pKa

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I'm having trouble with this in my mind...

I understand that if a drug with a pKa of say 7.4 were put into plasma with a pKa of 7.4, then 50% of the drug will be unionized and 50% will be ionized; the unionized form crosses membranes easier while the ionized doesn't (which is good or bad, depending on what action we want from the drug); the part I'm having trouble with is "at what pH is the drug more unionized vs ionized?"

alfentanil has a pKa of 6.5; does this mean that when injected into a body pH of 7.4 = more unionized which = faster onset?

for lower pKa drugs to be more unionized, do they need to be injected into closer to normal body pH's?

This is probably very simple, but I'm stuck and I don't have my G&G's with me today; can you guys please help...I can't see the forest from all the trees today!

-Gump

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ionized = water soluable = nonactive

unionized = lipid soluable = active

you are right - pKa is a number that signifies that at that pH 1/2 is ionized and 1/2 is unionized...

to know which direction the pH must go to make it more ionized/unionized you need to know if the drug is an acid or base.

most drugs we use are bases - the only significant acids we use are barbituates (barbituric acid)

so.... mepivicaine (an base) has a pKa of something like 2.4 (it is in the 2's) ... so ... at physiologic pH it is fully unionized and active because the medium you are putting it in is basic compared to it's pKa

like likes like... acid likes acid and base likes base...

so the more basic a solution you place a base in the more unionized it will become.....and the more acidic medium you place an acid in...the more unionized it will become...

so if you have a base with a pKa of 7.2 - at physiologic pH it is more unionized than ionized because you are placing it in a more basic medium than 7.2 (where it is a 50:50 ratio of ionized to unionized)

if you have a base with a pKa of 7.8 - at physiologic pH (7.4) it is more ionized than unionized because you are placing it in a medium that is more acidic than its pKa of 7.8...

picture your ionization on a line...

2-----------------------7.4---------------------------9

when given a pKa - chart it on that line

ex

2-----------------------7.4-------7.6-----------------9

pKa 7.6 - now - is it a base or an acid...

base??

a base w/ a pKa of 7.6 will be more ionized at physiological pH because that is a medium that is acidic compared to your pKa...

i hope this helps...

Andrea

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This is the topic my class strugled with the most the 1st semester, so yes it is very tricky and not just you.

Lets continue with alfentanil since you brought it up...

1st you have to know whether the actual drug compound is a base or an acid. As you know bases have a ph > 7.0 and acids have ph

2nd you need to know wether the drug solution is an acid or a base. This is easy if you know what the drug compound is. Alfentanil solution is an acid. It has to be for the drug to mix in the solution. If alfentanil were mixed with a basic solution it would stay unionized (hydrophobic) and precipitate. It must be mixed with a acidic solution where it turns ionized (hydrophilic) and can mix in solution. This is why you see a clear solution w/o precipitate when you look at a vial.

3rd you need to know the pka. For alfentanil is is 6.5. We know that alfenanil is in an acidic solution that is lower than 6.5 (probably somewhere less than 4.0 to make sure it is almost completely ionized).

4th you need to know physiologic ph which is usually around 7.4. So we inject the alfentanil solution into blood and the drug moves across its pka where it becomes about 90% nonionized (hydrophilic). This allows it to move across the BBB to its effect-site very quickly. It does it even faster than fentanyl or sufentanil for this reason.

That is it very basic drugs in acidic solutions. Then there are acidic drugs in basic solutions like thiopental. It is an acidic compound that disolves in a solution that has a ph of 10.5 (very basic). When it is injected it crosses its pka at 7.6 and becomes more nonionized.

Then there are drugs you don't want to change when injected like NDMR. Whe vecuronium is injected it does not cross its pka and remains entirely water soluble like it was in solution so it never crosses the BBB.

Then there are a few weird ones like propofol which is in an emulsion so is never in a water-soluble form of the drug. It never has to dissolve in anything.

As far as the ph of the blood varying, it matters more when the pka is closer to 7.4. You may see varying effects of thiopental b/c its pka is 7.6. But really in practice you give how much drug is needed and never consider this.

Hope this helps.

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Thanks guys, these explanations have been a big help! I'm going to insert some of both of these into my notes and beat it into my brain before next Thursday's test...

-Gump

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[color=#660033]principle of lechaterlier

( if the conditions of a system, originally in equilibrium, are changed, the new equilibrium shifts in such a direction as to restore the original conditions).

for a weak acid

ah « a- +h+

if [h+] increase(ph becomes lower) the reaction will be driven to the left by mass action, and the proportion of drug in the nonionized form will increase and, hence, the number of lipid soluble molecules. (acid in acid yields unionized, acid in base yields inonized)

for a weak base, the dissociation equilibrium is

bh + « b +h+

if [h+] increases the proportion of drug in the ionized form will increase. (base in acid yields ionized, base in base yields unionized)

a. for a weak acid, when the ph is

(nonionized) predominates. when the ph is > the pk, the unprotonated (ionized) form predominates.

b. for a weak base, when the ph is

(ionized) predominates. when the ph is > the pk, the unprotonated

(unionized) form predominates.

c. in the stomach (ph 2.0), weak acids are uncharged and will be absorbed into the bloodstream, whereas weak base are charged and will remain in the gi tract.

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Great explanation of pH and pKa, especially plotting it on a line. However, I would like to make one correction: Local anesthetics are basic drugs with pKas 7.6-8.9, mepivacaine's pKa is 7.6. Put a basic drug into a pH lower than it's pKa results in a larger ionized fraction than nonionized.

It's great to see these type of questions and replies on the board!!

so.... mepivicaine (an base) has a pKa of something like 2.4 (it is in the 2's) ... so ... at physiologic pH it is fully unionized and active because the medium you are putting it in is basic compared to it's pKa

An Yogi

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ooops...

you are absolutely right - i was thinking of benzocain (pKa 3.8)....

thannks!!

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Specializes in Operating Room.

OMG HELP ME!!! All I can say, is let me start praying now. Maybe by next year when I hope to start nursing school, I will understand all this! :rolleyes:

Good luck on your exam. :)

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