32.4 Nervous System Pharmacology I: Antiseizure Drugs and Status Epilepticus, Headache and Migraine, Vertigo, Stroke Thrombolysis and Secondary Prevention, Encephalopathy, Dementia, ADHD, Parkinson Disease and Movement Disorders, Raised Intracranial Pressure and CNS Infections

Why this area matters

The TOS nervous system area asks you to:

• explain drug action in neurologic disorders;
• link drugs to pathophysiology;
• plan treatment;
• anticipate adverse effects and interactions;
• monitor.

Epilepsy, stroke, dementia and Parkinson disease are common, and many antiseizure drugs are teratogenic or interact with other drugs.

Antiseizure drugs

• Interactions with contraception: enzyme inducers lower the effect of hormonal contraceptives, so IUDs are recommended. All women who may become pregnant should take folic acid.

Valproic Acid / Sodium Valproate

• Mechanism: Increases brain GABA concentrations (inhibits GABA transaminase and succinic semialdehyde dehydrogenase) and blocks voltage-gated $Na^+$ and T-type $Ca^{2+}$ channels.
• Clinical Indications: Broad-spectrum antiepileptic (focal, generalized tonic-clonic, absence, and myoclonic seizures) and acute bipolar mania.
• Adverse Effects: Hepatotoxicity (fatal hepatic necrosis, especially in children $< 2$ years; monitor LFTs), Acute Pancreatitis, weight gain, alopecia, thrombocytopenia, and severe teratogenicity (Neural Tube Defects / spina bifida in $1\text{--}2\%$ of exposed gestations).

Status Epilepticus Emergency Resuscitation Protocol

Status epilepticus is defined as continuous, unremitting seizure activity lasting $\ge 5\text{ minutes}$, or $\ge 2$ discrete seizures without complete return to baseline consciousness between episodes.

Headache, migraine and vertigo

• Acute migraine:
  • NSAIDs or paracetamol early in the attack, with an antiemetic (metoclopramide, domperidone);
  • triptans (sumatriptan, 5-HT1B/1D agonists) for moderate to severe attacks, contraindicated in coronary or cerebrovascular disease and uncontrolled hypertension;
  • avoid opioids;
  • limit acute drugs to fewer than 10 to 15 days a month to prevent medication-overuse headache.
• Migraine prevention for frequent or disabling attacks:
  • propranolol;
  • topiramate (weight loss, kidney stones, cognitive slowing, teratogenic);
  • amitriptyline;
  • flunarizine;
  • valproate (avoided in women of childbearing potential);
  • CGRP monoclonal antibodies.
• Tension-type headache: simple analgesics, and amitriptyline for prevention.
• Cluster headache: 100% oxygen or a subcutaneous triptan for attacks; verapamil for prevention.
• Vertigo:
  • vestibular suppressants (meclizine, dimenhydrinate, betahistine, promethazine) for short-term relief of acute peripheral vertigo, such as vestibular neuritis;
  • avoid prolonged use, because it delays central compensation;
  • BPPV is treated with the Epley maneuver, not drugs;
  • Meniere disease is managed with a low-salt diet, diuretics and betahistine.

