Psychopharmacology



Psychopharmacology


Donald L. Taylor




LEARNING OBJECTIVES



1. Describe the role of the nurse in psychopharmacological treatments.


2. Examine pharmacological actions, drug co-administration, and drug interactions.


3. Analyze the mechanism of action, clinical use, and side effects related to antianxiety, sedative-hypnotic, antidepressant, mood-stabilizing, and antipsychotic drugs.


4. Evaluate the implications of new psychopharmacological agents and genomics.


5. Discuss psychiatric nursing practice issues related to psychopharmacology.



This chapter discusses psychopharmacology and important principles of drug therapy in the treatment of patients with neurobiological brain disorders, or mental illnesses. The pharmacological agents described in this chapter are all approved by the U.S. Food and Drug Administration (FDA), although not always for the indications described. Dietary supplements and herbal preparations used to treat the symptoms of mental illness are described in Chapter 30.


This chapter views drug therapy as a complement to other evidence-based therapies, such as cognitive behavioral, psychosocial, interpersonal, psychodynamic, and complementary and alternative interventions. Drug therapy is not viewed as a quick fix or miracle pill. Psychopharmacological agents treat specific symptoms of neurobiological illnesses with significant effectiveness, although side effects and adverse reactions of drug therapy require expertise and sound clinical judgment on the part of the nurse.


Psychopharmacology is an established standard in the treatment of neurobiological illnesses. However, drugs alone do not treat the patient’s personal, social, or environmental components of or responses to these illnesses. This underscores the need for an integrated and comprehensive approach to the treatment of persons with mental illness.



Role of the Nurse in Psychopharmacology


Psychopharmacological treatment should be integrated with the principles of psychiatric nursing practice presented throughout this book. The psychiatric nurse has a wealth of knowledge and competencies that make the nursing care provided to people with psychiatric disorders unique in many ways. Following are some examples of the nurse’s role in psychopharmacological treatment of persons with neurobiological illness.



Patient Assessment


Psychoactive drugs treat specific symptoms of neurobiological brain disorders. However, not all patient behaviors are treated by drug therapy, and not every symptom of illness is targeted for treatment with drugs.


It is essential that a thorough patient baseline assessment—including history, physical, and laboratory examination (Chapter 5); psychiatric evaluation (Chapter 6); sociocultural assessment (Chapter 7); and a medication history (Box 26-1) be completed for each patient before beginning any treatment. This information helps distinguish aspects of the psychiatric illness from aspects of the patient’s personality that were present before the onset of illness.



BOX 26-1   MEDICATION ASSESSMENT TOOL


Prescribed and Over-the-Counter Medications


For each of the following categories of drugs taken by the patient:



Obtain the following information from the patient and other sources:




As a result of the baseline assessment a diagnosis is made and psychiatric symptoms are identified as appropriate targets for drug treatment. An integrated treatment plan is then developed. Residual symptoms of the patient’s illness may need specific interventions to enhance treatment effectiveness. Problematic personality characteristics not related to the psychiatric disorder can be addressed by nonpharmacological treatments as needed.


Drug side effects that emerge after treatment begins should be identified and appropriately treated as they appear. Symptoms of organ system dysfunction, being either a component of an illness or a side effect of drug treatment, should be identified and treated.


Current nonpsychiatric diagnoses and treatments are documented at the baseline level, as well as the use of over-the-counter remedies and complementary and alternative treatments the patient may be taking.


Finally, careful baseline assessment of each patient can help identify undiagnosed medical illnesses that co-exist with the psychiatric illness or that may be causing the psychiatric symptoms. See Box 26-1 for a medication assessment tool to guide the nurse in taking a drug and substance use history.





Monitoring Drug Effects


The nurse has the important role of consistently monitoring the effects of psychopharmacological drugs. This includes making standardized measurements of drug effects on baseline target symptoms, evaluating and minimizing side effects, treating adverse reactions, and noting the often subtle effects of the medication on the patient’s self-concept, trust, and confidence in the treatment.


A drug should be given within the recommended dose range and for the appropriate amount of time before determining whether it has had an adequate therapeutic trial for a particular patient. Therapeutic drug monitoring is important because some drugs have a narrow therapeutic range (e.g., lithium), some can cause sudden serious adverse reactions (e.g., neuroleptic malignant syndrome), and some drugs are often co-administered, thereby altering the drug metabolism and clearance rates.


Almost all drugs are metabolized by one of the many families of metabolic enzymes, or “cytochromes,” usually referred to as the CYP-450 system, found predominantly in the liver. Some drugs, called inducers, speed up one or more of these systems, thus decreasing the blood level of drugs metabolized by that system and potentially causing a lack of effectiveness of those drugs. Other drugs, called inhibitors, slow down one or more systems, thus increasing blood levels of the drugs metabolized by that system and potentially causing increased side effects or even toxicity from those drugs. This is known as cytochrome P-450 inhibition.


