CNS Drugs and Pharmacology Study Guide

Parkinson’s Disease (PD) and Treatment Overview

  • Definition of Parkinson’s Disease: It is a progressive neurological disorder of muscle movement.
  • Clinical Characterization: The disease is characterized by:
    • Tremors.
    • Muscle rigidity.
    • Bradykinesia (slowness of movement).
  • Demographics: Most cases involve individuals over the age of 6565 years.
  • Pathophysiology: PD is related to the reduction of dopaminergic neurons.
  • Secondary Parkinsonism:
    • This is induced by drugs.
    • Mechanism: Certain drugs act on dopamine receptors to block activity, thereby producing parkinsonian symptoms.
    • Alternative Name: Also known as pseudoparkinsonism.

Pharmacotherapy for Parkinson’s Disease

  • Treatment Goal: Drugs aim to maintain CNS (Central Nervous System) dopamine levels.
  • Levodopa and Carbidopa:
    • Levodopa: Dopamine itself cannot cross the blood-brain barrier (BBB). Levodopa serves as the precursor to dopamine; it is actively transported to the CNS and subsequently converted to dopamine.
    • Carbidopa: Acts as a dopamine decarboxylase inhibitor. It diminishes the metabolism of levodopa in the periphery, which increases the availability of levodopa to the CNS.
    • Rationale for Combination: If levodopa is administered without carbidopa, a large portion is decarboxylated to dopamine in the periphery. This results in adverse effects such as nausea, vomiting, arrhythmias, and hypotension.
    • Therapeutic Uses: Treatment of PD; it decreases rigidity, tremors, and other associated symptoms.
    • Adverse Effects: Nausea, vomiting, hypotension, brownish color of urine and saliva, visual and auditory hallucinations, dyskinesias (abnormal involuntary movement), mood changes, psychosis, and anxiety.
  • MAO-B Inhibitors (Selegiline and Rasagiline):
    • Mechanism: They inhibit the metabolism of dopamine by inhibiting monoamine oxidase B (MAO−BMAO-B) at low to moderate doses.
    • Combination: Selegiline may be administered along with levodopa.
    • Therapeutic Uses: Treatment of PD.
    • Adverse Effects: Insomnia and hypertensive crises.
  • Dopamine Agonists:
    • Bromocriptine: An ergot derivative, similar to levodopa.
    • Other Approved Agonists: Apomorphine, Pramipexole, and Rotigotine.
    • Adverse Effects of Agonists: Nausea, hallucination, insomnia, dizziness, constipation, and orthostatic hypotension.
  • Amantadine:
    • Origin: Originally an antiviral drug used to treat influenza.
    • PD Application: Used to treat PD, though it is less efficacious than levodopa.
    • Adverse Effects: Restlessness, agitation, confusion, hallucination, dry mouth, orthostatic hypotension; at high doses, it can produce toxic psychosis.

Anxiolytic and Hypnotic Drugs

  • Definitions:
    • Anxiety: An unpleasant state of uneasiness or tension.
    • Hypnotics: Drugs that induce sleep.
    • Anxiolytics: Drugs used to treat anxiety (antianxiety drugs).
  • Drug Classes:
    • Benzodiazepines.
    • Barbiturates.
    • Antidepressants.
    • Other hypnotic agents.
  • Benzodiazepines:
    • Mechanism: Action through the GABAAGABA_A receptor.
    • General Profile: Widely used and considered safer than other options.
    • Example Drugs: Alprazolam, Chlordiazepoxide, Clonazepam, Diazepam, Midazolam, Oxazepam, Lorazepam, and Flurazepam.
    • Therapeutic Uses:
      • Low doses: Used as anxiolytics to treat anxiety.
      • High doses: Produce sedation, treat convulsions, and relax skeletal muscle spasticity (e.g., treating muscle strain).
      • Midazolam: Used to facilitate amnesia while causing sedation prior to anesthesia.
    • Adverse Effects: Drowsiness, confusion, ataxia (at high doses), early morning insomnia, and daytime anxiety.
    • Dependence: Psychological and physical dependence can develop with high doses over prolonged periods. Abrupt discontinuation results in withdrawal symptoms: restlessness, tension, convulsion, agitation, anxiety, and confusion.
    • Antidote: Flumazenil is used for benzodiazepine toxicity. Common side effects of flumazenil include nausea, vomiting, and agitation.
  • Antidepressants for Anxiety:
    • SSRIs: Selective Serotonin Reuptake Inhibitors (e.g., Paroxetine, Escitalopram).
    • SNRIs: Serotonin Norepinephrine Reuptake Inhibitors (e.g., Venlafaxine, Duloxetine).
    • Usage: Used to treat chronic or daytime anxiety. Often given with low-dose benzodiazepines during the first week of treatment. Low potential for dependence/addiction.
  • Other Drugs (Buspirone):
    • Mechanism: Mediates effects through 5−HT5-HT serotonin and dopamine D2D_2 receptors.
    • Use: Acute anxiety states.
    • Dependency: No dependence noted.
    • Adverse Effects: Nausea, headache, dizziness, and nervousness.

