Classroom Lecture Immune Pharmacology Part 1
The Classroom Immune Lecture Part 1, you can complete the quizzes here https://residency.teachable.com/p/mobile
Find the book here: https://geni.us/iA22iZ
or here: https://www.audible.com/pd/B01FSR7HLE/?source_code=AUDFPWS0223189MWT-BK-ACX0-059486&ref=acx_bty_BK_ACX0_059486_rh_us
and subscribe to TonyPharmD YouTube Channel here: https://www.youtube.com/c/tonypharmd
Here is the Link to my Pharmacy Residency Courses: residency.teachable.com
Auto Generated Transcript:
All right, here we go with immune pharmacology one, and we're going to cover an introduction, penicillins, cephalosporins, but more specifically, we'll start with an antimicrobial introduction. Then antibiotics affecting cell walls like the penicillins, cephalosporins, vancomycin. Then go on to bacteriostatic protein synthesis inhibitors and bactericidal protein synthesis inhibitors. So let's get started with the antimicrobial introduction. One big separation between the bacteria are gram-positive versus the gram-negative, and Gram was a person, and he had a stain.
If it's gram-positive, then we expect there's a cell wall on the exterior. But if it's positive, that means the stain got through, and it doesn't have a second layer, or really, it's a third layer. Gram-negative means that it didn't take the stain. So it's really stained negative. We just shorten it to gram-negative, and the cell wall is covered by a peptidoglycan layer that's in orange. So I hate to say that gram-negative is harder to kill than gram-positive, but let's just say that gram-negative is more protected.
There are a number of targets that you would have with antimicrobials. You can target the cell wall, damage or disrupt the cell wall structure because humans don't have cell walls; they have cell membranes but not cell walls. You can use a DNA RNA synthesis inhibitor to prevent the creation of new DNA or RNA. You can use an anti-metabolite that prevents the usage of certain vitamins and minerals that we can take in through our food, but that bacteria have to make. You've got the protein synthesis inhibitor.
Protein synthesis, building proteins can be bacteriostatic, and static means that it keeps it from replicating but doesn't kill the bacteria. So it stops the proteins from being produced. It only slows the growth; it doesn't kill them. On the other hand, you can have a protein synthesis inhibitor that's bactericidal, and that stops the proteins from being produced, and it does kill the bacteria. But there are some issues with that as well. So the first thing you want to be able to do is match.
The target or the mechanism of action to actual antibiotics, and this is where it gets a little bit crazy. You can see how many drugs are on this slide. But let's go through the cell wall inhibitors. Amoxicillin and then amoxicillin with clavulanate to protect itself against beta-lactamase, and we'll talk about that later. But that's an enzyme bacteria produce to destroy the amoxicillin. Three cephalosporins, first generation cephalexin, third generation ceftriaxone, fourth-generation cefepime.
Vancomycin, which is not able to work against MRSA, doesn't have that beta-lactamase issue. DNA RNA synthesis inhibitors like ciprofloxacin and levofloxacin, these are the fluoroquinolones. An anti-metabolite like sulfamethoxazole with trimethoprim that affects folate, something we can take in through our food, the bacteria can't. Protein synthesis inhibitors, so these are bacteriostatic. Doxycycline, minocycline are both tetracyclines. Azithromycin, erythromycin, clarithromycin are all macrolides. Then clindamycin and linezolid in their own classes.
But the idea is that these drugs don't kill the bacteria, but they keep them from replicating. The immune system can come in and have a fighting chance. The protein synthesis inhibitor bactericidal, amino amikacin and gentamicin are both aminoglycosides, and we'll talk about those a little bit later. You would say, "Why don't you just use something that kills the bacteria instead of just affecting its growth?" But we also know that not only are the bad bacteria hurt but some of the good bacteria. So there are reasons to use either in different situations.
