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Chlorprothixene is a typical antipsychotic drug of the thioxanthine class. It has a low antipsychotic potency (half to 2/3 of chlorpromazine). Its principal indications are the treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occurring as part of bipolar disorders. more...

Calcium folinate
Chenodeoxycholic acid
Choriogonadotropin alfa
Chorionic gonadotropin
Clavulanic acid

The drug was introduced 1959 to the market on a global scale and is hence a first generation antipsychotic with 45+ years of clinical experience. It is still today of clinical and also some research interest.

Mechanisms of Action

Chlorprothixene exerts strong blocking effects at the following postsynaptic receptors:

  • 5-HT2 : anxiolysis, antipsychotic effects
  • D1, D2, D3 : antipsychotic effects
  • H1 : sedation, weight gain
  • muscarinic : anticholinergic side-effects, extrapyramidal side-effects attenuated
  • Alpha1 : hypotension, tachycardia


Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation linked due to use of selective serotonin reuptake inhibitors for depression and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.

An intrinsic antidepressant effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) analgesic effects. However, Chlorprothixene can be used as comedication in severe chronic pain. An antiemetic effect, as with most antipsychotics, exists.


Chlorprothixene has a strong sedative activity with a high incidence of anticholinergic side-effects. The types of side effects encountered (dry mouth, massive hypotension and tachycardia, hyperhidrosis, substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.

Chlorprothixene is structurally related to chlorpromazine, with which it shares in principal all side effects. Allergic side-effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side-effects of chlorprothixene (precipitation of narrow angle glaucoma, severe obstipation, difficulities in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.

Early and late extrapyramidal side-effects may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).


In any case, the initial doses of chlorprothixene should be as low as possible (e.g. 30mg at bedtime, 15mg morning dose) and be increased gradually. Patients receiving 90mg daily (and more) of the drug should be hospitalized, particularly during the initial phase of treatment. The theoretical maximum is 800mg daily which can usually not been given due to side-effects as stated above. Elderly and pediatric patients should be treated with particular low initial doses. Dose increments should be done slowly.


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Parkinson's disease and its treatment - Continuing Education; includes test questions - Inside Pharmacy - column
From Drug Store News, 2/19/90 by H. David Bergman

Parkinson's Disease and Its Treatment

H. David Bergman, Ph.D., Dean School of Pharmacy Southwestern Oklahmoma State University Feb. 19, 1990, lesson 679-401-90-02


To provide the practicing pharmacist with current concepts regarding Parkinson's Disease.


1. Discuss the historical development of theories regarding causes and treatments for Parkinson's disease. 2. Discuss the various etiologies of Parkinson's disease 3. Recognize and describe the major signs and symptoms associated with Parkinson's disease. 4. For each drug or group of drugs used to treat Parkinson's disease, identify the following: mechanism of action, advantages and disadvantages, dosage range and adverse effects.

The first concise description of the disorder known today as Parkinson's disease was provided by James Parkinson, a London general practitioner, in 1817. In a monograph entitled "An Essay on Shaking Palsy," Parkinson described a chronic progressive abnormality associated with the nervous system which begins insidiously in middle age as a mild tremore and weakness on one hand and later progresses to other limbs affecting posture and gait and eventually, causes invalidism. This description later became known as paralysis agitans and was described by a variety of individuals throughout the 1800s. However, despite the clinical features of the disease being clearly defined, the etiology and pathology remained unclear.

During the 1920s, Parkinson's disease was associated with a variety of neurological and infectious disorders, such as influenza and von Economo's disease, but no clear relationships could be established.

In recent years, information concerning the etiology of Parkinson's disease has focused on biochemical basis as the primary culprit. In particular, dopamine depletion has been considered to be an important contributor to the disease.

Recently, typical parkinsonism was reported in a group of individuals who had attempted to make a narcotic drug related to meperidine but actually synthesized and then took 1-methyl-4-phenyl-1, 2,5,6-tetrahydropyridine (MPTP). This compound selectively destroys dopaminergic neurons in the substantia nigra. This unfortunate incident provided further support for dopamine depletion as being a primary cause of Parkinson's disease.

Incidences of Parkinson's

The risk of developing Parkinson's disease during one's lifetime is two percent to three percent. About one percent of the nation's population over age 50 is affected with the disease, and each year there are an additional 20 new cases per 100,000 population. Although men and women appear to be equally subject to Parkinson's disease, the number of men seeking treatment is somewhat greater than women (1.3 to 1). The disease is encountered in all races throughout the world. More than 65 percent of those afflicted (men and women) have an onset of symptoms between 50 and 69 years of age. The average age of onset is 60 years, and onset under the age of 40 is rare.


