Side Effects Of Anti Psychotic Medications

Side Effects of Antipsychotic Medications: Understanding the Variables Antipsychotics are associated with an assortment of side effects, many of which can seriously affect a patient's physical health and quality of life. Side effects occur because neurotransmitters are affected by drugs, drug half-life, P450 liver enzyme system metabolism, and percentage of the drug bound to a given receptor. By understanding these concepts, clinicians can better understand why and how side effects occur, and also predict to some degree in which patients side effects will occur. The more factors involved in a given patient, the more likelihood side effects will occur. It is important to appreciate that while not all side effects are serious, some can be fatal

Neurotransmitter Involvement in Side Effects The tranquilizing effects of antipsychotic agents were originally discovered in the late 1940s when potent antihistamines were developed to alleviate postoperative shock. The initial antipsychotic effect was thought to be attributed to antihistaminic qualities. However, the high doses of chlorpromazine initially used to prevent postoperative shock caused numerous severe and sometimes permanently disabling multisystem side effects when used repeatedly.[1] Patients given doses in the range of 2000 mg daily started experiencing severe endocrine and neuromuscular side effects similar to those of Parkinson's disease as well as acute and tardive dystonic reactions and emotional flattening. The discovery in the 1960s of L-dopa, used to treat the dopamine deficits of Parkinson's disease, led to the serendipitous understanding of the relationships between dopamine blockade and the creation of antipsychotic effects, and provided the first window into understanding side effects. As a deductive

conclusion, the role of dopamine excess as etiologic in psychosis symptoms led to an explosion of available phenothiazine-related antipsychotic drugs over the next 30 years. These original phenothiazine-type drugs are referred to as typical or first-generation antipsychotics. Drugs in this category typically have side effects related to excessive blocking of 1 or more of the 4 major dopamine tracts in the brain, resulting in primarily neuromuscular and neuroendocrine side effects (Table 1). Eventually 2 major dopamine subsystems were identified: D1 and D2. The D2 system is the primary system involved in treating psychosis. Table 1. Dopamine Receptor Families

GABA = gamma aminobutyric acid Sources: Kandel ER, Schwartz JH, Jessell T M. Principles of Neural Science.4th ed. New York: McGraw-Hill; 2000 Stahl S. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. New York: Cambridge University Press; 2008 In 1961, clozapine was developed as 1 of nearly 2000 tricyclic compounds. It was tested in 1966 in patients with schizophrenia and was noted to have good antipsychotic effects and an absence of the typical tardive dyskinesia and Parkinsonian-like side effects of the phenothiazine-type drugs. It was thus referred to as an "atypical" antipsychotic. Clozapine was originally known to affect the levels of multiple neurotransmitters including epinephrine, norepinephrine, acetylcholine, and histamine, with a minimal effect on the nigrostriatal dopamine tracts.[1] Clozapine was pulled from the market briefly because of several deaths resulting from agranulocytosis, but it was released again to be used when all other treatments had failed and with the caveat that patients have a complete white blood cell count drawn monthly while taking the medication. In the late 1950s, the development and study of lysergic acid led to the suggestion that serotonin had a role in psychosis. After it was discovered that clozapine had a significant serotonin blocking action (antagonism) and much less blocking of dopamine, federal and industry research into brain function and pharmacologic therapies exploded. By 2000, the list of approved atypical or secondgeneration antipsychotics, also referred to as serotonin/dopamine antagonists (blockers), grew to include risperidone, olanzapine, quetiapine, and ziprasidone. Their effects on multiple neurotransmitters, however, produced a distinct set of side effects, including weight gain, diabetes mellitus, dyslipidemias, and sexual dysfunction. In 2002, the first antipsychotic to not fully block dopamine, aripiprazole, was approved by the US Food and Drug Administration. In addition to selective antagonism of various neurotransmitters, it has a partial agonist effect on dopamine 2 receptors. In May 2009, iloperidone, with a pharmacologic profile similar to that of risperidone, was approved. Because each atypical antipsychotic exerts various antagonist or reuptake blocking actions on multiple neurotransmitters, an understanding of the functions of the major neurotransmitters is helpful in teaching patients about both the desired therapeutic and side effect potentials of a given drug (Table 2).

Table 2. Selected Neurotransmitters

Adapted from Stahl S. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambridge University Press; 2008

Currently Available Antipsychotic Drugs A complete listing of currently available antipsychotic medications is found in Table 3. As a class, these drugs are effective in helping manage the many troublesome symptoms of psychosis, yet there is a great variation in the response and side effect profile that individual patients experience. Additionally, with the exception of indications for the use of risperidone and aripiprazole, this category of drugs is not yet approved for children and adolescents by the US Food and Drug Administration. There is also a black box warning for the entire category of drugs for use in the elderly. Table 3. Antipsychotic Medications

Adapted from: Moller M. Psychopharmacology. In: Mohr W, ed. Psychiatric-Mental Health Nursing: Evidenced Based Concepts, Skills, and Practices. 7th ed. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins; 2009:Chapter 16

