5.2 Neurologic Pharmacotherapy

5.2 Neurologic Pharmacotherapy

1. Epilepsy and Antiseizure Medications (ASMs)

Antiseizure Medication Classification and Mechanisms of Action

Antiseizure medications (ASMs) reduce seizure activity by decreasing excitatory neurotransmission (primarily mediated by glutamate) or enhancing inhibitory neurotransmission (primarily mediated by GABA). The primary mechanisms of action include:

1. Voltage-Gated Sodium Channel Blockade: Prolongs the inactivated state of sodium channels, preventing high-frequency repetitive firing of action potentials.
   • Key Agents: Phenytoin, Carbamazepine, Oxcarbazepine, Eslicarbazepine, Lamotrigine, Lacosamide, Rufinamide, Zonisamide.
2. Voltage-Gated Calcium Channel Modulation:
   • T-Type Calcium Channels: Essential for pacemaker activity in the thalamus, which is implicated in the pathogenesis of absence seizures.
     • Key Agents: Ethosuximide, Valproic Acid.
   • Alpha-2-Delta (α2δ) Subunit of Voltage-Gated Calcium Channels: Reduces calcium influx into presynaptic terminals, thereby decreasing the release of excitatory neurotransmitters.
     • Key Agents: Gabapentin, Pregabalin.
3. GABAergic Enhancement (Inhibition):
   • GABA-A Receptor Positive Allosteric Modulators: Increase the frequency or duration of chloride channel opening, hyperpolarizing the postsynaptic membrane.
     • Key Agents: Benzodiazepines (e.g., Clobazam, Clonazepam, Diazepam, Lorazepam), Phenobarbital, Primidone.
   • GABA Transaminase (GABA-T) Inhibition: Prevents the degradation of GABA in the synaptic cleft.
     • Key Agent: Vigabatrin.
   • GABA Reuptake Transporter-1 (GAT-1) Inhibition: Prevents the reuptake of GABA into presynaptic neurons and glial cells.
     • Key Agent: Tiagabine.
4. Synaptic Vesicle Protein 2A (SV2A) Ligand: Modulates vesicle fusion and calcium-dependent neurotransmitter release.
   • Key Agents: Levetiracetam, Brivaracetam.
5. Glutamate Receptor Blockade (AMPA/NMDA Antagonism):
   • AMPA/Kainate Receptor Antagonism: Blocks the fast-acting ionotropic glutamate receptors.
     • Key Agent: Topiramate (weakly), Perampanel (selective non-competitive AMPA antagonist).
   • NMDA Receptor Antagonism: Blocks the slow-acting calcium-permeable glutamate receptors.
     • Key Agent: Felbamate.

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Detailed Profiles of Key Antiseizure Medications

Valproate / Valproic Acid (Depakote, Depakene)

• Mechanism of Action: Multi-modal; blocks voltage-gated sodium channels, blocks T-type calcium channels, increases GABA synthesis and decreases its degradation.
• Dosing & Titration: Initial: 10–15 mg/kg/day PO; titrate by 5–10 mg/kg/day weekly to response; typical maintenance: 15–60 mg/kg/day. Extended-release (ER) tablets require a 10–20% dose increase when converting from delayed-release (DR) formulations due to lower bioavailability.
• Therapeutic Range & Monitoring:
  • Total Level: 50–100 mcg/mL (up to 125 mcg/mL in acute mania or refractory epilepsy).
  • Free Level: 5–15 mcg/mL.
  • Clinical Interpretation: Valproate is highly protein-bound (~90%) to albumin. Under conditions of hypoalbuminemia (elderly, liver disease, pregnancy, renal failure, or displacement by other highly bound drugs like aspirin), the free fraction increases. A total serum concentration may appear in the normal range while the active free level is toxic. Free level monitoring is recommended in these cohorts.
• Key Interacting Profiles: Inhibits CYP2C9, UGT, and epoxide hydrolase. Substantially increases concentrations of lamotrigine (doubling its half-life) and the active metabolite of carbamazepine.
• Major Toxicities & Boxed Warnings:
  • Hepatotoxicity (Boxed Warning): Usually occurs within the first 6 months of therapy. Increased risk in pediatric patients < 2 years and those with mitochondrial disorders (POLG gene mutation).
  • Pancreatitis (Boxed Warning): Life-threatening, hemorrhagic pancreatitis can occur shortly after initiation or after chronic use.
  • Teratogenicity (Boxed Warning): Major congenital malformations, particularly neural tube defects (e.g., spina bifida), craniofacial defects, and developmental delay. Avoid in women of childbearing potential unless absolutely necessary and fail other therapies.
  • Dose-Related & Chronic Adverse Effects: Thrombocytopenia (dose-related, monitor platelets), hyperammonemia (can cause encephalopathy without elevated LFTs; treated with L-carnitine), weight gain, alopecia, tremor, polycystic ovary syndrome (PCOS).

