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Neurodegenerative Diseases - Complete Drug Reference

What Are Neurodegenerative Diseases?

• Abnormal protein aggregation (amyloid plaques, tau tangles, alpha-synuclein, huntingtin)
• Mitochondrial dysfunction
• Excitotoxicity (overactivation of glutamate/NMDA receptors)
• Oxidative stress
• Neuroinflammation

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1. ALZHEIMER'S DISEASE (AD)

The Disease

1. Amyloid beta (Aβ) plaques - deposited extracellularly, beginning ~15 years before symptoms appear
2. Neurofibrillary tangles (NFTs) - intracellular tau protein hyperphosphorylation
3. Loss of cholinergic neurons from the nucleus basalis of Meynert (basal forebrain)

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AD Drugs

A. Acetylcholinesterase (AChE) Inhibitors

• Starting doses are half the maintenance dose for the first month
• BuChE (butyrylcholinesterase) is upregulated in AD brain; rivastigmine inhibits both enzymes
• Donepezil preferred for once-daily dosing; rivastigmine preferred in PD dementia
• Common adverse effects: nausea, diarrhea, bradycardia, increased gastric acid
• Galantamine's nicotinic receptor potentiation may provide additional cognitive benefit

B. NMDA Receptor Antagonist - Memantine

• Temporarily delays deterioration but does not cure
• Mild adverse effects: headache, dizziness
• Renal excretion - reduce dose in severe renal impairment
• Can be combined with AChE inhibitors for additive benefit

C. Amyloid Immunotherapy (Disease-Modifying Therapy)

• ARIA-E: cerebral edema
• ARIA-H: microhemorrhages
• Monitoring with serial MRI is mandatory during therapy
• Higher risk in APOE ε4 carriers

D. Treatment of Non-Cognitive Symptoms in AD

• Depression: SSRIs preferred (avoid tricyclics - anticholinergic effects worsen cognition)
• Agitation/Psychosis: Atypical antipsychotics (risperidone, quetiapine, olanzapine) used cautiously - FDA black box warning for increased mortality in elderly with dementia. Use lowest effective dose for shortest time.
• Citalopram: 30 mg/day improved agitation vs. placebo but causes QTc prolongation - not routinely recommended
• Brexpiprazole (Rexulti): Newer agent specifically approved for agitation in AD
• Dextromethorphan/quinidine (Nuedexta): Approved for pseudobulbar affect; also used for agitation
• Sun-downing: Maximize daytime light exposure, regular activity, limit daytime napping

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2. PARKINSON'S DISEASE (PD)

The Disease

• Tremor (resting, "pill-rolling")
• Rigidity (cogwheel)
• Bradykinesia/Akinesia (slowness of movement)
• Postural instability

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PD Drugs

A. Levodopa/Carbidopa - The Gold Standard

• Wearing off - benefit fades before next dose
• Dyskinesias - involuntary movements at peak dose
• On/off phenomenon - unpredictable switching between mobile ("on") and immobile ("off") states
• Therapeutic window narrows after several years of treatment

B. Dopamine Receptor Agonists (DAs)

C. COMT Inhibitors

D. MAO-B Inhibitors

E. Amantadine

1. Increases presynaptic dopamine release
2. Blocks muscarinic (cholinergic) receptors
3. Inhibits NMDA glutamate receptors (also reduces levodopa-induced dyskinesias)

F. Anticholinergics (Antimuscarinics)

G. Adenosine A2A Receptor Antagonist

• Istradefylline - Adjuvant to levodopa/carbidopa to reduce "off" episodes. Mechanism: antagonism of adenosine A2A receptors (which are co-localized with D2 receptors in the striatum). Adverse effects: dyskinesias, nausea, constipation, hallucinations, insomnia, impulse control issues.

