Pharmacology_Katzung

Pharmacology_Katzung. Tetanic stimulation consists of a very rapid (30–100 Hz) delivery of electrical stimuli for several seconds. During a non-depolarizing neuromuscular block (and a phase II block after succinylcholine), the response is not sustained and fade of the twitch responses is observed. Fade in response to tetanic stimulation is normally considered a presynaptic event. However, the degree of fade depends primarily on the degree of neuromuscular blockade. During a partial nondepolarizing blockade, tetanic nerve stimulation is followed by an increase in the posttetanic twitch response, so-called posttetanic facilitation of neuromuscular transmission. During intense neuromuscular blockade, there is no response to either tetanic or posttetanic stimulation. As the intensity of the block diminishes, the response to posttetanic twitch stimulation reappears. The reappearance of the first response to twitch stimulation after tetanic stimulation reflects the duration of profound (clinical) neuromuscular


Pharmacology_Katzung

Pharmacology_Katzung. response to posttetanic twitch stimulation reappears. The reappearance of the first response to twitch stimulation after tetanic stimulation reflects the duration of profound (clinical) neuromuscular blockade. To determine the posttetanic count, 5 seconds of 50 Hz tetany is applied, followed by 3 seconds of rest, followed by 1 Hz pulses for about 10 seconds (10 pulses). The counted number of muscle twitches provides an estimation of the depth of blockade. For instance, a posttetanic count of 2 suggests no twitch response (by TOF) for about 20–30 minutes, and a posttetanic count of 5 correlates to a no-twitch response (by TOF) of about 10–15 minutes (Figure 27–6, bottom panel).


Pharmacology_Katzung

Pharmacology_Katzung. The double-burst stimulation pattern is another mode of electrical nerve stimulation developed with the goal of allowing for manual detection of residual neuromuscular blockade when it is not possible to record the responses to single-twitch, TOF, or tetanic stimulation. In this pattern, three nerve stimuli are delivered at 50 Hz followed by a 700 ms rest period and then by two or three additional stimuli at 50 Hz. It is easier to detect fade in the responses to double-burst stimulation than to TOF stimulation. The absence of fade in response to double-burst stimulation implies that clinically significant residual neuromuscular blockade does not exist.


Pharmacology_Katzung

Pharmacology_Katzung. A more quantitative approach to neuromuscular monitoring involves monitoring using a force transducer for measuring the evoked response (ie, movement) of the thumb to TOF stimulation over the ulnar nerve at the wrist. This device has the advantage of being integrated in the anesthesia machine and also provides a more accurate graphic display of the percentage of fade to TOF stimulation. A. Nondepolarizing Relaxant Drugs


Pharmacology_Katzung

Pharmacology_Katzung. During anesthesia, administration of tubocurarine, 0.1–0.4 mg/kg IV, initially causes motor weakness, followed by the skeletal muscles becoming flaccid and inexcitable to electrical stimulation (Figure 27–8). In general, larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more resistant to neuromuscular blockade and recover more rapidly than smaller muscles (eg, facial, foot, hand). The diaphragm is usually the last muscle to be paralyzed. Assuming that ventilation is adequately maintained, no adverse effects occur with skeletal muscle paralysis. When administration of muscle relaxants is discontinued, recovery of muscles usually occurs in reverse order, with the diaphragm regaining function first. The pharmacologic effect of tubocurarine, 0.3 mg/kg IV, usually lasts 45–60 minutes. However, subtle evidence of residual muscle paralysis detected using a neuromuscular monitor may last for another hour, increasing the likelihood of adverse outcomes, eg, aspiration and


Pharmacology_Katzung

Pharmacology_Katzung. minutes. However, subtle evidence of residual muscle paralysis detected using a neuromuscular monitor may last for another hour, increasing the likelihood of adverse outcomes, eg, aspiration and decreased hypoxic drive. Potency and duration of action of the other nondepolarizing drugs are shown in Table 27–1. In addition to the duration of action, the most important property distinguishing the nondepolarizing relaxants is the time to onset of the blocking effect, which determines how rapidly the patient’s trachea can be intubated. Of the currently available nondepolarizing drugs, rocuronium has the most rapid onset time (60–120 seconds).


Pharmacology_Katzung

Pharmacology_Katzung. B. Depolarizing Relaxant Drugs Following the administration of succinylcholine, 0.75–1.5 mg/kg IV, transient muscle fasciculations occur over the chest and abdomen within 30 seconds, although general anesthesia and the prior administration of a small dose of a nondepolarizing muscle relaxant tend to attenuate them. As paralysis develops rapidly (<90 seconds), the arm, neck, and leg muscles are initially relaxed followed by the respiratory muscles. As a result of succinylcholine’s rapid hydrolysis by cholinesterase in the plasma (and liver), the duration of neuromuscular block typically lasts less than 10 minutes (Table 27–1). Vecuronium, cisatracurium, and rocuronium have minimal, if any, cardiovascular effects. The other nondepolarizing muscle relaxants (ie, pancuronium and atracurium) produce cardiovascular effects Isoflurane (1.25 MAC) Halothane (1.25 MAC) 1 min Tubocurarine (3 mg/m2) 23 min 1 min


Pharmacology_Katzung

Pharmacology_Katzung. Isoflurane (1.25 MAC) Halothane (1.25 MAC) 1 min Tubocurarine (3 mg/m2) 23 min 1 min FIGURE 27–8 Neuromuscular blockade from tubocurarine during equivalent levels of isoflurane and halothane anesthesia in patients. Note that isoflurane augments the block far more than does halothane. MAC, minimal alveolar concentration.


Pharmacology_Katzung

Pharmacology_Katzung. that are mediated by autonomic or histamine receptors (Table 27–3). Tubocurarine and, to a lesser extent, atracurium can produce hypotension as a result of systemic histamine release, and with larger doses, ganglionic blockade may occur with tubocurarine. Premedication with an antihistaminic compound attenuates tubocurarine-induced hypotension. Pancuronium causes a moderate increase in heart rate and a smaller increase in cardiac output, with little or no change in systemic vascular resistance. Although pancuronium-induced tachycardia is primarily due to a vagolytic action, release of norepinephrine from adrenergic nerve endings and blockade of neuronal uptake of norepinephrine may be secondary mechanisms. Bronchospasm may be produced by neuromuscular blockers that release histamine (eg, atracurium), but after induction of general anesthesia, insertion of an endotracheal tube is the most common cause of bronchospasm.


Pharmacology_Katzung

Pharmacology_Katzung. Succinylcholine can cause cardiac arrhythmias, especially when administered during halothane anesthesia. The drug stimulates autonomic cholinoceptors, including the nicotinic receptors at both sympathetic and parasympathetic ganglia and muscarinic receptors in the heart (eg, sinus node). The negative inotropic and chronotropic responses to succinylcholine can be attenuated by administration of an anticholinergic drug (eg, glycopyrrolate, atropine). With large doses of succinylcholine, positive inotropic and chronotropic effects may be observed. On the other hand, bradycardia has been repeatedly observed when a second dose of succinylcholine is given less than 5 minutes TABLE 27–3 Effects of neuromuscular blocking drugs on other tissues. 1Allergic reactions have been reported.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 27–3 Effects of neuromuscular blocking drugs on other tissues. 1Allergic reactions have been reported. after the initial dose. This transient bradycardia can be prevented by thiopental, atropine, and ganglionic-blocking drugs, and by pretreating with a small dose of a nondepolarizing muscle relaxant (eg, rocuronium). Direct myocardial effects, increased muscarinic stimulation, and ganglionic stimulation contribute to this bradycardic response. Other Adverse Effects of Depolarizing Blockade A. Hyperkalemia


Pharmacology_Katzung

Pharmacology_Katzung. Other Adverse Effects of Depolarizing Blockade A. Hyperkalemia Patients with burns, nerve damage or neuromuscular disease, closed head injury, and other trauma may develop proliferation of extrajunctional acetylcholine receptors. During administration of succinylcholine, potassium is released from muscles, likely due to fasciculations. If the proliferation of extrajunctional receptors is great enough, sufficient potassium may be released to result in cardiac arrest. The exact time course of receptor proliferation is unknown; therefore, it is best to avoid the use of succinylcholine in these cases. B. Increased Intraocular Pressure


Pharmacology_Katzung

Pharmacology_Katzung. B. Increased Intraocular Pressure Administration of succinylcholine may be associated with the rapid onset of an increase in intraocular pressure (<60 seconds), peaking at 2–4 minutes, and declining after 5 minutes. The mechanism may involve tonic contraction of myofibrils or transient dilation of ocular choroidal blood vessels. Despite the increase in intraocular pressure, the use of succinylcholine for ophthalmologic operations is not contraindicated unless the anterior chamber is open (“open globe”) due to trauma. C. Increased Intragastric Pressure In heavily muscled patients, the fasciculations associated with succinylcholine may cause an increase in intragastric pressure ranging from 5 to 40 cm H2O, increasing the risk for regurgitation and aspiration of gastric contents. This complication is more likely to occur in patients with delayed gastric emptying (eg, those with diabetes), traumatic injury (eg, an emergency case), esophageal dysfunction, and morbid obesity.


Pharmacology_Katzung

Pharmacology_Katzung. D. Muscle Pain Myalgias are a common postoperative complaint of heavily muscled patients and those who receive large doses (>1.5 mg/kg) of succinylcholine. The true incidence of myalgias related to muscle fasciculations is difficult to establish because of confounding factors, including the anesthetic technique, type of surgery, and positioning during the operation. However, the incidence of myalgias has been reported to vary from less than 1% to 20%. It occurs more frequently in ambulatory than in bedridden patients. The pain is thought to be secondary to the unsynchronized contractions of adjacent muscle fibers just before the onset of paralysis. However, there is controversy over whether the incidence of muscle pain following succinylcholine is actually higher than with nondepolarizing muscle relaxants when other potentially confounding factors are taken into consideration. Interactions with Other Drugs A. Anesthetics


Pharmacology_Katzung

Pharmacology_Katzung. Interactions with Other Drugs A. Anesthetics Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose-dependent fashion. Of the general anesthetics that have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following order: isoflurane (most); sevoflurane, desflurane, halothane; and nitrous oxide (least) (Figure 27–8). The most important factors involved in this interaction are the following: (1) nervous system depression at sites proximal to the neuromuscular junction (ie, CNS); (2) increased muscle blood flow (ie, due to peripheral vasodilation produced by volatile anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction; and (3) decreased sensitivity of the postjunctional membrane to depolarization.


