Welcome to pharmacology by Lecturio.
I'm Dr. PJ Shukle and we're going to talk about
local anesthetics and oral analgesics.
And I'm going to introduce you to the
interesting world of controlling pain.
Now, here's the problem with this particular type of
patient. We need to get a drug across a lipid membrane
and act on the inside of the cell, on the inside surface
of a channel, to stop the movement of sodium ions.
The problem is that the outside of the cell is water,
the membrane is lipid, the inside is water.
So, how do we change the properties of the drug
to be both lipophilic and hydrophilic?
Remember that membrane diffusion in this case
is going to be a passive process.
Unfortunately, there are no active transportase
to bring the drug across the membrane.
We want to block the receptor from the inside surface. And
we want to block movement of sodium channels across that membrane.
The reason why we do that is because blocking sodium
channels will reduce membrane depolarization.
And reducing membrane depolarization will prevent that
nerve from firing and therefore the pain response
will not reach your brain.
We need the polar form of the drug to turn into
a nonpolar drug, and then turn back into a polar drug
and then do its job. How do we do that?
Well, I'm going to bring back the pKa lecture. Now, you
thought you got away with never having to deal with pKa
once we finished our original pharmacology lectures,
I think it was the second lecture we did.
Well, here's where pKa really makes a different. So,
lidocaine is a local anesthetic. It has a pKa of 7.7.
And if you think back to that original lecture,
remember that pKa means that 50% of lidocaine is protonated,
and 50% of lidocaine is nonprotonated when the pH is 7.7.
Now, inflammed tissue may also have pH changes too. So,
the pH can be anywhere from 6.8 during active inflammation
to 7.4 under normal conditions.
Lidocaine, therefore, is sometimes given with bicarbonate
to alkalinize the area and make the drug more lipid soluble.
So, by giving bicarbonate with the subcutaneous lidocaine,
you can change the pH. Let's say it goes up to 8.7,
well now, you have a 1:10 ratio, or 10 % of your drug being
water soluble, and 90 % of your drug being lipid soluble.
Now, once it's inside the neuron or the cell, the pH is 6.9.
So, the molecule now becomes more polar and water soluble.
That's how we get the drug across the membrane. Once it's
in the nerve, there're other things that will affect
how well the drug works.
First of all, smaller fibres are usually easily blocked.
Larger fibres are less easily blocked.
Myelinated fibres are also more easily blocked.
Rapid firing nerves are more easily blocked,
like pain fibres.
And location within the nerve bundle will determine
how well that local anesthetic works.
Obviously, if the nerve is in the middle of the nerve bundle
it's going to be hard to get at it.
If it's on the surface of the nerve bundle,
it will be easier to get at.
There are some external tissue factors as well
that will determine how well the drug works.
Most block neuromuscular transmission.
Central effects can cause euphoria such as cocaine.
So, these external tissue factors are going to be very
important in determining what kind of drugs
we're going to be choosing to control our pain.
There're some chemical factors that you have to be aware of.
A high potassium concentration within the area
will enhance local activity of the drug.
High calcium levels on the other hand will inhibit local
activity. And pH levels as we already discussed
will affect the solubility of the drug.
So, those chemical factors are important too.
Now, most local anesthetics are
very quickly absorbed into the blood.
For example, lidocaine quickly goes from tissue into blood.
And remember that's not a good thing because now
the lidocaine is being carried away from the area you wanted.
The other problem is that it's going to give us side effects.
So, we don't want that. We want all of the lidocaine
to stay in one place. So sometimes, we add epinephrine
to our lidocaine mixture. So, you'll often see on the
bottle of lidocaine as we're going to inject somebody
before we do, say a stitch,
is it will have bicarbonate to make the area more alkali
and it will have epinephrine
to give us vasoconstrictor activity.
Now, longer acting agents are going to be
less dependent upon the vasoconstrictor,
but short acting agents like lidocaine is quite critical.
Now, cocaine is actually a potent vasoconstrictor due to
its intrinsic sympathomimetic function.