Barbiturates and Other Hypnotics

  • Barbiturates:
    • General Status: Used to induce and maintain sleep. These are controlled drugs, largely replaced by benzodiazepines due to severe physical dependence.
    • Examples by Duration of Action:
      • Phenobarbital: Long-acting (1−21-2 days).
      • Pentobarbital: Short-acting (3−83-8 hours).
      • Thiopental: Ultra-short acting (about 2020 minutes).
    • Therapeutic Uses:
      • Low dose: Induce sleep.
      • High dose: Hypnosis, followed by anesthesia, coma, and finally death.
      • Ultra-short acting (Thiopental): Formerly used IV to induce anesthesia.
      • Phenobarbital: Used to treat convulsions.
      • General: Used for anxiety, tension, and insomnia due to mild sedative properties.
    • Adverse Effects: Drowsiness, mental and physical sluggishness, and drug ’hangover’ (impaired function for hours after waking). Occasionally nausea and dizziness.
  • Other Hypnotic Agents (Nonbenzodiazepines):
    • Mechanism: Not structurally related to benzodiazepines but bind selectively to benzodiazepine receptor subtypes.
    • Examples: Zolpidem, Zaleplon, Ramelteon, and Eszopiclone.
    • Antihistamines: Certain types have sedative effects (e.g., Diphenhydramine, Hydroxyzine, Doxylamine) and are used for situational insomnia.

Antidepressant Medications

  • Definition of Depression: Symptoms include feelings of sadness and hopelessness and the inability to experience pleasure.
  • Drug Classes:
    1. SSRIs (Selective Serotonin Reuptake Inhibitors).
    2. SNRIs (Serotonin Norepinephrine Reuptake Inhibitors).
    3. TCAs (Tricyclic Antidepressants).
    4. MAOIs (Monoamine Oxidase Inhibitors).
    5. Atypical Antidepressants.
  • Selective Serotonin Reuptake Inhibitors (SSRIs):
    • Mechanism: Inhibit serotonin reuptake.
    • Examples: Citalopram, Escitalopram, Paroxetine, Fluoxetine, and Sertraline.
    • Therapeutic Uses: Depression and psychiatric disorders (Panic disorder, Generalized Anxiety Disorder, PTSD, Social Anxiety Disorder).
    • Adverse Effects: Headache, sweating, agitation, diarrhea, nausea, vomiting, weakness, fatigue, sexual dysfunction, weight changes, and suicidal ideation in teenagers.
  • Serotonin Norepinephrine Reuptake Inhibitors (SNRIs):
    • Mechanism: Inhibit reuptake of both serotonin and norepinephrine.
    • Examples: Venlafaxine, Duloxetine, and Desvenlafaxine.
    • Therapeutic Uses: Depression; also effective for pain associated with diabetic neuropathy, fibromyalgia, and low back pain.
    • Adverse Effects: Nausea, headache, sexual dysfunction, dizziness, insomnia, constipation; high doses can increase blood pressure and heart rate.
  • Tricyclic Antidepressants (TCAs):
    • Mechanism: Inhibit norepinephrine and serotonin reuptake.
    • Examples: Amitriptyline, Imipramine, Clomipramine, Nortriptyline, and Doxepin.
    • Therapeutic Effects: Mood elevation for moderate to severe depression.
    • Specific Uses:
      • Imipramine: Control bed wetting in children over 66 years old.
      • Amitriptyline: Prevention of migraine headache and neuropathic pain.
    • Adverse Effects: Blurred vision, xerostomia (dry mouth), urine retention, tachycardia, constipation, orthostatic hypotension, dizziness, and weight gain.
  • Monoamine Oxidase Inhibitors (MAOIs):
    • Mechanism: MAO is an enzyme in the liver and gut that degrades neurotransmitters (Norepinephrine, Dopamine, Serotonin). MAOIs inhibit this degradation.
    • Examples: Phenelzine, Isocarboxazid, Selegiline, and Tranylcypromine.
    • Therapeutic Effects: Last-line agents for patients nonresponsive or allergic to SSRIs/TCAs. Treats atypical depression. Selegiline is also used for PD.
    • Adverse Effects: Orthostatic hypotension, blurred vision, dry mouth, and constipation.
    • Interactions:
      • Tyramine: Foods containing tyramine cause hypertensive crisis (hypertension, stiff neck, tachycardia, nausea, seizures, stroke) because tyramine releases stored catecholamines.
      • Wash-out Period: MAOIs and SSRIs require a wash-out period of at least 1414 days between treatments to avoid hypertensive crisis.
  • Atypical Antidepressants:
    • Bupropion: Used for depression. Side effects include dry mouth, nervousness, tremor, and seizures.
    • Mirtazapine: Markedly sedating. Side effects include increased appetite and weight gain.

