Depolarizing Blockade

Depolarizing BlockadeSuccinylcholine (SCh), the only depolarizing NMBD, is composed of two ACh molecules linked together via an acetyl moiety. SCh binds to the α-subunits of the nicotinic AChR leading to depolarization of the postjunctional membrane. Because SCh is not degraded by AChE as rapidly as ACh, it persistently depolarizes the motor endplate, leading to inactivation of the voltage-gated sodium channels in the perijunctional zone that are necessary for propagation of the depolarization. Induction doses of SCh produce a rapid onset (about 1 minute) of a transient agonist effect (e.g., muscle twitch) followed by skeletal muscle paralysis lasting 4 to 6 minutes. These characteristics make SCh a common choice for facilitating rapid tracheal intubation.

1. SCh effect terminates when the drug diffuses away from the AChRs and is rapidly hydrolyzed by plasma cholinesterase (produced in the liver and also referred to as pseudocholinesterase) to succinylmonocholine and then, more slowly, to succinic acid and choline. This enzyme is not the same as AChE and is not found in the synaptic cleft. However, inhibitors of AChE affect both enzymes to different degrees.
2. Side effects of SCh are related to its agonist effects at both the nicotinic and muscarinic AChRs.
   1. Myalgia is common postoperatively, especially in the muscles of the abdomen, back, and neck. It is attributed to muscle fasciculations and observed more frequently in females and younger patients after minor surgical procedures.
   2. Cardiac dysrhythmias. SCh has no direct effect on the myocardium. However, ganglionic stimulation may increase heart rate and blood pressure in adults. Alternatively, SCh may stimulate muscarinic receptors at the sinus node, producing sinus bradycardia, a junctional rhythm, or even asystole, particularly in children and following repeated exposure within a short time interval (i.e., 5 minutes) in adults. Pretreatment of children with intravenous (IV) atropine immediately before SCh reduces the occurrence of bradyarrhythmias.
   3. SCh depolarization exaggerates the usual transmembrane ionic flux and normally induces elevation of serum potassium by 0.5 to 1.0 mEq/L. However, life-threatening hyperkalemia and cardiovascular collapse may occur in patients with major burns, massive tissue injuries, extensive denervation of skeletal muscle, or upper motor neuron diseases. This effect is attributed to a proliferation of extrajunctional AChRs or damaged muscle membranes and a massive release of potassium upon stimulation. In patients with burns, the period of greatest risk is from 2 weeks to 6 months after the burn has been sustained. However, it is recommended to avoid SCh after the first 24 hours and for 2 years from the time of the injury. Patients with mild elevations of potassium related to renal failure may usually safely receive SCh.
   4. A transient increase in intraocular pressure occurs 2 to 4 minutes following SCh, presumably due to contractions of the extraocular muscles with associated compression of the globe or cycloplegia causing obstruction of aqueous outflow via the trabecular meshwork. However, the use of SCh in open eye injuries is still acceptable for rapid sequence inductions (see Chapter 26).
   5. Increased intragastric pressure results from fasciculations of abdominal muscles. The pressure increase (averaging 15 to 20 mm Hg in an adult) is counterbalanced by an even greater increase in the lower esophageal sphincter tone.
   6. SCh produces a mild transient increase in intracranial pressure (see Chapter 25).
   7. A history of malignant hyperthermia (MH) is an absolute contraindication to the use of SCh. Some degree of masseter muscle spasm may be a normal response to SCh, but severe jaw rigidity increases the risk that a fulminant MH episode may follow. Generalized muscle rigidity, tachycardia, tachypnea, and profound hyperpyrexia after SCh should alert the clinician to this condition (see Chapter 19).
   8. Pretreatment with a subparalyzing dose of a nondepolarizing NMBD (e.g., cisatracurium 1 mg IV or rocuronium 3 mg IV) 2 to 4 minutes before SCh may blunt visible fasciculations but is not uniformly effective in attenuating the above-mentioned side effects. Moreover, awake patients pretreated with a nondepolarizing NMBD may experience diplopia, weakness, or dyspnea. When pretreating for a rapid sequence induction, the subsequent IV dose of SCh should be increased to 1.5 mg/kg.
3. Phase I blockade. Neuromuscular blockade produced by SCh can be separated into two phases. Phase I blockade (Fig. 13.2) is the usual response to SCh as previously described and is characterized by the following:
   1. Transient muscle fasciculations followed by relaxation.
   2. Absence of fade to tetanic or TOF stimulation.
   3. Absence of posttetanic potentiation (PTP)
   4. AChE inhibitors potentiate rather than reverse the block.
4. Phase II blockade is most likely to occur after repeated or continuous administration of SCh when the total dose exceeds 3 to 5 mg/kg. Phase II blockade is thought to be secondary to repeated channel opening, causing distortion of the normal electrolyte balance and desensitizing the junctional membrane to further depolarization. It has some of the characteristics of a nondepolarizing blockade:
   1. Fade after tetanic or TOF stimulation
   2. Presence of PTP
   3. Tachyphylaxis (increasing dose requirement)
   4. Prolonged recovery
   5. Partial or complete reversal by AChE inhibitors
5. Prolonged blockade following SCh may be caused by low levels of plasma cholinesterase, a drug-induced inhibition of its activity, or a genetically atypical enzyme.
   1. Decreased plasma cholinesterase levels are found in the last trimester of pregnancy and for several days postpartum, severe liver or kidney disease, starvation, carcinomas, hypothyroidism, burn patients, decompensated cardiac failure, and after therapeutic radiation.
   2. Inhibition of plasma cholinesterase occurs with the use of organophosphorus compounds (e.g., echothiophate eye drops and insecticides) and other drugs that inhibit AChE (e.g., neostigmine, pyridostigmine, and donepezil), chemotherapeutic agents (e.g., cyclophosphamide and nitrogen mustard), oral contraceptives, glucocorticoids, esmolol, and monoamine oxidase inhibitors. Plasma cholinesterase levels are not usually altered by hemodialysis.
   3. Several genetic variants of plasma cholinesterase exist: normal (N), atypical (A), fluoride resistant (F), and silent (S). Homozygous atypical cholinesterase (A–A, prevalence 0.04%) results in prolonged (2 to 3 hours) skeletal muscle paralysis and respiratory insufficiency following a conventional dose of SCh. Heterozygous atypical cholinesterase (N–A, prevalence 4%) results in only modest prolongation of effect.
   4. The dibucaine number is a laboratory assay used to characterize plasma cholinesterase abnormality. Normally, the local anesthetic dibucaine inhibits plasma cholinesterase activity by about 80% (dibucaine number of 80), whereas A–A plasma cholinesterase is inhibited by about 20% (dibucaine number of 20). In N–A, dibucaine numbers range from 30 to 65. The comparable fluoride number ranges from 0 to 60. N–F individuals (prevalence 0.005%) have slight prolongation of SCh effect, a normal dibucaine number, and a reduced fluoride number. A heterozygous silent N–S individual (incidence 0.005%) has slightly prolonged effect, but dibucaine and fluoride numbers are normal. Homozygotes F–F and S–S are extremely rare.
   5. Patients exhibiting prolonged blocks after a single administration of succinylcholine require sedation and continued intubation until there is a return of twitches. The neuromuscular blockade at this point is similar to that seen with nondepolarizing NMBD. Once fade with TOF is observed, reversal with neostigmine/glycopyrrolate is possible. Blood assays should be performed to determine total cholinesterase and, dibucaine number, and fluoride numbers.