The typical signs and symptoms of Parkinson's disease can be demonstrated by many different causes. Therefore, before the diagnosis of Parkinson's disease or idiopathic parkinsonism can be established, other causes must be examined. The major possible causes are idiopathic and chemical-induced Parkinson's disease.

The term "idiopathic" indicates an unknown cause. Many theories have been postulated, but lack of supporting evidence regarding etiologies, such as head injuries, viruses and allergic reactions, has resulted in the etiology remaining unknown. During recent years, substantial information regarding a biochemical basis for the disease has been generated.

Numerous chemicals cause symptoms resembling Parkinson's disease when large amounts are acutely ingested as well as during chronic exposure. Chronic exposure to certain heavy metals, such as lead or mercury, may result in symptoms similar to Parkinson's disease. Certain photographic dyes, carbon monoxide, carbon disulfide, cyanide and methylchloride have produced some of the signs associated with Parkinson's disease. (See Table 1)

Iatrogenic Parkinson's disease occurs with a variety of drugs, but is most commonly associated with the phenothiazine tranquilizers. These drugs produce extrapyramidal side effects which ultimately may produce a Parkinson-like disorder. The more common Parkinson-like syndrome becomes apparent after two or three months of therapy. The major symptoms of Parkinson's disease (i.e., rigidity, tremor, bradykinesia) are present. It occurs most frequently in patients over 50 years of age and responds well to conventional anticholinergic therapy (i.e., benztropine), but not to levodopa. Since phenothiazines probably reduce extrapyramidal side effects by blocking dopamine receptors, levodopa would be unable to counteract this side effect.

With regard to the phenothiazines, the piperazine compounds (i.e., trifluoperazine, prochlorperazine) can cause the highest incidence of extrapyramidal adverse effects, the aliphatic compounds (i.e., chlorpromazine) cause a moderate amount of extrapyramidal adverse effects, and the piperidine compounds (i.e., thioridazine) cause the lowest incidence of extrapyramidal adverse effects.

Other drugs with central nervous system activity including reserpine, carbamazepine, methyldopa, thiothixene, and chlorprothixene, have been implicated in causing extrapyramidal adverse effects with manifestations similar to Parkinson's disease. (Table 1)

Biochemical basis

After many theories and years of controversy, a biochemical basis for Parkinson's disease has emerged as the major cause. New histologic techniques have provided information regarding anatomic pathways and their primary functions. Of significant importance to an understanding of Parkinson's disease are the areas of the brain known as the substantia nigra, the basal ganglia, and particularly, the corpus striatum.

The substantia nigra, a bilaterally paired layer of pigmented gray matter in the mid-brain, is involved with dopamine transmission, while the normal basal ganglia function involves a series of interactions and feedback systems which are associated with the substantia nigra and mediated in part by dopamine, acetylcholine, gamma-aminobutyric acid, and other substances.

In Parkinson's disease, there appears to be a dysfunction in the dopaminergic activity of the substantia nigra which is caused by neuronal degeneration. This results in a state of dopamine deficiency and a shift in the balance of activity to a cholinergic predominance. Therefore, although there is no increase in the concentration of acetylcholine, the excitatory effects on the central nervous system (i.e., tremor) by this cholinergic mediator overwhelm the inhibitory effects of the depleted dopamine.

This simple theory substantiates a logical basis for treatment because anticholinergics are administered to decrease central nervous system cholinergic activity, while levodopa, as a precursor to dopamine, is prescribed for its ability to increase dopaminergic effects.

Clinical findings

The diagnosis of Parkinson's disease is difficult during the early stages of the disease because it has a gradual onset with vague complaints and symptoms. However, when the classic tremore appears, the diagnosis is easily made. The symptoms associated with the developed disease are unique. The classical symptoms include rigidity, bradykinesia, seborrhea, festination gait, flexed posture, salivation, and a "pill rolling" tremor. The patient often maintains a catatonic-like position with fixed stare.

