1. CNS Drugs Paul Algeo, PharmD/PA Candidate 2012 algeop@gmail.com 2-26-10

2. Objectives Recall the bolded brand/generic names for drugs under “Ranking of CNS drugs” slide. Identify major indications (uses) for each class of CNS drugs. List major counseling points for each class of CNS drugs, including common side effects. Describe the MOA for each class of CNS drugs.

3. The Big Picture What are Central Nervous System (CNS) drugs? –Antidepressants, Anti-Psychotics, Anxiolytics, Anti- epileptics, Stimulants, Skeletal Muscle Relaxants. How do these agents work? –They alter or modulate the CNS via binding to receptors and/or affecting neurotransmitter levels. What are they used for? –Depression, schizophrenia, anxiety, seizures, ADHD, neuropathy, muscle pain, and other mental health disorders. Do they have side effects? –Yes!

4. Non-Rx Treatment Eligible Indications: –Depression Exercise! Light Therapy (SAD) Cognitive Behavioral Therapy (CBT)! Avoid Stressors Communication –Anxiety CBT! Sleep patterns Avoid triggers Communication Non-Eligible Indications: Psychosis Seizures ADHD? Muscle spasms?

5. Ranking of CNS drugs SSRIs –Celexa 35 (citalopram) –Lexapro 24 (escitalopram) –Prozac 30 (fluoxetine) –Zoloft 20 (sertraline) –Paxil 48 (paroxetine) Other AntiDepressants –Wellbutrin/Zyban 36 (bupropion) –Cymbalta 59 (duloxetine) –Desyrel 47 (trazodone) –Effexor 44 (venlafaxine) “Atypical” Anti-Pyschotics –Abilify 149 (aripiprazole) –Zyprexa 185 (olanzapine) –Seroquel 81 (quetiapine) –Risperdal 112 (risperidone) Anxiolytics/Hypnotics Xanax 10 (alprazolam) BuSpar 155 (buspirone) Valium 60 (diazepam) Ativan 33 (lorazepam) Restoril 106 (temazepam) Ambien 16 (zolpidem) Anticonvulsants Klonopin 34 (clonazepam) Neurontin 37 (gabapentin) Lamictal 103 (lamotrigine) Keppra 213 (levetiracetam) Dilantin 147 (phenytoin) Lyrica 93 (Pregabalin) Topamax 107 (topiramate) Depakote 122 (Valproic Acid) Stimulants Strattera 216 (atomoxetine) Concerta/Ritalin 110 (methylphenidate) Adderall 57 (dextro/amphetamine salts) Skeletal Muscle Relaxants Soma 73 (carisoprodol) Flexeril 42 (cyclobenzaprine) Robaxin 190 (methocarbamol) TCAs –Elavil 63 (amitriptyline) –Remeron 143 (mirtazapine) –Pamelor 219 (nortriptyline)

6. Antidepressants I Escitalopram (Lexapro) Sertraline (Zoloft) Fluoxetine (Prozac) Paroxetine (Paxil) Citalopram (Celexa) I. Selective Serotonin Reuptake Inhibitors (SSRIs)

7. Selective Serotonin Reuptake Inhibitors (SSRIs) MOA - Block reuptake of serotonin into nerve terminal leading to increased serotonin levels at synapse Onset: 2-6 wks Admin: –Same time each day, w/ or w/o food –Titrate up when starting and at high doses do not d/c abruptly SE - Dry mouth, sexual dysfunction, drowsiness, sweating DDI - SSRIs are CYP2D6 inhibitors, therefore they will increase the concentration of drugs metabolized by CYP2D6. Not for use with MAOIs - 14 day washout period required when switching. Serotonin Syndrome

8. Black Box Warning for (Lexapro) Suicidality and antidepressant drugs: Antidepressants increased the risk compared with placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of escitalopram or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years of age; there was a reduction in risk with antidepressants compared with placebo in adults 65 years of age and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Appropriately monitor patients of all ages who are started on antidepressant therapy and closely observe for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescriber. Escitalopram is not approved for use in children younger than 12 years of age.