Epilepsy Treatment

  • Mechanism of Action: Antiepilepsy medications generally inhibit GABAGABA (̴-aminobutyric\,acid).
  • Function: Medications only suppress seizures; they do not cure or prevent epilepsy.
  • Benzodiazepines in Epilepsy:
    • Clobazam and Clonazepam: Used for emergency or acute seizures.
    • Diazepam: Administered rectally to control seizures.
  • Other Antiepileptics:
    • Carbamazepine: Blocks sodium channels. Used for focal seizures.
    • Eslicarbazepine: Blocks sodium channels. Used for partial-onset seizures.
    • Ethosuximide: Used for absence seizures.
    • Gabapentin: Treats focal and partial seizures.
    • Lacosamide: Treats focal seizures.
    • Lamotrigine: Blocks sodium channels.
    • Levetiracetam: Treats seizures in adults and children.
    • Oxcarbazepine: Treats seizures in adults and children.
    • Valproic Acid: Blocks sodium channels.
    • Pregabalin: Treats seizures.
    • General Adverse Effects: Dizziness, somnolence, headache, and rash.

Neuroleptic and Antipsychotic Drugs

  • Primary Use: Treatment of schizophrenia and other psychotic states.
  • Definition of Schizophrenia: A chronic psychosis characterized by hallucinations and disturbances in thinking and speech.
  • Classification of Neuroleptics:
    1. First Generation (Typical):
      • Low Potency: Chlorpromazine, Thioridazine.
      • High Potency: Haloperidol, Prochlorperazine, Pimozide.
    2. Second Generation (Atypical): Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone.
  • Mechanism and Choice:
    • Second-generation agents are first-line to minimize extrapyramidal symptoms (EPS).
    • Most block D2D_2 (dopamine) receptors in the brain and periphery.
    • Most second-generation drugs also inhibit serotonin receptors.
  • Therapeutic Uses: Schizophrenia (reverses hallucinations), Prochlorperazine (drug-induced nausea/vomiting), tranquilization, Chlorpromazine (hiccups), and depression treatment.
  • Adverse Effects:
    • Extrapyramidal symptoms (EPS): Parkinson’s-like symptoms (rigidity, tremors).
    • Tardive dyskinesia: Involuntary movements of the face and jaws.
    • Others: Confusion, weight gain, seizures, postural hypotension, urinary retention, arrhythmias, sudden cardiac death, and dry mouth.

Anesthetics

  • General Anesthesia Definition: A reversible state of CNS depression causing loss of response to stimuli.
  • Components of Anesthesia:
    • Sedation and anxiety reduction.
    • Amnesia and lack of awareness.
    • Skeletal muscle relaxation.
    • Analgesia.
    • Suppression of undesirable reflexes.
  • Patient Selection Factors:
    • CVS: Heart failure or coronary disease considerations (suppression).
    • Respiratory: Asthma or ventilation issues (suppression).
    • Liver/Kidney: Clearance and toxicity risks.
    • Nervous System: Epilepsy or neuromuscular disease risks.
    • Pregnancy: Fetal organogenesis risks (e.g., oral cleft from benzodiazepines).
  • Steps of Anesthesia:
    1. Induction: Usually via IV (e.g., Propofol), producing unconsciousness in 30−4030-40 seconds. Children may use inhaled nonpungent agents (e.g., Sevoflurane).
    2. Maintenance: Provided by volatile agents for control over depth (e.g., Fentanyl).
    3. Recovery: Reverse of induction; ensuring return of physiological functions.
  • Stages of Anesthesia Depth:
    • Stage I: Loss of pain sensation (conscious to drowsy/amnesia).
    • Stage II (Excitement): Delirium, combativeness, irregular BP, and respiration.
    • Stage III (Surgical Anesthesia): Loss of muscle tone/reflexes, regular respiration.
    • Stage IV (Medullary Paralysis): Severe CNS/respiratory depression. Requires support to prevent death.
  • Inhalation Anesthesia Profiles:
    • Nitrous Oxide: Potent analgesic, weak general anesthetic.
    • Halothane: Potent, hepatotoxic in adults (not children), used for uterine relaxation in obstetrics. Side effects: Bradycardia, arrhythmias, hyperthermia.
    • Isoflurane: Non-toxic to liver/kidney. Side effects: Hypotension, coughing, salivation.
    • Desflurane: Popular for out-patient procedures; not for induction.
    • Sevoflurane: Used for induction in children.
  • Comparative Effects Table Data:
    • Arrhythmias: Increased with Halothane; negligible with others.
    • Cardiac Output: Decreased across Halothane, Isoflurane, Desflurane, and Sevoflurane.
    • Blood Pressure: Decreased across all four agents.
    • Respiratory Reflex: Inhibited by Halothane and Sevoflurane; stimulated by Isoflurane and Desflurane.
    • Toxicity: Halothane carries hepatic risk. Sevoflurane carries some renal risk.

Intravenous and Local Anesthetics

  • IV Anesthetics:
    • Propofol: Induction and maintenance; onset in 30−4030-40 seconds; has replaced thiopental.
    • Thiopental: A barbiturate.
    • Benzodiazepines (Diazepam, Midazolam, Lorazepam): Used for sedation in conjunction with anesthetics.
    • Fentanyl: Opioid used for analgesia.
    • Etomidate: Hypnotic for induction; lacks analgesia; used in CV dysfunction patients.
    • Ketamine: Nonbarbiturate bronchodilator; used in asthmatics and short procedures for children/elderly.
    • Dexmedetomidine: Sedative for Intensive Care (ICU); provides sedation/analgesia without respiratory suppression.
  • Local Anesthetics:
    • Mechanism: Block nerve conduction of sensory impulses.
    • Types: Peripheral nerve blocks and neuraxial (spinal/epidural) blocks.
    • Examples: Bupivacaine, Lidocaine, Procaine, Tetracaine.
    • Duration: Can provide post-surgical analgesia for 2424 hours or longer.
    • Effects: Causes vasodilation and potential allergic reactions (urticaria, edema).

Opioids

  • Receptor Types: Mu\,(̴), Kappa\,(̴), and Delta\,(̴).
  • Strong Agonists:
    • Morphine (Avinza, Kadian, MS Contin).
    • Fentanyl (Abstral, Actiq, Duragesic).
    • Alfentanil, Sufentanil, Remifentanil.
    • Heroin, Meperidine (Demerol), Methadone (Dolophine).
    • Hydromorphone, Oxymorphone, Oxycodone.
  • Moderate/Low Agonists: Codeine.
  • Mixed Agonists-Antagonists/Partial Agonists: Buprenorphine, Butorphanol, Nalbuphine, Pentazocine.
  • Chemical Classification:
    • Natural: Morphine, Codeine.
    • Semisynthetic: Hydromorphone, Hydrocodone, Oxycodone, Oxymorphone.
    • Synthetic: Fentanyl, Meperidine, Methadone, Tapentadol, Tramadol.
  • Morphine Profile:
    • Uses: Analgesia, euphoria, antitussive (cough suppression), miosis (pupil constriction), treatment of diarrhea (decreases GI motility).
    • Adverse Effects: Respiratory depression, histamine release (urticaria, sweating, bronchoconstriction), physical dependence, constipation, hypotension, nausea, vomiting, bradycardia.
  • Other Specific Opioids:
    • Methadone: Used to control withdrawal in dependent abusers of opioids and heroin.
    • Buprenorphine: Partial agonist; little sedation/respiratory depression; treats opioid dependence and moderate-to-severe pain.
    • Tramadol: Centrally acting analgesic for moderate-to-severe pain; carries risk of abuse.
    • Antagonists: Naloxone and Naltrexone are used as antidotes for opioid overdose and toxicity.