Week 8 CNS Disorders & Misc Neurological Disorders

Diseases du jour Parkinson's Alzheimer's Epilepsy Muscle Spasm Brain Trauma Meningitis, Encephalitis CVA Peripheral –Multiple Sclerosis –Guillain-Barre Syndrome –Amyotrophic Lateral Sclerosis

CNS Pharmacology Peripheral neurotransmitters = 3 CNS neurotransmitters = at least 12 –Exact actions may be unknown –Areas of brain with no known transmitter Blood-brain barrier Pharmacologic considerations –Delayed full effect –Tolerance, decreased side effects –Physical dependence

Parkinson's Disease Extrapyramidal system –Neuronal network responsible for regulation of movement –Dyskinesias Tremor, Mask Postural instability Bradykinesia, akathisia –Psychologic disturbance Dementia, depression, impaired memory

Parkinson's Disease Balance Neurotransmitters in EPS striatum –Acetylcholine (excitatory) –Dopamine (inhibitory) Supplied by neurons in substantia nigra 70-80% of dopamine supplying neurons must be lost before Parkinson's symptoms appear

Parkinson's Treatment Currently unable to reverse degeneration Drugs improve dyskinesias, but not tremor and rigidity Drug Strategies –Increase dopamine (Dopaminergic) –Inhibit acetylcholine (Anticholinergic)

Dopaminergic Drugs Promote dopamine synthesis Stimulate dopamine receptors Inhibit dopamine breakdown Promote dopamine release Block dopamine reuptake Anticholinergics: all block muscarinic receptors

Drug Selection Mainstay –Levodopa: most effective, long term side effects –Dopamine agonists: less effective, fewer side effects –Combination

Levodopa Promotes dopamine synthesis in surviving neurons Highly effective, but fades over time (5 years) Adverse effects: long term dyskinesias Acute loss of effect –Gradual “Wearing off” –Abrupt “on-off”

Levodopa Kinetics –Well absorbed PO, delayed by food, esp protein –Most levodopa metabolized in periphery –Small amount crosses BBB Adverse effects (most dose dependent) –NV (take on empty stomach) –Dyskinesias (80%) –CV: postural hypotension –Psychosis (20%), neurotoxicity

Levodopa Drug holiday Drug Interactions –Conventional antipsychotics –MAO inhibitors –Anticholinergic Drugs Food Interactions

Levodopa plus Carbidopa Brand: Sinemet Most effective PD drug we have Carbidopa enhances levodopa action –Inhibits peripheral metabolism –Reduces NV, CV effects

Dopamine Agonists Four drugs –2 ergot derivatives (bromocriptine and pergolide) –2 nonergot (pramipexole and ropinirole) Ergots have more side effects –Nonselective –Also stimulare alpha and serotonin receptors Nonergot adverse effects: –Nausea, dizziness, day somnolence, insomnia, constipation, hallucinations

Other Parkinson's Drugs COMT inhibitors Selegine (MAO-B inhibitor) Amantidine –Anti-viral –Promotes release of dopamine –May block reuptake Anticholinergics: reduce tremor, not bradykinesia –Better tolerated, less effective

Alzheimer's Disease Progressive memory loss and decreased cognitive function Pathophysiology –Neuronal degeneration –Reduced Cholinergic Transmission Characteristic morphology –Amyloid plaques –Neurofibrillary tangles –Apo E4, ER-assoc binding protein, homocysteine

Risk Factors Age –90% older than 65 –Rises exponentially thereafter Early Symptoms –Memory Loss!!! –Disorientation –Changes in personality and judgment

Symptoms Cont Moderate symptoms –Difficulty with ADLs –Anxiety, suspiciousness, lack of recognition –Sleep disturbance –Wandering, pacing Severe symptoms –Loss of speech –Loss of appetite –Loss of bladder and bowel control

Evaluation and Treatment Diagnosis: exclusion Treatment –Typically die 4-8 years after diagnosis –Delay progression of symptoms long enough for them to die of something else. –The cardiologists are winning –Drug therapy Cholinesterase inhibitors Calcium channel stabilizer

Cholinesterase inhibitor In Alzheimer's, acetylcholine transmission in brain is 90% lower than with normal aging Acetylcholine essential for forming memories Inhibitors help ~30% mild-moderate patients Three agents –Donezepil (Aricept) –Rivastigmine (Exelon) –Galantamine (Razadyne)

Calcium Channel Stabilizer Amyloid plaques may cause excess influx of calcium into neurons Memantine (only CCS) –Downregulates calcium channel –“filters out the noise” –Moderate to severe dementia

Epilepsy Group of related disorders –Excessive neuron excitability in CNS –Seizure Unconsciousness Mild Twitching Convulsions 100,000 new cases/year – most in elderly 300,000 peds cases in U.S.

