PHARMACOLO NURS 251 MODULE 8 -PORTAGE LEARNING, Exams of Nursing

Download PHARMACOLO NURS 251 MODULE 8 -PORTAGE LEARNING and more Exams Nursing in PDF only on Docsity!

Module 8

8.1: Pain

Pain is a basic protective mechanism of the body. The sensation of pain may serve as a warning of imminent danger (fire) or that there is something wrong in the body (cancer). Alternatively, pain can accompany the normal healing process (inflammation). When the intensity and duration of a person’s pain begin to affect their ability to function, analgesics can become very helpful. Analgesics are defined as medications that relieve pain without causing a loss of consciousness. As there are different types of pain, the appropriate pharmacologic therapy may differ from one type of pain to another. Acute pain is sudden in onset and usually subsides when treated. Acute pain often lasts 6 weeks or less in duration. Chronic pain is persistent or recurring and often much more difficult to treat. It is classified as any pain lasting 3- months or pain lasting longer than 1 month after healing of an acute injury. Tolerance refers to a state in which the effectiveness of a drug is significantly reduced following its prolonged use. As the body adapts, more of the drug becomes required to achieve the same initial physiological effect. Should the drug be stopped abruptly or smaller dosages given, unpleasant physical and mental symptoms are often observed, a state referred to as withdrawal. Under such conditions, a physical dependence , which is a need to continue taking a drug to avoid the unwanted side-effects of its absence, is said to be established. In order to avoid withdrawal, the continual use of a drug may lead to addiction. Addiction is defined as a chronic neurobiological disease in which genetic, psychosocial, and environmental factors induce changes in the individual’s behavior to compulsively use drugs despite the harm they may cause. For these reasons, the treatment of chronic pain can be especially challenging and should be closely monitored. Most a nalgesics can be classified as either opioids or non-opioids. Opioid analgesics are synthetic drugs that bind to the opiate receptors in the brain and relieve pain. Opioid analgesics are strong painkillers and are capable of alleviating pain of any origin. They are known to cause tolerance and physical dependence and therefore should be reserved for moderate to severe pain. Nonopioid analgesics include painkillers that do not work on opioid receptors, the primary example being Non-Steroidal Anti-inflammatory Medications (NSAIDs) as introduced in Module 2. NSAIDs are a large, chemically diverse group of drugs that are analgesics and also possess anti-inflammatory and antipyretic activity. Neuropathic pain is a unique classification of pain and is defined as pain resulting from a damaged nervous system or damaged nerve cells. Due to its unique origin, neuropathic pain does not typically respond to traditional pain medications including opioids and NSAIDs. It can be extremely difficult to manage and is generally treated with a variety of medications from different classes that have shown to have some effect on neuropathic pain. Examples include antiseizure medications, antidepressants, and new classes that have been developed to treat neuropathic pain. Fibromyalgia is one of the most common neuropathic pain conditions and is defined as a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, and sleep, memory and mood issues. Researchers believe that fibromyalgia amplifies painful sensations by affecting the way your brain processes pain signals.

Drug Therapy

Opioids

Opioids are often referred to as narcotics. However, when referencing drugs being used medicinally, opioid is the correct term. Opioids are a class of very strong pain relievers originating from the opium poppy plant. Relatively basic chemical modifications of these natural opioids have produced three different chemical classes of opioids: (1) morphine-like

PHARMACOLO NURS 251 MODULE 8 -PORTAGE LEARNING

drugs, (2) meperidine-like drugs, and (3) methadone-like drugs. This can be important in selecting a drug for a patient who has had an adverse reaction to one type of opioid. Table 8.1 summarizes the chemical categories of several opioid analgesics. Mechanism of Action: Opioid analgesics work by binding to the opioid receptors in the brain causing an analgesic response. Most opioids used for their analgesic properties are classified as opioid agonists (meaning they stimulate opioid receptors). In order to elicit the effects of pain relief, opioids bind to different types of opioid receptors—the most prevalent being the mu, kappa, and delta receptors. It is also important to note that opioids differ in their relative potency. Proper knowledge of potency is critical when these medications are being used clinically, especially when transitioning from one opioid to another. In order to do this safely, the clinician must know the relative potency of each opioid. A system was devised whereby morphine would be the opioid that all other opioids are compared to in terms of potency, a practice referred to as morphine equivalents. Thus, by using morphine there is a standard drug to compare to that is consistently used when switching between opioids. This helps to standardize the process of converting patients to new regimens. Table 8. below summarizes some of the more common opioid analgesics and specifies their relative potency compared to morphine.

