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:• 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• 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

• 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

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• 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

GABAPENTIN• Indication

• Simple and complex seizures with or without secondary generalized tonic-clonic 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

• 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• Bicarbonate wasting syndrome• Nephrolithiasis• Paresthesia• Can suppress growth

LEVETIRACETAM• 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

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

Brain Tissue Intravascular Space

H20

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

• 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

HYPERTONIC SALINE

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:• 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

AMANTADINE FOR TBI

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• 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)

• 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

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

• 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

NEUROPATHIC PAIN TREATMENT

REFERENCES1. . Brain Trauma Foundation (2007). Guidelines for the management of severe traumatic brain injury (3 rd 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;367:746-524. . Giacino JT, Whyte J, BagiellaE, Et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012;366:819-265. Phelan HA. Pharmacologic Venous Thromboembolism Prophylaxis after Traumatic Brain Injury: A Critical Literature Review. Journal of Neurotrauma 2012;29:1821-1828

ACKNOWLEDGMENTThank you to Marc McDowell, Pharm.D., our ACMC PGY-1 Pharmacy Practice Resident, for his help with this presentation!

QUESTIONS