LINA PIECH, PHARM.D., BCPS
ADVOCATE CHRIST MEDICAL CENTER
MARCH 13, 2015

1. Understand various receptors in the central nervous system
2. Review indications for use of medications
3. Identify appropriate dosing of various medications
4. List side effects and considerations of common neuropharmaceuticals

NERVOUS SYSTEM

• Central Nervous System
• Encompass brain and spinal cord
• Peripheral Nervous System
• Somatic motor system
• Autonomic nervous system
• Parasympathetic system
• “Rest and Digest”
• Cholinergic and muscarinic receptors
• Activated by acetylcholine
• Sympathetic system
• “Fight or Flight”
• Alpha and Beta receptors
• Activated by epinephrine and norepinephrine

• Parasympathetic
• Slow heart rate
• Increase gastric secretions and motility
• Adjust eye for near vision
• Contraction of bronchial smooth muscle
• Sympathetic – Adrenergic Receptors
• Increase heart rate and blood pressure
• Shunt blood from skin to muscles
• Mobilization of stored energy: glucose, fatty acids
• Dilation of pupils and bronchi

• Widely distributed throughout the brain, spinal cord and digestive tract
• Delta (δ)
• Found in brain
• Responsible for analgesia and physical dependence
• Kappa (k)
• Found in brain and spinal cord
• Responsible for analgesia, sedation and anticonvulsant effects
• Mu (μ)
• Found in brain, spinal cord and GI tract
• Responsible for analgesia, respiratory depression, decreased GI motility
• All receptors are up-regulated with chronic use

• Site of action for Gamma-aminobutyric acid
(GABA)
• Main inhibitory neurotransmitter receptor
• Two different subtypes: α and β
• GABA agonists - Benzodiazepines

•
• Ionic – intracellular influx of sodium and calcium ions
• Neurotransmitter – mediated by excitatory transmitter glutamate
• Inhibition
• Ionic – Influx of Chloride anion and outflow of potassium
• Neurotransmitter – Mediated by inhibitory transmitter GABA

•
• Decrease frequency or severity of seizures
• Treat the symptom of seizures
• Maximize quality of life and minimize adverse effects
• Approximately 60% of patients with epilepsy can be seizure free with AED
•
• Seizure type
• Pharmacokinetic profile
• Drug interactions
• Adverse effects

• Good oral absorption and bioavailability
• Combination therapy may be utilized for maximum effect
• More novel agents associated with less severe adverse effects
• Many agents have narrow therapeutic windows necessitating monitoring of serum levels

• Phenytoin (Dilantin)
• Fosphenytoin (Cerebyx)
• Levetiracetam (Keppra)
• Carbamazepine (Tegretol)
• Oxcarbazepine (Trileptal)
• Valproic acid (Depakote)
• Phenobarbital (Luminal)
• Gabapentin (Neurontin)
• Lamotrigine (Lamictal)
• Topiramate (Topamax)

• Indication
• Generalized tonic-clonic seizures
• Mechanism
• Promotes Na efflux to stabilize neuronal membranes
• Dosing
• Bolus 15-20mg/kg IVPB
• Max rate 50mg/min
• Maintenance: 100mg q8h
• Therapeutic Level
• 10 – 20 mcg/dl
• Must be corrected for albumin and renal function
• Patient care considerations
• Must be in saline solutions
• Monitor cardiac function
• Multiple drug interactions (induces many CYP enzymes)
• Follows Michaelis-Menten pharmacokinetics
• Tube feeds must be held 1 hour before and after each oral suspension dose
• Adverse effects
• Nystagmus
• Dizziness
• Somnolence
• Gingival hyperplasia

• Prodrug of Phenytoin
• Mechanism
• Same as phenytoin
• Indication
• Status epilepticus
• Dosing
• Bolus 15-20 PE mg/kg IVPB
• Max rate 150 PE mg/min
• Patient care considerations
• Same as phenytoin
• May be administered IM
• Can be infused faster than phenytoin
• Adverse effects
• Nystagmus
• Dizziness
• Somnolence
• Gingival hyperplasia

•
• Partial, generalized and mixed type seizures
•
• 400mg PO q12h
•
• Limits the influx of sodium ions across the cell membrane
•
• 4-12mcg/dl
•
• Obtain baseline CBC and trend in the first few weeks
•
• Nystagmus
• Dizziness
• Dysrhythmia

• Indication
• Absence and partial seizures
• Mechanism of Action
• May enhance the action of GABA or mimic its action at postsynaptic sites
• Dosing
• 15mg/kg/day initially
• Therapeutic Level
• 50-100 mcg/dL
• Patient care considerations
• Monitor liver function tests
• May cause elevated ammonia levels
• Adverse effects
• Weight gain
• Platelet dysfunction