Pharmacology_Katzung

Pharmacology_Katzung. A rare interaction of succinylcholine with volatile anesthetics results in malignant hyperthermia, a condition caused by abnormal release of calcium from stores in skeletal muscle. This condition is treated with dantrolene and is discussed below under Spasmolytic & Antispasmodic Drugs and in Chapter 16. B. Antibiotics Numerous reports have described enhancement of neuromuscular blockade by antibiotics (eg, aminoglycosides). Many of the antibiotics have been shown to cause a depression of evoked release of acetylcholine similar to that caused by administering magnesium. The mechanism of this prejunctional effect appears to be blockade of specific P-type calcium channels in the motor nerve terminal. C. Local Anesthetics and Antiarrhythmic Drugs


Pharmacology_Katzung

Pharmacology_Katzung. C. Local Anesthetics and Antiarrhythmic Drugs In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block neuromuscular transmission. With these higher doses, local anesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking antiarrhythmic drugs such as quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher doses of bupivacaine have been associated with cardiac arrhythmias independent of the muscle relaxant used. D. Other Neuromuscular Blocking Drugs


Pharmacology_Katzung

Pharmacology_Katzung. D. Other Neuromuscular Blocking Drugs The end plate-depolarizing effect of succinylcholine can be antagonized by administering a small dose of a nondepolarizing blocker. To prevent the fasciculations associated with succinylcholine administration, a small nonparalyzing dose of a nondepolarizing drug can be given before succinylcholine (eg, d-tubocurarine, 2 mg IV, or pancuronium, 0.5 mg IV). Although this dose usually reduces fasciculations and postoperative myalgias, it can increase the amount of succinylcholine required for relaxation by 50–90% and can produce a feeling of weakness in awake patients. Therefore, “precurarization” before succinylcholine is no longer widely practiced. Effects of Diseases & Aging on the Neuromuscular Response


Pharmacology_Katzung

Pharmacology_Katzung. Effects of Diseases & Aging on the Neuromuscular Response Several diseases can diminish or augment the neuromuscular blockade produced by nondepolarizing muscle relaxants. Myasthenia gravis enhances the neuromuscular blockade produced by these drugs. Advanced age is associated with a prolonged duration of action from nondepolarizing relaxants as a result of decreased clearance of the drugs by the liver and kidneys. As a result, the dosage of neuromuscular blocking drugs should be reduced in older patients (>70 years). Conversely, patients with severe burns and those with upper motor neuron disease are resistant to nondepolarizing muscle relaxants. This desensitization is probably caused by proliferation of extrajunctional receptors, which results in an increased dose requirement for the nondepolarizing relaxant to block a sufficient number of receptors. Reversal of Nondepolarizing Neuromuscular Blockade


Pharmacology_Katzung

Pharmacology_Katzung. The cholinesterase inhibitors effectively antagonize the neuromuscular blockade caused by nondepolarizing drugs. Their general pharmacology is discussed in Chapter 7. Neostigmine and pyridostigmine antagonize nondepolarizing neuromuscular blockade by increasing the availability of acetylcholine at the motor end plate, mainly by inhibition of acetylcholinesterase. To a lesser extent, these cholinesterase inhibitors also increase the release of this transmitter from the motor nerve terminal. In contrast, edrophonium antagonizes neuromuscular blockade purely by inhibiting acetylcholinesterase activity. Edrophonium has a more rapid onset of action but may be less effective than neostigmine in reversing the effects of nondepolarizing blockers in the presence of profound neuromuscular blockade. These differences are important in determining recovery from residual block, the neuromuscular blockade remaining after completion of surgery and movement of the patient to the recovery room.


Pharmacology_Katzung

Pharmacology_Katzung. These differences are important in determining recovery from residual block, the neuromuscular blockade remaining after completion of surgery and movement of the patient to the recovery room. Unsuspected residual block may result in hypoventilation, leading to hypoxia and even apnea, especially if patients have received central depressant medications in the early recovery period.


Pharmacology_Katzung

Pharmacology_Katzung. Sugammadex is a novel reversal agent recently approved for rapid reversal of the steroid neuromuscular blocking agents rocuronium and vecuronium. Although it has been in clinical use in Europe since 2008, its approval in the USA was delayed over concerns that it may cause anaphylaxis and hypersensitivity reactions. Sugammadex is a modified γ-cyclodextrin (a large ring structure with 16 polar hydroxyl groups facing inward and 8 polar carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the circulation, where it is quickly bound by free sugammadex.


Pharmacology_Katzung

Pharmacology_Katzung. Currently, three dose ranges are recommended for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and 16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium. In patients with normal renal function (defined as a creatinine clearance [CrCl] > 80 mL/min), the sugammadexrocuronium complex is typically excreted unchanged in the urine within 24 hours. In patients with renal insufficiency, complete urinary elimination may take much longer. The plasma half-life of sugammadex in patients with renal impairment increases significantly as CrCl is reduced. In mild to moderate renal insufficiency (CrCl between 30 and 80 mL/min), the half-life varies between 4 and 6 hours. This increases dramatically in patients with severe renal impairment (CrCl < 30 mL/min), in whom the


Pharmacology_Katzung

Pharmacology_Katzung. renal insufficiency (CrCl between 30 and 80 mL/min), the half-life varies between 4 and 6 hours. This increases dramatically in patients with severe renal impairment (CrCl < 30 mL/min), in whom the half-life is extended to 19 hours. The ability to dialyze sugammadex is variable. Therefore, sugammadex is not recommended for use in patients with severe renal impairment.


Pharmacology_Katzung

Pharmacology_Katzung. Sugammadex is associated with a few significant adverse reactions. Most importantly, sugammadex may cause anaphylaxis, which occurred in 0.3% of patients who received the 16 mg/kg dose in the US Food and Drug Administration (FDA) studies. Hypersensitivity reactions, such as nausea, pruritus, and urticaria are more common than anaphylaxis, and also occur more frequently with higher doses of sugammadex. Other significant adverse reactions include marked bradycardia that may progress to cardiac arrest within minutes of administration and coagulopathy, with an approximately 25% elevation of activated partial thromboplastin time and prothrombin time/international normalized ratio values that may last up to 1 hour.


Pharmacology_Katzung

Pharmacology_Katzung. Because sugammadex binds the steroidal neuromuscular blocking agents rocuronium and vecuronium, it is not surprising that it can also block other steroidal drugs. The two most important of these drugs are progesterone-based contraceptives and the selective estrogen receptor modulator toremifene. When sugammadex is administered to a woman who is taking hormonal contraceptives that contain progesterone, the progesterone may be bound by sugammadex and the efficacy of the contraceptive is decreased as if the woman missed one or two doses. The manufacturer recommends that an alternative nonhormonal contraceptive be used for 7 days following sugammadex administration. Sugammadex also very tightly binds toremifene, which may be used to treat metastatic breast cancer (see Chapter 40). Not only will the efficacy of toremifene be reduced, but displacement of rocuronium from sugammadex may result, and prolonged neuromuscular blockade could occur. Uses of Neuromuscular Blocking Drugs


Pharmacology_Katzung

Pharmacology_Katzung. Uses of Neuromuscular Blocking Drugs A. Surgical Relaxation One of the most important applications of the neuromuscular blockers is in facilitating intracavitary surgery, especially in intra-abdominal and intrathoracic procedures. B. Endotracheal Intubation By relaxing the pharyngeal and laryngeal muscles, neuromuscular blocking drugs facilitate laryngoscopy and placement of an endotracheal tube. Endotracheal tube placement ensures an adequate airway and minimizes the risk of pulmonary aspiration during general anesthesia. C. Control of Ventilation


Pharmacology_Katzung

Pharmacology_Katzung. C. Control of Ventilation In critically ill patients who have ventilatory failure from various causes (eg, severe bronchospasm, pneumonia, chronic obstructive airway disease), it may be necessary to control ventilation to provide adequate gas exchange and to prevent atelectasis. In the ICU, neuromuscular blocking drugs are frequently administered to reduce chest wall resistance (ie, improve thoracic compliance), decrease oxygen utilization, and improve ventilator synchrony. D. Treatment of Convulsions Neuromuscular blocking drugs (ie, succinylcholine) are occasionally used to attenuate the peripheral (motor) manifestations of convulsions associated with status epilepticus, local anesthetic toxicity, or electroconvulsive therapy. Although this approach is effective in eliminating the muscular manifestations of the seizures, it has no effect on the central processes because neuromuscular blocking drugs do not cross the blood-brain barrier.


Pharmacology_Katzung

Pharmacology_Katzung. Skeletal muscle relaxants include neuromuscular blockers, spasmolytics, and antispasmodics. Spasmolytics and antispasmodics are used to treat two conditions: spasms from peripheral musculoskeletal conditions (antispasmodics) and spasticity from upper motor neuron lesions (spasmolytics).


Pharmacology_Katzung

Pharmacology_Katzung. Spasticity presents as intermittent or sustained involuntary contraction of skeletal muscle, causing stiffness that interferes with mobility and speech. It is characterized by an increase in tonic stretch reflexes and flexor muscle spasms (ie, increased basal muscle tone) together with muscle weakness. It is often associated with spinal injury, cerebral palsy, multiple sclerosis, and stroke. The mechanisms underlying clinical spasticity appear to involve not only the stretch reflex arc itself but also higher centers in the CNS, with damage to descending pathways in the spinal cord resulting in hyperexcitability of the alpha motor neurons in the cord. The important components involved in these processes are shown in Figure 27–9. Pharmacologic therapy may ameliorate some of the symptoms of spasticity by modifying the stretch reflex arc or by interfering directly with skeletal muscle (ie, excitation-contraction coupling).