Seizures Focus: group of hyperexcitable neurons –Causes Congenital defects Hypoxia at birth Head Trauma Cancer Seizure –Synchronous, high frequency depolarization of a focus that spreads to other parts of the brain –Manifestations depend on location of focus and recruitment of other parts of the brain

Seizure Types Partial: only part of the brain –Simple –Complex Generalized: throughout brain –Tonic-clonic (Grand mal) –Absence (Petit mal) –Atonic (head drop, drop attack) –Myoclonic –Status Epilepticus –Febrile: not associated with epilepsy

Seizures Stages –Aura –Seizure –Post-ictal Confusion Disorientation Weakness Hypoglycemia Status Epilepticus –Seizure that lasts >30 minutes

Anti-Epileptic Drugs Suppress discharge of neurons in a focus Suppress propagation of of seizure Three basic mechanisms –Suppression of Sodium influx –Suppression of Calcium influx –Potentiation of GABA Therapeutic Goal –Reduce seizures to extent that patients live a normal life; 60 – 70% controlled on therapy –Seizure control vs. tolerability of side effects

Therapy Non-drug therapy –Surgery –Vagal nerve stimulation –Ketogenic diet Drug selection –Drug must be matched to seizure type –Evaluation Hx: Symptoms and precipitating events Neurologic examination EEG, CT, PET, MRI

Drug Therapy Acute Seizure: benzo (diazepam, lorazepam) Trial Period – establish effectiveness –No driving, operating heavy machinery, swimming must be supervised, etc. –May need to switch agents or add a second Evaluation –Drug levels –Frequency chart Promoting Compliance –Undertreatment causes ~50% of all seizures Withdrawing therapy: slowly (6 months)

Anti-Seizure Medications Conventional (pre-1990) –Carbamazepine (Tegretol) –Ethosuximide (Zarontin) –Phenobarbital –Phenytoin (Dilantin) –Valproic acid (Depakote) Newer (post-1990) –Oxcarbazepine –Gabapentin (Neurontin) –Topiramate (Topamax)

Phenytoin Oldest selective seizure med Seizure activity –Partial –Generalized tonic-clonic Mechanism of Action –Slows sodium channel recovery –Does not affect non-excitable neurons

Phenytoin Kinetics Absoprtion –Varies greatly with individual –Instant vs. sustained release –Can be given IV (cautions) Metabolism –Liver has very limited capability to metabolize –Saturation kinetics Exponential vs. linear Must carefully monitor

Phenytoin Adverse Effects CNS –Mild sedation at therapeutic levels (10 – 20) –Toxic levels (>20): nystagmus, sedation, ataxia, diplopia, cognitive impairment Gingival hyperplasia (20%): hygiene!!! Rash Pregnancy: cleft palate, heart malformation, and other sundry badnesses

Phenytoin Interactions Decreases effects of: OCs, warfarin, steroids Increased by: diazepam, cimetidine, acute ETOH, valproic acid Decreased by: carbamazpine, phenobarbital, chronic ETOH Synergy: Other CNS depressants

Carbamazepine Seizure acitvity: partial, tonic-clonic Mechanism: same as phenytoin Preferred in children Also: Bipolar d/o & neuralgias Adverse effects –Visual disturbance, vertigo, unsteadiness, headache –Bone marrow suprression, rarely aplastic anemia –Birth defects Interactions: Ocs, Warfarin, Dilantin, Phenobarb, Grapefruit juice

Valproic Acid Seizure activity: Unique, can treat all types Mechanism: Sodium & Calcium channels, and GABA Uses: Seizures, Bipolar, Migraine Kinetics –Readily absorbed –Widely distributed –Hepatic metab –Renal excretion

Valproic Acid Adverse effects: –Nausea –Fatal hepatotoxicity Don't use in conjunction with other drugs <3 yrs Don't use in pre-existing liver conditions Check a baseline LFT Educate on symptoms: Reduced appetite, malaise, ABD pain, jaundice –Pancreatitis –Neural tube defects