Some racial and ethnic groups have genetic predispositions toward deficiencies in these enzymes, making them at greater risk for CYP-450 problems. The medication prescriber is responsible for anticipating these possibilities and prescribing accordingly. The nurse should be vigilant for signs of drug effects that seem inconsistent with the doses prescribed or that are adverse reactions (Howland, 2011a).






Prescriptive Authority


Legislation has been passed in every state in the United States authorizing advanced practice registered nurses (APRNs) to have at least some degree of authority to prescribe medications, and in some states APRNs have full autonomy in this role (Pearson, 2011). Psychiatric–mental health nurse practitioners, and in some states this includes clinical nurse specialists, who are qualified under their state nurse practice acts are thus able to prescribe pharmacological agents to treat the symptoms and improve the functional status of patients with psychiatric illnesses (NONPF, 2011).


Thus the role of nurses in psychopharmacological treatments has been expanded to include medication prescriptive authority in order to utilize the expertise of APRNs to increase patient access to quality and cost-effective health care. Collaborative relationships with supervisors, other health care providers, peers, and agencies involved in the care of patients are important aspects of the nurse prescriber’s role.



Critical Reasoning


Does your state grant medication prescriptive authority to psychiatric–mental health APRNs? If so, what are the requirements for prescriptive practice?



Pharmacological Principles


Pharmacokinetics


Pharmacokinetics is the study of how the body affects a drug. It answers the question: How does the body get drugs to and from their intended target? Pharmacokinetic properties include:



The time course and location of drug concentrations in the body can be predicted, appropriate dosing schedules can be designed, side effects can be anticipated, and the time it takes a drug to become effective can be estimated by using pharmacokinetic models. Additional pharmacokinetic properties that assist in understanding the mechanisms of psychopharmacological agents and how the body affects a drug are described in the following sections.



Bioavailability


Bioavailability is how much of the drug reaches systemic circulation unchanged. It is an estimate used to compare various drug preparations, particularly if several different manufacturers make the same generic drug.


In general, generic drugs are prescribed to ensure more accuracy of the bioavailability estimate since trade name drugs can differ from one another. Using generic drug names also takes advantage of price differences among manufacturers and prevents possible confusion when a drug later becomes available as a generic.


Once a drug does become a generic, the patient should be instructed to always use the same company brand of the drug because the bioavailability of psychoactive drugs may vary significantly from one company to another, thus affecting drug dose and steady state. The patient can be taught to use one pharmacy regularly, and the pharmacist can be asked to use the same manufacturer every time when filling generic prescriptions of a particular drug, again to ensure a constant bioavailability.



Half-life


A drug’s half-life is the time it takes for the dose amount of drug in the body to decrease by 50%. For example, the benzodiazepine (BZ) alprazolam has a half-life of approximately 11 hours, so it takes about 2.5 days for nearly all traces of the drug to be eliminated from the body after taking a single dose.


Half-life determines how long it will take the body to achieve steady state. Steady state is the point at which the plasma drug concentration remains relatively constant between doses because the amount of drug excreted equals the amount ingested. This equilibrium occurs in approximately five half-lives of any given drug.


Until steady state is reached, the drug level in the body continues to fluctuate, accounting for some acute side effects and preventing determination of the optimum dose for a particular patient. Assessing a blood level measurement is not an accurate method of determining a proper dose range. The daily dose may have to be divided in order to minimize the peak level of drug concentration after each ingestion.


Termination of drug treatment is also affected by half-life. The effects of drugs with a long half-life or with active metabolites can last a long time (sometimes weeks) after the last dose has been taken. Drugs with a shorter half-life usually must be discontinued gradually (tapered) over several days or weeks.


In general, most psychoactive drugs should be tapered to avoid uncomfortable discontinuation symptoms. Drugs with addiction potential, such as BZs, must be tapered gradually to avoid serious withdrawal symptoms.



Drug Interactions


Drug interactions can be the result of pharmacokinetic properties. One drug may interfere with the absorption, metabolism, distribution, and elimination of another drug, thus raising or lowering the levels of the second drug in the blood and tissue. As noted above, some drugs inhibit and others induce the activity of drug-metabolizing liver enzymes, thereby affecting the liver’s ability to keep levels of psychopharmacological drugs stable.


For example, most of the antidepressants, some of the typical antipsychotics, the mood stabilizers, and even grapefruit juice can inhibit drug-metabolizing liver enzymes in the CYP-450 system, potentially causing toxic levels of other drugs. The mood stabilizer carbamazepine, St. John’s wort, and even smoking cigarettes can markedly reduce many psychotropic drug levels, rendering them ineffective (Fuller and Sajatovic, 2009).



