Pharmacology Ch 5.pdf

Cholinergic Antagonists I. OVERVIEW 5 ANTIMUSCARINIC AGENTS The cholinergic antagonists (also called cholinergic blockers, parasympatholytics, or anticholinergic drugs) bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these agents...

Cholinergic Antagonists I. OVERVIEW 5 ANTIMUSCARINIC AGENTS The cholinergic antagonists (also called cholinergic blockers, parasympatholytics, or anticholinergic drugs) bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these agents selectively block muscarinic receptors of the parasympathetic nerves. The effects of parasympathetic innervation are, thus, interrupted, and the actions of sympathetic stimulation are left unopposed. A second group of drugs, the ganglionic blockers, show a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia. Clinically, they are the least important of the anticholinergic drugs. A third family of compounds, the neuromuscular-blocking agents, interfere with transmission of efferent impulses to skeletal muscles. These agents are used as skeletal muscle relaxant adjuvants in anesthesia during surgery, intubation, and various orthopedic procedures. Figure 5.1 summarizes the cholinergic antagonists discussed in this chapter. Atropine ISOPTO ATROPINE, Benztropine COGENTIN Cyclopentolate AK-PENTOLATE, CYCLOGYL Darifenacin ENABLEX Fesoterodine TOVIAZ Ipratropium ATROVENT Oxybutynin DITROPAN, GELNIQUE, OXYTROL Scopolamine ISOPTO HYOSCINE, SCOPACE, II. ANTIMUSCARINIC AGENTS GANGLIONIC BLOCKERS Commonly known as antimuscarinics, these agents (for example, atropine and scopolamine) block muscarinic receptors (Figure 5.2), causing inhibition of all muscarinic functions. In addition, these drugs block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands. In contrast to the cholinergic agonists, which have limited usefulness therapeutically, the cholinergic blockers are beneficial in a variety of clinical situations. Because they do not block nicotinic receptors, the antimuscarinic drugs have little or no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia. [Note: A number of antihistaminic and antidepressant drugs also have antimuscarinic activity.] A. Atropine Atropine [A-troe-peen] is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. It binds competitively and prevents acetylcholine (ACh) from binding to those sites (Figure 5.3). Atropine acts both centrally and peripherally. Its general actions last about 4 hours, except when placed topically in the eye, where the action may last for days. Neuroeffector organs have varying sensitivity to atropine. The greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva (Figure 5.4). TRANSDERM SCŌP Solifenacin VESICARE Tiotropium SPIRIVA HANDIHALER Tolterodine DETROL Trihexyphenidyl ARTANE Tropicamide MYDRIACYL, TROPICACYL Trospium chloride SANCTURA Mecamylamine NOT AVAILABLE Nicotine COMMIT, NICODERM, NICORETTE, NICOTROL INHALER NEUROMUSCULAR BLOCKERS Atracurium ONLY GENERIC Cisatracurium NIMBEX Pancuronium PAVULON Rocuronium ZEMURON Succinylcholine ANECTINE, QUELICIN Vecuronium ONLY GENERIC Figure 5.1 Summary of cholinergic antagonists. 60 5. Cholinergic Antagonists AUTONOMIC Sympathetic innervation of adrenal medulla Sympathetic SOMATIC Parasympathetic Preganglionic neuron Ganglionic transmitter Acetylcholine Acetylcholine Nicotinic receptor Nicotinic receptor Epinephrine and norepinephrine released into the blood Norepinephrine Adrenergic receptor Adrenergic receptor Site of action of antimuscarinic drugs Effector organs Figure 5.2 Sites of actions of cholinergic antagonists. Scopolamine Atropine Acetylcholine Muscarinic receptor Figure 5.3 Competition of atropine and scopolamine with acetylcholine for the muscarinic receptor. Sites of action of ganglionic blockers Nicotinic receptor Postganglionic neurons Adrenal medulla Neuroeffector transmitter No ganglia Acetylcholine Acetylcholine Muscarinic receptor Site of action of neuromuscular blockers Acetylcholine Nicotinic receptor Skeletal muscle 1. Actions: a. Eye: Atropine blocks all cholinergic activity on the eye, resulting in persistent mydriasis (dilation of the pupil, see Figure 4.6, p. 52), unresponsiveness to light, and cycloplegia (inability to focus for near vision). In patients with narrow-angle glaucoma, intraocular pressure may rise dangerously. Shorter-acting agents, such as the antimuscarinic tropicamide, or an α -adrenergic drug, such as phenylephrine, are generally favored for producing mydriasis in ophthalmic examinations. b. Gastrointestinal (GI): Atropine (as the active isomer, l-hyoscyamine) can be used as an antispasmodic to reduce activity of the GI tract. Atropine and scopolamine (which is discussed below) are probably the most potent drugs available that