Lidocaine
Lidocaine (pronounced /ˈlaɪdɵkeɪn/) (INN), (Xylocaine) or lignocaine (/ˈlɪɡnɵkeɪn/) (formerBAN) is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.
History
Lidocaine, the first amino amide-type local anesthetic, was first synthesized under the name Xylocaine by Swedish chemist Nils Löfgren in 1943. His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.[ It was first marketed in 1949. Etymology: from one of its many chemical names - [alpha-Diethylamino-2,6-dimethylacetani- ] - lide + ~ocaine.
Preparation
Lidocaine may be prepared in two steps by the reaction of 2,6-xylidine with chloroacetyl chloride, followed by the reaction with diethylamine:
Pharmacokinetics
Lidocaine is approximately 95% metabolized (dealkylated) in the liver by CYP3A4 to the pharmacologically-active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half life than lidocaine but also is a less potent sodium channel blocker.[
The elimination half-life of lidocaine is approximately 90–120 minutes in most patients. This may be prolonged in patients with hepatic impairment (average 343 minutes) or congestive heart failure (average 136 minutes)
Pharmacodynamics
Anesthesia
Lidocaine alters signal conduction in neurons by blocking the fast voltage gated sodium (Na+) channels in the neuronal cell membrane that are responsible for signal propagation. With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential. This creates the anaesthetic effect by not merely preventing pain signals from propagating to the brain but by stopping them before they begin. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations will also affect other modalities of neuron signaling.
Indications
Topical lidocaine has been shown to relieve postherpetic neuralgia (arising, for example, from shingles) in some patients, though there is not enough study evidence to recommend it as a first-line treatment. It also has uses as a temporary fix for tinnitus. Although not completely curing the illness, it has been shown to reduce the effects by around two thirds.
The efficacy profile of lidocaine as a local anesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block and surface anesthesia. Longer-acting substances such as bupivacaine are sometimes given preference for spinal and peridural anesthesias; lidocaine, on the other hand, has the advantage of a rapid onset of action. Adrenalinevasoconstricts arteries and hence delays the resorption of Lidocaine, almost doubling the duration of anaesthesia. For surface anesthesia several formulations are available that can be used e.g. for endoscopies, before intubations etc.
Lidocaine is also the most important class 1B antiarrhythmic drug: it is used intravenously for the treatment of ventricular arrhythmias (foracute myocardial infarction, digitalis poisoning, cardioversion or cardiac catheterization). However, a routine prophylactic administration is no longer recommended for acute cardiac infarction; the overall benefit of this measure is not convincing.
Lidocaine has also been efficient in refractory cases of status epilepticus.
Lidocaine has also proved effective in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge
Contraindications
Contraindications for the use of lidocaine include:
§ Heart block, second or third degree (without pacemaker)
§ Severe sinoatrial block (without pacemaker)
§ Serious adverse drug reaction to lidocaine or amide local anaesthetics
§ Concurrent treatment with quinidine, flecainide, disopyramide, procainamide (Class I antiarrhythmic agents)
§ Prior use of Amiodarone hydrochloride
§ Hypotension not due to Arrhythmia
Adverse drug reactions
Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, butallergic reactions only rarely occur.
Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth (also known as circumoral paraesthesia), tinnitus, tremor, dizziness, blurred vision, seizures) followed by depression, and with increasingly heavier exposure: drowsiness, loss of consciousness, respiratory depression and apnoea). Cardiovascular effects includehypotension, bradycardia, arrhythmias, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.
ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/minute). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension, bradycardia,arrhythmias, cardiac arrest, muscle twitching, seizures, coma, and/or respiratory depression.
Overdosage
Overdosage with lidocaine can be a result of excessive administration via topical or parenteral routes, accidental oral ingestion of topical preparations by children, accidental intravenous (rather than subcutaneous, intrathecal or paracervical) injection or prolonged use of subcutaneous infiltration anesthesia during cosmetic surgical procedures. These occurrences have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantitated in blood, plasma or serum to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. It is important in the interpretation of analytical results to recognize that lidocaine is often routinely administered intravenously as an antiarrhthymic agent in critical cardiac care situations.