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3. AMYOTROPHIC LATERAL SCLEROSIS (ALS)

The Disease

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ALS Drugs

1. Riluzole (Rilutek) - First-Line

2. Edaravone (Radicava)

3. Sodium Phenylbutyrate + Taurursodiol (Relyvrio / AMX0035)

4. Tofersen (Qalsody) - Gene-Targeted

5. Symptomatic/Supportive Treatments

• Spasticity: Baclofen (GABA-B agonist), tizanidine. Dantrolene is contraindicated in ALS - it acts directly on skeletal muscle to impair Ca2+ release from sarcoplasmic reticulum and would worsen muscular weakness (though it is useful in malignant hyperthermia and stroke/SCI spasticity).
• Sialorrhea (drooling): Anticholinergics, botulinum toxin
• Respiratory support: Non-invasive positive pressure ventilation (NIPPV)
• Nutrition: Percutaneous endoscopic gastrostomy (PEG) tube

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4. HUNTINGTON'S DISEASE (HD)

The Disease

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HD Drugs

1. VMAT2 Inhibitors - For Chorea

2. Antipsychotics - For Psychiatric Symptoms and Chorea

3. Antidepressants

4. Benzodiazepines

Note on Disease-Modifying Research

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5. MULTIPLE SCLEROSIS (MS)

The Disease

• Relapsing-remitting MS (RRMS): Episodic attacks with recovery between them (most common)
• Secondary progressive MS (SPMS): Steady worsening after initial RRMS
• Primary progressive MS (PPMS): Steady progression from onset (harder to treat)

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MS Drugs - Disease-Modifying Therapies (DMTs)

1. Injectable Interferons and Glatiramer

2. Sphingosine-1-Phosphate (S1P) Receptor Modulators (Oral)

3. Pyrimidine Synthesis Inhibitor

• Teriflunomide (Aubagio) - Inhibits DHODH enzyme in lymphocyte pyrimidine synthesis, reducing active lymphocytes in the CNS. Can elevate liver enzymes. Teratogenic - absolutely contraindicated in pregnancy (very long half-life; cholestyramine washout required if pregnancy is desired).

4. Nrf2 Activators / Fumarates (Oral)

5. Monoclonal Antibodies (High-Efficacy DMTs)

6. Drugs for ALS in the MS Section (as per textbook table)

7. Acute Relapse Treatment

• High-dose IV methylprednisolone (e.g., 1 g/day x 3-5 days) - shortens relapse duration but does not affect long-term disability. Oral prednisone after IV is optional.

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Summary Table: Key Mechanisms at a Glance

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Recent Evidence (2024-2026)

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• Goodman & Gilman's Pharmacological Basis of Therapeutics (Tables 21-23)
• Lippincott Illustrated Reviews: Pharmacology
• Stahl's Essential Psychopharmacology (Chapters 12-13)
• Bradley and Daroff's Neurology in Clinical Practice
• Goldman-Cecil Medicine

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Dopaminergic Drugs - Deep Pharmacology

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Part 1: Dopamine - The Neurotransmitter

Structure and Synthesis

L-Tyrosine → (Tyrosine Hydroxylase, TH) → L-DOPA → (Aromatic Amino Acid Decarboxylase, AADC) → Dopamine

• Tyrosine Hydroxylase (TH) is the rate-limiting enzyme - the key regulatory point
• After synthesis, dopamine is packaged into storage vesicles by VMAT2 (Vesicular Monoamine Transporter 2)
• Release is by exocytosis
• Reuptake occurs via the DAT (Dopamine Transporter) and, to a lesser extent, the NET (norepinephrine transporter)
• Metabolism: Cytosolic DA → degraded by MAO + ALDH → and by COMT in non-neuronal cells → final metabolite is HVA (homovanillic acid)

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Part 2: Dopamine Receptors - Full Classification

D1-Like Family (D1 and D5)

• G protein: Gs → activates adenylyl cyclase → increases cAMP
• Located postsynaptically on dopamine-receptive cells
• D1: Chromosome 5; high density in striatum (caudate-putamen), nucleus accumbens, olfactory tubercle, frontal cortex. Critical for motor control, reward, and cognition.
• D5: Chromosome 4; found in hippocampus and hypothalamus; lower expression

D2-Like Family (D2, D3, D4)

• G protein: Gi → inhibits adenylyl cyclase → decreases cAMP; also inhibits calcium channels and opens potassium channels (hyperpolarization)
• Located both pre- and postsynaptically
• D2: Chromosome 11; high density in striatum, nucleus accumbens, olfactory tubercle. The primary therapeutic target for antipsychotics and dopamine agonists. D2-short (presynaptic autoreceptor) and D2-long (postsynaptic) variants from alternative splicing.
• D3: Chromosome 11; limbic areas, especially nucleus accumbens shell. Also acts as autoreceptor. Target for some PD drugs (pramipexole is D3-preferring).
• D4: Lowest expression in the brain; frontal cortex, amygdala, hippocampus. Present in the retina.