The other thing we want to look at is the spectrum. So the antimicrobial spectrum, when you have a broad-spectrum antimicrobial, it covers a lot of different microbes. It's the jack of all trades, master of none. A lot of times when they're not sure exactly what it is, you might get a broad spectrum. But then they should be doing testing to get a narrow spectrum, know exactly what it is. A narrow-spectrum antimicrobial would cover very specific types of microbes. They're very hard hitters, and it's preferred once the microbe type is known.
You can show up in hiking boots, but they may not be appropriate for the situation. And then you would change into heels if the situation calls for it. The same thing, the boot covers a lot, but it doesn't hurt a lot when someone is stepped on by it. But the heel covers very little, but it really hurts when someone steps on your toe with a heel because of the pounds per square inch. So hopefully, that's an analogy that's helpful to explain broad spectrum versus narrow-spectrum antibiotics.
Antimicrobial resistant mechanisms: There are four major mechanisms that you have. You reduce the drug concentrations at the site. You can alter the drug molecules. You can create an antagonist. Or you can inactivate the drug. So bacteria are able to make changes because while a human generation might be 20 or 30 years, a bacterial generation can be hours. So millions and millions of bacteria can form, and all these changes happen, giving some resistance and some of these abilities or resistance mechanisms.
A superinfection is a new infection that starts when you're treating a current one. Anyone that's taken an antibiotic and had gotten a yeast infection knows, okay, that's a superinfection. So "super" comes from Latin, which means "over and above." So just like a supervisor is above a subordinate, a superior is above someone that you're. So you would go to your superiors if you're going to your manager or something like that. The same thing is true here; it's over and above the original infection. So most commonly occurs after a broad spectrum antibiotic. So, for example, you're treating an ear infection with a broad-spectrum antibiotic, and one of the following develops: maybe a vaginal yeast infection, oral thrush, or Clostridium difficile, which can cause terrible diarrhea. Oral thrush and vaginal yeast infections are both candida infections.
MRSA or methicillin-resistant Staphylococcus aureus. This is resistant to penicillins and most cephalosporins because it can create altered PBPs or penicillin-binding proteins. So the antibiotics have a low affinity to these altered proteins, and it's a serious infection. I hate to use the word "strong" antibiotics, but maybe antibiotics that we reserve for these particular cases. And because fewer antibiotics work against MRSA, we try not to use them for other things as best as we can.
Antibiotics affecting the cell walls. So amoxicillin is our first example. It binds to the penicillin-binding protein on the bacterial cytoplasmic membrane. What does that mean in plain English? There's a protein on the bacteria that this binds to, and it keeps it from creating a new cell wall. So the cells, if they can't create these cell walls, then weaken, or they lyse or burst just like balloons. And these are most effective against gram-positive bacteria. So again, if it's gram-positive, that means that it doesn't have that extra layer. But bacteria have mutated to become resistant. One specific resistance that we'll talk about is the beta-lactamase enzyme that bacteria produce. So all penicillins and cephalosporins have what's called a beta-lactam ring. If you've had organic chemistry, you know exactly what this is. But it's just a chemical structure, and it's an important one because this is the target for resistance. So bacteria can create beta-lactamase. When you see "-ase" at the end, it might be an enzyme, which is, in this case, it is, and that changes the ring structure. It renders the medication useless. And what we do is we kind of add a bodyguard to amoxicillin. That bodyguard is clavulanate, and Augmentin just like it sounds, it augments amoxicillin by itself. And a beta-lactamase inhibitor is a compound to distract beta-lactamases, so the antibiotic is still effective. Clavulanic acid does basically a way to have the bacteria go after the clavulanate instead of the amoxicillin, and because of that, the amoxicillin can still be effective. You can see that in clavulanate; we have a beta-lactam ring very similar to the amoxicillin.
