LOCAL ANAESTHETICS PDFS Notes | What are the local anesthetic drugs? | Classification Local anaesthetics PDF |
LOCAL ANAESTHETICS
Local anaesthetic agents act locally to abolish the sensory perception over a local area. They vary in their pharmacological properties and are used in the following local anaesthesia techniques:
1) Topical anaesthesia (surface),
2) Infiltration,
3) Plexus block,
4) Epidural (extradural block), and 5
) Spinal anaesthesia (subarachnoid block).
Local anaesthetics bind to cell membrane sodium channels and inhibit sodium ion passage, thus prevent the membrane depolarisation of nerve cells. Sodium channel is liable to local anaesthetic binding in the open state; therefore the frequently stimulated nerves are blocked easily. The ability of local anaesthetics to block a nerve depends on the length of the nerve ex posed, nerve diameter, myelination, and the anaesthetic used.
17.1.2. Classification Local anaesthetics are classified as follows:
1) Natural Agents: Cocaine.
2) Synthetic Nitrogenous Compounds
i) Derivatives of benzoic acid.
ii) Derivatives of para-amino benzoic acid
a) Freely Soluble: Procaine and Amethocaine.
b) Poorly Soluble: Benzocaine and Orthocaine.
iii) Derivatives of Acetanilide: Lignocaine, Mepivacaine, Bupivacaine, Prilocaine, and Etidocaine.
iv) Derivatives of Quinoline: Cinchocaine and Dimethisoquin.
3) Synthetic Non-Nitrogenous Agents: Benzyl alcohol and Propanediol.
4) Miscellaneous Drugs with Local Action: Chlorpromazine and Diphenhydramine.
Based on Duration of Action
1) Injectable Anaesthetics
i) Clove oil, Phenol, Low Potency and Short Duration: Procaine and Chloroprocaine.
ii) Intermediate Potency and Duration: Lignocaine and Prilocaine.
iii) High Potency and Long Duration: Tetracaine, Bupivacaine, Ropivacaine, and Dibucaine.
2) Surface Anaesthetics
i) Soluble: Cocaine, Lignocaine, Tetracaine, and Benoxinate.
ii) Insoluble: Benzocaine, Butyl aminobenzoate, and Oxethazaine.
5) Newer Drugs: Ropivacaine and Levobupivacaine.
17.1.3. Mechanism of Action
Local anaesthetics prevent the voltage-dependent increase in Na+ ion conduction, thus block the initiation propagation of nerve impulse . Entry of Na+ ions through voltage-gated channels is either reduced by a similar effect on the membrane as that induced by inhalation general anaesthetics, or by specifically plugging Na +ion channels. The nerve conduction blocking activity of local anaesthetics is ordered as small and large myelinated axons (motor). Thus, initially n ociceptive and sympathetic transmission is blocked, and motor nerves are blocked last.
17.1.4. Uses
Local anaesthesia is the loss of sensation in a body part without the loss of consciousness or impairment of central regulation of vital functions. It is used during minor surgical methods. Local anaesthetics are used for surface application, infiltration, nerve blocks, epidural, spinal and intravenous regional block anaesthesia. Local anaesthetics are classified as follows according to their administration method:
1) Topical Anaesthesia:
The mucous membranes of nose, throat, tracheobronchial tree, oesophagus, and genito-urinary tract can be anaesthetised by direct application of aqueous solutions of salts of various local anaesthetics or by suspension of the poorly so luble local anaesthetics. Vasoconstriction is achieved for prolonged duration of action by adding a low concentration of a vasoconstrictor , e.g., phenylephrine (0.005%), lignocaine (2-10%), cocaine (1-4%), and tetracaine (2%).
2) Infiltration Anaesthesia:
Local anaesthetics are injected direc tly into the superficial tissue of the skin or deeper structures including intra-abdominal organs. The duration of infiltration anaesthesia is doubled by adding epinephrine (5µg/ml) to the injection solution, e.g., lignocaine (0.5-1.0%), procaine (0.5-1.0%), and bupivacaine (0.125-0.25%).
3) Field Block Anaesthesia:
This is produced by subcutaneous injection of a local anaesthetic solution to anaesthetise the region distal to the injection. The advantage of field block anaesthesia is that less drug is used for providing a greater area of anaesthesia in comparison to infiltration anaesthesia, e.g., lignocaine (0.5-1.0%), procaine (0.5-1.0%), and bupivacaine (0.125-0.25%).
4) Nerve Block Anaesthesia :
This involves injecting a soluti on of local anaesthetic into or around individual pe ripheral nerves or nerve plexus, e.g., lignocaine (1.0-1.5%), m epivacaine (up to 7mg/kg of 1.0-2.0%), and bupivacaine (2-3mg/kg of 0.25-0.375%). Duration is prolonged by adding 5µg/ml of epinephrine.
