NURS 2210 Comprehensive Final Exam Study Guide: Neuropharmacology and CNS Agents

Basic Principles of Neuropharmacology

Neuropharmacology is the study of drugs that alter processes within the nervous system. These drugs function through two primary mechanisms: axonal conduction and synaptic transmission. Axonal conduction refers to the process of conducting an action potential down the axon. Drugs that act on this process, such as local anesthetics, are generally not selective because the process of axonal conduction is essentially the same in all neurons. In contrast, synaptic transmission is highly selective because synapses differ from one another; they use different transmitters and different receptors. Consequently, most neuropharmacological drugs act by altering synaptic transmission rather than axonal conduction. The final effects of these drugs depend entirely on their ability to alter receptor activity on the target cell.

Drugs can influence synaptic transmission through several specific mechanisms. In transmitter synthesis, drugs may increase, decrease, or modify the effectiveness of the transmitter being produced. Interference with transmitter storage leads to decreased receptor activation because the amount of transmitter available for release is reduced. Regarding transmitter release, drugs can either promote or inhibit the release of the transmitter into the synaptic cleft. Once in the cleft, receptor binding occurs; here, drugs can directly activate receptors (agonists), enhance their natural activation, or block them (antagonists). Finally, drugs can affect the termination of transmitter action by blocking the re-uptake of a transmitter back into the neuron or by inhibiting the enzymatic degradation of the transmitter, both of which prolong the transmitter's effect.

Physiology of the Peripheral Nervous System

The autonomic nervous system (ANS) is divided into the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS). The PNS is often associated with "rest and digest" functions (P for peace). Stimulation of the PNS results in several physiological changes: slowing of the heart rate, increased gastric secretion, emptying of the bowel and bladder, focusing the eye for near vision, constricting the pupil (miosis), and contracting bronchial smooth muscle. Conversely, the SNS regulates the "fight or flight" response (S for stress). It is responsible for regulating the cardiovascular system, increasing heart rate, maintaining body temperature, and managing the acute stress response.

Regulation of the ANS is maintained through feedback loops and reflexes. Feedback regulation involves a message loop between a sensor and an effector sent via nerve signals. A primary example is the baroreceptor reflex, which is critical for blood pressure regulation. This reflex sends signals from baroreceptors via ANS nerves to regulate vasoconstriction or vasodilation and maintain cardiac output (CO). The primary transmitters in the peripheral nervous system are acetylcholine ($Ach$), norepinephrine, and epinephrine. Receptors are categorized as cholinergic or adrenergic. Cholinergic receptors mediate responses to $Ach$ and include subtypes $M_1$, $M_2$, and $M_3$. Adrenergic receptors mediate responses to epinephrine and norepinephrine and include subtypes alpha-1, alpha-2, beta-1, beta-2, and dopamine receptors.

Muscarinic Agonists and Antagonists

Muscarinic agonists, such as bethanechol, are primarily approved to treat urinary retention. Because they mimic the parasympathetic nervous system, their adverse effects include hypotension, bradycardia, excessive salivation, diarrhea, increased gastric acid, abdominal cramps, and bronchoconstriction. These drugs are strictly contraindicated in patients suffering from low blood pressure, asthma, hypothyroidism, or physical obstructions within the urinary tract.

Muscarinic antagonists, such as atropine, work by competitively blocking acetylcholine at muscarinic receptors. Atropine is used clinically to treat bradycardia, dilate pupils during ophthalmic exams, decrease intestinal tone and motility, treat muscarinic agonist poisoning, and manage peptic ulcer disease, asthma, and biliary colic. It can be administered topically to the eye, or via IM, SubQ, or IV routes. Adverse effects include xerostomia (dry mouth), blurred vision, photophobia, elevation of intraocular pressure, urinary retention, and constipation. Nurses must monitor for these "anticholinergic" side effects.

Oxybutynin is another muscarinic antagonist that acts primarily at $M_3$ receptors and is specifically approved for the treatment of overactive bladder. By blocking $M_3$ receptors on the bladder detrusor muscle, it decreases bladder contractions and the urge to void. It is administered PO or transdermally. It carries significant risks for pediatric and elderly populations: hallucinations and agitation have been reported in children, while increased sedation and confusion are noted in older adults. Common side effects include dry mouth (high incidence), constipation, tachycardia, urinary hesitancy, blurred vision, and dry eyes.

Introduction to Central Nervous System Pharmacology

Drugs acting on the Central Nervous System (CNS) are used for pain relief, seizure suppression, anesthesia production, and the treatment of mental health disorders. To be effective, these drugs must be able to cross the blood-brain barrier (BBB). While they target specific neurotransmitters, their exact mechanisms of action are often based on hypotheses. Prolonged use of CNS drugs can lead to adaptation, which may result in increased therapeutic effects, decreased side effects over time, or the development of tolerance and physical dependence.

