Pharmacology of Local Anesthetics. Outline. • History. • Chemistry and Structure- Activity Relationships. • Mechanism of Action. • Pharmacological effects and. Local anaesthetics reversibly block generation and conduction of nerve impulses . ▫ Cocaine is the first naturally derived local anaesthetic agent discovered in. PDF | On Dec 1, , Akram Uddin and others published Local Anaesthetics: Pharmacology and Digital Anaesthesia.
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Local anesthetics produce a reversible loss of sensation in a portion of the body. Local Amide and ester local anesthetics follow different paths of metabolism. Local anaesthetic drugs are chemical compounds the primary pharmacological activity of which involves inhibition of the excitation—conduction process in. No part of this book may be reproduced or transmitted without publisher's prior permission. Violators will be prosecuted. iii Handbook of Local Anesthesia 6th ed .
Also, smaller fibers are generally more susceptible, because a given volume of local anesthetic solution can more readily block the requisite number of sodium channels for impulse transmission to be entirely interrupted. For these reasons the tiny, rapid-firing autonomic fibers are most sensitive, followed by sensory fibers and finally somatic motor fibers. As patients recover from spinal anesthesia they first regain voluntary motor function, then sensation returns, and finally they can micturate autonomic control.
The dentist is generally spared this consideration because the trigeminal nerve branches anesthetized for dental procedures are comprised only of small, rapid-firing sensory fibers.
However, the many classes of sensory fibers also vary in their diameters and firing rates. For example, pain fibers are more sensitive than those carrying pressure and proprioception. A patient may remain disturbed by a sense of pressure despite complete anesthesia of pain fibers.
Table 1 Suggested dosing recommendations for commonly used local anesthetic agents. Data from Berde and Strichartz. Regional anesthesia in children. Miller RD Ed. Elsevier; Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: Pediatrics ; Patients at the extremes of age have consistently been shown to be at the greatest risk of LAST.
Elderly patients have reduced clearance of LA due to reduced metabolic organ perfusion and pharmacodynamic function, thereby increasing the potential of drug accumulation with repeated boluses of LA or continuous infusions. Elderly patients may have multiple comorbidities, and degenerative changes might render the elderly more susceptible to the systemic effects of LA, despite relatively unchanged levels of protein binding.
As the skeletal muscle may act as a reservoir for LA, reduced skeletal muscle mass has also been implicated in increasing the risk of LAST.
Together, these lead to accelerated perfusion of injection sites, rapid LA absorption, and higher peak free LA concentrations. For the combination of aforementioned reasons, parturients are at an increased risk of LAST, and therefore, it is recommended that doses of peripheral and central neuraxial LAs be reduced. As a result, free plasma concentrations are largely unchanged and dose reduction is often unnecessary, unless the patient is uremic with metabolic acidosis.
Patients with cardiac disease are at an increased risk of LAST.
Those with pre-existing conduction disorders may be predisposed to cardiovascular toxicity, and careful dosing as well as the use of less cardiotoxic drugs such as ropivacaine or levobupivacaine is recommended.
Patients with severe cardiac dysfunction are particularly susceptible to LA-induced myocardial depression and arrhythmias due to reduced hepatic and renal perfusion leading to reduced metabolism and elimination, respectively. Poor perfusion to the injection site may reduce the peak plasma concentration of LA, but if the circulation time is prolonged, the detection of an intravenous injection of LA by detection of a tracer substance such as epinephrine may be delayed.
Dose reduction is unnecessary in mild—moderate heart failure where tissue perfusion is preserved, but is recommended in severe heart failure. Isolated hepatic dysfunction per se does not necessitate dose adjustment for single-shot regional anesthetic techniques despite a reduced hepatic clearance of LAs.
However, in patients receiving repeated boluses or continuous infusions of LA, or those with coexisting cardiac or renal disease, dose reduction is recommended.
Data from large registries and published case reports indicate that the risk of LAST differs between block types. Vasques et al 36 and Gitman and Barrington 27 have summarized the published case report data between and and between and , respectively, identifying a total of cases. Possible factors that may have influenced these results include the dose of LA typically administered and the vascularity of the site involved.
This again may reflect the relative vascularity of the sites of injection and the corresponding plasma concentration of LA that results from a given dose. Fascial plane blocks have become increasingly popular in recent years as a method of providing regional anesthesia of the torso.
The time to peak plasma concentration following a TAP block is 30 minutes on average, but can be as long as 90 minutes in some individuals. The risk of LAST appears to be higher with continuous peripheral nerve blockade compared to single-shot techniques, 48 and this is likely related to the accumulating dose of LA. However, it was reassuring to note that the unbound ropivacaine concentration was much lower and remained well below toxic threshold.
LIA is an increasingly popular technique that involves high-volume periarticular LA infiltration by surgeons, usually in the context of joint replacement surgery. Available studies in total hip and knee arthroplasty indicate that the average peak LA plasma concentrations remain below toxic thresholds. There is presently no available pharmacokinetic data related to LIA for shoulder arthroplasty, but it is worth noting that the baseline incidence of LAST is higher compared to lower limb arthroplasty.