The major clinical features are encompassed within three general categories. These are bradykinesia, rigidity and tremor. Bradykinesia and akinesia are a slowing down of voluntary actions with obvious difficulty in initiating movements. This may be severe and results in an immobility. These symptoms can be evaluated by requiring the patient to perform rapid, alternating movements. The rigidity is an abnormal plasticity of muscles which results in a resistance to movement. Consequently, the patient cannot coordinate fine movements and usually makes gross movements. While walking, the patient may begin to trot (festination gait) because of the rigidity. Muscle control and normal associated movements are hampered.

The tremor is usually present at rest and briefly disappears during purposeful movement (i.e., reaching for a glass). The patient exhibits a "pill rolling" tremor by movement of the thumb over the middle and index finger. The tremor may cause a loss of dexterity and simple tasks, such as buttoning clothing, tying shoes, and writing, may become difficult. Tremor may cause handwriting to become smaller (micrographia) and irregular (shaky). The patient writes smaller to minimize the irregular appearance.

Flexed posture is indicative of advanced Parkinson's disease, while seborrhea is related to hypothalamic dysfunction. The salivation accompanying the disease is attributed to a decrease in the frequency of swallowing.

General treatment

Physical therapy is useful in some patients to lessen bradykinesia and akinesia. However, tremor and rigidity, which are purely neurological symptoms, do not respond to physical therapy. The major objective is to alter the automatic movement, such as walking, to a conscious voluntary movement, so that the patient concentrates on a sequence of a specific series of functions. Walking would be divided into a series of precise units and the patient would perform these functions in a coordinated motion.

Exercises are useful in preventing flexion contractions, while head and massage are frequently used to relieve and reduce muscle cramps. In some instances, a well designed physical therapy program will impede the progression of the disabling symptoms of Parkinson's disease and provide the patient with many years of independence.

In some instances, the symptoms of Parkinson's disease can be aggravated by psychological factors. The obvious symptoms of the disease frequently cause the patient to become defensive, hostile and/or introverted. In addition, some of the drugs used to treat Parkinson's disease may produce adverse effects that influence psychological function. Since the patient's motivation is an important factor in the general treatment, sympathetic understanding, encouragement, and reassurance by family and all health care team members is an essential component of the general treatment of the patient.

Whenever possible, patients should be encouraged to work until normal retirement age and participate in activities that they enjoy. Short walks and attendance at recreational events, such as ball games and concerts, provide both physical and psychological therapy. Family members should encourage these activities and provide adequate support without fostering an atmosphere of total dependence for the patient.

Drug therapy

Levodopa and carbidopa; Levodopa is the drug of choice for Parkinson's disease patients who are symptomatic and have sufficient locomotor impairment to limit productivity.

The exact mechanism of action of levodopa is unclear. Levodopa penetrates the CNS and is enzymatically converted to dopamine in the basal ganglia. Since the current theory suggests that the symptoms of Parkinson's disease are related to a depletion of dopamine, it is believed that levodopa exerts its effects primarily by increasing dopamine concentration in the brain.

Concurrent administration of a decarboxylase inhibitor such as carbidopa (alpha methyldopa hydrazine) inhibits the peripheral decarboxylation of levodopa without affecting the metabolism of the drug within the CNS. Therefore, more levodopa is available for transport to the brain.

Levodopa is rapidly and well absorbed from the gastrointestinal tract eventhough significant amounts of the drug are metabolized in the lumen of the stomach and intestines. Concurrent administration of levodopa with food results in slower absorption and reduced peak plasma levels of the drug, but reduces some of the major gastrointestinal adverse effects. However, there are wide variations among patients and within the same patient regarding equidose plasma levels as well as the relationship between dose and clinical effects. Between 40 and 70 percent of an oral dose of carbidopa is absorbed.

Levodopa is distributed to most body tissues with considerable uptake by the liver, pancreas, kidneys, salivary glands, and skin. Somewhat less than one percent of the absorbed levodopa penetrates the CNS and a small amount of this enters the brain. The plasma half-life of levodopa is approximately one hour. However, when levodopa is administered with carbidopa, the plasma half-life of levodopa doubles. Carbidopa is similar to levodopa with regard to these properties, but it does not cross the blood brain barrier. It is widely distributed to body tissues and has a plasma half-life of one to two hours.

Daily doses of approximately 100 mg of carbidopa will saturate peripheral dopa decarboxylase, the major inhibitor of levodopa therapeutic activity.

Unlike levodopa, carbidopa is not extensively metabolized with approximately 30 percent of an oral dose being excreted unchanged in the urine within 24 hours. When carbidopa and levodopa are administered concurrently, the amount of levodopa excreted unchanged in the urine increases significantly.