produce this effect. Although gastric motility is reduced, hydrochloric acid production is not significantly affected. Thus, the drug is not effective in promoting healing of peptic ulcer. [Note: Pirenzepine (see p. 51), an M1-muscarinic antagonist, does reduce gastric acid secretion at doses that do not antagonize other systems.] In addition, doses of atropine that reduce spasms also reduce saliva secretion, ocular accommodation, and micturition (urination). These effects decrease patient compliance with the use of these medications. II. Antimuscarinic Agents 61 c. Urinary system: Atropine-like drugs are also used to reduce hypermotility states of the urinary bladder. It is still occasionally used in enuresis (involuntary voiding of urine) among children, but α-adrenergic agonists with fewer side effects may be more effective. e. Secretions: Atropine blocks the salivary glands, producing a drying effect on the oral mucous membranes (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. [Note: Inhibition of secretions by sweat glands can cause elevated body temperature, which can be dangerous in children and the elderly.] 2. Therapeutic uses: a. Ophthalmic: In the eye, topical atropine exerts both mydriatic and cycloplegic effects, and it permits the measurement of refractive errors without interference by the accommodative capacity of the eye. [Note: Phenylephrine or similar α-adrenergic drugs are preferred for pupillary dilation if cycloplegia is not required]. Shorter-acting antimuscarinics (cyclopentolate and tropicamide) have largely replaced atropine due to the prolonged mydriasis observed with atropine (7–14 days versus 6–24 hours with other agents). Atropine may induce an acute attack of eye pain due to sudden increases in eye pressure in individuals with narrow-angle glaucoma. b. Antispasmodic: Atropine (as the active isomer, l-hyoscyamine) is used as an antispasmodic agent to relax the GI tract and bladder. c. Antidote for cholinergic agonists: Atropine is used for the treatment of overdoses of cholinesterase inhibitor insecticides and some types of mushroom poisoning (certain mushrooms contain cholinergic substances that block cholinesterases). Massive doses of the antagonist may be required over a long period of time to counteract the poisons. The ability of atropine to enter the central nervous system (CNS) is of particular importance. The drug also blocks the effects of excess ACh resulting from acetylcholinesterase (AChE) inhibitors such as physostigmine. d. Antisecretory: The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery. >10.0 mg Dose of atropine d. Cardiovascular: Atropine produces divergent effects on the cardiovascular system, depending on the dose (Figure 5.4). At low doses, the predominant effect is a decreased cardiac rate (bradycardia). Originally thought to be due to central activation of vagal efferent outflow, the effect is now known to result from blockade of the M1 receptors on the inhibitory prejunctional (or presynaptic) neurons, thus permitting increased ACh release. With higher doses of atropine, the M2 receptors on the sinoatrial node are blocked, and the cardiac rate increases modestly. This generally requires at least 1 mg of atropine, which is a higher dose than ordinarily given. Arterial blood pressure is unaffected, but, at toxic levels, atropine will dilate the cutaneous vasculature. 5.0 mg Hallucinations and delirium; coma Rapid heart rate; palpitation; marked dryness of the mouth; dilation of pupil; some blurring of near vision 2.0 mg 0.5 mg Slight cardiac slowing; some dryness of the mouth; inhibition of sweating Figure 5.4 Dose-dependent effects of atropine. 62 5. Cholinergic Antagonists 3. Pharmacokinetics: Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in urine. It has a half-life of about 4 hours. Scopolamine For nausea due to... Motion sickness Figure 5.5 Scopolamine is an effective anti– motion sickness agent. Blurred vision 4. Adverse effects: Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, and constipation. Effects on the CNS include restlessness, confusion, hallucinations, and delirium, which may progress to depression, collapse of the circulatory and respiratory systems, and death. Low doses of cholinesterase inhibitors, such as physostigmine, may be used to overcome atropine toxicity. In older individuals, the use of atropine to induce mydriasis and cycloplegia is considered to be too risky, because it may exacerbate an attack of glaucoma due to an increase in intraocular pressure in someone with a latent condition. It may also induce troublesome urinary retention in this population. Atropine may be dangerous in children, because they are sensitive to its effects, particularly to the rapid increases in body temperature that it may elicit. B. Scopolamine Confusion Mydriasis Constipation Scopolamine [skoe-POL-a-meen], another tertiary amine plant alkaloid, produces peripheral effects similar to those of atropine. However, scopolamine has greater action on the CNS (unlike with atropine, CNS effects are observed at therapeutic doses) and a longer duration of action in comparison to those of atropine. It has some special actions as indicated below. 