Ethosuximide & Phenobarbital Ethosuximide –Seizure activity: absence –Mechanism: Calcium channels –Adverse effects: drowsiness, dizziness Phenobarbital –Barbiturate, but can reduce seizures without causing sedation –Usually used adjunct –Persistent Status epilepticus (Barbiturate coma)

Newer Anti-Epileptics Generally used if do not respons to older drugs –Exception: Oxcarbazepine Carbamazepine derivative As effective, fewer side effects, more expensive Gabapentin (Neurontin) –Seizures: Used only as adjunct for partial seizures –PHN, Invest: bipolar, neuropathic pain, migraine, leg cramps Topiramate (Topamax) –Seizures: Used only as adjunct for partial seizures –Bipolar, cluster headaches, migraines

Brain Trauma Most common causes –MVC –Falls –Sports –Violence Coup vs Contrecoup Focal Brain Injury: contusions, epidural hemorrhage, subdural hematoma Diffuse brain injury

Concussion Mild –Grade I: Confusion, disorientation, moment amnesia –Grade II: retrograde amnesia develops 5-10 min post –Grade III: Retrograde amnesia at moment 5-30 min Moderate (Classic) –Grade IV: LOC less than 6 hours; retrograde and anterograde amnesia (no axonal damage) Moderate Diffuse Axonal Injury Severe Diffuse Axonal Injury

Cerebrovascular Diseases >50% patients admitted with neuro symptoms have cerebrovascular diseases –Ischemia with or without infarction Cerebrovacular Accident (CVA, Stroke Syndrome) Vascular dementia –Hemorrhage

CVA 500,000 people/year 3 rd leading cause of death in U.S. Leading cause of disability in U.S. 70% in persons >65 years Types –Thrombotic Stroke TIA (symptoms clear within 24 hours) –Embolic stroke –Hemorrhagic stroke –Lacunar infarct

CVA Manifestations Cerebral edema peak 72 hours, lasts 2 weeks –Cerebral edema is usually cause of death –Basilar infarcts of brain stem usually fatal Symptoms vary widely depending on location –Sensation, Cognitive, Motor, Expressive or receptive aphasia, dysphagia, loss of vision, etc. –Intracranial hemorrhage Onset of Excruciating headache becoming unresponsive Headache with consciousness Sudden lapse of consciousness

CVA Eval and TX Time is Brain –Treatment should begin < 6 hours –Hx, physical, MRA, CT, PET Thrombotic –Anticoagulation –Thrombolytics –Vasodilation, Antioxidant therapy Hemorrhagic –Stop bleeding –Reduce/Tx ICP

Meningitis & Encephalitis Meningitis: infectious or toxic –Viral usually benign and self-limiting –Bacterial: life threatening, may cause retardation in children –Manifestations: sudden fever, headache, nucchal rigidity; also malaise, nausea, vomiting, malaise Encephalitis: inflammation of parenchyma –Usually viral –Manifestations: mengingeal, decreased LOC, seizures, focal symptoms

Multiple Sclerosis Central patchy destruction of myelin Attack and remission  progressive deterioration Manifestations –Sensory: paresthesias, proprioception, dizziness –Visual: diplopias, blurred –Spastic weakness of limbs –Cerebellar: nystagmus, ataxia –Bladder: hesitancy, frequency, retention –Mood: euphoria, memory loss

Multiple Sclerosis Tx –Usually aimed at symptoms –Episodic nature makes evaluation of treatment difficult –Most drugs anti-inflammatory or anti-immune Steroids Immunosuppressants –Diet therapy

Misc D/Os Guillain-Barre symptoms –Acute ascending, progressive demyelinization –Precipitating events (1-3 weeks prior) Mild viral or bacterial illness Surgery Immunizations Most frequent: Campylobacter jejuni –Negative symptoms: muscle weakness/paralysis, decreased DTRs, loss of sensation –Positive symptoms: pain and paresthesias

Misc D/Os Guillain-Barre –Usually self limiting –Severity peaks at 2 weeks –Recovery 6 weeks to several years –If paralysis is severe, may require mechanical ventilation –Tx Plasmapheresis decreases severity

Misc D/Os Huntington’s Disease (aka Huntington’s Chorea) –Autosomal Dominant –Onset of disease usually late 40s – early 50s –Insidious onset: chorea & cognitive loss Amyotrophic Lateral Sclerosis (ALS) –Progressive degeneration of motor neurons –Fine coordination  gross movement  breathing –2 – 6 year average lifespan after dx