Risks of Multiple Medication Use in General Practice and Psychiatry

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Mon, 07 Nov 2005 21:28:49 -0000

Subject:[drugawareness] Risks of Multiple Medication Use in General

Practice and Psychiatry

 

| drugawareness

 

 

 

Half of all Americans over the age of 18 are taking at least one long

term prescription medication and one in six Americans take at least

three or more prescription medications.

 

I quote from the following article: " Polypharmacy is associated with

increased health risks and costs (Preskorn, 2005; Silkey et al.,

2005), and can result in potential pharmacokinetically and/or

pharmacodynamically mediated DDIs. These, in turn, set the stage for

increased vulnerability to side effects, increased number of

prescription drugs used, compliance problems, increased patient

morbidity and mortality, and increased health care costs. "

 

It is time for Americans to wake-up and realize that the 'cure' is

killing us!

 

Dr. Ann Blake Tracy, Executive Director,

International Coalition For Drug Awareness

www.drugawareness.org & author of Prozac: Panacea

or Pandora? - Our Serotonin Nightmare (800-280-0730)

 

 

http://www.psychiatrictimes.com/showArticle.jhtml?articleId=172901304

 

 

Multiple Medication Use in General Practice and Psychiatry: So What?

By Ahsan Y. Khan, M.D., and Sheldon H. Preskorn, M.D.

 

 

Psychiatric Times October 2005 Vol. XXII Issue 12

 

 

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Multiple Medication Use in General Practice and Psychiatry: So What?

by Ahsan Y. Khan, M.D., and Sheldon H. Preskorn, M.D.

 

Multiple medication use is the rule rather than exception in modern

therapeutics. Factors affecting the recent increase in utilization of

medications include the growth of third-party insurance coverage for

drugs; increased marketing efforts to promote new medications to

prescribers and directly to consumers; and clinical guidelines

recommending long-term treatment for chronic conditions such as high

cholesterol, acid reflux disease, heart disease, diabetes, asthma and

clinical depression.

 

This issue is particularly important for those treating patients with

psychiatric illness. According to the data from the 1989 National

Ambulatory Medical Care Survey, patients seen by a psychiatrist were

six times more likely to receive multiple psychotropic medications,

as compared with those seen by a primary care physician (Nichol et

al., 1995). A recent pharmacoepidemiology study found Veterans

Affairs Administration outpatients on antidepressants were on more

medications than age-matched and gender controls not on

antidepressants (Preskorn, 2005).

 

Multiple medication use poses questions for clinicians: What is the

extent of polypharmacy in general practice and psychiatry? What

factors impact the increase in polypharmacy seen today? What should

the clinician consider when treating a patient taking two or more

medications concurrently?

The Incidence of Polypharmacy

 

 

According to the annual report, " Health, United States, 2004, "

prescription drug use is rising among people of all ages, and

increases with age (National Center for Health Statistics, 2004).

Almost half of those over 18 in the United States are taking at least

one prescription medicine, and one in six is taking three or more.

These percentages are substantially higher for Americans 65 or older

( Table).

 

The reason is, at least in part, the increasing ability to treat and

even prevent chronic illnesses. As a result, patients accumulate

drugs as they age and are on them for years, during which time other

drugs can be added and stopped. Prescription drug use is on the rise,

and there are an increasing number of medications available for the

chronic treatment of hypertension, diabetes and hyperlipidemia, the

three leading causes of death in United States (National Center for

Health Statistics, 2004).

 

The National Center for Health Statistics (2004) reported a number of

data regarding the increasing incidence of polypharmacy. Among its

findings: The use of multiple psychoactive drugs is an increasingly

common practice in both primary care and psychiatric practice; the

use of antidepressants in the U.S. adult population almost tripled

between 1988 to 1994 and 1999 to 2000; 10% of women age 18 or older

and 4% of men now take antidepressants; three times as many white

adults in the United States took antidepressants as did blacks or

Mexican Americans in the most recent year for which data are

available. There is also an increased use of specific psychoactive

medications in younger patients, and use is also increasing among

younger patients including psychoactive medication for attention-

deficit/hyperactivity disorder and antidepressants (National Center

for Health Statistics, 2004).

 

 

Factors Affecting Polypharmacy

 

 

A number of risk factors in primary care and psychiatric practice may

lead to the increasing incidence of multiple medication use.