1. Actions: Scopolamine is one of the most effective anti–motion sickness drugs available (Figure 5.5). Scopolamine also has the unusual effect of blocking short-term memory. In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria and is susceptible to abuse. 2. Therapeutic uses: Although similar to atropine, therapeutic use of scopolamine is limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory. [Note: As with all such drugs used for motion sickness, it is much more effective prophylactically than for treating motion sickness once it occurs. The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures.] 3. Pharmacokinetics and adverse effects: These aspects are similar to those of atropine. Urinary Retention Figure 5.6 Adverse effects commonly observed with cholinergic antagonists. C. Ipratropium and tiotropium Inhaled ipratropium [i-pra-TROE-pee-um] and inhaled tiotropium [ty-ohTROPE-ee-um] are quaternary derivatives of atropine. These agents are approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), both chronic bronchitis and emphysema. These agents are also pending approval for treating asthma in patients who are unable to take adrenergic agonists. Because of their positive charges, these drugs do not enter the systemic circulation or the CNS, isolating their effects to III. Ganglionic Blockers the pulmonary system. Tiotropium is administered once daily, a major advantage over ipratropium, which requires dosing up to four times daily. Both are delivered via inhalation. Important characteristics of the muscarinic antagonists are summarized in Figures 5.6 and 5.7. D. Tropicamide and cyclopentolate These agents are used similarly to atropine as ophthalmic solutions for mydriasis and cycloplegia. Their duration of action is shorter than that of atropine. Tropicamide produces mydriasis for 6 hours, and cyclopentolate for 24 hours. E. Benztropine and trihexyphenidyl These agents are centrally acting antimuscarinic agents that have been used for many years in the treatment of Parkinson disease. With the advent of other drugs (for example, levodopa/carbidopa), they have been largely replaced. However, benztropine and trihexyphenidyl are useful as adjuncts with other antiparkinsonian agents to treat all types of parkinsonian syndromes, including antipsychotic-induced extrapyramidal symptoms. These drugs may be helpful in geriatric patients who cannot tolerate stimulants. F. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride These synthetic atropine-like drugs are used to treat overactive urinary bladder disease. By blocking muscarinic receptors in the bladder, intravesicular pressure is lowered, bladder capacity is increased, and the frequency of bladder contractions is reduced. Side effects of these agents include dry mouth, constipation, and blurred vision, which limit tolerability of these agents if used continually. Oxybutynin is available as a transdermal system (topical patch), which is better tolerated because it causes less dry mouth than do oral formulations, and is more widely accepted with greater patient acceptance. The overall efficacies of these antimuscarinic drugs are similar. III. GANGLIONIC BLOCKERS Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs mentioned in this category are nondepolarizing, competitive antagonists. The responses of the nondepolarizing blockers are complex, and nearly all the physiological responses to these agents can be predicted by knowledge of the predominant tone of a given organ system. For example, the predominant tone in the arterioles is sympathetic. In the presence of a nondepolarizing blocker, this system is affected the most, leading to vasodilation. The parasympathetic nervous system is the predominant tone in many organ systems (see p. 39). Thus, the presence of a ganglionic blocker will also produce atony of the bladder and GI tract, cycloplegia, xerostomia, and tachycardia. Therefore, ganglionic blockade is rarely used therapeutically, but often serves as a tool in experimental pharmacology. 