Local anesthetics cardiac inhibition

The action of norepinephrine is terminated by reuptake mechanisms, two of which have been identified. Biogenic amine Uptake 1 is located in the presynaptic membrane, requires energy for the transport, is sodium and temperature dependent, and is inhibited by ouabain (a cardiac glycoside), cocaine (a local anesthetic), and imipramine (an antidepressant). Biogenic amine Uptake 2 is located extraneuronally in various smooth muscles and glands, requires energy, and is temperature dependent. Approximately 20% of the amine is either taken up by the Uptake 2 mechanism or is metabolized. 

Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult. However, prompt resuscitation has been successful with standard cardiopulmonary support, including the prompt correction of acidosis by hyperventilation and administration of bicarbonate as well as epinephrine, atropine, and bretylium. Local anesthetics, especially bupivacaine, also inhibit basal and epinephrine-stimulated cAMP production. This finding places greater emphasis on aggressive epinephrine therapy during bupivacaine-induced cardiotoxicity. The (SJ-isomer, levobupivacaine, appears to have a lower propensity for cardiovascular toxicity than the racemic mixture or the (R)-isomer and has recently been approved for clinical use. Ropivacaine, another newer local anesthetic, has clinical effects similar to those of bupivacaine but may be associated with a lower potential for cardiovascular toxicity. Ropivacaine is available only as the (S)-stereoisomer, which has inherently less affinity for the cardiac sodium channel. 

There have been no recent studies on the pharmacology of samandarine alkaloids. Samandarine is a potent local anesthetic 48). Cardiac depressant effects (48,49) and inhibition of binding of a radiolabeled batracho-toxin analog to sodium channels (50) are consonant with the potent local anesthetic activity of samandarine. Samandarine alkaloids show antimicrobial activity (51 and references therein). 

Animal studies have detected a variety of pharmacological and biochemical changes in response to chlordimeform exposure. The cause of death following acute exposure appears to be cardiovascular collapse. Chlordimeform interacts directly with and inhibits a2-adrenergic receptors in mammalian systems. Lethal doses of chlordimeform cause decreases in cardiac contractility and peripheral resistance resulting in severe hypotension. Respiratory arrest also occurs but is thought to be secondary to the cardiovascular effects. The effects of chlordimeform on the cardiovascular system share similarities with those seen with local anesthetics such as procaine. Chlordimeform also inhibits monoamine oxidase and acts as an uncoupler of oxidative phosphorylation. 

Lidocaine [2-(diethylamino)-N-(2, 6-dimethylphenyl) acetamide monohydrochloride] is the most commonly used amino amide-type local anesthetic. Lidocaine is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester-type local anesthetics, such as procaine and tetracaine. It can be administered parenterally (with or without epinephrine) or topically either by itself or in combination with prilocaine or etidocaine as a eutectic mixture that is very popular with pediatric patients. The use of lidocaine-epinephrine mixtures should be avoided, however, in areas with limited vascular supply to prevent tissue necrosis. Lidocaine also frequently is used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias, both because it binds and inhibits sodium channels in the cardiac muscle and because of its longer duration of action than amino ester-type local anesthetics. 

Erythrophleum alkaloids have cardiac activity (they increase contractile strength) and a very strong local anesthetic action. Although the latter action is more potent than cocaine, it is accompanied by intense irritation at the site of administration. Cassaine (39) inhibits (Na K )-ATPase (Wink, 1993), When the double bond is saturated, almost all biological activity disappears. Erythrophleum bark is used as a cancer remedy in Africa (Suffness and Cordell, 1985). 

Lidocaine, like other local anesthetics, binds axonal membrane voltage-gated fast Na channels and thus prevents Na+ transport across the channels, thus inhibiting cell membrane depolarization. It is by this same mechanism that lidocaine exerts its effect as a class Ib antiarrhythmic to inhibit cardiac smooth muscle excitability and as an anti-epileptic drug to inhibit cortical excitability. Its lipophilic aromatic group allows the molecule to penetrate the nerve membrane, while its hydrophilic charged amine group is the portion of the molecule that actually binds the Na chaimel [1-3]. 

---