bactericidal, meaning they will kill off the bacteria.
TMP/SMX is most commonly used to treat traveler's diarrhea and simple urinary tract infections, but it’s also effective in treating pneumonia and sinus infections caused by haemophilus influenzae and moraxella catarrhalis.
It’s the first line therapy for the treatment and prevention of pneumocystis jirovecii infections, which are caused by a yeast-like fungus that can affect immunocompromised people.
Finally, it’s effective against Methicillin Resistant Staph. Aureus, or MRSA.
A few bacteria exist that are notably not susceptible to antimetabolites, and those are Pseudomonas aeruginosa and bacteria from the Mycoplasma family.

Side effects4:34–6:37

Okay for side effects, some people are allergic to sulfonamide and can develop a hypersensitivity reaction to these antibiotics.
They can also develop a cross reaction with other drugs that contain the sulfonamide functional group such as glyburide, a diabetic medication, and thiazide diuretics.
Sulfonamides can also cause nonspecific gastrointestinal disturbances such as nausea and photosensitivity, or increased sensitivity to sunlight.
In the kidneys, they can precipitate as crystals in the urine causing crystalluria and nephritis. In rare cases, life threatening conditions such as Stevens-Johnson syndrome, or SJS, and fulminant hepatic necrosis, can occur.
Finally, in people with G6PD deficiency, they can cause hemolytic anemia. This medication can bind to albumin and prevent bilirubin from binding, which leads to increased plasma bilirubin levels, leading to kernicterus and jaundice in neonates.
Trimethoprim on the other hand, also inhibits dihydrofolate reductase found in humans. This matters the most to cells that are rapidly dividing, like the ones found in our bone marrow.
So it can cause bone marrow suppression, which results in megaloblastic anemia, leukopenia, and granulocytopenia. This problem can be fixed by giving folic acid supplements.
Another problem is that trimethoprim is teratogenic and can cause neural tube defects in babies. Both trimethoprim and sulfonamides are cytochrome p450 inhibitors, so they can increase the plasma level of drugs that are broken down by it, like warfarin.
To make things worse, sulfonamides can bind to the proteins that also bind to warfarin, which increases its plasma concentration even more!
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! So let’s start with a hot spring which smells like sulfur for the sulfonamides.

Memory palace6:37–9:35

Next there’s a temple for TMP, which is further down the road. In the middle, between the two, there’s a signpost that says TMP/SMX.
For the sulfonamides, let’s put a pair of socks in the sulfur hot spring. One of the socks has a “M” on it for sulfamethoxazole and the other represents sulfisoxazole.
Sulfadiazine will be a diamond floating on the water. At the edge of the water, let’s have some purple gram positive and pink gram negative bacterias crawling around, to help you remember sulfonamides are effective against both.
A giant clam is also there for chlamydia, and instead of a pearl, it has a blackened shriveled heart inside, for nocardia.
The trimethoprim temple also has the pink and purple bacteria crawling around since it’s also effective against both. Okay, for TMP/SMX, let’s have a toilet and a urinal by the sign, since it’s used to treat urinary tract infection and traveller’s diarrhea.
One of the travellers is holding a pair of balloons that look like a pair of lungs. One of the lungs has a bunch of cysts on it for pneumocystis jirovecii, while the other has a big nose on it for pneumonia and sinus infections.
This person is riding on a Mars rover to help you remember TMP/SMX is effective against MRSA. Okay, for side effects, the sulfur spring is rather dirty, and the person soaking in it has developed a bad rash to represent the hypersensitivity reaction.
He also found a large kidney with crystals growing out of it for crystalluria. The other occupant is a 2 headed zombie named Steve and John for Stevens-Johnson syndrome.
Steve has a bottle of sunscreen to represent photosensitivity, while John is eating a liver to represent hepatotoxicity.
The next person is an infant whose head is sticking out of the water. His big eyes are a weird yellow color to help you remember these medications can cause jaundice and kernicterus in neonates.
Finally let’s put some cut-up red blood cells in the water, along with little flags that say G-6, like the G6 in the European union.
This will help you remember that hemolysis can occur in people with G6PD deficiency. Next, by the temple, there’s a pile of broken bones for bone marrow suppression.
A pregnant mother who came to pray is disappointed at how unkempt this temple is, which represents contraindication during pregnancy.
Finally let’s put a dead chrome colored cell in the sulfur pool and another on the pile of bones, since both medications inhibit cytochrome p450.
All right, as a quick recap. Sulfonamides and trimethoprim are both antimetabolite antibiotics that inhibit the synthesis of folic acid.

Review9:35–10:13

Sulfonamides like sulfamethoxazole inhibits DHPS while trimethoprim inhibits DHFR. They are often used together as TMP/SMX due to their synergistic effect against gram positive and negative bacteria, pneumocystis jirovecii, and even MRSA.
Its main uses include the treatment of urinary tract infections, diarrhea, pneumonia, and sinus infections. But wait, there's more: Here's a mind map with all of the mnemonics from the video.

Mind map10:13–10:26

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers at the end.