Pharmacology of Neurology Review Nicholas Cascone, PA-C

Drugs used in dementia Acetylcholinesterase inhibitors: donepezil (Aricept ® ), galantamine (Razadyne ® ), rivastigmine (Exelon ® ) MOA: inhibit the action of cholinesterase enzymes, increase the level and duration of action for acetylcholine in the brain Uses: symptomatic relief in mild to moderate Alzheimer’s disease; donepezil approved for advanced Alzheimer’s; galantamine, rivastigmine approved for use in dementia with Lewy bodies Side effects: nausea and vomiting

Drugs used in dementia NMDA glutamate receptor blocker: memantine (Namenda ® ) MOA: inhibits overstimulation and excitotxicity of NMDA glutamate receptors Uses: symptomatic relief in moderate to severe Alzheimer’s, often combined with donepezil Side effects: rare – dizziness, drowsiness, headache, confusion, agitation, hallucinations Also used in dementia: antidepressants, antipsychotics, sleep medications

Drugs used in multiple sclerosis Corticosteroids (e.g., methylprednisone) Used to manage acute attacks; no effect on long term course of illness Disease-modifying agents – reduce number and severity of exacerbations: β-interferon (several brand names): anti-inflammatory, may help rebuild blood-brain barrier; side effects are flu-like symptoms and injection site disorders – can be considerable glatiramer acetate (Copaxone ® ): poorly-understood MOA; injection site reactions, flu-like symptoms

Drugs for neuropathic pain GABA analogs: gabapentin (Neurontin ® ), pregabalin (Lyrica ® ) MOA: poorly-understood, thought to mimic inhibitory effects of GABA Uses: symptomatic relief of painful neuropathy, fibromyalgia, postherpetic neuralgia, RLS; adjunctive tx with anticonvulsives, antianxiety, antidepressants Side effects: dizziness, drowsiness; visual changes, ataxia, tremor, memory impairment, sexual dysfunction, weight gain Others: TCAs, opioids, cannabinoids, Botox, memantine

Drugs used in myasthenia gravis Quarternary acetylcholinesterase inhibitors: pyridostigmine (Mestinon ® ), neostigmine (Prostigmin ® ) MOA: reversible inhibition of acetylcholinesterase in peripheral muscle Uses: symptomatic relief of muscle weakness in myasthenia gravis; neostigmine also used to reverse non- depolarizing muscle relaxants after anesthesia and in Ogilvie syndrome (acute colonic pseudo-obstruction) Side effects: N/V/D, abdominal cramps, salivation, tearing, increased bronchial secretions Edrophonium (Tensilon ® ): used to diagnose MG Administration of edrophonium temporarily reduces muscle weakness

Anticonvulsants Carbamazepine (Tegretol ® ) MOA: inhibits sodium channels, potentiates GABA receptors Uses: epilepsy, trigeminal neuralgia, mood stabilization Side effects: drowsiness, headache, ataxia, SIADH, decreased tolerance for EtOH; teratogenic Drug interactions: very common – CYP450 inducer Related drug: oxcarbazepine – fewer, less serious side effects

Anticonvulsants Phenytoin (Dilantin ® ) MOA: sodium channel blocker Uses: epilepsy Side effects: sedation, ataxia, gingival hyperplasia, drug-induced lupus, SJS/TEN, fetal hydantoin syndrome Related drug: fosphenytoin – prodrug of phenytoin

Anticonvulsants Valproic acid (Depakote ® ) MOA: blocks sodium and calcium channels, potentiates GABA receptors Uses: epilepsy, mood stabilization, migraine prophylaxis, neuropathic pain Side effects: dyspepsia, weight gain, sedation, dizziness, drowsiness/fatigue, tremors; neural tube defects in fetuses