63 Drug Therapeutic uses Muscarinic blockers Trihexyphenidyl Treatment of Parkinson Benztropine Darifenacin Fesoterodine Oxybutynin Solifenacin Tolterodine Trospium disease Treatment of overactive urinary bladder Cyclopentolate Tropicamide Atropine* In ophthalmology, to Atropine* To treat spastic disorders produce mydriasis and cycloplegia prior to refraction of the GI and lower urinary tract To treat organophosphate poisoning To suppress respiratory secretions prior to surgery Scopolamine In obstetrics, with morphine to produce amnesia and sedation To prevent motion sickness Ipratropium Nicotine Treatment of COPD Ganglionic blockers None Figure 5.7 Summary of cholinergic antagonists. *Contraindicated in narrow-angle glaucoma. GI = gastrointestinal; COPD = chronic obstructive pulmonary disease. 64 5. Cholinergic Antagonists Nicotine Dopamine Pleasure, appetite suppression Norepinephrine Arousal, appetite suppression Acetylcholine Arousal, cognitive enhancement Glutamate Learning, memory enhancement Serotonin Mood modulation, appetite suppression β-Endorphin Reduction of anxiety and tension GABA Reduction of anxiety and tension Figure 5.8 Neurochemical effects of nicotine. GABA = γ-Aminobutyric acid. A. Nicotine A component of cigarette smoke, nicotine [NIK-oh-teen] is a poison with many undesirable actions. It is without therapeutic benefit and is deleterious to health. Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis of all ganglia. The stimulatory effects are complex and result from increased release of neurotransmitter (Figure 5.8), due to effects on both sympathetic and parasympathetic ganglia. For example, enhanced release of dopamine and norepinephrine may be associated with pleasure as well as appetite suppression, the latter of which may contribute to lower body weight. The overall response of a physiological system is a summation of the stimulatory and inhibitory effects of nicotine. These include increased blood pressure and cardiac rate (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and secretions. At higher doses, the blood pressure falls because of ganglionic blockade, and activity in both the GI tract and bladder musculature ceases. (See p. 124 for a full discussion of nicotine.) B. Mecamylamine Mecamylamine [mek-a-MILL-a-meen] produces a competitive nicotinic blockade of the ganglia. Mecamylamine has been supplanted by superior agents with fewer side effects. IV. NEUROMUSCULAR-BLOCKING DRUGS These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular endplate of skeletal muscle (see Figure 5.2). These neuromuscular blockers are structural analogs of ACh, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the endplate of the NMJ. Neuromuscular blockers are clinically useful during surgery for producing complete muscle relaxation, without having to use higher anesthetic doses to achieve comparable muscular relaxation. Such agents are also useful in orthopedic surgery and in facilitating tracheal intubation as well. A second group of muscle relaxants, the central muscle relaxants, are used to control spastic muscle tone. These drugs include diazepam, which binds at γ-aminobutyric acid (GABA) receptors; dantrolene, which acts directly on muscles by interfering with the release of calcium from the sarcoplasmic reticulum; and baclofen, which probably acts at GABA receptors in the CNS. A. Nondepolarizing (competitive) blockers The first drug that was found to be capable of blocking the skeletal NMJ was curare [koo-RAH-ree], which native South American hunters of the Amazon region used to paralyze prey. The drug tubocurarine [tooboe-kyoo-AR-een] was ultimately purified and introduced into clinical practice in the early 1940s. Although tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents because of its adverse side effects (see Figure 5.11). This agent is no longer available in the United States. The neuromuscular-blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery. [Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing recovery time after surgery.] Neuromuscular blockers should not be used to substitute for inadequate depth of anesthesia. IV. Neuromuscular-Blocking Drugs 65 1. Mechanism of action: a. At low doses: Nondepolarizing neuromuscular-blocking drugs interact with the nicotinic receptors to prevent the binding of ACh (Figure 5.9). Thus, these drugs prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with ACh at the receptor without stimulating it, they are called competitive blockers. Their action can be overcome by increasing the concentration of ACh in the synaptic gap, for example, by administration of such cholinesterase inhibitors as neostigmine, pyridostigmine, and edrophonium. Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade. In addition, at low doses the muscle will respond to direct electrical stimulation from a peripheral nerve stimulator to varying degrees, depending on the extent of neuromuscular blockade. Tubocurarine Acetylcholine Na + Nicotinic receptor at neuromuscular junction Figure 5.9 Mechanism of action of competitive neuromuscularblocking drugs. b. At high doses: Nondepolarizing blockers can block the ion channels of the endplate. This leads to further weakening of neuromuscular transmission, thereby reducing the ability of AChE inhibitors to reverse the actions of the nondepolarizing muscle relaxants. With complete blockade, no direct electrical stimulation is seen. 2. Actions: Not all muscles are equally sensitive to blockade by competitive blockers. Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck, and trunk muscles are paralyzed. Next, the intercostal muscles are affected, and, lastly, the diaphragm muscles are paralyzed. The muscles recover in the reverse manner, with the diaphragm muscles recovering first and contracting muscles of the face and the eye recovering last. Those agents that release histamine (for example, atracurium) can produce a fall in blood pressure, flushing, and bronchoconstriction. 3. Therapeutic uses: These blockers are used therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle. They are also used to facilitate intubation as well as during orthopedic surgery (for example, fracture alignment and dislocation corrections). 4. Pharmacokinetics: All neuromuscular-blocking agents are injected intravenously because their uptake via oral absorption is minimal. These agents possess two or more quaternary amines in their bulky ring structure, making them orally ineffective. They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier. Many of the drugs are not metabolized, and their actions are terminated by redistribution (Figure 5.10). For example, pancuronium is excreted unchanged in urine. Atracurium is degraded spontaneously in plasma and by ester hydrolysis. [Note: Atracurium has been replaced by its isomer, cisatracurium. Atracurium releases histamine and is metabolized to laudanosine, which can provoke seizures. Cisatracurium, which has the same pharmacokinetic properties as atracurium, is less likely to have these effects.] The amino steroid drugs (vecuronium and rocuronium) are deacetylated in the liver, and their clearance may be prolonged in patients with hepatic disease. These drugs are also excreted unchanged in bile. The choice Agents do not readily enter cells IV Vecuronium and rocuronium and metabolites appear mainly in bile Most drugs excreted primarily unchanged in urine Neuromuscular-blocking drugs Figure 5.10 Pharmacokinetics of the neuromuscular-blocking drugs. IV = intravenous. 66 5. Cholinergic Antagonists Time to maximal blockade (min) Time to recover 25% of maximal response (min) Atracurium 2 40 Cisatracurium spontaneously degrades in plasma and is the only nondepolarizing neuromuscular blocker whose dose need not be reduced in patients with renal failure. It is often used in patients with multisystem organ failure because its metabolism is independent of hepatic or renal function. Cisatracurium is useful in mechanical ventilation of critically ill patients. Cisatracurium 3 90 Vagolytic (increased heart rate) of an agent will depend on how quickly muscle relaxation is needed and on the duration of the muscle relaxation. The onset and duration of action, as well as other characteristics of the neuromuscularblocking drugs, are shown in Figure 5.11. 5. Adverse effects: In general, agents are safe with minimal side effects. The adverse effects of the specific neuromuscular blockers are shown in Figure 5.11. 6. Drug interactions: a. Cholinesterase inhibitors: Drugs such as neostigmine, physostigmine, pyridostigmine, and edrophonium can overcome the action of nondepolarizing neuromuscular blockers, but, with increased dosage, cholinesterase inhibitors can cause a depolarizing block as a result of elevated ACh concentrations at the endplate membrane. If the neuromuscular blocker has entered the ion channel, cholinesterase inhibitors are not as effective in overcoming blockade. b. Halogenated hydrocarbon anesthetics: Drugs such as halothane act to enhance neuromuscular blockade by exerting a stabilizing action at the NMJ. These agents sensitize the NMJ to the effects of neuromuscular blockers. Pancuronium 3 86 c. Aminoglycoside antibiotics: Drugs such as gentamicin and tobramycin inhibit ACh release from cholinergic nerves by competing with calcium ions. They synergize with pancuronium and other competitive blockers, enhancing the blockade. Rocuronium 1 43 d. Calcium-channel blockers: These agents may increase the neuromuscular block of competitive blockers as well as depolarizing blockers. B. Depolarizing agents Postoperative muscle pain is common; hyperkalemia and increased intraocular and intragastric pressure may occur. Drug may trigger malignant hyperthermia. Rapid onset makes succinylcholine useful for tracheal intubation in patients with gastric contents. Succinyl- 1.1 choline 8 Tubocurarine 2 38 Vecuronium 2 44 Figure 5.11 Onset and duration of action of neuromuscular-blocking drugs. Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to the action of ACh. However, these agents are more resistant to degradation by AChE, and can thus more persistently depolarize the muscle fibers. Succinylcholine [suk-sin-il-KOEleen] is the only depolarizing muscle relaxant in use today. 1. Mechanism of action: The depolarizing neuromuscular-blocking drug succinylcholine attaches to the nicotinic receptor and acts like ACh to depolarize the junction (Figure 5.12). Unlike ACh, which is instantly destroyed by AChE, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing constant stimulation of the receptor. [Note: The duration of action of succinylcholine is dependent on diffusion from the motor endplate and hydrolysis by plasma pseudocholinesterase.] The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor (Phase I). This leads to a transient twitching of the muscle (fasciculations). Continued binding of the depolarizing agent renders the receptor incapable of transmitting further impulses. With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked. This causes a resistance to depolarization (Phase II) and flaccid paralysis. IV. Neuromuscular-Blocking Drugs 2. Actions: The sequence of paralysis may be slightly different, but, as with the competitive blockers, the respiratory muscles are paralyzed last. Succinylcholine initially produces brief muscle fasciculations and a ganglionic block except at high doses, but it does have weak histamine-releasing action. [Note: Administering a small dose of nondepolarizing neuromuscular blocker prior to succinylcholine helps decrease or prevent the fasciculations which cause muscle soreness.] Normally, the duration of action of succinylcholine is extremely short, because this drug is rapidly broken down by plasma pseudocholinesterase. However, succinylcholine that gets to the NMJ is not metabolized by AChE, allowing the agent to bind to nicotinic receptors, and redistribution to plasma is necessary for metabolism (therapeutic benefits last only for a few minutes). [Note: Genetic variants in which plasma pseudocholinesterase levels are low or absent leads to prolonged neuromuscular paralysis.] 3. Therapeutic uses: Because of its rapid onset and short duration of action, succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia (a rapid action is essential if aspiration of gastric contents is to be avoided during intubation). It is also used during electroconvulsive shock treatment. 4. Pharmacokinetics: Succinylcholine is injected intravenously. Its brief duration of action (several minutes) results from redistribution and rapid hydrolysis by plasma pseudocholinesterase. Therefore, it is sometimes given by continuous infusion to maintain a longer duration of effect. Drug effects rapidly disappear upon discontinuation. 67 PHASE I Membrane depolarizes, resulting in an initial discharge that produces transient fasciculations followed by flaccid paralysis. Succinylcholine b. Apnea: Administration of succinylcholine to a patient who is genetically deficient in plasma cholinesterase or who has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm. The rapid release of potassium may also contribute to prolonging apnea in patients with electrolyte imbalances who receive this drug. Patients with electrolyte imbalances who are also receiving digoxin or diuretics (such as congestive heart failure patients) should use succinylcholine cautiously or not at all. c. Hyperkalemia: Succinylcholine increases potassium release from intracellular stores. This may be particularly dangerous in burn patients and patients with massive tissue damage in which potassium has been rapidly lost from within cells. + - - - Depolarized ++ + Nicotinic receptor at a neuromuscular junction + ++ Na + PHASE II Membrane repolarizes, but receptor is desensitized to the effect of acetylcholine. 5. Adverse effects: a. Hyperthermia: When halothane (see p. 139) is used as an anesthetic, administration of succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity, metabolic acidosis, tachycardia, and hyperpyrexia) in genetically susceptible people (see Figure 5.11). This is treated by rapidly cooling the patient and by administration of dantrolene, which blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells, thereby reducing heat production and relaxing muscle tone. Na - - - - Succinylcholine ++ ++ ++ ++ Repolarized - - - - - - - - Figure 5.12 Mechanism of action of depolarizing neuromuscularblocking drugs.