CNS DrugsPaul Algeo, PharmD/PA Candidate 2012

algeop@gmail.com2-26-10

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.

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!

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?

Ranking of CNS drugs • SSRIs

– Celexa35 (citalopram)

– Lexapro24 (escitalopram)

– Prozac30 (fluoxetine)

– Zoloft20 (sertraline)

– Paxil48 (paroxetine)

• Other AntiDepressants

– Wellbutrin/Zyban36 (bupropion)

– Cymbalta59 (duloxetine)

– Desyrel47 (trazodone)

– Effexor44 (venlafaxine)

• “Atypical” Anti-Pyschotics

– Abilify149 (aripiprazole)

– Zyprexa185 (olanzapine)

– Seroquel81 (quetiapine)

– Risperdal112 (risperidone)

•Anxiolytics/Hypnotics•Xanax10 (alprazolam)•BuSpar155 (buspirone)•Valium60 (diazepam)•Ativan33 (lorazepam)•Restoril106 (temazepam)•Ambien16 (zolpidem)

•Anticonvulsants•Klonopin34 (clonazepam)•Neurontin37 (gabapentin)•Lamictal103 (lamotrigine)•Keppra213 (levetiracetam)•Dilantin147 (phenytoin)•Lyrica93 (Pregabalin)•Topamax107 (topiramate)•Depakote122 (Valproic Acid)

•Stimulants•Strattera216 (atomoxetine)•Concerta/Ritalin110 (methylphenidate)•Adderall57 (dextro/amphetamine salts)

•Skeletal Muscle Relaxants•Soma73 (carisoprodol)•Flexeril42 (cyclobenzaprine)•Robaxin190 (methocarbamol)

•TCAs–Elavil63 (amitriptyline)–Remeron143 (mirtazapine)–Pamelor219 (nortriptyline)

Antidepressants I

• Escitalopram (Lexapro)

• Sertraline (Zoloft)

• Fluoxetine (Prozac)

• Paroxetine (Paxil)

• Citalopram (Celexa)

I. Selective Serotonin Reuptake Inhibitors (SSRIs)

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

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.

Antidepressants IIII. Tricyclic Antidepressants (TCAs)

–Amitriptyline (Elavil)

–Nortriptyline (Pamelor)

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.

Antidepressants III• III. Miscellaneous Antidepressants:

– Venlafaxine (Effexor)

– Mirtazapine (Remeron)

– Duloxetine (Cymbalta)

– Bupropion (Wellbutrin/Zyban)

– Trazodone (Desyrel)

Drug MOA S/E Admin/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-Chol At bedtime. Commonly used as a non-habit forming sleep aid.

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)

“Atypical” Antipsychotics• Quetiapine (Seroquel)

• Risperidone (Risperdal)

• Olanzapine (Zyprexa)

• Aripiprazole (Abilify)

“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).

“Atypical” Antipsychotics II: Side Effects

Drug Weight GainGlucose Intolerance/DM II

Abnormal Lipids

Cardiac Dysfunction (arrhythmia)

Quetiapine (Seroquel) X X XRisperidone (Risperdal) X XOlanzapine (Zyprexa) X X X

Aripiprazole (Abilify) X

•General S/E: GI upset, hypotension, NMS!

Anxiolytics, Sedative Hypnotics

• Zolpidem (Ambien)

• Buspirone (BuSpar)

• Benzodiazepines (“Benzos”):

– Temazepam (Restoril)

– Alprazolam (Xanax)

– Diazepam (Valium)

– Lorazepam (Ativan)

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

Anticonvulsants• Antiepileptics:

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

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)

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).

Stimulants

• Dextro/Amphetamine (Adderall)

• Methylphenidate (Concerta, Ritalin)

• Atomoxetine (Strattera)

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

Skeletal Muscle Relaxants

• Cyclobenzaprine (Flexeril)

• Methocarbamol (Robaxin)

• Carisoprodol (Soma)

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.

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.

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.

“FYI” Slides

The following slides are for YOUR INFORMATION, in other words, they will NOT show up on any exam question!

“What am I suppose to learn from this lecture? What are the expectations?!”

Bloom’s Taxonomy

Neurotransmitters: Brain’s Chemical Messengers

Neurotransmitter Normal Function Malfunction

Dopamine Mood, energy level, and ability to feel pleasure

Depression

Serotonin 5 senses (touch, hearing, sight, taste, smell), sleep, aggression, and hunger

Depression, aggressive or mellow behavior, altered sleep pattern, and altered hunger

GABA Seizures threshold, and depression

Seizures, and depression

Norepinephrine Heart, respiration, body temperature, and blood pressure

Classic withdrawal symptoms, and hallucination

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).

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.