Opioids – Weak Acid or Weak Base

Opioids – Weak Acid or Weak Base

Question

A question arose in a class about opioids and whether they are weak acids or weak bases from reading the following in Butterworth 7th ed.p.939:

“Albumin binds acidic drugs (e.g., barbiturates, benzodiazepines, opioid agonists). Alpha-1-acid glycoprotein binds basic drugs (eg, local anesthetics). Concentration of these binding proteins may vary depending upon diseases associated with aging.”

The following is what other textbooks have to say

Miller 9th ed.p.711

Miller is particular and states: “Opioids are weak bases.”

“All opioids are to some extent bound to plasma proteins, including albumin and alpha-1-acid glycoprotein. It is only the unbound and unionized fraction that constitutes the diffusible fraction and provides the concentration gradient that promotes diffusion of opioid from blood to the tissue of interest. Thus, the speed of onset of opioid effects is affected by both lipid solubility and protein binding.“

Stoelting/Flood 6th ed.p.215

Stoelting/Flood is less blunt, but we can deduce the same answer from them. Reasons for poor penetration of morphine into the CNS include

  1. relatively poor lipid solubility
  2. high degree of ionization at physiologic pH
  3. protein binding
  4. rapid conjugation with glucuronic acid

“Alkalinization of the blood, as produced by hyperventilation of the patient’s lungs, will increase the nonionized fraction of morphine and thus enhance its passage into the CNS.”

pKa for morphine is 7.9, with a nonionized percentage at human physiologic pH of 7.4 = 23% (p.215, chart)

Storm Anesthesia explains

Let’s look at how weak acids and bases dissociate when placed in acidic and alkalotic environments:

  • Weak acid + acidic environment = nonionized fraction is increased
  • Weak base + alkalotic environment = nonionized fraction is increased
  • Weak acid + alkalotic environment = ionized fraction is increased
  • Weak base + acidic environment = ionized fraction is increased

To summarize:

  • acid + acid and base + base = nonionized
  • acid + base and base + acid = ionized
  1. Let’s try to look at the pH line and place a weak acid with a pKa of 7.9 into human blood (pH = 7.4)

As seen from this situation, a weak acid with a pKa of 7.9 placed in a relatively acidic environment, such as the human body (pH = 7.4), will be mostly nonionized.

  1. Take a new pH line and place a weak base with a pKa of 7.9 into human blood (pH = 7.4)

We now see that a weak base in a relatively acidic environment (again, human pH = 7.4) is mainly in the ionized form.

Now, when re-examining the above two statements from Stoelting/Flood, it should be evident that morphine (pKa 7.9), which is the classic opioid agonist, is a weak base.

Nagelhout 7th ed.p.140-141

Multiple factors influence the use of opioids, such as patient characteristics, perception, severity, and duration of pain, as well as smoking and alcohol intake. Age, weight, renal and/or hepatic failure, bypass surgery, acid-base changes, and shock also influence the pharmacokinetics and pharmacodynamics of opioids.

Nagelhout uses the same numbers for pKa and ionization as in Stoelting/Flood above. Opioids work on effector sites in the CNS and thus cross biological membranes to get to their receptors on neural cell membranes. That ability depends on molecular size, ionization, lipid solubility, and protein binding.

Using the same concepts as above under Stoelting/Flood, it can then be deduced from Nagelhout Table 11.3 on pg.141 that the lower the pKa for the opioid agonist the more of the drug exists in the nonionized form:

  • alfentanil pKa = 6.5 ~ 89% nonionized
  • remifentanil pKa = 7.26 ~ 58% nonionized

Whereas when the opioid agonist has a higher pKa, there is much less of it in the nonionized form:

  • fentanyl pKa = 8.4 ~ 8.5% nonionized
  • morphine pKa = 7.9 ~ 23% nonionized

Remember from above: a basic drug + an acid environment = an ionized form of the drug. As can be seen here, the higher the opioid's pKa, the more of it exists in the ionized form, which explains why an opioid agonist is a weak base.

Summary

I will state the consensus is clear: opioids are weak bases. I’m not sure what Butterworth is referring to in their Geriatric chapter, but we will conclude:
OPIOIDS ARE WEAK BASES.