We have many agents used to treat Mycobacterium tuberculosis.
We have the first line agents, we have other TB agents and we have some new agents.
We'll go over them in some detail.
Now, let's start with isoniazid, and you'll see that we have letter designations or codes that we use.
And they were very popular probably a few years ago.
They're falling out of favor now because there's so many drugs.
There's so many abbreviations and there's a tendency to get them mixed up.
Isoniazid is similar to pyridoxine or vitamin B6.
It is a prodrug which means that the bacteria itself converts it into the active drug.
Now, what we want to do with isoniazid
is we wanna inhibit cell wall production of the Mycobacterium species.
So just like a penicillin will and other bacteria, isoniazid works this way in a Mycobacterium.
In fact we sometimes call isoniazid, the penicillin of the anti-TB drugs.
It is bacteriocidal.
Now, when we have bacteriocidal medications and we give it to organisms that are slow-growing,
they may not be as effective in terms of therapy.
So we have to add other agents to really improve the effectiveness of the therapy.
Therapeutic concentrations have to be achieved in multiple tissues,
so we need to have blood levels that reach therapeutic concentrations in the serum,
in the cerebrospinal fluid, and even in things like caseating granuloma in the lung.
So, you can see how using a medication isn't just about achieving good blood levels,
it's about getting to where the disease is at.
If a person has central TB or if a person has TB and a caseating granuloma,
just giving drugs to a certain therapeutic level in the blood isn't enough.
Now, the metabolism of isoniazid is actually quite interesting.
Isoniazid needs to be acetylated and it's acetylated into its active form.
There are two forms of the enzyme in any given population.
So when we look at the EC50 of a population, there -
it actually has a bimodal distribution on the effectiveness curve.
So there are people who are fast metabolizers.
They fit under that first bump on the curved there. Theyâ€™re fast metabolizers.
Their serum concentrations peak at an hour.
There's another group of people who are slow metabolizers of this drug
and they will actually peak at three hours.
If you wanna go over that concepts between fast and slow metabolizers,
go back to the original pharmacology lectures looking at pharmacokinetics
and you'll see what we're talking about.
Isoniazid resistance is a real problem,
in fact it's a problem with all of the anti-TB drugs.
Resistance can be very rapid if you don't use isoniazid in combination with other medications.
This is why we use multidrug regiments.
Now, how resistance occurs, it's due to a point mutation in the genome of the bacteria
that code for those critical enzymes that make isoniazid an active drug.
So if you think about it, if the bacteria is dormant, this drug isn't going to work
because it's not going to become activated.
So this is an important consideration that we have to have when you're using INH.
Toxicity is very common with this drug.
Up to 20% or one in five people will have some sort of neurotoxicity
associated with the symptoms with this drug.
I've often seen patients complain of paresthesia which is a fairly mild form of neurotoxicity.
Hepatotoxicity is common. You can have psychiatric problems.
You can have vitamin B6 related problems and G6PD issues as well.
So let's go into each of those a little bit more detail.
In terms of neurotoxicity, they can manifest in many different ways.
You can have a restless leg. You can have a peripheral neuritis which is actually quite painful.
And you treat these with pyridoxine which is actually vitamin B6.
The hepatotoxicity can be quite problematic
and in fact, we've actually seen rare cases of fulminant hepatitis
where people are running the risk of actually dying from the hepatitis due to the drug.
Often, we'll see abnormal liver function tests.
10 to 20% of all of our patients are going to have some kind of an abnormality to this drug with -
in terms of their liver function.
We often will see jaundice in patients
and we'll sometimes see a hepatomegaly in long-term treatment of patients.
Psychiatric problems are also common.
Patients who are on isoniazid often have a suicidal risk,
and depression can be particularly harmful to these individuals.
We also see other kinds of psychiatric issues like a poor memory, poor mental function,
poor mental concentration and sometimes,
even just the idea of taking part in a drug regimen is quite off putting to these patients.
So the actual drug reduces the patients desire to be compliant with their therapy.
You can see where the problem comes from that.
Vitamin B6 depletion is a concern in patients around INH,
so of course we need to replete vitamin B6.
The vitamin B6 maybe the cause of the suicide risk that we were talking about before
and maybe a cause of the poor memory.
But also the vitamin B6 is important because of the peripheral neurological function as well.
So when I put vitamin B6 as a different category,
it kind of matches up with the neurotoxicity and the psychiatric toxicity of this medication.
But I put it separately because we're not entirely sure
that all of the neurological or psychiatric side effects of this drug are necessarily due to vitamin B6 depletion.
I wanna talk now about G6PD deficiency.
Glucose-6-phosphate deficiency is a disease that you will read about and you will come across.
And in some areas of the world like in India, it's actually quite common.
It is the most common enzymopathy with over 400 million people around the world affected by this particular problem.
Now the issue is with these G6PD patients is that isoniazid can actually trigger hemolysis.
And what we want to be aware of is the particular interaction between isoniazid
and that particular disease.
Patients with a severe form called non-spherocytic hemolytic anemia
are particularly prone to this problem with INH.