Carbamazepine (Tegretol)

• Mechanism of Action: Blocks voltage-gated sodium channels.
• Dosing & Titration: Initial: 200 mg BID PO (or 100 mg QID for suspension); titrate by 200 mg/day weekly to therapeutic response. Usual maintenance: 800–1200 mg/day.
• Therapeutic Range & Monitoring:
  • Therapeutic Level: 4–12 mcg/mL.
  • Monitoring: Baseline and periodic CBC (risk of aplastic anemia/agranulocytosis), liver enzymes, serum sodium (hyponatremia risk), ophthalmic exams, and serum carbamazepine levels.
• Autoinduction Phenomenon: Carbamazepine is a potent substrate and inducer of the CYP3A4 enzyme system. It induces its own metabolism (autoinduction). The half-life is initially ~30 hours at initiation but decreases to ~15 hours after 3–4 weeks of continuous dosing. Autoinduction is usually complete within 3–5 weeks. Consequently, dosing must be titrated upward over this period, and steady-state levels cannot be accurately assessed before this window has closed.
• Pharmacogenomic Screening (HLA-B*1502):
  • Carrying the HLA-B*1502 allele increases the risk of severe, life-threatening cutaneous eruptions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
  • Mandatory Screening: Required for patients of Asian ancestry prior to starting carbamazepine. A positive result is an absolute contraindication to carbamazepine.
• Major Toxicities & Boxed Warnings:
  • Serious Dermatologic Reactions (Boxed Warning): SJS/TEN.
  • Aplastic Anemia & Agranulocytosis (Boxed Warning): Rare but severe bone marrow suppression. Monitor for fever, sore throat, or easy bruising.
  • Hyponatremia / SIADH: Induced by an increase in antidiuretic hormone (ADH) sensitivity; occurs in up to 10% of patients.
  • Teratogenicity: Associated with neural tube defects.

Lamotrigine (Lamictal)

• Mechanism of Action: Blocks voltage-gated sodium channels and inhibits the presynaptic release of glutamate.
• Titration Schedules (Crucial for Safety):
  • Slow titration is mandatory to minimize the risk of SJS/TEN. The presence of concurrent medications alters lamotrigine clearance, necessitating distinct titration regimens:
  • Standard Regimen (No interacting medications):
    • Weeks 1–2: 25 mg daily PO.
    • Weeks 3–4: 50 mg daily PO.
    • Week 5: 100 mg daily PO.
    • Maintenance: 225–375 mg/day in two divided doses.
  • Inhibitor Regimen (With Valproic Acid): Valproate inhibits UGT enzymes, doubling the half-life of lamotrigine. Doses must be halved:
    • Weeks 1–2: 25 mg every other day PO.
    • Weeks 3–4: 25 mg daily PO.
    • Week 5: 50 mg daily PO.
    • Maintenance: 100–150 mg/day (divided BID or daily; target ~100 mg/day).
  • Inducer Regimen (With Phenytoin, Carbamazepine, Phenobarbital, Primidone): Enzyme inducers accelerate UGT-mediated clearance, halving lamotrigine's half-life. Doses must be doubled:
    • Weeks 1–2: 50 mg daily PO.
    • Weeks 3–4: 100 mg daily PO (in divided doses).
    • Week 5: 200 mg daily PO (in divided doses).
    • Maintenance: 300–500 mg/day in two divided doses.
• Major Toxicities & Boxed Warnings:
  • Serious Dermatologic Reactions (Boxed Warning): SJS/TEN. Highest risk is associated with rapid titration, high starting doses, or co-administration with valproate. Any skin rash must be immediately evaluated, and lamotrigine should typically be discontinued.
  • Aseptic Meningitis: Non-infectious inflammation of the meninges; requires permanent discontinuation.
  • Hemophagocytic Lymphohistiocytosis (HLH): Rare, life-threatening immune system overactivation.
  • Cardiac Conduction Prolongation: Can prolong the PR interval; use caution in patients with structural heart disease or bundle branch blocks.

