Bupivacaine action

Chloroprocaine hydrochloride [3858-89-7] is characterized by low potency, rapid onset, short duration of action, and low systemic toxicity. It is indicated for infiltration anesthesia at 1—2% and for extradural anesthesia at 2—3% when short surgical procedures are performed under regional anesthesia. Chloroprocaine may be mixed with long duration agents such as bupivacaine (22, R = n-Q [) to afford a more rapid onset and shorter duration of action than bupivacaine alone. 

Clarkson CW, Hondeghem LM (1985) Mechanism for bupivacaine depression of cardiac conduction fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62 396-405... 

The primary site of action of epidurally administered agents is on the spinal nerve roots. As with spinal anesthesia, the choice of drug to be used is determined primarily by the duration of anesthesia desired. However, when a catheter has been placed, short-acting drugs can be administered repeatedly. Bupivacaine is typically used when a long duration of surgical block is needed. Lidocaine is used most often for intermediate length procedures chloroprocaine is used when only a very short duration of anesthesia is required. 

Bupivacaine is an anaesthetic with a slow onset but a long duration of action. It is indicated for continuous epidural analgesia in labour. Xylocoine is the proprietary preparation of lidocaine (lignocoine). Lidocoine injections ore used in dentistry. 

Levobupivacaine hydrochloride (Chirocaine) is the S-enantiomer of bupivacaine. It too has long action. Animal studies show that it has less CNS and cardiac toxicity than does bupivacaine. It also is slightly more motor sparing than is bupivacaine. 

C. Lidocaine is well tolerated and has a rapid onset and an adequate duration of action for most procedures. Bupivacaine has a particularly long duration of action. This may be advantageous in certain procedures, but not in most. Procaine has a relatively slow onset of action as well as a short duration of action. Etidocaine shows a preference for motor rather than sensory block this limits its effectiveness in obstetrics. 

Answer Bupivacaine use for local anesthesia of this type is very safe and commonly done. However, SOMETIMES inadvertent vascular injection results in a large amount of anesthetic in the systemic circulation. Because the heart is beating, the excitable tissue in the heart is being depolarized repetitively. Local anesthetics bind to rapidly depolarizing tissues more than tissues at rest (frequency-dependent block). Also, bupivacaine has a long duration of action because of its long residence time at receptors (sodium channel). Thus, this combination of factors contributed to the catastrophic outcome of this case. Had the same case involved lidocaine, the resuscitation would have likely been successful. 

Action on CVS Local anaesthetics are myocardial depressant and decrease heart rate and amplitude of myocardial contraction. In high doses, they produce changes in the ECG and may precipitate ventricular fibrillation. Bupivacaine is more cardiotoxic and can produce ventricular tachycardia or fibrillation. 

Local anaesthetics are readily absorbed through mucous membranes and damaged skin. These are weak bases and at tissue pH diffuse through the connective tissue and cellular membranes to reach the nerve fibres where ionization can occur. Amide type local anaesthetics (lignocaine, bupivacaine) are metabolised in the liver and in some cases the kidneys. These are considerably protein bound. For certain procedures the duration of action is prolonged by adding... 

A further property which is of central importance in diffusion is the tissue-binding capacity (or affinity) of a drug. Drugs that are highly lipid-soluble and protein-bound, such as bupivacaine and ropivacaine, are extensively bound to tissue. This limits the rate at which they are transferred from their intracellular sites of action to the vascular compartment. When tissue affinity is great the local anaesthetic effect is prolonged. 

Ester and amide local anaesthetics differ in the manner, site and rate of metabolism. There is little relation between the elimination of local anaesthetics and their duration of action. Amethocaine has a prolonged action due to its high affinity for nerve tissue despite being rapidly removed from plasma. Bupivacaine can be detected in the plasma many hours after its effects have worn off due to continuing absorption from the site of injection. The renal excretion of unchanged local anaesthetics is minimal. 

Bupivacaine is an amide compound with a duration of nerve blocking effect of around 3 hours. It is about four times more potent than lidocaine (lignocaine) and has an intermediate-to-slow onset of action. Bupivacaine is prepared as the hydrochloride salt in aqueous solutions in concentrations of 0.25%, 0.50%, and 0.75%. The incidence of motor block increases with increasing concentration. High doses of bupivacaine are associated with cardiac toxicity. Particular care must be exercised to avoid inadvertent overdosage or when the drug is administered to patients taking concurrent cardioactive medication. 

The choice of local anesthetic for infiltration, peripheral nerve blocks, and central neuraxis (spinal/epidural) blockade is usually based on the duration of action required. Procaine and chloroprocaine are short-acting lidocaine, mepivacaine, and prilocaine have an intermediate duration of action and tetracaine, bupivacaine, levobupivacaine, and ropivacaine are long-... 

