Pharmacology of the Nervous System

Introduction to the Autonomic Nervous System (ANS)

• The ANS regulates involuntary vital functions such as heart rate, breathing, digestions, and glandular secretion.
• Functional division:
  • Sympathetic: prepares the body for emergency situations ("fight or flight").
  • Parasympathetic: promotes rest and energy conservation ("rest and digest").
• Importance in nursing: understanding these systems allows predicting and monitoring the effects of many medications.

Organization of the Nervous System

• Central Nervous System (CNS): Brain and spinal cord.
• Peripheral Nervous System (PNS):
  • Afferent division: Input to CNS from the periphery (sensory and visceral stimuli).
  • Efferent division: Output from CNS to the periphery.
  • Somatic nervous system: Motor neurons controlling skeletal muscles.
  • Autonomic nervous system: Controls smooth muscle, cardiac muscle, exocrine and some endocrine glands.
    • Sympathetic nervous system.
    • Parasympathetic nervous system.
  • Enteric nervous system: Digestive organs only.

Neurotransmitters of the Autonomic Nervous System

• Parasympathetic preganglionic neuron releases acetylcholine.
• Parasympathetic postganglionic neuron releases acetylcholine.
• Sympathetic preganglionic neuron releases acetylcholine.
• Sympathetic postganglionic neuron releases noradrenaline (norepinephrine).
• Motor neuron releases acetylcholine.

Parasympathetic vs. Sympathetic Divisions

• Parasympathetic Division:
  • Eyes: Constricts pupil; adjusts eye for near vision.
  • Salivary glands: Stimulates secretion.
  • Heart: Decreases heart rate.
  • Lungs: Constricts bronchioles (airways).
  • Stomach: Stimulates stomach activity.
  • Liver: Inhibits glucose release.
  • Intestines: Stimulates activity.
  • Bladder: Stimulates contraction (emptying).
  • Genitals: Stimulates penile or clitoral arousal.
• Sympathetic Division:
  • Eyes: Dilates pupil; adjusts eye for far vision.
  • Salivary glands: Inhibits secretion.
  • Heart: Increases heart rate.
  • Lungs: Dilates bronchioles.
  • Stomach: Inhibits stomach activity.
  • Liver: Stimulates glucose release.
  • Intestines: Inhibits activity.
  • Bladder: Relaxes bladder muscles.
  • Genitals: Inhibits penile or clitoral arousal.

Adrenergic (Sympathetic) Pharmacology

• Adrenergic drugs act on the sympathetic system.
• They stimulate or inhibit the effects of neurotransmitters like noradrenaline and adrenaline.
• Main receptors:
  • Alpha ($\alpha1$, $\alpha2$)
  • Beta ($\beta1$, $\beta2$, $\beta3$)
• Location and function: determine the response in each tissue (vessels, bronchi, heart, fat, etc.).

Adrenergic Receptors and Their Effects

• $\alpha1$: Vasoconstriction → ↑ blood pressure, ↓ nasal congestion.
  • Example: Phenylephrine (nasal use).
• $\alpha2$: Inhibits noradrenaline release → ↓ sympathetic tone.
  • Example: Clonidine (hypertension, sedation).
• $\beta1$: Increases heart rate and contractility.
  • Example: Dobutamine (cardiogenic shock).
• $\beta2$: Relaxes bronchi and uterus.
  • Example: Salbutamol (asthma), Terbutaline (threat of premature labor).
• $\beta3$: Lipolysis → mobilizes energy in stress.
  • Example: Research in obesity.

Sympathomimetics

• Mimic the action of the sympathetic system.
• Mechanism of action:
  • Direct: Activate adrenergic receptors.
  • Indirect: Stimulate the release of neurotransmitters.
• Clinical examples:
  • Adrenaline: Anaphylaxis, cardiac arrest.
  • Dopamine: Septic shock (dose-dependent).
  • Pseudoephedrine: Nasal decongestion.

Sympatholytics

• Block the effects of the sympathetic system.
• Types:
  • Alpha-blockers: ↓ peripheral vascular resistance.
  • Example: Prazosin (hypertension, Raynaud's).
  • Beta-blockers: ↓ heart rate and contractility.
  • Example: Propranolol, Metoprolol (MI, AF, migraine).
• Precautions: in asthma (bronchoconstriction) and diabetes (mask hypoglycemia).

