Pharmacology/Anesthesia Question - 101

[doctor712]

Was reading a cool case on NEJM because I found out my post-bac school allows me to log into the journal for free. Here's the important paragraph from the case, I quote:

"...Because of this patient's renal dysfunction, she was not a candidate for high-dose systemic methotrexate, which crosses the blood–brain barrier and is the backbone of treatment for lymphoma involving the nervous system..." (The paragraph went onto read that the patient's cancer was treated with radiation therapy in lieu methotrexate...)

So, my question is as follows:

Caveat first: Please keep in mind my point of learning in all this...pre med. To those who know me, you'll respond accordingly because you know my level of interest and observing experience with anesthesia. To those who hate these neophyte questions, let's keep this thread full of . You never know what comes of a question, maybe a nice discussion...

Question:

If this drug crosses the blood-brain barrier, when others don't, are there contraindications in using certain anesthetics in the presence of Methotrexate, or other drugs that cross the barrier? My (insane perhaps) hypothesis is that if this molecule crosses, then couldn't it, in theory, act as an enzyme that piggy backs other molecules across with it, molecules that wouldn't normally cross? Molecules/meds that you would not want to cross and have a greater than normal, or less than normal, effect?

Just askin'. Curious. And when do you learn this stuff? M1? M2? PGY-1? CA-1?

Thanks
D712

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[pgg]

My (insane perhaps) hypothesis is that if this molecule crosses, then couldn't it, in theory, act as an enzyme that piggy backs other molecules across with it, molecules that wouldn't normally cross? Molecules/meds that you would not want to cross and have a greater than normal, or less than normal, effect?

No, this doesn't happen. Typically things don't cross the BBB or the placenta if they're large or charged molecules. Those properties aren't influenced by other drugs except in extraordinary circumstances (eg drug A altering blood pH which alters drug B's ionization).

Just askin'. Curious. And when do you learn this stuff? M1? M2? PGY-1? CA-1?

Certainly by pharm/physiology which are usually MS2 classes. Probably sooner ... enzymes, membranes, channel proteins, diffusion etc are covered in undergrad biology so the concepts should be there before starting med school, even if this particular instance hasn't been explicitly addressed.

 

[psychbender]

Question:

If this drug crosses the blood-brain barrier, when others don't, are there contraindications in using certain anesthetics in the presence of Methotrexate, or other drugs that cross the barrier? My (insane perhaps) hypothesis is that if this molecule crosses, then couldn't it, in theory, act as an enzyme that piggy backs other molecules across with it, molecules that wouldn't normally cross? Molecules/meds that you would not want to cross and have a greater than normal, or less than normal, effect?

Just askin'. Curious. And when do you learn this stuff? M1? M2? PGY-1? CA-1?

Thanks
D712

No. Simplified version: The blood-brain barrier is composed of very tightly packed endothelial cells, with additional astrocyte biochemical support, and functions as a semi-permeable membrane allowing certain molecules to pass through it based on their physical/chemical characteristics (lipophilicity). Some drugs that are used in the OR are able to penetrate the barrier because of their tertiary amine structure (they are less polar / hydrophilic). I believe this is true with methotrexate, as well. One molecule diffusing across the membrane does not make it easier for another molecule, which does not possess the necessary lipophilicity to cross on its own, to freely diffuse.

Now, there do exist some transport molecules on the surface of the endothelial cells that make up the barrier, which actively transport some molecules such as glucose and some amino acids. These transport proteins are being investigated as an additional means to introduce drugs to the CNS, by coupling the drugs to the normal transport mechanism (along with other novel approaches such as liposomal nanoparticles packed with drug). However, again, the passage of one molecule through such a transport protein does not make it easier for another molecule, that has no affinity for the transport proteins, to cross as well.

You'll learn this during biochemistry as an MS1, and review it again during pharmacology as a med student.

 

[doctor712]

No. Simplified version: The blood-brain barrier is composed of very tightly packed endothelial cells, with additional astrocyte biochemical support, and functions as a semi-permeable membrane allowing certain molecules to pass through it based on their physical/chemical characteristics (lipophilicity). Some drugs that are used in the OR are able to penetrate the barrier because of their tertiary amine structure (they are less polar / hydrophilic). I believe this is true with methotrexate, as well. One molecule diffusing across the membrane does not make it easier for another molecule, which does not possess the necessary lipophilicity to cross on its own, to freely diffuse.

Now, there do exist some transport molecules on the surface of the endothelial cells that make up the barrier, which actively transport some molecules such as glucose and some amino acids. These transport proteins are being investigated as an additional means to introduce drugs to the CNS, by coupling the drugs to the normal transport mechanism (along with other novel approaches such as liposomal nanoparticles packed with drug). However, again, the passage of one molecule through such a transport protein does not make it easier for another molecule, that has no affinity for the transport proteins, to cross as well.

You'll learn this during biochemistry as an MS1, and review it again during pharmacology as a med student.

Thanks for the answer! Stuff in bold is familiar (though they really just glance over the concepts in UG Bio) but helps me make sense of what you're saying. I seemed to combine two ideas in the question. Thanks a lot PBender, (to PGG as well).

D712