Adverse Effects: All opioid drugs have a strong potential for being abused. In addition to the potential for abuse, opioids can cause histamine release which may cause itching, rash and hemodynamic changes such as flushing and orthostatic hypotension (a drop in blood pressure upon standing up from a seated position). How much histamine an opioid release is related to which chemical category they fall into. For example, morphine-like opioids release the most histamine, whereas meperidine-like opioids release the least amount of histamine. The most serious adverse effect is CNS depression that can lead to respiratory depression. Patients need to be monitored for signs of respiratory depression. When people die from an opioid overdose it is almost always from respiratory depression. Less serious, but very common, are the GI tract adverse effects that occur with opioid medications. There are opioid receptors in the GI tract that, when stimulated, cause nausea, vomiting, and constipation. The stimulation of GI opioid receptors stimulates the chemoreceptor trigger zone in the brain which results in nausea and vomiting. Constipation results from opioids working to slow peristalsis and increasing the absorption of water from the intestines. Nausea and vomiting often dissipate over time. Constipation, however, does not. In fact, most patients on longer-term opioids need to be treated with a bowel regimen to prevent constipation. Toxicity and Overdose: Naloxone and naltrexone are two opioid antagonists available to treat opioid overdose. Because they are such strong antagonists, they can actually reverse adverse effects such as respiratory depression caused by an opioid overdose. Naloxone is available under the trade name Narcan (nasal spray) and Evzio (autoinjector). Due to the growing overdose

epidemic in the United States, many states (41 as of August 2018) have now put standing orders in place, making Naloxone available to people without a prescription. The hope is that increasing the accessibility of a lifesaving medication can minimize deaths due to overdose and allow more people the chance to seek help through addiction and recovery programs. Drug Interactions: Coadministration of opioids with other CNS depressants can result in additional respiratory depression. Examples of this drug include barbiturates, benzodiazepines, and alcohol. Non-opioids: NSAIDs Non-Steroidal Anti-inflammatory Drugs (NSAIDs) are considered mild analgesics and are typically used to relieve low- intensity pain associated with inflammation. They are often used in treating arthritis, headaches, joint, and muscle pain. In addition to their analgesic effect, they also have anti-inflammatory and anti-pyretic effects. They are considered the drug of choice in many different conditions listed in Table 8.3. There are currently over 23 different NSAIDs available as outlined in Table 8.4. The degree of response to any particular NSAID is patient dependent. Prior to understanding how NSAIDs work within the body to relieve pain, we must first review the process of inflammation. Inflammation is defined as a localized protective response stimulated by injury to tissues that serve to destroy, dilute, or wall off both the injurious agent and the injured tissue. As a direct result of enhanced blood flow to the site of injury, typical signs of inflammation include pain, fever, redness, swelling, and loss of function. The inflammatory response is triggered when there is an injury. The first response of the body is to release arachidonic acid from phospholipids in the cell membrane. There are then two pathways by which the arachidonic acid can be metabolized: (1) the prostaglandin pathway or (2) the leukotriene pathway. The ultimate effects of both of these pathways are inflammation, edema, headache, and other pain characteristics.

The prostaglandin pathway involves an enzyme cyclooxygenase (COX) that converts arachidonic acid into various prostaglandins that then go on to cause inflammation by increasing vasodilation and vasopermeability. This then, in turn, increases the action of other proinflammatory substances like histamine and bradykinin. The leukotriene pathway is not as understood but involves the enzyme lipoxygenase that converts the arachidonic acid to various leukotrienes and increases the body’s inflammatory response. Mechanism of Action: In very general terms, the NSAIDs work by inhibiting the leukotriene or prostaglandin pathway or both. They specifically work by blocking the enzyme cyclooxygenase or COX. It is now known that there are at least two types of cyclooxygenase referred to as COX-1 and COX-2. COX-1 has been shown to have many beneficial effects within the body such as maintaining an intact GI tract. COX-2 conversely has been shown to have more of a primary role in the conversion of prostaglandins that lead to inflammation. The inhibition of COX-1 makes NSAIDs ulcerogenic and puts patients at risk for a GI bleed. Aspirin is unique in that it also inhibits platelet aggregation. This happens via irreversible inhibition of COX-1 receptors within platelets. This blocking of the COX-1 receptors reduces thromboxane A2 which typically promotes platelet aggregation. Aspirin is a primary drug used in the treatment of myocardial infarctions (heart attacks) as well as other clotting disorders. Other NSAIDs do not have these same antiplatelet effects. In 1998, a new class of COX-2 specific NSAIDs was developed. These new COX-2 selective enzymes were designed to have anti-inflammatory effects without the prevalence of GI side effects like ulcer formation due to the lack of COX- inhibition. Notably, prior to the COX-2 selective NSAIDs, NSAIDs inhibited both COX-1 and COX-2. The leukotriene pathway is also inhibited by NSAIDs but is not as understood. It is known that salicylates do not inhibit the leukotriene pathway. Adverse Effects: Despite their wide use and availability, NSAIDs are known to have some serious side effects. The primary negative effect is on the GI tract. These effects can vary ranging from mild heartburn to more serious gastrointestinal bleeds. Another serious adverse event is the risk of acute renal (kidney) failure. More recently, it has been shown that NSAIDs can also play a role in increasing the risk of a patient having a heart attack or stroke. Drug Interactions: NSAIDs can interfere with a variety of drugs. Common examples include: increased risk of bleeding when taken with anticoagulants, increased GI toxicity when taken with aspirin or other salicylate type NSAIDs, increased risk of ulcers when taken with corticosteroids, reduced hypotensive and diuretic effects of ACE-inhibitors, and diuretics due to inhibiting renal prostaglandin synthesis. Neuropathic Pain Management As a result of neuropathic pain not being fully understood, the medications used to treat this type of pain are also not fully understood. Two of the most common medications used to treat neuropathic pain are classified as antiseizure medications and are structurally related to each other: (1) gabapentin and (2) pregabalin Gabapentin (Neurontin) Mechanism of action is not fully understood. Structurally, gabapentin is a chemical analogue of GABA which is a neurotransmitter that inhibits brain activity. It is thought to work in part by building up GABA in the brain, possibly minimizing the brain activity that is signaling the sensation of pain.