 

 

Comorbid medical and psychiatric conditions. Patients with

psychiatric disorders may have significant comorbidity with medical

conditions including HIV infection, heart disease, diabetes, cancer,

fibromyalgia, irritable bowel syndrome, liver disease, renal failure

and many more. So overall, psychiatric illness increases a person's

risk of developing a number of general medical conditions (Goldman,

2000). The Figure shows the prevalence of major depression in

specific medically ill populations.

 

Patients with mood and anxiety disorders have also been found to

utilize more health care services than those without these disorders

and thus to have higher incidence and greater complexity of

concomitant medication usage. Patients with substance abuse or

dependence are another group at increased risk for drug-drug

interactions (DDIs) resulting from polypharmacy (George and Krystal,

2000).

 

Increase in number of approved psychoactive drugs. With more drugs

approved for use by the U.S. Food and Drug Administration, there is

more potential for drug interactions. Frye et al. (2000) found a

substantial increase in polypsychopharmacy from 1974 to 1996. Since

1990, the FDA has approved more than 20 new psychotropics, including

antidepressants, antipsychotics, and medications for bipolar

disorder, dementia, insomnia, sexual dysfunction, narcolepsy and ADHD

(Table 2).

 

Increase in use of nonprescription drugs. Many well-educated patients

increasingly turn to alternative medicine because they find such

therapies more congruent with personal values and holistic views of

health care (Astin, 1998). A wealth of such alternative medicines is

available, including prescription drugs, over-the-counter (OTC)

medicines, herbal preparations, illicit substances and dietary

supplements. Adverse drug reactions stemming from concurrent use of

such alternative medications with prescription drugs can present in

almost any way clinically imaginable, from a sudden, catastrophic

adverse event to a mild increase in nuisance side effects. Drug-drug

interactions can also present as a loss of efficacy on a previously

effective drug regimen, withdrawal symptoms, emergence of a new

illness or worsening of an existing one.

 

For example, ibuprofen, an OTC analgesic, can cause serious and even

life-threatening elevations in lithium (Eskalith, Lithobid) levels by

affecting its rate of tubular reabsorption (Ragheb et al., 1980). St.

John's wort (Hypericum perforatum) is a substantial inducer of CYP3A

and can accelerate the clearance of oral contraceptives, potentially

rendering them ineffective (Hall et al., 2003). Smoking can induce

the metabolism of drugs such as clozapine (Clozaril), which are

normally cleared by smoking-induced CYP1A2 (Hasegawa et al., 1993).

 

In addition, a case report describes clozapine-induced seizures in a

man when he gave up smoking (McCarthy, 1994).

Increased Internet availability. It is now common for patients to buy

medications on the Internet for general medical and psychiatric

disorders. In 2004, the FDA reiterated its warning against online

drug purchases after it purchased so-called generic versions of

sildenafil (Viagra), atorvastatin (Lipitor) and zolpidem (Ambien)

from a Canadian-advertised Web site. The FDA reported that all three

were " fake, substandard and potentially dangerous " (Rados, 2004).

Clinicians should discourage this method of obtaining medications

until approved by the FDA.

 

 

Syndromic nature of psychiatric disorders. Common psychiatric

conditions such as mood, psychotic and anxiety disorders usually have

multiple signs and symptoms involving more than one bodily system,

treatment of which can lead to multiple medication use. Nichol et al.

(1995) found that patients diagnosed with mania were four times more

likely to receive multiple psychotropic medications, and those

diagnosed with schizophrenia were three times more likely. There is

also a substantial overlap in the diagnostic and ancillary features

outlined in DSM-IV for bipolar disorder, schizoaffective disorder and

borderline personality disorder (Preskorn and Baker, 2002). A patient

with borderline personality disorder may be treated with lithium for

mood lability, an antidepressant for depressive symptoms, an

anxiolytic for anxiety symptoms and an antipsychotic for brief

psychotic symptoms.

 

Treatment of side effects. Treatment for a primary illness or

disorder sometimes produces side effects that must be treated by the

use of adjunctive pharmacotherapy. For example, benztropine

(Cogentin) may be used to treat the extrapyramidal symptoms of

antipsychotics. Antinausea medication may be given to a patient

receiving cancer chemotherapy. Increasingly common is the treatment

of metabolic syndrome (i.e., hyperglycemia, hyperlipidemia, diabetes

and hypertension) resulting from treatment with some atypical

antipsychotics (Toalson et al., 2004).