Pharmacodynamics


Pharmacodynamics is the study of the effects of a drug on the body and, in particular, the interaction of a drug on the receptor that is its targeted site of action. Pharmacodynamics answers the question: What does a drug do once it gets where it is going?


By using pharmacodynamic models, the time course and intensity of drug effects on the body can be determined; drug interactions can be better understood; and safety profiles that affect clinical decision making can be developed. Several pharmacodynamic properties related to how drugs affect the body include those listed here.



Receptor Mechanisms


Receptors are channels on cells that act as gatekeepers of brain communication. They recognize and respond to molecules (messengers) that affect their biological function. Thus receptors are targets for drugs acting as messengers, which modify the biological activity of the receptors, bringing a dysfunctional system back toward normal.


A drug modifies a receptor by attaching (binding) to one subtype of receptor (like a key in a single lock) or many subtypes of receptors (like a master key for many locks) in several ways. A drug can act as the following:



For example, BZs are agonists for the gamma-aminobutyric acid (GABA) system because they enhance the activity of GABA, an inhibitory neurotransmitter. Most antipsychotic drugs are antagonists at dopamine (DA) receptors because they inhibit the activity of dopamine.




Therapeutic Index


The therapeutic index is a relative measure of the safety and toxicity of a drug. The ratio produced by measuring the amount of drug necessary for 50% of patients to experience a therapeutic effect (median effective dose) and the highest amount of drug at which a toxic effect is produced in 50% of patients (median toxic dose) is called the therapeutic index. It answers the questions: What is the lowest dose of this drug needed to begin to produce a therapeutic effect, and what is the highest dose at which a toxic effect is produced in the average patient?


A low therapeutic index means that the difference between the amount of drug needed to achieve the desired effect and the amount that would cause toxic effects has a narrow range (like a window with a narrow opening). For example, the mood stabilizer lithium has a low therapeutic index and requires frequent blood level checks and careful monitoring and stabilizing measures to ensure its safe use.


On the other hand, the typical antipsychotic haloperidol has a high therapeutic index and thus is safely prescribed in a wide range of doses (like a window opened very wide). Individual patient differences, such as age, gender, and race, also can affect the therapeutic index of a specific drug.



Tolerance, Dependence, and Withdrawal Symptoms


Some patients become less responsive to the same dose of a particular drug over time, which is called tolerance, requiring that higher doses of the drug be given over time to obtain the same initial therapeutic effect. The development of tolerance to some drugs, such as BZs or opioids, also may be associated with physical dependence on the drug, requiring tapering during discontinuation to avoid uncomfortable withdrawal symptoms (Chapter 23).


Abruptly stopping many psychotropic medications, including antidepressants, BZs, and atypical antipsychotics, can trigger discontinuation syndrome, characterized by the following:



Gradual tapering from medication can help to prevent this syndrome (Preskorn, 2011).



Drug Co-Administration


Once generally discouraged, the use of more than one psychopharmacological drug in the same patient at the same time has become standard clinical practice under specific circumstances. Patients who are prescribed multiple medications or are taking over-the-counter medications in addition to their prescribed medications can potentially receive benefits from these combinations but also may be at risk for increased side effects, drug interactions, confusion about which drug is causing which effect, complex dosing schedules, and higher costs of treatment.



• Box 26-2 lists guidelines for drug co-administration.



BOX 26-2   GUIDELINES FOR DRUG CO-ADMINISTRATION




• Identify specific target symptoms for each drug.


• If possible start with one drug and evaluate effectiveness and side effects before adding a second drug.


• Be alert for adverse drug interactions.


• Consider the effects of a second drug on the absorption and metabolism of the first drug.


• Consider the possibility of additive side effects.


• Change the dose of only one drug at a time, and evaluate results.


• Be aware of increased risk of medication errors.


• Be aware of increased cost of treatment.


• Be aware of decreased patient adherence when medication regimen is complex.


• In follow-up treatment eliminate as many drugs as possible and establish the effective dose of the drugs used.


• Patient education programs regarding concomitant drug regimens must be particularly clear, organized, and effective.


• Patient follow-up contacts should be more frequent.


• If a patient has more than one prescriber, integration of care is required.


• Box 26-3 alerts the nurse to patients who may be at higher risk for drug interactions.



BOX 26-3   INCREASED RISK FACTORS FOR DEVELOPMENT OF DRUG INTERACTIONS




• Table 26-1 is a reference list for the more common interactions of psychotropic drugs and other substances.