Adverse Events: Dizziness, drowsiness, nausea, visual and speech changes, and edema. Drug Interactions : Increased CNS depression when combined with alcohol. Pregabalin (Lyrica) Mechanism of Action is not fully understood. It is structurally similar to gabapentin, but it does not bind to GABA but rather to alpha2-delta receptor sites. This affects the calcium channels in the CNS tissue. Adverse Events : Dizziness, drowsiness, peripheral edema, and blurred vision. Drug Interactions : None. Potential to have additive CNS depression with other sedating drugs. Other medications that can be used to treat neuropathic pain include antidepressants such as the newer medication called milnacipran (Savella) as well as amitriptyline (Elavil), venlafaxine (Effexor) and duloxetine (Cymbalta). For drug details, see the section ‘Antidepressants’ below. Milnacipran (Savella) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), which is the same pharmacologic class as duloxetine. The difference being that it is not indicated for depression but rather is only indicated for fibromyalgia. Mechanism of Action: The exact mechanism of action of milnacipran and its ability to improve the symptoms of fibromyalgia is still uncertain. Preclinical studies have shown milnacipran is a potent inhibitor of norepinephrine and serotonin reuptake without directly affecting the uptake of dopamine or other neurotransmitters. Adverse Events: Nausea, headache, constipation, dizziness, insomnia, hot flush, excessive sweating, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Drug Interactions: Use of Savella with digoxin may be associated with potentiation of adverse hemodynamic effects such as postural hypotension and tachycardia. Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine’s anti-hypertensive effect. Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action.

8.2: Mental Illness

There are several different mental health disorders of which the exact cause is not fully understood. One of the primary theories involves a chemical imbalance of neurotransmitters within the brain. Neurotransmitters are endogenous chemicals that serve to conduct nerve impulses between nerve cells. Examples of this include dopamine, norepinephrine, and serotonin. It is thought that the levels of these neurotransmitters in the brain specifically play an important role in maintaining mental health. Many of the drugs used to treat different mental illnesses work by blocking or stimulating the release of different neurotransmitters. In general, the symptoms of different psychiatric disorders can overlap, making it very difficult to accurately diagnose. Complicating matters further, the symptoms are also very subjective in nature as they are based on the patient’s subjective experience of them. Examples of disorders include (1) anxiety, (2) affective disorders, and (3) psychosis.

Anxiety- is defined as an unpleasant state of mind in which real or imagined dangers are anticipated and/or

exaggerated. Clinically, different types of anxiety have been classified. Common examples include: General anxiety disorder (GAD), panic disorder, obsessive compulsive disorder (OCD), and Post traumatic stress disorder (PTSD). The drugs used to treat anxiety are called anxiolytics and are primarily the benzodiazepines drug class and the miscellaneous drug buspirone. In addition to these medications, some antidepressants are also effective in treating anxiety.

