Drugs for Parkinsonism and Alzheimer Disease PDF - Pharm Textbook

20 Drugs for Parkinsonism and Alzheimer Disease http://evolve.elsevier.com/McCuistion/pharmacology OBJECTIVES ummarize the pathophysiology of Parkinson disease and Apply the Clinical Judgment [Nursin...

20 Drugs for Parkinsonism and Alzheimer Disease http://evolve.elsevier.com/McCuistion/pharmacology OBJECTIVES ummarize the pathophysiology of Parkinson disease and Apply the Clinical Judgment [Nursing Process] to anticholinergics, Alzheimer disease. dopaminergics, and acetylcholinesterase inhibitors. Contrast the actions of anticholinergics, dopaminergics, dopamine Differentiate the various phases of Alzheimer disease with agonists, monoamine oxidase B (MAO-B) inhibitors, and corresponding symptoms. catechol-O-methyltransferase (COMT) inhibitors in the treatment Compare the side effects/adverse effects of acetylcholinesterase of Parkinson disease. inhibitors used to treat Alzheimer disease. Compare the side effects of various antiparkinson drugs. OUTLINE Parkinson Disease, 228 Clinical Judgment [Nursing Process]—Antiparkinson Parkinsonism and Extrapyramidal Symptoms, 229 Dopaminergic Agents: Carbidopa-Levodopa, 234 Nonpharmacologic Measures, 229 Precautions for Drugs Used to Treat Parkinson Disease, 236 Pathophysiology, 229 Alzheimer Disease, 237 Anticholinergics, 229 Pathophysiology, 237 Clinical Judgment [Nursing Process]—Antiparkinson Acetylcholinesterase/Cholinesterase Inhibitors, 237 Anticholinergic Agents, 230 Clinical Judgment [Nursing Process]—Drug Treatment for Dopaminergics, 231 Alzheimer Disease: Rivastigmine, 238 Dopamine Agonists, 232 lgG1 Monoclonal Antibody, 238 Monoamine Oxidase B Inhibitors, 232 Critical Thinking Case Study, 240 Catechol-O-Methyltransferase Inhibitors, 232 Review Questions, 240 Dopamine Receptor Antagonists, 232 Parkinson disease (PD) is a chronic, progressive neurologic dis- order that affects the extrapyramidal motor tract, which controls PARKINSON DISEASE posture, balance, and locomotion. PD is the most common form of PD was first medically described as a neurologic syndrome by James parkinsonism, which is considered a syndrome, or a combination Parkinson in 1817, although fragments of parkinsonism can be found of similar symptoms, because of its major features: rigidity (abnor- in earlier descriptions. Dr. James Parkinson described PD as having mal increased muscle tone), bradykinesia (slow movement), gait “shaking palsy.” Three symptoms were described: (1) involuntary trem- disturbances, and tremors. Rigidity increases with movement. Pos- ors of the limbs, (2) rigidity of muscles, and (3) slowness of movement tural changes caused by rigidity and bradykinesia include the chest with a propensity to bend the trunk forward and to pass from a walking and head thrust forward with the knees and hips flexed, a shuffling to a running pace. In the United States approximately 1 million people gait, and the absence of arm swing. Other characteristic symptoms have PD, and 60,000 new cases are diagnosed each year. PD generally are masked facies (no facial expression), involuntary tremors of the affects patients 50 to 60 years of age and older, men are more likely to head and neck, and pill-rolling motions of the hands. The tremors have PD than women, and the number of those diagnosed with PD may be more prevalent at rest. increases with age, regardless of sex. Alzheimer disease (AD) is a chronic, progressive, neurode- PD is a long-term (chronic) condition that gets worse over time generative disorder with marked cognitive dysfunction, such as (is progressive). PD results from a loss of neurons in a specific part of impairment of memory, reasoning, language, and perception. Var- the brain called the substantia nigra. Some chemicals in the substantia ious theories exist as to the cause of Alzheimer disease, such as nigra make an important brain chemical called dopamine (DA). DA is neuritic plaques (also known as senile plaques), degeneration of the needed to control movement. As PD worsens, neurons make less DA. cholinergic neurons, and deficiency in acetylcholine (ACh) among This makes it hard to control movement. The cardinal symptoms of PD them. are rigidity, tremors, gait disturbance, and bradykinesia. Normally the 228  CHAPTER 20 Drugs for Parkinsonism and Alzheimer Disease 229 symptoms have a gradual onset and are usually mild and unilateral in The two neurotransmitters within the neurons of the striatum of the the beginning but worsen over time. brain are DA, an inhibitory neurotransmitter, and ACh, an excitatory neu- rotransmitter. DA is released from the dopaminergic neurons, and ACh Parkinsonism and Extrapyramidal Symptoms is released from the cholinergic neurons. DA normally maintains control Certain drugs may cause parkinsonism and lead to extrapyramidal of ACh and inhibits its excitatory response. In PD, an unexplained degen- symptoms: neuroleptics (antipsychotics and dopamine receptor block- eration of the dopaminergic neurons occurs, and an imbalance between ers). The lack of dopamine often mimics idiopathic pathologies of the DA and ACh results. With less DA production, the excitatory response of extrapyramidal system. These include acute dyskinesias (involuntary ACh exceeds the inhibitory response of DA. An excessive amount of ACh movement) and dystonic reactions (sustained involuntary contractions stimulates neurons that release gamma-aminobutyric acid (GABA). With of muscles), tardive dyskinesia (repetitive movements), parkinsonism increased stimulation of GABA, the symptomatic movement disorders of (a condition that causes a combination of the movement abnormali- PD occur. The striatal neurons synthesize DA from levodopa and release ties seen in PD), akinesia (loss of ability to move muscles voluntarily), DA as needed. Before the next dose of levodopa, symptoms such as slow akathisia (feeling of muscle quivering, restlessness, inability to sit still), walking and loss of dexterity return or worsen, but within 30 to 60 minutes and neuroleptic malignant syndrome (an adverse reaction to medica- of receiving a dose, the patient’s functioning is much improved. tions with dopamine receptor-antagonist properties). Drugs used to treat PD replace the DA deficit and reduce the symptoms. These drugs fall into five categories: (1) anticholinergics, Nonpharmacologic Measures which increase the effects of DA in the brain by reducing the effects Symptoms of PD can be lessened using nonpharmacologic measures of ACh; (2) dopaminergic replacement therapy, which stimulates the such as patient teaching, exercise, nutrition, and group support. Exercise production of DA in the brain; (3) dopamine agonists, which mimic can improve mobility and %exibility; the patient with PD should enroll in the effects of DA in the brain by directly stimulating DA receptors; (4) a therapeutic exercise program tailored to this disorder. A balanced diet monoamine oxidase B (MAO-B) inhibitors, which inhibit the inacti- with fiber and %uids helps prevent constipation and weight loss. Patients vation of DA in the brain; (5) catechol-O-methyltransferase (COMT) with PD and their family members should be encouraged to attend a inhibitors, which inhibit the COMT enzyme that inactivates DA; and support group to help cope with and understand this disorder. (6) dopamine antagonists, which disrupt the activity of DA by block- Medical marijuana (cannabis) is legalized in many states, and there ing DA receptor sites without activating them. Table 20.1 compares the is strong interest in its therapeutic properties for PD. Despite several various drugs for PD. clinical studies, it has not been demonstrated that cannabis can directly benefit people with PD. Researchers issue caution for people with PD Anticholinergics who use cannabis because of its effect on thinking. PD can impair the Anticholinergic drugs increase the effects of DA in the brain by reduc- executive function—the ability to make plans and limit risky behavior. ing the effects of ACh. This reduces the rigidity and some of the trem- People with a medical condition that impairs executive function should ors characteristic of PD but has a minimal effect on bradykinesia. The be cautious about using any medication that can compound this effect. anticholinergics are parasympatholytics that inhibit the release of ACh. Anticholinergics are still used to treat drug-induced parkinsonism, or Pathophysiology pseudoparkinsonism, a side effect of the antipsychotic phenothiazine PD is caused by an imbalance of the neurotransmitters DA and ACh, drug group. Examples of anticholinergics used for PD include trihexy- and it is marked by degeneration of neurons of the extrapyramidal phenidyl and benztropine. (motor) tract in the substantia nigra of the midbrain. The reason for Table 20.2 lists the anticholinergics and their dosages, uses, and the degeneration of neurons is unknown, but there is some evidence considerations. Anticholinergics, also referred to as cholinergic antag- for the role of genetics and environmental factors. onists, are discussed in