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that modify the reflex arc may modulate excitatory or inhibitory synapses (see Chapter 21). Thus, to reduce the hyperactive stretch reflex, it is desirable to reduce the activity of the Ia fibers that excite the primary motor neuron or to enhance the activity of the inhibitory internuncial neurons. These structures are shown in greater detail in Figure 27–10. A variety of pharmacologic agents described as depressants of the spinal “polysynaptic” reflex arc (eg, barbiturates [phenobarbital] and glycerol ethers [mephenesin]) have been used to treat these conditions of excess skeletal muscle tone. However, as illustrated


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 27–9 Schematic illustration of the structures involved in the stretch reflex (right half) showing innervation of extrafusal (striated muscle) fibers by alpha motor neurons and of intrafusal fibers (within muscle spindle) by gamma motor neurons. The left half of the diagram shows an inhibitory reflex arc, which includes an intercalated inhibitory interneuron. (Reproduced, with permission, from Waxman SG: Clinical Neuroanatomy, 26th edition. McGraw-Hill, 2009. Copyright © The McGraw-Hill Companies, Inc.) in Figure 27–10, nonspecific depression of synapses involved in the stretch reflex could reduce the desired GABAergic inhibitory activity, as well as the excitatory glutamatergic transmission. Currently available drugs can provide significant relief from painful muscle spasms, but they are less effective in improving meaningful function (eg, mobility and return to work).


Pharmacology_Katzung

Pharmacology_Katzung. As described in Chapter 22, benzodiazepines facilitate the action of GABA in the CNS. Diazepam acts at GABAA synapses, and its action in reducing spasticity is at least partly mediated in the spinal cord because it is somewhat effective in patients with cord transection. Although diazepam can be used in patients with muscle spasm of almost any origin (including local muscle trauma), it also produces sedation at the doses required to reduce muscle tone. The initial dosage is 4 mg/d, and it is gradually increased to a maximum of 60 mg/d. Other benzodiazepines have been used as spasmolytics (eg, midazolam), but clinical experience with them is limited.


Pharmacology_Katzung

Pharmacology_Katzung. Meprobamate and carisoprodol are sedatives that have been used as central muscle relaxants, although evidence for their efficacy without sedation is lacking. Carisoprodol is a schedule IV drug; it is metabolized to meprobamate, which is also a schedule IV drug. Withdrawal of carisoprodol and meprobamate after extensive use elicits physical withdrawal, with anxiety, tremors, muscle twitching, insomnia, and auditory and visual hallucinations. Baclofen (p-chlorophenyl-GABA) was designed to be an orally active GABA-mimetic agent and is an agonist at GABAB receptors. Activation of these receptors by baclofen results in


Pharmacology_Katzung

Pharmacology_Katzung. Baclofen (p-chlorophenyl-GABA) was designed to be an orally active GABA-mimetic agent and is an agonist at GABAB receptors. Activation of these receptors by baclofen results in ActionpotentialsTizanidineGABAGABABGluAMPAMuscleCorticospinalpathwayinterneuronBaclofenBenzodiazepinesDantroleneMotorneuron–––––GABABGABAA˜2˜2FIGURE 27–10 Postulated sites of spasmolytic action of tizanidine (α2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Tizanidine may also have a postsynaptic inhibitory effect. Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle. Glu, glutamatergic neuron.


Pharmacology_Katzung

Pharmacology_Katzung. hyperpolarization by three distinct actions: 1) closure of presynaptic calcium channels, 2) increased postsynaptic K+ conductance, and 3) inhibition of dendritic calcium influx channels. Through reduced release of excitatory transmitters in both the brain and the spinal cord, baclofen suppresses activity of Ia sensory afferents, spinal interneurons, and motor neurons (Figure 27–10). Baclofen may also reduce pain in patients with spasticity, perhaps by inhibiting the release of substance P (neurokinin-1) in the spinal cord.


Pharmacology_Katzung

Pharmacology_Katzung. Baclofen is at least as effective as diazepam and tizanidine (discussed below) in reducing spasticity and is less sedating than diazepam. Baclofen does not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma half-life of 3–4 hours. Dosage is started at 15 mg twice daily, increasing as tolerated to 100 mg daily. Studies have confirmed that intrathecal catheter administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration. Owing to the poor egress of baclofen from the spinal cord, peripheral symptoms are rare. Therefore, higher central concentrations of the drug may be tolerated. Partial tolerance to the effect of the drug may occur after several months of therapy, but can be overcome by upward dosage adjustments to maintain the beneficial effect. This tolerance was not confirmed in a recent study and decreased response may


Pharmacology_Katzung

Pharmacology_Katzung. after several months of therapy, but can be overcome by upward dosage adjustments to maintain the beneficial effect. This tolerance was not confirmed in a recent study and decreased response may represent unrecognized catheter malfunctions. Although a major disadvantage of this therapeutic approach is the difficulty of maintaining the drug delivery catheter in the subarachnoid space, risking an acute withdrawal syndrome upon treatment interruption, long-term intrathecal baclofen therapy can improve the quality of life for patients with severe spastic disorders. Adverse effects of high-dose baclofen include excessive somnolence, respiratory depression, and coma. Patients can become tolerant to the sedative effect with chronic administration. Increased seizure activity has been reported in epileptic patients. Withdrawal from baclofen must be done very slowly. Baclofen should be used with caution during pregnancy; although there are no reports of baclofen directly causing human fetal


Pharmacology_Katzung

Pharmacology_Katzung. in epileptic patients. Withdrawal from baclofen must be done very slowly. Baclofen should be used with caution during pregnancy; although there are no reports of baclofen directly causing human fetal malformations, animal studies using high doses show that it causes impaired sternal ossification and omphalocele.


Pharmacology_Katzung

Pharmacology_Katzung. Oral baclofen has been studied in many other medical conditions, including patients with intractable low back pain, stiff person syndrome, trigeminal neuralgia, cluster headache, intractable hiccups, tic disorder, gastroesophageal reflux disease, and cravings for alcohol, nicotine, and cocaine (see Chapter 32).


Pharmacology_Katzung

Pharmacology_Katzung. As noted in Chapter 11, α2-adrenoceptor agonists such as clonidine and other imidazoline compounds have a variety of effects on the CNS that are not fully understood. Among these effects is the ability to reduce muscle spasm. Tizanidine is a congener of clonidine that has been studied for its spasmolytic actions. Tizanidine has significant α2-agonist effects, but it reduces spasticity in experimental models at doses that cause fewer cardiovascular effects than clonidine or dexmedetomidine. Tizanidine has approximately one tenth to one fifteenth of the blood pressure-lowering effects of clonidine. Neurophysiologic studies in animals and humans suggest that tizanidine reinforces both presynaptic and postsynaptic inhibition in the cord. It also inhibits nociceptive transmission in the spinal dorsal horn. Tizanidine’s actions are believed to be mediated via restoration of inhibitory suppression of the group II spinal interneurons without inducing any changes in intrinsic muscle


Pharmacology_Katzung

Pharmacology_Katzung. the spinal dorsal horn. Tizanidine’s actions are believed to be mediated via restoration of inhibitory suppression of the group II spinal interneurons without inducing any changes in intrinsic muscle properties.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical trials with oral tizanidine report efficacy in relieving muscle spasm comparable to diazepam, baclofen, and dantrolene. Tizanidine causes markedly less muscle weakness but produces a different spectrum of adverse effects, including drowsiness, hypotension, dizziness, dry mouth, asthenia, and hepatotoxicity. The drowsiness can be managed by taking the drug at night. Tizanidine displays linear pharmacokinetics, and dosage requirements vary considerably among patients. Treatment is initiated at 2 mg every 6–8 hours and can be titrated up to a maximum of 36 mg/d. Dosage must be adjusted in patients with hepatic or renal impairment. Tizanidine is involved in drug-drug interactions; plasma levels increase in response to CYP1A2 inhibition. Conversely, tizanidine induces CYP11A1 activity, which is responsible for converting cholesterol to pregnenolone. In addition to its effectiveness in spastic conditions, tizanidine also appears to be effective for management of chronic migraine.


Pharmacology_Katzung

Pharmacology_Katzung. Gabapentin is an antiepileptic drug (see Chapter 24) that has shown considerable promise as a spasmolytic agent in several studies involving patients with multiple sclerosis. Pregabalin is a newer analog of gabapentin that may also prove useful in relieving painful disorders that involve a muscle spasm component. Progabide and glycine have also been found in preliminary studies to reduce spasticity. Progabide is a GABAA and GABAB agonist and has active metabolites, including GABA itself. Glycine is another inhibitory amino acid neurotransmitter (see Chapter 21) that appears to possess pharmacologic activity when given orally and readily passes the blood-brain barrier. Idrocilamide and riluzole are newer drugs for the treatment of amyotrophic lateral sclerosis (ALS) that appear to have spasm-reducing effects, possibly through inhibition of glutamatergic transmission in the CNS.


Pharmacology_Katzung

Pharmacology_Katzung. The therapeutic use of botulinum toxin (BoNT) for ophthalmic purposes and for local muscle spasm was mentioned in Chapter 6. This neurotoxin produces chemodenervation and local paralysis when injected into a muscle. Seven immunologically distinct toxins share homologous subunits. The single-chain polypeptide BoNT has little activity until it is cleaved into a heavy chain (100 kDa) and a light chain (50 kDa). The light chain, a zinc-dependent protease, prevents release of acetylcholine by interfering with vesicle fusion, through proteolytically cleaving SNAP*-25 (BoNT-A, BoNT-E) or synaptobrevin-2 (BoNT-B, BoNT-D, BoNT-F). Local facial injections of botulinum toxin are widely used for the short-term treatment (1–3 months per treatment) of wrinkles associated with aging around the eyes and mouth. Local injection of botulinum toxin has also become a useful treatment for generalized spastic disorders (eg, cerebral palsy). Most clinical studies to date have involved administration in one


Pharmacology_Katzung

Pharmacology_Katzung. mouth. Local injection of botulinum toxin has also become a useful treatment for generalized spastic disorders (eg, cerebral palsy). Most clinical studies to date have involved administration in one or two limbs, and the benefits appear to persist for weeks to several months after a single treatment. BoNT has virtually replaced anticholinergic medications used in the treatment of dystonia. More recently, FDA approval was granted for treatment of incontinence due to overactive bladder and for chronic migraine. Most studies have used several formulations of type A BoNT, but type B is also available.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include respiratory tract infections, muscle weakness, urinary incontinence, falls, fever, and pain. While immunogenicity is currently of much less concern than in the past, experts still recommend that injections not be administered more frequently than every 3 months. Studies to determine safety of more frequent administration are underway. Besides occasional complications, a major limitation of BoNT treatment is its high cost. Future research developing other serotypes such as BoNT-C and BoNT-F is expected to result in the development of new agents that can provide chemodenervation with long-term benefits and at lower cost.