 

Increased prescription medicine coverage. Private health insurance

covered almost 50% of prescription drug costs in 2002, as compared to

25% in 1990 (National Center for Health Statistics, 2004). When cost

is not an issue, use goes up.

(While the percentage of prescription drugs has increased, the amount

of shared costs shifted to patients through co-payments to third-

party health insurance providers has also seen a steady increase. The

jury is still out on how this impacts the cost of care. For example,

many formularies disallow newer medications, while providing

increased coverage for older drugs. At least in the case of

antipsychotics, the side-effect burden of older drugs makes their use

less preferred. Furthermore, some studies have shown that even a

modest increase in co-payments can have a significant impact on

patient use of prescription medications. The interested reader may

want to see Nelson et al. [1984] and Stuart and Zacker [1999]­Ed.)

Lack of communication. In the absence of a primary provider to

coordinate drug therapy, multiple doctors often prescribe

prescription drugs to the same patient (Colley and Lucas, 1993;

Rolland and Verdaris, 2003).

 

Decreased use of behavioral and social techniques. Primary care

physicians may never have been trained in psychosocial intervention

for patients suffering from psychiatric disorders and frequently they

do not have time to do them. Mintz et al. (2004) found that

psychiatrists practicing under utilization-management protocols of

managed care plans may also not have time to discuss behavioral

techniques with their patients (for example, encouraging proper sleep

hygiene in patients complaining of insomnia) and often instead

prescribe a medication. Once a medication is prescribed, the

psychiatrist may be reluctant to take their patient off the

medications, especially if they are doing well (Mintz et al., 2004).

 

 

Aging. Older patients take more medications in general, and this

situation is compounded if patients have a psychiatric illness

because adverse DDIs involving these medications can mimic

psychiatric symptoms. For example, geriatric patients frequently are

exposed to a number of highly anticholinergic drugs including

antispasmodics, tricyclic antidepressants (e.g., amitriptyline),

antihistamines, anti-Parkinson's drugs, antipsychotics and OTC cold

medicines, which if used in combination with other drugs can produce

delirium (Beresin, 1988; Cadieux, 1989). Antihypertensives are the

most likely to induce a depression in the elderly. Common offenders

are methyldopa (Aldomet, Amodopa), propranolol (Inderal), clonidine

(Catapress), guanethidine (Ismelin) and reserpine (Serpalan,

Serpasil) (Marsh, 1997). The akathisia of antipsychotic agents or the

selective serotonin reuptake inhibitors can resemble anxiety in the

elderly (Marsh, 1997). Other commonly prescribed drugs that can

produce anxiety symptoms in elderly patients are bronchodilators,

calcium-channel blockers, steroids, OTC preparations with adrenergic-

like agents and antihistaminic agents (Cadieux, 1989; Marsh, 1997).

Treatment Considerations

 

 

Polypharmacy is associated with increased health risks and costs

(Preskorn, 2005; Silkey et al., 2005), and can result in potential

pharmacokinetically and/or pharmacodynamically mediated DDIs. These,

in turn, set the stage for increased vulnerability to side effects,

increased number of prescription drugs used, compliance problems,

increased patient morbidity and mortality, and increased health care

costs. Clinicians must keep in mind a number of factors.

Potential DDIs. A DDI is a measurable change in magnitude, nature or

duration of the action of one drug as a result of the presence of

another drug (Khan and Preskorn, 2003). Drug-drug interactions are

not limited to or determined by therapeutic class. Individual patient

response to a given combination of drugs may be influenced by three

main factors: pharmacodynamics, pharmacokinetics and biological

variability between patients. Pharmacodynamics refers to a drug's

affinity for the site of action in the body, or its biochemical and

physiological effect and mechanism of action. Pharmackinetics refers

to the concentration of the drug at the site of action, or its action

in the body over a period of time, including the processes of

absorption, distribution, localization in tissues, biotransformation

and excretion. Biological variability refers to the fact that a given

drug may not produce identical effects in different patients and may

be influenced by such factors as the patient's genotype, age,

environment and the presence of disease. The presence of other drugs

can quantitatively or qualitatively alter the patient's response to a

medication by altering its pharmacodynamic or pharmacokinetic

properties. The clinician should weigh these factors carefully when

deciding on the treatment for their patient, including what drug to

prescribe and at what doses.