Phenytoin (Dilantin)

• Mechanism of Action: Blocks voltage-gated sodium channels.
• Dosing & Administration:
  • Loading Dose: 15–20 mg/kg.
  • Maintenance Dose: 300–400 mg/day (100 mg TID or 300 mg ER daily).
  • IV Formulation Guidelines: IV phenytoin contains 40% propylene glycol (as a solubilizer) which is highly cardiotoxic.
    • Maximum Infusion Rate: 50 mg/minute (to prevent severe hypotension and QTc prolongation/arrhythmias).
    • Dilution: Dilute only in Normal Saline (NS); it precipitates in dextrose-containing solutions.
    • Filter: Must be administered through an in-line 0.22-micron filter.
    • Extravasation Risk: Causes Purple Glove Syndrome, a severe local tissue necrosis, swelling, and discoloration that can lead to amputation. Avoid peripheral IV administration in hand veins; use a large-bore peripheral or central line.
  • Fosphenytoin (Cerebyx): A water-soluble prodrug of phenytoin.
    • Dosed in Phenytoin Equivalents (PE). 1.5 mg fosphenytoin = 1 mg PE.
    • Maximum Infusion Rate: 150 mg PE/minute.
    • Advantages: Can be diluted in D5W or NS; lower risk of local tissue damage/Purple Glove Syndrome; can be administered IM.
• Michaelis-Menten Kinetics:
  • Phenytoin exhibits non-linear, saturable elimination kinetics. The liver enzymes (CYP2C9/2C19) that metabolize phenytoin saturate within the therapeutic range.
  • Once saturated, the clearance rate becomes fixed, and elimination transitions from first-order to zero-order kinetics. A small dosage increase (e.g., from 300 mg to 330 mg daily) can lead to a disproportionately large, toxic spike in serum concentration.
  • Winter-Tozer Correction Formula: In patients with hypoalbuminemia (albumin < 3.5 g/dL), the total measured phenytoin level is falsely low because a larger fraction of the drug is unbound (free). Calculate the corrected total level using: $C_{\text{corrected}} = \frac{C_{\text{measured}}}{(0.2 \times \text{Albumin}) + 0.1}$ If the patient has end-stage renal disease (CrCl < 10 mL/min or on hemodialysis), the binding affinity of albumin for phenytoin decreases, requiring a modified formula: $C_{\text{corrected}} = \frac{C_{\text{measured}}}{(0.1 \times \text{Albumin}) + 0.1}$
• Therapeutic Range & Monitoring:
  • Total Level: 10–20 mcg/mL.
  • Free Level: 1–2 mcg/mL.
• Major Toxicities:
  • Acute / Concentration-Dependent: Nystagmus (level > 20 mcg/mL), ataxia and slurred speech (> 30 mcg/mL), lethargy, confusion, and coma (> 40 mcg/mL).
  • Chronic: Gingival hyperplasia, hirsutism, peripheral neuropathy, osteomalacia (vitamin D deficiency), folate deficiency (megaloblastic anemia), lupus-like syndrome, and coarsening of facial features.