Cholinergic (Parasympathetic) Pharmacology

• Cholinergic drugs act by stimulating or inhibiting acetylcholine receptors.
• Receptors:
  • Muscarinic: glands, heart, smooth muscle.
  • Nicotinic: ganglia, neuromuscular junction.
• Clinical importance: control of secretions, heart rate, muscle tone, among others.

Parasympathomimetics

• Stimulate the parasympathetic system.
• Therapeutic uses:
  • Pilocarpine: glaucoma (reduces intraocular pressure).
  • Bethanechol: neurogenic bladder, postoperative ileus.
  • Neostigmine: myasthenia gravis.
• Common side effects: diarrhea, bradycardia, bronchoconstriction.

Parasympatholytics (Anticholinergics)

• Block the action of acetylcholine on muscarinic receptors.
• Clinical uses:
  • Atropine: bradycardia, organophosphate poisoning.
  • Ipratropium: COPD, asthma.
  • Oxybutynin: urinary incontinence.
• Precautions: glaucoma, older adults, hyperthermia.

Acetylcholinesterase Inhibitors

• Inhibit the degradation of acetylcholine → prolong its action.
• Examples:
  • Donepezil: Alzheimer's disease.
  • Neostigmine: myasthenia gravis, antidote for neuromuscular blockers.
• Side effects: bronchoconstriction, hypotension, muscle spasms.

Considerations in Special Populations

• Older adults: greater sensitivity to side effects → close monitoring.
• Young children: immature system, risk of hyperthermia and dehydration.
• Pregnancy: some drugs cross the placenta, should be used with caution.

Central Nervous System: Sedatives and Hypnotics

• Sedatives and hypnotics are CNS depressants used to reduce excitation, induce sleep, or control convulsions.
  • Sedatives: Calm without inducing deep sleep.
  • Hypnotics: Induce sleep similar to physiological sleep.

Barbiturates

• Mechanism of action: Potentiate the effect of GABA by opening chloride channels, which inhibits neuronal activity.
• Examples and uses:
  • Phenobarbital: Anticonvulsant.
  • Pentobarbital: Treatment of insomnia.
  • Thiopental: Short-duration anesthesia.
• Side effects: Tolerance, dependence, severe withdrawal syndrome.
• Clinical note: Produce many interactions with other drugs (hepatic enzyme induction).

Benzodiazepines

• Mechanism of action: Increase GABA action, but without directly opening the chloride channel (safer than barbiturates).
• Examples and uses:
  • Diazepam: Anxiety, convulsions.
  • Midazolam: Sedation in procedures.
  • Temazepam: Insomnia.
• Advantages: Less REM sleep suppression, less tolerance.
• Warning: Risk of dependence with prolonged use (> 4 weeks). Avoid in sleep apnea or COPD.

Non-Benzodiazepines (Z hypnotics)

• Mechanism of action: Act on GABA receptors, but with fewer effects on muscle relaxation or memory.
• Examples:
  • Zopiclone: Insomnia, fewer nocturnal awakenings.
  • Zolpidem: Induces sleep quickly, fewer side effects.
• Considerations: Short-term use. Gradual discontinuation to avoid rebound insomnia.

Alcohol

• Potent CNS depressant.
• Effects: Sedation, drowsiness, euphoria, motor and cognitive impairment.
• Danger: Its combined use with other CNS depressants (such as sedatives) can be deadly.

Other Sedative-Hypnotics

• Chloral hydrate:
  • Old sedative, short-acting.
  • Side effects: GI irritation, dependence.
  • Used with midazolam in conscious sedation.
• Over-the-counter sleep aids:
  • Contain antihistamines such as diphenhydramine.
  • Useful for mild occasional insomnia.
  • Caution in asthma, glaucoma, and with alcohol.

Safety Considerations for Nursing

• Monitor vital signs, especially respiratory rate.
• Assess risk of falls, especially in older adults.
• Educate the patient about the correct use and risks of self-medication.
• Gradual discontinuation in prolonged therapies to avoid withdrawal syndrome.

Antidepressant, Antipsychotic, and Mood-Stabilizing Agents

• Common mental disorders:
  • Anxiety, affective disorders (depression and bipolarity), psychosis.
  • Clinical example: patient with major depression and family history of MDD.