TABLE 26-1


INTERACTIONS OF PSYCHOTROPIC DRUGS AND OTHER SUBSTANCES

















































PSYCHOTROPIC CATEGORY POSSIBLE INTERACTIONS
Antianxiety Agents
Benzodiazepines with:
Central nervous system (CNS) depressants (alcohol, barbiturates, antipsychotics, antihistamines, cimetidine)
Selective serotonin reuptake inhibitors (SSRIs), disulfiram, estrogens
Antacids, tobacco		 Potential additive CNS effects, especially sedation and decreased daytime performance
Increased benzodiazepine effects
Decreased benzodiazepine effects
Sedative-Hypnotics with:
CNS depressants (alcohol, antihistamines, antidepressants, narcotics, antipsychotics)Anticoagulants (oral)∗ Enhancement of sedative effects; impairment of mental and physical performance; may result in lethargy, respiratory depression, coma, death
Decreased warfarin plasma levels and effect; monitor and adjust dose of warfarin
Antidepressants
Tricyclic Antidepressants (TCAs) with:
Monoamine oxidase inhibitors (MAOIs)∗
Alcohol and other CNS depressants
Antihypertensives∗ (guanethidine, methyldopa, clonidine)
Antipsychotics and antiparkinsonian agents
Anticholinergics
Antiarrhythmics (quinidine, procainamide, propranolol)
Selective serotonin reuptake inhibitors (SSRIs)∗
Anticonvulsants
Tobacco		 May cause hypertensive crisis
Additive CNS depression; decreased TCA effect
Antagonism of antihypertensive effect
Increased TCA effect; confusion, delirium, ileus
Additive anticholinergic effects
Additive antiarrhythmic effects; myocardial depression
Increased TCA serum level/toxicity through inhibition of cytochrome P-450 system
Decreased TCA effect; seizures
Decreased TCA plasma levels
SSRIs with:
Clomipramine, maprotiline, bupropion, clozapine
MAOIs∗
Barbiturates, benzodiazepines, narcotics
Carbamazepine
Aripiprazole
Risperidone
Selegiline∗
St. John’s wort, naratriptan, rizatriptan, sumatriptan, zolmitriptan, tramadol∗
Haloperidol
Calcium channel blockers
 Valproate
 Cimetidine, erythromycin, isoniazid, fluconazole
 Clozapine∗
 Rifampin		 Increased risk of seizures
Serotonin syndrome
Increased CNS depression
Neurotoxicity: nausea, vomiting, vertigo, tinnitus, ataxia, lethargy, blurred vision
Fluoxetine and paroxetine lower levels; increased blood levels of aripiprazole
Fluoxetine and paroxetine may increase risperidone to toxic levels
Hypertensive crisis; increased serotonergic effects; mania
Serotonin syndrome
Decreased effect of either drug
Neurotoxicity: dizziness, nausea, diplopia, headache
Decreased valproate serum concentration
Somnolence, lethargy, dizziness, blurred vision, ataxia, nausea; increased carbamazepine levels
Avoid because of increased risk of agranulocytosis
Decreased carbamazepine levels
Antipsychotics with:
Antacids, tea, coffee, milk, fruit juice
CNS depressants (narcotics, antianxiety drugs, alcohol, antihistamines, barbiturates)
Anticholinergic agents (levodopa)∗
SSRIs		 Decreased phenothiazine effect
Additive CNS depression
Additive atropine-like side effects and increased antiparkinsonian effects
Increased neuroleptic serum level and extrapyramidal side effects (EPS)
Antipsychotic
Clozapine with:
Carbamazepine∗
Benzodiazepines∗
SSRIs∗
 Additive bone marrow suppression
Circulatory collapse, respiratory arrest
Increased risk of seizures
Anticonvulsant
Lamotrigine with:
Carbamazepine
Valproate
Oral hormonal contraceptives		 Carbamazepine increases metabolism of lamotrigine
Valproate decreases metabolism of lamotrigine; increased risk of serious rash
Oral contraceptive products (OCPs) increase metabolism of lamotrigine; carbamazepine and oxcarbazepine increase metabolism of OCPs, thereby possibly decreasing the efficacy


image


∗Potentially clinically significant.


The following drug co-administration principles will guide the nurse when multiple medications are prescribed.





Augmentation or Adjunctive Therapy


Augmentation is the addition of another class of medication to supplement the effectiveness of the primary medication. It is becoming a widely accepted clinical practice. This is done when the primary medicine falls short of expectation and needs to have its effectiveness augmented.


An example is the addition of a BZ (e.g., lorazepam) to the primary antidepressant paroxetine (an SSRI) to treat persistent anxiety symptoms or to alleviate only partial remission of symptoms in a patient with generalized anxiety disorder. This is also done when the primary drug treats target symptoms effectively, but other symptoms remain. For example, an antidepressant is added to the primary antipsychotic drug for persistent symptoms of depression in a patient with schizophrenia.