Pharmacology_Katzung

Pharmacology_Katzung. Dantrolene is a hydantoin derivative related to phenytoin that has a unique mechanism of spasmolytic activity. In contrast to the centrally acting drugs, dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers. The normal contractile response involves release of calcium *SNAP, Soluble N-ethylmaleimide sensitive factor Attachment Protein. from its stores in the sarcoplasmic reticulum (see Figures 13–1 and 27–10). This activator calcium brings about the tension-generating interaction of actin with myosin. Calcium is released from the sarcoplasmic reticulum via a calcium channel, called the ryanodine receptor (RyR) channel because the plant alkaloid ryanodine combines with a receptor on the channel protein. In the case of the skeletal muscle RyR1 channel, ryanodine facilitates the open configuration.


Pharmacology_Katzung

Pharmacology_Katzung. Dantrolene interferes with the release of activator calcium through this sarcoplasmic reticulum calcium channel by binding to the RyR1 and blocking the opening of the channel. Motor units that contract rapidly are more sensitive to the drug’s effects than are slower-responding units. Cardiac muscle and smooth muscle are minimally depressed because the release of calcium from their sarcoplasmic reticulum involves a different RyR channel (RyR2). Treatment with dantrolene is usually initiated with 25 mg daily as a single dose, increasing to a maximum of 100 mg four times daily as tolerated. Only about one third of an oral dose of dantrolene is absorbed, and the elimination half-life of the drug is approximately 8 hours. Major adverse effects are generalized muscle weakness, sedation, and occasionally hepatitis.


Pharmacology_Katzung

Pharmacology_Katzung. A special application of dantrolene is in the treatment of malignant hyperthermia, a rare heritable disorder that can be triggered by a variety of stimuli, including general anesthetics (eg, volatile anesthetics) and neuromuscular blocking drugs (eg, succinylcholine; see also Chapter 16). Patients at risk for this condition have a hereditary alteration in Ca2+-induced Ca2+ release via the RyR1 channel or impairment in the ability of the sarcoplasmic reticulum to sequester calcium via the Ca2+ transporter (Figure 27–10). Several mutations associated with this risk have been identified. After administration of one of the triggering agents, there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid production, and increased body temperature. Prompt treatment is essential to control acidosis and body temperature and to reduce calcium release. The latter is accomplished by administering intravenous dantrolene, starting with a dose of 1 mg/kg IV, and


Pharmacology_Katzung

Pharmacology_Katzung. is essential to control acidosis and body temperature and to reduce calcium release. The latter is accomplished by administering intravenous dantrolene, starting with a dose of 1 mg/kg IV, and repeating as necessary to a maximum dose of 10 mg/kg.


Pharmacology_Katzung

Pharmacology_Katzung. ANTISPASMODICS: DRUGS USED TO TREAT ACUTE LOCAL MUSCLE SPASM


Pharmacology_Katzung

Pharmacology_Katzung. A large number of less well-studied, centrally active drugs (eg, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine) are promoted for the relief of acute muscle spasm caused by local tissue trauma or muscle strains. It has been suggested that these drugs act primarily at the level of the brainstem. Cyclobenzaprine may be regarded as the prototype of the group. Cyclobenzaprine is structurally related to the tricyclic antidepressants and produces antimuscarinic side effects. It is ineffective in treating muscle spasm due to cerebral palsy or spinal cord injury. As a result of its strong antimuscarinic actions, cyclobenzaprine may cause significant sedation, as well as confusion and transient visual hallucinations. The dosage of cyclobenzaprine for acute injury-related muscle spasm is 20–40 mg/d orally in divided doses. This drug class carries risks of significant adverse events and abuse potential.


Pharmacology_Katzung

Pharmacology_Katzung. • d-Tubocurarine Competitive antagonist at nACh receptors, especially at neuromuscular junctions Prevents depolarization by ACh, causes flaccid paralysis •cancausehistaminereleasewith hypotension •weakblockofcardiacmuscarinic ACh receptors Prolonged relaxation for surgicalprocedures•supersededby newer nondepolarizing agents Renalexcretion•duration,~40–60min•Toxicities: Histamine release•hypotension•prolongedapnea • CisatracuriumSimilar to tubocurarine Like tubocurarine but lacks histamine release and antimuscarinic effects Prolonged relaxation for surgical procedures•relaxationofrespiratory muscles to facilitate mechanical ventilation in intensive care unit Not dependent on renal or hepaticfunction•duration~25–45min•Toxicities: Prolonged apnea but less toxic than atracurium • RocuroniumSimilar to cisatracurium Like cisatracurium but slight antimuscarinic effect Likecisatracurium•usefulinpatients with renal impairment Hepaticmetabolism•duration~20–35min•Toxicities: Like cisatracurium


Pharmacology_Katzung

Pharmacology_Katzung. to cisatracurium Like cisatracurium but slight antimuscarinic effect Likecisatracurium•usefulinpatients with renal impairment Hepaticmetabolism•duration~20–35min•Toxicities: Like cisatracurium • Vecuronium: Intermediate duration; metabolized in liver • Cyclobenzaprine Poorly understood inhibition of muscle stretch reflex in spinal cord


Pharmacology_Katzung

Pharmacology_Katzung. Acute spasm due to muscle injury Hepatic metabolism • duration, ~4–6 h • Toxicities: Strong antimuscarinic effects • Chlorphenesin, methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of antimuscarinic effect. Class side effect: strong central nervous system depression; note carisoprodol is a schedule IV drug.


Pharmacology_Katzung

Pharmacology_Katzung. • DantroleneBlocks RyR1 Ca2+-release channels in the sarcoplasmic reticulum of skeletal muscle Reduces actin-myosin interaction •weakensskeletalmusclecontraction IV: Malignant hyperthermia •Oral:Spasmduetocerebralpalsy, spinal cord injury, multiple sclerosis IV,oral•duration4–6h•Toxicities: Muscleweakness•Blackboxwarning: hepatotoxicity • BotulinumtoxinInhibits synaptic exocytosis through clipping of vesicle fusion proteins in presynaptic nerve terminal Flaccid paralysis Upper and lower limb spasm due to cerebral palsy, multiple sclerosis; cervical dystonia, overactive bladder, migraine, hyperhidrosis Direct injection into muscle •duration2–3months•Toxicities: muscle weakness, falls DIRECT-ACTING MUSCLE RELAXANTS Cisatracurium Generic, Nimbex Rocuronium Generic, Zemuron Succinylcholine Generic, Anectine, Quelicin Vecuronium Generic, Norcuron SPASMOLYTICS, ANTISPASMODICS Baclofen Generic, Lioresal, Gablofen Botulinum toxin type A Botox, Dysport, Xeomin


Pharmacology_Katzung

Pharmacology_Katzung. Succinylcholine Generic, Anectine, Quelicin Vecuronium Generic, Norcuron SPASMOLYTICS, ANTISPASMODICS Baclofen Generic, Lioresal, Gablofen Botulinum toxin type A Botox, Dysport, Xeomin Carisoprodol Generic, Soma, Vanadom Cyclobenzaprine Generic, Amrix, Fexmid, Flexeril Dantrolene Generic, Dantrium, Revonto Diazepam Generic, Valium, Diastat Gabapentin Generic, Neurontin, Gabarone Note: This drug is labeled for use only in epilepsy and postherpetic neuralgia. Metaxalone Generic, Skelaxin Methocarbamol Generic, Robaxin Orphenadrine Generic, Norflex, others Riluzole Generic, Rilutek Note: This drug is labeled only for use in amyotrophic lateral sclerosis. Tizanidine Generic, Zanaflex Belmont MR et al: Clinical pharmacology of GW280430A in humans. Anesthesiology 2004;100:768. Brull SJ, Murphy GS: Residual neuromuscular block: Lessons unlearned. Part II: Methods to reduce the risk of residual weakness. Anesth Analg 2010;111:129.


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Pharmacology_Katzung. Brull SJ, Murphy GS: Residual neuromuscular block: Lessons unlearned. Part II: Methods to reduce the risk of residual weakness. Anesth Analg 2010;111:129. De Boer HD et al: Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular blockade by sugammadex. Anesthesiology 2007;107:239. Gibb AJ, Marshall IG: Preand postjunctional effects of tubocurarine and other nicotinic antagonists during repetitive stimulation in the rat. J Physiol 1984;351:275. Hemmerling TM, Russo G, Bracco D: Neuromuscular blockade in cardiac surgery: An update for clinicians. Ann Card Anaesth 2008;11:80. Hirsch NP: Neuromuscular junction in health and disease. Br J Anaesth 2007;99:132. Kampe S et al: Muscle relaxants. Best Prac Res Clin Anesthesiol 2003;17:137. Lee C: Structure, conformation, and action of neuromuscular blocking drugs. Br J Anaesth 2001;87:755. Lee C et al: Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium. Anesthesiology 2009;110:1020.


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Pharmacology_Katzung. Lien CA et al: Fumarates: Unique nondepolarizing neuromuscular blocking agents that are antagonized by cysteine. J Crit Care 2009;24:50. Llauradó S et al: Sugammadex ideal body weight dose adjusted by level of neuromuscular blockade in laparoscopic bariatric surgery. Anesthesiology 2012;117:93. Mace SE: Challenges and advances in intubation: Rapid sequence intubation. Emerg Med Clin North Am 2008;26:1043. Marshall CG, Ogden DC, Colquhoun D: The actions of suxamethonium (succinyldicholine) as an agonist and channel blocker at the nicotinic receptor of frog muscle. J Physiol (Lond) 1990;428:155. Martyn JA: Neuromuscular physiology and pharmacology. In: Miller RD (editor): Anesthesia, 7th ed. Churchill Livingstone, 2010. Meakin GH: Recent advances in myorelaxant therapy. Paed Anaesthesia 2001;11:523.


