Sshp_newsletter_fall_2004.doc

Newsletter –Fall Edition 2004
Richard Cramer, Pharm D
Kimberly Chandler, Pharm D
Bob Delaney, M.S.
Dan Gillis, Pharm D
Steve McDonald, Pharm D
Update on Treatment of Parkinson’s Disease
Christal Smith Taylor, PharmD Candidate
Samford University McWhorter School of Pharmacy
Since James Parkinson’s publication on The Shaking Palsy in 1817, the treatment of Parkinson’s disease (PD) has undergone several transformations. Over a century elapsed devoid of any effective treatments for this devastating disease and PD was considered to be a terminal illness. It is estimated that one million people suffer from PD in the United States, and about 60,000 new cases appear each year. PD is a neurodegenerative disorder of the brain resulting in dopamine deficiency caused by the progressive death of dopaminergic neurons. Due to dopamine loss, tremors develop as well as rigidity of the limbs and trunk, postural instability, and bradykinesia. Although there is no cure for PD, several pharmacological options are available to treat symptoms and possibly slow disease progression. The most common types of treatment are described b elow: Levodopa is the cornerstone of therapy. It is initially effective in most patients, but often loses its efficacy after several years of treatment. It is given in combination with carbidopa to increase brain levels of dopamine. Long-term use of levodopa causes dyskinesias, and unpredictable “on-off” periods. “On-off” periods can be managed by giving smaller more frequents doses or adding a dopamine agonist or selegiline. Levodopa is recommended for initial therapy in patients over age 70 and those wit h dementia or significant cognitive impairment. It is best to take on an empty stomach one hour before or after eating to reduce GI upset. Dopamine agonists are becoming first line therapy. They act by directly stimulating dopamine receptors. Dopamine agonists are prescribed as monotherapy in early PD and in combination with levodopa/carbidopa in advanced disease. The agonists currently available include: bromocriptine, pergolide, pramipexole, and ropinirole. Side effects are similar to those of levodopa, but psychiatric effects are more common especially at higher doses and in the elderly. Dopamine agonists have a longer half-life than levodopa which protects against the pulsatile stimulation of dopamine receptors; this property makes these drugs less likely to cause dyskinesias. Additional benefits include no protein competition for absorption or transport into the brain as well as possible neuroprotective effects. Unfortunately, dopamine agonists do not completely prevent motor complications, or treat freezing episodes, autonomic dysfunction, or dementia. Catechol-O-methyltransferase (COMT) inhibitors are used in combination with levodopa/ carbidopa in advanced PD. The COMT enzyme inactivates dopamine. COMT inhibitors increase the half- life of levodopa by fifty percent, allowing more continuous and stable stimulation of dopamine receptors. There are two available agents: tolcapone and entacapone. These medications increase motor performance and amounts of “on” time. Common side effects include dyskinesia, diarrhea, nausea, postural hypotension, headache, hallucinations, and discolored urine. Tolcapone has been associated with liver failure and therefore liver function tests are recommended every two weeks for the first year, every four weeks for six months, then every eight weeks thereafter. Anticholinergic drugs reduce the amount of acetylcholine present in the brain helping to restore balance and to diminish symptoms such as tremor, drooling and rigidity. Various preparations are available including trihexyphenidyl and benztropine. Common side effects include dry mouth, constipation, urinary retention, and blurred vision. Confusion and hallucinations are common and troublesome in the elderly. To reduce side effects dosages must be carefully adjusted for age and weight. Anticholinergics are often used in early PD and as adjunct therapy to enhance levodopa/carbidopa effects. Selegiline is a selective monoamine oxidase B inhibitor that inhibits dopamine metabolism. It is approved as an adjunct to levodopa because it can modestly increase “on” time and reduce motor fluctuations. Selegiline has possible neuroprotective properties, although it does not stop disease progression. Adverse effects include nausea, confusion, hallucination, loss of balance, and hypotension. Acute toxic interactions may occur with meperidine, tricyclic drugs, and serotonin reuptake inhibitors. Selegiline is metabolized to amphetamine and methamphetamine causing many patients to experience anxiety or insomnia. Rasagiline is a new, MAO-B inhibitor with structural similarity to selegiline; however, it is devoid of amphetamine-like effects. Rasagiline has moderate efficacy as monotherapy in early PD and as adjunctive therapy to levodopa. Adverse effects include infection, headache, and dizziness. Studies indicate that rasagiline may decrease “off” time and slow disease progression. There are no documented drug-drug or drug-food interactions with rasagiline. Possible advantages include once daily dosing, no amphetamine-like reactions, no interaction with tyramine containing