Published data in the peer-reviewed literature on the risk of LAST with liposomal bupivacaine remain scarce. It is reassuring to note that the maximum plasma concentrations of bupivacaine at the maximum US Food and Drug Administration-recommended dose mg or 3.
The presentation of toxicity mirrors that reported from bupivacaine hydrochloride-induced LAST. Tumescent anesthesia for plastic surgical procedures such as liposuction involves the injection of extremely large volumes of lidocaine into subcutaneous tissues, usually with the addition of epinephrine for added safety.
Mortality has been exclusively reported in patients receiving general anesthesia, but clinical features may be insidious and may present late. LAST has been reported following topical anesthesia of the oropharynx and airway for a variety of procedures, including transesophageal echocardiography 65 and bronchoscopy. Systemic absorption of lidocaine depends, to an extent, on the mode of delivery.
A significant proportion is lost to the atmosphere with nebulization and atomization, or swallowed and cleared through first-pass metabolism. Susceptible patients may exhibit LAST with lower dosing regimens, 73 , 74 and careful patient selection is important in considering intravenous lidocaine administration. Intravenous regional anesthesia Bier block is associated with a significant risk of major complications, with symptoms and signs across the entire spectrum of LAST.
Seizures have been reported with doses as low as 1. Accumulated data from case reports, databases, and case series have highlighted several other risk factors for the development of LAST. Notably, a fifth of cases of LAST occur outside of the traditional hospital settings, and half of LAST occurs in the hands of non-anesthesiology specialists. Prevention should be the priority for reducing the frequency and severity of LAST. Increased accuracy of delivery permits reduction in volume and, therefore, dose of LA; the incidence of vascular puncture may be reduced; and visual cues signaling intravascular injection allow termination of injection before a significant dose is delivered.
Restricting the drug dosage may contribute to LAST risk-reduction. Practical interventions such as clear labeling of LA-containing syringes and meticulous handling of these syringes may be of benefit. The transition from Luer connectors to new ISO standard small-bore connecters might also reduce the risk of wrong route injection. All patients receiving injections of LA in doses sufficient to cause LAST should have oxygen, standard monitoring, and intravenous access applied.
Monitoring should continue for at least 30 minutes after completion of injection, as delayed presentations are increasingly occurring. Despite data suggesting inconsistent adherence to standardized protocols, the value of these guidelines cannot be understated. Immediate management involves the general safety and resuscitation measures that are essential in any emergency. First, stop LA injection and call for help.
The immediate priority is to manage the airway, breathing, and circulation. Prompt and effective airway management is crucial to prevent hypoxia, hypercapnia, and acidosis metabolic or respiratory , which are known to potentiate LAST. Recent advances in understanding of the mechanisms of action of lipid emulsion underscore the importance of this therapeutic modality in the management of LAST.
Data suggest that lipid emulsion may shuttle any LA agent from high blood flow organs — such as the heart or brain — to storage or detoxification organs such as muscles or the liver. Convergence of the different administration regimes between the American Society of Regional Anesthesia and Pain Medicine 47 and the Association of Anesthetists of Great Britain and Ireland guidance 89 has led to increased consistency in therapeutic protocols.
An initial bolus of mL should be administered over 2—3 minutes 1.
If circulatory stability is not attained, re-bolusing up to two further times or increasing the infusion to 0. Seizure activity may exacerbate metabolic acidosis, and prompt prevention and termination is crucial. Due to their cardiostable profile, benzodiazepines are the first-line therapy. Propofol should be avoided where there are signs of cardiovascular compromise, in view of the effect of large doses on depressing cardiac function, but small doses may be used.
If seizures persist despite all efforts, low-dose neuromuscular blockade can be considered to reduce metabolic acidosis and hypoxia from ongoing muscular contraction.
Advanced Cardiac Life Support algorithms for cardiopulmonary resuscitation must be followed should cardiac arrest occur. Chest compressions should be initiated immediately and continued until return of spontaneous circulation. In the absence of rapid recovery following advanced life support measures and intravenous lipid emulsion therapy, early consideration should be given to cardiopulmonary bypass for circulatory support.
The inotropic effect of lipid emulsion therapy only occurs once the myocardial LA levels are below a threshold that corresponds to ion channel blocking concentrations. This emphasizes the importance of effective chest compressions to ensure coronary perfusion is sufficient to reduce LA tissue levels in order to obtain the benefit of lipid emulsion therapy. If cardiac output is maintained but there are deleterious CVS effects — such as arrhythmias, conduction block, progressive hypotension, and bradycardia — standard Advanced Cardiac Life Support algorithms should be followed with the omission of LA, such as lidocaine, for the treatment of arrhythmia.
Amiodarone is the first-line antiarrhythmic in the event of ventricular dysrhythmia. Following an episode of LAST with CVS features, patients should be monitored for at least 6 hours, while isolated and rapidly terminating CNS features require patient monitoring for a minimum of 2 hours.