Currently, levodopa is the most effective drug for relieving the symptoms of Parkinson's disease and is considered by many clinicians to be the drug of choice for idiopathic Parkinson's disease. Levodopa is more effective in young, robust patients than in elderly, frail patients, and more effective in treating idiopathic Parkinson's disease than symptoms attributed to other causes (i.e., lethargica encephalitis, chemical intoxication). Administration of carbidopa with levodopa decreases levodopa dosage requirements by approximately 75 percent and often provides a better response to levodopa. In some patients, this combination provides a better response than levodopa and reduces the incidence of nausea and vomiting.

Levodopa and levodopa with carbidopa completely or partially relieves rigidity, tremor, and akinesia in approximately 80 percent of the patients treated. Levodopa improves functional ability and a variety of other motor manifestations including facial expression, gait, speech and handwriting. Levodopa therapy often produces an increased vitality and attitude, which are beneficial in the overall treatment program.

Levodopa may be used in combination with other drugs used in Parkinson's disease, such as diphenhydramine, anticholinergic drugs (i.e., benztropine, trihexyphenidyl), and/or amantadine. In some patients, these combinations are more effective than either drug alone and/or may reduce the side effects of the drugs. These combinations, particularly levodopa and amantadine, are especially beneficial in patients who cannot tolerate large doses of levodopa.

The dosage must be adjusted to meet individual requirements, but usually should not exceed eight grams daily. The usual initial dosage is 0.5 to one gram per day administered in two or more equally divided doses. The daily dosage is usually increased twice a week or weekly by 100 to 750 mg per day until the desired response is achieved, side effects occur, or the maximum of eight grams daily is reached. The typical optimal dosage is three to six grams per day administered in five to eight divided doses. This dose is usually achieved after approximately two months of therapy, but the desired response may not be evident for three to six months. Treatment with levodopa requires patience by both physician and patient.

When levodopa is administered with carbidopa, a 1:10 ratio of carbidopa to levodopa is usually used. The usual initial dose of levodopa is 100 mg, while the maximum dose should not exceed two grams a day. Doses of levodopa can be increased by 100 mg every other day until the desired therapeutic response is achieved, side effects occur, or the maximum amount of levodopa (two grams) is reached.

In some patients, who are well controlled with doses of levodopa of less than 700 mg/day, the 1:10 ratio of carbidopa/levodopa does not provide enough carbidopa to saturate peripheral dopa decarboxylase. These patients may use the 1:4 combination of carbidopa 25 mg, levodopa 100 mg. Use of increased amounts of carbidopa may reduce the incidence of nausea and vomiting. The daily dose of carbidopa should not exceed 200 mg. If a patient is switched from levodopa to the combination, then levodopa should be discontinued for at least eight hours (i.e., no bedtime dose) before the combination is initiated. In addition, the patient must be carefully monitored because both therapeutic and adverse effects, particularly involuntary movements, occur more rapidly with the combination of carbidopa and levodopa than with levodopa alone.

A major problem with the use of levodopa is that most patients experience multiple side effects, which are usually dose dependent and reversible. Nausea, vomiting and anorexia occur frequently in patients receiving levodopa. These side effects usually occur early in therapy and may be relieved by temporary reduction of the dosage or administration with food. Nausea and vomiting occur less frequently when carbidopa and levodopa are administered concurrently.

Involuntary movements occur in approximately half of the patients on chronic levodopa therapy. These include gnawing, chewing, twisting, grimacing, and slow rhythmic movements of the extremities, mouth or head. Body jerks during sleep, increased hand tremor, ataxia, and muscle twitching are other involuntary movements which can occur and may be an early indication of excessive dosage.

Several types of bradykinetic episodes may occur in patients on chronic levodopa therapy. In some patients, Parkinson's disease symptoms return near the end of the dosing period, while others experience and "on-off" phenomenon which involves a sudden loss of effectiveness which may last from one minute to an hour followed by a sudden return of effectiveness. These "on-off" effects can occur many times a day. Each of these types of episodes may be reduced by more frequent administration of levodopa, but are frequently very annoying to the patient. Another type of bradykinetic episode is akinesia paradoxica which is sudden freezing followed frequently by falling just as the patient begins to walk. This problem may be relieved by a reduction of levodopa dosage.