foods, and possible neuroprotection. Rasagiline will be available the first of 2005. Apomorphine is a dopamine agonist and is available as a subcutaneous injection. Apomorphine is indicated for the acute, intermittent treatment of unpredictable “on-off”, hypomobility, or “end-of-dose wearing off” in advanced PD. Hepatic and renal impairment would require an initial dose adjustment due to increases in AUC and Cmax values. Side effects include yawning, nausea, postura l hypotension, hallucination, swelling of extremities, and dyskinesia or exacerbation of pre-existing dyskinesia’s. Apomorphine is associated with numerous possible medication errors. Intravenous administration should be avoided due to crystallization of apomorphine, leading to thrombus formation and pulmonary embolism. Healthcare providers should be educated on the sound-alike/look-alike potential with morphine through verbal and written communication. Apomorphine should be administered with an anti-nausea regimen. The manufacturer recommends the use of trimethobenzamide (Tigan ) 300mg TID orally to be started three days prior to the initial dose. It should not be administered with a 5HT3 antagonist (ondansetron, granisetron, dolasetron, palonosetron, and alosetron) due to the possibility of hypotension and loss of consciousness. Metoclopramide is another anti-nausea agent that should not be administered with apomorphine due to possible worsening of PD. The drug also has the potential to cause prolongatio n of the QTc interval, this effect may be intensified with other QTc prolongation agents (Table 1). Compared to the other anti-PD medications, the main advantage of apomorphine is its rapid onset of action. The spectrum of treatments for PD has dramatically changed in the last decade. The advances in pharmacotherapy provide better management of motor symptoms and allow for an improved quality of life. Future research (Table 2) will undoubtedly lead to more effective treatments and new discoveries, which may lead to a cure for Parkinson’s disease. Table 1. Pharmaceuticals in Late-Stage Development
New Drugs
Product Type
FDA status/notes
ο Oral formulation of kinase ο Phase 2/3 Table 2. Drugs Associated with Prolonged QTc Intervals
Erythromycin, clarithromycin, Septra DS®, ketoconazole, fluoroquinolones References available upon request. Proverbs for People
? It is impossible rightly to govern the world without God and the Bible. – George ? An investment in knowledge always pays the best interest. – Benjamin Franklin ? Freedom is one of the deepest and noblest aspirations of the human spirit. ? Peace, like charity, begins at home. – Franklin D. Roosevelt ? The noblest service comes from nameless hands. And the best servant does his Patients and Patches
By Jennifer Lightfoot, Pharm. D. Candidate Transdermal drug delivery has been in practice for over 20 years. The transdermal patch drug products range from a contraceptive to analgesic to medicated temporary tattoos. The transdermal system is an effective alternate route for drug delivery into the systemic circulation. In some cases, this alternative allows for greater patient compliance. The key to effectiveness, as with many dosage forms, is patient education and consistency. Since many of the transdermal systems can be dosed once weekly, more and more patients are requesting transdermals for their personal convenience. The patches are constructed with either a reservoir system or matrix system. The reservoir patches have a membrane that separates the drug from the skin and controls the rate of drug release. In the matrix system, the active drug is contained in a polymer matrix, which controls the release of the drug. The matrix patches have a slower diffusion rate and thus the patches do not have to be changed as frequently. Understanding the variations of human skin is one of the most important factors for adequately utilizing the delivery system. The effects of different skin textures can alter the permeability of the transdermal system. For example, the elderly and neonatal populations have thinner, more permeable skin, and African Americans’ skin is less permeable when compared to Caucasians. The condition of the skin also affects the permeability. For example, skin that is hydrated, broken, irritated, or warmer will be more permeable, and therefore will absorb more of the active drug from the patch. Patches should be avoided in patients whose skin is burned or not intact, as this could lead to excessive drug absorption and an incre ased possibility of adverse outcomes. An advantage to using the patches is maintaining a steady amount of drug permeating across the skin that allows a more consistent serum drug level. The consistency in drug levels may decrease the incidence of adverse drug events. However, if too much drug enters the system or toxicity is suspected, removing the patch can decrease the effects. One important disadvantage of using the transdermal patches is the associated dermatological reactions, such as irritation, itching, or erythema at the application site. Another disadvantage is that the patches may come off if they lose their adherence to the skin’s surface. Furthermore, the patches can be expensive (Refer to Table 1). The transdermal