Drug Therapy Benzodiazepines- are the primary drugs used to treat anxiety both acutely and for patients with chronic anxiety disorders. Unlike most mental health medications, benzodiazepines can be used as needed to treat anxiety symptoms quickly. They can also be used to treat alcohol withdrawal, insomnia, and seizure disorders. See Table 8.5 for a list of commonly used benzodiazepines. Mechanism of Action: In general, these drugs work by reducing the over-activity in a person’s brain causing the unwanted anxiety. They do this by increasing the action of an inhibitory neurotransmitter called GABA (gamma aminobutyric acid). Adverse Events: Most commonly, they cause excessive CNS depression (symptoms include: sedation, lethargy, fatigue, confusion, drowsiness, and dizziness) which is essentially a sign of excess therapeutic effect. They can also cause hypotension. Most importantly, all benzodiazepines can be habit-forming and addictive, making them a schedule IV- controlled substance. Drug Interactions: As expected, when benzodiazepines are combined with other CNS depressants (including alcohol), additional CNS depression and even death can occur. Buspirone (Buspar)- is a unique medication in a class of its own. Unlike benzodiazepine, buspirone cannot be used “as needed.” It needs to be used on a daily basis to exert its effect. It is not known to cause the sedation that benzodiazepines cause nor is it addictive. Mechanism of Action: Buspirone’s mechanism of action is not completely understood. It is thought to work on both serotonin and dopamine receptors. Buspirone takes about 2-3 weeks to exert its full effect. Adverse Events: Dizziness, blurred vision, headache, and nausea. Drug Interactions: Buspirone levels increase when combined with CYP3A4 inhibitors like ketoconazole, verapamil, and diltiazem. It should not be taken with MAOI and increases the risk of serotonin syndrome when combined with other drugs that increase serotonin like the antidepressants. Affective Disorders (mood disorders) are defined as emotional disorders characterized by changes in mood and include Major Depressive Disorder (also called clinical depression) and Bipolar Disorder. Major Depressive Disorder is a mood disorder that causes persistent feelings of sadness and loss of interest that interfere with one’s ability to do normal activities. Bipolar , formerly called manic depressive illness, is specifically defined as a psychological disorder characterized by episodes of mania or hypomania cycling with depression. Mania is an acute illness characterized by an expansive emotional state including extreme excitement, elation, hyperactivity, agitation, talkativeness, flight of ideas, reduced attention span, increased psychomotor activity, impulsivity, insomnia, anorexia, and sometimes violent destructive and self-destructive behavior.

Depression is defined as an abnormal emotional state characterized by exaggerated feelings of sadness, melancholy, dejection, worthlessness, emptiness, and hopelessness. Signs include withdrawal from social contact, loss of appetite, and insomnia. Drug Therapy Mood Stabilizers are the primary drugs used to treat bipolar disorder. There is evidence to suggest that episodes of mania are related to dopamine and norepinephrine levels in the brain. It is likely that serotonin also plays a role. Interestingly, many of the drugs of choice for bipolar disorder are antiepileptic drugs or antipsychotic drugs (see drug specifics under the ‘Psychosis’ section below). Lithium is the only drug uniquely used as a mood stabilizer specifically for the symptoms of acute mania and for maintenance treatment in bipolar disorder. See Table 8.6 for a list of the drugs used to treat bipolar disorder. Lithium has been used for many symptoms to both prevent and alleviate the symptoms of acute mania. The mechanism of action is not completely understood but is thought to occur because lithium ions alter sodium ion transport which alters the metabolism of both dopamine and norepinephrine. Importantly, the therapeutic level of lithium is very close to the toxic level. As such, blood levels need to be monitored. See Table 8.7 for a list of the adverse effects and drug interactions associated with lithium. The adverse effects correlate with the level of lithium in the body. Antiepileptics, listed above in Table 8.6, are often the drugs of choice for bipolar disorder. They are effective in treating mania, hypomania and depressive symptoms. The exact mechanism of action of how these antiepileptics work in not fully understood. In general, they work to stabilize neurons in order to keep them from becoming hyperexcited and generating excessive nerve impulses. Antiepileptic drugs are known to have many adverse effects and drug interactions (primarily mediated through the CYP450 system) to be aware of, as outlined below in Table 8..

8.3: Antidepressants

Antidepressants are the drug of choice for the treatment of major depressive disorder. Most often, they work by increasing the neurotransmitter concentration in the CNS. They specifically target serotonin, dopamine, and norepinephrine. The theory is that there are alterations in the levels of these specific chemicals in the brain that causes the depression. What specifically is out of balance is still a topic of scientific research. However, research does show that early and aggressive treatment with antidepressants increases a patient’s chance for a full remission. The treatment approach consists of an acute phase where the goal is to see an improvement in the patient’s symptoms in the first 6- weeks. Once you find a drug therapy that works, and the patient exhibits a response in the acute phase, it is recommended to continue treatment for an additional 8-14 months after the remission of depressive symptoms. Response to drug therapy is primarily subjective based on the patient’s feedback. Selection of drug therapy should take psychotropic drug history, family history, and side effect profile of the drugs all into account. A non-response to an antidepressant is defined as failure to respond after at least 6 weeks at an adequate dose. If a patient is not responding, the first step should be dose optimization followed by a trial of an alternate drug. There are several different classes of antidepressant. The First generation (Tricyclic Antidepressants, Monoamine Oxidase Inhibitors) have almost been completely replaced by the newer second generation due to better side effect profiles and less interactions. As such, the focus will be on second-generation antidepressants including (1) Selective Serotonin Reuptake Inhibitors (SSRIs), (2) Selective Norepinephrine Reuptake Inhibitors (SNRIs), and (3) a few miscellaneous antidepressants. See Table 8.9 for a listing of the available antidepressants.