Levetiracetam (Keppra)

• Mechanism of Action: Binds to synaptic vesicle protein 2A (SV2A), preventing synaptic neurotransmitter release.
• Dosing & Titration: Initial: 500 mg BID PO/IV; increase by 1000 mg/day every 2 weeks to a maximum of 3000 mg/day.
• Renal Dose Adjustments (CrCl-based):
  • CrCl 50–80 mL/min: 500–1000 mg Q12H.
  • CrCl 30–49 mL/min: 250–750 mg Q12H.
  • CrCl < 30 mL/min: 250–500 mg Q12H.
  • Hemodialysis: 500–1000 mg Q24H (plus a 250–500 mg supplemental dose post-dialysis).
• Monitoring: Renal function, mood/behavioral changes.
• Major Toxicities:
  • Neuropsychiatric Side Effects: High incidence of irritability, hostility, aggression, anxiety, depression, and mood swings (often clinically termed "Kepprage"). Pyridoxine (Vitamin B6) 100–200 mg daily may be used as an adjunctive treatment to manage behavioral side effects.
  • CNS Depression: Somnolence, asthenia, dizziness, gait instability.

Topiramate (Topamax)

• Mechanism of Action: Blocks sodium channels, enhances GABA-A receptor activity, antagonizes AMPA/kainate glutamate receptors, and acts as a weak carbonic anhydrase inhibitor.
• Dosing & Titration: Initial: 25 mg daily or BID; titrate by 25–50 mg/day weekly to a target of 200 mg BID.
• Renal Dose Adjustments: If CrCl < 70 mL/min, reduce the starting and maintenance dose by 50%; titrate more slowly.
• Monitoring: Serum bicarbonate levels (baseline and periodically), renal function, intraocular pressure.
• Major Toxicities:
  • Cognitive Slowing: Psychomotor slowing, word-finding difficulty, concentration impairment (colloquially referred to as "Dope-a-max").
  • Non-Gap Metabolic Acidosis: Due to renal carbonic anhydrase inhibition resulting in renal bicarbonate wasting.
  • Nephrolithiasis: Carbonic anhydrase inhibition increases urine pH and decreases urinary citrate excretion, promoting calcium phosphate kidney stones. Counsel patients to maintain high fluid intake.
  • Oligohidrosis & Hyperthermia: Reduced sweating and elevated body temperature; primarily occurs in pediatric patients during warm weather.
  • Acute Angle-Closure Glaucoma: Characterized by ocular pain and rapid visual loss, typically within 1 month of initiation. Requires immediate drug discontinuation.
  • Paresthesias: Tingling in extremities; related to carbonic anhydrase inhibition.

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2. Acute Ischemic Stroke (AIS)

Hyperacute Reperfusion Therapy

Rapid identification and treatment of AIS with IV thrombolytics are critical to salvaging ischemic penumbral brain tissue.

Thrombolytic Agents and Dosing

1. Alteplase (rt-PA):
   • Dosing: 0.9 mg/kg (based on actual body weight; maximum total dose of 90 mg).
   • Administration: Give 10% of the total dose as an IV bolus over 1 minute, and the remaining 90% as a continuous IV infusion over 60 minutes.
   • Reconstitution: Reconstitute with sterile water to a concentration of 1 mg/mL. Do not shake the vial.
2. Tenecteplase (TNK-tPA):
   • Dosing: 0.25 mg/kg as a single IV bolus over 5–10 seconds (maximum total dose of 25 mg).
   • Clinical Context: Tenecteplase has a longer half-life, higher fibrin specificity, and greater resistance to plasminogen activator inhibitor-1 than alteplase. It is preferred for patients who are candidates for mechanical thrombectomy or in mobile stroke units due to ease of bolus administration.

Treatment Windows

• Standard 3-Hour Window: Thrombolytic therapy should be administered to all eligible patients within 3 hours of symptom onset (last known normal).
• Extended 3 to 4.5-Hour Window: Thrombolysis can be administered up to 4.5 hours after onset in select patients.
  • Relative Exclusion Criteria for the 3 to 4.5-Hour Window:
    1. Age > 80 years.
    2. Severe stroke severity (baseline NIHSS score > 25).
    3. Concomitant history of both diabetes mellitus and prior ischemic stroke.
    4. Taking any oral anticoagulant (regardless of INR).