What Are Antipsychotic Medication Side Effects? Side effects are problems that occur when treatment goes beyond the desired effect, such as the patient sleeping for 24 hours when only mild sedation is desired, or problems that occur in addition to the desired therapeutic effect such as blocking dopamine transmission to stabilize acute psychosis that culminates in creating a Parkinsonian-type tremor. Unfortunately, antipsychotic medications are not site-specific like an antibiotic developed to combat a specific bacterium. Because of the miniscule size and nature of the structure of the neuron and the fact that neural networks are multifunctional, each neurotransmission can affect many different neurons in a process referred to as a "chemical puff".[2] The resulting effect is a "dusting" and thereby unintentional interruption of normal functioning of adjacent neurons, creating side effects. To further complicate the situation, there is a reciprocal relationship between dopamine and acetylcholine in the sympathetic and parasympathetic (cholinergic) nervous systems. When dopamine is blocked, acetylcholine levels increase and cause very uncomfortable potentially widespread parasympathetic side effects such as dry mouth, blurred vision, constipation, urinary retention, tachycardia, mydriasis, and even paralytic ileus. Additionally, there is an inverse relationship in the sympathetic (adrenergic) nervous system between dopamine and serotonin. If dopamine is blocked, serotonin increases, resulting in both therapeutic effects and side effects. Increasing serotonin can block dopamine in selected brain regions -- again with both therapeutic and side effects. Some antipsychotic medications block serotonin in certain brain regions with the net result of increasing dopamine where there are few dopamine transporter neurons. The net result of these actions on dopamine and serotonin, however, is to decrease psychosis. This is a very delicate balancing act, one that is often difficult to predict. The prescriber and the patient have to discuss the risk/benefit ratio of therapeutic and side effect consequences and arrive at a mutual decision. The possibility of the occurrence of widespread effects on multiple body systems must be discussed with patients (Table 4). The following side effects must be reported immediately: shuffling walk; stiffness of arms and/or legs; twitching or jerky movements

especially of the head, face, mouth, or neck; restlessness or inability to sit still; trembling and/or shaking of hands and fingers; difficulty swallowing; vision problems; muscle spasms; lack of coordination; weakness; difficulty urinating; menstrual changes; rash, fever, yellow skin, sore throat, or hives; unusual bleeding or bruising; face or mouth movements that occur after a few months; drooling; and involuntary movements of the tongue. There are, however, distinct differences between the individual drugs ( Table 5 ). The Glasgow antipsychotic side effect scale is a useful tool for helping patients track their symptoms over time.[3] Table 4. Possible Systemic Side Effects of Antipsychotic Medications

Adapted from: Moller M. Psychopharmacology. In: Mohr W, ed. Psychiatric-Mental Health Nursing: Evidenced Based Concepts, Skills, and Practices. 7th ed. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins; 2009.

The Role of Receptor Binding in Antipsychotic Side Effects Because major neurotransmitter systems parallel each other in the same circuits, histamine, acetylcholine, alpha- and beta-adrenergic, and muscarinic receptors are also often recipients of unwanted blockade and side effects are created (Table 6). Side effects occur based on the specific receptors affected by the various drugs. However, the degree of blockade (receptor occupancy) and length of time a drug is on the receptor are what actually determine the degree of the side effect. There is also a close correlation to the half-life of a drug and the length of drug occupancy on a given receptor.[4] The level of receptor occupancy is called Ki binding. The closer the Ki is to 1, the higher

the affinity of the drug for a given receptor (Table 7). For example, a patient on haloperidol with a Dopamine 2 receptor Ki value of 0.7 would be much more likely to experience extrapyramidal side effects than a patient on quetiapine that has a 160 Ki value. In looking at weight gain, it is predictable that olanzapine will have the highest likelihood because of a muscarinic Ki value of 2 when compared to > 1000 for both aripiprazole and ziprasidone and > 10,000 for risperidone. It is important to realize that tremendous variations can occur in individual patients. Table 6. Effects of Receptor Blockade

Adapted from: Moller M. Psychopharmacology. In: Mohr W, ed. Psychiatric-Mental Health Nursing: Evidenced Based Concepts, Skills, and Practices. 7th ed. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins; 2009:Chapter 16 Table 7 gives some approximations of Ki values, although there is tremendous variability in ranges reported for each. The National Institute of Mental Health's Psychoactive Drug Screening Program provides an online database of receptor values at http://pdsp.med.unc/edu/index.htm. Table 7. Binding of Antipsychotic Medications to Specific Receptors

Sources: Preskorn S. Classification of neuropsychiatric medications by principal mechanism of action: a meaningful way to anticipate pharmacodynamically mediated drug interactions. J Psychiatr Pract. 2003;9: 376-384 (chart adapted and used with permission); Farah A. Atypicality of antipsychotics. Primary Care Companion. J Clin Psychiatry. 2005;7:268-274; Goldstein JM. The new generation of antipsychotic drugs: how atypical are they? Int J Neuropsychopharmacol. 2003;3:339-349; Kalkman HO, Subramanian N, Hoyer D. Extended radioligand binding profile of iloperidone: a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist for the management of psychotic disorders. Neuropsychopharmacology. 2001;25:904-914