D1 (stimulatory) and D2 (inhibitory) receptor subtypes in the striatum form the basis of the direct and indirect pathway of basal ganglia circuitry (see diagram below).

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Part 3: The Major Dopaminergic Pathways in the CNS

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Part 4: Basal Ganglia Circuit - Direct vs. Indirect Pathway

Normal State

• Cortex sends glutamate (excitatory) to the striatum
• SNpc sends dopamine to both D1 and D2 receptor-bearing striatal neurons
• Direct pathway (D1): Striatum → SNpr/GPi via GABA (inhibitory). D1 activation stimulates this pathway → net disinhibition of thalamus → motor facilitation
• Indirect pathway (D2): Striatum → GPe → STN → SNpr/GPi. D2 activation inhibits this pathway → also leads to disinhibition of thalamus → motor facilitation
• Net effect of dopamine: facilitates movement through both pathways

In Parkinson's Disease (Loss of SNpc dopamine)

• Direct pathway becomes less active (D1 under-stimulated)
• Indirect pathway becomes overactive (D2 under-stimulated = loss of inhibition)
• Result: GPi/SNpr overactive → excessive inhibition of VA/VL thalamus → reduced cortical excitation → bradykinesia, rigidity, tremor

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Part 5: Dopaminergic Drug Classes - Full Pharmacology

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CLASS 1: DOPAMINE PRECURSOR - Levodopa + Carbidopa

Levodopa

• Without a peripheral AADC inhibitor, >99% of oral levodopa is decarboxylated in gut mucosa and peripheral tissues
• Only ~1% reaches the CNS
• Peripheral DA causes severe nausea, vomiting, orthostatic hypotension

• Oral absorption: peaks 0.5-2 hours after dose
• Plasma t½: very short - 1-3 hours
• Absorption influenced by: gastric emptying rate, gastric pH, exposure to degradative enzymes in gut mucosa
• High-protein meals delay absorption (aromatic amino acids compete for the same intestinal transporter)
• Enters CNS via aromatic amino acid transporter
• Metabolized by AADC, COMT, and MAO → final products include HVA and 3-O-methyl DOPA

Carbidopa

• Peripheral AADC inhibitor (aromatic amino acid decarboxylase inhibitor)
• Cannot cross the BBB - this is the key pharmacological feature
• Blocks peripheral conversion of levodopa → dopamine
• Result: increased fraction of levodopa available to cross BBB; reduces peripheral dopamine-related side effects (nausea, hypotension)
• A daily dose of 75 mg carbidopa is generally sufficient to prevent nausea
• Most common formulation: carbidopa/levodopa 25/100 (25 mg carbidopa + 100 mg levodopa)

Motor Complications of Long-Term Levodopa Therapy

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CLASS 2: DOPAMINE RECEPTOR AGONISTS (DAs)

Non-Ergot DAs (Preferred - no fibrotic risk)

• Directly activate D2/D3 receptors in the striatum, mimicking dopamine
• D3 receptor activation by pramipexole also provides benefit for restless legs syndrome and may modulate limbic function (also causes impulse control disorders - gambling, hypersexuality)
• As autoreceptor agonists (presynaptic D2/D3), they can also reduce the firing rate and DA synthesis - used clinically at lower doses for RLS

• Nausea, vomiting
• Orthostatic hypotension
• Somnolence / sudden sleep attacks (must warn patients not to drive)
• Hallucinations, psychosis (less than levodopa but significant)
• Peripheral edema
• Impulse control disorders (pathological gambling, hypersexuality, compulsive eating/shopping) - more common with DAs than levodopa
• Augmentation of restless legs (with chronic use in RLS)

Ergot-Derived DAs (Generally Avoided Due to Fibrosis Risk)

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CLASS 3: COMT INHIBITORS (Catechol-O-Methyltransferase Inhibitors)

• Peripheral COMT: converts levodopa → 3-O-methyl DOPA (3-OMD), reducing the fraction reaching the CNS
• Central COMT: converts dopamine → 3-methoxytyramine (an inactive metabolite)