Levodopa produces many CNS and psychiatric disturbances which vary in intensity from mild to severe. These include memory loss, agitation, anxiety, malaise, fatigue, nervousness, and a reduction in attention span.

A variety of cardiovascular adverse effects are associated with levodopa therapy. Orthostatic hypotension occurs frequently following therapeutic doses of levodopa, particularly during the first few months of therapy. If symptoms (i.e., syncope, dizziness) occur, the dose of levodopa should be reduced and then gradually increased to the desired amount. Levodopa should be administered with extreme caution to patients with a history of myocardial infarction who have residual arrhythmias.

Although levodopa possesses multiple side effects, some of the minor side effects may be somewhat attributed to the age of the Parkinson's disease patient for the fact that levodopa has relieved many of the major symptoms of the disease so that minor patient problems are more evident.

A variety of drug interactions occur with levodopa. Monamine oxidase inhibitors should not be administered during levodopa therapy because hypertensive crises may result. In addition, before levodopa therapy is initiated, monamine oxidase inhibitors should be discontinued for at least two weeks. Pyridoxine hydrochloride, in doses greater than 5 mg, causes a reversal of the effects of levodopa, but does not appear to alter the effects of levodopa when it is used with adequate amounts of carbidopa.

Levodopa should be used with caution in patients receiving methlydopa or guanethidine, since the hypotensive effect of levodopa may necessitate dosage reduction of these drugs.

Although tricyclic antidepressants may be administered to patients receiving levodopa, these drugs can enhance postural hypotension as well as antagonize the absorption of levodopa.

Phenothiazines and butyrophenones as well as other antipsychotic agents antagonize the therapeutic effects of levodopa and should be used with caution or not at all during levodopa therapy. Similar effects have been encountered with benzodiazepines, papaverine, and phenytoin.

Levodopa has also been implicated in causing false positive reactions for urinary glucose when cupric sulfate reagent is employed and false negative reactions when glucose oxidase tests are used.

In summary, although levodopa may not be a panacea, it is a major therapeutic discovery. It not only has provided a unique mechanism for treating Parkinson's disease, but has created a new area of research for developing treatment modalities for a disease that was treated by the same method for a century.

Amantadine: Amantadine hydrochloride is an antiviral drug which is also a valuable drug in the treatment of idiopathic Parkinson's disease and iatrogenic extrapyramidal reactions.

The mechanism of action of amantadine in Parkinson's disease is unknown, but does not appear to be associated with its antiviral effects. Amantadine does not exhibit significant anticholinergic activity, but appears to have CNS dopaminergic activity as well as blocking the reuptake of dopamine into presynaptic neurons.

Amantadine is well absorbed from the gastrointestinal tract and produces steady state blood levels within several days. Cerebrospinal fluid levels may be as high as half that of steady state blood levels. Amantadine is excreted unchanged in the urine and has an average elimination half-life of 24 hours.

Like levodopa, amantadine does not alter the course of Parkinson's disease. Amantadine is not as effective as levodopa, but appears to be a least as effective as the anticholinergic drugs in the treatment of Parkinson's disease. In addition, amantadine is very effective in treating iatrogenic extrapyramidal symptoms and is particularly useful when anticholinergic drugs are contraindicated (i.e., urinary retention, glaucoma).

In approximately 50 percent of the patients treated, amantadine produces improvement in total functional disability as well as rigidity, gait, tremor, akinesia and salivation. Altered attitude responses, such as an elevation of mood, also occur and contribute positively to the overall therapeutic program. Improvement in extrapyramidal symptoms occurs within several days and optimum results usually occur within four to eight weeks.

However, although improvement may last up to two or more years, some patients experience a reduction in benefit after several months of amantadine therapy. Combinations of amantadine with other drugs used in Parkinson's disease, particularly levodopa, are often more effective than either drug alone. This is especially beneficial in those patients who cannot tolerate large doses of levodopa and during the initial phases of levodopa therapy, since objective improvement occurs rapidly with amantadine and very slowly with levodopa.

The usual oral dose of amantadine in treating Parkinson's disease is 100 mg twice daily. If other drugs are being used, then the initial dose of amantadine should be 100 mg a day for at least the first week. A maximum of 400 mg daily may be administered. However, most patients who receive more than 200 mg daily experience a significant increase in adverse effects and only a small increase in beneficial effects.

