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• 3rd 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