systems have gained a great deal of attention because of their infrequent dosing regimens. There is much importance placed on the application duration and the preferred application locations of certain transdermal patches. In order to be effective, the correct dosing conversion to the transdermal systems must be accurate. Patients may become supra -therapeutic or subtherapeutic if the patch’s dose is not equivalently converted from the previous dosage form. Furthermore, some concerns have been raised on whether or not specific patches can be cut to provide more individualized doses as many patches lose their drug delivery integrity if cut. Another concern is if the patch contains metal or not, in order to provide patient safety during a MRI. Table 1 illustrates the duration and recommended application site of a selected number of patches along with whether the patch can be cut and contains metal according to product guidelines. Table 1: Selected Transdermal Patches and Application Techniques *Company recommends removing the patch before MRI. The most important factor in counseling patients about transdermal patches is to be consistent about changing their patch. Practitioners should instruct patients on when their patch needs to be changed,
so that they do not keep the patch on longer than intended or change the patch too early. Patients need to
know where they can properly place the patch in order to rotate the application site if needed. Furthermore,
patients should be informed of the proper disposal of the patches. Many transdermal patches contain 20
times greater than the amount of drug in the delivery system that would eventually be absorbed; thus upon
discarding the patch, about 95% of the active drug is still contained in the patch. Inform patients to fold the
patch upon itself (sticky sides together) and flush down the toilet in order to avoid potential risk for
children and pets.
Transdermal patches provide an alternative for drug delivery to many patients. Many have convenient once
or twice weekly dosing, which is appealing to patients. They have low adverse reaction profiles and are
easy to apply. Pharmacists should remember that in order to effectively treat their patients with transdermal
drug systems, the condition of the p atient’s skin, sites of application and rotation, and duration of patch
application should all be considered. Providing convenient and efficient drug delivery to patients is the
health care provider’s main focus and with transdermal drug systems, patient care goals can adequately be
achieved.
References available upon request.
First, Do No Harm - - A Drug Safety Update

Atypical Anti-psychotics – The FDA has requested that all manufacturers of atypical antipsychotics include a
warning regarding hyperglycemia and diabetes mellitus in their product labeling. The FDA made this request to
the following manufacturers: Astra-Zeneca (Seroquel), Bristol-Myers Squibb (Abilify), Eli Lilly (Zyprexa),
Novartis (Clozaril), Janssen (Risperdal) and Pfizer (Geodon).
Seroflurane (Ultane®) – Isolated reports have been received of fire or extreme heat occurring when Ultane® was
used in conjunction with desiccated CO2 absorbent; ongoing investigation has not identified the exact etiology.
Steps to prevent occurrence should be developed (i.e. timely replacement of CO2 absorbent, temperature
monitoring of absorbent canisters, verification of absorbent package integrity prior to use, others).
Risperidone – A new warning has been issued concerning an increased risk of stroke in dementia patients
receiving risperidone for agitation or psychosis; additional research will further characterize this association.
Viagra type drugs and alpha-blockers – There is a new precaution about possible dizziness/hypotension with this
combination. Viagra and similar drugs can lower blood pressure after a dose and hypotensive effects may be
additive.
FDA Approval Of Campral® (Acamprosate):
Its Role In The Treatment Of Alcoholism
Harrison School of Pharmacy, Auburn Univ. Everyday in the United States, there are over 700,000 patients treated in inpatient or outpatient settings for alcoholism.1 For most patients, treatment begins with a detoxification period that may or may not include pharmacological therapy for the harsh withdrawal symptoms associated with alcohol dependence. Once the patient achieves initial abstinence from alcohol, prevention of relapse becomes the ultimate battle. Although psychosocial therapies may help patients with alcohol dependence achieve and sustain abstinence, 40 to 70 percent of patients resume drinking within one year.4 The use of medications as adjunctive treatment is based on the premise that cravings and other manifestations of alcoholism are mediated by neurobiological mechanisms. The neurochemical pathways in the CNS that are thought to initiate and maintain the craving to drink include dopaminergic, GABAergic, opioid, and glutamatergic systems.1-3 In July 2004, the FDA approved acamprosate (Campral®) for the treatment of alcohol abuse. This is the first new drug to be approved for this indication in over a decade. The greatest benefit from treatment with acamprosate has been seen in alcohol dependent patients who have already stopped drinking and desire