It has been suggested that bupivacaine may be more cardiotoxic than other long-acting local anesthetics (eg, ropivacaine). This reflects the fact that bupivacaine-induced blockade of sodium channels is potentiated by the long action potential duration of cardiac cells compared with nerve fibers. The most common electrocardiographic finding in patients with bupivacaine intoxication is a slow idioventricular rhythm with broad QRS complexes and eventually electromechanical dissociation. 

The racemic compound bupivacaine, which was first synthesized by Ekenstam et al. in 1957, is an amide-type LA with a high lipophilicity, protein binding and pKa giving rise to an intermediate onset and a long duration of action. At the same time, bupivacaine has a high toxicity potential relatively often associated with convulsions and life-threatening cardivascular collapse (Moore et al., 1978). Levobupivacaine, the (S)-enantiomer of bupivacaine, has recently been developed for clinical use addressing the enantioselectivity of side-effects of bupivacaine (see below). 

Clinical use Because of its long duration of action, bupivacaine is indicated for long surgical anesthesia where a considerable amount of postoperative pain is expected such as dental and oral surgeries. Infiltration using a 0.25 % solution of bupivacaine produces sensory anesthesia with an onset of 2 to 5 min and a duration of 2 to 4 h or greater (Tetzlaff, 2000). A nerve conduction block with a duration of between 4 to 8 h and occasionally up to 24 h is achieved with injection of 0.5 to 0.75 %... 

In addition to levobupivacaine, ropivacaine is a new long-lasting amide-type LA that has been produced in order to address the enantioselectivity of the cardiotoxicity of bupivacaine. Ropivacaine, which is an (S)-enantiomer containing an n-propyl instead of the butyl moiety of bupivacaine, was launched in 2000. Clinical data indicate a late onset and long duration of action and the anesthetic potency of ropivacaine is comparable to that of bupivacaine (for review see McClellan and Faulds, 2000 Whiteside and Wildsmith, 2001). In animal models, the... 

The action of several anesthetics has also been associated with a modulation of K+ channels. In addition to blocking Na+ currents in spinal neurones of the superficial dorsal horn the local anesthetics bupivacaine, lidocaine and mepivacaine reduce transient, A-type K+ currents in these cells whereas delayed rectifier K+ currents proved to be resistant (Olschewski et al., 1998). Since the A-type K+ current determines the frequency pattern of repetitively firing neurones (Hille, 2001) their suppression in dorsal... 

Bupivacaine, which is more potent than lidocaine, has a prolonged duration of action. 

Most local anesthetic agents consist of a lipophilic group (frequently an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine Table 26-1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers for a few compounds, eg, bupivacaine, ropivacaine. Since ester links (as in procaine) are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. 

Liu JC, Steinemann TL, McDonald MB, et al.Topical bupivacaine and proparacaine a comparison of toxicity, onset of action, and duration of action. Cornea 1993 12 228-232. 

Cataract patients, in general, have relatively little immediate postoperative pain. This absence of pain is, at least in part, due to the long duration of action (up to 12 hours) of bupivacaine used in retrobulbar anesthesia. Some practitioners recommend the use of oral analgesics, such as acetaminophen or ibuprofen, as needed, if the patient experiences minor discomfort in the immediate postsur-gical period.Topical NSAIDs are also reported to decrease immediate postoperative pain. Significant or persistent postoperative pain is considered to be abnormal and may be a symptom of such complications as corneal abrasion, bullous keratopathy, high lOP, or endophthalmitis. 

Bupivacaine has a potent depressant effect on electrical conduction in the heart, primarily via an action on voltage-gated sodium channels that govern the initial rapid depolarization of the cardiac action potential. 

The actions of bupivacaine on channels other than voltage-gated sodium channels probably contribute to the dose-dependent cardiotoxic effects of bupivacaine. 

Inadvertent administration of bupivacaine can lead to fatal cardiovascular collapse that may be refractory to conventional resuscitation. A study in rats has suggested that in addition to its direct cardiotoxic effect, bupivacaine may have a toxic action on the brainstem, and that cardiovascular collapse may result from dysfunction of vital cardiorespiratory control systems (12). 

In the elderly, some local anesthetics (including lidocaine and bupivacaine) have longer durations of action (18). 

A patient who was receiving modified-release morphine for mahgnant pain had a respiratory arrest after intrathecal bupivacaine 12.5 mg. She recovered after treatment with naloxone. Another patient who was taking modified-release morphine was given intrathecal morphine 10 mg and bupivacaine 7.5 mg. He had respiratory distress and became comatose. Morphine-induced respiratory depression was not diagnosed and the patient subsequently died. In both cases, respiratory distress and sedation was probably due to opioid action in the absence of the stimulating effect of pain on respiration, due to the intrathecal bupivacaine (198). 

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