Strict Contraindications to IV Thrombolysis (Both Agents)

Thrombolytic therapy is contraindicated if any of the following are present:

• Hemorrhage Risk: Active internal bleeding, history of intracranial hemorrhage (ICH), or head CT showing acute intracranial hemorrhage.
• Recent Trauma/Surgery: Serious head trauma or intracranial/intraspinal surgery within the preceding 3 months.
• Vascular Pathology: Intracranial neoplasm, arteriovenous malformation, or giant aneurysm.
• Uncontrolled Hypertension: Blood pressure > 185/110 mmHg that cannot be safely lowered using IV antihypertensives.
• Coagulopathy:
  • Platelet count < 100,000/mm³.
  • Warfarin use with INR > 1.7 or PT > 15 seconds.
  • Use of direct thrombin inhibitors (e.g., dabigatran) or factor Xa inhibitors (e.g., apixaban, rivaroxaban) within the past 48 hours, unless specific coagulation assays (e.g., aPTT, ECT, TT, or anti-Xa activity) are normal.
• Hypoglycemia: Blood glucose < 50 mg/dL (must correct blood glucose first; stroke symptoms may resolve if hypoglycemia was the mimic).

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Blood Pressure Management in Acute Ischemic Stroke

Tight blood pressure control is necessary to prevent hemorrhagic transformation of the ischemic core while maintaining cerebral perfusion pressure.

Acute Antihypertensive Agents & Dosing

• Labetalol: 10–20 mg IV push over 1–2 minutes; may repeat once. If continuous control is needed, transition to infusion.
• Nicardipine Infusion: Initiate at 5 mg/hour IV; titrate by 2.5 mg/hour every 5–15 minutes to a maximum of 15 mg/hour.
• Clevidipine Infusion: Initiate at 1–2 mg/hour IV; double the dose every 2–5 minutes to a maximum of 21 mg/hour.

BP Management in Non-Thrombolytic Candidates

In patients who do not receive thrombolysis, elevated blood pressure is a physiological response to maintain collateral perfusion to the ischemic penumbra.

• Threshold for Treatment: Do not initiate antihypertensive therapy unless blood pressure exceeds 220/120 mmHg.
• Target Reduction: If treatment is required, lower the mean arterial pressure by no more than 15% within the first 24 hours of stroke onset.
• Exceptions: Immediate blood pressure lowering is indicated if the patient has a comorbid compelling condition, such as:
  • Acute myocardial infarction / coronary syndrome.
  • Aortic dissection.
  • Acute heart failure / pulmonary edema.
  • Hypertensive encephalopathy.

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Secondary Prevention of Ischemic Stroke

Antiplatelet Therapy

• Aspirin: 160–325 mg PO administered within 24–48 hours of stroke onset.
  • Thrombolysis Delay: In patients who received IV thrombolysis, antiplatelet therapy must be held for at least 24 hours post-infusion. A follow-up head CT must confirm the absence of intracranial hemorrhage before antiplatelets are initiated.
• Dual Antiplatelet Therapy (DAPT) with Aspirin and Clopidogrel:
  • Indications: Recommended for patients with a minor ischemic stroke (NIHSS score ≤ 3) or high-risk TIA (ABCD² score ≥ 4) who present within 24 hours of symptom onset.
  • Regimen: Load with clopidogrel 300–600 mg, followed by clopidogrel 75 mg daily combined with aspirin 81 mg daily.
  • Duration: DAPT should be continued for 21 days, followed by single antiplatelet monotherapy (typically clopidogrel 75 mg daily or aspirin 81 mg daily).
  • Clinical Trials (CHANCE and POINT):
    • The CHANCE trial (conducted in China) and the POINT trial (conducted globally) demonstrated that 21 days of DAPT reduced the risk of recurrent ischemic stroke by ~25% compared to aspirin monotherapy.
    • The POINT trial highlighted that continuing DAPT for 90 days significantly increased the risk of major hemorrhage (primarily gastrointestinal and intracranial) without offering additional protection against recurrent stroke compared to stopping DAPT at 21 days.
  • Alternative DAPT: Aspirin + Ticagrelor (loading dose 180 mg, then 90 mg BID) for 30 days in patients with mild-to-moderate ischemic stroke (NIHSS ≤ 5) or TIA (based on the THALES trial).
• Clopidogrel Monotherapy: Preferred for long-term secondary prevention in patients with a true contraindication or allergy to aspirin.

