Transcript Lina Piech`s - AANN Northern Illinois Chapter

NEUROPHARMACOLOGY
REVIEW
LINA PIECH, PHARM.D., BCPS
ADVOCATE CHRIST MEDICAL CENTER
MARCH 13, 2015
OBJECTIVES
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
NEURORECEPTORS
NERVOUS SYSTEM
NEURORECEPTORS
• 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
PERIPHERAL NEUROTRANSMITTERS
• 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
OPIOID RECEPTORS
• 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
GABA RECEPTOR
• Site of action for Gamma-aminobutyric acid
(GABA)
• Main inhibitory neurotransmitter receptor
• Two different subtypes: α and β
• GABA agonists - Benzodiazepines
WE WILL REVIEW:
Antiepileptics
Hyperosmolar therapy
Amantadine for Traumatic Brain Injury
Treatment of Neuropathic pain
ANTIEPILEPTICS
MECHANISM OF A SEIZURE
• Over-excitation
• 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
ANTIEPILEPTIC DRUGS (AED)
• Goals of therapy
• 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
• Considerations when choosing an agent:
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Seizure type
Pharmacokinetic profile
Drug interactions
Adverse effects
AED BACKGROUND
• 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
AED AGENTS
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Phenytoin (Dilantin)
Fosphenytoin (Cerebyx)
Levetiracetam (Keppra)
Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
Valproic acid (Depakote)
Phenobarbital (Luminal)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Topiramate (Topamax)
PHENYTOIN
• Indication
• Generalized tonic-clonic seizures
• Mechanism
• Promotes Na efflux to stabilize
neuronal membranes
• Dosing
• Bolus 15-20mg/kg IVPB
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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
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Nystagmus
Dizziness
Somnolence
Gingival hyperplasia
FOSPHENYTOIN
• 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
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Nystagmus
Dizziness
Somnolence
Gingival hyperplasia
CARBAMAZEPINE
• Indication
• Partial, generalized and mixed type seizures
• Dosing
• 400mg PO q12h
• Mechanism of Action
• Limits the influx of sodium ions across the cell membrane
• Therapeutic Level
• 4-12mcg/dl
• Patient care considerations
• Obtain baseline CBC and trend in the first few weeks
• Adverse effects
• Nystagmus
• Dizziness
• Dysrhythmia
VALPROIC ACID
• 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
PHENOBARBITAL
• Indication
• 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
• Indication
GABAPENTIN
• Simple and complex seizures with or without secondary generalized tonicclonic seizures
• Mechanism of Action
• Binds to gabapentin binding sites in the brain and may modulate the
release of excitatory neurotransmitters
• Dosing
• 300mg PO TID
• May increase up to 2400mg/day
• Dose must be renally adjusted
• Therapeutic Level
• Not clinically followed
• Patient care considerations
• May be confused with Lyrica (pregabalin)
• Adverse effects
• Sedation
• Dizziness
• Peripheral edema
LAMOTRIGINE
• Indication
• Partial seizures, adjunctive
• Mechanism of Action
• Inhibits release of glutamate
• Dosing
• Dependent on concomitant therapy
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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
TOPIRAMATE
• 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
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Bicarbonate wasting syndrome
Nephrolithiasis
Paresthesia
Can suppress growth
LEVETIRACETAM
• Indication
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Adjunctive therapy for myoclonic, tonic-clonic and partial seizures
• Mechanism of Action
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Unknown
• Dosing
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Bolus: 20mg/kg IVPB
Oral maintenance: 1000 – 3000mg/day
• Therapeutic Level
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12 – 46 mcg/dL
Not routinely monitored
Does not clinically correlate to seizure control
• Patient care considerations
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Monitor mood especially in children or elderly
• Adverse effects
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Elevated blood pressure
Behavioral problems (aggression, anger or anxiety)
GI upset
HYPEROSMOLAR THERAPY
HYPEROSMOLAR THERAPY
• 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
HYPEROSMOLAR THERAPY
• Mechanism of action
• Mobilization of water through an osmotic gradient
• Decreases intracranial pressure and cerebral edema
H20
Brain Tissue
Intravascular Space
MANNITOL
• 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
MANNITOL
• 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
HYPERTONIC SALINE
• 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
HYPERTONIC SALINE
• 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
AMANTADINE
• Mechanism of action
• Dopamine agonist
• N-methyl-D-aspartate (NMDA) antagonist
• FDA indications:
• Influenza A treatment and prophylaxis
• Parkinson’s disease
• Adverse Effects:
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Confusion
Dizziness
Hallucinations
May decrease seizure threshold
AMANTADINE FOR TBI
• 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
NEUROPATHIC PAIN
NEUROPATHIC PAIN
• 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
NEUROPATHIC PAIN
• 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
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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:
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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
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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
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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
• Antiepileptics – Gabapentin and Pregabalin
• 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
• Analgesics
• 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
REFERENCES
1. . Brain Trauma Foundation (2007). Guidelines for the management of severe traumatic brain injury (3rd ed). Journal of
Neurotrauma, 24 (suppl 1):S1-S106.
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
ACKNOWLEDGMENT
Thank you to Marc McDowell, Pharm.D., our ACMC PGY-1 Pharmacy Practice Resident, for his
help with this presentation!
QUESTIONS