 

Intestinal motility. Drug absorption, distribution, metabolism and

excretion can be altered by changes in gastric pH or gastrointestinal

motility, including gastric emptying. Examples include pyloric

stenosis, gastroparesis secondary to diabetes mellitus, systemic

sclerosis, postvagotomy states, celiac disease, Whipple's disease,

Crohn's disease and therapy with anticholinergic agents. Also gastric

and intestinal surgeries and/or radiation will affect absorption of

drugs. Likewise, lower gastric acidity produced by proton pump

inhibitors like omeprazole (Prilosec), or by histamine H2 receptor

blockers like cimetidine (Tagamet), or by antacids can increase

absorption of weak bases such as tricyclic antidepressants,

benzodiazepines and some antipsychotics (Janicak et al., 2001; Khan

and Preskorn, 2003).

 

 

Liver disease. Most psychoactive medications require oxidative

metabolism as a necessary step in their eventual elimination, which

principally occurs in the liver. For this reason, diseases that lead

to hepatic insufficiency (like cirrhosis, viral infections, collagen

vascular diseases and metabolic disorders) can significantly reduce

the clearance of drugs. This effect can be compounded by the

concurrent use of multiple medications. For example, diazepam

(Valium) requires extensive biotransformation as a necessary step in

its elimination, but can persist in the body in case of liver disease

(Janicak et al., 2001). On the other hand, the clearance of drugs

that undergo only glucuronidation is not affected by even significant

liver damage. For example, all of the 3-hydroxybenzodiazepines

(clonazepam [Klonopin], lorazepam [Ativan], oxazepam [serax] and

temazepam [Restoril]) can be readily cleared by patients with normal

renal function (Kahn and Preskorn, 2003).

 

Liver diseases can alter plasma proteins that may significantly

affect free drug concentration and distribution and hence

concentration at the site of action, thus altering the magnitude of

the drug's effect. As the majority of psychiatric medications are

highly protein bound, protein binding can affect therapeutic drug

monitoring results.

 

Renal disease. While most drugs require oxidative metabolism to be

converted into polar metabolites as a necessary step in their

elimination, the final route of elimination is via the kidneys.

 

Classic examples of psychiatric drugs cleared principally, if not

exclusively, via the kidneys include lithium and gabapentin

(Neurontin), according to the PDR (2004). Slow dose titration and

careful monitoring of blood levels may be necessary when prescribing

medications dependent on renal filtration in patients with

significant renal disease.

 

Medications used for physical/medical conditions can also affect

psychiatric medications. For example, ritonavir (Norvir), a protease

inhibitor used in the treatment of HIV and AIDS, is a significant

inhibitor of CYP3A4. This means it can increase levels of certain

heterocyclic antidepressants (e.g., imipramine [Tofranil],

clomipramine [Anafranil] and amitriptyline), triazolobenzodiazepines

(e.g., alprazolam [Xanax] and triazolam [Halcion]), zolpidem

(Ambien), methadone and clozapine if taken concurrently (Flexner,

1998). Anti-migraine drugs (e.g., sumatriptan [imitrex], zolmitriptan

[Zomig] and rizatriptan [Maxalt]) are all 5-HT1 agonists and can

produce serotonin syndrome if used in combination with SSRIs like

sertraline (Zoloft), and monoamine oxidase inhibitors like phenelzine

(Nardil). Itraconazole (Sporanox), an antifungal agent, is also a

potent inhibitor of CYP3A4 and can increase levels of buspirone

(BuSpar) and haloperidol (Haldol) (Goldman, 2000). Rifampin (Rifadin,

Rimactane), an anti-tuberculosis agent, induces CYP3A4 and CYP1A2,

which can lead to decreased levels of clozapine, buspirone and

zaleplon (Sonata) when taken concurrently with any one of them

(Goldman, 2000).

 

Older patients.Elderly patients are particularly susceptible to the

effects of polypharmacy as aging is associated with diminution in the

functional capacity of many organ systems including the

cardiovascular system, the liver, the kidneys and the brain. The

latter includes mental slowing due the development of numerous

neuronal degenerative diseases, particularly including Alzheimer's

disease. For these reasons clinicians should be familiar with the

physical status of elderly patients before prescribing any

psychoactive medications.