Chapter 16. TABLE 20.1 Comparison of Drugs Used to Treat Parkinson Disease Drug Purpose Anticholinergics Benztropine The first group of drugs used to treat PD before levodopa and dopamine agonists were introduced, these were useful in decreasing tremors Trihexyphenidyl related to PD. The major use of these agents currently is to treat drug-induced parkinsonism. Treatment starts with a low dosage that is gradually increased. Older adults are more susceptible to the many side effects of anticholinergics, and patients with memory loss or dementia should not be on anticholinergic therapy (see Table 20.2). Dopaminergics Levodopa inhalation Levodopa inhalation is administered via an inhalation pump directly into the lungs. It is used “as needed” for Parkinson disease (PD) patients who are affected by an off period. These periods may come on slowly between regularly scheduled carbidopa/levodopa doses or abruptly at unpredictable times. Carbidopa-levodopa To decrease symptoms of PD and parkinsonism; carbidopa, a decarboxylase inhibitor, permits more levodopa to reach the striatum nerve terminals, where levodopa is converted to dopamine. With the use of carbidopa, less levodopa is needed. Dopamine Agonists (DA) Apomorphine Apomorphine, a nonnarcotic derivative of morphine. Approved as a sublingual film for treatment of acute, intermittent “off” episodes of PD and as a subcutaneous injection in advanced PD. Coadministration with antiemetic is suggested due to high incidence of nausea. Also used as a diagnostic test for dopaminergic responsiveness. 230 UNIT V Central and Peripheral Nervous System Drugs TABLE 20.1 Comparison of Drugs Used to Treat Parkinson Disease—cont’d Drug Purpose Bromocriptine A synthetic dopamine agonist, an ergot derivative, bromocriptine can be used for early treatment of Parkinson disease. With increasing motor symptoms, it can be given with levodopa therapy. It was the first dopamine agonist marketed for the treatment of PD in adults as monotherapy or as an adjunct to levodopa-based treatment; however, newer dopamine agonists have largely replaced bromocriptine in the treatment of PD. Cabergoline A synthetic ergoline-derived dopamine agonist beneficial for motor fluctuations associated with PD. Its advantage over bromocriptine is once-daily dosing due to its longer half-life. Used after other approved treatments have been unsuccessful due to risk of cardiac valvulopathy. Pramipexole A DA that differs from other DA in that it is not an ergot alkaloid and is less likely to cause fibrotic and valvular complications. Ropinirole An oral, non-ergot, alkaloid dopamine agonist for the treatment of idiopathic PD in adults as early monotherapy and in combinaton with levodopa. Rotigotine A transdermal nonergoline dopamine agonist used for the treatment of idiopathic PD and restless leg syndrome (RLS). Effective with and without concomitant levodopa treatment was established in advanced and early stage PD patients. Monoamine Oxidase B (MAO-B) Inhibitors Safinamide Safinamide is a selective and reversible inhibitor of monoamine oxidase (MAO) Type B. MAO exists as two catabolic isoenzymes, MAO-A and MAO-B. The neurotransmitters serotonin and norepinephrine are primarily catabolized by MAO-A and dopamine is primarily catabolized by MAO-B. Due to its dopaminergic properties, safinamide is effective in the treatment of PD and is FDA approved as an adjunct to levodopa; carbidopa therapy to treat “off” episodes in adults with PD. Selegiline Selegiline is a selective monoamine oxidase type-B inhibitor (MAO-B). It works by inhibiting the catabolic enzymes of dopamine and extends its action. Available orally for treatment of PD as an adjunct to levodopa/carbidopa. Recommend decreasing dietary tyramine intake to decrease the risk of hypertensive crisis. Rasagiline Rasagiline is a potent, irreversible MAO-B that inhibits the breakdown of dopamine at synapses in the brain and allows neurons to reabsorb more dopamine for use later. It is 5 times more potent an inhibitor than selegiline. If dosing guidelines are followed, tyramine restrictions are not required; however, very high doses of tyramine (aged cheese) may result in hypertensive reaction. Catechol-O-Methyltransferase (COMT) Inhibitors Entacapone A reversible inhibitor of the COMT enzyme that increases the concentration of levodopa and is used in combination with levodopa-carbidopa. Opicapone Opicapone is an oral COMT inhibitor used once daily as adjunctive treatment to levodopa-carbidopa in adults with PD experiencing “off” episodes. Tolcapone An oral peripherally and centrally acting COMT inhibitor used as an adjunct to levodopa-carbidopa therapy in the treatment of PD. By improving levodopa availability in the CNS, the patient’s dose of levodopa can be lowered. Dopamine Receptor Antagonist (DRA) Amantadine Amantadine decreases the symptoms of PD and drug-induced extrapyramidal reactions. Amantadine is a synthetic antiviral agent that was found to cause symptomatic improvement in PD. It is a weak, uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. It is used for early treatment of PD, which will delay the necessity of levodopa. Istradefylline Istradefylline is a xanthine derivative and an oral adenosine A2A receptor antagonist. It is used as an adjuvant with levodopa-carbidopa therapy in adult PD patients who experience “off” episodes. Atypical Antipsychotic Pimavanserin Pimavanserin is an atypical antipsychotic, indicated for the treatment of hallucinations and delusions associated with PD psychosis. CLINICAL JUDGMENT [NURSING PROCESS] Antiparkinson Anticholinergic Agents Concept: Mobility Obtain a drug history on the patient. Report any probable drug-drug inter- Mobility refers to the ability to move and refers to walking, exercise, and per- actions, such as with phenothiazines, tricyclic antidepressants (TCAs), and forming self-care. In nursing care, nurses assist the patient in the preserva- antihistamines, which increase the effect of trihexyphenidyl. tion and rehabilitation of mobility as well as the identification and avoidance Assess baseline vital signs for future comparisons. (The pulse rate may of problems with immobility. increase.) Assess the patient’s knowledge regarding the medication regimen. Recognize Cues [Assessment] Assess the patient’s ability to ambulate and perform self-care interven- Obtain a health history on the patient. Report any history of glaucoma, gastro- tions. intestinal (GI) dysfunction, urinary retention, angina, or myasthenia gravis. All Determine usual urinary output as a baseline for comparison. Urinary reten- anticholinergics are contraindicated if a patient has glaucoma. tion may occur with continuous use of anticholinergics.  CHAPTER 20 Drugs for Parkinsonism and Alzheimer Disease 231 CLINICAL JUDGMENT [NURSING PROCESS]—CONT’D Antiparkinson Anticholinergic Agents Analyze Cues and Prioritize Hypothesis [Patient Problems] Patient Teaching Confusion General Elimination Advise patients to avoid alcohol, cigarettes, caffeine, and aspirin to decrease Decreased mobility gastric acidity. Potential for falls Side Effects Generate Solutions [Planning] Encourage patients to relieve dry mouth with hard candy, ice chips, or sugar- The patient will have decreased involuntary symptoms caused by PD or drug- less chewing gum. Anticholinergics may decrease salivation. induced parkinsonism. Suggest that patients use sunglasses in direct sunlight because of possible photophobia. Take Action [Nursing Interventions] Advise patients to void before taking the drug to minimize urinary retention. Monitor vital signs, urine output, and bowel sounds. Increased pulse rate, Counsel patients who take an anticholinergic for control of symptoms of urinary retention, and constipation are side effects of anticholinergic drugs. PD to have routine eye examinations because anticholinergics are contraindi- Observe and assess the patient for involuntary movements. cated in patients with glaucoma. Assess personal beliefs of patients and family, and modify communications to meet the patient’s needs; use an interpreter and community nurse follow-up Diet as needed. Encourage patients to ingest foods high in fiber and to increase fluid intake to prevent constipation. Safety Instruct patients to avoid alcohol, cigarettes, and caffeine when taking anti- Discuss with patient and family the need for “safety always.” Depending on cholinergic drugs. the progression of the disease, the patient may need assistance ambulating. Discuss bathroom changes such as: A safety bar in the shower, an elevated Evaluate Outcomes [Evaluation] toilet seat, and a shower chair. Evaluate the patient’s response to trihexyphenidyl or benztropine mesylate Discuss with the patient and family a home safety assessment: Remove all to determine whether PD symptoms are controlled and patient can perform self- throw rugs, add extra lighting, and avoid anything that can block the patient’s care. view when ambulating. TABLE 20.2 Antiparkinson Drugs: Anticholinergics Drug Route and Dosage Uses and Considerations Benztropine A: PO/IM: Start 0.5–1 