Special Populations


Although this chapter focuses on the adult patient, special populations, such as youth (Chapters 35 and 36), the elderly (Chapter 37), and members of racially and ethnically diverse or disadvantaged groups, are regularly given psychoactive drugs, even though these drugs may not have been adequately tested in randomized clinical trials on these populations. An understanding of relevant issues will help the nurse administer psychopharmacological agents safely to persons who are members of special populations.




Elderly Patients


Drug distribution, hepatic metabolism, and renal clearance are all affected by age. This often results in the elderly having slower metabolism and elimination of drugs and increased susceptibility to side effects. The FDA has issued an advisory stating that atypical antipsychotic medications increase mortality among elderly patients. Some research suggests that conventional antipsychotics may carry a similar risk. Both antipsychotics and BZs can impair cognitive functioning in the elderly.


With the elderly it is important to begin with a lower than recommended adult dose and titrate up at a rate slower than the usual recommended adult rate—or “start low and go slow.” Geriatric patients often take multiple medications, so the nurse should be aware of the increased risk for drug interactions, complex dosing regimens, and cost.



Pregnant and Lactating Women


If a pregnant woman takes psychoactive drugs, the unborn infant may experience drug effects in utero and even withdrawal symptoms after birth. Because pregnant women are systematically excluded from randomized clinical trials, knowledge of drug reactions in animal studies and in human anecdotal reports is often the primary source of information when prescribing for pregnant and lactating women, as is the FDA rating system for pregnancy risk of drugs.


The FDA categories related to use during pregnancy are as follows:



The FDA has not approved any psychotropic medication for use during pregnancy or lactation; therefore it is up to the provider and patient to individually weigh the risks and benefits of medication use (Howland, 2009). A careful risk-benefit analysis of the psychiatrically symptomatic mother should include these risks: inattention to prenatal care, poor maternal health, adverse effect on mother-infant bonding, increased stress levels on the fetus and infant, history of adverse drug effects on the fetus, and blood levels of the drug measured in breast milk (Bansil et al, 2010). When the benefits of psychotropic treatment outweigh the risks, some psychotropic drugs may be given during pregnancy and breast-feeding (Meltzer-Brody et al, 2008; Pilowsky et al, 2008).



Cross-Cultural Perspectives, Ethnopsychopharmacology, and Gender


Various cultural groups can differ in the ways in which their members seek help for illness, express symptoms of illness, relate to health care professionals of different backgrounds, and believe in the effectiveness of treatments. Cultural heritage can affect individual and family attitudes, beliefs, and practices regarding health and illness. This diversity challenges the communication needed for accurate diagnosis and successful treatment outcomes.


Race, ethnicity, and gender also can affect biological response to medications. Genetic differences can affect how an individual or a group with common genetic ancestry may metabolize psychotropic drugs. Pharmacokinetic and pharmacodynamic processes that are biologically or biochemically mediated have the potential to exhibit differences among racial and ethnic groups.


The field of psychopharmacogenetics deals with genetic and environmental factors that control or influence psychotropic drug–metabolizing enzymes, such as the CYP-450 metabolic enzyme system. Differences in the genetically determined structure of these enzymes can account for the ethnic variations that have been reported in drug responses (Chaudhry et al, 2008).


There is an increasing interest in these individual differences because the population is increasingly more diverse and new psychopharmacological agents are continuing to be developed. In addition, provider bias toward racially and ethnically diverse or disadvantaged patients has been shown to negatively affect treatment selection, thereby increasing disparities in health status associated with racial and ethnic populations.


Gender differences in pharmacokinetics, pharmacodynamics, and reproductive changes should be taken into account when psychotropic drugs are prescribed. Compared with men, women receive more prescriptions and experience more side effects. Women are at higher risk for tardive dyskinesia from conventional antipsychotics and for activating side effects caused by antidepressants.


The following issues should be considered when prescribing psychotropic drugs for women (Seeman, 2010):



• Differences in pharmacokinetics: Gastric emptying is slower, gastric acidity is lower, blood volume is lower, renal clearance of drugs is decreased, and percentage of body fat is higher. Thus women experience greater biological activity than men and often require lower doses of most psychotropic medicines.


• Dosage adjustment across the menstrual cycle and after menopause: Pharmacokinetics can differ significantly at different phases of a woman’s menstrual cycle, necessitating dosage adjustment across the cycle for some drugs. Women of reproductive age require lower doses of antipsychotic drugs. Increased prolactin levels caused by some antipsychotic drugs can inhibit ovulation and cause menstrual cycle irregularity.


