A quote from a published paper states: On a smaller set of compounds (n = 53) wi
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Question
A quote from a published paper states: On a smaller set of compounds (n = 53) with known capacity to cross or not cross the blood-brain barrier (BBB) it was concluded that “compounds with minimally one charge with a pKa <4 for acids and correspondingly a pKa >10 for bases do not cross the BBB by passive diffusion.” (Perspect Medicin Chem. 2007; 1: 25–38.) Consider the blood-brain barrier (BBB) to be like an organic solvent such as hexane Assume the pH of the blood is 7. Explain why the statement above about drugs not passing the BBB with different pKa values is not an earth-shattering surprise (or as you would say after taking this course – a chemistry “no-brainer.”).
Explanation / Answer
Firstly let us discuss about Passive diffusion and its characteristics
Passive diffusion is also called as Non ionic diffusion. It is regarded as the important process for absorption of more than 90% of the drugs. Passive diffusion is expressed by Fick's first law of diffusion which states that drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained and that the rate of diffusion is directly proportional to the concentration gradient across the membrane.
Characteristics of Passive diffusion: (Only the points relevant to the given question are mentioned)
1. The drug moves down the concentration gradient indicating downhill transport.
2. The process is energy independent and non saturable
3. Greater the area and lesser the thickness of the membrane, faster the diffusion
4. The process is rapid over short distances and slower over long distances
5. The rate of transfer of unionised species is 3-4 times the rate of ionised drugs
6. Greater the partition coefficient of the drug, faster the absorption.
7. The process is dependent on molecular size of the drug. Drugs with molecular weight between 100-400 daltons are effectively absorbed.
Now, let us know about pKa
pKa is the negative logarithm of acid dissociation constant. Higher the value of pKa stronger will be the acid and weaker will be the base.
pKa less than 4 represents a Strong Acid and pKa greater than 10 represents Strongest base.
Example:
H2SO4: pKa= -9
HNO3: pKa= -1.4
Ammonia: pKa= 38
Stronger acid or base is the one which is completely ionised.
Now about the answer:
Assuming Blood barrier as an organic solvent with pH maintained at 7.
The given drug which is having pKa less than 4 represents a strong acid. The strong acid completely ionises and not soluble in the organic solvent. Similar thing happens with strong base which is also completely ionised and does not partition into the organic solvent.
In blood barrier, only unionised drugs can pass through by passive diffusion (hence called as non ionic diffusion) whereas ionised drugs are impermeable. The partition coefficient (ko/w and log P) also donot support permeation across lipoidal Blood brain barrier. As the given drugs are strong acids and strong bases, they remain completely ionised at physiological pH (7) and thus cannot be absorbed into blood barrier.
Hence, strong acids like Disodium chromolgycate and strong bases like mecamylamine, guanethedine cannot be absorbed across blood brain barrier
Lipinski rule of five for drug permeation lists the following characteristics for absorption of drugs:
Molecular weight of drug should be < 500
Lipophilicity of the drug, log P < 5
Number of H-bond acceptors < 10
Number of H bond donors < 5
So, hence, it is not surprising that Drugs with different pKa values cannot pass through Blood brain barrier