to remain abstinent.2 It will be least effective in patients who have just started treatment for alcohol withdrawal, and those who abuse other substances in combination with alcohol.2 Acamprosate comes as 333mg tablets. It should be given with meals and dosed -Adults > 60kg six tablets (1998mg) in 3 or 4 divided doses daily. -Adults < 60kg four tablets (1332mg) in 3 or 4 divided doses daily. Patients should be started on half of these doses and tapered up by one tablet per week. The recommended duration of therapy is one year.2, 3 Studies suggest that acamprosate has dose-dependent efficacy, with generally no dose-limiting adverse effects.2 The oral bioavailability of acamprosate is 10%, of which 90% is excreted unchanged in the urine.3 The most common adverse events associated with the use of acamprosate are gastrointestinal complaints, e.g., diarrhea and mild abdominal pain.2, 3 Acamprosate is contraindicated in patients with known hypersensitivity to the drug, renal insufficiency, or cirrhosis with severe hepatic decompensation.3 In controlled trials, acamprosate was more effective than placebo in preventing relapse in alcohol dependent individuals.3 However, abstinence rates decline over time in both groups after the initial treatment period.3 The PRAMA trial found that 39% of acamprosate patients remained abstinent after 48 months, compared with 17% in the control group.3 This represents the largest difference seen in any trial. Typical results in other studies have shown one year post treatment abstinence rates of 18-19% versus 7-11% for acamprosate versus placebo, and 12% versus 5% abstinence at two years for acamprosate and placebo respectively.3 Acamprosate’s mechanism of action appears to be distinctly different from those of the other FDA approved drugs for the treatment of alcohol dependence.2 Chronic exposure to alcohol causes a decrease in the inhibitory GABAergic system, and a corresponding increase in activity of the excitatory glutamate system in the CNS.2, 4 Acamprosate is a synthetic derivative of homotaurine, a naturally occurring structural analogue of GABA. Because it possesses this structure, it enhances GABA transmission by increasing the number of sites for GABA-uptake. 2, 4 It also interferes with action of glutamate at various sites, including NMDA receptors.2 Finally, it has effects on calcium channels, which tend to increase in number as alcohol dependence develops.2 Although its exact mechanism of action is unknown, the previously mentioned pharmacologic effects are thought to work in combination to decrease alcoholic cravings and increase the duration of abstinence.3-5 Naltrexone, a potent opioid receptor antagonist, is another drug approved for relapse prevention in alcohol dependent patients.3, 4 Naltrexone and acamprosate were used in Europe for a number of years prior to their approval in the United States. Both drugs are tolerated, and there is no interaction between alcohol and either agent.3, 5 The relative efficacy of the two drugs is not well characterized, but available comparative trials tend to favor naltrexone.6,7 One double blind, placebo controlled study compared acamprosate, naltrexone, and a combination of the two. Time to first drink, time to relapse, and the cumulative abstinence time were the primary outcome measures. The naltrexone group showed a tendency for a better outcome regarding time to first drink and time to relapse. The combined medication showed lower relapse rates than placebo and acamprosate but not naltrexone.8 Not all patients respond to these drugs. And, though many studies of pharmacologic therapy for alcohol dependence have shown statistically significant efficacy compared to placebo, the overall response rates are modest. Additionally, no studies have reported a reduction in mortality following the use of any pharmacological treatment for alcohol dependence.3, 5 More studies are needed to identify the patients who are most likely to benefit from pharmacologic therapy, as well as the role of combined pharmacologic modalities. When used, drug therapy should always be accompanied by appropriate interdisciplinary psychosocial support. Alcoholism continues to be one of our country’s most serious and persistent health problems. Much more work is needed towards the improvement of our understanding of its
neurobiologic mechanisms in order to identify new and optimal treatment options.
References available upon request.

Drugs in the Literature
§ Ten Eick, AP. Gormley A. Phosphodiesterase inhibitors and persistant pulmonary hypertension of the newborn. Hosp Pharm 2004; 39(9): 831-834. § DeDenus S. Hardy AM. Olson KL. Robinette B. Key articles and guidelines in the management of hypertension. Pharmacotherapy 2004; 24(10): 1385-1399. § Burda AM. Sigg T. Pharmacy preparedness for incidents involving nuclear, biological, and chemical weapons. Journ Pharm Pract 2004; 17 (4): 251-256. § Baroletti SA. Maden A. Durg-elicting stents: a pharmacy management perspective. Formulary 2004; 39(9): 446-457. § Schumock GT. Blackburn JC. Nutescu E. Walton SM. Finley JM. Lewis RK. Impact of prescribing guidelines for impatient anticoagulation. Ann Pharmacother 2004; 38(10): 1570-1575.

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