• Interactions between psychotropic agents and prescribed hormones: Oral contraceptives can magnify pharmacokinetic differences, sometimes requiring dosage adjustments. Drugs that induce hepatic enzymes, such as carbamazepine, can increase the metabolism of oral contraceptives, resulting in unwanted pregnancy. In women with bipolar disorder, hormone replacement therapy can trigger rapid cycling.




Biological Basis for Psychopharmacology


All communication in the brain involves neurotransmission, or neurons “talking” to each other across synapses at receptors. Neurons are the basic functional unit of the brain structures of the nervous system (Chapter 5). The following description is a basic frame of reference from which to understand neuropharmacological mechanisms.


The synapse is a narrow gap separating two neurons: the presynaptic cell and the postsynaptic cell (Figure 26-1). Most receptors are three-dimensional “gates” (channels) located on cells (neurons) that are targets for chemical first messengers (e.g., neurotransmitters, peptides, drugs).


image
FIG 26-1 Neurotransmission and drug effects at the synapse. ChE, Cholinesterase; GABA, gamma-aminobutyric acid; MAO, monoamine oxidase.

Depending on the message it receives, the receptor opens or closes its channel, allowing or stopping a flow of electrolytes (ions) into and out of the neuron, affecting the electrical nerve impulse of the neuron (stimulating or inhibiting its biological activity).


This process causes a cascade of activity by the chemical second messengers within the neuron, activating the neuron’s genetic code (gene expression). Gene expression is what tells the neuron how to respond and continue the process of communication to the next neuron. This genetically determined communication within and between neurons controls how the brain functions and ultimately how the body responds and the person behaves.


Neurochemical messengers are synthesized (manufactured) from certain dietary amino acids (called precursors) by a chain of enzyme activity within the cell. These messengers are then stored in the presynaptic cell waiting to be released into the synapse.


After neurotransmission takes place at a synapse, neurochemicals remaining in the synapse either are reabsorbed (reuptake) and stored by the presynaptic cell for later use or are metabolized (broken down) by enzymes, such as monoamine oxidase (MAO) and cholinesterase (ChE).


Many psychiatric disorders are thought to be caused by a dysregulation (imbalance) in the complex process of brain structures communicating with each other through neurotransmission. For example:



If a particular psychiatric illness is known to result from a dysregulation or imbalance of neurotransmission in a particular neurotransmitter system, and if the mechanism of action of psychiatric drugs is understood, it provides guidance to selecting the pharmacological strategies that could be used in treatment.


This process of cell-to-cell communication at the synapse resulting in brain function can be affected by drugs in several important ways:



• Release: More neurotransmitter is released into the synapse from the storage vesicles in the presynaptic cell.


• Blockade of postsynaptic receptors: The neurotransmitter is prevented from binding to the target receptor.


• Blockade of alpha2 presynaptic autoreceptors: This negative feedback system is prevented from turning off the release of norepinephrine into the synapse.


• Receptor sensitivity changes: The receptor becomes more or less responsive to the neurotransmitter.


• Reuptake inhibition: The presynaptic cell does not reabsorb the neurotransmitter well, leaving more neurotransmitter in the synapse and therefore enhancing or prolonging its action.


• Interference with storage vesicles: The neurotransmitter is either released again into the synapse (more neurotransmitter) or released to metabolizing enzymes (less neurotransmitter).


• Precursor chain interference: The process that makes the neurotransmitter is either facilitated (more is synthesized) or disrupted (less is synthesized).


• Synaptic enzyme inhibition: Less neurotransmitter is metabolized, so more remains available in the synapse and the presynaptic neuron.


• Second-messenger cascade: A chemical chain reaction within the cell is initiated by neurochemical effects at the receptor during neurotransmission, activating genetically determined brain function.


Not all of these strategies have yielded clinically relevant treatments to date. Those that have are emphasized in this chapter (see Figure 26-1):



Understanding synaptic and cellular functions has led to various treatment approaches in pharmacotherapy that attempt to modify one or more steps in neurotransmission. It has also led to research focused on developing drugs with more specificity (drugs that go to areas in the brain specifically targeted for their action, such as the brain regions implicated in mental illness, rather than also going to nonspecific or untargeted areas, causing drug side effects).


The future of psychopharmacology holds much promise as new discovery techniques, changes in the way drugs are developed, and new theories about drug metabolism are proven. Drug effects on gene expression and receptor function are most likely the bases of psychopharmacological efficacy in the treatment of psychiatric disorders.



Antianxiety and Sedative-Hypnotic Drugs


Anxiety is a normal response to threat and is part of the fight-or-flight instinct necessary for survival (Chapter 15). The diagnosis of anxiety (symptoms of anxiety that are disproportionate to the circumstances) is based on the patient’s description, the nurse’s observation of behaviors, assessment of DSM-IV-TR (APA, 2000) diagnostic criteria, and the elimination of alternative diagnoses.