mg/d; increase as needed, To decrease involuntary symptoms of Parkinson disease, tremor, and drug-induced 0.5 mg at 5- to 6-d intervals; max: 8 mg/d parkinsonism Drug-induced extrapyramidal symptoms: May cause constipation, blurred vision, ocular hypertension, xerostomia (dry mouth), A: PO/IM/IV: Initially 1–2 mg bid/tid; nausea, anhidrosis, and urinary retention maint: 1–4 mg qd/bid; max: 8 mg/d Contraindications: Dementia, tachycardia, cardiac disease, autonomic neuropathy, prostatic hypertrophy, psychosis, glaucoma, myasthenia gravis, hyperthermia, alcoholism; contraindicated for use in older adults and children PB: UK; t½: UK Trihexyphenidyl A: PO: Initially 1 mg, then increase by 2 mg every Used for parkinsonism and drug-induced EPS; contraindicated for use in older adults 3–5 d; maint: 6–10 mg/d, usually tid with meals May cause dizziness, anxiety, confusion, insomnia, nausea, vomiting, restlessness, and at bedtime; max: 15 mg/d tachycardia, weakness, glaucoma, NMS, and urinary retention Extended release: Precautions: Abrupt discontinuation, alcoholism, cardiac disease, wide-angle glaucoma, A: PO: 5–10 mg after breakfast in two divided hepatic disease; contraindicated for use in older adults doses 12 h apart; max: 15 mg/d May cause drug interaction: phenothiazine, tricyclic antidepressant, antihistamine PB: UK; t½: 5.6–10.2 h A, Adult; bid, two times a day; d, day; h, hour; EPS, extrapyramidal symptoms; IM, intramuscular; IV, intravenous; maint, maintenance; max, maxi- mum; mg, milligram; NMS, neuroleptic malignant syndrome; PB, protein binding; PO, by mouth; t½, half-life; tid, three times day; UK, unknown. Dopaminergics in the peripheral nervous system and allows 99% of levodopa to be Levodopa converted to DA before it reaches the brain. Therefore only about 1% of The first dopaminergic drug was levodopa, which was introduced in levodopa taken is available to be converted to DA once it reaches the 1961. When introduced, levodopa was effective in diminishing symp- brain, and large doses are needed to achieve a pharmacologic response. toms of PD and increasing mobility; this is because the blood-brain These high doses may cause many side effects, including nausea, vom- barrier admits levodopa but not DA. The enzyme dopa decarboxylase iting, dyskinesia, orthostatic hypotension, cardiac dysrhythmias, and converts levodopa to DA in the brain, but this enzyme is also found psychosis. 232 UNIT V Central and Peripheral Nervous System Drugs A Levodopa B Carbidopa-Levodopa carbidopa-levodopa, usually the drug dosages are reduced, and side effects and drug intolerance decrease. Dopamine Decarboxylase Dopamine Apomorphine is a DA agonist and a nonnarcotic derivative of the drug morphine. It contains DA receptor agonist properties and is used Brain for acute, intermittent treatment of off episodes and with advanced Levodopa Levodopa PD. Apomorphine has a short duration of action and is inconvenient in the subcutaneous injection form (other forms of administration are being researched); however, the drug has several advantages. These advantages include a quick onset of action, a significant effect Blood-brain barrier on parkinsonian hypomobility (off episodes) unresponsive to oral medications, safety in patients who have a history of psychosis from Enzyme other DA agonists, and a therapeutic effect comparable to levodopa. decarboxylase Apomorphine is administered under close supervision of the health Periphery care provider (HCP) to observe the effect of the drug on the patient’s Bl oc blood pressure and heart rate. k Carbidopa/ Levodopa Dopamine Dopamine Levodopa Monoamine Oxidase B Inhibitors The enzyme MAO-B causes catabolism (breakdown) of DA. Selegiline inhibits MAO-B and thus prolongs the action of levodopa. It may be Fig. 20.1 (A) When levodopa is used alone, only 1% reaches the brain ordered for patients newly diagnosed with PD. The use of selegiline because 99% converts to dopamine while in the peripheral nervous could delay carbidopa-levodopa therapy by 1 year. It decreases on/off system. (B) By combining carbidopa with levodopa, carbidopa can %uctuations. Large doses of selegiline may inhibit MAO-A, an enzyme inhibit the enzyme decarboxylase in the periphery, thereby allowing that promotes metabolism of tyramine in the GI tract. If not metabo- more levodopa to reach the brain. lized by MAO-A, ingestion of foods high in tyramine—such as aged cheese, red wine, and bananas—can cause a hypertensive crisis. evere adverse drug interactions can occur between selegiline and various tri- Levodopa has been unavailable in the United States until recently. In cyclic antidepressants (TCAs) or selective serotonin reuptake inhibi- early 2019 the first and only inhaled levodopa used for intermittent treat- tors (SSRIs). ment of “off episodes” in people with PD taking carbidopa-levodopa was approved by the US Food and Drug Administration (FDA). Off episodes, Catechol-O-Methyltransferase Inhibitors also known as off periods, are defined as the return of Parkinson symp- The enzyme COMT inactivates DA. When taken with a levodopa toms that result from low levels of DA between doses of oral carbidopa/ preparation, COMT inhibitors increase the amount of levodopa levodopa (FDA.gov). concentration in the brain. Tolcapone was the first COMT inhibitor to be given with levodopa for advanced PD. This drug can affect Carbidopa-Levodopa liver cell function; therefore serum liver enzymes should be closely Due to the side effects of levodopa and the fact that so much levodopa is monitored. metabolized before it reaches the brain, an alternative drug, carbidopa, Entacapone does not affect liver function. The FDA has approved was developed to inhibit the enzyme dopa decarboxylase. By inhibiting a combination drug of dopaminergics (carbidopa and levodopa) and the enzyme in the peripheral nervous system, more levodopa reaches a COMT inhibitor (entacapone). With various dosage strengths avail- the brain. The carbidopa is combined with levodopa in a ratio of 1 part able, this drug combination of carbidopa, levodopa, and entacapone carbidopa to 10 parts levodopa. Fig. 20.1 illustrates the comparative provides greater dosing %exibility and individualization to the patient. action of levodopa and carbidopa-levodopa. By combining levodopa This drug combination lessens the “wearing off ” effects of levodopa with carbidopa, more DA reaches the basal ganglia and smaller doses that are sometimes experienced before the next dose. Table 20.3 lists of levodopa are required to achieve the desired effect. The disadvan- dopaminergics, dopamine agonists, MAO-B inhibitors, COMT inhib- tage of the carbidopa-levodopa combination is that with more avail- itors, dopamine receptor antagonists, and atypical antipsychotics with able levodopa, more side effects may occur, which may include nausea, their dosages, uses, and considerations. vomiting, dystonic movement (involuntary abnormal movement), and psychotic behavior. The peripheral side effects of levodopa are not Dopamine Receptor Antagonists as prevalent; however, angioedema, palpitations, and orthostatic hypo- Amantadine tension may occur. Amantadine, a synthetic antiviral agent, acts on DA receptors. It was Prototype Drug Chart: Carbidopa-Levodopa lists the pharmaco- introduced as an agent for prophylaxis of seasonal in%uenza and was logic behavior of carbidopa-levodopa. later found to cause symptomatic improvement in PD. Although FDA-approved for the prophylaxis and treatment of in%uenza, the Dopamine Agonists Centers for Disease Control and Prevention (CDC) recommends DA agonists, also called dopaminergics, stimulate DA receptor activa- against using amantadine due to the development of resistant viral tion and provide relief from PD symptoms such as tremor and rigidity. strains. The exact mechanism of amantadine in the treatment of Bromocriptine acts directly on DA receptors in the CNS, cardiovascular PD is unknown. Amantadine may be taken alone or in combina- system, and GI tract. Bromocriptine is an effective anticholinergic in tion with carbidopa-levodopa or an anticholinergic drug. Initially, its class; however, it is not as effective as carbidopa-levodopa in allevi- it produces improvement in symptoms of PD in approximately two- ating PD symptoms. Patients who do not tolerate carbidopa-levodopa thirds of patients, but this improvement is usually not sustained are frequently given bromocriptine. If bromocriptine is taken with because drug tolerance develops. Amantadine can also be used to  CHAPTER 20 Drugs for Parkinsonism and Alzheimer Disease 233 PROTOTYPE DRUG CHART Carbidopa-Levodopa Drug Class Dosage Dopaminergic Immediate release: Antiparkinson: Dopamine replacement A: PO: Initially 1 tablet containing 25 mg carbidopa/100 mg levodopa tid; maint: 70–100 mg of carbidopa per day; max: 200 mg/800 mg/dose using 25 mg/100 mg tab A: Extended-release tablets: Initially 50 mg carbidopa/200 mg levodopa bid; max: 1600 mg/d A: Extended-release capsules: Initially 23.75 mg carbidopa/95 mg levodopa tid; max: 612.5 mg/2450 mg/d Enteral suspension: max: 