First-Generation Antipsychotics
First-generation antipsychotics are also referred to as conventional antipsychotics and typical antipsychotics. An overactivity of the dopamine system in the mesolimbic system may be
responsible for at least some of the symptoms of schizophrenia. These drugs are strong antagonists (blocking the action) of the D2 receptors for dopamine. By binding to these receptors and blocking the attachment of dopamine, they reduce dopaminergic stimulation. These drugs may be most effective on the “positive” symptoms of schizophrenia, such as delusions (e.g., paranoid and grandiose ideas) and hallucinations (e.g., hearing or seeing things not present in reality). Refer to Chapter 12 for a more detailed discussion of schizophrenia and its symptoms.
These drugs are also antagonists—to varying degrees—of the muscarinic receptors for acetylcholine, α1 receptors for norepinephrine, and (H1) receptors for histamine. Although it is unclear if this antagonism plays a role in the beneficial effects of the drugs, it is certain that antagonism is responsible for some of their major side effects.
Fig. 3.17 illustrates the proposed mechanism of action of the first-generation antipsychotics, which include the phenothiazines, thioxanthenes, butyrophenones, and pharmacologically related agents. As summarized in Fig. 3.18, many of the unpleasant side effects are logical given their receptor-blocking activity. For example, because dopamine (D2) in the basal ganglia plays a major role in the regulation of movement, it is not surprising that dopamine blockade can lead to motor abnormalities known as extrapyramidal symptoms (EPS). These EPS include acute dystonic reactions, parkinsonism, akathisia, and tardive dyskinesia.
Nurses and physicians often monitor patients for evidence of involuntary movements after administration of the first-generation antipsychotic agents. One popular scale is called the
Abnormal Involuntary Movement Scale (AIMS). Refer to Chapter 12 for an example of AIMS and a discussion of the clinical use of antipsychotic drugs, side effects, specific nursing interventions, and patient teaching strategies.
An important physiological function of dopamine is that it acts as the hypothalamic factor that inhibits the release of prolactin from the anterior pituitary gland. Therefore blockade of dopamine transmission can lead to increased pituitary secretion of prolactin. In women, this
hyperprolactinemia can result in amenorrhea (absence of the menses) or galactorrhea (excessive or inappropriate breast milk production), and in men, it can lead to gynecomastia (development of the male mammary glands) and galactorrhea.
Acetylcholine is a neurotransmitter that attaches to muscarinic receptors and helps regulate internal function. Blockade of the muscarinic receptors by phenothiazines and a wide variety of other psychiatric drugs can lead to a constellation of adverse effects. These side effects usually involve blurred vision, dry mouth, constipation, and urinary hesitancy. These drugs can also impair memory since acetylcholine is important for memory function.
FIG. 3.18 Adverse effects of receptor blockage of antipsychotic agents. From Varcarolis, E. [2004]. Manual of psychiatric nursing care plans [2nd ed.]. St. Louis, MO: Elsevier.
Many of the first-generation antipsychotic drugs also act as antagonists for norepinephrine. These receptors are found on smooth muscle cells that contract in response to norepinephrine from sympathetic nerves. For example, the ability of sympathetic nerves to constrict blood vessels is dependent on the attachment of norepinephrine to α1 receptors. Therefore blockade of these
receptors can bring about vasodilatation and a consequent drop in blood pressure. Vasoconstriction mediated by the sympathetic nervous system is essential for maintaining normal blood pressure when the body is in the upright position; blockade of the α1 receptors can lead to orthostatic hypotension.
Finally, many of these first-generation antipsychotic agents, as well as a variety of other psychiatric drugs, block the H1 receptors for histamine. The two most significant side effects of blocking these receptors are sedation and substantial weight gain. Sedation may be beneficial in severely agitated patients. Nonadherence to the medication regimen is a significant issue because of these troublesome side effects.
Second-Generation Antipsychotics
Second-generation antipsychotics are also known as atypical antipsychotics. These drugs produce fewer EPS and target both the negative and positive symptoms of schizophrenia (Chapter 12). These newer agents are often chosen as first-line treatments over the first-generation antipsychotics due a more favorable side effect profile.
Most of the available second-generation antipsychotics, however, can increase the risk of metabolic syndrome with increased weight, blood glucose, and triglycerides. The simultaneous blockade of receptors 5-HT2C and H1 is associated with weight gain from increased appetite stimulation via the hypothalamic eating centers. Strong anti-muscarinic properties at the M3 receptor on the pancreatic beta cells can cause insulin resistance leading to hyperglycemia. The receptor responsible for elevated triglycerides is currently unknown (Stahl, 2013). Clozapine and olanzapine have the highest risk of causing metabolic syndrome, while aripiprazole and
ziprasidone are among the lowest risk in this classification.
The second-generation antipsychotics are predominantly D2 (dopamine) and 5-HT2A (serotonin) antagonists (blockers). The blockade at the mesolimbic dopamine pathway decreases psychosis, similar to the way the first-generation antipsychotics work. Decreasing D2 stimulation can decrease psychosis, but cause adverse effects in the:
• Nigrostriatal area, which can cause the movement side effects of EPS.
• Mesocortical area, which can worsen cognitive and negative symptoms of schizophrenia.
galactorrhea, amenorrhea, and low libido.
Most second-generation antipsychotics have more 5-HT2A than D2 antagonist effects. Blocking the 5-HT2A receptors increases dopamine and norepinephrine. This may explain why the second- generation antipsychotics have less effect on causing EPS, cognitive impairment, and prolactin effects.
