Structure Activity Relationship Dr AKSHIL 1. of procaine with an amide linkage led to procainamide hydrochloride Active as a. Proc West Pharmacol Soc. ; Antiarrhythmic structure activity relationships in a series of lidocaine procainamide derivatives. Ehring GR. Quantitative structure activity studies of antiarrhythmic properties in a series a series of lidocaine and procainamide derivatives was studied in guinea pig papillary muscles. Sodium/metabolism; Structure-Activity Relationship; Time Factors.
Thus, localize the local anesthetic at the desired site to limit systemic toxicity. The second one is to prolong duration of action.
Procaine is used to form an insoluble salt with penicillin G.
Procainamide | C13H21N3O - PubChem
The low solubility accounts for the prolonged action of this salt. The amide derivative of procaine procainamide HCl is a cardiac depressant. It has quicker onset and longer duration of action and more potent than procaine. It is used by injection for nerve block and infiltration anesthesia. Its solutions are more stable to hydrolysis than procaine and it may be sterilized by boiling.
Sulfonamides are considered competitive inhibitors of PABA in the biosynthesis of dihydrofolate. Its aqueous solutions are stable to sterilization by autoclaving. It is recommended for eye, nose and throat. It is essential for activity. This is a portion of aromatic acid whereas benzoic and p-amino-benzoic acids are the preferred ones. The carbonyl group must be conjugated with an aromatic nucleus whereas reversed esters have no local anesthetic activity.
The esters of cinnamic acid are more active than those of phenyl acetic acid due to interruption of the extended conjugation by methylene gp between the aromatic ring and carbonyl gp. NH2 procaine ,an alkylamino tetracaine or an alkoxy gp propoxycaine increase electron density to the aromatic ring by both resonance and inductive effects, While the opposite occur in case of electron-withdrawing NO2, CO and CN.
Conjugated not conjugated not conjugated Cinnamic acid phenyl acetic acid b-phenyl propionic acid 17 Tetracaine is fold more potent than procaine Tetracaine is fold more potent than procaine. This may be due to the n-butyl gp increase lipid solubility propoxycaine, the presence of o-propoxy gp increase duration of action due to protection of ester gp from hydrolysis due to plasma esterases This is contrary to chloroprocaine which has shorter duration of action due to negative inductive effect of o-chloro gp which pulls the electron density away from the carbonyl function.
The propylene gp — CH2 3— provides the most active compounds, next ethylene, — CH2 2— while methylene gp, —CH2—, makes the compounds too irritant. The branching with small alkyl gp around the ester function e. The hydrophilic portion It is amine part of amino alcohols used to esterifies aromatic acids.
Its advantage is its ability to form salts with inorganic acids producing water soluble compounds. Thus, 3ry amine is needed for formation of water soluble salts, suitable for pharmaceutical preparations.
The anesthetic activity increases with the size of the alkyl gps R1, R2the maximum being at C3-C4. R1 and R2 may be identical, unsaturated groups or hydrogen and alkyl group. Lidocaine xylocaine is the first non-irritating, amide-type local anesthetic agent with lesser allergic reactions than esters. Its aqueous solution is stable because of the stablility of amide functionality. Structurally, lidocaine can be viewed as an open-chain analog of isogramine and thus is a bioisosteric analog of isogramine.
Isogramine Lidocaine 2- Dimethylaminomethyl indole 21 B amino-amides or isogramine-type lidocaine-type. The salt is used for infiltration, peripheral nerve block and epidural anesthesia. Lidocaine is effective as antiarrhythmics. It is the most potent, toxic and longest acting one Used topically and in spinal anesthesia.
The lipophilic portion is essential for activity and consists of phenyl group attached to CO function sp2 carbon through NH gp. Substitution of the phenyl with a methyl gp in the 2- or 2- and 6-position enhances activity. The intermediate chain In lidocaine series, lengthening of the alkylene chain from one to two or three increases pKa from 7.
Here, branching around the amide function etidocainealso hinders amidase catalyzed hydrolysis prolonging the duration of action.
Advantages of lidocaine derivatives over procaine ones More stable to hydrolysis. Can be sterilized by autoclaving.
Used as alternatives for patients sensitive to procaine type local anesthetic. It used for patient sensitive to epinephrin. The adverse effects occur even more often if the daily doses are increased.
Procainamide may also lead to drug fever and other allergic responses. There is also a chance that systemic lupus erythematosus occurs, which at the same time leads to polyarthralgiamyalgia and pleurisy. Most of these side effects may occur due to the acetylation of procainamide. The hydroxylamine and nitroso metabolites are also toxic to bone marrow cells and can cause agranulocytosis.
Procainamide - Wikipedia
These metabolites are formed due to the activation of polymorphonuclear leukocytes. These leukocytes release myeloperoxidase and hydrogen peroxidewhich oxidize the primary aromatic amine of procainamide to form procainamide hydroxylamine.
The release of hydrogen peroxide is also called a respiratory burstwhich occurs for procainamide in monocytes but not in lymphocytes.
Furthermore, the metabolites can be formed by activated neutrophils. These metabolites could then bind to their cell membranes and cause a release of autoantibodies which would react with the neutrophils. Hydroxylamine can also generate methemoglobina protein that could hinder further oxygen exchange. A toxic level of procainamide leads to decrease in ventricular conduction velocity and increase of the ventricular refractory period.
This results in a disturbance in the artificial membrane potential and leads to a supraventricular tachycardia which induces failure of the pacemaker and death. It induces rapid block of the batrachotoxin BTX -activated sodium channels of the heart muscle and acts as antagonist to long-gating closures.
The block is voltage-dependent and can occur from both sides; either from the intracellular or the extracellular side.
Antiarrhythmic structure activity relationships in a series of lidocaine procainamide derivatives.
Blocking from the extracellular side is weaker than from the intracellular side because it occurs via the hydrophobic pathway. Procainamide is present in charged form and probably requires a direct hydrophobic access to the binding site for blocking of the channel. Furthermore, blocking of the channel shows a decreased voltage sensitivity, which may result from the loss of voltage dependence of the blocking rate. Due to its charged and hydrophilic form, procainamide has its effect from the internal side, where it causes blockage of voltage-dependent, open channels.