Pharmacology

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Pharmacology Brain Injury

• Gregory J. OShanick, M.D.
• National Medical Director,
• Brain Injury Association of America
• Medical Director,
• Center for Neurorehabilitation Services,
• Richmond, VA

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Lobes of the brain
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Neurochemistry basics

• Neuronal function
• Neurotransmitters in CNS
• Pharmacologic sites of action Dopamine
  (DA) Norepinephrine (NE) Serotonin
  (5HT) GABA Acetylcholine
  (ACh) Endorphin/ Enkephlin (ED)

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Pathophysiology of TBI

• Shear- strain forces cause mechanical diffuse
  axonal injury
• Glutamate release followed by metabolic
  depression causes later onset DAI
• Focal contusions and bony prominences
• Increased intracranial pressure/edema
• Mass effects EDH, SDH, ICH
• Excitotoxin cascade

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Neurotransmitter changes after TBI

• Activity correlates with better outcome
• Increased catecholamine activity correlates with
  better outcome
• Decreased serotonergic activity noted in frontal
  contused/agitated
• Decline in catecholamine activity over time

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Neuropharmacology and Brain Injury

• Predicated on studies in other populations
• Few large, well-designed RCTs in brain injury
• Uses are off label
• Treatment of co-morbid or pre-morbid conditions
• Third party reimbursement problems
• Patient assistance program complexities

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Classes of agents used in brain injury

• Anticonvulsants
• Antispasticity agents
• Antidepressants
• Antianxiety agents
• Antipsychotics
• Antiparkinsonian agents
• Anti-impulsivity/Antimanic agents
• Opiate antagonists
• Cognitive enhancers

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AnticonvulsantsTypes and Target Symptoms

• Tegretol, Carbatrol (carbamazepine)
• Trileptal (oxcarbazepine)
• Dilantin (phenytoin)
• Depakote (valproic acid)
• Neurontin (gabapentin)
• Klonopin (clonazepam)
• Lamictal (lamotrigine)
• Topamax (topiramate)
• Keppra (levetiracetam)
• Zonegran (zonisamide)
• Lyrica (pregabalin)
• Phenobarbital

• Posttraumatic seizures
• Epilepsy spectrum disorder
• Posttraumatic headache
• Intermittent explosive disorder
• Impulsivity/ mania
• Positive psychotic symptoms
• Kluver-Bucy Syndrome
• Chronic pain syndromes

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Antispasticity agentsTypes and Target Symptoms

• Dantrium (dantrolene)
• Flexeril (cyclobenzaprine)
• Baclofen (lioreseal)
• Robaxin (methocarbamol)
• Skelaxin (metaxolone)
• Zanaflex (tizanidine)
• Botox (botulinum toxin)

• Increased muscle tone
• Acute muscle spasm
• Headache due to muscle tension

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AntidepressantsTypes and Target Symptoms

• Tricyclics imipramine, amitriptyline,
  nortriptyline, desipramine, clomipramine,
  doxepin, amoxapine
• Tetracyclics maprotiline (Ludiomil)
• SSRI Prozac, Zoloft, Luvox, Paxil, Serzone,
  Desyrel (trazodone), Celexa, Lexapro
• SNRI Effexor, Cymbalta, Pristiq
• Bupropion (Wellbutrin, Zyban)
• Mirtazapine (Remeron)
• MAO Inhibitors Nardil, Parnate

• Neurovegetative symptoms IN SAD CAGES
• Post traumatic stress disorder
• DIMS
• Enuresis
• Explosive episodes
• Chronic pain syndromes
• Migraine prophylaxis

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Antianxiety agentsTypes and Target Symptoms

• Benzodiazepines Ativan, Valium, Xanax, Librium,
  Tranxene, Klonopin, Halcion, Restoril, Dalmane
• Buspirone (Buspar)
• Hydroxyzine (Atarax, Vistaril)

• Initial insomnia
• Anticipatory anxiety
• Spasticity
• Seizure
• Acute aggressive behavior
• Chronic agitation (buspirone)
• Ethanol detox (except buspirone)

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PsychostimulantsTypes and Target Symptoms

• methylphenidate (Ritalin, Concerta, Metadate,
  Daytrana)
• d-amphetamine (Dexedrine)
• dexmethylphenidate (Focalin)
• amphetamine salts (Adderall)
• lisdexamfetamine (Vyvanse)
• atomoxetine (Strattera)
• modafanil (Provigil)

• Decreased attention/concentration
• Fatigue
• Narcolepsy / posttraumatic sleep disorder
• Apathy/amotivation

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Anti-impulsivity(antimanic)agentsTypes and
Target Symptoms

• Lithium
• Clonidine (Catapres)
• Propranolol (Inderal)
• Carbamazepine (Tegretol)
• Valproic acid (Depakote)
• Lamotrigine (Lamictal)
• Olanzepine (Zyprexa)

• Cyclic mood disorders
• Refractory mood disorders
• Aggressive behavior
• Interictal behavior disturbance

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Cognitive enhancersTypes and Target Symptoms

• Cognex (tacrine)
• Aricept (donepezil)
• Exelon (rivastigmine)
• Razadyne (galantamine)
• Namenda (memantine)
• Gingko biloba
• Estrogen

• Alzheimers disease
• Vascular dementia
• Hypoxic brain injury
• Traumatic brain injury - ? Elders - ? APOE4
  genotypes

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AntipsychoticsTypes and Target Symptoms

• Clozapine (Clozaril)
• Olanzepine (Zyprexa)
• Quetiapine (Seroquel)
• Phenothiazines (Thorazine, Mellaril, Compazine,
  Trilafon, Phenergan, Stelazine, Prolixin)
• Buterophenones (Haldol, Risperdal,
  Geodon)
• Aripiprazole (Abilify)

• Vomiting
• Analgesic potentiation
• Decreased GI motility
• Positive psychotic symptoms
• Agitation / aggression - short term use

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Antiparkinson agentsTypes and Target Symptoms

• Dopamine agonists bromocriptine (Parlodel)
  pergolide (Permax)
  ropinirole (ReQuip) pramipexole
  (Mirapex)
• DA production enhancers L-DOPA
• DA potentiators amantadine, selegiline
• Anticholinergics Cogentin, Artane

• Classic Parkinsons Syndrome
• ? Initiation /amotivation
• Dysphagia
• ?Attention and concentration
• Fatigue
• ? cognitive endurance
• Drooling
• Vestibular dysfunction
• Tactile defensiveness
• Coma

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Neuropharmacology and Brain Injury

• Predicated on studies in other populations
• Few large, well-designed RCTs in brain injury
• Uses are off label
• Treatment of co-morbid or pre-morbid conditions
• Third party reimbursement problems
• Patient assistance program complexities

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Therapeutic trial General concepts

• Adequate drug available to the CNS
• Duration appropriate to half-life CNS effect
• Monitor target symptoms (? blinded)
• Change only one variable at a time
• If trial (), withdraw agent to assess if
  spontaneous remission or drug effect

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Thanks for your attention and remember to join
the Brain Injury Association