Clozapine
Clozapine (Clozaril) is an antipsychotic drug that is relatively free of the motor side effects of the phenothiazines and other second-generation antipsychotics. Clozapine preferentially blocks the D1
and D2 receptors in the mesolimbic system rather than those in the nigrostriatal area. This allows it to exert an antipsychotic action without leading to difficulties with EPS. However, it can cause a potentially fatal side effect. Clozapine has the potential to suppress bone marrow and induce agranulocytosis. Any deficiency in white blood cells renders a person prone to serious infection.
Therefore regular measurement of absolute neutrophil count (ANC) is necessary. Typically, the count is measured weekly for the first 6 months. If results are normal, counts will be measured every other week for the next 6 months and every month thereafter.
Clozapine has the potential for inducing convulsions, a dose-related side effect, in 3.5% of patients. Patients should use caution with other drugs that can increase the concentration of clozapine. Note that smoking cessation reduces CYP 1A2 enzymes and can increase clozapine’s concentration.
Risperidone
Risperidone (Risperdal) has a low potential for inducing agranulocytosis or convulsions. However, high therapeutic dosages (>6 mg/day) may lead to motor difficulties. As a potent D2 antagonist, it has the highest risk of EPS among the second-generation antipsychotics and may increase prolactin, which may lead to sexual dysfunction. Because risperidone blocks α1 and H1 receptors, it can cause orthostatic hypotension and sedation, respectively. Keep in mind that orthostatic hypotension can lead to falls, which are a serious problem among older adults.
Weight gain, sedation, and sexual dysfunction are adverse effects that may affect adherence to the medication regimen and should be discussed with patients. Risperdal Consta is an injectable form of the drug that is administered every 2 weeks, providing an alternative to the depot form of first-generation antipsychotics.
Quetiapine
Quetiapine (Seroquel) has a broad receptor-binding profile. Its strong blockade of H1 receptors accounts for the high sedation. The combination of H1 and 5-HT2C blockade leads to the weight gain associated with use of this drug and also to a moderate risk for metabolic syndrome. It causes moderate blockade of α1 receptors and associated orthostasis. Quetiapine has a low risk for EPS or prolactin elevation from low D2 binding due to rapid dissociation at D2 receptors. This drug is too commonly prescribed for sleep problems when other drugs should be considered.
Olanzapine
Olanzapine (Zyprexa) is similar to clozapine in chemical structure. It is an antagonist of 5-HT2, D2, H1, alpha-1, and muscarinic receptors. Side effects include sedation, weight gain, hyperglycemia with new-onset type 2 diabetes, and higher risk for metabolic syndrome. Olanzapine is also available in a long-acting intramuscular agent under the trade name of Zyprexa Relprevv.
Ziprasidone
Ziprasidone (Geodon) is a serotonin-norepinephrine reuptake inhibitor at multiple receptors: 5-HT2, D2, alpha-1, and H1D. Ziprasidone is contraindicated in patients with a known history of QT interval prolongation, recent acute myocardial infarction, or uncompensated heart failure. Each dose should be taken with food to enable absorption.
Aripiprazole
Aripiprazole (Abilify) is a unique second-generation antipsychotic known as a dopamine
modulator in addition to its 5-HT2A antagonist activity. Depending on endogenous dopamine levels and signaling status, aripiprazole has varying effects on the D2 receptor due to its partial agonist properties. In areas of the brain with excess dopamine, it lowers the dopamine level by acting as a receptor antagonist. However, in regions with low dopamine, it stimulates receptors to raise the dopamine level (De Bartolomeis et al., 2015). Aripiprazole lacks H1 and 5-HT2C properties, which explains its lack of sedation and weight gain, respectively.
Paliperidone
Paliperidone (Invega) is the major active metabolite of risperidone. It has similar side effects with regard to prolactin elevation. Other than the D2 and 5-HT2A antagonistic properties as an
antipsychotic, paliperidone is also an antagonist at alpha-1 receptors and H1 receptors, which explains the side effects of orthostasis and sedation, respectively. The Osmotic Release Oral System (OROS) provides consistent 24-hour release of the medication, leading to minimal peaks and troughs in plasma concentrations. It also has two long-acting injectable formulations: Invega Sustenna (every month) and Invega Trinza (every 3 months).
Iloperidone
Iloperidone (Fanapt) possesses minimal binding affinity for H1 receptors and has minimal affinity for cholinergic muscarinic receptors. A common adverse effect is orthostatic hypotension from the α1 blockade, which necessitates a slow dosage titration over the first few days to minimize
orthostatic hypotension. There was a significant increase in the mean QT interval, although no deaths or serious arrhythmias were noted in the clinical trials. Another limitation of this medication is the risk of orthostatic hypotension (Holmes & Zacher, 2012).
Lurasidone
Lurasidone (Latuda) has high affinity for 5-HT2A and D2 receptors in addition to other serotonergic receptors such as 5-HT1A. Lurasidone has similar pharmacological properties to the tetracyclic antidepressant mirtazapine. Lurasidone has high affinity for serotonergic (such as 5HT2A and 5HT2C), noradrenergic, and dopaminergic receptors (D3 and D4). There is minimal muscarinic receptor activity. Each dose must be taken with 350 calories to ensure optimal absorption.
Asenapine
Asenapine (Saphris) is unique among the antipsychotics as being administered in a sublingual formulation, which enhances its direct absorption. Therefore it avoids much of the hepatic metabolism that restricts its availability when administered orally. Bioavailability of asenapine is reduced from 35% with sublingual administration to less than 2% with oral administration. Patients should avoid food and water for 10 minutes after sublingual administration (Holmes & Zacher, 2012). It has a higher affinity for 5-HT2A receptors than D2 receptors. It also has antagonistic activity at alpha-1 receptor that accounts for the orthostatic hypotension, and H1 antagonistic activity, which causes sedation. Chapter 12 discusses the first- and second-generation antipsychotic drugs in detail including the indications for use, adverse reactions, nursing implications, and patient and family teaching.