First Generation Antidepressants Tricyclic Antidepressants (TCAs) are named for their characteristic three rings chemical structure. They work by correcting the imbalance of serotonin and norepinephrine in the nerve endings of the CNS. Specifically, they block the reuptake making them available to transmit nerve impulses. Uses: Although TCAs were developed to treat depression, the SSRIs and SNRIs have for the most part replaced them. However, they are still used clinically, most often for neuropathic pain. There are also unique instances where TCA usage is appropriate, such as the use of clomipramine for OCD while imipramine is used to treat enuresis (bedwetting) in childhood. Adverse Events: Primary adverse effects are a result of their blockade of the anticholinergic receptors. This causes unwanted anticholinergic side effects such as urinary retention and constipation. Additionally, the blockade of adrenergic and dopaminergic receptors can cause cardiac side effects. Histamine blockade is associated with sedation. Lastly, serotonergic blockade can result in a lower seizure threshold and cause sexual dysfunction. In an overdose situation, the increased risk of seizure and cardiac conduction issues can both be lethal. Drug Interactions: TCAs should not be combined with MAOIs due to the risk of increased serotonergic effects and potential for serotonin syndrome. Serotonin syndrome can result when there is too much serotonin in a person’s body leading to symptoms of confusion, agitation, rapid heart rate, sweating, headache, muscle rigidity, fever, and in severe cases seizures, irregular heartbeat, and unconsciousness. MAOIs are now rarely used to treat depression; however, they are sometimes still used to treat Parkinson’s disease. Adverse effects include dry mouth, urinary retention, constipation, blurred vision, hypotension, weight gain, sexual dysfunction, CNS disturbances such as restlessness, dizziness, insomnia, tremors, and seizures. All of these are intensified with overdose. They can also cause liver damage which can be fatal. They are also known to cause a hypertensive crisis (BP greater than 180/110mgHg) when combined with certain medications, like stimulants or in combination with tyramine-containing foods. MAOIs exert their effect by inhibiting monoamine oxidase, an enzyme system that breaks down neurotransmitters. Second Generation Antidepressants Second Generation Antidepressants began to be introduced in the 1980’s and include the SSRIs and the SNRIs. Fluoxetine (Prozac) was the first SSRI approved and is considered the prototypical SSRI. They have replaced the TCAs and

MAOIs for the treatment of depression because of their superior side effect profiles—they are associated with far fewer anticholinergic and cardiac side effects. Similar to TCAs and MAOIs, it takes about 4-6 weeks to see the full clinical effect. SSRIs and SNRIs Mechanism of action: The SSRIs work primarily by blocking the reuptake of serotonin. The SNRIs work by inhibiting the reuptake of both serotonin and norepinephrine. Use: The primary indication is depression. However, they have been shown to have benefits in treating other disorders as well. Examples of these disorders include bipolar disorder, obesity, eating disorders, OCD, panic attacks, social anxiety, and PTSD. Their uses continue to grow as research continues. Adverse Events: They do have improved side effect profiles over the first-generation antidepressants. However, many patients still find their side effects unwanted and discontinue treatment. Although they may not be as serious as with the TCAs and MAOIs, they can be problematic to patients. Examples include insomnia, weight gain, and sexual dysfunction. These drugs can also cause serotonin syndrome when combined with other drugs that increase serotonin levels. Drug Interactions: SSRIs have a risk of serotonin syndrome when combined with MAOIs, lithium, and buspirone. They can increase the potential for benzodiazepine toxicity when used in combination. They also increase warfarin (anticoagulant) and phenytoin (antiepileptic) levels. SNRIs have a risk for serotonin syndrome when combined with SSRIs or triptans (migraine medications) and may also increase the risk of bleeding when combined with warfarin or NSAIDs. Select Miscellaneous Antidepressants Bupropion is a unique antidepressant that seems to exert its effect on dopamine and norepinephrine. It was originally indicated for depression and is often still used, especially as add-on therapy. However, it has also been shown to be effective in smoking cessation. It is important to note, that bupropion is also known to lower the seizure threshold and as such should not be used in a patient with a seizure disorder. Bupropion should not be taken with MAOIs. Adverse effects of this include dizziness, confusion, tachycardia, agitation, tremor, and dry mouth. Trazodone is another unique antidepressant that falls into the triazolopyridine class. It was the first of the second- generation antidepressants that could selectively inhibit serotonin reuptake without affecting norepinephrine. It has minimal cardiac side effects and is indicated for depression. It is also commonly used to treat insomnia because of known sedative qualities. Vilazodone (Viibryd) is similar to trazodone although it acts both on serotonin and 5-HT1A receptors. Psychotic Illness Psychosis - A type of serious mental illness associated with being out of touch with reality. The individual is unable to distinguish the imaginary from real circumstances and events. Schizophrenia is a major form of psychosis where behavior is inappropriate. Symptoms of this include bizarre behavior, auditory and visual hallucinations, lack of motivation and emotional expression, and diminished speech and thought processes. The dopamine hypothesis of psychosis asserts patients have excessive dopaminergic activity in the brain. Therefore, drug therapy is aimed at reducing this activity. Drug Therapy Antipsychotics are the drugs of choice to treat these severe mental illnesses. Similar to antidepressants, there are first- generation antipsychotics and second-generation antipsychotics. The first-generation drugs are used much less frequently now that the second generation of “atypical antipsychotics” has been introduced. The atypical antipsychotics have better adverse event profiles. Table 8.10 lists out the different types of antipsychotics.