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Pharmacology_Katzung. Meakin GH: Recent advances in myorelaxant therapy. Paed Anaesthesia 2001;11:523. Murphy GS, Brull SJ: Residual neuromuscular block: Lessons unlearned. Part I: Definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg 2010;111:120. Naguib M: Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575. Naguib M, Brull SJ: Update on neuromuscular pharmacology. Curr Opin Anaesthesiol 2009;22:483. Naguib M, Kopman AF, Ensor JE: Neuromuscular monitoring and postoperative residual curarisation: A meta-analysis. Br J Anaesth 2007;98:302. Naguib M et al: Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology 2002;96:202. Nicholson WT, Sprung J, Jankowski CJ: Sugammadex: A novel agent for the reversal of neuromuscular blockade. Pharmacotherapy 2007;27:1181. Pavlin JD, Kent CD: Recovery after ambulatory anesthesia. Curr Opin Anaesthesiol 2008;21:729.


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Pharmacology_Katzung. Pavlin JD, Kent CD: Recovery after ambulatory anesthesia. Curr Opin Anaesthesiol 2008;21:729. Puhringer FK et al: Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points. Anesthesiology 2008;109:188. Sacan O, Klein K, White PF: Sugammadex reversal of rocuronium-induced neuromuscular blockade: A comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg 2007;104:569. Savarese JJ et al: Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: A comparison with mivacurium. Anesthesiology 2004;100:835. Sine SM: End-plate acetylcholine receptor: Structure, mechanism, pharmacology, and disease. Physiol Rev 2012;92:1189. Staals LM et al: Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: A pharmacokinetic study. Br J Anaesth 2010;104:31.


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Pharmacology_Katzung. Staals LM et al: Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: A pharmacokinetic study. Br J Anaesth 2010;104:31. Sugammadex: BRIDION (sugammadex) Injection, for intravenous use initial U.S. Approval: 2015. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/ label/2015/022225lbl.pdf. Sunaga H et al: Gantacurium and CW002 do not potentiate muscarinic receptor-mediated airway smooth muscle constriction in guinea pigs. Anesthesiology 2010;112:892. Viby-Mogensen J: Neuromuscular monitoring. In: Miller RD (editor): Anesthesia, 5th ed. Churchill Livingstone, 2000. Caron E, Morgan R, Wheless JW: An unusual cause of flaccid paralysis and coma: Baclofen overdose. J Child Neurol 2014;29:555. Corcia P, Meininger V: Management of amyotrophic lateral sclerosis. Drugs 2008;68:1037. Cutter NC et al: Gabapentin effect on spasticity in multiple sclerosis: A placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000;81:164.


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Pharmacology_Katzung. Cutter NC et al: Gabapentin effect on spasticity in multiple sclerosis: A placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000;81:164. Draulans N et al: Intrathecal baclofen in multiple sclerosis and spinal cord injury: Complications and long-term dosage evolution. Clin Rehabil 2013;27:1137. Frydrych V, Oderda G: Skeletal muscle relaxants drug class review: University of Utah College of Pharmacy. Final Report 2016. Retrieved from https://www. medicaid.utah.gov/pharmacy/. Gracies JM, Singer BJ, Dunne JW: The role of botulinum toxin injections in the management of muscle overactivity of the lower limb. Disabil Rehabil 2007;29:1789. Groves L, Shellenberger MK, Davis CS: Tizanidine treatment of spasticity: A meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Adv Ther 1998;15:241. Jankovic J: Medical treatment of dystonia. Mov Disord 2013;28:1001.


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Pharmacology_Katzung. Jankovic J: Medical treatment of dystonia. Mov Disord 2013;28:1001. Kheder A, Nair KPS: Spasticity: Pathophysiology, evaluation and management. Pract Neurol 2012;12:289. Krause T et al: Dantrolene—A review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004;59:364. Lopez JR et al: Effects of dantrolene on myoplasmic free [Ca2+] measured in vivo in patients susceptible to malignant hyperthermia. Anesthesiology 1992;76:711. Lovell BV, Marmura MJ: New therapeutic developments in chronic migraine. Curr Opin Neurol 2010;23:254. Malanga G, Reiter RD, Garay E: Update on tizanidine for muscle spasticity and emerging indications. Expert Opin Pharmacother 2008;9:2209. Mast N, Linger M, Pikuleva IA: Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents. Mol Cell Endocrinol 2013;371:100.


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Pharmacology_Katzung. Mast N, Linger M, Pikuleva IA: Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents. Mol Cell Endocrinol 2013;371:100. Mirbagheri MM, Chen D, Rymer WZ: Quantification of the effects of an alpha-2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique. J Neuroeng Rehabil 2010;7:29. Neuvonen PJ: Towards safer and more predictable drug treatment—Reflections from studies of the First BCPT Prize awardee. Basic Clin Pharmacol Toxicol 2012;110:207. Nolan KW, Cole LL, Liptak GS: Use of botulinum toxin type A in children with cerebral palsy. Phys Ther 2006;86:573. Reeves RR, Burke RS: Carisoprodol: Abuse potential and withdrawal syndrome. Curr Drug Abuse Rev 2010;3:33. Ronan S, Gold JT: Nonoperative management of spasticity in children. Childs Nerv Syst 2007;23:943. Ross JC et al: Acute intrathecal baclofen withdrawal: A brief review of treatment options. Neurocrit Care 2011;14:103.


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Pharmacology_Katzung. Ross JC et al: Acute intrathecal baclofen withdrawal: A brief review of treatment options. Neurocrit Care 2011;14:103. Vakhapova V, Auriel E, Karni A: Nightly sublingual tizanidine HCl in multiple sclerosis: Clinical efficacy and safety. Clin Neuropharmacol 2010;33:151. Verrotti A et al: Pharmacotherapy of spasticity in children with cerebral palsy. Pediatr Neurol 2006;34:1. Ward AB: Spasticity treatment with botulinum toxins. J Neural Transm 2008;115:607. Zanaflex Capsules Package insert. Prescribing information. Acorda Therapeutics, 2006.


Pharmacology_Katzung

Pharmacology_Katzung. Because of trauma and associated pain, it is assumed that gastric emptying will be significantly delayed. To avoid pos-sible aspiration at the time of intubation, a very rapid-acting muscle relaxant should be used so the airway can be secured with an endotracheal tube. Usually, succinylcholine would be the agent of choice in this case; however, the patient has a ruptured (open) globe. Succinylcholine is contraindicated in patients with an open globe because it raises intraocular pressure and could possibly result in extrusion of aqueous or vitreous humor. Therefore, a rapid sequence intubation should be performed with high-dose (up to 1.2 mg/kg) rocuronium, a nondepolarizing muscle relaxant. At this dose, rocuronium has a very rapid onset, which approaches but does not quite equal that of succinylcholine. In the case vignette, you are unable to intubate the patient and may be unable to mask ventilate the patient. In this setting, use of the reversal agent sugammadex is indicated.


Pharmacology_Katzung

Pharmacology_Katzung. of succinylcholine. In the case vignette, you are unable to intubate the patient and may be unable to mask ventilate the patient. In this setting, use of the reversal agent sugammadex is indicated. Since a large dose of rocuronium was just given, a dose of 16 mg/kg of sugammadex needs to be given to rapidly and completely reverse the effects of the neuromuscular block-ing agent and allow return of spontaneous ventilation. In order to proceed with surgery, another technique (such as an awake fiberoptic-assisted intubation) should be used to secure the airway.


Pharmacology_Katzung

Pharmacology_Katzung. Pharmacologic Management of Parkinsonism & Other Movement Disorders Michael J. Aminoff, MD, DSc, FRCP


Pharmacology_Katzung

Pharmacology_Katzung. A 76-year-old retired banker complains of a shuffling gait with occasional falls over the last year. He has developed a stooped posture, drags his left leg when walking, and is unsteady on turning. He remains independent in all activi-ties of daily living, but he has become more forgetful and occasionally sees his long-deceased father in his bedroom. Examination reveals hypomimia, hypophonia, a slight rest tremor of the right hand and chin, mild rigidity, and impaired rapid alternating movements in all limbs. Neuro-logic and general examinations are otherwise normal. What is the likely diagnosis and prognosis? The patient is started on a dopamine agonist, and the dose is gradually built up to the therapeutic range. Was this a good choice of medications? Six months later, the patient and his wife return for follow-up. It now becomes apparent that he is falling asleep at inappropriate times, such as at the dinner table, and when awake, he spends much of the time in arranging and


Pharmacology_Katzung

Pharmacology_Katzung. and his wife return for follow-up. It now becomes apparent that he is falling asleep at inappropriate times, such as at the dinner table, and when awake, he spends much of the time in arranging and rear-ranging the table cutlery or in picking at his clothes. To what is his condition due, and how should it be managed? Would you recommend surgical treatment?


Pharmacology_Katzung

Pharmacology_Katzung. Several types of abnormal movement are recognized. Tremor consists of a rhythmic oscillatory movement around a joint and is best characterized by its relation to activity. Tremor at rest is characteristic of parkinsonism, when it is often associated with rigidity and an impairment of voluntary activity. Tremor may occur during maintenance of sustained posture (postural tremor) or during movement (intention tremor). A conspicuous postural tremor is the cardinal feature of benign essential or familial tremor. Intention tremor occurs in patients with a lesion of the brainstem or cerebellum, especially when the superior cerebellar peduncle is involved; it may also occur as a manifestation of toxicity from alcohol or certain other drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Chorea consists of irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impair voluntary activity. In some instances, the proximal muscles of the limbs are most severely affected, and because the abnormal movements are then particularly violent, the term ballismus has been used to describe them. Chorea may be hereditary or acquired and may occur as a complication of a number of general medical disorders and of therapy with certain drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Abnormal movements may be slow and writhing in character (athetosis) and, in some instances, are so sustained that they are more properly regarded as abnormal postures (dystonia). Athetosis or dystonia may occur with perinatal brain damage, with focal or generalized cerebral lesions, as an acute complication of certain drugs, as an accompaniment of diverse neurologic disorders, or as an isolated inherited phenomenon of uncertain cause known as idiopathic torsion dystonia or dystonia musculorum deformans. Various genetic loci have been reported depending on the age of onset, mode of inheritance, and response to dopaminergic therapy. The physiologic basis is uncertain, and treatment is unsatisfactory. Patients with dystonia commonly have psychiatric complications, such as depression, that affect the quality of life. These may be secondary to the dystonia or a nonmotor manifestation of the underlying disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Tics are sudden coordinated abnormal movements that tend to occur repetitively, particularly about the face and head, especially in children, and can be suppressed voluntarily for short periods of time. Common tics include repetitive sniffing or shoulder shrugging. Tics may be single or multiple and transient or chronic. Gilles de la Tourette syndrome is characterized by chronic multiple tics; its pharmacologic management is discussed at the end of this chapter. Many of the movement disorders have been attributed to disturbances of the basal ganglia. The basic circuitry of the basal ganglia involves three interacting neuronal loops that include the cortex and thalamus as well as the basal ganglia themselves (Figure 28–1). However, the precise function of these anatomic


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 28–1 Functional circuitry between the cortex, basal ganglia, and thalamus. The major neurotransmitters are indicated. In Parkinson’s disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus. structures is not yet fully understood, and it is not possible to relate individual symptoms to involvement at specific sites.