Although amantadine does not exhibit as many side effects as levodopa, it does possess a variety of undesired properties. Many of these side effects are displayed as psychic or CNS abnormalities which are reversible, frequently dose related, and may appear within a few hours or days after initiation of amantadine therapy or an increase in drug dosage. These side effects include fatigue, mental depression, anxiety, insomnia, confusion, headache, visual hallucinations, and nervousness.

Livedo reticularis, a reddish blue, netlike mottling of the skin, is a common adverse effect which appears within a few months in patients receiving amantadine for Parkinson's disease. It occurs predominantly on the legs and diminishes when the legs are elevated. If required, amantadine should be discontinued gradually because abrupt discontinuation has resulted in exacerbation of Parkinson's disease symptoms within 24 hours after discontinuation of the drug. Amantadine should be administered with caution to patients receiving anticholinergic drugs because this combination has resulted in severe anticholinergic side effects (i.e., hallucinations, nocturnal confusion).

Drugs with central anticholinergic activity

The anticholinergic drugs were the treatment of choice for Parkinson's disease for many years. The efficacy of these drugs appears to be related to their central cholinergic blocking action because the quaternary ammonium anticholinergic drugs (i.e., propantheline), which do not readily cross the blood brain barrier, are not effective in treating the symptoms associated with Parkinson's disease.

The belladonna alkaloids, scopolamine, and atropine were the first centrally acting anticholinergic drugs used to treat Parkinson's disease. These drugs have been replaced by synthetic drugs which are equally effective, but produce fewer peripheral adverse affects. The drugs frequently used include trihexyphenidyl, benztropine, biperiden, cyrimine, and procyclidine. Trihexyphenidyl and its analogues, biperiden, procyclindine, and cycrimine, differ chemically from benztropine. In addition, several antihistamines, diphenhydramine, chlorphenoxamine, and orphenadrine and ethpropazine, a phenothiazine compound, are useful in some Parkinson's disease patients because of their anticholinergic effects.

Although the anticholinergic drugs are not the drugs of choice in the treatment of Parkinson's disease, they are still useful in mild cases of the disease, in combination with levodopa, and in those patients who cannot tolerate levodopa. The anticholinergics seldom produce more than 20 percent improvement and symptoms of Parkinson's disease continue to progress. This probably can be attributed to the fact that Parkinson's disease is associated with abnormalities in dopamine.

When initiating therapy with anticholinergic drugs, the dose should be small and gradually increased until maximum benefits are achieved or undesirable effects occur. Any alterations in the dosage regimen should be gradual because sudden withdrawal of anticholinergic drugs has resulted in a marked exacerbation of symptoms. If one drug fails, then a drug from another chemical class could be considered (i.e., benztropine-trihexyphenidyl-diphenhydramine). In some instances, combinations of drugs from various classes are beneficial. Other than individual patient variation, these drugs are very similar to each other.

Initially, trihexyphenidyl or benztropine is usually used. Diphenhydramine is considered a primary adjunct and may be better tolerated in the elderly. When used in combination with levodopa, the anticholinergic drugs are often beneficial. These drugs are also used to control the extra-pyramidal symptoms produced by the antipsychotic drugs.

Unfortunately, in many instances, side effects occur before the desired therapeutic response can be obtained. Most undesired effects are related to the peripheral or central cholinergic blocking activity of these drugs. The most common side effects of the anticholinergic drugs are constipation, psychic distrubances, urinary retention, and tachycardia. Mental confusion and excitement occur with large doses of anticholinergic drugs. This is more common in elderly patients, those with existing mental dysfunction, and those who are taking other drugs with anticholinergic effects. Paranoid reactions and hallucinations are serious mental abnormalities which can occur with large doses of anticholinergic drugs and in patients with mental disorders.

The antihistamines have some side effects that are unrelated to their anticholinergic action. Dizziness and drowsiness are frequent adverse effects which can occur with normal therapeutic doses, while euphoria, hypotension and tingling occur with larger doses.

Although the central anticholinergic and related drugs are no longer the drugs of choice for Parkinson's disease, they are still beneficial in mild cases and as adjunctive drugs.

Bromocriptine: Bromocriptine is an ergot alkaloid that is a prolactin inhibitor and also a valuable drug in treating Parkinson's disease. It is usually used in those patients who have problems associated with levodopa therapy (i.e., "on-off" phenomenon).

