pH & Drugs – Relationship

pH & DRUGS – RELATIONSHIP


Electrolytic nature of drugs:

  • 2 types of electrolytes – Weak & strong electrolytes.
  • Most drugs are weak electrolytes.

pH & electrolytic nature of drugs – Relationship:

  • Weak electrolytic drugs = Drug ionization is pH dependent.
  • Strong electrolytic drugs = Drug ionization is pH independent.
    • Due to complete ionization at both acidic & alkaline pH.

Estimating of drug ionization:

  • HA – Weak acid.
  • pKa – Negative logarithm of acidic dissociation constant of weak electrolyte.
  • [A¯] = Concentration of ionized drug.
  • [HA] = Concentration of unionized drug.

Formula:

  • Calculated from simplified form of Henderson-Hasselbach equation: pH = pKa + log [A]/[HA].

1. If [A] = [HA] = 1:

  • Concentration of ionized drug = Concentration of unionized drug.
  • Then, pH = pKa (pKa is numerically equal to pH)
  • Drug is 50% ionized & 50% unionized.

2. If [A¯] / [HA] = 10:

  • Here, pH is increased by 1 in scale.
    • Ie., pH > than pKa  (medium becomes more alkaline/weakly acidic drugs).
  • Ionize more at alkaline pH.
    • Ie., Forms salt with cations.
  • For basic drugs, un-ionized form increases & ionized form decreases.
  • 1 scale change in pH causes 10 fold change in ionization.
    • Eg: Sod. phenobarbitone, sod. Sulfadiazine & pot. penicillin-V.

3. If [A¯] / [HA] = 1/10:

  • Here, pH is reduced by 1 in scale.
  • Drug is more acidic (weakly basic drugs).
  • Ionize more at acidic pH.
    • Ie., Forms salt with anions.
  • For acidic drugs, ionized form increases & non-ionized form decreases.
    • Eg: Atropine sulfate, ephedrine HCl & chloroquine phosphate.

Ionization fraction:

  • Ionized or unionized fraction depends on difference (d) between pH & pKa.
  • If pH = pKa (d=0):
    • Ionization is 50% & un-ionized fraction is 50%.
  • If pH-pKa=1 
  • If d=1:
    • Ionized form is 90% & un-ionized form is 10%.
  • If d=2:
    • Ionized form is 99% & un-ionized form is 1%.
  • If d=3:
    • Ionized form is 99.9% & un-ionized form is 0.1%.

Implications:

1. Acidic drugs with pKa 3.5:

  • Largely unionized at acid gastric pH & absorbed from stomach.
  • Eg: Aspirin.

2. Basic drugs with pKa 10:

  • Largely ionized & are absorbed only in intestines.
  • Eg: Atropine

3. Unionized form is lipid soluble & ionized form is water soluble.

  • Medium is same, hence drugs cross membrane.

4. Acidic drugs are lipid soluble (un-ionized form) in acidic medium.

  • Eg: In acidic gastric pH these acidic drugs are more likely to be absorbed from stomach.
    • Due to presence of unionized (lipid soluble) form.
  • Hence, aspirin is more likely to be absorbed in stomach than morphine or atropine (basic drugs).
    • This is reason for aspirin-induced gastric mucosal irritation.
5. Ion trapping:
  • Unionized drugs reverts back to ionized form within cell (pH 7.0) before passing to ECF.
    • Referred as “ion trapping”.
    • Ie., Weak electrolyte crossing a membrane to encounter a pH from which it is not able to escape easily.

6. Basic drugs attain higher concentration intracellularly (pH 7.0 vs 7.4 of plasma).

7. Acidic drugs are ionized more in alkaline urine.

  • Do not diffuse back in kidney tubules & are excreted faster.
  • Hence, basic drugs excreted faster if urine is acidified.

8. Lipid-soluble nonelectrolytes (e.g. ethanol, diethyl-ether) readily cross biological membranes & their transport is pH independent.

Exam Important

  • The lower the pKa of a drug, the more acidic it is. Higher the pKa, the more basic is the drug.
  • Most drugs are weak electrolytes.
  • For weak electrolytic drugs, drug ionization is pH dependent.
  • For strong electrolytic drugs, drug ionization is pH independent.
  • Estimating of drug ionization is calculated from simplified form of Henderson-Hasselbach equation: pH = pKa + log [A]/[HA].
  • If [A] = [HA] = 1, where concentration of ionized drug is equal to concentration of unionized drug.
  • If [A¯] / [HA] = 10, where pH > than pKa  (medium becomes more alkaline/weakly acidic drugs).
  • If pH = pKa (d=0), then ionization is 50% & un-ionized fraction is 50%.
  • If pH-pKa=1, then ionized form is 90% & un-ionized form is 10%.
  • Acidic drugs are lipid soluble (un-ionized form) in acidic medium.
  • Unionized drugs revert back to ionized form within cell (pH 7.0) before passing to ECF, which is referred to as “ion trapping”.
  • Aspirin is more likely to be absorbed in stomach than morphine or atropine (basic drugs)
  • In acidic gastric pH, aspirin is more likely to be absorbed from stomach, because of the fact that acidic drugs are lipid soluble (unionized form) in acidic medium.
  • Lipid-soluble nonelectrolytes (e.g. ethanol, diethyl-ether) readily cross biological membranes & their transport is pH independent.

 

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