Pseudocholinesterase deficiency

Remifentanil, recently approved for use in the United States and Europe, is the first truly ultra-shortacting opioid. Remifentanil s uifique ester linkage allows it to be rapidly degraded to an inactive carboxylic acid metabolite by nonspecific esterases found in tissue and red blood cells. Since it is not a good substrate for plasma pseudocholinesterase, deficiency of the enzyme does not influence its duration of action. Also, hepatic and renal insufficiencies do not influence remifentanil s pharmacokinetics, so it is useful when liver or kidney failure is a factor. Because of its rapid clearance following infusion, remifentanil has gained popularity as an agent for maintenance of anesthesia when an IV technique is practical. 

Other hereditary enzyme deficiencies that may result in adverse reactions to certain drugs are comparatively rare, often familial, and of worldwide distribution. Examples of these conditions are pseudocholinesterase deficiencies in certain people who, when given succinylcholine or suxamethonium, develop a profound, general neuromuscular blockade with apnea (38). 

J Theodore, JE Millen, HV Murdaugh. Prolonged postoperative apnea with pseudocholinesterase deficiency. Am Rev Respir Dis 96 508, 1967. 

Pseudocholinesterase deficiency. The neuromuscular blocking action of suxamethonium is terminated by plasma pseudocholinesterase. True cholinesterase (acetylcholinesterase) hydrolyses acetylcholine released by nerve endings, whereas various tissues and plasma contain other nonspecific, hence pseudo, esterases. Affected individuals form so little plasma pseudocholinesterase that metabolism of suxamethonium is seriously reduced. The deficiency characteristically comes to light when a patient fails to breathe spontaneously after a surgical operation, and assisted ventilation may have to be undertaken for hours. Relatives of an affected individual—for this as for other inherited abnormalities carrying avoidable risk—should be sought out, checked to assess their own risk, and told of the result. The prevalence of pseudocholinesterase deficiency in the UK population is about 1 in 2500. 

About 10% of an intravenous dose of suxamethonium is excreted unchanged in the urine with a half-life of 1-2 minutes (1). The half-life is prolonged in patients with pseudocholinesterase deficiency or an abnormal pseudocholinesterase. 

P20. Putnam, L. P., Pseudocholinesterase deficiency An additional preoperative consideration in outpatient diagnostic procedures. South. Med. J. 70, 831-832 (1977). 

Common ICU use for long-term immobilization Inactivated by spontaneous breakdown Prolonged action in pseudocholinesterase deficiency Stimulates cardiac muscarinic receptors... 

D. 0stergaard, F. S. Jensen and J Viby-Mogensen, Pseudocholinesterase deficiency and anticholinesterase toxicity in Clinical and Experimental Toxicology of Organophosphates and Carbamates, ed. B. Ballantyne and T. C. Marrs, Butterworth-Heinemann, Oxford, 1992, pp. 520-527. 

W. Hodgkin, E. R. Giblett, H. Levine, W. Bauer and A. G. Motulsky, Complete pseudocholinesterase deficiency genetic and immunologic characterization, J. Clin. Invest., 1965, 44, 486-493. 

F. K. Soliday, Y. P. Conley and R. Henker, Pseudocholinesterase deficiency a comprehensive review of genetic, acquired, and drug influences, AANA J., 2010, 78, 313-320. 

Salmon et al., 1970), pseudocholinesterase deficiency (Hodgkin et al., 1965), myophosphorylase deficiency (Robbins, 1960), acatalasia (Nishi-mura et al., 1961 Takahara et al., 1962), a variant of factor VIII deficiency (hemophilia) (Feinstein et al., 1969), and several others (Boyer et al., 1973). Because of the absence of any identifiable protein in these conditions, it has been cautioned that enzyme or nonenzyme replacement be carefully weighed, since the patient may treat such replacement as foreign protein (Boyer et al., 1973). 

Pseudocholinesterase is a polymorphic enzyme. Succinylcholine is a paralyzing agent used during surgery to prevent muscle twitching. When succinylcholine is used in patients who are deficient in pseudocholinesterase, they wake up from the anesthetic but remain paralyzed for a prolonged period of time. 

The effect of a standard dose of succinylcholine lasts only about 10 min. It is often given at the start of anesthesia to facilitate intubation of the patient. As expected, choUnesterase inhibitors are unable to counteract the effect of succinylcholine. In the few patients with a genetic deficiency in pseudocholinesterase (= nonspecific cholinesterase), the succinylcholine effect is significantly prolonged. 

N-acetyltransf erase, NAT2) hydroxylation status (CYP2D6 CYPC19) esterase deficiency (pseudocholinesterase). 

Resistance to suxamethonium. This rare condition is characterised by increased pseudocholinesterase activity and failure of normal doses of suxamethonium to cause muscular relaxation (cf Cholinesterase deficiency, above). 

Atypical (deficient) pseudocholinesterase. There is a delay in the metabolism of suxamethonium and mivacurium. The duration of neuromuscular block depends on the type of pseudocholinesterase. 

Genetic factors are particularly important in humans and can influence the response to the compound or the disposition of the compound and hence its toxicity. Several genetic factors affecting metabolism are known in which a non-functional or less functional form of the enzyme is produced in a particular phenotype, e.g. acetylator phenotype (N-acetyltransferase NAT2) hydroxylator status (cytochrome P-450 2D6) esterase deficiency (pseudocholinesterase). 

Age does not seem to alter the pharmacokinetics. Tests in patients with genetic deficiency of pseudocholinesterase also showed no significant difference in tm. The half-life of succinylcholine, on the other hand, increased from 2.6 minutes to 4 hours in patients devoid of this enzyme. It appears that the ester group activation of the Hofmann elimination reaction mutually promotes ester hydrolysis as well. The goal of chemical- over enzyme-catalyzed metabolism in vivo seems to have been achieved. The possibility that ester hydrolysis may be catalyzed by nonspecific esterases is likely that plasma cholinesterase is not utilized is established. 

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