Genetics of Schizophrenia

• Susceptibility:
  1. First-degree relative: ~10% risk.
  2. Second-degree relative: 3% risk.
  3. Monozygotic twins: 48% risk if the other twin has schizophrenia.
  4. Dizygotic twins: 12-14% risk if the other twin has schizophrenia.
  5. Children with both parents having schizophrenia: ~40% risk.

Affective Disorders

• Major Depressive Disorder (MDD): intense sadness, anhedonia, guilt, fatigue.
• Bipolar I disorder: manic + depressive episodes.
• Bipolar II disorder: hypomania + depression.

Psychosis and Schizophrenia

• Loss of contact with reality: delusions, hallucinations.
• Schizophrenia: positive and negative symptoms.
• Frequent onset in young adults.
• CNS: alterations in dopamine, serotonin, noradrenaline, and acetylcholine.
• Monoaminergic hypothesis: deficiency of monoamines.
• Genetic and environmental role.

Brain Function and Conditions Associated with Neurotransmitters

• Noradrenaline (Norepinephrine) (NA)
  • Brain Region: Hypothalamus, reticular activating system
  • Brain Function: Arousal, sleep, mood, appetite, hormone release, body temperature
  • Receptors: Adrenergic: $\alpha1, \alpha2, \beta1, \beta2, \beta3$
  • Possible Diseases: Depression, insomnia, eating disorders
• Dopamine (D)
  • Brain Region: Hypothalamus, Extrapyramidal pathway, Limbic system, Chemoreceptor trigger zone (CTZ)
  • Brain Function: Muscle movement, skeletal, behavior, emesis, hormone release
  • Receptors: D1, D2, D3, D4, D5
  • Possible Diseases: Parkinson's disease, narcolepsy, ADHD, schizophrenia, aberrant behavior, psychosis
• 5-Hydroxytryptamine (5-HT, Serotonin)
  • Brain Region: Hypothalamus, Reticular activating system
  • Brain Function: Regarding NA plus behavior, pain transmission, emesis
  • Receptors: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7
  • Possible Diseases: Depression, ADHD, Headaches, Eating Disorders, Insomnia
• Acetylcholine
  • Brain Region: Cerebral Cortex, Thalamocortical tracts, Pyramidal pathway, Reticular Activation System
  • Brain Function: Cognition, skeletal muscle movement, memory, consciousness
  • Receptors: Muscarinic and Nicotinic
  • Possible Diseases: Parkinson's disease, dementia, Alzheimer's disease
• Gamma-Aminobutyric Acid (GABA)
  • Brain Region: All regions
  • Brain Function: Motor control, memory, consciousness
  • Receptors: GABAA, GABAB, GABAC
  • Possible Diseases: Anxiety, insomnia, aberrant behavior, epilepsy

Antidepressants - Introduction

• Uses: depression, anxiety, ADHD, chronic pain.
• Non-pharmacological treatment: cognitive-behavioral therapy.
• TCAs (Tricyclic Antidepressants): imipramine, amitriptyline.
• SSRIs (Selective Serotonin Reuptake Inhibitors): fluoxetine, sertraline.
• MAOIs (Monoamine Oxidase Inhibitors): phenelzine.
• SNRIs: venlafaxine, duloxetine.
• NRIs: reboxetine.

Mechanism of Action of Antidepressants

• Inhibition of neurotransmitter reuptake.
• Serotonergic and noradrenergic potentiation.
• Onset of action: 2-4 weeks.

Adverse Effects and Considerations

• SSRIs: sexual dysfunction, insomnia, initial anxiety.
• TCAs: anticholinergic effects, cardiotoxicity.
• Risk of overdose and serotonin syndrome.

Antipsychotic Agents - Introduction

• Uses: schizophrenia, psychosis, mania.
• Typical (1st gen): haloperidol, chlorpromazine.
• Atypical (2nd gen): risperidone, olanzapine, quetiapine.

Mechanism of Action of Antipsychotics

• Blockade of D2 (dopamine) receptors.
• Atypical: additional action on 5-HT (serotonin).