Anticonvulsants Other drugs Ethosuximide – used in absence seizures d/t lower hepatotoxicity Phenobarbital – neonatal seizures, second line in status epilepticus Newer agents: lamotrigine (Lamictal ® ), topiramate (Topamax ® ), both also used as mood stabilizers; levetiracetam (Keppra ® ), also used for neuropathic pain Status epilepticus: Lorazepam or diazepam, followed by loading dose of phenytoin or fosphenytoin; phenobarbital is second line; third line is general anesthesia with propofol or midazolam

Drugs used in migraine Serotonin agonists – sumatriptan (Imitrex ® ), rizatriptan (Maxalt ® ), eletriptan (Relpax ® ), almotriptan (Axert ® ) MOA: bind to serotonin receptors, causing vasoconstriction and inhibition of inflammatory neuropeptides Uses: abort migraine attacks that have failed NSAID treatment Drug interactions: serotonin syndrome with other serotonin- modulating drugs Prophylaxis of attacks: β-blockers – propranolol, atenolol TCAs – amitriptyline (Elavil ® ) Anticonvulsants – valproic acid, topiramate

Drugs used in Parkinson’s dz Amantadine (Symmetrel ® ) MOA: poorly understood antiparkinsonian effect Uses: antiviral; used early in Parkinson’s alone or with L-DOPA to relieve symptoms Side effects: nervousness, agitation, insomnia, anxiety, exacerbation of seizure/psychiatric disorders; livedo reticularis

Drugs used in Parkinson’s dz Anticholinergics: benztropine (Cogentin ® ), trihexyphenidyl (Artane ® ) MOA: antagonize the effects of acetylcholine, blocking impulses in parasympathetic system Uses: relief of tremor in Parkinson’s, treatment of parkinsonism d/t antipsychotic meds Side effects: dry mouth, constipation, urinary retention, tachycardia, orthostasis; drowsiness, dizziness, headache, anxiety, confusion, lower seizure threshold

Drugs used in Parkinson’s dz Dopamine agonists Ergot-derived: bromocriptine (Parlodel ® ), cabergoline (Dostinex ® ), pergolide no longer available in US Uses: Parkinson’s, management of pituitary prolactinoma Side effects: valve dz, N/V/C, hypotension, peripheral edema, somnolence/insomnia, dyskinesia, depression, hallucinations, gambling behavior

Drugs used in Parkinson’s dz Dopamine agonists Non-ergot-derived: ropinirole (Requip ® ), pramipexole (Mirapex ® ) Uses: Parkinson’s, restless leg syndrome Side effects: nausea, dizziness, somnolence/insomnia, dyskinesia, compulsive behaviors (gambling, hypersexuality, overeating)

Drugs used in Parkinson’s dz Monoamine oxidase-B inhibitor: selegiline (Eldepryl ® ) MOA: inhibits MAO-B, which breaks down dopamine Uses: when used with L-DOPA, delays necessity to increase dosage of L-DOPA; used as transdermal patch for depression (Emsam ® ) Side effects: dizziness, insomnia, dry mouth, nausea/constipation, tyramine effect

Drugs used in Parkinson’s dz Levodopa/carbidopa (Sinemet ® ) MOA: converted to dopamine in CNS; side effects caused by conversion in PNS are prevented by coadministration of carbidopa Uses: delays progression and relieves symptoms of Parkinson’s dz Side effects: hypotension, arrhythmia, GI bleed, insomnia, disorientation, anxiety, hallucinations, somnolence Chronic L-DOPA adminstration: end-of-dose loss of effect, on-off phenomenon, dyskinesia, dysphoria upon withdrawal, impulse control disorders

Drugs used in Parkinson’s dz COMT inhibitors – tolcapone (Tasmar ® ), entacapone (COMTan ®, included with levodopa/carbidopa in Stalevo ® ) MOA: inhibits alternative pathway of dopamine breakdown Uses: adjunct to L-dopa therapy in Parkinson’s dz Side effects: entacapone – increased effects of L- dopa, GI effects; tolcapone – hepatotoxicity