5) Intravenous Regional Anaesthesia :
This technique relies on using the vasculature to bring the local anaesthetic solution to the nerve trunks and endings. Mostly, it is used for the forearm and hand, and also for foot and distal leg, e.g., lignocaine (0.5%) and procaine (0.5%).
6) Spinal Anaesthesia:
This local anaesthetic is injected into the cerebrospinal fluid in the lumbar space, e.g., lignocaine, tetracaine, and bupivacaine.
7) Epidural Anaesthesia:
This local anaesthetic is injected into the epidural space (the space bounded by the ligamentum flavum posteriorly, the spina periosteum laterally, and the dura anteriorly ), e.g., bupivacaine (0.5-0.75%), etidocaine (1.0-1.5%), lignocaine (2%), and chloroprocaine (2-3%).
7.1.5. SAR of Local Anaesthetics
SAR of Benzoic Acid Derivatives Mostly, the benzoic acid derivatives are tertiary amines found as HCl salts having pKa in the range of 7.5-9.0. Any structural modificati on in these local anaesthetics that may alter the pKa will have a pronounced effect to reach hypothetical receptor or the binding sites.
1) Lipophilic Portion
i) A local anaesthetic of this class that is clinically useful is highly lipophilic and has an aryl radical directly attached to the carbonyl group. This plays an important role in the binding of local anaesthetics to the channel receptor protein.ii) Placing the aryl group with substituents that increases the electron density of carbonyl oxygen enhances the activity of local anaesthetics.iii) Structural modification changes the physical and chemical properties of local anaesthetics . Placement of e lectron withdrawing substituents at ortho or para or both the positions increase s the activity of local anaesthetics.iv) Amino (procaine, butacaine) , alkyl amino (tetracaine) , and alkoxyl (cyclomethycaine) groups contribute to electron density in the aromatic ring by resonance and inductive effects. This increases the activity of local anaesthetics.
v) Any substitution that enhances the formation of Zwitter ion will be more potent. Hence substitution at m-position decreases the activity of local anaesthetics.vi) The potency of tetracaine is 40-50 times more than that of procaine. Although the butyl group present in it increases lipid solubility, the potentiation is partially due to ele ctron releasing property of the n-butyl group via inductive effect, which increases the formation of Zwitter ion.vii) Electron withdrawing group (Cl–) if present ortho to carbonyl pulls the electron density away from carbonyl group, and makes it more susceptible to nucleophilic attack by the esterase
2) Intermediate Portion
3) Hydrophilic Portion
i) The amino alkyl group is not necessary for local anaesthetic activity, but for forming water-soluble salts such as HCl salts.
ii) Tertiary amines are more useful. Secondary amines have a longer duration of action, but are more ir ritating. Primary amines are inactive and cause irritation.
iii) Placement of tertiary amino group (diethyl amino, piperidine, or pyrrolidino) forms a product with same degree of activity. iv) Placement of a more hydrophilic morpholino group reduces the potency.
v) The local anaesthetic drug should have increased lipid solubility and lower pKa values to increase the onset of action and decrease toxicity.
SAR of Anilides
Given below is the general structure of anilides:
1) Aryl Group
i) The clinically useful local anaesthetic belonging to class of anilides has a phenyl group attached via nitrogen bridge to the sp2 carbon atom.
ii) Placement of substituents on the phenyl ring with a methyl group at 2 (or) 2 and 6-position increases the local anaesthetic activity. The methyl substituent also provides steric hindrance to hydrolysis of the amide bond and enhances the coefficient of distribution.
iii) A substituent on the aryl ring that enhances the formation of Zwitter ion will be more potent.
2) Substituent X:
3) Amino Alkyl Group
i) The amino group can lead to salt formation and is the hydrophilic portion of the local anaesthetic molecule.ii) Tertiary amines (diethyl amine or piperidine) are more useful than the primary and secondary amines, as they are more irritating to tissues.
17.1.6. Recent Developments
The cardiovascular system in comparison to the central nervous system is more resistant to the toxic effects of local a naesthetics. However, if sufficient doses and blood levels of local anaesthetics are achieved, signs of cardiovascular depression may be observed. Different local anaesthetics have different potential for cardiotoxicity. Cardiotoxicity of local anaestheti cs can be compared using the CC/CNS dose ratio, which is the ratio of the dose causing Cardiac Collapse (CC) to the dose causing seizure or convulsions. The CC/CNS ratio for lidocaine is more than that for bupivacaine and eti docaine. Bupivacaine may also precipitate ventricular arrhythmias and ventricular fibrillation. Local tissue toxicity can also occur on administering local anaesthetics. The neural tissue is relatively resistant to the irritant effects of local anaesthetic s. However, large doses of chloroprocaine solutions administered intrathecally may cause prolonged sensory-motor deficits in some patients due to low pH and presence of sodium bisulfite in the chloroprocaine solutions. The occurrence of toxic reactions to local anaesthetic agents is generally very low. However, as with any class of pharmacological agents, local anaesthetics may cause severe toxic reactions, due to improper use.
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