High-Intensity Statins

• All patients with an ischemic stroke of atherosclerotic origin should receive high-intensity statin therapy to reduce stroke recurrence.
  • Regimen: Atorvastatin 80 mg daily or Rosuvastatin 20–40 mg daily.
  • Lipid Targets: Target an LDL-C reduction of ≥ 50% from baseline, or an absolute target of < 70 mg/dL (or < 55 mg/dL for patients with multiple major ASCVD events).

Long-Term Blood Pressure Target

• In patients with established stroke/TIA history, long-term blood pressure control reduces recurrent stroke risk.
  • Target: < 130/80 mmHg is generally recommended.
  • Preferred Agents: Thiazide diuretics, ACE inhibitors, or ARBs (either monotherapy or in combination, e.g., perindopril + indapamide).

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3. Parkinson's Disease (PD)

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor (tremor, rigidity, bradykinesia, postural instability) and non-motor symptoms.

Carbidopa/Levodopa (Sinemet) Fundamentals

• Mechanism of Action:
  • Levodopa: A dopamine precursor. Dopamine itself cannot cross the blood-brain barrier (BBB). Levodopa crosses the BBB via the large neutral amino acid transporter. Once in the CNS, it is converted to active dopamine by dopa decarboxylase (DDC).
  • Carbidopa: A peripheral inhibitor of dopa decarboxylase. It is polar and cannot cross the BBB, leaving CNS DDC unaffected.
• The Carbidopa Daily Threshold:
  • A minimum daily dose of 70 to 100 mg of carbidopa is required to fully saturate peripheral dopa decarboxylase.
  • Inadequate Dosing Effects: If less than 70–100 mg/day of carbidopa is administered, levodopa undergoes extensive peripheral conversion to dopamine. This leads to systemic dopaminergic side effects, including severe nausea, vomiting, orthostatic hypotension, and tachycardia. Additionally, the amount of levodopa reaching the CNS is drastically reduced, necessitating higher, more toxic doses of levodopa.

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Management of Motor Fluctuations in Parkinson's Disease

As Parkinson's disease progresses, the loss of presynaptic dopaminergic storage capacity leads to motor fluctuations.

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Profiles of Adjunctive Agents in Parkinson's Disease

COMT Inhibitors: Entacapone (Comtan)

• Mechanism of Action: Reversibly inhibits peripheral catechol-O-methyltransferase (COMT). When peripheral dopa decarboxylase is blocked by carbidopa, COMT becomes the primary pathway for levodopa metabolism, converting it to 3-O-methyldopa (3-OMD). Inhibiting COMT prevents this pathway, prolonging the half-life of levodopa and increasing brain penetration.
• Dosing: 200 mg PO administered simultaneously with each dose of carbidopa/levodopa (maximum of 1600 mg/day or 8 doses/day).
• Key Patient Counseling Points:
  • Urine Discoloration: Causes a benign orange, brown, or reddish discoloration of urine, sweat, and saliva.
  • Dyskinesia: Because it increases levodopa levels, it can trigger or exacerbate dyskinesia; the baseline levodopa dose may need to be reduced by 10–30% upon initiation.
  • Diarrhea: Severe, persistent watery diarrhea may develop weeks to months after starting; requires drug discontinuation.