2000 mg/d over 16 h Contraindications Drug-Lab-Food Interactions Hypersensitivity to carbidopa-levodopa, narrow-angle glaucoma, Drug: Increased hypertensive crisis with MAOIs, decreased levodopa effect with severe cardiovascular disease, renal impairment, hepatic anticholinergics and antipsychotics; with TCAs, may cause dyskinesia and hypertension; disease, suspicious skin lesions (activates malignant melanoma), with methyldopa, may cause psychosis. MAOI therapy, dyskinesia, pulmonary disease Food: High-protein foods decrease levodopa absorption. Caution: Peptic ulcer, impulse control syndrome, orthostatic Lab: May increase BUN, AST, ALT, ALP, and LDH hypotension, psychosis, seizure disorder; avoid abrupt discontinuation. May cause neuroleptic malignant syndrome (NMS), suicidal ideation, open-angle glaucoma ( contraindicated in glaucoma patients), phenylalanine-containing forms (PKU). Pharmacokinetics Pharmacodynamics Absorption: PO: Well absorbed (99%) PO: Onset: UK Distribution: PB: Widely distributed Peak: 2 h Metabolism: t½: 1–2 h Duration: 5 h Excretion: 70%–80% (in urine as metabolites) ER: Onset: UK Peak: 3 h Duration: 4–6 h Therapeutic Effects/Uses To treat Parkinson disease and parkinsonism; relieves tremor and rigidity. Mechanism of Action: Transmission of levodopa to brain cells for conversion to dopamine; carbidopa blocks the conversion of levodopa to dopamine in the intestine and peripheral tissues. Carbidopa is added to levodopa to inhibit the peripheral destruction of levodopa; thus more levodopa is available for transport to the brain cells for conversion to dopamine. Side Effects Adverse Reactions Anorexia, nausea, vomiting, dysphagia, dyskinesia, erythema, Involuntary movements, angioedema, palpitations, orthostatic hypotension, urinary retention, fatigue, dizziness, headache, dry mouth, constipation, bitter taste, priapism, psychosis, depression with suicidal ideation, hallucinations, sudden sleep onset, twitching, blurred vision, insomnia, excess dark sweating, urine impulse control symptoms discoloration (red, brown, or black) Life-threatening: Agranulocytosis, hemolytic anemia, leucopenia, thrombocytopenia, cardiac dysrhythmias; abrupt discontinuation may cause neuroleptic malignant syndrome A, Adult; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, two times a day; BUN, blood urea nitro- gen; d, day; h, hour; LDH, lactic dehydrogenase; maint, maintenance; MAOI, monoamine oxidase inhibitor; max, maximum; min, minute; PB, protein binding; PO, by mouth; qid, four times a day; t½, half-life; TCA, tricyclic antidepressant; tid, three times a day; UK, unknown. treat drug-induced parkinsonism. It has few side effects, but the medications are not working well, causing an increase in PD symp- side effects may intensify when the drug is combined with other PD toms, such as tremors and difficulty walking. It is a selective antagonist. drugs. Amantadine is contraindicated in patients with renal failure, patients undergoing dialysis, and patients with hypersensitivities to Atypical Antipsychotic amantadine and rimantadine. Pimavanserin is a DA antagonist further classified as an atypical anti- psychotic and is the first drug approved by the FDA to treat hallucina- Istradefylline tions and delusions associated with PD psychosis. Hallucinations or Istradefylline is an adenosine receptor antagonist used to treat PD. It delusions may occur in as many as 50% of patients with PD at some reduces “off ” periods resulting from long-term treatment with the anti- time during their illness. People who experience them see or hear parkinson drug levodopa. An “off ” period is a time when a patient’s things that are not there (hallucinations) and/or have false beliefs 234 UNIT V Central and Peripheral Nervous System Drugs CLINICAL JUDGMENT [NURSING PROCESS] Antiparkinson Dopaminergic Agents: Carbidopa-Levodopa Concept: Mobility Safety Mobility refers to the ability to move and refers to walking, exercise, and per- Ask the doctor for an occupational/physical therapist order to visit the forming self-care. In nursing care, nurses assist the patient in the preserva- patient’s home after discharge. Depending on how the disease progresses, tion and rehabilitation of mobility as well as the identification and avoidance safety changes must be made in the patient’s home. of problems with immobility. Patient Teaching Recognize Cues [Assessment] General Obtain vital signs to use for future comparisons. Urge patients not to abruptly discontinue the medication. Rebound PD Assess patients for signs and symptoms of PD, including stooped forward (increased symptoms of PD) can occur. posture, shuffling gait, masked facies, and resting tremors. Inform patients that urine may be discolored and will darken with exposure to Obtain a patient history that includes glaucoma, heart disease, peptic ulcers, air. Perspiration may also be dark. Explain that both are harmless, but clothes kidney or liver disease, and psychosis. may be stained. Obtain a drug history. Report if drug-drug interaction is probable. Drugs that Advise patients to avoid chewing or crushing extended-release tablets. should be avoided or closely monitored are carbidopa-levodopa, bromocrip- tine, and anticholinergics. Side Effects Instruct patient in side effects to report to health care provider. Analyze Cues and Prioritize Hypothesis [Patient Problems] Encourage patients to report symptoms of dyskinesia. Reduced motor function Explain that it may take weeks or months before side effects are controlled. Decreased functional ability Potential for falls Diet Need for health teaching Suggest to patients that taking carbidopa-levodopa with food may decrease gastrointestinal (GI) upset, but food will slow the rate of drug absorption. Generate Solutions [Planning] Urge patients who take high doses of selegiline to avoid foods high in tyra- Patient’s symptoms of PD will be decreased or absent after 1 to 4 weeks of mine such as aged cheese, red wine, cream, yogurt, chocolate, bananas, and drug therapy. raisins to prevent hypertensive crisis. Take Action [Nursing Interventions] Amantadine and Bromocriptine Monitor vital signs and electrocardiogram. Orthostatic hypotension may occur Urge patients taking amantadine to report any signs of skin lesions, seizures, during early use of carbidopa-levodopa and bromocriptine. Instruct patients to or depression. rise slowly to avoid faintness. A history of health problems should have been previously reported to a health Observe for weakness, dizziness, or syncope, which are symptoms of ortho- care provider; however, it is important for the nurse to review health problems static hypotension. with the patient. Administer carbidopa-levodopa with low-protein foods. High-protein diets Advise patients taking bromocriptine to report symptoms of lightheadedness interfere with drug transport to the central nervous system (CNS). when changing positions, a symptom of orthostatic hypotension. Observe for symptoms of PD. Warn patients to avoid alcohol when taking bromocriptine. Recognize that elderly patients will need guidance in understanding the dis- Teach patients to check their heart rate and report rate changes or irregularity. ease process of PD. Counsel patients not to abruptly stop the drug without first notifying the Support the patient and their family members who may be dismayed about health care provider. the diagnosis of PD and lack knowledge of the disease process. Secure an interpreter for patients who may have a language barrier. Evaluate Outcomes [Evaluation] Instruct the patient in side effects to report to the health care provider. Evaluate effectiveness of drug therapy in controlling symptoms of PD. Determine whether there is an absence of side effects. Determine whether the patient and family have increased knowledge of the drug regimen. TABLE 20.3 Antiparkinson Medications Drug Route and Dosage Uses and Considerations Dopaminergics Levodopa Oral inhalation: Inhale contents of 2 capsules (42 Uses: mg each), total 84 mg, up to 5 times a day; max: Oral inhalation: Treatment of “off” episodes of PD 420 mg/d divided into equal doses Absolute contraindications: Closed-angle glaucoma and MAOI therapy. May cause cough, dyskinesia, chest pain, infection, and pharyngitis; t½: 3 h Carbidopa-levodopa See Prototype Drug Chart: Carbidopa-Levodopa  CHAPTER 20 Drugs for Parkinsonism and Alzheimer Disease 235 TABLE 20.3 Antiparkinson Medications—cont’d Drug Route and Dosage Uses and Considerations Dopamine Agonists (DA) Apomorphine A: SQ: Initially 2 mg. If tolerable, 1 mg every few Apomorphine is administered in a health care setting where the HCP can monitor days, not to exceed 6 mg; max: 6 mg per SQ the patient’s BP and pulse. Used as acute, intermittent treatment of “off” injection not to exceed 20 mg/d in 5 doses episodes and advanced PD. Absolute contraindications: sulfite hypersensitivity. A: SL: Initially 10 mg. If tolerable, 10 mg up to 5 May cause angina, (unspecified) chest pain, dizziness, drowsiness, dyskinesia, doses daily; increase in 5-mg increments; max: ecchymosis, edema, hallucinations, hypotension, injection site reaction, 30 mg/day in 5 doses nausea, orthostatic hypertension, peripheral edema, rhinorrhea, vomiting, and yawning. PB: 90%–96%; SQ: t½: 30–60 min; SL: t½: 0.8–3 h Bromocriptine A: PO: Initially 1.25 mg bid, gradually increase to Used for or treatment of idiopathic or postencephalitic PD. May cause asthenia usual dose range: 10–30 mg/day PO, in divided (weakness), rhinitis, sinusitis, headache, fatigue, nausea, constipation, GI doses (with food); max: 30 mg/day PO bleeding, hypoglycemia, hypotension. Avoid alcohol use. PB: 90%–96%; t½: 4.8–6 h Cabergoline A: Oral: Initially 0.5 mg/d, titrate up as needed; Used for motor fluctuations resulting from PD. May cause constipation, dizziness, doses range from 1–4 mg/d; max: 1 mg 2x/wk headache, and nausea. PB: 40%–42%; t½: 63–69 h Caution: Only used if other treatments fail due to risk for cardiac valvulopathy. A full cardiac exam is required before use Pramipexole PD: Used for PD and moderate to severe RLS. May cause dizziness, drowsiness, Immediate release: headache, confusion, abnormal dreams, insomnia, asthenia (weakness), A: PO: Initially: 0.125 mg PO tid; max: 4.5 mg/d orthostatic hypotension, hallucinations, dyskinesia, nausea, and constipation. Extended release: (Taper off drug gradually.) PB: 15%; t½: 8–12 h A: PO: Initially 0.375 mg/d; up to 0.75 mg/d In patients with cardiac disease or hypotension, close monitoring is required; abrupt discontinuation of drug is prohibited; taper off drug gradually Ropinirole PD: Used for PD and restless leg syndrome. May cause dizziness, drowsiness, Immediate release: headache, syncope, dyskinesia, asthenia (weakness), nausea, vomiting, A: PO: Initially: 0.25 mg tid; titrate up on weekly dyspepsia, hypertension, back pain, hallucination, and orthostatic hypotension. basis; max: 24 mg/d PB: 40%; t½: 6–10 h Extended release: Monitor for cardiac adverse effects: hypotension, hypertension, syncope, A: PO: Initially 2 mg/d for 1–2 wk, titrate up changes in heart rate; taper before d/c over 7-day period weekly; max: 24 mg/d Rotigotine Transdermal patch: Used for idiopathic PD and RLS. May cause arthralgia, asthenia, dizziness, 2 mg/24 h; titrate up 2 mg/24 h per week drowsiness, dyskinesia, fatigue, headache, hyperhidrosis, hypoglycemia, Taper before d/c; max: 6 mg/24 h insomnia, nausea, orthostatic hypotension, peripheral edema, pharyngitis, and vomiting. PB: 89.5%; t½ 5–7 h Monoamine Oxidase B (MAO-B) Inhibitors Safinamide A: 50 mg/PO initially; may increase to 100 mg/d; Used for adjunctive treatment to levodopa-carbidopa therapy in patients with PD max: 100 mg/d experiencing “off” episodes. May cause dyskinesia, elevated hepatic enzymes, and orthostatic hypertension. PB: 76%; t½ 20–26 h Selegiline A: PO: 5 mg bid with breakfast and lunch; max: 10 Used for PD and parkinsonism in combination with levodopa or levodopa- mg/d carbidopa. May cause dizziness, headache, orthostatic hypotension, nausea A: PO: ODT tab: 1.25 mg/d for 6 wk, increase to 2.5 (most reported), hallucinations, constipation, depression, confusion, insomnia, mg/d; max: 2.5 mg/d; taken without liquid before and ataxia. PB: 85%–90%; t½: 1.3–2 h breakfast Contraindicated with any other MAOI, SSRI, or SNRI; titrate off drug; never abruptly d/c; avoid foods high in tyramine, such as aged cheese, red wine, and bananas Black Box Warning: Absolute contraindication for use in children; increased risk for suicidal ideation Rasagiline A: PO: 1 mg/d due to risk of HTN; max: 1 mg/d Used for PD in early disease and as an adjunct to levodopa in later disease. May cause headache, orthostatic HTN, ataxia, dyskinesia, and GI bleed. PB: 88%–94%; t½: 3 h Catechol-O-Methyltransferase (COMT) Inhibitors Entacapone A: PO: 200 mg with each dose of levodopa- Used for PD. Used in combination with levodopa-carbidopa, it prolongs half-life carbidopa (up to 8 doses/d); max: 1600 mg/d of levodopa and decreases “on/off” fluctuations. Levodopa dose should be decreased when taken with a COMT inhibitor. May cause dizziness, nausea, diarrhea, abdominal pain, dyskinesia, hyperkinesia, orthostatic HTN, dyspnea. PB: 98%; t½: 1–2 h Continued 236 UNIT V Central and Peripheral Nervous System Drugs TABLE 20.3 Antiparkinson Medications—cont’d Drug Route and Dosage Uses and Considerations Opicapone A: PO: 50 mg/d at bedtime (on an empty stomach); Used as a treatment of “off” episodes of PD as an adjunct to carbidopa- max: 50 mg/d levodopa. May cause dyskinesia, constipation, hallucinations, HTN, hypotension, neuroleptic malignant syndrome. PB: 99%, t½: 1–2 h Contraindicated with MAOI therapy and pheochromocytoma Tolcapone A: PO: Initially 100 mg tid; max: 600 mg/d Used for PD. May cause dizziness, drowsiness, headache, confusion, dystonic reaction, insomnia, anorexia, nausea, constipation, dyskinesia, muscle cramps, hallucinations, vomiting, constipation, and orthostatic hypotension. PB: 99.9%; t½: 2–3 h Black Box Warning: Dyskinesia and hepatatoxicity Dopamine Receptor Antagonist (DRA) Amantadine Immediate release: Used for treatment of PD and drug-induced extrapyramidal reactions. May cause Young: A: PO: 100 mg bid dizziness, headache, anxiety, confusion, insomnia, nausea, blurred vision, Geriatric: A: PO: 100 mg daily for several weeks, ataxia, orthostatic hypotension, and peripheral edema. Do not abruptly stop then increase to 100 mg/bid; max: 400 mg/d in taking (titrate off drug). PB: 67%; t½: 17 h divided doses Extended release: A: PO: 129 mg/d in morning (increase at weekly intervals as needed); max: 322 mg/d Istradefylline A: Oral: 20 mg/d; max: 40 mg/d Used as add-on treatment to levodopa and carbidopa in adult PD patients experiencing “off” episodes. May cause dyskinesia, confusion, constipation, delirium, hallucinations, mania, difficulty with impulse control. Use with caution in hepatic disease. PB: 98%; t½: 83 h Atypical Antipsychotic Pimavanserin A: PO 34 mg/d without titration; max: 34 mg/d Used for the treatment of hallucinations and delusions associated with PD psychosis. May cause confusion, constipation, hallucinations, infection, nausea, peripheral edema, QT prolongation, and stroke Black Box Warning: Not approved for dementia-related psychosis unrelated to hallucinations and delusions associated with PD psychosis; increases mortality risk in elderly patients on antipsychotic treatment for dementia-related psychosis. A, Adult; bid, twice daily; BP, blood pressure; COMT, catechol-O-methyltransferase; d, day; d/c, discontinue; h, hour; HCP, health care provider; HTN, hypertension; incr, increase; max, maximum; maint, maintenance; MAOI, monoamine oxidase inhibitor; mg, milligrams; min, minutes; mL, milliliters; NMS, neuroleptic malignant syndrome; ODT, orally disintegrating; PD, Parkinson disease; PB, protein binding; PO, by mouth; RLS, restless leg syn- drome; SL, sublingual; SSRI, serotonin reuptake inhibitor; SNRI, norepinephrine reuptake inhibitor; SQ, subcutaneous; t½, half-life; tid, three times a day; tx, treatment; w, with; wk, weeks. (delusions). These are serious symptoms that can lead to thinking and slows the absorption rate. Dyskinesia, impaired voluntary movement, emotions that are so impaired that people experiencing them may not may occur with high levodopa dosages. Cardiovascular side effects relate to loved ones well or take appropriate care of themselves. In Jan- include orthostatic hypotension and increased heart rate during early uary 2018 the nonprofit Institute for Safe Medication Practices (ISMP) use of levodopa. Nightmares, sudden sleep onset, impulse control requested that the FDA include stronger warnings on the label for symptoms, mental disturbances, and suicidal tendencies may occur. pimavanserin, such as that it may lead to severe adverse effects, includ- Pramipexole and ropinirole can cause nausea, dizziness, somno- ing death (https //www.pdlink.org/safety-watchdog-ismp-issues-alert lence, weakness, and constipation. These drugs intensify the dyskine- for Parkinson drug). sia and hallucinations caused by levodopa. Pramipexole is also FDA approved for treatment of restless legs syndrome. Precautions for Drugs Used to Treat Parkinson Disease Tolcapone may cause fatal hepatotoxicity. It is recommended that Side Effects and Adverse Reactions liver enzymes be drawn frequently. Abrupt discontinuation of tol- The common side effects of anticholinergics include dry mouth and capone can cause pyrexia, confusion, and neuroleptic malignant dry secretions, urinary retention, constipation, blurred vision, and an syndrome (NMS). The side effects for tolcapone are GI related (e.g., increase in heart rate. Mental effects such as restlessness and confusion nausea, anorexia, diarrhea, and vomiting). may occur in older adults. Entacapone is not known to affect liver function. With entaca- The side effects of carbidopa-levodopa are numerous. GI distur- pone, the urine can have a brownish orange discoloration. Abrupt bances are common because DA stimulates the chemoreceptor trig- discontinuation of entacapone may cause NMS. Both tolcapone and ger zone (CTZ) in the