pharmacology 2 section 1
pharmacology 2 section 1 NURS 406 001
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Nursing 406 Glen E. Farr, Pharm.D. SECTION #1 PSYCHOACTIVE MEDICATIONS Schizophrenia, Mood Disorders, Sleep Disorders, Anxiety Disorders, AttentionDeficit Hyperactivity Disorder, Obesity, Alzheimer’s Disease, Parkinson’s Disease, and Seizure Disorders General Principles of Mental Health Science has made great strides in understanding the neurobiology of these disorders and in the psychopharmacologic and psychosocial treatment of those with disabling mental disorders. As health professionals, we need to understand that psychiatric disorders or mental illness and physical illness have much in common, i.e., both may involve an excess or a deficiency in one or more chemical mediators. o For example, schizophrenia seems to be associated with an excessive amount of dopamine, whereas depression is linked to a lack of 5 hydroxytriptamine (serotonin). Always keep in mind in evaluating psychiatric symptoms that many drugs can cause these type symptoms. o Psychiatric symptoms that emerge during drug treatment may also be due to the underlying illness, previously unrecognized psychopathology, or psychosocial factors. The withdrawal of some drugs can cause symptoms such as anxiety, psychosis, delirium, agitation or depression. The Medical Letter, December 15/29, 2008 has a good review of this issue: “Drugs That May Cause Psychiatric Symptoms.” Drug classes cited by The Medical Letter include: o Amphetaminelike drugs o Corticosteroids o Anabolic steroids o Dopamine agonists o ACE inhibitors o Estrogens o Anticholinergics o Fluoroquinolone antibiotics o Antidepressants, tricyclic o Antihistamines, H1 and H o Antiepileptics 2 blockers o Barbiturates o Monoamine oxidase (MAO) o Benzodiazepines inhibitors o ßblockers o Opioids o Calcium channel blockers o Cephalosporins Psychoactive Medications 1 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Procaine derivatives o Salicylates (procainamide, procaine o SSRIs penicillin G) o Sulfonamides Psychoactive Medications Section #1 2 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard criteria for diagnosing mental disorders. o o o o DSM5 Questioned o Ann Intern Med. Published online May 17, 2013 o At the launch of the 5 edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM5), Allen Frances, MD, chair of the DSMIV Task Force and one of the new manual's staunchest critics, is advising physicians to use the DSM5 "cautiously, if at all." o o "Psychiatric diagnosis is facing a renewed crisis of confidence caused by diagnostic inflation," he writes in a new commentary published online May 17, 2013 in the Annals of Internal Medicine. o Unlike the DSMIV, which held the line against diagnostic inflation, he states, "The DSM5, the recently published fifth edition of the diagnostic manual, ignored this risk and introduced several highprevalence diagnoses at the fuzzy boundary with normality." Examples: o o Normal grief may be misdiagnosed as major depressive disorder, and the forgetfulness of old age may now be interpreted as mild neurocognitive disorder. o o Other changes in the DSM5 will allow clinicians to label a child with temper tantrums as having disruptive mood dysregulation disorder, and overeating can now be called binge eating disorder. o o Premenstrual Dysphoric Disorder (PMDD) is classified as a “mental illness.” o Several Hollywood films have been made that provide a good example of the clinical manifestations of some of these disorders. o Schizophrenia: A Beautiful Mind Psychoactive Medications 3 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. General mental illness: One Flew Over the Cuckoo’s Nest. This movie included “Nurse Ratched.” ObsessiveCompulsive Disorder (OCD): As Good As It Gets Psychoactive Medications Section #1 4 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Schizophrenia o o o Schizophrenia is a debilitating mental illness that affects ~1% of the population in all cultures. If affects equal numbers of men and women, but the onset is often later in women than in men. There is a 10% lifetime risk of suicide in clients with schizophrenia. o DSM5 states that schizophrenia is characterized by delusions, hallucinations, disorganized speech and behavior, and other symptoms that cause social or occupational dysfunction. For a diagnosis, symptoms must have been present for six months and include at least one month of active symptoms. o DSM5 raises the symptom threshold, requiring that an individual exhibit at least two of the specified symptoms. o o In the manual’s previous editions, that threshold was one. Additionally, the diagnostic criteria no longer identify subtypes. o Characteristic symptoms o o Two (or more) of the following, each present for a significant portion of time during a 1month period (or less if successfully treated). o Delusions Hallucinations Disorganized