Drugs for Parkinson’s Disease

Parkinson's disease is a neuromuscular disorder caused by an imbalance between dopamine and acetylcholine ($Ach$) in the brain, specifically characterized by a dopamine deficiency and an abundance of $Ach$. This imbalance leads to extrapyramidal symptoms often summarized by the acronym TRAP: Tremor, Rigidity, Ataxia/Akinesia (bradykinesia), and Postural instability. The goal of treatment is to restore the balance between dopamine and acetylcholine using dopaminergic or anticholinergic agents to improve the patient's quality of life and ability to perform activities of daily living (ADLs).

Levodopa-carbidopa (Sinemet) is the first-line treatment for Parkinson's. Levodopa is a dopamine precursor that increases dopamine synthesis, while carbidopa blocks the peripheral destruction of levodopa. It is administered PO with highly individualized, gradually increasing dosages. Ideally, it is taken on an empty stomach, though food can be used to mitigate N/V (high-protein meals should be avoided). Therapeutic effects may take weeks or months. Adverse effects include N/V, dyskinesias, orthostatic hypotension, psychosis, and signs of excessive cardiac stimulation such as palpitations and dysrhythmias. Interactions occur with antipsychotics, MAO inhibitors, and anticholinergics.

Pramipexole (Mirapex) is a nonergot dopamine receptor agonist. While less effective than levodopa for motor symptoms, it is less likely to cause motor fluctuations and is also used for restless leg syndrome (RLS). It can be taken with or without food. Adverse effects include nausea, dizziness, insomnia, constipation, weakness, and significant issues like "sleep attacks" and impulse control disorders. When combined with levodopa, there is an increased risk for orthostatic hypotension, dyskinesias, and hallucinations. Caution is required in older adults and those with psychiatric disorders or renal dysfunction.

Drugs for Alzheimer’s Disease

Alzheimer’s disease involves progressive memory loss, impaired thinking, and neuropsychiatric symptoms (delusions, hallucinations) caused by neurotic plaques, neurofibrillary tangles, and the degeneration of cholinergic neurons in the hippocampus and cerebral cortex. There is no cure; treatment focuses on symptom management. Donepezil (Aricept) is a selective cholinesterase inhibitor that increases $Ach$ availability. It is approved for mild to severe symptoms and has a long half-life of approximately $70$ hours due to being highly protein-bound. It is typically taken at bedtime. Adverse effects include nausea, diarrhea, bradycardia, and a high risk for fainting and falls.

Memantine (Namenda) is an NMDA receptor antagonist that regulates calcium influx into neurons based on glutamate levels. It is indicated only for moderate to severe symptoms. Side effects include dizziness, bradycardia, angina, and confusion. For patients with concurrent neuropsychiatric symptoms like agitation or aggression, non-pharmacological interventions and assessment for underlying causes (like infection) are primary. If drugs are needed, Olanzapine (Zyprexa), an atypical antipsychotic, may be used, though it carries a risk for increased mortality from cardiovascular events or infection in this population.

Drugs for Seizure Disorders

Seizures are caused by synchronous, high-frequency discharges from hyperexcitable neurons called a focus. Epilepsy is the disorder of recurrent seizures. Seizures are classified as generalized (involving both hemispheres, e.g., tonic-clonic, absence) or focal (one section). Antiseizure drugs work by suppressing sodium or calcium influx, promoting potassium efflux, blocking glutamate receptors, or potentiating gamma-aminobutyric acid ($GABA$). Goals include reducing seizures to allow a normal life through highly individualized therapy. Drugs must be withdrawn slowly to avoid triggering seizures and carry a risk for suicidal ideation.

Phenytoin (Dilantin) is a first-generation drug that suppresses sodium influx. It has a narrow therapeutic range. If given IV, it is a vesicant requiring slow administration and cardiac monitoring. Side effects include CNS effects, gingival hyperplasia (requiring good oral hygiene), skin rash, hirsutism, and "purple glove syndrome." It is considered teratogenic. Gabapentin (Neurontin) is a newer generation drug used for epilepsy and off-label for neuropathic pain and migraines. Its first dose should be taken at bedtime to reduce daytime somnolence. For Status Epilepticus (SE), the goal is to terminate the seizure and maintain ventilation. Lorazepam, a benzodiazepine, is the first-line agent, typically given as a $4\,mg$ IV push over $2$ minutes.

Drugs for Muscle Spasm and Spasticity

Spasticity is a CNS-originated movement disorder characterized by increased muscle tone and loss of dexterity. Baclofen acts within the spinal cord to suppress hyperactive reflexes. It is used for spinal cord injury (SCI) and multiple sclerosis. It can cause significant CNS depression; an overdose may lead to decreased level of consciousness (LOC) and respiratory depression. Abrupt withdrawal can cause seizures and hallucinations. Cyclobenzaprine (Flexaril) acts in the brainstem to reduce tonic motor activity and is the drug of choice for acute muscle spasms. It has anticholinergic effects and can cause serotonin syndrome if combined with SSRIs. Tizanidine (Zanaflex) is an alpha-2 agonist used for spasticity and back pain; it requires liver function monitoring due to potential hepatotoxicity.