All antipsychotics are able to impact the positive symptoms of schizophrenia. Positive symptoms include delusions, hallucinations, and mental confusion—things appear to be present that should not be actually present. However, the conventional drugs are not as effective at treating the negative symptoms. Negative symptoms include apathy, social withdrawal, blunted affect, and monotone speech. While possibly less obvious, these symptoms are the ones that cause the most disruption to people’s lives in terms of being able to interact socially and hold a steady job. Fortunately, the newer atypical antipsychotics are able to treat both the positive and negative symptoms. These drugs were primarily developed to be used to treat psychotic illnesses, most commonly schizophrenia. However, many antipsychotics are now used to treat other mental disorders such as bipolar disorder, depression (when used in combination with an antidepressant), and even autism. Mechanism of Action: Antipsychotics all work by blocking dopamine receptors in the brain, thus decreasing the concentration of dopamine in the CNS. The phenothiazine class block receptors in areas of the brain such as the limbic system and basal ganglia, which are areas associated with cognitive function, motor function, and emotions. Both the therapeutic effects of antipsychotics and the toxic effects are a result of this dopamine blockade. The newer, atypical antipsychotics are more selective in the dopamine blockade targeting a specific dopamine receptor, dopamine 2 (D 2 ) in addition to some serotonin (5-HT 2 ) receptors. This more targeted mechanism leads to an improved efficacy and safety profile. Adverse Effects: Antipsychotics exert their therapeutic effect primarily by blocking the dopamine receptors in the brain, but they also block other neurotransmitter receptors leading to many of their adverse effects. Although the dopamine blockade is the mechanism by which most of the therapeutic effects stem from, this blockade is also where some of the more serious and unique side effects are derived. Three of the most notable being: (1) extrapyramidal symptoms, (2) tardive dyskinesia, and (3) neuroleptic malignant syndrome. Extrapyramidal Symptoms (EPS )- The term for signs and symptoms that resemble pathologic changes to the pyramidal portions of the brain. Such symptoms include various motion disorders similar to those seen in Parkinson’s disease and are adverse effects associated with various antipsychotic drugs. Specific symptoms include akathisia (motor restlessness) and dystonia (painful muscle spasms). Tardive Dyskinesia- Drug-induced involuntary movements of the lips, jaw, tongue, and extremities. Neuroleptic malignant syndrome (NMS) - An uncommon but serious adverse event associated with the use of antipsychotic drugs. Symptoms include fever, cardiovascular instability, and muscle breakdown. Other adverse effects are listed by receptor type in Table 8.11. These adverse effects may vary between the specific drugs based on the degree of affinity for their individual receptors. Atypical antipsychotics, in general, tend to show less of these receptor-mediated side effects.

Atypical antipsychotics have been shown to have other adverse effects related to their unwanted effect on the endocrine system. Insulin resistance, weight gain, and changes in lipids have all been shown to occur. This is referred to as metabolic syndrome and should be monitored for in all patients taking these medications. Drug Interactions: The main two drug classes to consider are other drugs that act on the CNS and antihypertensives. When used in combination with other CNS depressants, there may be additive CNS depressant effects. Secondly, there may be additional antihypertensive effects when taken with antihypertensives. Question 1 Describe the characteristics of different types of pain including acute, chronic, and neuropathic. Acute pain is sudden in onset and usually subsides when treated lasting 6 weeks or less in duration. Chronic pain on the other hand is persistent or recurring and often much more difficult to treat. It is classified as any pain lasting 3-6 months or pain lasting longer than 1 month after healing of an acute injury. Chronic pain is especially hard to treat because changes can occur in how the body responds to analgesics over time. Neuropathic pain is a unique classification of pain and is defines as pain resulting from a damaged nervous system or damaged nerve cells. Due to its unique origin it does not typically respond to traditional pain medications including opioids and NSAIDs. It can be extremely difficult to manage and is generally treated with a variety of medications from different classes that have shown to have some effect on neuropathic pain. Question 2 Define key terms: addiction, analgesic, opioids analgesics, NSAIDs, opioid tolerance, physical dependence. Addiction is defined as a chronic neurobiological disease in which genetic, psychosocial, and environmental factors induce changes in the individual’s behavior to compulsively use drugs despite the harm they may cause. Analgesics are defined as medications that relieve pain without causing loss of consciousness. Opioid analgesics are synthetic drugs that bind to the opiate receptors in the brain and relieve pain Non-Steroidal Anti-inflammatory Medications (NSAIDs) are a large chemically diverse group of drugs that are analgesics and also possess anti-inflammatory and antipyretic activity Tolerance refers to the state in which repetitive exposure to a given drug over time induces changes in the drug receptors that reduce the drug’s effects. Physical dependence is a condition in which a patient takes a drug over a period of time and unpleasant physical symptoms (withdrawal) occur if the drug is stopped abruptly or smaller doses are given and is another sign that tolerance has developed.