9. Antidepressants II II. Tricyclic Antidepressants (TCAs) –Amitriptyline (Elavil) –Nortriptyline (Pamelor)

10. Tricyclic Antidepressants(TCAs) While labeled for depression, off-label uses can include: –Peripheral neuropathy –Pain/Fibromyalgia –Migraine prophylaxis –Irritable Bowel Syndrome (IBS) MOA: Increases the synaptic concentration of serotonin and/or norepinephrine by inhibition of their reuptake by the nerve terminal. Admin - Best at night due to drowsiness Onset: up to 4 weeks. SE - Sedation, weight gain, Anti- Chol effects. DDI: CYP2D6 inhibitors (i.e. SSRIs), aspirin, phenytoin and other CNS agents. Not to be used with MAOIs - 14 day washout period required Monitoring: 30 day supply enough to fatally overdose (don’t tell pt this). Overdose can lead to the 3 “C”s: Coma, Convulsions, Cardiotoxicity.

11. Antidepressants III III. Miscellaneous Antidepressants: –Venlafaxine (Effexor) –Mirtazapine (Remeron) –Duloxetine (Cymbalta) –Bupropion (Wellbutrin/Zyban) –Trazodone (Desyrel)

12. DrugMOAS/EAdmin/Notes Venlafaxine (Effexor) re-uptake inhibitor of 5HT, NE, DA Anti-Chol, insomnia, HTN, NMS, some sexual dysfunction. W/food; XR capsules may be sprinkled on applesauce and swallow whole. Mirtazapine (Remeron) Antagonizes alpha-2 receptors centrally, which increases [5HT] and [NE]. Increased appetite, dry mouth, constipation, drowsiness At bed time Duloxetine (Cymbalta) SNRI: Re-uptake inhibitor of 5HT and NE. Anti-Chol,  appetite, fatigue,  risk of bleeding, hepatitis. W/ or w/o food. Bupropion (Wellbutrin/ Zyban) Dual DA/NE reuptake inhibitor, with NO serotonin activity. Insomnia, Anti-Chol, seizures (w/high dose). C/I in pts w/bulimia and anorexia. W/ or w/o food. Lacks 5HT activity, therefore, no sex dysf, weight gain, excessive sedation. Trazodone (Desyrel) Probably a serotonin reuptake inhibitor. Drowsiness, Anti-CholAt bedtime. Commonly used as a non-habit forming sleep aid.

13. Miscellaneous Antidepressants (con’t) General Themes for drugs from Prior Slide: –Onset: 2-6 weeks –Not to be used with MAOIs: 14 day washout period required. –Suicidal Risk for all antidepressants –Less sexual side effects (except for Effexor) –Should NOT d/c drug abruptly; need to taper down (or up). Other indications/uses: Duloxetine (neuropathic pain) Zyban (smoking cessation) Trazodone (sleep aid)

14. “Atypical” Antipsychotics Quetiapine (Seroquel) Risperidone (Risperdal) Olanzapine (Zyprexa) Aripiprazole (Abilify)

15. “Atypical” Antipsychotics I MOA - All work to antagonize dopamine (DA) receptors, which  [DA] centrally. (Some are mixed DA/5HT antagonists). Onset: 3-6 weeks Uses: Schizophrenia, Bipolar Disorder, even depression and sleep disorders. Admin: w/ or w/o food. “Typical” Antipsychotics: drugs developed prior to the “atypicals” with higher incidence of serious s/e such as: –Extra-pyramidal Symptoms (EPS) –Tardive Dyskinesia (TD) –Neuroleptic Malignant Syndrome (NMS).

16. “Atypical” Antipsychotics II: Side Effects DrugWeight Gain Glucose Intolerance/ DM II Abnormal Lipids Cardiac Dysfunction (arrhythmia) Quetiapine (Seroquel) XXX Risperidone (Risperdal) XX Olanzapine (Zyprexa) XX X Aripiprazole (Abilify) X General S/E: GI upset, hypotension, NMS!