speech Grossly abnormal psychomotor behavior, such as catatonia Negative symptoms, i.e., restricted affect or avolition o Psychoactive Medications 5 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Antipsychotic Agents (Neuroleptics or Psychotropic Agents) o o History o The first drugs used to treat psychosis were the phenothiazines in the early 1950s in Paris, France. The phenothiazine chlorpromazine (Thorazine®) was introduced into the U.S. in 1954. It was considered a major therapeutic advancement and continues to be used today to treat psychotic disorders such as schizophrenia and bipolar disorder. o In the 1990s the “atypical” antipsychotics were introduced that allowed effective treatment with fewer adverse effects. o o Mechanism of Action o Schizophrenia is thought to be due, at least in part, to overactive dopaminergic pathways, i.e., excessive dopamine levels in the brain. These agents decrease or block dopamine’s effects. o Dopamine is associated with feelings of pleasure and wellbeing—it is the neurotransmitter that is associated with all “addicting” agents, e.g., alcohol, narcotics. These agents dopamine. Thus, these agents are not generally subject to abuse and are not controlled substances. o “Typical” antipsychotics (e.g., chlorpromazine—Thorazine®) block postsynaptic dopamine receptors in the mesolimbic system and increase dopamine turnover by blockade of the 2 somatodendritic autoreceptor. This decrease in dopamine neurotransmission has been correlated to the antipsychotic effects of the phenothiazines. o Psychoactive Medications 6 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o This D 2 blockade is also responsible for their adverse extrapyramidal effects (EPS) leading to tardive dyskinesia (TD). o o It is also responsible for their beneficial antiemetic effects and their use in preventing and treating nausea and vomiting and relief of intractable hiccups. o The newer “atypical” or 2 generation antipsychotic drugs are mixed neuroreceptor antagonists (low affinity dopamine 2 receptor blockade) and high affinity for antagonist effect on 52A serotonin receptors. o The “atypical” agents are reportedly less likely to cause EPS, TD, and hyperprolactinemia. o Both the “typical” and the “atypical” agents innervate several receptors to varying degrees which cause multiple effects, including: o o Recept o Expected Effects or Blocka de o Causes EPS o Dopami prolactin levels—causes gynecomastia ne D2 Antiemetic effect intractable hiccups o Mitigation of some EPS o 5HT2 Anxiety and insomnia o H1 Drowsiness in appetite and weight o Alpha Orthostatic hypotension and dizziness 1 Reflex tachycardia adrener gic o Dry mouth o Muscar Constipation inic Blurred vision (Cholin Urinary retention ergic) o o First Generation “Typical Antipsychotics” o Dopamine D Antagonists Psychoactive Medications 7 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Phenothiazines o o 1) chlorpromazine (Thorazine®)—also has many other uses, e.g., hiccups, nausea. o 2) thioridazine (Mellaril®)—Black box warning for prolonging the QTc resulting in torsades de pointes arrhythmias and sudden death. Rarely used. o 3) trifluoperazine (Stelazine®)—high potency and has the most EPS. o 4) fluphenazine decanoate (Prolixin®)—longacting form for injection, effects last o 34 weeks; helps ensure compliance. o o NonPhenothiazines—Uses similar to phenothiazines o o 1) thiothixene (Navane®) o 2) loxapine (Loxitane®) o o Butyrophenones o o 1) haloperidol (Haldol®—short acting and Haldol Decanoate®—long acting). Like the fluphenazine decanoate, the longacting form helps ensure ahderence. Psychoactive Medications 8 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Extrapyramidal Symptoms [EPS] of the Antipsychotic Agents o Psychoactive Medications 9 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o o Akathisia A sensation of motor restlessness and psychic agitation o (pacing, rocking, and inability to sit or stand in one place for extended periods of time). Akathisia can aggression. Develops within days to weeks after initiating antipsychotic therapy. Least understood of EPS. Adrenergic system may be involved since blockers may be helpful. Dopamine cholinergic imbalance may not be directly involved because of the poor response to antiparkinsonian medications. o o o Parkinsonian Bradykinesia, apathy, social withdrawal, expressionless symptoms faces, flattened affect, “pillrolling” movement. o o o Dystonia Reversible dystonic reaction (acute muscle spasm), e.g., oculogyric crisis, that can sometimes be treated/prevented with Artane®, Cogentin® or Benadryl®. o o o Tardive A syndrome of persistent and involuntary hyperkinetic Dyskinesia abnormal movements. Exact cause is unknown. [TD] Occurs in ~ 1025% of clients taking traditional o antipsychotics longterm. Characterized by buccolingualmasticatory movements, i.e., repetitive, uncontrolled movements of the tongue (chewing, protrusion), face (blinking, grimacing), lips (smacking, pursing), neck & trunk (torsion, torticollis), and limbs (toetapping, pillrolling). Symptoms fluctuate daily and often remit during sleep. May persist for years after antipsychotic drugs are discontinued. An in antipsychotic dose can clinically mask the symptoms of TD and a in dose can unmask TD; therefore dopamine probably has at least a partial role in the etiology. To help diagnose TD, some recommend a reduction in dose or withdrawal (“drug holiday”) of the neuroleptic agent since symptoms generally appear quickly and certainly within 4 weeks. Reversible in some rare cases. Large doses of vitamin E or B6 have been tried for treatment, with limited success. Potential for developing TD is lessened, but not eliminated, by using the atypical agents. o Section #1ve Medications 10 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Psychoactive Medications 11 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. Other Significant Common Side Effects of the Antipsychotic Agents o o Sexual dysfunction (Impotence) o o Alpha ()adrenergic blockade causes orthostatic hypotension o o Anticholinergic effects o o Temperature regulation abnormalities (poikilothermia) o o Increased prolactin levels causing amenorrhea, gynecomastia and galactorrhea (Hyperprolactinemia) o o Tranquilization. Often used parenterally, e.g., haloperidol 2.5 – 10 mg IM or IV, for rapid tranquilization in situations such as combative delirium. o o Cardiac toxicity. Many studies have found at least a doubling in the risk of sudden cardiac death. o o Neuroleptic Malignant Syndrome (NMS) o A rare (<1%), rapidly developing, occasionally lethal (~10%) reaction thought to be caused by an acute reduction in dopamine activity as a result of druginduced dopamine blockade. o It is characterized by rigidity, hyperthermia, tachycardia, hypertension, diaphoresis, incontinence and confusion. o Treat with the skeletal muscle blocker dantrolene (Dantrium®, Ryanodex®) or the dopamine agonist bromocriptine (Parlodel®) o Psychoactive Medications 12 Section #1 Fall Semester, 2016 Glen E. Farr, Pharm.D. Black Box for use in Dementia o o The FDA requires manufacturers of all antipsychotic drugs to warn about an increased risk of death associated with the offlabel use of these drugs to treat behavioral problems in older people with dementia. o o o Increased Mortality in Elderly Patients with DementiaRelated Psychosis o o Elderly patients with dementiarelated psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebocontrolled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drugtreated patients of between 1.6 to 1.7 times that seen in placebotreated patients. Over the course of a typical 10 week controlled trial, the rate of death in drugtreated patients was about 4.5% compared to a rate of about 2.5% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. o o o Clinical Comparison of Traditional (Typical) Antipsychotic Agents o (You are not responsible for specific number of pluses, but consider that different drugs cause different effects.) o o o o o o o o Agen o o Ant t o o o icho U S line rgic effe cts o o Chlorp o o o o o ++ Psychoactive Medications 13 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. romazi 3 + + ne o (Thora zine ) o Thiori o o o o o +++ dazine 1 + + (Mella ril ) o Mesori o o o o o +++ dazine 3 + + (Seren til ) o Perphe o o o o o + nazine 1 + + o (Trilaf on , Etrafo n ) o Prochl o o o o o + orpera 1 + + zine (Comp azine ) o Fluphe o o o o o + nazine 0 + + (Prolix in ) o Trifluo o o o o o + perazi 2 + + ne (Stelaz ine ) o Halop o o o o o + eridol 1 + + (Haldo l ) o Thioth o o o o o + ixene 8 + + (Nava ne ) o Psychoactive Medications 14 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o “Atypical” Antipsychotics o Low affinity D 2 Antagonists and High Affinity 5HT A2Aagonists o “SerotoninDopamine Receptor Antagonists” o Since the advent of the second generation, atypical antipsychotic medications, therapeutic choices for the treatment of psychosis have expanded rapidly. Most of these agents are also approved for the manic phase of bipolar disease. o Unlike the firstgeneration typical agents, the atypical agents are more complex and influence multiple neurotransmitters in diverse neuroanatomic locations. o They initially represented an advance in the treatment of psychosis—not so much from the efficacy standpoint—but from the safety standpoint, primarily lack of EPS. However the metabolic side effects (weight gain, diabetes, metabolic syndrome) may outweigh the lack of EPS in some cases. o The Medical Letter, April 25, 2016 states: o o With the exception of clozapine (Clozaril®), secondgeneration antipsychotics are not clearly more effective than firstgeneration antipsychotics for treatment of schizophrenia, but in usual doses they are much less likely to cause tardive dyskinesia. o o Clozapine is usually reserved for refractory