The next group of antibiotics is the cephalosporins, and they all have beta-lactam rings just like penicillins. They work the same as penicillins; they still inhibit cell wall synthesis, and there are five generations. So four of them that I'll go over are cephalexin, brand Keflex, ceftriaxone, Rocephin, cefepime, Maxipime, and ceftaroline, which is Teflaro. As we go up, and again this is in general, as we go to the fourth to the fifth things get a little weird. But three good things happen: we increase the coverage for gram-negative and anaerobic bacteria, we increase the resistance to beta-lactamases, and we increase the penetration into the CSF or the cerebrospinal fluid. As we go on, we can see that what kind of coverage do we have, and when we look at Keflex, we see we definitely have gram-positive coverage, but the gram-negative coverage is not that good, and we have no activity against MRSA. We go to the next; we see the gram coverage is a little bit weaker, and then no MRSA. But then as we get to the third generation, that was really the big change when we said, "Oh wow, we've got some better gram-negative coverage." We still don't have MRSA coverage, but it's getting better. Cefepime, Maxipime, we have very good gram-positive and gram-negative coverage, but not really with MRSA. And then ceftaroline, we don't have the greatest gram-negative coverage, but we do have MRSA coverage, and that's a big deal.
But that's the cephalosporins. Something we should talk about, though, are allergies. They're over-reported and poorly documented, but because we are a very litigious nation, that is, we have a lot of lawyers, there are a lot of issues in terms of as soon as somebody says penicillin allergy, put it in the chart. All of a sudden, they can never get a penicillin or a beta-lactam, even though more than 80 percent of "allergies" can be ruled out with objective measures like skin testing. So 95 percent of the patients with the allergy tolerate the penicillin, and 10 percent of all patients report a penicillin allergy. So what we see is that very few have this true allergy, and what's the big deal? Penicillin allergies are associated with worse health outcomes and increased costs. You have to use stronger and more toxic antibiotics instead of the penicillins. So we want to clarify the type of reaction that they have. Was it an intolerance?
So, like an adverse drug event, or was it a true allergy? If an intolerance, didn't remove it from the patient's profile. If an allergy, consider testing to confirm. So intolerance means, "Oh, my stomach kind of hurt a little bit." True allergies are usually forgotten by the body after 10 years. But again, it's a litigious nation we're in, and the concern is that someone's going to get sued. In terms of numbers, when we're looking at this, it becomes kind of a muddled mess. But really, if you're looking at penicillins and cephalosporins, the penicillin-cephalosporin cross-reactivity is a common concern because they're the most used. But if you want to break it down, a patient has a true penicillin allergy, they have less than a five percent chance of being allergic to cephalosporins. If they have a true allergy, they have a one to five percent chance of being allergic to penicillins. So again, caveat emptor. You just have to be careful with this. But the truth is that for most patients, it would be better for them to use a penicillin, and unfortunately, the allergy is misreported.
So antibiotics glycopeptide, vancomycin or Vancocin. This is a huge molecule relative to the other antibiotics. It doesn't have a beta-lactam ring, so beta-lactamases don't do anything to it. And it doesn't bind to the penicillin-binding proteins. Rather, it works by binding to these kinds of bricks that are used to make the cell walls. It's the drug of choice for MRSA or methicillin-resistant Staph aureus and C-diff or Clostridium difficile. But we want to save it for severe infections. There's usually probably a vancomycin protocol that says this is when you can use it, this is when you don't. We don't want to get resistance at this hospital or wherever we are. As far as drug monitoring, we want to be very careful because if we go too high, then the patient can become nephrotoxic, damage to their kidneys, or ototoxic, damage to their ears. But go too low, then it's not effective, and the infection is still active. So we dose it based on levels at the highest and lowest points. It can also cause red man syndrome where the skin turns red all over, so we use a very slow infusion time of 60 minutes to prevent that particular issue.