Insensitivity to lidocaine
Relative insensitivity to lidocaine is genetic. In hypokalemic sensory overstimulation, relative insensitivity to lidocaine has been described in people who also have attention deficit hyperactivity disorder. In dental anesthesia, a relative insensitivity to lidocaine can occur for anatomical reasons due to unexpected positions of nerves. Some people with Ehlers-Danlos syndrome are insensitive to lidocaine.[12]
Dosage forms
Lidocaine, usually in the form of lidocaine hydrochloride, is available in various forms including:
§ Injected local anesthetic (sometimes combined with epinephrine to reduce bleeding)
§ Dermal patch (sometimes combined with prilocaine)
§ Intravenous injection (sometimes combined with epinephrine to reduce bleeding)
§ Intravenous infusion
§ Nasal instillation/spray (combined with phenylephrine)
§ Oral gel (often referred to as "viscous lidocaine" or abbreviated "lidocaine visc" or "lidocaine hcl visc" in pharmacology; used as teething gel)
§ Oral liquid
§ Topical liquid
§ Topical patch (lidocaine 5% patch is marketed as "Lidoderm" in the US (since 1999) and "Versatis" in the UK
§ Topical aerosol spray
§ Inhaled via a nebulizer
Adulterant in cocaine
Mexiletine
Mexiletine (INN, sold under the trade name Mexitil) belongs to the Class IB anti-arrhythmicgroup of medicines. It is used to treat arrhythmias within the heart - or seriously irregular heartbeats. It slows nerve impulses in the heart and makes the heart tissue less sensitive. Dizziness, heartburn, nausea, nervousness, trembling, unsteadiness are common side effects. It is available in injection and capsule form.
Class IB antiarrhythmics decrease action potential duration by shortening the repolarization phase. This is achieved by blocking sodium channels.
Mexiletine may also be of use in patients experiencing refractory pain and is also effective for treating muscle stiffness resulting from myotonia congenita (Thomsen disease) or myotonic dystrophy (Steinert's disease).
Tocainide
Quick look at the Pharmacokinetics
Tocaine is a lidocaine analog, that does not have significant 1st pass metabolism. It is found in two enantiomers. The R isomer is 4x as potent as the S. Oral bioavaliability is 0.9-1.0. In the blood tocainide is 10-20% protein bound. The Volume of distribution is 2.5-3.5 L/kg. 30-50% is excreted unchanged in the urine. The more active R-isomer is cleared faster in anephric patients or those with severe renal dysfunction. The main metabolite is the glucuronidated tocainide carbamic acid. The glucuronosyl transferase is apparently induced by rifampin. Weak inhibition of Cyp1A2 leads to a mild theophylline interaction. (Not verbatim)
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin (fœnit'oin, IPA) acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels. Aside from seizures, it is an option in the treatment of trigeminal neuralgia in the event that carbamazepineor other 1st line treatment is deemed inappropriate.
It is sometimes considered a class 1b antiarrhythmic.
Trade names
Phenytoin sodium has been marketed as Phenytek by Mylan Laboratories, previously Bertek Pharmaceuticals, and Dilantin; Australia also Dilantin Kapseals and Dilantin Infatabs in theUSA, Eptoin by Abbott Group in India and as Epanutin in the UK and Israel, by Parke-Davis, now part of Pfizer. In the USSR
History
Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908. Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, outside scientists including H. Houston Merritt and Tracy Putnam phenytoin's usefulness for controlling seizures, without the sedative effects associated with phenobarbital.
According to Goodman and Gilman's Pharmacological Basis of Therapeutics,
In contrast to the earlier accidental discovery of the antiseizure properties of bromide andphenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals.