The most well-known of the micro bacterial agents is rifampin.
Rifampin is an inhibitor of DNA -dependent RNA polymerases.
But we can also remember rifampin from our earlier lectures
as being the prototypical Cytochrome inducer.
So obviously, this drug is responsible for a lot of drug interactions.
I spoke briefly about the resistance to this particular medication
and it's important in using multiple drug therapies.
In terms of how that resistance occurs,
it's usually because the polymerase itself somehow doesn't bind to the drug.
Or there's changing in the drug binding pharmacokinetics of the polymerase and the rifampin.
Toxicity. Toxicity is always a concern with rifampin mostly itâ€™s due to drug interactions
but also, the drug itself can be associated with light chain proteinuria
that can be associated with skin rash, it can be associated with thrombocytopenias,
it can be associated with nephritis and it can also be associated with certain types of liver dysfunction.
Let's move on to ethambutol. Ethambutol is a bacteriostatic drug,
so remember that this is a drug that is going to stop the division and growth of this medication - of this bacteria.
It is not going to kill the bacteria that are already alive.
And it does so by cell wall production inhibition.
Now specifically in the cell wall, it inhibits this enzyme.
Now, arabinogalactan is a component of all cell walls.
If you inhibit the transferase, you have increased permeability of that cell wall, of the bacteria.
And so it becomes very brittle and you end up having depolarization of the cell
or you're gonna have breakup of the cell. It this very well absorbed.
As a drug, it's excreted in the urine.
We're always giving it in combination with other anti-TB agents just like rifampin and others.
In terms of the toxicity of this medication; neurological, you get visual disturbances
and itâ€™s a kind of an interesting visual disturbance.
Specifically, you will get a red/green color blindness.
So your ability to distinguish between red and green is impaired
and you can only really pick it up in rare instances without doing a detailed red/green vision test.
Sometimes you can get an optic neuritis and you can actually get retinal damage.
So it's important to look in the eyes of every patient that is on ethambutol.
Now, a very common side effect of this medication is headache.
I see patients with this all the time. Sometimes patients can also be quite confused by it.
A metabolic issue that we sometimes see is hyperuricemia.
And finally, you can also get a peripheral neuritis with ethambutol which is very simple -
similar to the peripheral neuritis you get with other TB drugs.
Finally, we can talk about pyrazinamide.
Now it's always, again given in combination with other medications.
It's well absorbed. It crosses inflamed tissues as well.
So if you have a meningitis, you can still give pyrazinamide,
it will cross that inflamed meninges which is very handle - handy for a TB meningitis.
It's an essential part of treating bacterial tuberculosis meningitis.
So this is going to be an important exam question.
If you have a TB patient on your exam and they have bacterial -
pardon me, tuberculosis meningitis, really think about making sure that this drug is in part -
is in your armamentarium.
Again, like the previous drug, it's excreted in urine. It's removed by hemodialysis.
The half-life is really changed, it's increased in patients who have renal failures.
So remember that this is a renally excreted drug, it's excreted through hemodialysis.
Now, liver failure can also increase the half-life of this medication,
so you have to keep that in mind in people who have any kind of hepatitis.
How does this drug work? It's kind of a unique mechanism of action.
Now inside the Mycobacterium organism, there's an enzyme that converts pyrazinamide into pyrazinoic acid.
Okay. Now, at low pHs, at a pH of say, five or six that pyrazinoic acid leaks out of the organism
and it gets protonated. Okay? So go back to your old lectures on pH and PKA
and just try and understand what's going on here.
It crosses the membrane back into the bacterium at this acid pH.
Now, the more acidic the tissue, the more concentrated the intracellular amount of pyrazinoic acid becomes.
So the agent is actually more effective against bacteria that are existing in an acidic environment.
Now in terms of your toxicity, one of the common problems
that we see with this drug is non-gauty polyarthralgist.
Patients will complain of joint pains.
It seems like - initially, you think that it's kind of a gout kind of sensation
because a lot of people will complain of ankle and toe pain.
But you'll start to realize that it is migratory.
Sometimes you'll get enlarged joints, sometimes you'll get it in the hands.
People will also have an asymptomatic hyperuricemia.
This makes it very hard to diagnose what is going on
because if you assume that the toe pain that they're complaining of is gout in this situation,
you could be quite wrong. Myalgias and rashes can occur.
Hepatic dysfunction with porphyria can occur with this drug.
And finally, this medication is not safe in pregnancy.
Remember, because it's interfering with normal metabolism of a growing fetus
and because it's crossing barriers so well, you have avoid this medication
because it can cause fetal abnormalities.
How do bacteria become resistant to the pyrazinimide?
If the bacteria has a change in this particular gene mentioned here,
there are changes in the enzymatic activity within the bacterial cell.
And that reduces the conversion into that pyrazinoic acid,
and therefore you don't have as much active drug. This happens in about 16% of all cases.
And in patients who have multidrug-resistant TB or MDR-TB,
60% of people are resistant to pyrazinimide.