disease because of its potential for serious toxicity, including seizures and agranulocytosis. Olanzapine (Zyprexa®) may be the most effective of the other secondgeneration antipsychotics, but it is also the most likely to cause metabolic adverse effects. o o Patients who do not respond to one antipsychotic may respond to another. Psychoactive Medications 15 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Longacting injectable formulations may be useful when adherence is a problem. o o o o Clozapine (Clozaril®, Fazaclo®) o o The first “atypical” introduced. It is probably the most effective antipsychotic agent, but because of its potential for neutropenia, it is usually reserved for refractory patients. o It causes little or no EPS, but has a risk of agranulocytosis, seizures and myocarditis. o Distributed via a monitored program that requires certification and authorization due to required lab work for a neutrophil count. A single new registry and REMS established in 2015 streamlines the use of clozapine. o Olanzapine (Zyprexa®, Zyprexa Zydis an orally disintegrating tablet, and Zyprexa Relprevv® a longacting injection of olanzapine pamoate) o o Chemically similar to clozapine, but no agranulocytosis reported. o Many clients gain weight and many develop type 2 diabetes: 30% gain more than 20 pounds. o Combined with fluoxetine as Symbyax® to treat bipolar disease. o 2016 FDA waring that this agent can cause Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). o 2013 report from the FDA of 2 unexplained deaths of patients who received an IM injection of Zyprexa Relprevv®. o Psychoactive Medications 16 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. Under a risk evaluation and mitigation strategy (REMS), patients are required to receive the olanzapine pamoate injection at a certified healthcare facility, to be continuously monitored for at least 3 hours after an injection, and to be accompanied home from the facility. The drug's label contains warnings about the risk for postinjection delirium sedation syndrome (PDSS), a serious condition in which the drug enters the blood too fast after an intramuscular injection, causing greatly elevated blood levels with marked sedation (possibly including coma) and/or delirium. o Risperidone (Risperdal® tablets; Risperdal Consta® long acting injection; Risperdal MTabs® “melt in your mouth”) o o At higher doses (>3 mg/day), it causes more EPS than the other atypical agents. o Approved as the first medication for use in children and adolescents with autism. Reports of gynecomastia in children o Trivial note: This is the drug Dr. John Nash started taking in 1994 in the movie “A Beautiful Mind.” o o o Quetiapine (Seroquel®) o o Similar side effect profile to the other “atypicals” that contain a dibenzothiazepine ring (clozapine and olanzapine). o There are recent reports that some people are abusing quetiapine (Seroquel®) for its sedating and antianxiety effects, especially among jail inmates or substance abusers. Some people claim to have psychiatric symptoms to get it. Others with legitimate prescriptions skip doses and sell them. It's known on the street as "quell" or "baby heroin." It is not a controlled substance. o Ziprasidone (Geodon ) o o Concern about potential arrhythmias—prolonged QT interval in higher doses. o o 2014 FDA warning on Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) which may start as a rash and spread all over. FDA warns that patients on the drug who have a fever with a rash and/or swollen lymph glands should seek urgent care. o Psychoactive Medications 17 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. Aripiprazole (Abilify®) o o Reportedly has better efficacy and less side effects, (e.g., less weight gain, no cardiac toxicity), than the other atypical agents, but comparative studies are lacking. o o In May 2016, the FDA warned of impulse control problems associated with the aripiprazole (Abilify®). o The drug has been associated with compulsive gambling, eating, shopping, and sexual activity. According to FDA, these urges reportedly cease when the drug is discontinued or the dose is reduced. The FDA also notes that although these effects are rare, they have the potential to cause harm to patients and others if they go unrecognized. o o 2013 approval of a longacting, onceamonth injectable aripiprazole (Abilify Maintena®). 