Adverse Effects of Antipsychotics

• EPS: dystonias, tremors, tardive dyskinesia.
• NMS (Neuroleptic Malignant Syndrome).
• Metabolic alterations: obesity, dyslipidemia.
• Prolonged use in patients with low adherence.
• Do not start with depot formulation.
• Liquid oral forms: alternative for patients with swallowing difficulties.

Mood Stabilizers

• Lithium: drug of choice in bipolar disorder.
• Anticonvulsants: valproate, carbamazepine, lamotrigine.
• Atypical antipsychotics also used.
• Monitoring of serum levels.

Lithium - Clinical Considerations

• Toxicity: vomiting, tremors, ataxia.
• Contraindicated in pregnancy (1st trimester) and lactation.

Drug Interactions

• Lithium + NSAIDs/diuretics: risk of toxicity.
• Caution with sodium restriction.
• Patient education.
• Monitoring of adverse effects.
• Promoting therapeutic adherence.

Antidepressant Medications - Adverse Effects and Nursing Considerations

• Irreversible MAOIs (Monoamine Oxidase Inhibitors)
  • Adverse Effects: Antimuscarinic, Antiadrenergic; Tyramine-containing foods can cause hypertensive crises.
  • Nursing Considerations: Contraindicated in epilepsy, cardiovascular diseases, and liver failure; Drug interactions include sympathomimetics and narcotic analgesics; Do not combine with other antidepressants
• RIMAs (Reversible Inhibitors of Monoamine Oxidase)
  • Adverse Effects: Nausea, insomnia, dizziness
  • Nursing Considerations: Low-tyramine diet not necessary; Relatively non-toxic in overdose; Administer early in the afternoon to avoid insomnia
• SNRIs (Serotonin and Noradrenaline Reuptake Inhibitors)
  • Adverse Effects: Headache, nausea, anxiety, anorexia, fatigue; Withdrawal effects are common if doses are missed
  • Nursing Considerations: Regularly monitor blood pressure; Venlafaxine and duloxetine should be taken with food to reduce gastrointestinal upset; Overdose may cause seizures; Controlled-release preparations available; Advise client to avoid driving and operating heavy machinery
• SSRIs (Selective Serotonin Reuptake Inhibitors)
  • Adverse Effects: Headache, dizziness, insomnia, drowsiness, nausea, gastrointestinal upset, anxiety; Sexual dysfunction; Serotonin syndrome (euphoria, hyperthermia, sweating, abnormal muscle movements)
  • Nursing Considerations: Do not administer concomitantly with other antidepressants, especially MAOIs; Monitor for signs of SSRI overdose: serotonin syndrome; Drug interactions include oral anticoagulants, other SSRIs, St. John's Wort, serotonergics, etc.

Agents Used as Central Nervous System Stimulants

• CNS stimulants, such as caffeine, have been used for centuries.
• Found in coffee, energy drinks, sodas, and chocolate.
• Side effect: decreased appetite.

Anorexigenic Agents

• Reduce appetite and are used in the short term in weight loss regimens.
• Controversy: little evidence of their effectiveness.
• Common adverse effects.

Mechanism and Effects of Anorexigenic Agents

• Act as sympathomimetics suppressing appetite centers.
• Effects: anxiety, tachycardia, hypertension, insomnia, arrhythmias.
• Limited use due to the risk of dependence.

Use of Anorexigenic Agents in Narcolepsy

• Some anorexigenics are also used to treat narcolepsy.
• Promote the regulation of sleep and wakefulness.

Stimulants for ADHD

• ADHD: attention deficit, hyperactivity, and impulsivity.
• Affects children and adults.
  Use of amphetamines, methylphenidate, lisdexamfetamine, and atomoxetine.

Mechanism of Action of Stimulants for ADHD

• Amphetamines: release dopamine and noradrenaline.
• Methylphenidate: inhibits reuptake of catecholamines.
• Atomoxetine: selective inhibitor of noradrenaline reuptake.

Adverse Effects of Stimulants for ADHD

• In children: nausea, abdominal pain, dyspepsia.
• In adults: insomnia, erectile dysfunction, dizziness, dry mouth.

Analeptics

• Treatment of respiratory depression (alcohol, barbiturates).
• Use has decreased due to preference for mechanical support.

Toxicity of Stimulants

• Symptoms: tremors, paranoia, convulsions, arrhythmias.
• Treatment: benzodiazepines for sedation and seizure control.