Antipsychotic Agents

Antipsychotics are used for schizophrenia, bipolar disorder, and Tourette syndrome. First-generation antipsychotics (FGAs), like Haloperidol, produce a strong blockade of dopamine receptors ($D_2$) in the mesolimbic area, leading to a high risk of extrapyramidal symptoms (EPS). EPS include acute dystonia (spasms of tongue/face), parkinsonism (bradykinesia, tremor), akathesia (restless movement), and tardive dyskinesia (oral-facial dyskinesia). Tardive dyskinesia has no reliable treatment and requires prevention.

Haloperidol is a high-potency FGA used for acute psychosis; adverse effects include Neuroleptic Malignant Syndrome (NMS), QT prolongation, and agranulocytosis. Second-generation antipsychotics (SGAs), like Quetiapine (Seroquel), block both dopamine and serotonin receptors. They have a lower risk for EPS but a higher risk for metabolic effects like weight gain and diabetes. SGAs should not be used for dementia-related psychosis due to increased mortality risks.

Antidepressants

Antidepressants take several weeks to show therapeutic effects and carry an increased suicide risk at the start of therapy. Selective Serotonin Reuptake Inhibitors (SSRIs), including Fluoxetine (Prozac) and Sertraline (Zoloft), block serotonin reuptake. Side effects include sexual dysfunction and weight gain. Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs), like Venlafaxine, block both transmitters and can cause diastolic hypertension. Tricyclic Antidepressants (TCAs), such as Amitriptyline, are second-line due to cardiac toxicity in overdose; toxicity is treated with gastric lavage, activated charcoal, and sodium bicarbonate for dysrhythmias.

Monoamine Oxidase Inhibitors (MAOIs) are used when other drugs fail. They require strict dietary avoidance of tyramine-rich foods (cheese, wine, fermented meats) to prevent a life-threatening hypertensive crisis (symptoms include elevated BP, tachycardia, and severe headache). Atypical antidepressants like Bupropion (Wellbutrin) do not cause sexual dysfunction but can cause seizures at doses exceeding $450\,mg/day$. Serotonin Syndrome is a major risk when combining drugs; signs include agitation, hyperthermia, tachycardia, hyperreflexia, and tremors.

Drugs for Bipolar Disorder

Bipolar disorder involves fluctuations between mania and depression. Lithium is the primary mood stabilizer used for manic episodes. It has a very low therapeutic index, requiring precise plasma drug level monitoring. The goal level is $0.4$ to $1.0\,mEq/L$; levels should not exceed $1.5\,mEq/L$, and death can occur above $2.5\,mEq/L$. Lithium is excreted by the kidneys, and its excretion is reduced if the patient is hyponatremic. Nursing considerations include encouraging fluid intake to prevent dehydration and monitoring sodium levels, especially if the patient is on diuretics or has diarrhea.

Sedative-Hypnotic and Anti-Anxiety Drugs

Benzodiazepines, such as Lorazepam, amplify the effects of $GABA$. They are used for anxiety, insomnia, and seizures. Chronic use leads to physical dependence. Overdose is treated with Flumazenil, a competitive receptor antagonist. Benzodiazepine-like drugs, such as Zolpidem (Ambien), are used for short-term management of insomnia and carry risks of sleep-related behaviors. For long-term anxiety management, SSRIs and SNRIs are first-line. Buspirone is also used for Generalized Anxiety Disorder (GAD). Beta blockers may be used for performance-related social anxiety, taken $1$ to $2$ hours prior to the event.

Drugs for ADHD and Rheumatoid Arthritis

Stimulants like Amphetamine (Adderall) and Methylphenidate (Ritalin) increase NE and dopamine. They improve wakefulness and task performance but can cause weight loss, growth suppression in children, and insomnia. "Drug holidays" help minimize growth suppression. In Rheumatoid Arthritis, Methotrexate is a DMARD that suppresses B and T lymphocytes. It is co-administered with folic acid to reduce GI and liver toxicity. It is highly teratogenic and patients should not receive live vaccines during therapy.

Drugs for Gout and Bone Health

Gout flare-ups are treated with NSAIDs, glucocorticoids, or Colchicine. Colchicine has a narrow therapeutic index and should not be taken with grapefruit juice or statins. Allopurinol is used long-term to inhibit uric acid formation, with a target serum level of less than $6\,mg/dL$. For osteoporosis, Alendronate (a bisphosphonate) reduces bone resorption by osteoclasts. It must be taken in the morning on an empty stomach with a full glass of water, and the patient must remain upright for at least $30$ minutes to prevent esophagitis.

Cumulative Content and Discussion

Several other standard medications are relevant to this final exam. Aspirin and Naproxen are NSAIDs used for pain and inflammation; Aspirin also decreases platelet aggregation. Acetaminophen treats pain and fever but requires monitoring for hepatotoxicity. Albuterol is a short-acting beta agonist (SABA) for bronchospasm. Heparin is an anticoagulant requiring aPTT monitoring. Digoxin, a cardiac glycoside with a narrow range, requires monitoring heart rate (hold if less than $60\,bpm$) and potassium levels. Hydromorphone (Dilaudid) is a potent opioid treated with Naloxone (Narcan) in cases of overdose or respiratory depression (low RR). Ondansetron (Zofran) treats N/V but can cause QT prolongation. Senna is a stimulant laxative where persistent use can lead to abuse.