Pharmacology_Katzung

Pharmacology_Katzung. Parkinsonism is characterized by a combination of rigidity, bradykinesia, tremor, and postural instability that can occur for a variety of reasons but is usually idiopathic (Parkinson’s disease or paralysis agitans). Bradykinesia should be present before a diagnosis of Parkinson’s disease is made. Focal dystonic features may be present. Cognitive decline occurs in many patients as the disease advances. Other nonmotor symptoms include affective disorders (anxiety or depression); confusion, cognitive impairment, or personality changes; apathy; fatigue; abnormalities of autonomic function (eg, sphincter or sexual dysfunction, dysphagia and choking, sweating abnormalities, sialorrhea, or disturbances of blood pressure regulation); sleep disorders; and sensory complaints or pain. The disease is incurable, is generally progressive, and leads to increasing disability with time, but pharmacologic treatment may relieve motor symptoms and improve the quality of life for many years.


Pharmacology_Katzung

Pharmacology_Katzung. The pathogenesis of parkinsonism seems to relate to a combination of impaired degradation of proteins, intracellular protein accumulation and aggregation, oxidative stress, mitochondrial damage, inflammatory cascades, and apoptosis. Studies in twins suggest that genetic factors are important, especially when the disease occurs in patients under age 50. Recognized genetic abnormalities account for 10–15% of cases. Mutations of the α-synuclein gene at 4q21 or duplication and triplication of the normal synuclein gene are associated with Parkinson’s disease, which is now widely recognized as a synucleinopathy. Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen, and the UCHL1 gene may also cause autosomal dominant parkinsonism. Mutations in the parkin gene (6q25.2–q27) cause early-onset, autosomal recessive, familial parkinsonism, or sporadic juvenile-onset parkinsonism. Several other genes or chromosomal regions have been associated with familial forms of the disease.


Pharmacology_Katzung

Pharmacology_Katzung. early-onset, autosomal recessive, familial parkinsonism, or sporadic juvenile-onset parkinsonism. Several other genes or chromosomal regions have been associated with familial forms of the disease. Environmental or endogenous toxins may also be important in the etiology of the disease. Epidemiologic studies reveal that cigarette smoking, coffee, anti-inflammatory drug use, and high serum uric acid levels are protective, whereas the incidence of the disease is increased in those working in teaching, health care, or farming, and in those with lead or manganese exposure or with vitamin D deficiency.


Pharmacology_Katzung

Pharmacology_Katzung. The finding of Lewy bodies (intracellular inclusion bodies containing α-synuclein) in fetal dopaminergic cells transplanted into the brain of parkinsonian patients some years previously has provided some support for suggestions that Parkinson’s disease may represent a prion disease. Staining for α-synuclein has revealed that pathology is more widespread than previously recognized, developing initially in the olfactory nucleus and lower brainstem (stage 1 of Braak scale), then the higher brainstem (stage 2), the substantia nigra (stage 3), FIGURE 28–2 Schematic representation of the sequence of neurons involved in parkinsonism. Top: Dopaminergic neurons (red) originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons (green) exert an excitatory effect. Bottom: In parkinsonism, there is a selective loss of dopaminergic neurons (dashed, red).


Pharmacology_Katzung

Pharmacology_Katzung. the mesocortex and thalamus (stage 4), and finally the entire neocortex (stage 5). The motor features of Parkinson’s disease develop at stage 3 on the Braak scale.


Pharmacology_Katzung

Pharmacology_Katzung. The normally high concentration of dopamine in the basal ganglia of the brain is reduced in parkinsonism, and pharmacologic attempts to restore dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder. An alternative but complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs. The pathophysiologic basis for these therapies is that in idiopathic parkinsonism, there is a loss of dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum (Figure 28–2). Drugs that induce parkinsonian syndromes either are dopamine receptor antagonists (eg, antipsychotic agents; see Chapter 29) or lead to the destruction of the dopaminergic nigrostriatal neurons (eg, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine [MPTP]; see below). Various other neurotransmitters, such as norepinephrine, are also


Pharmacology_Katzung

Pharmacology_Katzung. to the destruction of the dopaminergic nigrostriatal neurons (eg, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine [MPTP]; see below). Various other neurotransmitters, such as norepinephrine, are also depleted in the brain in parkinsonism, but these deficiencies are of uncertain clinical relevance.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (–)-3-(3,4-dihydroxyphenyl)-l-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an l-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6–5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine receptors are discussed in detail in Chapters 21 and 29. They exist in five subtypes. D1 and D5 receptors are classified as the D1 receptor family based on genetic and biochemical factors; D2, D3, and D4 are grouped as belonging to the D2 receptor family. Dopamine receptors of the D1 type are located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra. The D2 receptors are located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia. The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors. However, D1-receptor stimulation may also be required for maximal benefit, and one of the newer drugs is D3 selective. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and bromocriptine that are powerful stimulators of the D2


Pharmacology_Katzung

Pharmacology_Katzung. for maximal benefit, and one of the newer drugs is D3 selective. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and bromocriptine that are powerful stimulators of the D2 receptors have antiparkinsonism properties, whereas certain dopamine blockers that are selective D2 antagonists can induce parkinsonism.


Pharmacology_Katzung

Pharmacology_Katzung. Dopa is the amino acid precursor of dopamine and norepinephrine (discussed in Chapter 6). Its structure is shown in Figure 28–3. Levodopa is the levorotatory stereoisomer of dopa.


Pharmacology_Katzung

Pharmacology_Katzung. Levodopa is rapidly absorbed from the small intestine, but its absorption depends on the rate of gastric emptying and the pH of the gastric contents. Ingestion of food delays the appearance of levodopa in the plasma. Moreover, certain amino acids from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain. Plasma concentrations usually peak between 1 and 2 hours after an oral dose, and the plasma half-life is usually between 1 and 3 hours, although it varies considerably among individuals. About two thirds of the dose appears in the urine as metabolites within 8 hours of an oral dose, the main metabolic products being 3-methoxy-4-hydroxyphenyl acetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC). Unfortunately, only about 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate


Pharmacology_Katzung

Pharmacology_Katzung. only about 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the blood-brain barrier. Accordingly, levodopa must be given in large amounts when used alone. However, when given in combination with a dopa decarboxylase inhibitor that does not penetrate the blood-brain barrier, the peripheral metabolism of levodopa is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and more dopa is available for entry into the brain (Figure 28–4). Indeed, concomitant administration of a peripheral dopa decarboxylase inhibitor such as carbidopa may reduce the daily requirements of levodopa by approximately 75%.


Pharmacology_Katzung

Pharmacology_Katzung. The best results of levodopa treatment are obtained in the first few years of treatment. This is sometimes because the daily dose FIGURE 28–3 Some drugs used in the treatment of parkinsonism.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 28–3 Some drugs used in the treatment of parkinsonism. of levodopa must be reduced over time to avoid adverse effects at doses that were well tolerated initially. Some patients become less responsive to levodopa, perhaps because of loss of dopaminergic nigrostriatal nerve terminals or some pathologic process directly involving striatal dopamine receptors. For such reasons, the benefits of levodopa treatment often begin to diminish after about 3 or 4 years of therapy, regardless of the initial therapeutic response. Although levodopa therapy does not stop the progression of parkinsonism, its early initiation lowers the mortality rate. However, long-term therapy may lead to a number of problems in management such as the on-off phenomenon discussed below. The most appropriate time to introduce levodopa therapy must therefore be determined individually.


Pharmacology_Katzung

Pharmacology_Katzung. When levodopa is used, it is generally given in combination with carbidopa (Figure 28–3), a peripheral dopa decarboxylase inhibitor, which reduces peripheral conversion to dopamine. Combination treatment is started with a small dose, eg, carbidopa 25 mg, levodopa 100 mg three times daily, and gradually increased. It should be taken 30–60 minutes before meals. Most patients ultimately require carbidopa 25 mg, levodopa 250 mg three or four times daily. It is generally preferable to keep treatment with this agent at a low level (eg, carbidopa-levodopa 25/100 three times daily) when possible, and if necessary, to add a dopamine agonist, to reduce the risk of development of response fluctuations. A controlled-release formulation of carbidopalevodopa is available and may be helpful in patients with established response fluctuations or as a means of reducing dosing frequency. Even more helpful for response fluctuations is a new extended-release formulation (Rytary) that is now available in


Pharmacology_Katzung

Pharmacology_Katzung. with established response fluctuations or as a means of reducing dosing frequency. Even more helpful for response fluctuations is a new extended-release formulation (Rytary) that is now available in the USA. A formulation of carbidopa-levodopa (10/100, 25/100, 25/250) that disintegrates in the mouth and is swallowed with the saliva (Parcopa) is available commercially and is best taken about 1 hour before meals. The combination (Stalevo) of levodopa, carbidopa, and a catechol-O-methyltransferase (COMT) inhibitor (entacapone) is discussed in a later section. Finally, therapy by infusion of carbidopa-levodopa into the duodenum or upper jejunum appears to be safe and is superior to a number of oral combination therapies in patients with advanced levodopa-responsive parkinsonism with response fluctuations. A permanent access tube is inserted via a percutaneous endoscopic gastrostomy in patients who have responded well to carbidopa-levodopa gel administered through a nasoduodenal tube. A


Pharmacology_Katzung

Pharmacology_Katzung. fluctuations. A permanent access tube is inserted via a percutaneous endoscopic gastrostomy in patients who have responded well to carbidopa-levodopa gel administered through a nasoduodenal tube. A morning bolus (100–300 mg of levodopa) is delivered via a portable infusion pump, followed by a continuous maintenance dose (40–120 mg/h), with supplemental bolus doses as required.