medulla, which stimulates the vomiting center. entacapone can intensify the adverse reactions of levodopa (e.g., hal- Taking the drug with food can decrease nausea and vomiting, but food lucinations, orthostatic hypotension, constipation, dizziness) because  CHAPTER 20 Drugs for Parkinsonism and Alzheimer Disease 237 these drugs prolong the effect of levodopa. Both tolcapone and enta- Normal capone may lead to intense, uncontrollable urges (sex, gambling, spending money) in addition to suddenly falling asleep. Patients Microtubules should be warned to avoid driving and other potentially dangerous activities. Contraindications Anticholinergics or any drugs that have anticholinergic effects are con- traindicated for patients with glaucoma. Those with severe cardiac, renal, or psychiatric health problems should avoid levodopa drugs because of adverse reactions. Patients with chronic obstructive lung A diseases such as emphysema can have dry, thick mucus secretions caused by large doses of anticholinergic drugs. Alzheimer disease Neurofibrillary tangles Drug-Drug Interactions Antipsychotic drugs block the receptors for DA. Carbidopa-levodopa taken with a monoamine oxidase inhibitor (MAOI) antidepressant can cause a hypertensive crisis. ALZHEIMER DISEASE Alzheimer disease (AD) is an irreversible neurodegenerative disorder Neuritic plaques characterized by a decline in a patient’s activities of daily living (ADL) B and cognitive abilities, as well as changes in behavior. Fig. 20.2 Histologic Changes in Alzheimer Disease. (A) Healthy neu- ron. (B) Neuron affected by Alzheimer disease shows characteristic Pathophysiology neuritic plaques and cellular neurofibrillary tangles. Many physiologic changes contribute to AD. Currently, theories related to the changes that cause AD include the following: 4. Impaired language functions (speaking, reading, writing): difficulty Degeneration of the cholinergic neuron and de ciency in ACh thinking of common words while speaking, hesitations, and errors Neuritic plaques that form mainly outside of the neurons and in the in speech, spelling, and writing cerebral cortex 5. Changes in personality, behavior, or comportment: uncharacteristic Apolipoprotein E4 (apoE4), which promotes formation of neuritic mood %uctuations, such as agitation; impaired motivation and ini- plaques, which binds beta-amyloid in the plaques tiative; apathy; loss of drive; social withdrawal; decreased interest in Beta-amyloid protein accumulation in high levels that may contrib- previous activities; loss of empathy; compulsive or obsessive behav- ute to neuronal injury iors; and socially unacceptable behaviors Presence of tau and neuro brillary tangles that block the neurons When the diagnosis of AD is unclear, neuropsychological testing is and disrupt signals conducted and includes advanced imaging, cerebrospinal %uid analy- Fig. 20.2 illustrates a normal healthy neuron and the neuron affected sis, and positron emission tomography (PET). by AD. The etiology of AD is unknown, although factors thought to in%uence the occurrence of AD are genetic predisposition, virus, infec- Acetylcholinesterase/Cholinesterase Inhibitors tion, or in%ammation that attacks brain cells as well as nutritional, The cure for AD is unknown. FDA-approved medications to treat AD environmental, and immunologic factors. symptoms include acetylcholinesterase (AChE) inhibitors. AChE is The three phases of AD—(1) preclinical (initial stage), (2) mild an enzyme responsible for breaking down ACh and is also known as cognitive impairment (MCI), and (3) Alzheimer dementia (final cholinesterase. The AChE inhibitors are donepezil, galantamine, and stage)—have been modi ed to assist the clinicians without access to rivastigmine, a drug that permits more ACh in the neuron receptors. neuropsychological testing, advanced imaging, and cerebrospinal %uid Rivastigmine has effective penetration into the CNS; thus cholinergic analysis. The modified criteria listed below are reliable for a probable transmission is increased. These AChE inhibitors increase cognitive AD diagnosis. function for patients with mild to moderate AD. A reversible AChE In addition, the patient’s deficit must involve at least 2 of the fol- inhibitor used to treat mild to moderate AD is galantamine. Meman- lowing 5 areas: tine is an N-methyl-d-aspartate (NMDA) receptor antagonist for the 1. Impaired ability to acquire and remember new information: management of moderate to severe AD. It can be used alone or along repetitive questions or conversations, misplacing personal with the AChE inhibitor donepezil. belongings, forgetting events or appointments, getting lost on a familiar route Rivastigmine 2. Impaired reasoning and handling of complex tasks, poor judgment: Rivastigmine, an AChE inhibitor, is prescribed to improve cognitive poor understanding of safety risks, an inability to manage finances, function for patients with mild to moderate AD (see Prototype Drug poor decision-making ability, and an inability to plan complex or Chart: Rivastigmine). This drug increases the amount of ACh at the sequential activities cholinergic synapses. Rivastigmine tends to slow the disease process 3. Impaired visuospatial abilities: an inability to recognize faces or and has fewer drug interactions than donepezil. Table 20.4 lists the common objects or to find objects in direct view despite good acu- AChE inhibitors used to treat AD. ity, an inability to operate simple implements, and difficulty in ori- Pharmacokinetics. Rivastigmine is absorbed faster through the GI enting clothing to the body tract without food. It has a relatively short half-life and is given twice a day. 238 UNIT V Central and Peripheral Nervous System Drugs The dose is gradually increased. The protein-binding power is average. It medications. The process is long, tedious, and expensive to get drugs readily crosses the blood-brain barrier and is widely distributed. approved and ready for marketing. Currently there are several prom- Pharmacodynamics. Rivastigmine has been successful in ising drugs in clinical trials. improving memory in mild to moderate AD. The onset of action is 0.5 to 1.0 hour for topical application; peak action is 8 to 16 hours. When lgG1 Monoclonal Antibody given orally, the peak is 1 hour. This drug is contraindicated for patients Aducanumab is an IV administered amyloid beta-directed antibody with liver disease because hepatotoxicity may occur. Cumulative drug indicated for the treatment of adults with AD. It was approved effect is likely to occur in older adults and in patients with liver and under the FDA’s accelerated approval program, which provides renal dysfunction. patients suffering from a serious disease earlier access to drugs Many organizations are tackling AD research. Drug companies, when there is an expectation of clinical benefit as measured by a the US government, and the Alzheimer Association are funding surrogate endpoint despite some uncertainty about the overall clin- research to learn more about the disease and to find treatments that ical benefit of the drug. The surrogate endpoint that allowed for will reduce symptoms and prevent or cure the disease. Only through accelerated approval in 2021 was a reduction of amyloid beta plaque clinical research can we gain insights and answers about the safety in treated patients. Treatment with aducanumab should be initiated and effectiveness of new drugs to treat AD. Drug companies are in patients with mild cognitive impairment or mild dementia state making huge strides in the development and research of Alzheimer of disease (see Table 20.4). CLINICAL JUDGMENT [NURSING PROCESS] Drug Treatment for Alzheimer Disease: Rivastigmine Concept: Cognition Monitor for side effects related to continuous use of acetylcholinesterase Cognition is the mental action or process of acquiring knowledge and under- (AChE) inhibitors. standing through thought, experience, and the senses. Nurses care for Record vital signs periodically. Note signs of bradycardia and hypotension. patients with problems in cognition because they may face problems with Observe any patient behavioral changes, and note any improvement or their physical position or direction, attention span, memories, speaking, and decline. thinking processes. Monitor and assist patient closely to maintain the correct use of the drug dosing plan. Recognize Cues [Assessment] Provide an interpreter during instruction for the patient and family if a lan- Assess the patient’s mental and physical abilities. Note limitation of cognitive guage barrier exists. function and self-care. Assist family members in understanding about Alzheimer as a neurologic Obtain a history that includes any liver or renal disease or dysfunction. problem that may be part of the aging process. Explain how symptoms may Assess for memory and judgment losses. Elicit from family members a history become more progressive. of behavioral changes such as memory loss, declining interest in people or home, difficulty in following through with simple activities, and a tendency to Safety wander from