Membrane permeability is related to ionisation, and many drug molecules exist as weak acids or bases and therefore in an ionised and un-ionised form. The ratio of the two forms varies with pH.
Weak base: BH+ = B + H+
Dissociation constant pKa is given by the Henderson-Hasselbach equation
pKa = pH + log [BH+]/[B]
In an ACID ENVIRONMENT, the above equation will shift towards the left, i.e. the ionised form
In an ALKALINE ENVIRONMENT, the above equation will tend towards the right, i.e. un-ionised form
A base in an alkaline solution will be non-ionised and have a greater ability to cross lipid membranes. However, in an acid environment, it will be trapped, as it is ionised. The result is that an alkaline drug will be concentrated in a compartment with a low pH.
Weak acid: AH = A- + H+
pKa = pH + log [AH]/[A-]
In an ACID ENVIRONMENT, the equation will tend to the left, i.e. the un-ionised form
In an ALKALINE ENVIRONMENT, the equation will tend towards the right, i.e. the ionised form
A weak acid in an acid solution will be mainly in its un-ionised form. However, in an alkaline solution, it will be trapped, as it is ionised. The result is that an acid drug will be concentrated in a compartment with a high pH.
Local anaesthetics as an example of the situation above
- A weak acid is more likely to be absorbed from the stomach
- Urinary acidification will accelerate the excretion of weak bases and retard that of weak acids
- Increasing the plasma pH will cause weakly acidic drugs to be extracted from the CNS to the plasma.
LOCAL ANAESTHETICS ARE INEFFECTIVE IN INFECTED TISSUE (ACIDIC).
- Local anaesthetics block action potential generated by blocking Na+ channels
- Most local anaesthetics are weak bases, with a pKa between 8 and 9, so that they are mainly but not completely ionised at physiological pH. The un-charged species (B) penetrates the nerve sheath and axonal membrane and is then converted to the BH+ active form, which then blocks the Na+ channels. Increasing the acidity of the external solution would favour ionisation and render local anaesthetics ineffective.
- Quaternary derivatives of local anaesthetics (Q+) do not work when applied outside but can block channels if introduced directly into cytoplasm.
Extra information on local anaesthetics
- Many local anaesthetics are use-dependent (depth of block increases with action potential frequency) because the molecule gains access more readily when the channel is open
- Local anaesthetics block conduction in the following order: small myelinated > non-myelinated > large myelinated. Therefore, nociceptive and sympathetic transmission is blocked first.
||% Protein bound
||% Equiv. conc|
N.B. Partition coeffcient is between oil:gas and measures the lipid solubility. It is the main determinant of potency.
- Most of the ester linked local anaesthetics (prilocaine) are rapidly hydrolysed by plasma cholinesterase, so plasma half-life is short.
- The amine-linked drugs (lidocaine and prilocaine) are metabolised by the liver (via N-dealkylation) and metabolites are often active.
Effects on other physiological systems
- CNS: causes stimulation, restlessness, tremor and even convlusions and CNS depression (including respiratory depression)
- CVS: myocardial depression (inhibition of Na+ current in cardiac muscle, thereby reducing intracellular Ca2+ stores) and vasodilatation (direct effect on smooth muscle and inhibition of sympathetic nervous system)
- Hypersensitivity rare