2015 approval of a generic equivalent of aripiprazole (Aristada®) as an every 4 to 6week injection. o o o o Aripiprazole has a slightly different mechanism of action than the other atypical antipsychotics. Some call it a 'dopamine system stabilizer' (DSS). o Unlike other antipsychotics which are dopamine antagonists, aripiprazole is a potent partial agonist of dopamine2D receptors (“adjusting dopamine instead of completely blocking it”). o Paliperidone (Invega®, Invega Sustenna® a monthly longacting injection, Invega Trinza® a 3month longacting injection) o The oral form is a 24hour extendedrelease formulation marketed basically as a longacting risperidone (Risperdal®) o o It is the active metabolite of risperidone. o Psychoactive Medications 18 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Iloperidone (Fanapt®) o Is being promoted as better tolerated than some of the others. o It can prolong the QT interval like Geodon®. Asenapine (Saphris®) o It is a sublingual tablet that is inactive if swallowed. o Clients who may “cheek” other antipsychotics to avoid therapy; can just swallow this one. o o FDA warning about possible severe allergic reactions, including anaphylaxis and angioedema, to this agent. o o o Lurasidone (Latuda®) o th o Approved 2010, this is the 10 atypical. Psychoactive Medications 19 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Marketing claim is “less metabolic effects and onceaday dosing.” o Brexpiprazole (Rexulti®) o In July 2015, the FDA approved brexpiprazole (Rexulti®) for the treatment of adults with schizophrenia. In addition, the drug was approved as an addon treatment to an antidepressant medication for adults with major depressive disorder (MDD). o o The Medical Letter, August 2015 concluded: “Brexpiprazole (Rexulti®) was more effective than placebo in shortterm trials in reducing symptoms of schizophrenia and depression. It appears to be generally well tolerated with relatively mild metabolic adverse effects, but direct comparisons with other antipsychotics are lacking, and its longterm safety is unknown. There is no reason to prescribe brexpiprazole over generic aripiprazole, which has a much longer record of efficacy and safety and should soon cost much less.” o Cariprazine (Vraylar®) o o Approved in 2015 for the treatment of schizophrenia and bipolar disorder in adults. o o The drug, along with all other FDAapproved drugs for the treatment of schizophrenia and bipolar disorder, carries a boxed warning alerting health care professionals to the higher risk of death linked to the use of these drugs in older adults with dementiarelated psychosis; none of the drugs in this class are approved to treat these patients. o o Common adverse events include tremor, slurred speech, and involuntary muscle movements. o Psychoactive Medications 20 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Efficacy o Treatment Guidelines from The Medical Letter, May, 2010 o o Atypical Antipsychotic & o Efficacy Daily Dose o Aripiprazole (Abilify®) 1030 mg o ++ o Clozapine (Clozaril®) 25900 mg o ++++ o Olanzapine (Zyprexa®) 3.520 o +++ mg o Quetiapine (Seroquel®) 150800 o ++ mg o Risperidone (Risperdal®) 0.56 o +++ mg o Ziprasidone (Geodon®) 40160 o ++ mg o o Adverse Effects o The Medical Letter, April 25, 2016 o (You are not responsible for specific number of pluses, but consider that different drugs cause different effects.) o o o Monitoring Parameters o American Family Physician, March 1, 2010 o (You are not responsible for specifics, but remember that monitoring is important) Psychoactive Medications 21 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o The FDA has ordered a class labeling change for all atypical antipsychotics that patients should be monitored for diabetes mellitus, obesity and hypercholesterolemia when taking any of the atypical antipsychotics. o o o o o o o o o As B Q A o o o o o o o o Fa x x o o o o o o o o We x x o o o o o o o o Wa x x o o o o o o o o BP x x o o o o o o o o BG x x o o o o o o o o Fas x o o The Medical Letter, April 25, 2016 Psychoactive Medications 22 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o o LongActing Injectable Antipsychotics o The Medical Letter, November 9, 2015 Psychoactive Medications Section #1 23 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Concern Over Atypical Antipsychotics in Children o Prescriber’s Letter, January 2010 o There seems to be increasing concern over the use of atypicals. o Abilify® is now approved for autism in children, and Zyprexa® and Seroquel® are approved for bipolar and schizophrenia in adolescents. In some areas, 25% of Rxs for atypicals are from pediatricians. o Kids experience the usual side effects of weight gain, hyperglycemia, sedation, restlessness, involuntary movement disorders, etc. o Risperidone is still a good first choice. It has the most evidence to support its use in kids...and it's available generically. o Abilify® has a low potential for weight gain and dyslipidemia...and it can be more activating than sedating. Zyprexa® is the worst metabolic offender and one of the most sedating. o Recommend monitoring weight, blood pressure, blood glucose, and lipids at least every 6 months in kids taking atypicals. o The following website tells a dramatic story of overmedicated children: o http://abcnews.go.com/2020/video/fosterkidsprescribedpsychotropic drugsheavydutydrugtreatmentsneglect202015077792 o Psychoactive Medications 24 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o "Substantial" Weight Gain in Children Treated with Atypical Antipsychotics JAMA. 2009;302(16):18111812 o An October 27, 2009 JAMA study reported that treatmentnaive children who took atypical antipsychotics for 11 weeks had mean weight gain ranging from 4.4 kg to 8.5 kg, depending on the drug prescribed. o o Lead author Christoph Correll commented that "weight gain was pervasive even in medications usually considered to be weight neutral in adults." o The study involved 272 children aged 4 years to 19 years of age with bipolar disorder, schizophrenia or other behavioral disorders. o Specifically, weight gain was reported as follows: o o Zyprexa® (olanzapine) = 8.5 kg (18.7 pounds) o Seroquel® (quetiapine) = 6.1 kg (13.4 pounds) o Risperdal® (risperidone) = 5.3 kg (11.7 pounds) o Abilify® (aripiprazole) = 4.4 kg (9.7 pounds) o o Antipsychotics May Raise Type 2 Diabetes Risk in Children and Youth o JAMA Psychiatry, August 21, 2013 o Dr. Wayne Ray of Vanderbilt reported that "diabetes can develop relatively soon after beginning these drugs," adding that the "risk may need to be considered even for relatively short periods of use." o As part of the retrospective cohort study, investigators reviewed the records of 28,858 children and young people aged 6 to 24 years in the TennCare program who had recently started taking antipsychotic medication. o o Children treated with antipsychotic drugs had a threefold increased risk of developing type 2 diabetes, compared with those who took other psychiatric medicines, which translates to an estimated 16 additional cases of type 2 diabetes per 10,000 children taking an antipsychotic for one year. o o Psychotropic Drug Use in Children o American Journal of Public Health January, 2015 o Psychoactive Medications 25 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. Although there is little evidence to support the use of psychotropic medications in preschoolage children, research shows that they are still being prescribed such drugs for behavioral problems. o Investigators looked at Medicaid Analytic Extract data from 36 states for children who were up to 4 years of age in 20002003. Overall, 1.19% of children received at least one psychotropic drug for ADHD, depression or anxiety, and psychotic illness or bipolar. Prescriptions for ADHD treatment were most common. o AfricanAmerican and Hispanic children were less likely to receive a prescription, while male children, those of other/unknown race, and those with insurance other than fee for serviceonly were more likely to receive a prescription. o o Atypical Antipsychotics for Treating Depression o Prescriber’s Letter, May 2009 o Some atypical antipsychotics are approved for resistant depression since more than half of patients with depression still have symptoms despite use of an antidepressant. o Atypical antipsychotics are especially useful for patients who also have bipolar or psychotic symptoms, but they can also be used for patients without psychotic symptoms. o o o o o o The Centers for Medicare and Medicaid Services (CMS) o "2012 Partnership to Improve Dementia Care in Nursing Homes" o o By the end of 2013, CMS targets a national goal of reducing antipsychotic drug use among nursing home residents by 15%. By lowering the use of unnecessary antipsychotic medications, the residents' quality of life is improved and overall cost of care reduced. Specific recommendations for action included in the letter being sent to administrators and directors of nursing are as follows: o Evaluate the necessity of all antipsychotic medications written as "PRN". Because antipsychotics take 37 days before the effects start, using them "PRN" can be deemed 'unnecessary'. Evaluate for possible discontinuation for each patient. o Psychoactive Medications 26 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. Evaluate the necessity of all antipsychotic medications in use for three months or more. Assess the possibility of discontinuation or gradual dosing reductions, i.e., low doses or static dosing with no change in strength or frequency. Cumulative benefits begin to be outweighed by cumulative risks as these medications are used for longer periods of time. o Evaluate the necessity of all antipsychotics in use on individuals admitted with these medication orders. Investigate absences of psychotic indicators as opportunities to gradually decrease these medications. o Evaluate the necessity of all antipsychotics initiated during night/weekend shifts. Implement a review process to ensure that all antipsychotic prescriptions initiated in the facility are critically evaluated within one week. o Evaluate the necessity of all "off label" antipsychotics being used for behavior management, sedation, appetite stimulation, smoking cessation, eating disorders or insomnia. Evaluate if a nonpharmacological approach to these disorders might be more effective. o o Psychoactive