home. Instruct family in “home safety”; for example, remove area throw rugs, Observe for signs of behavioral disturbances such as hyperactivity, hostility, ensure pathways are clear, and keep electrical cords behind furniture to avoid and wandering. injury when the patient wanders. Examine the patient for signs of aphasia or difficulty in speech. Note patient’s physical and motor functions. Patient Teaching Determine family members’ ability to cope with the patient’s mental and General physical changes. Explain to the patient and family the purpose for the prescribed drug therapy. Clarify times for drug dosing and schedule to the family member responsible Analyze Cues and Prioritize Hypothesis [Patient Problems] for the patient’s medications. Weight loss Inform family members of available support groups such as the Alzheimer’s Decreased self-concept Association. Bowel incontinence Confusion Side Effects Decreased adherence Inform patients and family members that the patient should rise slowly to Decreased coping avoid dizziness and loss of balance. Injury Monitor routine liver function tests because hepatotoxicity is an adverse effect. Generate Solutions [Planning] Monitor patient for GI distress. Patient’s memory will be improved. Patient will maintain self-care of body functions with assistance. Diet Patient will be provided with assistance for self-care maintenance. Inform family members about foods that may be prepared for the patient’s consumption and tolerance. Take Action [Nursing Interventions] Maintain consistency in care. Evaluate Outcomes [Evaluation] Assist the patient in ambulation and activity. Evaluate effectiveness of the drug regimen by determining whether the patient’s mental and physical status shows improvement from drug therapy.  CHAPTER 20 Drugs for Parkinsonism and Alzheimer Disease 239 TABLE 20.4 Acetylcholinesterase Inhibitors and Other Drugs for Alzheimer Disease Drug Route and Dosage Uses and Considerations Donepezil A: PO: Initially 5 mg/d, upward titration to 10 mg/d should not occur until 4–6 wk; Used for the treatment of mild to moderate Alzheimer disease. May maint: 5–10 mg/d; max: 23 mg/d cause GI side effects from mild to severe: diarrhea, headache, infection, vomiting and nausea. Use with caution in older adults. PB: 96%; t½: 70 h Rivastigmine See Prototype Drug Chart: Rivastigmine Memantine Immediate release: Used for moderate to severe Alzheimer disease. May cause A: PO: Initially 5 mg/d, may increase dose slowly over 3 wk serious rash, Stevens-Johnson syndrome, dizziness, in 5-mg increments; maint: 10 mg bid (wk 4); max: 20 mg/d headache, drowsiness, confusion, diarrhea, depression, Extended release: hallucinations, hypertension, hypotension, urinary A: PO: Initially 7 mg/d, increase weekly; maint: 28 mg/d; incontinence and constipation. PB: 45%; t½: 60–80 h max: 28 mg/d Combination memantine and donepezil (extended release): A: 28 mg memantine with 10 mg donepezil once daily in evening; max: 228/10 mg/d Galantamine Immediate release: Used for treatment of mild to moderate Alzheimer disease. A: PO: Initially 4 mg bid with food; if well tolerated, after 4 wk may increase 8 mg GI symptoms are most reported: anorexia, abdominal pain, PO bid; if well tolerated, after 4 wk may increase to maint: 12 mg bid; max: 24 nausea, vomiting, diarrhea, weight loss, and dyspepsia. May mg/d cause dizziness, headache, insomnia, fatigue, and suicidal Extended release: ideation. Use with caution in older adults. PB: 18%; t½: 7 h A: PO: Initially 8 mg/d in the morning with food; increase in 4 wk to maint: 16 mg PO daily; max: 24 mg/d Combination memantine and donepezil (extended release): A: 28 mg memantine with 10 mg donepezil once daily in evening; max: 228/10 mg/d Immunoglobulin Gamma Monoclonal Antibody Aducanumab A: IV: titration schedule: (wk 1, wk 2) 1 mg/kg IV; (wk 3, wk 4) 3 mg/kg IV; (wk 5, wk Reduces amyloid beta plaques in the brain by binding to forms of 6) 6 mg/kg IV; maint: (wk 7 and beyond) 10 mg/kg IV infusion over 60 min every 4 beta amyloid protein wk (at least 21 d apart) Side effects include hypersensitivity, headache, confusion, visual impairment, angioedema, cerebral edema, intracranial bleeding. t{½}: 24.8/d A, Adult; bid, twice a day; d, day; h, hour; kg, kilogram; maint, maintenance; max, maximum; mg, milligrams; PB, protein binding; PO, by mouth; t½, half-life; wk, week. PROTOTYPE DRUG CHART Revastigmine Drug Class Dosage Acetylcholinesterase inhibitor A: PO: Initially: 1.5 mg bid with food; increase gradually after 4 wk to 3 mg bid Maintenance: 3–6 mg bid; max: 12 mg/d Transdermal: Initially 4.6 mg/24 h; may increase after 4 wk to 9.5 mg/d; max: 13.3 mg/24 h Caution Drug-Lab-Food Interactions Liver and renal diseases, urinary tract obstruction, Drug: Increased effect of theophylline, general anesthetics; TCAs decrease effect; increased effect with orthostatic hypotension, bradycardia, asthma, COPD, cimetidine; NSAIDs increase GI effects; alcohol and tobacco can increase clearance of rivastigmine seizures, peptic ulcer disease Lab: Increased ALT, AST Pharmacokinetics Pharmacodynamics Absorption: PO: Food decreases absorption rate PO: Onset: UK Distribution: PB: 40% Peak: 1 h Metabolism: t½: 1–2 h Duration: UK Excretion: In urine Transdermal: Onset: 30 min–1 h Peak: 8–16 h Duration: 24 h Therapeutic Effects/Uses Improves memory loss in mild to moderate Alzheimer disease Mechanism of Action: Elevates acetylcholine concentration Continued 240 UNIT V Central and Peripheral Nervous System Drugs PROTOTYPE DRUG CHART—CONT’D Revastigmine Side Effects Adverse Reactions Anorexia, abdominal pain, GI distress, nausea, vomiting, Seizures, bradycardia, orthostatic hypotension, cataracts, myocardial infarction, heart failure diarrhea, constipation, weight loss, dizziness, Life-threatening: Hepatotoxicity, dysrhythmias, suicidal ideation, Stevens-Johnson syndrome headache, depression, confusion, peripheral edema, dry mouth, dehydration, nystagmus, photophobia A, Adult; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, two times a day; COPD, chronic obstructive pulmonary disease; d, day; GI, gastrointestinal; h, hour; max, maximum; min, minute; mg, milligram; NSAID, nonsteroidal antiinflammatory drug; PB, protein binding; PO, by mouth; t½, half-life; TCA, tricyclic antidepressant; UK, unknown; wk, weeks. CRITICAL THINKING CASE STUDY A 79-year-old man was diagnosed with Parkinson disease 10 years ago. is the same as carbidopa-levodopa and, if not, whether their family During his early treatment, he took selegiline. The drug dosage was member can take amantadine instead of carbidopa-levodopa. increased to alleviate symptoms. 5. What is the effect of amantadine on symptoms of Parkinson dis- 1. How does selegiline alleviate symptoms of Parkinson disease? ease? 2. Which dietary changes are most important to adhere to when a 6. What would be an appropriate response to the family’s question patient is prescribed selegiline? concerning the use of amantadine? The patient has developed nausea, depression, and ataxia to sele- 7. What are the uses for dopamine agonists and COMT inhibitors? giline. The HCP stops selegiline and orders carbidopa-levodopa. 8. Certain anticholinergic drugs may be used to control Parkinson 3. What are the similarities and differences between selegiline and disease symptoms. What is the action of these drugs, and what are carbidopa-levodopa? their side effects? These anticholinergic drugs are usually prescribed 4. What are the advantages of carbidopa-levodopa? for parkinsonism symptoms resulting from what? The family knows of a patient with Parkinson disease who takes the antiviral drug amantadine and does well. They ask whether amantadine REVIEW QUESTIONS 1. Which of the following assessment findings would the nurse see in 5. hich is a Take Action [Nursing Intervention] for a patient taking a patient with Parkinson disease? (Select all that apply.) carbidopa-levodopa for Parkinson disease? a. Abrupt onset of symptoms a. Encourage the patient to adhere to a high-protein high sodium b. Muscle rigidity diet. c. Involuntary tremors b. Inform the patient that perspiration may be dark and may stain d. Bradykinesia clothing. e. Bilateral muscle weakness c. Advise the patient that glucose levels should be checked with 2. A patient is receiving carbidopa-levodopa for Parkinson disease. urine testing. What is most important for the nurse know about this drug? d. Warn the patient that it may take 4 to 5 days before symptoms a. Carbidopa-levodopa may lead to bronchitis. are controlled. b. Carbidopa-levodopa may lead to increased salivation. 6. What would the nurse teach a patient who is taking anticholinergic c. Dopaminergics may lead to drowsiness. therapy for Parkinson disease? (Select all that apply.) d. Dopaminergics are contraindicated in glaucoma. a. Avoid alcohol and tobacco. 