In the next group, we want to go over the bacteriostatic protein synthesis inhibitors, and let's make clear the difference between bacteriostatic and bactericidal. So bacteriostatic means that we're suppressing bacterial growth and replication, and the body's immune system is required to fully eliminate the infecting bacteria. We didn't kill the bacteria, but in some way, we've stopped its growth or slowed its growth. Bactericidal, on the other hand, just like homicidal is killing a person, suicidal is one who kills themselves, bacteriocidal is killing a bacterium. So killing the bacteria outright, the body's immune system is not required for bacterial elimination. But these are often a bit more toxic.
We'll refer back to this train analogy with bacteriostatic inhibitors and bacterial ribosomes. There are two subunits, the 50s, which we can think of as the train station, and the 30s, which we can think of like the parking lot, and then the peptide chain, which is the train. So macrolides and lincosamides would work on the train station, oxazolidinones would work on the train, and then the tetracyclines would work on the parking lot. And we'll see how this is as we go through these.
So let's start with the first bacteriostatic class, the tetracyclines. Minocycline, brand Minocin, and doxycycline, brand Doryx. They bind to that 30s ribosomal subunit, and they prevent the binding of transfer RNA to messenger RNA. So people can't get out of the parking lot; the peptide chain's production is halted, and the train can't leave the station without the passengers. Is there MRSA coverage? Yes, it's not the best, but again, it does have some coverage. The issue with the tetracyclines is binding and forming these insoluble complexes or chelating with aluminum, calcium, iron, magnesium, or zinc. Where we find these are dairy and calcium supplements, calcium, for example, iron supplements, obviously, iron, and then antacids, which can contain aluminum, calcium, or magnesium. So take one hour before or two hours after meals. Of course, antacids are always used after a meal, so that would be after meals only. Adverse drug reactions, you could get a yellow-brown tooth discoloration that's lifelong, so we avoid it in pregnancies, avoiding children under eight. The only way to really fix that discoloration is to cover it up with veneers.
Bacteriostatic macrolides. So we've got azithromycin, brand Zithromax, clarithromycin, brand Biaxin, erythromycin, brand E-mycin. So you bind to the 50s ribosomal subunit, which is the train station in this case. We prevent the amino acids from adding to the peptide, and passengers can't get on the train. So erythromycin, though, is a SIP 450 inhibitor, which leads to lots of drug interactions, whereas azithromycin and clarithromycin are a bit safer. The other issue is that really erythromycin, you have to take four times a day. Clarithromycin even twice a day, that's where the Biaxin name comes from. And then azithromycin is nice because you only take it once a day.
So we see that compliance, or how often the patient takes their medicine as they should, is much better with Z-pak than the others. And again, QT prolongation isn't also an issue.
Clindamycin or Cleocin is a lincosamide. This binds to the 50s subunit, prevents protein synthesis. Again, passengers can't get onto the train. It's more associated with toxicity than it is therapeutically. So C diff or Clostridium difficile-associated diarrhea. You can get a superinfection of the bowel. So we want to use it for the least amount of time. But a lot of times, you'll see this dermatologically for acne and things like that. So much safer dermatologically than it is orally.
Linezolid or Zyvox. This binds to the 50s subunit, prevents the formation of the initiation complex. So it prevents the train from coming into the station. It's a unique mechanism. It prevents that initiation complex and it leads to little resistance. So it interacts with SSRIs and SNRIs, those antidepressant classes, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, potentially causing serotonin syndrome. But it does have MRSA coverage. Not only does it have MRSA coverage, but also VRE coverage, which is vancomycin-resistant enterococcus due to a lack of resistance.
Bactericidal protein synthesis inhibitors. So now we're moving from bacteriostatic to bactericidal. We're going to kill the bacteria rather than prevent their or delay their growth. And so, again, we're working in that parking lot, the 30s subunit.