The Role of the P450 System in Antipsychotic Medication Side Effects The general rule is that any person can experience any side effect at any time from any medication, but the likelihood varies tremendously. Patients who have no general health problems, are not overweight, eat a healthy diet, get plenty of exercise, and are not elderly face fewer risks. The fewer medications a person takes, the lower the likelihood of side effects. The level of liver metabolic enzymes plays a strong part in this aspect of evaluating the potential for side effects. Most medications require metabolism by specific liver enzymes, referred to as the cytochrome P450 enzyme system. If a patient takes several drugs and drug A blocks a given liver enzyme system and drug B requires that enzyme for metabolism, then drug B will continue to exert its effect, sometimes for days. Conversely, if drug A induces a given liver enzyme system and drug B requires that enzyme for metabolism the effect of drug B will be greatly diminished. More than 90% of human drug oxidation is controlled by 6 CYP isoenzymes: 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. The 2D6 system metabolizes at least 30% of common medications including selective serotonin reuptake inhibitors, pain relievers, beta-blockers, and many of the antipsychotic drugs. However, the 3A4 system metabolizes at least 50% of all other common medications including antihistamines, antibiotics, lipid lower medications, protease inhibitors, antifungals, and antipsychotics. The 3A4 also often serves as the second isoenzyme system or "safety net" involved in drug metabolism. Except for trazodone, the following psychotropics are metabolized by another isoenzyme in addition to CYP3A4: • Antidepressants: imipramine, paroxetine, sertraline; • Antipsychotics: aripiprazole, clozapine, haloperidol, iloperidone, olanzapine, pimozide, risperidone; and • Benzodiazepines: most except for lorazepam, oxazepam, and temazepam. Many antidepressants and antipsychotic medications are metabolized by either CYP2C19 or CYP2D6. This often results in clinically significant drug-drug interactions when treating an individual (eg, psychotic depression) with both an antidepressant and an antipsychotic. Likewise, concerns about toxicity arise when co-prescribing both a tricyclic antidepressant and a selective serotonin reuptake inhibitor (an accepted practice for treatment-resistant depression). Table 8 depicts the metabolic pathways for the atypical antipsychotics. Most antipsychotics actually inhibit their own metabolism, which also makes it difficult to predict response and the actual number of milligrams a given patient will require. The identification of cruciferous vegetables, arial hydrocarbons, caffeine, and St. John's Wort as enzyme inducers and grapefruit juice as an enzyme inhibitor adds to the complexity of both patient assessment and education related to watching for side effects created by foods, smoke, caffeine,

and herbal supplements. Table 8. Metabolic Pathways for Atypical Antipsychotics

TCAs = tricyclic antidepressants Sources: Cozza KL, Armstrong SC, Osterheld JR. Concise Guide to Drug Interaction Principles for Medical Practice. 2nd ed. Washington DC: American Psychiatric Publishing, Inc; 2003; Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management. Freeland, Washington: H&H Publications; 2008; Indiana University School of Medicine Division of Clinical Pharmacy. Drug-drug interactions. Available at: http://www.medicine.iupui.edu/clinpharm/DDIs/table.asp Accessed May 17, 2009 Variations in Metabolism CYP2C19 and CYP2D6 are bimodally distributed in the population allowing classification of individuals as either extensive or poor metabolizers. This is referred to as genetic polymorphism. Tremendous research is going on to develop quick office-based tests to determine who may be at risk for these significant metabolic variations.[5,6] Adverse effects and/or toxicity from high levels of unmetabolized drugs are more likely to develop in poor metabolizers. Approximately 7% of whites and upward of 33% of Asians and African Americans are poor metabolizers.[7] Extensive metabolizers are more likely to be nonresponders at the usual therapeutic dose range. It is now possible through genotyping to predict up to 90% of individuals who will be poor metabolizers for CYP2C19 and CYP2D6. Summary The purpose of this article was to acquaint and alert the clinician to the complexities and oftensubtle nuances behind drug side effects. The prevention and early detection of antipsychotic side effects requires both art and science. The art of predicting, detecting, and managing side effects includes a thorough assessment of lifestyle including the use of alcohol and smoking, dietary and beverage choices, use of herbal supplements, and exercise and sleep patterns. The science of predicting, detecting, and managing side effects requires knowledge of the pharmacokinetic and pharmacologic action of prescribed drugs in combination with a thorough understanding of comorbid medical conditions and the medications used to treat them. Clinicians are encouraged to consult with a pharmacist whenever a question of a potential drug-drug, drug-disease, and/or drug-diet interaction is suspected. By using the charts and tables in this article, clinicians will be better informed to educate the patient in a variety of interventions that will diminish the potential for medication side effects, promote better pharmacologic efficacy from prescribed medications, and improve the overall quality of life.