1. NEUROPHARMACO LOGY REVIEW LINA PIECH, PHARM.D., BCPS ADVOCATE CHRIST MEDICAL CENTER MARCH 13, 2015

2. 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

3. NEURORECEPTO RS

4. NERVOUS SYSTEM

5. 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

6. 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

7. 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

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

10. WE WILL REVIEW: Antiepileptics Hyperosmolar therapy Amantadine for Traumatic Brain Injury Treatment of Neuropathic pain

11. ANTIEPILEPTICS

12. 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

13. 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

14. 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

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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

26. HYPEROSMOLAR THERAPY

27. 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

28. HYPEROSMOLAR THERAPY Mechanism of action Mobilization of water through an osmotic gradient Decreases intracranial pressure and cerebral edema Brain TissueIntravascular Space H20

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

36. 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

37. NEUROPATHIC PAIN

38. 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

39. 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

40. 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

41. 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)

42. 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

43. 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

44. 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

46. REFERENCES 1.. 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;367:746-52 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 !

47. QUESTIONS