Medications 27 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o It Worked! o http://www.medpagetoday.com/Geriatrics/Dementia/41230 o Use of antipsychotic drug treatment in nursing home patients is on the decline, according to data from the Center for Medicare and Medicaid Services (CMS). o Following the launch of the National Partnership to Improve Dementia Care, use of antipsychotic medication fell 9.1% among longstay nursing home residents from the last quarter of 2011 to the first quarter of 2013. o That translated to roughly 30,000 fewer residents receiving such drugs. o The goal of the partnership, which was established in 2012, is to reduce antipsychotic drug use among the longstay nursing home population by 15% by the end of 2013. According to 2010 data, more than 17% of nursing home residents received daily doses of antipsychotic medications that exceeded recommended amounts. o o Tennessee Reduces Use of Psychotropic Agents in Nursing Homes o AP, August 28, 2013 o Tennessee nursing homes have dramatically decreased the use of antipsychotic drug use for residents living with dementia. o According to the state Health Department, antipsychotic drugs cost hundreds of millions of Medicare and Medicaid dollars and increase the risk of stroke, heart attack, falls with fractures, hospitalizations and other complications. Lowering the use of unnecessary antipsychotic medications improves residents' quality of life and reduces health care costs. o Tennessee led the nation for antipsychotic use in nursing homes in the fourth quarter of 2011. By the first quarter of this year the state had dropped to 48 in the nation. o Tennessee reduced the use of the drugs by conducting training sessions for nursing home staff members across the state. The training was part of a nationwide initiative to improve dementia care. o Psychoactive Medications 28 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Antidepressants o o o Complete remission of symptoms is the goal of antidepressant therapy; partial response is associated with an increased risk of relapse. Improvement can occur within the first two weeks of drug therapy, but it may take 48 weeks to achieve a substantial benefit. Fewer than 50% of patients with depression respond to first line pharmacotherapy, and the rate of response decreases with each subsequent drug trial. o A 2009 report from the Substance Abuse and Mental Health Administration shows that Tennessee had the country’s highest rate of people with a major depressive episode in the past year. The report listed 9.8% of Tennesseans age 18 and older had such an occurrence. Hawaii had the lowest at 5%. o According to the June, 2013 issue of Science Daily, 25% of women aged 50 to 64 are on an antidepressant o The January 2002 issue of JAMA reports that the number of Americans treated for depression soared from 1.7 million to 6.3 million between 1987 and 1997. o o 1987 was the year Prozac® was introduced. o Psychoactive Medications 29 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. DSM5 Criteria for Diagnosis—5 of the following 9 symptoms must be present: o o Depressed mood o Loss of interest or pleasure in usual activities o Weight change o Sleep disturbance o Psychomotor agitation or retardation o Fatigue or loss of energy o Feelings of worthlessness or excessive inappropriate guilt o Loss of ability to concentrate o Suicide ideation/recurrent thoughts of death with or without a specific plan In DSMIV, chronic depression was known as dysthymia (as opposed to euthymia or normal feelings). In DSM5 dysthymia also called persistent depressive disorder. o Antidepressants often take ~2 weeks to produce improvement, but may take as long as 6 weeks to achieve benefit, and even longer for maximum benefits. o Most antidepressants are effective in ~50% to 60% of patients with major depression, but patients who do not respond to one may respond to another, and 80% or more will respond to at least one antidepressant drug. o o Primary Neurotransmitters/Receptors Involved in the Pharmacology of Depression and other Conditions o o Norepinephrine (NE) o Alpha1 Psychoactive Medications 30 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Alpha2 Dopamine (DA) Serotonin (5HT)—The following serotonin receptors have been identified, but pharmacologist predict as many as 15 different receptors are in the human body. o o 5HT1A—stimulation will ↓ transmission of nerve impulses (somatodendritic autoreceptor) o 5HT1D—stimulation will ↓ serotonin, e.g., sumatriptan (Imitrex®) o 5HT2—blockade will ↓ depression and psychosis o 5HT3—blockade will ↓ nausea/vomiting, e.g., ondansetron (Zofran®) o 5HT4—stimulation will ↑ GI motility o Psychoactive Medications 31 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Which Antidepressant is Best? o The Medical Letter, July 4, 2016 o o Psychoactive Medications Section #1 32 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Tertiary