Question 3 Provide examples of drugs classified as NSAIDs, opioids and neuropathic pain medications and list the common side effects of each. NSAIDs side effects: The primary one being their negative effect on the GI tract. These effects can vary ranging from mild heartburn to more serious gastrointestinal bleeds. Another serious adverse event is the risk of acute renal failure. More recently, it has been shown that NSAIDs can also play a role in increasing the risk of a patient having a heart attack or stroke. Salicylates Cyclooxygenase-2 Inhibitors Aspirin (generic only) Celecoxib (Celebrex) Diflunisal (Dolobid) Salsalate (Salistab) Enolic Acid Derivative Choline salicylate (Arthrpan) Nabumetone (Relafen) Meloxicam (Mobic) Acetic Acid Derivatives Piroxicam (Feldene) Diclofenac sodium (Voltaren) Indomethacin (Indocin) Propionic Acid Derivative Sulindac (Clinoril) Fenoprofen (Nalfon) Tolmetin (Tolectin) Flurbiprofen (Ansaid) Etodolac (Lodine) Ibuprofen (Motrin, Advil) Ketorolac (Toradol) Ketoprofen (Orudis KT) Meclofenamate (generic only) Naproxen (Naprosyn, Aleve) Mefenamic acid (Ponstel) Oxaprozin (Daypro) Opioid side effects: They can cause histamine release that can cause itching, rash and hemodynamic changes such as flushing and orthostatic hypotension. Morphine like opioids release the most histamine whereas meperidine like opioids have the least histamine response. The most serious adverse effect is CNS depression that can lead to respiratory depression. Less serious but very common are the GI tract adverse effects. There are opioid receptors in the GI tract that when stimulated cause nausea, vomiting, and constipation. This stimulation of GI opioid receptors stimulates the chemoreceptor trigger zone in the brain which results in nausea and vomiting. Constipation results from opioids working to slow peristalsis and increasing absorption of water into the intestines. Opioid Analgesics Codeine Hydrocodone Oxycodone Morphine Methadone Meperidine Oxymorphone Hydromorphone Fentanyl Neuropathic Pain Medications Gabapentin- dizziness, drowsiness, nausea, visual and speech changes, edema Pregabalin- dizziness, drowsiness, peripheral edema, and blurred vision. Milnacipran- nausea, headache, constipation, dizziness, insomnia, hot flush, excessive sweating, vomiting, palpitations, heart rate increased, dry mouth, and hypertension

Duloxetine, Venlafaxine- insomnia, weight gain, sexual dysfunction. These drugs can also cause serotonin syndrome when combines with other drugs that increase serotonin levels. Amitriptyline- unwanted anticholinergic side effects such as urinary retention and constipation. Additionally, the blockade of adrenergic and dopaminergic receptors and cause cardiac side effects. Histamine blockade causes sedation and serotonergic blockade can result in a lower seizure threshold and cause sexual dysfunction. The risk of seizure and cardiac conduction issues can be lethal in an overdose situation. Question 4 Review the basic mechanism of action for NSAIDs and Opioids. NSAIDs- In very general terms the NSAIDs work by inhibiting the leukotriene or prostaglandin pathway or both. They specifically work by blocking the enzyme cyclooxygenase or COX. Opioids- Opioid analgesics work by binding to the opioid receptors in the brain causing an analgesic response. Most opioids used for their analgesic properties classified as opioid agonists. There are different types of opioid receptors that opioids bind to in order to relieve pain. The mu, kappa, and delta are the most prevalent. Question 5 Discuss opioid antagonists (naloxone), specifically how it is used and how its availability has recently changed. Naloxone and naltrexone are two opioid antagonists available to treat opioid overdose. Because they are such strong antagonists, they can actually reverse the effects such as respiratory depression caused by an opioid overdose. Naloxone is available under the trade name Narcan as a nasal spray and Evzio, which is an autoinjector. Due to the growing overdose epidemic in the United States, many states (41 as of August 2018) have now put standing orders in place, making Naloxone available to people without a prescription. The hope is that increasing the accessibility of a lifesaving medication can minimize deaths due to overdose and allow more people the chance to seek help through addiction and recovery program. Question 6 Define some key terms related to psychotherapeutic drugs: anxiety, bipolar disorder, depression, mania, psychosis, schizophrenia. Anxiety is defined as an unpleasant state of mind in which real or imagined dangers are anticipated and/or exaggerated. Bipolar specifically, is characterized by both mania and depression and is defined as a psychological disorder characterized by episodes of mania or hypomania cycling with depression. Formerly called manic depressive illness. Depression is defined as an abnormal emotional state characterized by exaggerated feelings of sadness, melancholy, dejection, worthlessness, emptiness, and hopelessness. Signs include withdrawal from social contact, loss of appetite, and insomnia Mania is an acute illness characterized by an expansive emotional state including extreme excitement, elation, hyperactivity, agitation, talkativeness, flight of ideas, reduced attention span, increased psychomotor activity, impulsivity, insomnia, anorexia, and sometimes violent destructive and self-destructive behavior. Psychosis A type of serious mental illness that is associated with being out of touch with reality where the individual is unable to distinguish imaginary from real circumstances and events. Schizophrenia is a major form of psychosis where behavior is inappropriate. Symptoms include bizarre behavior, auditory and visual hallucinations, lack of motivation and emotional expression, and diminished speech and thought processes.