There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA. Jack Dreyfus, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and depression when he received a prescription for Dilantin in 1966. He is believed to have supplied large amounts of the drug to Richard Nixon throughout the late 1960s and early 1970s. Dreyfus' experience with phenytoin is outlined in his book, A Remarkable Medicine Has Been Overlooked,.[4] Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. This was partially because Parke-Davis was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies. It was approved by the USA Food and Drug Administration in 1953 for use in seizures.
Dilantin made an appearance in the 1962 novel One Flew Over the Cuckoo's Nest by Ken Kesey, both as an anticonvulsant and as a mechanism to control inmate behavior.
In 2008, the drug was put on the FDA's Potential Signals of Serious Risks List to be further evaluated for approval. The list means that the FDA has identified a potential safety issue, but does not mean that FDA has identified a causal relationship between the drug and the listed risk.
According to the FDA's New Safety Information Identified by the Adverse Event Reporting System (AERS) Phenytoin Injection (Dilantin) has been associated with the risk of Purple Glove Syndrome.
Side-effects
Neurologic
At therapeutic doses, phenytoin produces horizontal gaze nystagmus, which is harmless but occasionally tested for by police as a marker for alcohol intoxication (which can also produce nystagmus). At toxic doses, patients experience sedation, cerebellar ataxia, andophthalmoparesis, as well as seizures. Idiosyncratic side-effects of phenytoin, as with other anticonvulsants, include rash and severe allergicreactions.
Phenytoin may accumulate in the cerebral cortex over long periods of time, as well as causing atrophy of the cerebellum when administered at chronically high levels. Despite this, the drug has a long history of safe use, making it one of the more popular anti-convulsants prescribed by doctors, and a common "first line of defense" in seizure cases.
Hematologic
It has been suggested that phenytoin causes a reduction in folic acid levels, predisposing patients to megaloblastic anemia. Folic acid is presented in foods as polyglutamate, which is then converted into monoglutamates by intestinal conjugase. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency. Other side effects may include: agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia.
Teratogenicity
Phenytoin is a known teratogen. The syndrome consists of craniofacial anomalies (broad nasal bridge, cleft lip and palate, microcephaly) and a mild form of mental retardation (average IQ=71). This syndrome resembles the well-described Fetal Alcohol Syndrome] and has also been called the "fetal hydantoin syndrome".[] Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.
Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data do not provide clear answers.[
Carcinogenicity
There is no good evidence that phenytoin is a human carcinogen.
Gingival
Phenytoin has been associated with drug induced gingival enlargement (hyperplasia) in the oral cavity probably due to above mentioned folate defiency. Plasma concentrations needed to induce gingival lesions has not been clearly defined. Effects consist of the following: bleeding upon probing, increased gingival exudate, pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment.
Suicide risk
Following almost 200 studies of 11 anti-seizure drugs, the FDA has also warned of an increased suicide risk for any patients treated with certain anti-seizure drugs. The study of 44,000 patients found that patients whose epilepsy is treated with drugs face about twice the risk of suicidal thoughts compared to placebo-takers. Although phenytoin was not named in the study, the FDA announced that it expected the risk applied to every epilepsy drug.[
Dermatologic
Hypertrichosis, rash, exfoliative dermatitis, pruritis.
In autoimmune disease
Phenytoin has been known to cause drug-induced lupus.
Phenytoin therapy has been linked to the life-threatening skin reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis(TEN). These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B*1502.This allele occurs almost exclusively in patients with ancestry across broad areas of Asia , including South Asian Indians.
In immunodeficiency disease
Phenytoin is also associated with induction of reversible IgA deficiency.[1
Interactions
Phenytoin is an inducer of the CYP3A4 and CYP2C19 families of the P450 enzyme responsible for the hepatic degradation of various drugs.
COUMARIN and WARFARIN increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism.
§ ethotoin
No comments:
Post a Comment