The two bactericidal aminoglycoside drugs that I'll go over are amikacin, brand Amikin, and gentamicin, brand Garamycin. So bacteriocidal drugs work against gram-negative aerobes. It binds to the 30s subunits and causes three different things: either it inhibits protein synthesis (the train can't leave the station), it prematurely terminates the protein synthesis (train departure is canceled), or the production of abnormal proteins where the wrong train leaves the station. So those are the three ways that it can work against these gram-negative aerobes. However, we have to really, really monitor these because of the two main toxicities. You've got nephrotoxicity and permanent kidney damage, and ototoxicity.
Kind of said two things at once there. On the left side is nephrotoxicity. It can increase kidney damage. And then on the right is ototoxicity with the hearing damage and potential balance issues. Both are produced by high trough levels over time. So thinking of the peak where the top of the concentration and the trough is the bottom. If the bottom is too high, then we haven't let it wash out enough, and that's where the toxicity comes from. It's just too high a concentration for too long.
The DNA RNA synthesis inhibitors. So the examples we'll use are the fluoroquinolones, and we'll get to the actual drugs in a sec. But enzymes coil and uncoil bacterial DNA for replication. So fluoroquinolones inhibit that process with DNA gyrase and topoisomerase IV. So you've got relaxed DNA, which is ready for replication, and supercoiled DNA, which is ready for storage. Remember S for storage.
So the two examples we have are ciprofloxacin, which is brand Cipro, and levofloxacin, which is Levaquin. They're broad-spectrum antibiotics, and the ADRs include phototoxicity, which is burning in the sun much quicker or even in a tanning bed, confusion, superinfections like a fungal infection, and then rare but serious is the concern about tendon rupture. So if any time you have somebody that their tendon is getting warm or they're just feeling it's not right, definitely watch out there. The administration, just like those tetracyclines, we've got to watch the dairy, calcium, plus vitamins like zinc and iron, and then the antacids like aluminum, calcium, and magnesium. We saw that chelation interaction just like the tetracyclines.
And then some of the miscellaneous antibiotics, they just didn't really fit neatly into the other class, but one are those that are anti-metabolites. And metabolites are just a fancy way of saying what comes out at the end. So cells require folate for DNA, RNA, and protein production. And mammals can eat food with folate, but bacteria cannot. So we can target this folate production as our prime target, and we make sure that it doesn't happen.
So PABA is used to make folate. It's the building block. And sulfamethoxazole, you can see, looks an awful lot like PABA. So sulfamethoxazole gets used instead of the PABA by the bacteria because it is similar in structure. And the result is that it stops production of folate. You've got to watch out though for sun sensitivity with sulfamethoxazole and trimethoprim, or brand Bactrim. You'll notice that Bactrim is just a shortening of bacterium. They both work to prevent folate from being used to create more DNA and RNA and proteins.
Serious adverse drug reactions include Stevens-Johnson syndrome, hemolytic anemia, kernicterus, bilirubin in the brain, crystalluria, and renal damage. But it does have some MRSA coverage.
The last one are the nitroimidazoles, brand Flagyl, or metronidazole, brand Flagyl. It's a unique antibiotic. It's only effective for obligate anaerobic bacteria. It has to be activated, so there's a structural change to be effective. It's only done by obligate anaerobes and causes DNA strand breaks, microbe death. So it causes extreme vomiting if mixed with alcohol. So we want to make sure to let patients know 24 hours before, 24 hours after, don't take this with any kind of alcohol. And that doesn't have to be a beverage like a beer or wine. It can also be the alcohol that's in certain mouthwashes and things like that. So I need to be careful with alcohol and metronidazole.
Like to learn more?
Find my book here: https://geni.us/iA22iZ
or here: https://www.audible.com/pd/B01FSR7HLE/?source_code=AUDFPWS0223189MWT-BK-ACX0-059486&ref=acx_bty_BK_ACX0_059486_rh_us
and subscribe to my YouTube Channel TonyPharmD here: https://www.youtube.com/c/tonypharmd
Here is the Link to my Pharmacy Residency Courses: residency.teachable.com