Question 7 Describe the importance of neurotransmitter function in the cause and treatment of depression. Antidepressants are the drug of choice for the treatment of major depressive disorder. In general, they work by increasing the neurotransmitter concentration in the CNS. They specifically target serotonin, dopamine and norepinephrine. The theory is that there are alterations in the levels of these specific chemicals in the brain that causes the depression. What specifically is out of balance is still a topic of scientific research. Question 8 Describe the importance of dopamine and serotonin in relationship to psychosis and antipsychotic drug therapy. The dopamine hypothesis of psychosis is that these patients have excessive dopaminergic activity in the brain. Therefore, drug therapy is aimed at reducing this activity. Antipsychotics all work by blocking dopamine receptors in the brain, thus decreasing the concentration of dopamine in the CNS. Both the therapeutic effects of antipsychotics and the toxic effects are a result of this dopamine blockade. The newer, atypical antipsychotics are more selective in the dopamine blockade targeting a specific dopamine receptor, dopamine 2 (D 2 ) in addition to some serotonin (5-HT 2 ) receptors. This more targeted mechanism leads to an improved efficacy and safety profile. Question 9 List the various psychotherapeutic drug classes such as anxiolytic drugs, antidepressants, mood stabilizers, and antipsychotics. Anxiety: benzodiazepines and buspirone Antidepressants: Tricyclic antidepressants, MAOIs, SSRIs, SNRIs Mood Stabilizers: Lithium, antiepileptic, antipsychotics Antipsychotics: Conventional antipsychotics, atypical antipsychotics Question 10 Describe general mechanism of action of each of the above drug classes. Benzodiazepines: In general, these drugs work by reducing the overactivity in a person’s brain that is causing the unwanted anxiety. They do this by increasing the action of an inhibitory neurotransmitter called GABA (gamma aminobutyric acid). Buspirone: Buspirone’s mechanism of action is not completely understood. It is thought to work on both serotonin and dopamine receptors. Tricyclic antidepressants: work by correcting the imbalance or serotonin and norepinephrine in the nerve endings of the CNS. Specifically, they block the reuptake making them available to transmit nerve impulses. MAOIs: They exert their effect my inhibiting monoamine oxidase, an enzyme system that breaks down neurotransmitters. SSRIs: The SSRIs work primarily by blocking the reuptake of serotonin. SNRIs: The SNRIs work by inhibiting the reuptake of both serotonin and norepinephrine. Lithium: The mechanism of action is not completely understood, but is thought to occur because lithium ions alter sodium ion transport which alters the metabolism of both dopamine and norepinephrine. Antiepileptic: The exact mechanism of action of how these antiepileptics work in not fully understood. In general, they work to stabilize neurons and keep them from becoming hyperexcited and generating excessive nerve impulses

Conventional antipsychotics: Antipsychotics all work by blocking dopamine receptors in the brain, thus decreasing the concentration of dopamine in the CNS. The phenothiazine class block receptors in areas of the brain such as the limbic system and basal ganglia which are areas associated with cognitive function, motor function, and emotions. Atypical antipsychotics: The newer, atypical antipsychotics are more selective in the dopamine blockade targeting a specific dopamine receptor, dopamine 2 (D 2 ) in addition to some serotonin (5-HT 2 ) receptors. Question 11 Describe the risks associated with BZDs. Most commonly, they cause excessive CNS depression (symptoms include: sedation, lethargy, fatigue, confusion, drowsiness, dizziness) which is essentially a sign of excess therapeutic effect. Most importantly, all benzodiazepines can by habit-forming and addictive making them a schedule IV-controlled substance. Question 12 Define some of the serious adverse events associated with antipsychotics: EPS, neuroleptic malignant syndrome, and dyskinesias. Extrapyramidal Symptoms (EPS)- The term for signs and symptoms that resemble pathologic changes to the pyramidal portions of the brain. Such symptoms include various motion disorders similar to those seen in Parkinson’s disease and are adverse effects associated with various antipsychotic drugs. Specific symptoms include: akathisia or motor restlessness, dystonia or painful muscle spasms. Tardive Dyskinesia- drug induced involuntary movements of the lips, jaw, tongue, and extremities Neuroleptic malignant syndrome (NMS)- An uncommon but serious adverse event associated with the use of antipsychotic drugs. Symptoms include: fever, cardiovascular instability, and muscle breakdown.