 

 

Noncompliance. Noncompliance is common when the patient is taking one

medication and even more prevalent when several medications are taken

concurrently. Col et al. (1990) found that the complexity of

medication regimen (as reflected in greater number of doses per day

and greater number of both scheduled and as needed medications) was

directly related with an increased risk of noncompliance, contributed

to a more frequent need for hospitalization.

 

Fatal outcomes. Fatal drug reactions can result from the combined

ingestion of tranylcypromine (Parnatte) and imipramine, resulting in

hyperpyrexia, excruciating headache, palpitations, muscle rigidity,

opisthotonus, cyanosis and convulsions (Otte et al., 2003).

Combination of MAOIs and meperidine (Demerol) can result in

excitement, muscle rigidity, hyperpyrexia, flushing, sweating,

unconsciousness and respiratory depression (Meyer and Halfin, 1981;

Miller, 2004). Another fatal combination can be MAOIs and SSRIs,

e.g., fluoxetine (Prozac). It can result in the development of

serotonin syndrome with chills, confusion, sedation, exhaustion,

hyperpyrexia, tachycardia, muscle rigidity and coma (Feighner et al.,

1990). Pimozide (Orap) is partly metabolized through CYP3A and

clarithromycin (Biaxin) substantially inhibits this enzyme, resulting

in serious cardiotoxicity.

 

Health care cost. Increased costs can result from the costs of each

individual drug in the patient's regimen and from DDIs. These DDIs

can present in a multitude of ways ranging from nuisance to more

serious adverse effects, which can mimic the development of a new

disease or the worsening of an existing disease. DDIs can of course

result in lawsuits, which further increase health care costs. Johnson

and Bootman (1995) found that morbidity and mortality related to drug

therapy in ambulatory patients in the United States costs $76.6

billion annually.

 

Although prescription drugs comprise only one-tenth of total national

medical expenses, they remain the fastest growing expenditure

(National Center for Health Statistics, 2004). In 2002, the overall

cost of prescription medications and medical supplies rose above 5%,

but increased use of prescription drugs pushed total expenditure for

prescription medications up 15.3%. The United States spent 14.9% of

its gross domestic product on health care in 2002, up from 14.1% in

2001. Only two other countries, Switzerland and Germany, spent as

much as 11% of their gross domestic produce in health care in 2001.

 

Conclusion

Patients with psychiatric illnesses may be at higher risk for the

development of certain medical problems because of the physiologic

derangements of their psychiatric conditions, or as a result of the

somatic treatment used to help them, hence at risk for drug-drug

reactions from taking several medications concurrently.

 

Psychopharmacological treatment of psychiatric disorders can be

successfully and safely accomplished in the medically ill taking

multiple medications when the psychiatrist is cognizant of potential

difficulties stemming from both their different medical illnesses and

the medications the patient is taking for the treatments of those

illnesses by following the principles outlined in (Table 3). Each

patient should be assessed for potential disease-related

pharmacokinetic and pharmacodynamic changes altering drug

distribution, metabolism and clearance, as well as possible drug

interactions and vulnerability to the side effects.

 

 

As the use of multiple drugs increases and drug expenditures rise,

trade-offs between the cost and benefits of medications are becoming

major clinical and policy issues. As a result of all of these

variables, there is a growing and urgent need for further research to

evaluate the potential risks associated with polypharmacy, such as

developing drug classifications or groupings based on pharmacodynamic

and pharmacokinetic characteristics. Research can identify the most

prevalent drug regimens and evaluate their potential to interact.

 

There is a clear need to implement online drug screening or

computerized drug alert systems. Expert consensus guidelines

regarding specific combinations can be developed.

 

Dr. Khan is assistant professor in the department of psychiatry and

behavioral sciences at the University of Kansas School of Medicine in

Wichita and director of the resident outpatient clinic.

 

Dr. Preskorn is professor and chair for the department of psychiatry

and behavioral sciences at the University of Kansas School of

Medicine in Wichita. He is also CEO and president of the Clinical

Research Institute, which is affiliated with the University of Kansas

School of Medicine.

 

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Suggested Reading

Levy RH, Thummel KE, Trager WF et al. (2000), Metabolic Drug

Interactions. Philadelphia: Lippincott Williams & Wilkins.