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pH and local anaesthetics

Created: 23/6/2004
Updated: 16/11/2009

 
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.

Important consequences

  • 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 as an example of the situation above
  • 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.
LOCAL ANAESTHETICS ARE INEFFECTIVE IN INFECTED TISSUE (ACIDIC).
  • 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.
Name Duration pka Partition coefficient % Protein bound % Equiv. conc
Lidocaine 1 h 7.8 110 64 1
Prilocaine 1.5 h 7.7 50 55 1
Ropivicaine 2-4 h 8.1 230 94 0.25
Bupivicaine 2-4 h 8.1 560 95 0.25

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

ArticleDate:20040623
SiteSection: Article
 
   
    
                                            
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