•
• Generalized tonic-clonic seizures
• Alcohol withdrawal
• Mechanism of Action
• Enhances the effects of GABA
• Dosing
• Bolus 15-20 mg/kg IV
• 50-100mg 2-3 times per day initially
• Therapeutic Level
• 15-40mcg/dL
• Patient care considerations
• Obtain baseline CBC and trend in the first few weeks
• Adverse effects
• Sedation
• Respiratory depression
• Bradycardia

•
• Simple and complex seizures with or without secondary generalized tonicclonic seizures
•
• Binds to gabapentin binding sites in the brain and may modulate the release of excitatory neurotransmitters
•
• 300mg PO TID
• May increase up to 2400mg/day
• Dose must be renally adjusted
•
• Not clinically followed
•
• May be confused with Lyrica (pregabalin)
•
• Sedation
• Dizziness
• Peripheral edema

• Indication
• Partial seizures, adjunctive
• Mechanism of Action
• Inhibits release of glutamate
• Dosing
• Dependent on concomitant therapy
• Doses range from 225 – 700mg/day
• Therapeutic Level
• 3-18 mcg/dL
• Must monitor serum levels of other AEDs
• Patient care considerations
• Liver function tests must be drawn at baseline
• Adverse effects
• Nausea
• Peripheral edema
• Dizziness
• Dysmenorrhea

• Indication
• Partial and generalized seizures, mono and adjunctive therapy
• Mechanism of Action
• Blocks neuronal voltage-dependent sodium channels, enhances GABA activity, and antagonizes glutamate receptors
• Dosing
• 25-200mg/day
• Therapeutic Level
• Not routinely monitored
• Patient care considerations
• In children, monitor hydration status and serum electrolytes
• Adverse effects
• Bicarbonate wasting syndrome
• Nephrolithiasis
• Paresthesia
• Can suppress growth

• Indication
• Adjunctive therapy for myoclonic, tonic-clonic and partial seizures
• Mechanism of Action
• Unknown
• Dosing
• Bolus: 20mg/kg IVPB
• Oral maintenance: 1000 – 3000mg/day
• Therapeutic Level
• 12 – 46 mcg/dL
• Not routinely monitored
• Does not clinically correlate to seizure control
• Patient care considerations
• Monitor mood especially in children or elderly
• Adverse effects
• Elevated blood pressure
• Behavioral problems (aggression, anger or anxiety)
• GI upset

• Cornerstone of intracranial pressure management
• Mannitol and Hypertonic Saline are the two most widely used osmotic agents
• ↑ serum osmolality and create an osmotic force that draws fluid from the interstitial space into the vascular space
• End result: ↓ volume of the brain parenchyma and ↓ intracranial pressure
• Cause plasma expansion, reduce blood viscosity, improve
CBF and oxygen delivery

• Mechanism of action
• Mobilization of water through an osmotic gradient
• Decreases intracranial pressure and cerebral edema
Brain Tissue
H20
Intravascular Space

• Sugar alcohol that acts as an osmotic diuretic
• Poorly metabolized and excreted almost completely unchanged in the urine
• Freely filtered at the glomerulus, producing an osmotic force that ↓ reabsorption of water and sodium
• Produces a transient ↑ in intravascular volume
• Dose: 1g/kg IV x 1 then 0.25-0.5g/kg IV q4-8h as needed
• Administer over 30min
• Reduction in ICP seen in minutes and effects can last ~6 hours

• Adverse effects
• Hypovolemia, acute kidney injury, pulmonary edema, ↑Na, heart failure, ↓blood pressure
• Adverse effects are most prevalent with continuous infusions
• Can cause rebound cerebral edema
• Maintain serum osmolality <320 mOsm/L

• Similar rheologic effects as mannitol
• Directly increases serum osmolality
• Benefits : Less hypotension, no renal failure, prolonged increase in intravascular volume
• Available as a 3% - 23.4% solution
• Dose: Calculated dose based on sodium deficit or bolus doses
• NaCl 3% 250mL, NaCl 7% 100mL, NaCl 23.4% 30mL

• Target sodium 145-155 mmol/L
• Continuous infusions of NaCl 3% not as effective
• Concentrations >3% must be infused via central line
• Adverse effects: Fluid overload, heart failure, tissue necrosis, central pontine myelinolysis, coagulopathy
• Monitor Na levels and serum osmolality

TBI AROUSAL STRATEGIES
• Traumatic brain injury is associated with a decrease in dopamine levels
• Many dopaminergic agents have been studied in this population in attempts to improve awakening:
• Methylphenidate
• Bromocriptine
• Levodopa/carbidopa
• Amantadine

• Mechanism of action
• Dopamine agonist
• N-methyl-D-aspartate (NMDA) antagonist
• FDA indications:
• Influenza A treatment and prophylaxis
• Parkinson’s disease
• Adverse Effects:
• Confusion
• Dizziness
• Hallucinations
• May decrease seizure threshold