It is advisable that cases should be reported to the registry at www. LAST is a life-threatening adverse event, and recent advances in understanding the pathophysiological basis of the condition and its therapy will improve patient safety. It is imperative that practitioners who use LA in their clinical practice are cognizant of the mechanisms, risk factors, prevention, and therapeutic modalities.
All authors made substantial contributions to the conception and design of this manuscript, drafting the article, and final approval of the published version. All authors agree to be held accountable for all aspects of the work. The authors report no conflicts of interest in this work. El-Boghdadly K, Pawa A. The erector spinae plane block: The Erector Spinae Plane Block. Reg Anesth Pain Med. Ilfeld BM. Continuous peripheral nerve blocks: Anesth Analg. Combined thoracic paravertebral and pectoral nerve blocks for breast surgery under sedation: Tumescent anaesthesia.
Dillane D, Finucane BT. Local anesthetic systemic toxicity. Butterworth JF. Models and mechanisms of local anesthetic cardiac toxicity: Tucker GT. Pharmacokinetics of local anaesthetics. Br J Anaesth. Local anesthetics: Anesth Prog. Such supply can be derived from the mylohyoid nerve, the auriculotemporal nerve and the upper cervical nerves. The mylohyoid branch leaves the main inferior alveolar trunk more than a centimeter superior to the mandibular foramen 21 so may not be affected by a conventional approach to the latter nerve.
However, it may be anaesthetised using the techniques of Gow-Gates and Akinosi. Alternatively, a lingual infiltration adjacent to the tooth of interest may be effective. The auriculotemporal nerve occasionally sends branches to the pulps of the lower teeth through foramina high on the ramus. When removing third molar teeth it is not unusual to discover that, despite an apparently effective lingual block, the disto-lingual gingiva is not anaesthetised.
This accessory supply is readily countered by injecting just disto-lingual to the third molar. In fact this finding is so common that a routine injection of about 0. When using regional block anaesthesia structures in the mid-line may not be satisfactorily anaesthetised as they receive bilateral innervation.
A classic example is the failure of inferior alveolar or mental and incisive nerve blocks to anaesthetise a lower central incisor. The solution is to block the contralateral nerve with an inferior alveolar nerve block, incisive nerve block or buccal infiltration. Alternatively, an infiltration, intraligamentary or intra-osseous injection may be administered at the outset in this area. Barriers to anaesthetic diffusion The most obvious barrier to anaesthetic diffusion is the thick cortical plate of the mandibular alveolus which precludes infiltration anaesthesia in adults with the possible exception of the mandibular mid-line.
The first molar region in the adult maxilla occasionally presents a similar problem. In this region the thick zygomatic buttress can prevent passage of the anaesthetic to the dental apices.
The answer to this problem is to inject mesial and distal to the first molar away from the buttress as the first molar can obtain supply from both posterior and middle superior alveolar nerves a posterior superior alveolar nerve block may be unsuccessful.
Pathological causes of failure of anaesthesia Factors precluding access Factors which can preclude access include trismus because of a number of causes and anatomical changes because of trauma or surgery. Trismus is the most likely factor in practice and this is often because of an infective cause. Buccal infiltrations in the maxilla are still possible with the mouth closed. A way to anaesthetise the palatal tissues in the patient with trismus is to inject while advancing a needle toward the palate through the mesial and distal gingival papillae from the buccal side.
The best way to achieve inferior alveolar anaesthesia in the patient with trismus is to use the Akinosi closed-mouth technique described above. There are extra-oral approaches but these are not recommended in practice.
Although methods of anaesthetising the nerve supply to the teeth are possible in the patient with trismus the practitioner must question the appropriateness of administering the injection. Can the proposed treatment be completed in such patients?
It may be that half-completed treatment is worse than none at all. It may be prudent to allow the trismus to resolve prior to dental treatment. Inflammation It is apparent to all practitioners that teeth with inflamed pulps can be difficult to anaesthetise. A number of suggestions have been proposed to explain this finding. The classic explanation for this is that the low tissue pH in areas of inflammation affects the activity of the local anaesthetic solution by decreasing the concentration of the unionised lipophilic fraction which diffuses through nerve sheaths.
Similarly areas of inflammation have an increased blood supply due to vasodilatation and this might increase anaesthetic 'wash-out'. However, these answers do not explain the failure of regional block techniques where the solution may be deposited 4 or 5 cm from the area of inflammation. The most plausible explanation is that inflammation makes nerves hyperalgesic.
However, no tooth is resistant to local anaesthesia. The practitioner therefore has to decide on the maximum volume of local anaesthetic he is willing to inject for that patient and be prepared to use up to that maximum to anaesthetise that tooth. This may mean limiting treatment to only one tooth but if it takes the maximum safe dose — so be it.
On no account should the predetermined safe maximum dose be exceeded. In healthy patients there is usually sufficient room for manoeuvre to administer a dose sufficient to halt conduction in the tooth without producing generalised central nervous system effects.
The answer is to inject more solution. This does not have to be at the same site, eg the combination of infiltration and regional block anaesthesia can be used in the maxilla eg infiltration at the apex of an upper lateral incisor plus an infra-orbital nerve block.