Pharmacology_Katzung

Pharmacology_Katzung. Levodopa can ameliorate many of the clinical motor features of parkinsonism, but it is particularly effective in relieving bradykinesia and any disabilities resulting from it. When it is first introduced, about one third of patients respond very well and one third less well. Most of the remainder either are unable to tolerate the medication or simply do not respond at all, especially if they do not have classic Parkinson’s disease. A. Gastrointestinal Effects


Pharmacology_Katzung

Pharmacology_Katzung. When levodopa is given without a peripheral decarboxylase inhibitor, anorexia and nausea and vomiting occur in about 80% of patients. These adverse effects can be minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly. Antacids taken 30–60 minutes before levodopa may also be beneficial. The vomiting has been attributed to stimulation of the chemoreceptor trigger zone located in the brainstem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. If not, an additional dose of carbidopa (Lodosyn; 25 mg) taken with the regular carbidopa-levodopa dose is often helpful, even though the usual maximum requirement of carbidopa is 75 mg daily. Domperidone (not available in the USA) may also relieve persistent nausea. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease.


Pharmacology_Katzung

Pharmacology_Katzung. When levodopa is given in combination with carbidopa, adverse gastrointestinal effects are much less frequent and troublesome, occurring in less than 20% of cases, so that patients can tolerate proportionately higher doses. Metabolism Peripheral in the tissues GI tract (toxicity) Levodopa with carbidopa Metabolism Peripheral in the tissues GI tract (toxicity) FIGURE 28–4 Fate of orally administered levodopa and the effect of carbidopa, estimated from animal data. The width of each pathway indicates the absolute amount of the drug at each site, whereas the percentages shown denote the relative proportion of the administered dose. The benefits of co-administration of carbidopa include reduction of the amount of levodopa required for benefit and of the absolute amount diverted to peripheral tissues and an increase in the fraction of the dose that reaches the brain. GI, gastrointestinal. (Data from Nutt JG, Fellman JH: Pharmacokinetics of levodopa. Clin Neuropharmacol 1984;7:35.)


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects A variety of cardiac arrhythmias have been described in patients receiving levodopa, including tachycardia, ventricular extrasystoles, and rarely, atrial fibrillation. This effect has been attributed to increased catecholamine formation peripherally. The incidence of such arrhythmias is low, even in the presence of established cardiac disease, and may be reduced still further if the levodopa is taken in combination with a peripheral decarboxylase inhibitor. Postural hypotension is common, but often asymptomatic, and tends to diminish with continuing treatment. Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or sympathomimetics or when massive doses of levodopa are being taken. C. Behavioral Effects


Pharmacology_Katzung

Pharmacology_Katzung. A wide variety of adverse mental effects have been reported, including depression, anxiety, agitation, insomnia, somnolence, sleep attacks, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality. Such adverse effects are more common in patients taking levodopa in combination with a decarboxylase inhibitor rather than levodopa alone, presumably because higher levels are reached in the brain. They may be precipitated by intercurrent illness or surgery. It may be necessary to reduce or withdraw the medication. Several atypical antipsychotic agents that have low affinity for dopamine D2 receptors (clozapine, olanzapine, quetiapine, and risperidone; see Chapter 29) are now available and may be particularly helpful in counteracting such behavioral complications. Pimavanserin (34 mg daily), a selective serotonin 5-HT2A inverse agonist, is also helpful for treating the hallucinations and delusions of Parkinson’s disease psychosis and has recently


Pharmacology_Katzung

Pharmacology_Katzung. Pimavanserin (34 mg daily), a selective serotonin 5-HT2A inverse agonist, is also helpful for treating the hallucinations and delusions of Parkinson’s disease psychosis and has recently been approved for use in the USA. It should not be used for dementia-related psychosis and should be avoided in patients with QT prolongation.


Pharmacology_Katzung

Pharmacology_Katzung. The dopamine dysregulation syndrome is characterized by compulsive overuse of dopaminergic medication as well as by other impulsive behaviors; such impulse control disorders are more common with dopamine agonists than levodopa and are discussed later. Management involves the close regulation of dopaminergic intake. Punding designates the performance of stereotyped, complex, but purposeless motor activity, such as sorting or lining up various objects or repetitive grooming behavior. It responds to reduction in dose of dopaminergic agents or to atypical antipsychotic agents. D. Dyskinesias and Response Fluctuations


Pharmacology_Katzung

Pharmacology_Katzung. Dyskinesias occur in up to 80% of patients receiving levodopa therapy for more than 10 years. The character of dopa dyskinesias varies between patients but tends to remain constant in individual patients. Choreoathetosis of the face and distal extremities is the most common presentation. The development of dyskinesias is dose related, but there is considerable individual variation in the dose required to produce them. Their pathogenesis is unclear, but they may relate to an unequal distribution of striatal dopamine. Dopaminergic denervation plus chronic pulsatile stimulation of dopamine receptors with levodopa has been associated with development of dyskinesias. A lower incidence of dyskinesias occurs when levodopa is administered continuously (eg, intraduodenally or intrajejunally) and with drug delivery systems that enable a more continuous delivery of dopaminergic medication. Reduction of levodopa dose will alleviate dyskinesias, but motor symptoms of parkinsonism then worsen. Mild


Pharmacology_Katzung

Pharmacology_Katzung. drug delivery systems that enable a more continuous delivery of dopaminergic medication. Reduction of levodopa dose will alleviate dyskinesias, but motor symptoms of parkinsonism then worsen. Mild dyskinesias require no treatment. Amantadine may help to reduce more troublesome dyskinesias, as may clozapine; a number of other compounds are being studied as possible antidyskinetic agents.


Pharmacology_Katzung

Pharmacology_Katzung. Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to the timing of levodopa intake (wearing-off reactions or end-of-dose akinesia). In other instances, fluctuations in clinical state are unrelated to the timing of doses (on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. For patients with severe off-periods who are unresponsive to other measures, subcutaneously injected apomorphine may provide temporary benefit but may increase dyskinesias. The on-off phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown. E. Miscellaneous Adverse Effects


Pharmacology_Katzung

Pharmacology_Katzung. E. Miscellaneous Adverse Effects Mydriasis may occur and may precipitate an attack of acute glaucoma in some patients. Other reported but rare adverse effects include various blood dyscrasias; a positive Coombs’ test with evidence of hemolysis; hot flushes; aggravation or precipitation of gout; abnormalities of smell or taste; brownish discoloration of saliva, urine, or vaginal secretions; priapism; and mild—usually transient—elevations of blood urea nitrogen and of serum transaminases, alkaline phosphatase, and bilirubin.


Pharmacology_Katzung

Pharmacology_Katzung. A drug holiday (discontinuance of the drug for 3–21 days) may temporarily improve responsiveness to levodopa and alleviate some of its adverse effects but is usually of little help in the management of the on-off phenomenon. Furthermore, a drug holiday carries the risks of aspiration pneumonia, venous thrombosis, pulmonary embolism, and depression resulting from the immobility accompanying severe parkinsonism. For these reasons and because of the temporary nature of any benefit, drug holidays are not recommended. Pharmacologic doses of pyridoxine (vitamin B6) enhance the extracerebral metabolism of levodopa and may therefore prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance because such a combination can lead to hypertensive crises.


Pharmacology_Katzung

Pharmacology_Katzung. Levodopa should not be given to psychotic patients because it may exacerbate the mental disturbance. It is also contraindicated in patients with angle-closure glaucoma, but those with chronic open-angle glaucoma may be given levodopa if intraocular pressure is well controlled and can be monitored. When combined with carbidopa, the risk of cardiac dysrhythmia is slight, even in patients with cardiac disease. Patients with active peptic ulcer must be managed carefully, since gastrointestinal bleeding has occasionally occurred with levodopa. Because levodopa is a precursor of skin melanin and conceivably may activate malignant melanoma, it should be used with particular care in patients with a history of melanoma or with suspicious undiagnosed skin lesions; such patients should be monitored regularly by a dermatologist.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs acting directly on postsynaptic dopamine receptors may have a beneficial effect in addition to that of levodopa (Figure 28–5). Unlike levodopa, they do not require enzymatic conversion to an active metabolite, act directly on the postsynaptic dopamine receptors, have no potentially toxic metabolites, and do not compete with other substances for active transport into the blood and across the blood-brain barrier. Moreover, drugs selectively affecting certain (but not all) dopamine receptors may have more limited adverse effects than levodopa. A number of dopamine agonists have antiparkinsonism activity. The older dopamine agonists (bromocriptine and pergolide) are ergot (ergoline) derivatives (see Chapter 16) and are rarely—if ever—used to treat parkinsonism. Their side effects are of more concern than those of the newer agents (pramipexole and ropinirole).


Pharmacology_Katzung

Pharmacology_Katzung. L-DOPA L-DOPA Dopamine Dopamine Adverse effects Brain Periphery COMTMAO-B DOPA decarboxylase COMT 3-OMD DOPA decarboxylase Carbidopa Entacapone, tolcapone 3-MTDOPAC L-amino acid transporter ++ – –– – +Dopamine receptors Pramipexole, ropinirole Bromocriptine, pergolide Tolcapone Selegiline, rasagiline FIGURE 28–5 Pharmacologic strategies for dopaminergic therapy of Parkinson’s disease. Drugs and their effects are indicated (see text). COMT, catechol-O-methyltransferase; DOPAC, dihydroxy-phenylacetic acid; L-DOPA, levodopa; MAO, monoamine oxidase; 3-MT, 3-methoxytyramine; 3-OMD, 3-O-methyldopa.