17. Anxiolytics, Sedative Hypnotics Zolpidem (Ambien) Buspirone (BuSpar) Benzodiazepines (“Benzos”): –Temazepam (Restoril) –Alprazolam (Xanax) –Diazepam (Valium) –Lorazepam (Ativan)

18. Anxiolytics, Sedative Hypnotics MOA: –Benzos: bind to the GABA receptor, which leads to a less excitable neuronal state (less anxiety, more sedation). –Zolpidem: binds to a different site on the GABA receptor, eliciting only sedation effects (and not anxiolytic effects). –Buspirone: does not interact with with the GABA receptor, but rather is an agonist for a serotonin receptor. Uses: –Anxiety (Benzos) –Insomnia (Zolpidem) –Off Label uses include phobias, OCD, panic disorders Onset: hours (benzos, zolpidem), weeks (buspirone). Admin - At bedtime for insomnia, before anxiety promoting activity (flights, dental appt, etc). SE - drowsiness, hypotension, bradycardia, non-EtOH hangover effect, CNS depressive effects Notes –Alcohol intensifies effects** –Caution with falls in elderly –Dependence is possible** –All are scheduled (C-IV/V) drugs** **Not with buspirone

19. Anticonvulsants Antiepileptics: –Lamotrigine (Lamictal) –Gabapentin (Neurontin) –Valproic Acid (Depakote) –Topiramate (Topamax) –Levetiracetam (Keppra) –Pregabalin (Lyrica) –Phenytoin (Dilantin) –Clonazepam (Klonipin)

20. Anticonvulsants I MOA: Prevents/antagonizes seizure activity via multiple mechanisms including decreasing the release of excitatory neurotransmitters (NT), increasing the activity of inhibitory NTs, keeping cells depolarized and/or stabilizing their membranes. Primary Use: prevent/treat seizures. Other uses: –Peripheral neuropathy (Gabapentin) –Prophylaxis for migraines (Topamax) –Bipolar I disorder (Lamotrigine & Valproic Acid) –Fibromyalgia (Lyrica)

21. Anticonvulsants II Onset: hours (most) to weeks (Lyrica) Admin: –If GI upset a risk - take w/ food –Titrate dose up to therapeutic effect Notes: –Often have narrow therapeutic index (NTI) for seizures. –Many DDIs –Take meds regularly; interruptions can cause seizures. SE - drowsiness, fatigue, N/V(most) – rash (Lamictal) – weight gain (Depakote) – weight loss (Topamax) –Phenytoin: –Gingival hyperplasia –Nystagmus –Steven-Johnson Syndrome More Notes: Keppra is the most benign newer agent (less sedation).

22. Stimulants Dextro/Amphetamine (Adderall) Methylphenidate (Concerta, Ritalin) Atomoxetine (Strattera)

23. Stimulants MOA: Block the reuptake of NE or NE/DA. Brings ADHD pts “down”, but brings non- ADHD pts “up” Uses - ADD, ADHD, Narcolepsy Onset: hours Admin: –Prefer taken in AM –W/ or w/o food (food delays onset). S/E (dangerous) - tachycardia, HTN, hallucinations, insomnia, decreased appetite (esp kids) Not to be used with MAOIs: 14 day washout period required. Notes: –All are C-II, except Strattera, which is NOT a controlled drug. –Concerta: ADHD, Narcolepsy –Ritalin: ADHD only –Commonly abused by college students as study aid

24. Skeletal Muscle Relaxants Cyclobenzaprine (Flexeril) Methocarbamol (Robaxin) Carisoprodol (Soma)

25. Skeletal Muscle Relaxers (CNS Acting) MOA: Causes CNS depression, which leads to skeletal muscle relaxation. Onset: 30-60min Uses - Acute muscle spasms, muscle pain, supportive therapy in tetanus (Robaxin) Admin - Generally 3-4x daily, for acute use. S/E: Anti-Chol effects, drowsiness, dizziness, vertigo (whirling). Notes: Alcohol will intensify effects Soma is now a C-IV in WA! S/E are similar to other CNS drugs, be aware. Flexeril LOT NTE 2-4 wks.

