This article throws light upon the three main factors affecting local anaesthetic action. The factors are: 1. Type of Nerve Fibre 2. pH and pKa 3. Potentiators.
Factor # 1. Type of Nerve Fibre:
Small (thinner) nerve fibres such as thinner sensory and postganglionic sympathetic fibres (C-type) and preganglionic sympathetic fibres (B-type) are most sensitive to conduction blockade by local anaesthetics. Large (thicker) sensory fibres (A-delta type) are moderately sensitive.
A-beta and A-gamma fibres (more thicker), sub-serving muscle tone and proprioception, are less sensitive while somatic motor fibres (A- alpha, thickest) are least sensitive to local anaesthetic action. Myelination does not appear to affect nerve sensitivity to the blockade.
The sensory modality disappears in the following order, and reappears following recovery in the reverse order: pain, cold, warmth, touch and deep pressure. Nerve membrane is more permeable to local anaesthetic molecules during depolarization state than during resting state.
This renders sensory fibres in general and the pain fibres in particular more susceptible to the blockade as they tend to generate long-duration action potentials (up to 5 ms) and at higher frequency while motor fibres generates short-duration action potentials/(less than 0.5 ms) and at lower frequency. Thinner size also favours blockade as such fibres have shorter critical lengths over which an impulse can be propagated passively.
Factor # 2. pH and pKa:
Commonly used, local anaesthetics are weak organic bases with pKa in the range 8 to 9. Tissue pH (about 7.4) favours their ionization (protonation) such that more than 60% of the drug molecules exist in protonated form. Un-protonated form is responsible for diffusion through the lipid matrix.
Protonated form is presumed to enter the membrane through the ion-channel (during depolarization state) and to bind specifically to the binding sites. Activity spectrum of local anaesthetic agents is not, however, comparable to change in pKa values from 7.65 (e.g. mepivacaine) to 8.92 (e.g. procaine). Besides, benzocaine with pKa 2.5 (largely unionized at tissue pH) also possesses some local anaesthetic activity.
These observations suggest that cationic species is not critically required for local anaesthetic activity. Tissue pH is definitely an important factor that would affect diffusion of the base across the membrane; thus local anaesthetics with varying pKa values are expected to diffuse the membranes at varying rates.
Inability of local anaesthetics to block conduction from purulent sites is related to the abnormal environment at purulent sites. Such sites are relatively acidic and contain higher potassium levels as well as are rich in anions (e.g. proteins, organic phosphates and nucleotides) due to high cell destruction.
Acidic pH decreases hydrolysis of acid salt (i.e. hydrochloride) thus reducing release of active organic base. Acidic pH would favour ionization and hence reduce diffusion of the active base. Hydrogen ions are known to block sodium ion channels directly by occupying its anionic sites.
Indicates per cent ionization over extracellular to intracellular pH gradient; R.P. and R.T. refer to relative potency and relative toxicity with respect to procaine; the values have been approximated to project an overall comparison as ranges for each drug vary widely with respect to test system including concentrations used, route of administration and species.
Per cent ionized base 100/(1) + Antilog (pH _ pKa ) organic anionic environment would localize the organic base at the site (presumably anionic-cationic attractions). High extracellular potassium is known to block sodium channels and hyperpolarize the membrane. All these factors appear to interfere with local anaesthetic action at purulent sites.
Factor # 3. Potentiators:
Vasoconstrictor:
Adrenaline or any other vasoconstrictor reduces rate of absorption of local anaesthetic from the site of deposition. Reduced rate of systemic availability tends to reduce systemic toxicity. Duration of action is accordingly prolonged in presence of a vasoconstrictor.
The effect is pronounced with local anaesthetics having pronounced vasodilator action such as procaine and lidocaine. Prilocaine has little vasoconstrictor action so can be used without adrenaline. Cocaine is vasoconstrictor so adrenaline is not required.
On the other hand use of adrenaline is contraindicated with cocaine as later tends to potentiate its sympathomimetic effects by preventing uptake of catecholamines at nerve terminals. Adrenaline is contraindicated while attempting intravenous retrograde regional anaesthesia as it would reduce diffusion of local anaesthetic from blood to active sites.
It is also contraindicated to use adrenaline on extremities as it would favour ischemia and development of gangrene. Adrenaline can be used at concentration range from 1: 2 lakh to 1: 0.5 lakh; however, 1: 1 lakh concentration is often favoured for use.
Hyaluronidase:
The enzyme hydrolyses ground substance (i.e. hyaluronic acid) so increases area of diffusion and hence area of effect of local anaesthetics. Increased diffusion tends to reduce duration of effect and increase chances of toxicity as the drug would reach systemic circulation faster.
The benefits are discernible only when vasoconstrictor is also used along with the hyaluronidase; duration and area of effect are nearly doubled.
Use of hyaluronidase in veterinary practice is not recommended:
(i) It is costly,
(ii) Tends to interfere with local anaesthetic action especially when used alone,
(iii) Chances of systemic toxicity by local anaesthetics are increased, and
(iv) Its use has limited applications i.e. infiltration or subcutaneous anaesthesia.