• Multi-center prospective, blinded, placebo-controlled trial evaluated the effects of amantadine on patients in a persistent vegetative or minimally conscious state
• 184 patients enrolled 4-16 weeks after initial injury
• Randomized to either placebo or escalating dose of amantadine
(target: 200mg BID) x 4 weeks
• Assessed for rate of recovery during treatment as well as after a washout
• Amantadine group recovered more often to a moderately severe to severe condition vs. placebo and at a faster rate
• After washout, both scores were similar between the two groups

• What is neuropathic pain?
• Pain initiated or caused by a primary lesion or dysfunction in the nervous system
• Can occur after an injury to an extremity
• Signs of neuropathic pain:
• Hyperalgesia: exaggerated painful response to noxious stimuli
• Allodynia: painful response to normally non-noxious stimuli (light touch or temperature)
• Pain described as burning, aching, pins and needles

• Pathophysiology
• Spontaneous discharge in the peripheral nervous system
• Delaying, decreasing and attenuating neuronal discharges are drug therapy targets
• Receptors/neurotransmitters involved:
• GABA receptors, opioid receptors, serotonin, NMDA, sodium channels, calcium channels
• Etiology
• Diabetic neuropathy
• Shingles
• Trigeminal neuralgias
• Malignancy
• Immunologic- rheumatoid arthritis, lupus, etc

NEUROPATHIC PAIN TREATMENT
• Response defined as 30-50% reduction in pain severity
• Combination therapy often needed:
• Antidepressants
• Antiepileptics
• NMDA receptor antagonists
• NSAIDs and opioids
• GABA receptor agonists
• Topical anesthetics
• Start at low dose, titrate to efficacy and adverse effect profile
• Adverse effects
• Sedation
• Dizziness
• Cardiac conduction abnormalities
• Polypharmacy increases side effects

NEUROPATHIC PAIN TREATMENT
• Antidepressants
• Tricyclic antidepressants (TCA):
• Block reuptake of norepinephrine and serotonin, antagonize NMDA receptors, block voltage gated sodium channels
• Also improve mood and sleep disorders
• Most data for: amitriptyline, imipramine, and desipramine
• Doses usually lower than antidepressant dose
• Adverse effects include: QTc prolongation, sedation, anticholinergic effects, weight gain, orthostatic hypotension
• Pain responds more quickly (3-10 days) than depression (4-6 weeks)

NEUROPATHIC PAIN TREATMENT
• SSRIs
• Less consistent effects
• Inhibit CNS neuron serotonin reuptake
• Some efficacy with fluoxetine, paroxetine, and citalopram
• Side effects include: insomnia, somnolence, weight gain
• SNRIs
• Duloxetine is the first drug approved for diabetic peripheral neuropathy
• A balanced and potent inhibitor of serotonin and norepinephrine reuptake in the CNS
• No anticholinergic effects or cardiotoxicity
• Adverse reactions include: headache, drowsiness, nausea

NEUROPATHIC PAIN TREATMENT
•
• Bind to a subunit of a voltage gated calcium channel within the CNS and inhibit excitatory neurotransmitter release including glutamate
• May also affect pain transmission pathways from the brainstem to the spinal cord
• Relatively well tolerated
• Adverse effects include: sedation, dry mouth, peripheral edema
• Pregabalin is a controlled substance

NEUROPATHIC PAIN TREATMENT
• Tramadol
• A mu opioid receptor agonist and weak inhibitor of serotonin and norepinephrine reuptake
• Studies have shown benefit on paresthesias and
Allodynia
• Adverse effects include: dizziness, constipation, nausea
• Controlled substance
• Capsaicin
• Neurotoxin found in hot peppers
• Desensitizes sensory axons and inhibits pain transmission
• Depletes the neuron of substance P
• Responsible for pain impulses from the periphery to the CNS

1. . Brain Trauma Foundation (2007). Guidelines for the management of severe traumatic brain injury (3 rd
Neurotrauma, 24 (suppl 1):S1-S106.
ed). Journal of
2 . Forsyth LL, et al. Role of Hypertonic Saline for the Management of Intracranial Hypertension After Stroke and Traumatic
Brain Injuryl Pharmacotherapy 2008;28(4):46-484.
3. Ropper AH. Hyperosmolar Therapy for Raised Intracranial Pressure. N Engl L Med 2012;367:746-52
4. . Giacino JT, Whyte J, BagiellaE, Et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J
Med 2012;366:819-26
5. Phelan HA. Pharmacologic Venous Thromboembolism Prophylaxis after Traumatic Brain Injury: A Critical Literature
Review. Journal of Neurotrauma 2012;29:1821-1828
Thank you to Marc McDowell, Pharm.D., our ACMC PGY-1 Pharmacy Practice Resident, for his help with this presentation !