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CLASS 4: MAO-B INHIBITORS (Monoamine Oxidase B Inhibitors)

• MAO-A: preferentially deaminates serotonin, NE, tyramine
• MAO-B: the predominant form in the striatum - responsible for most oxidative metabolism of dopamine in the brain

• Meperidine (pethidine): Risk of serotonin syndrome - absolute contraindication
• SSRIs/SNRIs/TCAs: Risk of serotonin syndrome - use with caution
• Sympathomimetics: Risk of hypertensive crisis (less with selective MAO-B inhibitors)
• Tramadol, dextromethorphan: Serotonin syndrome risk

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CLASS 5: DOPAMINE PRECURSOR SYNTHESIS ENHANCERS / RELEASER

Amantadine

1. Increases presynaptic dopamine release from surviving terminals
2. Blocks muscarinic (M1) cholinergic receptors - corrects DA/ACh imbalance
3. Non-competitive NMDA glutamate receptor antagonist - reduces excitotoxicity AND is the main mechanism for reducing levodopa-induced dyskinesias

• Oral bioavailability ~90%
• Renally excreted unchanged (dose-reduce in renal impairment)
• t½: ~10-14 hours

• Livedo reticularis (mottled purplish skin - hallmark side effect)
• Peripheral edema (ankle swelling)
• Restlessness, agitation, confusion, hallucinations, acute toxic psychosis (at high doses)
• Orthostatic hypotension, urinary retention, dry mouth
• Tolerance develops with chronic use

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CLASS 6: ADENOSINE A2A RECEPTOR ANTAGONIST

Istradefylline

• A2A receptors are highly co-localized with D2 receptors in the striatum (especially on indirect pathway neurons)
• Activation of A2A receptors inhibits D2 receptor signaling, possibly via A2A-D2 heterodimer formation
• By antagonizing A2A receptors, istradefylline boosts dopamine (D2) signaling in the striatum even without directly activating D2
• Effectively increases "off-time" to "on-time" ratio when used with levodopa

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CLASS 7: ANTICHOLINERGICS (INDIRECT DOPAMINERGIC EFFECT)

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CLASS 8: ERGOT-DERIVED DA AGONISTS (Pituitary-Specific Use)

• Bromocriptine (Cycloset): FDA-approved for type 2 diabetes - activates hypothalamic dopaminergic activity, which modulates circadian regulation of insulin sensitivity. Taken within 2 hours of waking.
• Quinagolide: D2 agonist used in Europe for hyperprolactinemia.

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Part 6: Peripheral Dopaminergic Pharmacology

Dopamine as a Vasopressor (IV use in shock/critical care)

Fenoldopam

• Selective D1 receptor agonist (no α or β activity)
• Used IV for hypertensive emergencies - causes renal and mesenteric vasodilation
• Increases GFR and natriuresis (renal protective in some settings)
• Does not cross BBB

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Part 7: Drug Interactions Summary

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Quick Reference: Mechanism at the Synaptic Level

[Presynaptic terminal]
Tyrosine → L-DOPA → Dopamine (stored in vesicles via VMAT2)
↓ Exocytosis (depolarization)
[Synaptic cleft]
↓ 
Postsynaptic D1 (Gs→↑cAMP) or D2 (Gi→↓cAMP) receptors
↓
Presynaptic D2/D3 autoreceptors (feedback inhibition of synthesis/release)
↓
Reuptake via DAT → MAO/ALDH degradation → HVA
COMT in non-neuronal cells → 3-methoxytyramine → HVA

Drugs targeting each step:
- Synthesis enhancement: levodopa (substrate loading)
- VMAT2 inhibition: tetrabenazine (depletes DA)
- Direct receptor agonism: pramipexole, ropinirole, rotigotine
- Reuptake inhibition: cocaine, methylphenidate (not therapeutic in PD)
- MAO-B inhibition: selegiline, rasagiline, safinamide
- COMT inhibition: entacapone, tolcapone, opicapone
- DA release enhancement: amantadine

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• Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapters 14, 15, 21
• Katzung's Basic and Clinical Pharmacology 16e, Chapter 29
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry
• Lippincott Illustrated Reviews: Pharmacology, Chapter 15