MAO-B Inhibitors: Selegiline, Rasagiline, Safinamide

• Mechanism of Action: Selective, irreversible (selegiline, rasagiline) or reversible (safinamide) inhibition of monoamine oxidase type B (MAO-B) in the CNS. This decreases the breakdown of synaptic dopamine.
• Selegiline (Eldepryl, Zelapar ODT):
  • Metabolism: Metabolized to L-amphetamine and L-methamphetamine metabolites.
  • Clinical Pearls: These metabolites cause significant insomnia, jitteriness, and cardiovascular effects.
  • Dosing Counseling: Avoid dosing selegiline late in the day; the second daily dose of oral selegiline (5 mg) should not be taken after 2 PM (standard dosing is 5 mg at breakfast and 5 mg at lunch). Zelapar ODT (orally disintegrating) bypasses first-pass hepatic metabolism, producing fewer amphetamine metabolites.
• Rasagiline (Azilect):
  • Metabolism: Metabolized to aminoindan (non-amphetamine).
  • Clinical Pearls: Does not cause insomnia; can be dosed once daily (0.5–1 mg daily).
• Drug Interactions & Safety:
  • Serotonin Syndrome: Potential risk when MAO-B inhibitors are co-administered with other serotonergic agents (SSRIs, SNRIs, TCAs, tramadol, meperidine, linezolid).
  • Hypertensive Crisis: Selectivity for MAO-B is dose-dependent. At recommended doses, dietary tyramine restriction is generally not required. However, at supratherapeutic doses, MAO-A is also inhibited, necessitating avoidance of tyramine-rich foods (e.g., aged cheeses, cured meats, red wine).

Dopamine Agonists: Pramipexole, Ropinirole, Rotigotine

• Mechanism of Action: Direct agonists at dopamine D2 and D3 receptors, bypassing the need for presynaptic enzymatic conversion.
• Agents: Pramipexole (Mirapex), Ropinirole (Requip), Rotigotine (Neupro patch).
• Major Adverse Effects & Safety Profiles:
  • Impulse Control Disorders: Pathological gambling, hypersexuality, compulsive buying, and binge eating. This is a class effect mediated by D3 receptor stimulation in the mesolimbic "reward" pathway.
    • Counseling: Patients and caregivers must be screened for behavioral changes at every visit; if they occur, the dopamine agonist must be slowly tapered off.
  • Sudden Sleep Attacks: Patients may suddenly fall asleep during active tasks, such as driving, without prior warning of somnolence.
  • Hallucinations and Psychosis: More common than with levodopa; avoid in patients with pre-existing psychotic disorders.
  • Peripheral Edema & Orthostatic Hypotension.

Subcutaneous Apomorphine (Apokyn) Rescue

• Indication: Acute, intermittent rescue treatment for "off" episodes (stiffness, freezing) in patients with advanced Parkinson's disease.
• Pharmacokinetics: Injected subcutaneously; onset of action is 10–20 minutes, with a duration of ~60 minutes.
• Emetic Profile & Prophylaxis:
  • Apomorphine is an extremely potent activator of the area postrema, causing severe nausea and vomiting.
  • Trimethobenzamide (Tigan) 300 mg PO TID must be initiated 3 days prior to the first dose of apomorphine and continued for at least the first 2 months of therapy.
• Absolute Contraindication:
  • 5-HT3 Receptor Antagonists (e.g., Ondansetron, Granisetron, Dolasetron): Co-administration with apomorphine is strictly contraindicated. The combination can precipitate severe, profound hypotension and loss of consciousness.

Anticholinergic Agents: Benztropine (Cogentin) and Trihexyphenidyl (Artane)

• Mechanism of Action: Antagonizes central muscarinic acetylcholine receptors, helping to normalize the dopamine/acetylcholine balance in the striatum.
• Clinical Role: Used as monotherapy or adjunctive therapy in younger patients (< 65 years) where tremor is the primary disabling symptom.
• Geriatric Precautions (Beers Criteria):
  • Strongly contraindicated in the elderly.
  • Adverse Effects: High risk of cognitive impairment, confusion, visual hallucinations, dry mouth, blurred vision, urinary retention, and constipation.

Amantadine (Gocovri, Osmolex ER)

• Mechanism of Action: Weak NMDA receptor antagonist, increases dopamine release, and blocks dopamine reuptake.
• Clinical Role: Primarily used to manage levodopa-induced dyskinesias without worsening parkinsonian motor symptoms.
• Major Adverse Effects:
  • Livedo Reticularis: A benign, reversible, reddish-purple reticulated (lacy) vascular discoloration of the skin, most prominent on the thighs and lower legs. It is caused by local vasoconstriction and resolves upon drug discontinuation.
  • CNS Toxicities: Visual hallucinations, confusion, nightmares, and sleep disturbance. Requires dose reduction in patients with renal impairment.