Pharmacology_Katzung

Pharmacology_Katzung. There is no evidence that one agonist is superior to another; individual patients, however, may respond to one but not another of these agents. Moreover, their duration of action varies and is lengthened by extended-release preparations. Apomorphine is a potent dopamine agonist but is discussed separately in a later section in this chapter because it is used primarily as a rescue drug for patients with disabling response fluctuations to levodopa.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine agonists have an important role as first-line therapy for Parkinson’s disease, and their use is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. Dopaminergic therapy is therefore often initiated with a dopamine agonist, although, compared with levodopa, the agonists generally provide less symptomatic benefit and are more likely to cause mental side effects, somnolence, and edema. In other instances, a low dose of carbidopa plus levodopa (eg, Sinemet-25/100 three times daily) is introduced, and a dopamine agonist is then added. In either case, the dose of the dopamine agonist is built up gradually depending on response and tolerance. Dopamine agonists may also be given to patients with parkinsonism who are taking levodopa and who have end-of-dose akinesia or on-off phenomenon or are becoming resistant to treatment with levodopa. In such circumstances, it is generally necessary to lower the dose of


Pharmacology_Katzung

Pharmacology_Katzung. are taking levodopa and who have end-of-dose akinesia or on-off phenomenon or are becoming resistant to treatment with levodopa. In such circumstances, it is generally necessary to lower the dose of levodopa to prevent intolerable adverse effects. The response to a dopamine agonist is generally disappointing in patients who have never responded to levodopa.


Pharmacology_Katzung

Pharmacology_Katzung. Bromocriptine is a D2 agonist; its structure is shown in Table 16–7. This drug has been widely used to treat Parkinson’s disease in the past but is now rarely used for this purpose, having been superseded by the newer dopamine agonists. The usual daily dose of bromocriptine for parkinsonism varies between 7.5 and 30 mg. To minimize adverse effects, the dose is built up slowly over 2 or 3 months depending on response or the development of adverse reactions. Pergolide, another ergot derivative, directly stimulates both D1 and D2 receptors. It too has been widely used for parkinsonism but is no longer available in the United States because its use has been associated with the development of valvular heart disease. It is nevertheless still used in some countries.


Pharmacology_Katzung

Pharmacology_Katzung. Pramipexole is not an ergot derivative, but it has preferential affinity for the D3 family of receptors. It is effective as mono-therapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. A possible neuroprotective effect has been suggested by its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures.


Pharmacology_Katzung

Pharmacology_Katzung. Pramipexole is rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 2 hours, and is excreted largely unchanged in the urine. It is started at a dosage of 0.125 mg three times daily, doubled after 1 week, and again after another week. Further increments in the daily dose are by 0.75 mg at weekly intervals, depending on response and tolerance. Most patients require between 0.5 and 1.5 mg three times daily. Renal insufficiency may necessitate dosage adjustment. An extended-release preparation is now available and is taken once daily at a dose equivalent to the total daily dose of standard pramipexole. The extended-release preparation is generally more convenient for patients and avoids swings in blood levels of the drug over the day.


Pharmacology_Katzung

Pharmacology_Katzung. Another nonergoline derivative, ropinirole (now available in a generic preparation) is a relatively pure D2 receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. It is introduced at 0.25 mg three times daily, and the total daily dose is then increased by 0.75 mg at weekly intervals until the fourth week and by 1.5 mg thereafter. In most instances, a dosage between 2 and 8 mg three times daily is necessary. Ropinirole is metabolized by CYP1A2; other drugs metabolized by this isoform may significantly reduce its clearance. A prolonged-release preparation taken once daily is available.


Pharmacology_Katzung

Pharmacology_Katzung. The dopamine agonist rotigotine, delivered daily through a skin patch, is approved for treatment of early Parkinson’s disease. It supposedly provides more continuous dopaminergic stimulation than oral medication in early parkinsonism; its efficacy in more advanced disease is less clear. Benefits and side effects are similar to those of other dopamine agonists but reactions may also occur at the application site and are sometimes serious. Adverse Effects of Dopamine Agonists A. Gastrointestinal Effects Anorexia and nausea and vomiting may occur when a dopamine agonist is introduced and can be minimized by taking the medication with meals. Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur. Bleeding from peptic ulceration has been reported. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects Postural hypotension may occur, particularly at the initiation of therapy. Painless digital vasospasm is a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or pergolide). When cardiac arrhythmias occur, they are an indication for discontinuing treatment. Peripheral edema is sometimes problematic. Cardiac valvulopathy may occur with pergolide. C. Dyskinesias Abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopaminergic drugs being taken. D. Mental Disturbances


Pharmacology_Katzung

Pharmacology_Katzung. C. Dyskinesias Abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopaminergic drugs being taken. D. Mental Disturbances Confusion, hallucinations, delusions, and other psychiatric reactions may develop as a feature of Parkinson’s disease or as complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa. They tend to occur earlier in older patients and become more common as the disease advances. There appears to be no difference between the various dopamine agonists in their ability to induce these disorders. They may respond to atypical anti-psychotic agents such as clozapine, olanzapine, quetiapine, and risperidone or to pimavanserin.


Pharmacology_Katzung

Pharmacology_Katzung. Disorders of impulse control may occur either as an exaggeration of a previous tendency or as a new phenomenon and may lead to compulsive gambling, shopping, betting, sexual activity, and other behaviors (see Chapter 32). Their prevalence varies in different reports but may be as high as 15–25% in parkinsonian patients treated with dopamine agonists. They relate to activation of D2 or D3 dopamine receptors in the mesocorticolimbic system, may occur with one dopamine agonist and not another, and may occur at any time after the initiation of treatment. They are not dose-dependent, but in some patients, a dose reduction may ameliorate them; they resolve on withdrawal of the offending medication. Impulse control disorders are generally under-reported by patients and their families and often unrecognized by health care professionals. Risk factors include an impulsive personality, a history of drug use or other addictive behaviors, and a family history of gambling disorders.


Pharmacology_Katzung

Pharmacology_Katzung. E. Miscellaneous Headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis, and erythromelalgia are other reported adverse effects of the ergot-derived dopamine agonists. Erythromelalgia consists of red, tender, painful, swollen feet and, occasionally, hands, at times associated with arthralgia; symptoms and signs clear within a few days of withdrawal of the causal drug. In rare instances, an uncontrollable tendency to fall asleep at inappropriate times has occurred, particularly in patients receiving pramipexole or ropinirole; this requires discontinuation of the medication. Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction, or with active peptic ulceration. The ergot-derived agonists are best avoided in patients with peripheral vascular disease.


Pharmacology_Katzung

Pharmacology_Katzung. Two types of monoamine oxidase have been distinguished in the nervous system. Monoamine oxidase A metabolizes norepinephrine, serotonin, and dopamine; monoamine oxidase B metabolizes dopamine selectively. Selegiline (deprenyl) (Figure 28–3), a selective irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits monoamine oxidase A as well), retards the breakdown of dopamine (Figure 28–5); in consequence, it enhances and prolongs the antiparkinsonism effect of levodopa (thereby allowing the dose of levodopa to be reduced) and may reduce mild on-off or wearing-off phenomena. It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa. The standard dose of selegiline is 5 mg with breakfast and 5 mg with lunch. Selegiline may cause insomnia when taken later during the day.


Pharmacology_Katzung

Pharmacology_Katzung. Selegiline has only a minor therapeutic effect on parkinsonism when given alone. Studies in animals suggest that it may reduce disease progression, but trials to test the effect of selegiline on the progression of parkinsonism in humans have yielded ambiguous results. The findings in a large multicenter study were taken to suggest a beneficial effect in slowing disease progression but may simply have reflected a symptomatic response.


Pharmacology_Katzung

Pharmacology_Katzung. Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP-induced parkinsonism and is being used for early treatment in patients with mild symptoms. The standard dosage is 1 mg/d. Rasagiline is also used as adjunctive therapy at a dosage of 0.5 or 1 mg/d to prolong the effects of carbidopa-levodopa in patients with advanced disease and response fluctuations. A large double-blind, placebo-controlled, delayed-start study (the ADAGIO trial) to evaluate whether it had neuroprotective benefit (ie, slowed the disease course) yielded unclear results: a daily dose of 1 mg met all the end points of the study and did seem to slow disease progression, but a 2-mg dose failed to do so. These findings are difficult to explain and the decision to use rasagiline for neuroprotective purposes therefore remains an individual one.


Pharmacology_Katzung

Pharmacology_Katzung. A third monoamine oxidase B inhibitor, safinamide, was approved by the FDA while this book was in production. It is used to reduce response fluctuations in patients taking carbidopalevodopa, diminishing off-periods in patients with wearing-off effect or on-off phenomena. It is not effective as monotherapy for Parkinson’s disease. The starting dose is 50 mg orally once daily, increased after 2 weeks to 100 mg once daily.


Pharmacology_Katzung

Pharmacology_Katzung. Monoamine oxidase B inhibitors should not be taken by patients receiving meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s wort. The antitussive dextromethorphan should also be avoided by patients taking one of the monoamine oxidase B inhibitors; indeed, it is wise to advise patients to avoid all over-the-counter cold preparations. Rasagiline, selegiline, or safinamide should not be taken with other monoamine oxidase inhibitors and should be used with care in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syndrome type (see Chapter 16), but this is rarely encountered in practice. The adverse effects of levodopa, especially dyskinesias, mental changes, nausea, and sleep disorders, may be increased by these drugs. Hypertension may be precipitated or aggravated.


Pharmacology_Katzung

Pharmacology_Katzung. The combined administration of levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided, because it may lead to hypertensive crises, probably due to the peripheral accumulation of norepinephrine.


Pharmacology_Katzung

Pharmacology_Katzung. Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol-O-methyltransferase (COMT), and this increases plasma levels of 3-O-methyldopa (3-OMD). Elevated levels of 3-OMD have been associated with a poor therapeutic response to levodopa, perhaps in part because 3-OMD competes with levodopa for an active carrier mechanism that governs its transport across the intestinal mucosa and the blood-brain barrier. Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism (Figure 28–5). Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased. Neither the time to reach peak concentration nor the maximal concentration of levodopa is increased. These agents may be helpful in patients receiving levodopa who have developed response fluctuations—leading to a smoother response, more prolonged on-time, and the


Pharmacology_Katzung

Pharmacology_Katzung. of levodopa is increased. These agents may be helpful in patients receiving levodopa who have developed response fluctuations—leading to a smoother response, more prolonged on-time, and the option of reducing total daily levodopa dose. Tolcapone and entacapone are both widely available, but entacapone is generally preferred because it has not been associated with hepatotoxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily; some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to six times daily.