The mechanism of action of bromocriptine in Parkinson's disease involves a variety of very complex neurochemical changes in the nervous system. It appears that bromocriptine and/or its metabolites have a direct dopamine receptor stimulant action which may differ at various dopamine receptor sites in the CNS. However, the major effect of bromocriptine in Parkinson's disease is to mimic the action of dopamine in the CNS.

Bromocriptine is rapidly and well absorbed from the gastrointestinal tract with peak plasma levels occurring approximately 100 minutes after an oral dose and about the same time as the maximum clinical response. Bromocriptine has a half-life of six to eight hours, is extensively metabolized, and eliminated primarily by biliary pathways.

The initial dosage of bromocriptine is 1.25 mg twice daily, while typical daily maintenance doses usually are between 10 and 30 mg.

The incidence of side effects for bromocriptine is quite high, especially with large doses (i.e., more than 20 mg daily) and during the initial stages of therapy. Adverse effects are usually minimized by initiating therapy with small doses and increasing the dose gradually until effective levels are achieved. Nausea is a very common side effect of bromocriptine, while other mild gastrointestinal adverse effects, such as vomiting, anorexia, constipation and diarrhea, as well as serious gastrointestinal side effects, such as hemorrhage and peptic ulcer, are less common and rare, respectively.

A variety of CNS side effects occur with bromocriptine. These vary from mild headache to migraine and light-headedness to hallucinations and delusions. These CNS effects are more common at higher doses and in the older patients with Parkinson's disease. Another common side effect is dyskinesia, which occurs in more than half of the patients and is manifested in a variety of abnormal movements. Bromocriptine causes a decrease in blood pressure which is persistent and may vary from a very mild effect to severe hypotension. Other vascular adverse effects are not common, but Raynaud's phenomenon and livedo reticularis are examples of undesired effects. A unique "first-dose" reaction occurs in approximately one percent of the patients. These individuals may faint and collapse for as long as an hour, but usually tolerate subsequent treatment without these effects. Other reported adverse effects include leg cramps, metallic taste, nasal congestion, dryness of the mouth, and urticaria. Additive effects with levodopa and antihypertensive drugs administered concurrently with bromocriptine can occur. When these drugs are administered concomitantly, dosage adjustments should be made.

Other supportive medications

Many of the minor symptoms of Parkinson's disease can be easily treated. Constipation, which is often drug induced or aggravated by the major drugs used in therapy, can usually be alleviated by a mild laxative (milk of magnesia) or stool softener (dioctyl sodium sulfosuccinate). Blurred vision, which often occurs while watching television and is attributed to infrequent blinking of the eyes or adverse drug effects, can usually be relieved with a lubricant such as methylcellulose eye drops. Many patients with Parkinson's disease complain about insomnia.

Although some patients associate this problem with levodopa therapy, it is probably that levodopa has relieved many daytime symptoms and the patient has become more aware of sleeping difficulties. The drug of choice for insomnia is diphenhydramine because it is effective, provides some antiparkinson effects as well, and does not antagonize the beneficial actions of other therapy for Parkinson's disease.

Surgical treatment of Parkinson's disease

Surgical treatment of Parkinson's disease is greater than 70 percent effective for periods of five years or more in selected patients. However, surgery usually does not correct many of the major symptoms and requires a post-operative physical rehabilitation program. In most instances, the patient is responding in some manner to drug therapy and does not require surgery.

Recent investigational techniques have utilized brain tissue transplants to treat Parkinson's disease. Although only preliminary results have been obtained, the procedure appears to be valuable in some instances and future studies will probably be conducted.


Parkinson's disease is an insidious, progressive disorder. Drugs, especially levodopa, often relieve many of the major symptoms, but do not cure the disease.

Before the introduction of levodopa, Parkinson's disease significantly shortened life with a mortality rate of about three times the similar general population.

Since the introduction of levodopa, the mortality rate of individuals with Parkinson's disease is similar to that of the general population (1.3 to 1). It is possible that this will improve because many of the original patients receiving levodopa suffered from advanced disease.

Since treatment success is dependent on continued encouragement and appropriate monitoring and counseling, the patient with Parkinson's disease is an ideal candidate for outpatient monitoring by the pharmacist because the diagnosis is known, the drugs used are for long term effects and may cause multiple adverse effects, and a variety of other therapeutic components often require counseling by health professionals. [Tabular Data 1 to 2 Omitted]

COPYRIGHT 1990 Reproduced with permission of the copyright holder. Further reproduction or distribution is prohibited without permission.
COPYRIGHT 2004 Gale Group

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