26. Let’s Recap! “I know that I have told you a lot of information, so to make sure I didn’t forget anything important, can you tell me about…” Brand/generic names for: Lexapro, Zyban/Wellbutrin, Cymbalta, Abilify, Zyprexa, Ambien, Keppra, Lyrica, Strattera, Effexor. Major indication (uses) for all the classes of drugs we discussed today. i.e. TCAs can be used for depression and neuropathy (off-label). Describe major counseling points and common side effects for each class of drugs (and HOW you would articulate these points). i.e. suicidal risk for antidepressants, alcohol-intensifying effects of benzos, anti-cholinergic effects, admin PM vs AM, etc. Know, in general, the major MOAs for these CNS drus classes. i.e. antidepressants inhibit reuptake of certain NTs.

27. More Recap! General Themes: 1.Time to effect for many of the classes of drugs is weeks. Which classes take days? Which take hours? 2.Potentially long washout periods when switching from a MAOI to certain drugs, vice- versa. 3.Suicidal Risk. 4.Many of these drugs have Anti-Chol effects, sedation, and sexual dysfunction s/e. Which drugs/classes do not? Some quick Pearls: TCA overdose Phenytoin S/E Keppra = benign anticonvulsant. Strattera is only stimulant that is NOT controlled. Soma recently became a controlled drug in WA.

28. “FYI” Slides The following slides are for YOUR INFORMATION, in other words, they will NOT show up on any exam question!

29. “What am I suppose to learn from this lecture? What are the expectations?!” Bloom’s Taxonomy 

30. Neurotransmitters: Brain’s Chemical Messengers NeurotransmitterNormal FunctionMalfunction DopamineMood, energy level, and ability to feel pleasure Depression Serotonin5 senses (touch, hearing, sight, taste, smell), sleep, aggression, and hunger Depression, aggressive or mellow behavior, altered sleep pattern, and altered hunger GABASeizures threshold, and depression Seizures, and depression NorepinephrineHeart, respiration, body temperature, and blood pressure Classic withdrawal symptoms, and hallucination

31. Glossary I 5HT: serotonin. ADHD: Attention Deficit Hyperactivity Disorder Antiepileptic: anti seizure drug Anxiolytic: anti anxiety drug DDI: drug-drug interaction EPS (extra-pyramidal symptoms): includes dystonic (twitching, repetitive movements) reactions and akathisia (can’t sit still). Fibromyalgia: chronic widespread pain and allodynia, a heightened and painful response to pressure. Hypnotic: a sleep-inducing drug. LOT: length of therapy. MAOI: monoamine oxidase inhibitor MOA: mechanism of action NE: norepinephrine Neurotransmitters: serotonin (5HT), (GABA), Dopamine (DA), Norepinephrine (NE).

32. Glossary II NMS (neuroleptic malignant syndrome): consists of high fever, muscle rigidity, delirium. Can be life threatening; 10-20% mortality. Nystagmus: involuntary eye movement. OCD: obsessive compulsive disorder. SSRI: selective serotonin reuptake inhibitor Serotonin Syndrome: can be life threatening. Classically described as the triad of: (1) mental status changes: anxiety, agitated delirium, restlessness, and disorientation (2) autonomic hyperactivity: excessive sweating, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea (3) neuromuscular abnormalities: tremor, muscle rigidity, myoclonus (involuntary muscle twitching), hyperreflexia. SNRI: serotonin (5HT) and noradrenergic (NE) reuptake inhibitor. TCA: tricyclic antidepressant TDS (tardive dyskinesia syndrome): Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements.