Comprehensive Study Guide for Parkinson's, Psychosis, Depression, Anxiety, and Seizures, and Alzheimer's

Parkinson's Disease (PD): Pathophysiology and Clinical Presentation

• Pathophysiology: Parkinson's Disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra, specifically within the nigrostriatal pathway. This loss results in a neurochemical imbalance defined by a decrease ($\downarrow$) in dopamine and a relative increase ($\uparrow$) in acetylcholine ($\text{ACh}$) within the basal ganglia.
• Therapeutic Goal: The primary objective is to restore neurotransmitter balance. This is achieved by either increasing dopamine levels (through agonists, precursors, or enzyme inhibitors) or by decreasing $\text{ACh}$ levels (via anticholinergics).
• Clinical Presentation (TRAP):
  • T: Tremor, specifically occurring at rest.
  • R: Rigidity, often described as "cog-wheel."
  • A: Akinesia or bradykinesia, characterized by slowness in initiating movement.
  • P: Postural instability.
• Additional Symptoms:
  • Dystonia (sustained muscle contractions).
  • Autonomic symptoms: Orthostasis (low blood pressure upon standing), sexual disturbance, and bladder/bowel disturbances.
  • Mental status changes: Dementia and sleep disturbances.

Parkinson's Disease Medications

• Dopamine Agonist: Pramipexole (Mirapex®):
  • Mechanism of Action: Binds directly to dopamine receptors to stimulate activity.
  • Adverse Effects: High incidence of nausea ($\sim 50\%$), orthostasis, postural changes, and dose-dependent CNS effects. Issues may arise with dose escalation and abrupt discontinuation.
  • Precautions/Notes: Caution in patients with a psychiatric history, dementia, cardiovascular (CV) disease, renal impairment, or dyskinesia. Classified as Pregnancy Category C.
• Levodopa (Dopar®):
  • Mechanism of Action: A dopamine precursor that crosses the blood-brain barrier (BBB). It is converted to dopamine centrally (the desired effect) and peripherally (leading to adverse effects). It is rarely administered as a monotherapy.
  • Adverse Effects: Nausea, vomiting, cardiac arrhythmias, and orthostasis due to peripheral conversion.
• Carbidopa/Levodopa (Sinemet®):
  • Mechanism of Action: Carbidopa blocks peripheral decarboxylation, allowing more levodopa to reach the BBB and reducing peripheral dopamine levels.
  • Adverse Effects: Reduced peripheral side effects compared to levodopa alone, though nausea/vomiting, arrhythmia, and orthostasis are still possible.
  • Administration: Should be taken on an empty stomach; high-protein meals should be avoided as they interfere with absorption.
• MAO-B Inhibitors: Selegiline (Eldepryl®), Rasagiline (Azilect®):
  • Mechanism of Action: Inhibits the Monoamine Oxidase B (MAO-B) enzyme to block the breakdown of dopamine.
  • Adverse Effects: Insomnia and jitteriness. Unlike MAO-A inhibitors, these are NOT typically associated with tyramine reactions or hypertensive crises.
  • Notes: Possible neuroprotection is suggested, but conclusive evidence is currently lacking.
• COMT Inhibitor: Entacapone (Comtan®):
  • Mechanism of Action: Inhibits Catechol-O-methyltransferase (COMT), prolonging the effect of levodopa by blocking dopamine catabolism.
  • Adverse Effects: Harmless brownish-orange urine, hepatotoxicity, exacerbation of orthostasis, GI upset, and dizziness.
  • Notes: Must only be used in conjunction with carbidopa/levodopa; never used as monotherapy.
• Amantadine (Symmetrel®):
  • Mechanism of Action: The exact mechanism in PD is unknown, but it appears to increase dopaminergic activity by decreasing dopamine reuptake at the nerve terminal.
  • Adverse Effects: Sedation, vivid dreams, dry mouth, and livedo reticularis (mottling of the skin).
  • Notes: Use caution in patients with renal impairment.
• Anticholinergic: Benztropine (Cogentin®):
  • Mechanism of Action: Blocks the effects of the relatively high levels of $\text{ACh}$.
  • Adverse Effects: Constipation, urinary retention, dry mouth, blurred vision, sedation, anxiety, and depression.
  • Notes: Most effective for treating tremor and certain features of dystonia.

Parkinson's Treatment Complications and Interactions

• Interactions:
  • MAO-A inhibitors: Increased risk of hypertensive crisis.
  • Typical Antipsychotics: These may antagonize the therapeutic effects of levodopa.
• Treatment Complications:
  • "Wearing Off": The medication effect dissipates before the next scheduled dose. Management includes increasing the frequency or dose, switching to extended-release (ER), or adding a COMT inhibitor, dopamine agonist, or selegiline.
  • "On/Off" Effect: Unpredictable return of Parkinsonian symptoms at any time. Management involves adding a COMT inhibitor and redistributing dietary protein.
  • Dyskinesia: Involuntary abnormal movements. Management involves removing selegiline, decreasing the levodopa dose, or adding/increasing an anticholinergic.
• Monitoring:
  • Efficacy: Mobility, tremor severity, presence of on-off or wearing-off effects, and adherence to timing (empty stomach/protein).
  • Safety: CNS effects (hallucinations, sedation), dyskinesia, orthostasis, and checking for drug interactions.

Psychosis and Antipsychotic Pharmacotherapy

• Key Concept: Parkinson's and Psychosis involve the same neurotransmitter (dopamine) but represent opposite problems in opposite pathways.
  • PD: Lack of dopamine. Treatment increases dopamine; spill-over into the mesolimbic pathway causes psychosis.
  • Psychosis: Excessive dopamine. Treatment decreases dopamine; spill-over into the nigrostriatal pathway causes movement disorders (Extrapyramidal Symptoms or EPS).
• Typical (First-Generation) Antipsychotics: Primary mechanism is blocking $\text{D}_2$ receptors.
  • Agents: Chlorpromazine (Thorazine®), Haloperidol (Haldol®) — Haloperidol is a highly potent $\text{D}_2$ blocker.
  • Receptor-Specific Adverse Effects:
    • Muscarinic ($\text{ACh}$): Anticholinergic effects.
    • Peripheral alpha-1: Hypotension.
    • Central histamine: Sedation.
    • $D_2$ (Basal Ganglia): EPS (Haloperidol has the highest risk).
    • Other: Photosensitivity (Chlorpromazine) and lowered seizure threshold.
• EPS Classification:
  • Early (Acute Dystonic Reaction): Facial grimacing.
  • Early (Akathisia): Internal restlessness and a compelling urge to move.
  • Early (Pseudoparkinsonism): Slowed movement, rigidity, and resting tremor.
  • Early (Neuroleptic Malignant Syndrome/NMS): Life-threatening; symptoms include fever, altered mental status, muscle rigidity, and nephrotoxicity.
  • Delayed (Tardive Dyskinesia): Repetitive involuntary movements of the face, extremities, and trunk. It may worsen when medication is stopped and can be permanent.
• Atypical (Second-Generation) Antipsychotics: Block $\text{D}_2$ and $5\text{-HT}_2$ receptors (higher affinity for $5\text{-HT}_2$ and $D_4$).
  • Agents: Clozapine (Clozaril®), Olanzapine (Zyprexa®), Quetiapine (Seroquel®), Risperidone (Risperdal®), Ziprasidone (Geodon®), Aripiprazole (Abilify®).
  • Adverse Effects: EPS is rare (few $D_4$ receptors in the substantia nigra); sedation, QT prolongation, weight gain, and diabetes risk.
  • Clozapine Specifics: Risk of agranulocytosis ($\sim 1\%$). FDA mandates WBC monitoring: weekly for the first $6$ months, then biweekly for months $6\text{-}12$, then monthly thereafter.

Depression: Impact, Diagnosis, and Pathophysiology

• Statistics (NIH 2020): Affects $8.4\%$ of US adults, $17\%$ of adolescents ($12\text{-}17$), and $15\text{-}30\%$ of UMN students. More common in women.
• Diagnostic Symptoms (DSM-based):
  • Core symptoms: Depressed mood and loss of interest or pleasure.
  • Other symptoms: Fatigue/decreased energy, worthlessness/guilt, impaired concentration, insomnia/hypersomnia, recurring thoughts of death/suicide, restlessness, and significant weight changes.
• Causes: Biochemical imbalances (Norepinephrine (NE), $5\text{-HT}$, dopamine; receptor sensitivity changes), environmental stressors, psychological factors, and genetics.

Antidepressant Medications

• SSRIs: Fluoxetine (Prozac®), Citalopram (Celexa®), Escitalopram (Lexapro®), Sertraline (Zoloft®), Paroxetine (Paxil®).
• SNRIs: Venlafaxine (Effexor®), Duloxetine (Cymbalta®).
  • Mechanism: Block reuptake of Serotonin (SSRI) and/or Norepinephrine (SNRI).
  • Kinetics: Long half-life ($2\text{-}5\,\text{days}$ for Fluoxetine allows weekly dosing; others are daily).
  • Common Adverse Effects: GI distress (diarrhea, nausea), sexual dysfunction, weight changes, and sleep disturbances. SNRIs also cause sweating and increased blood pressure.
• SSRI Comparison Profile:
  • Fluoxetine: High insomnia ($++++$), High Anxiety ($++++$), High Drug Interactions ($++++$).
  • Paroxetine: High Sedation ($++++$), High Sexual Dysfunction ($+++$), High Weight Gain ($+++$).
  • Citalopram/Sertraline: Moderate GI effects ($+++$).
• Precautions:
  • Time to Effect: $4\text{-}6\,\text{weeks}$.
  • Black Box Warning: Increased suicidality risk in children, adolescents, and young adults.
  • Serotonin Syndrome: Risk with high doses or interactions.
  • MAOI Washout: Wait $2\text{-}5\,\text{weeks}$ after stopping SSRI/SNRI before starting MAOI; wait $2\,\text{weeks}$ after MAOI before starting SSRI/SNRI.
• Dopamine Reuptake Inhibitor (SDRI): Bupropion (Wellbutrin®):
  • Mechanism: Inhibits reuptake of Dopamine and NE (weakly).
  • Adverse Effects: Headache, insomnia, dry mouth, weight loss. Notably lacks sexual dysfunction.
  • Contraindications: Seizure disorders, anorexia/bulimia, and abrupt sedative/alcohol withdrawal.
• Tricyclic Antidepressants (TCAs): Amitriptyline (Elavil®), Nortriptyline (Aventyl®), Desipramine (Norpramin®).
  • Adverse Effects: Strong anticholinergic effects, sedation, orthostasis, weight gain. HIGH FATAL OVERDOSE POTENTIAL.
• St. John’s Wort: Dietary supplement targeting serotonin reuptake. Many drug interactions (induces $\text{CYP3A4}$).

Anxiety and Insomnia Pharmacotherapy

• Anxiety Types: GAD, OCD, Panic Disorder, PTSD, SAD.
• Acute Anxiety Treatment: Benzodiazepines (Alprazolam/Xanax®, Diazepam/Valium®) enhance GABA. Hydroxyzine (Atarax®, Vistaril®) is an $H_1$ antagonist.
• Chronic Anxiety Treatment: Buspirone (BuSpar®) (takes $2\text{-}3\,\text{weeks}$) and SSRIs/SNRIs (Paroxetine approved for all types).
• Insomnia - OTC Options:
  • Diphenhydramine (Benadryl®): First-generation antihistamine with sedative and anticholinergic properties.
  • Melatonin: Receptor agonist for circadian regulation. Dose: Adult ($3\text{-}5\,\text{mg}$), Pediatric ($1\text{-}5\,\text{mg}$ depending on age).
  • Doxylamine: Safe in pregnancy (Category A).
• Insomnia - Prescription Options:
  • Trazodone (Desyrel®): $5\text{-HT}_2$ antagonist; causes sedation and dose-related orthostasis. Potential for priapism.
  • Zolpidem (Ambien®): Non-barbiturate hypnotic. Risk of complex sleep-related behaviors (sleep driving) and amnesia. Limit use to $4\,\text{weeks}$.

Anti-Seizure Drugs (ASD)

• Terminology: Seizure (transient alteration of behavior); Epilepsy (recurrent, unpredictable seizures); Status Epilepticus ($>5\,\text{min}$ duration, medical emergency).
• Mechanisms:
  • Increase Inhibition (GABA): Phenobarbital, Benzodiazepines, Topiramate, etc.
  • Reduce Excitation (Glutamate/Channels): Carbamazepine, Gabapentin, Lamotrigine, Levetiracetam, etc.
• Pharmacokinetics: Most are hepatically metabolized with significant interactions and narrow therapeutic indices.
• Key Drug Adverse Effects:
  • Carbamazepine (Tegretol®): Rash ($7\%$), SJS/TEN risk linked to $\text{HLA-B*15:02}$ and $\text{HLA-A*31:01}$.
  • Lamotrigine (Lamictal®): High incidence of diplopia ($24\text{-}49\%$) and risk of SJS.
  • Divalproex (Depakote®): Tremor ($1\text{-}57\%$) and hepatotoxicity.
• Serious Cutaneous Adverse Reactions (SCAR):
  • SJS: Involves $<10\%$ Body Surface Area (BSA).
  • TEN: Involves $>30\%$ BSA; high mortality/sepsis risk.

Alzheimer’s Disease (AD) Pharmacotherapy

• Pathophysiology: $\beta$-amyloid plaques and tau tangles. Loss of cholinergic neurons and excess glutamate leading to NMDA mediated excitotoxicity.
• Drug Classes:
  • Acetylcholinesterase Inhibitors: Donepezil, Rivastigmine, Galantamine. Increase $\text{ACh}$ levels. Side effects: GI distress and bradycardia.
  • NMDA Antagonist: Memantine (Namenda®). Standardizes glutamate activity. Indicated for moderate-severe cases.
  • Anti-Amyloid mAbs: Lecanemab, Donanemab. Clear plaques via immune activation. Risks include ARIA (Amyloid-Related Imaging Abnormalities) and infusion reactions.
• PT Pearls: Monitor for falls, syncope, and "sundowning." Avoid use of extra anticholinergics (e.g., oxybutynin) or benzodiazepines.