Amine or "Tricyclic" Antidepressants (TCAs) o (Used much less for depression since the introduction of SSRIs) o amitriptyline (Elavil®) imipramine (Tofranil®)—also used for enuresis nortriptyline (Pamelor®) desipramine (Norpramin®) clomipramine (Anafranil®)—for obsessive compulsive disorder OCD. doxepin (Sinequan®, Adapin®)—more sedative effects than other TCAs, so often used in treating anxiety or insomnia. Topical form available as Zonalon® for itching and Silenor® for insomnia. o o Pharmacological Effects of TCAs o The precise mechanism of action is not fully understood. It is believed that these drugs interfere with the reuptake of various neurotransmitters, particularly norepinephrine, at the neuronal membrane. o Anticholinergic effects (dry mouth, constipation, urinary retention, tachycardia, flushing, etc.). o Elderly are more sensitive to the anticholinergic effects and may develop confusion or delirium. o Cardiotoxic effects (dysrhythmias)—treat with lidocaine or other antidysrhythmic agents. Use another class of antidepressant for clients with heart disease. o Weight gain. o o Dosing Considerations with TCAs o Bedtime dosing is effective and also decreases the awareness of anticholinergic side effects. o Generally takes a few weeks to reach full antidepressant effects, but side effects can be seen within a few hours. o Psychoactive Medications 33 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o Selective Serotonin Reuptake Inhibitors (SSRIs) o Selective serotonin reuptake inhibitors (SSRIs) are generally recommended for firstline treatment of major depression. There is no convincing evidence that any one SSRI is more effective than any other. Fluoxetine has been shown to be effective and is the only SSRI approved by the FDA for treatment of major depressive disorder in children. Fluoxetine and escitalopram are both approved for treatment of major depressive disorder in adolescents. o The precise action of SSRIs is not fully understood, but it is believed that the most important effect is the inhibition of a protein that transports serotonin (5HT), thus enhancement of the actions of serotonin (5HT) due to highly specific serotonin reuptake blockade at the neuronal membrane. o As to how SSRIs treat anxiety disorders is not fully understood. A study in JAMA Psychiatry, June 17, 2015, looked at this. Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively. The study concluded that neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. These findings could provide important new insights into the etiology of anxiety disorders. o Psychoactive Medications 34 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o o SSRIs have less sedative and cardiovascular effects than do the tricyclic antidepressant drugs due to dramatically decreased binding to receptors of histamine, acetylcholine, and norepinephrine. o Anticholinergic activity with SSRIs is virtually absent. o These agents exert selective effects on serotonin and are the firstline antidepressant agents in the primary care setting because of their: o proven efficacy favorable adverse effect profile longterm tolerance oncedaily dosing wide therapeutic index o Since the SSRIs can cause CNS stimulation, jitteriness and sleep disturbances, so they are usually dosed in the morning. However, they can cause drowsiness. o Serotonin is increased when light is present; when darkness occurs serotonin converts to melatonin. Many people with depression have low serotonin levels, leading to low melatonin levels and an inability to sleep. o Many of these agents are also approved for other indications, e.g., OCD (ObsessiveCompulsive Disorder), PMDD, PTSD, bulimia, acute anxiety disorder, severe social phobia and Generalized Anxiety Disorder (GAD). Many consider them to be firstline therapy for anxiety disorders. o o SSRI Agents Fluoxetine (Prozac®) o Psychoactive Medications 35 Section #1 Fall Semester, 2016 Nursing 406 Glen E. Farr, Pharm.D. o Long halflife (46 days for fluoxetine and 4 to 16 days for its active metabolite norfluoxetine), so need a 5week “washout” period prior to initiating therapy with a MAOI. o Other SSRIs halflife is ~2448 hours o o Combined with olanzapine (Zyprexa® as Symbyax®) to treat bipolar disease and treatmentresistant depression (TRD). o o Approved for PMDD as Sarafem in 10 & 20 mg 7day blister packs and for onceweekly administration in stabilized (not for initial therapy) clients as Prozac Weekly . o The onceweekly formulation consists of a 4week supply containing 90 mg of fluoxetine with an enteric coating that delays release of the ingredient into the bloodstream. o o Approved in pediatric patients > age 8 years for major depressive disorder) and > age 7 years for obsessivecompulsive disorder. o Sertraline (Zoloft®) o Paroxetine (Paxil®, Paxil CR®) o o Should not be used in pregnancy due to “heart de
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