3. The nurse has initiated teaching for a family member of a patient b. Relieve dry mouth with hard candy or ice chips. with Alzheimer disease. The nurse realizes more teaching is needed c. Use sunglasses to reduce photophobia. when the family member makes which of the following statements? d. Urinate 2 hours after taking the drug. a. As the disease progresses, the memory loss will get worse. e. Receive routine eye examinations. b. There are several theories about the cause of the disease. 7. A patient is taking rivastigmine to improve cognitive function. c. Personality changes, wandering, and hostility may occur. hat should the nurse teach the patient/family member to do? d. It may take several medications over time to cure the disease. (Select all that apply.) 4. A patient is taking rivastigmine. The nurse should teach the patient a. Rise slowly to avoid dizziness that may cause injury. and family which information about rivastigmine? b. Remove obstacles from pathways to avoid injury. a. Hepatotoxicity and jaundice are side effects. c. Closely follow the medication dosing schedule. b. The initial dose is 6 mg three times a day. d. Have daily blood pressure checks for hypertension. c. Gastrointestinal distress is a common side effect. e. Receive a monthly glucose panel. d. Increased appetite and weight gain is a side effect.  21 Drugs for Neuromuscular Disorders and Muscle Spasms http://evolve.elsevier.com/McCuistion/pharmacology OBJECTIVES Discuss the pathophysiology of myasthenia gravis and multiple Differentiate between the muscle relaxants used for spasticity and sclerosis. those used for muscle spasms. Explain the drug group used to treat myasthenia gravis. Apply the Clinical Judgment [Nursing Process] to drugs used to Discuss the drug group used to treat multiple sclerosis. treat myasthenia gravis and muscle spasms. OUTLINE Myasthenia Gravis, 241 Immunomodulators, 245 Pathophysiology, 241 Skeletal Muscle Relaxants, 248 Acetylcholinesterase Inhibitors, 242 Centrally Acting Muscle Relaxants, 248 Clinical Judgment [Nursing Process]—Drug Treatment for Clinical Judgment [Nursing Process]—Muscle elaxant Myasthenia Gravis, 244 Cyclobenzaprine, 252 Multiple Sclerosis, 244 Critical Thinking Case Study, 252 Classifications of Multiple Sclerosis, 244 Review Questions, 252 Myasthenia gravis (MG) is an acquired autoimmune disease that Pathophysiology impairs the transmission of messages at the neuromuscular junction, MG is an autoimmune process in which antibodies attack ACh receptors resulting in varying degrees of skeletal muscle weakness that increases (AChRs). The result is a decreased amount of AChR sites at the neuromus- with muscle use. Although MG can affect any voluntary muscle, those cular junction. This prevents ACh molecules from attaching to receptors that control eye and eyelid movement (ptosis), facial expression, chew- and stimulating normal muscular contraction. The result is ineffective ing, and swallowing are most frequently affected due to cranial nerve muscle contraction and muscle weakness. About 90% of patients with involvement. MG also affects the muscles of the respiratory system. MG have anti-AChR antibodies that can be detected through serum test- Respiratory arrest may result from respiratory muscle paralysis. The ing. The other 10% have muscle weakness related to autoantibodies to symptoms of MG are caused by autoimmune destruction of acetylcho- muscle-specific tyrosine kinase or to other unknown antigens. line (ACh) sites and a resultant decrease in neuromuscular transmission. Thymic hyperplasia and tumors are common in patients with MG. Multiple sclerosis (MS) is a neuromuscular autoimmune disorder that The thymus gland is involved in systemic immunity that is active during attacks the myelin sheath of nerve fibers, causing lesions known as plaques. infancy and early childhood, but the gland normally shrinks during Although there are no definitive diagnostic tests, the sclerotic plaques are adulthood. Approximately 70% of MG patients have thymic hyperpla- usually detected and measured by magnetic resonance imaging (MRI). Phar- sia. A thymectomy (removal of the thymus gland) is most beneficial macologic treatment is necessary to control the symptoms of this disorder. because it can cause a reduction of symptoms after the surgery. Muscle spasms have various causes, including injury of motor MG is characterized primarily by weakness and fatigue of the skeletal neuron disorders that are associated with conditions such as MS, MG, muscles. In 90% of cases, eyelid or extraocular muscles are involved. The cerebral palsy, spinal cord injuries (paraplegia [paralysis of the legs]), patients experience ptosis (drooping eyelids) and diplopia (double vision). cerebrovascular accident (CVA [stroke]), or hemiplegia (paralysis of Other characteristics of MG include dysphagia (di%culty chewing and swal- one side of the body). Spasticity of muscles can be reduced with the use lowing), dysarthria (slurred speech), and respiratory muscle weakness. of skeletal muscle relaxants. The group of drugs used to control MG is the acetylcholinesterase (AChE) inhibitors. They inhibit the action of the enzyme AChE. As a result of this action, more ACh is available to activate the cholinergic MYASTHENIA GRAVIS receptors and promote muscle contraction. The AChE inhibitors are MG is a chronic autoimmune neuromuscular disease that affects approx- classified as parasympathomimetics. imately 20 in 100,000 persons. It is estimated that 60,000 Americans are When muscular weakness in the patient with MG becomes gener- affected. MG can occur in people of any ethnicity and sex; however, more alized, myasthenic crisis can occur. This complication is a severe, gen- men are affected than women. MG peaks in women around the childbear- eralized muscle weakness that involves the muscles of respiration, such ing years (20 to 30 years of age), whereas the peak onset in men is after as the diaphragm and intercostal muscles. Triggers of myasthenic cri- 50 years of age. MG can also occur in people outside of this age range. sis include inadequate dosing of AChE inhibitors, infection, emotional Although it is not a genetic disorder, a familial tendency may be apparent. stress, menses, pregnancy, surgery, trauma, hypokalemia, temperature 241 242 UNIT V Central and Peripheral Nervous System Drugs extremes, and alcohol intake. Myasthenic crisis can also occur 3 to 4 free transmission of nerve impulses across the neuromuscular junc- hours after taking certain medications (e.g., aminoglycoside and fluo- tion. It has an intermediate action and is given in divided doses. Pyr- roquinolone antibiotics, beta blockers, phenytoin, and neuromuscular idostigmine is presented in Prototype Drug Chart Pyridostigmine. blocking agents; Box 21.1). If muscle weakness remains untreated, death Additional uses of pyridostigmine include reversal of neuromuscular can result from paralysis of the respiratory muscles. Neostigmine, a fast- acting AChE inhibitor, can relieve myasthenic crisis. Overdosing with AChE inhibitors may cause another complication of BOX 21.1 Medications That May MG called cholinergic crisis, which is an acute exacerbation of symptoms. Exacerbate Myasthenia Gravis A cholinergic crisis usually occurs within 30 to 60 minutes after taking Aminoglycoside antibiotics (gentamicin, neomycin, and tobramycin) anticholinergic drugs. This complication is due to continuous depolariza- Beta blockers tion of postsynaptic membranes that create a neuromuscular blockade. The Botulinum toxin patient with cholinergic crisis often has severe muscle weakness that can D-Penicillamine lead to respiratory paralysis and arrest. Accompanying symptoms include aFluoroquinolone antibiotics (moxifloxacin to ciprofloxacin and levofloxacin) miosis (abnormal pupil constriction), pallor, sweating, vertigo, excessive Chloroquine, hydroxychloroquine salivation, nausea, vomiting, abdominal cramping, diarrhea, bradycardia, Immune inhibitors (pembrolizumab, nivolumab, atezolizumab, avelumab, and fasciculations (involuntary muscle twitching). durvalumab, and ipilimumab) Acetylcholinesterase Inhibitors Iodine radiologic contrast agents Macrolides (erythromycin, azithromycin, and clarithromycin) Acetylcholinesterase inhibitors (AChE inhibitors) are also called cholines- Magnesium terase inhibitors (C EI). Doses of AChE inhibitors must be individualized Neuromuscular blocking agents (tubocurarine chloride, pancuronium, to the patient’s needs. Patients should always receive the correct dose, at the succinylcholine) correct time, to avoid myasthenia crisis and cholinergic crisis. Phenytoin The first drug used to manage MG is neostigmine methylsulfate, a Quinine, quinidine, procainamide parasympathomimetic agent (AChE inhibitor). All other AChE drugs Corticosteroids should be discontinued 8 hours before administration of neostigmine. Statins (atorvastatin, pravastatin, rosuvastatin, simvastatin) Parenteral doses of neostigmine should be accompanied by intrave- aTelithromycin nous (IV) atropine about 30 minutes before administering to counter- Zithromax act the adverse muscarinic effects of neotigimine (Table 21.1). Pyridostigmine is a reversible AChE inhibitor, preventing the a See http://2019myastheniagravisfoundationofAmerica/ destruction of acetylcholine by cholineste