Stroke and intracranial hemorrhage

• Acute ischemic stroke:
  • IV thrombolysis with alteplase (0.9 mg/kg, maximum 90 mg) or tenecteplase within 4.5 hours of onset, after CT excludes hemorrhage;
  • BP must be below 185/110 before treatment;
  • contraindications include intracranial hemorrhage, recent major stroke or head trauma, active bleeding, platelets below 100,000, recent anticoagulation with a raised INR, and glucose below 50 mg/dL;
  • mechanical thrombectomy for large-vessel occlusion.
• Antithrombotics:
  • aspirin 160 to 325 mg within 24 to 48 hours if not thrombolysed;
  • short-term aspirin plus clopidogrel (21 days) for minor stroke or high-risk TIA.
• Secondary prevention:
  • an antiplatelet (or an anticoagulant for atrial fibrillation);
  • a high-intensity statin;
  • BP and glucose control;
  • stopping smoking.
• Intracerebral hemorrhage and intracranial hematoma:
  • reverse anticoagulation: vitamin K plus prothrombin complex concentrate for warfarin, idarucizumab for dabigatran, and protamine for heparin;
  • control systolic BP (to about 140 mmHg);
  • treat raised intracranial pressure with head elevation, mannitol or hypertonic saline and brief hyperventilation as a bridge;
  • surgical evacuation of epidural or subdural hematomas with mass effect;
  • steroids do not help traumatic brain injury or hemorrhage.
• Nimodipine prevents delayed ischemia after subarachnoid hemorrhage.

Encephalopathy, dementia and ADHD

• Hepatic encephalopathy:
  • lactulose traps ammonia as ammonium in the acidified colon and speeds its transit; titrate to 2 to 3 soft stools a day;
  • rifaximin is added to prevent recurrence;
  • correct precipitants such as GI bleeding, infection, hypokalemia, sedatives and constipation.
• Wernicke encephalopathy:
  • confusion, ophthalmoplegia and ataxia in malnourished or alcoholic patients;
  • give IV thiamine before glucose.
• Alzheimer dementia:
  • cholinesterase inhibitors (donepezil, rivastigmine, galantamine) for mild to moderate disease. Adverse effects are nausea, diarrhea, bradycardia and syncope.
  • Memantine, an NMDA antagonist, is used for moderate to severe disease.
  • Avoid anticholinergic drugs that worsen cognition.
  • Antipsychotics for behavioral symptoms increase mortality in dementia and are used sparingly.
• ADHD:
  • stimulants (methylphenidate, amphetamines) increase dopamine and norepinephrine. They cause appetite loss, insomnia, slowed growth, tachycardia and BP rise, and carry abuse potential (methylphenidate is a dangerous drug needing an S-2 prescription);
  • atomoxetine, a non-stimulant, carries a suicidality warning;
  • behavioral therapy comes first in preschool children.

Parkinson disease and movement disorders

• Levodopa with carbidopa:
  • the most effective drug;
  • carbidopa blocks peripheral dopa decarboxylase, which reduces nausea and hypotension and lets more levodopa reach the brain;
  • long-term problems are wearing-off, on-off fluctuations and dyskinesias;
  • protein meals reduce its absorption.
• Dopamine agonists (pramipexole, ropinirole): used in younger patients. They cause sleep attacks, hallucinations, edema and impulse-control disorders (gambling, shopping, hypersexuality).
• MAO-B inhibitors (selegiline, rasagiline) and COMT inhibitors (entacapone) prolong the effect of levodopa.
• Amantadine helps dyskinesias and causes livedo reticularis.
• Anticholinergics (trihexyphenidyl, benztropine) are used for tremor in younger patients. Avoid them in older patients because of confusion.
• Drug-induced parkinsonism: antipsychotics, metoclopramide and flunarizine can cause it. Stop the offending drug instead of adding levodopa.
• Other movement disorders:
  • Huntington chorea: VMAT2 inhibitors (tetrabenazine);
  • essential tremor: propranolol or primidone.

CNS infections

• Empiric therapy for bacterial meningitis:
  • adults: ceftriaxone plus vancomycin, with ampicillin added over 50 years of age or in immunocompromised patients for Listeria;
  • neonates: ampicillin plus cefotaxime or gentamicin;
  • dexamethasone with or before the first antibiotic dose in suspected pneumococcal meningitis.
• HSV encephalitis: IV acyclovir, with hydration to prevent crystalline nephropathy.
• Cryptococcal meningitis: amphotericin B plus flucytosine, then fluconazole.
• Neurocysticercosis: albendazole with corticosteroids.
• TB meningitis: anti-TB drugs plus dexamethasone.