The possibility of a nonpsychiatric cause for anxiety symptoms also must be considered. Hyperthyroidism, hypoglycemia, cardiovascular illness, severe pulmonary disease, and a variety of medications and substances are often associated with high levels of anxiety. In addition to a careful physical assessment and a review of laboratory tests, the patient should be asked about the use of prescription and over-the-counter drugs, as well as “recreational” substances, such as alcohol, caffeine, nicotine, and street drugs.


Anxiety also accompanies many psychiatric disorders. For example, depression and anxiety are often co-morbid illnesses. In general, the primary disorder should be treated with the appropriate medication. For example, anxiety associated with a primary diagnosis of schizophrenia or major depression often decreases when the target symptoms for the primary disorder are treated successfully.


This section divides antianxiety and sedative-hypnotic drugs into two categories: the BZs and several non-BZ antianxiety drugs. The BZs are the most widely prescribed drugs in the world. Their popularity is related to their effectiveness, prompt onset of action, and wide margin of safety. Concerns that are largely unfounded regarding physiological dependence, withdrawal, and abuse potential have limited their use somewhat.


Although BZs have almost entirely replaced barbiturates in the treatment of anxiety and sleep disorders, they recently have been considered to be second-line agents after the antidepressants in the long-term treatment of anxiety disorders such as panic disorder and social phobia. Antidepressants are discussed in detail in the following section.



Critical Reasoning


What sociocultural factors may help explain why BZs are the most commonly prescribed medications in the United States?



Benzodiazepines


The BZs are thought to reduce anxiety because they are powerful receptor agonists of the inhibitory neurotransmitter GABA. A postsynaptic receptor site specific for the BZ molecule is located next to the GABA receptor. The BZ molecule and GABA bind to each other at the GABA receptor site. The result is an enhancement of the actions of GABA, resulting in an inhibition of neurotransmission (a decrease in the firing rate of neurons) and thus a clinical decrease in the person’s level of anxiety.



Clinical Use


The major indications for the use of BZs include anxiety and anxiety disorders, insomnia, alcohol withdrawal, anxiety associated with medical disease, skeletal muscle relaxation, seizure disorders, anxiety and apprehension experienced before surgery, and substance-induced (except for amphetamines) and psychotic agitation in emergency rooms.


Used in higher doses, the high-potency BZs alprazolam and clonazepam have been effective in the treatment of panic disorder and social phobia. The target symptoms for the use of BZs are listed in Box 26-4.



BOX 26-4   TARGET SYMPTOMS FOR ANTIANXIETY AND SEDATIVE-HYPNOTIC BENZODIAZEPINES


Psychological





Another clinical indication for the use of BZs is as a sedative-hypnotic to improve sleep. Insomnia includes difficulty falling asleep, difficulty staying asleep, or awakening too early with an inability to go back to sleep. It is a symptom with many causes and often responds to nonpharmacological strategies, such as talking about problems, increased daytime exercise, elimination of stimulants such as caffeine, and incorporating physical comfort measures into the nighttime routine (Chapter 16).


When used as hypnotics, the BZs should induce sleep rapidly, and their effect should be gone by morning. Any BZ can be an effective sedative-hypnotic when administered at bedtime, although the choice of drug should be tailored to the patient’s complaints. For example, BZs with a short half-life are effective for patients who have trouble falling asleep, but they may wear off too soon to help patients with early-morning awakening.


Because the BZs are in the same pharmacological class as alcohol, they can be used to suppress the alcohol withdrawal syndrome and are the treatment of choice for this indication (Chapter 23). The ingestion of these two substances together is contraindicated, particularly for the patient using dangerous equipment or driving a car, because it can produce extreme sedation.


The BZs have no significant clinical advantages over each other, although differences in half-life can be clinically useful (Table 26-2). For example, patients with persistent high levels of anxiety should take a drug with a long half-life. Patients with fluctuating anxiety might do better with either a short-acting drug or a drug with a sustained-release formulation (alprazolam, clorazepate, diazepam). Sustained-release BZs blunt the peaks of toxicity and the lows of symptom breakthrough and are a popular alternative to the original formulations.



In addition, the lipid solubility of each BZ determines the rapidity of onset and the intensity of effect. This should be considered when selecting a BZ. For example, diazepam is more lipid soluble than lorazepam; thus it more readily moves into and then out of the central nervous system (CNS) and is more extensively distributed to peripheral sites, particularly to fat cells.


The rate of absorption from the gastrointestinal tract varies considerably among the different BZs, thus affecting the rapidity and intensity of onset of their acute effects. Antacids and food in the stomach slow down absorption when these drugs are taken by mouth.


The injectable BZs (lorazepam, midazolam) have proven reliable when administered in the deltoid muscle. Diazepam results in predictable and rapid rises in the blood level when used intravenously. Concentrations of BZs in the blood have not yet been firmly correlated to clinical effects, so blood level measurements are not clinically helpful.


Some patients may need to take antianxiety drugs for extended periods of time. Because of the potential disadvantages of BZs, they should always be used along with nonpharmacological treatments for the patient with chronic anxiety or insomnia. Psychotherapy, behavioral techniques, environmental changes, stress management, sleep hygiene, and an ongoing therapeutic relationship continue to be important in the treatment of anxiety disorders and insomnia.


Treatment with BZs generally should be brief and used during a time of specific stress or for a specific indication. The patient should be observed frequently during the early days of treatment to assess target symptom response and monitor side effects so that the dose can be adjusted as needed. Some patients, such as those with panic disorder, may require regular daily dosing and long-term BZ treatment.



Side Effects and Adverse Reactions


BZ side effects are common, dose related, usually short-term, and almost always harmless. Table 26-3 summarizes these reactions and nursing considerations.



The BZs generally do not live up to their reputation of being strongly addictive, especially if they are discontinued gradually, have been used for appropriate purposes, and their use has not been complicated by other factors, such as long-term use of other CNS depressants (e.g., barbiturates or alcohol). Because of BZs’ calming effects, they have the reputation of being frequently misused.


Tolerance can develop to the sedative effects of BZs, but it is unclear whether tolerance also develops to induced sleep or antianxiety effects. These drugs should be tapered to minimize withdrawal symptoms (Box 26-5) and rebound symptoms of insomnia or anxiety. If these symptoms occur, the dose should be raised until symptoms are gone and then tapering resumed at a slower rate.



BOX 26-5   BENZODIAZEPINE WITHDRAWAL SYMPTOMS




Because the BZs have a very high therapeutic index, overdoses of BZs alone almost never cause fatalities. The BZ antagonist flumazenil (Romazicon) can reverse all BZ actions and is marketed as a treatment for BZ overdose.


Elderly patients are more vulnerable to side effects because the aging brain is more sensitive to sedatives. Dosing ranges from one half to one third of the usual daily dose used for adults. The BZs with no active metabolites (see Table 26-2) are less affected by liver disease, the age of the patient, or drug interactions.


BZs have been used successfully in children in single doses to allay anticipatory anxiety and to treat panic, sleepwalking, generalized anxiety disorder (GAD), and avoidant personality disorder. In general, however, they can increase anxiety and produce or aggravate behavior disorders, especially attention deficit hyperactivity disorder (ADHD).


Use of BZs during pregnancy has been associated rarely with palate malformations and intrauterine growth retardation, especially when used during the first trimester. When used late in pregnancy or during breast-feeding, these drugs have been associated with floppy infant syndrome, neonatal withdrawal symptoms, and poor sucking reflex. Thus they are not recommended for use during pregnancy or while breastfeeding.



Nonbenzodiazepine Antianxiety Agents


Buspirone, a non-BZ anxiolytic drug, is a potent antianxiety agent with no addictive potential and has FDA approval for the treatment of GAD (Table 26-4). Buspirone does not exhibit muscle-relaxant or anticonvulsant activity, interaction with CNS depressants, or sedative-hypnotic properties. It is not effective in the management of drug or alcohol withdrawal or panic disorder. Generally it takes several weeks for buspirone’s antianxiety effects to take effect. It probably is most effective in patients who have never taken BZs and therefore are not expecting immediate effects from drug treatment.



Propranolol (a beta-blocker) and clonidine (an alpha2 receptor agonist) have been used for the off-label treatment of anxiety. These classes of drugs act by blocking peripheral or central noradrenergic (norepinephrine) activity and many of the manifestations of anxiety (e.g., tremor, palpitations, tachycardia, sweating). Propranolol is used in the treatment of performance anxiety found in some forms of social phobia and in panic disorder if rapid heartbeat is a significant deterrent to the patient’s ability to function.


Clonidine is also used to block physiological symptoms of opioid withdrawal and the tachycardia and excessive salivation seen with the atypical antipsychotic clozapine (Schatzberg et al, 2010).


Pregabalin, an anticonvulsant medication, is showing positive results in both research and off-label treatment for anxiety disorders. Pregabalin acts by binding to a subunit of voltage-gated calcium channels, thus affecting the neuron’s reactivity to stimulation.


Despite the delayed onset of symptom relief, SSRIs and the newer antidepressants are taking first-line status in the treatment of anxiety disorders. Most of these antidepressants are showing beneficial actions for the majority of anxiety symptoms and have received FDA approval for the following indications:


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Feb 25, 2017 | Posted by in NURSING | Comments Off on Psychopharmacology
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