Local anesthetics act at the nerve cell membrane, where they restrict the movement of Na+ and K+ across the membrane. This in turn increases the threshold value for cell firing, and thus decreases the excitability of the cell. The earliest known local anesthetic was cocaine, shown below, (1884), but the agent is not used widely as an anesthetic due to a variety of problems (allergy, tissue irritation, poor aqueous solubility, and the obvious problem with abuse and addiction).
Currently used local anesthetics can be structurally classified as either the procaine type or the lidocaine type. Each molecule has three general areas, as shown below: a lipophilic portion containing an aromatic ring, an intermeduate chain, and a hydrophilic amine functionality. The structure/activity relationships for local anesthetics can be described in terms of structural modifications to each of these three areas.
Primary amines have low activity, and are generally too irritating to use.
Secondary and tertiary amines have good activity; however, secondary amines are more irritating.
Quaternary amines have activity, but poor penetration of tissues; therefore none are used clinically.
The size of the nitrogen substituent is critical. Generally, the greater the number of carbons, the greater the potency (and toxicity), up to 3-4 carbons. After this, the activity drops off, since the analogues are too lipid soluble. Branching also increases potency. Usually the N-substituent is methyl, ethyl or propyl, or is included in a ring structure such as a piperidine. Addition of polar substituents on the N-substituent, such as a hydroxyl, will greatly diminish activity.
Some analogues have no amino group at all, such as benzocaine. They are active, but have poor water solubility.
In procaine-like analogues, branching (especially at the alpha carbon) will increase duration of action. This effect is not seen in the lidocaine series.
Increasing the chain length will increase potency but will also increase toxicity.
There is some variability in the functional group seen in the intermediate chain, as shown below. Esters are the most common functional group. The carbonyl must be in conjugation with the aromatic ring for activity. Reverse esters are inactive, and compounds with a methylene inserted between the carbonyl and the aromatic ring have poor activity and anticholinergic side effects. Thioesters have increased activity, but are more rapidly hydrolyzed than esters.
Amides can also be active, but their activity depends on the overall structure. Conversion of procain to procainamide destroys anesthetic activity and reduces lipid solubility, but does increase the stability of the analogue. However, dibucaine has sufficient lipid solubility for anesthetic activity, even though it is an amide.
Reverse amides are active in the lidocaine series, but the ortho positions must be substituted to reduce hydrolysis of the amide.
Replacement of the ester by a ketone, ether, thioether or sulfone results in analogues with little or no activity.
Simple esters of benzoic acid, such as benzocaine, have low but discernable activity. Their activity increases as branched or straight chain alkylamino groups are added, or with branching of the intermediate chain.
As mentioned above, lidocaine-type local anesthetics (reverse amides) must be ortho substituted.
Simple ketones have low activity unless the aromatic ring is substituted, as in dyclonine.
Electron donating groups (alkoxy, alkyl, amino, alkylamino) on the aromatic ring increase duration of action, since they stabilize the ester or amide finctional group. Conversely, electron withdrawing groups (nitro, cyano, halogen, COOEt) reduce duration, since they destabilize the hydrolyzable functional group of the intermediate chain.
Adding a second substituent to the aromatic ring increases activity (e.g. procaine vs. propoxycaine). The size of this substituent follows the same rules as those for the nitrogen substituent (activity increases up to 3-4 carbons, then drops off).
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