Central Nervous System Medications PDF

Central Nervous System Medications ELIZABETH COHE N, PHARMD BCPS Objectives Review the mechanisms of action and adverse effects of commonly used CNS agents Identify important counseling points for patients prescribed CNS agents Develop an optimal psychotropic regimen considering patient and medicat...

Central Nervous System Medications ELIZABETH COHE N, PHARMD BCPS Objectives Review the mechanisms of action and adverse effects of commonly used CNS agents Identify important counseling points for patients prescribed CNS agents Develop an optimal psychotropic regimen considering patient and medication specific characteristics Summarize clinically significant drug interactions, key monitoring parameters and contraindications for CNS agents Neurotransmitters Neurotransmitters Gamma-aminobutyric acid (GABA) Glycine Glutamate Serotonin (5-HT) Norepinephrine (NE) Dopamine (DA) Acetylcholine (ACh)  GABA & Glycine Major INHIBITORY neurotransmitters in CNS GABA Glycine Glycine Present in spinal cord & brainstem GABA Present throughout CNS GABA= Gamma-Aminobutyric Acid  Glutamate Major EXCITATORY neurotransmitter in CNS Glutamate Interacts with several receptors: AMPA (all neurons), KA (hippocampus, cerebellum, spinal cord), NMDA (all neurons in CNS) Most important pharmacological target of glutamate NMDA receptors confirming signalson relay ns NMDA= N-methyl-D-aspartate KA= kainic acid AMPA= α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid Serotonin (5-HT) Many pathways come from raphe or midline region of pons/upper brainstem a excote BOTH inhibit Responsible for variety of effects pain perceptionmood anxiety temp control Target for many antidepressants and antipsychotics 5-HT= 5-Hydroxytryptamine Serotonin Receptors Norepinephrine (NE) Norepinephrine α1, α2, β1 agonist with little β2 activity Present in locus caeruleus (LC) or lateral tegmental area Effects Vasoconstriction, tachycardia, increased cardiac output, increased peripheral resistance, hypertension Comment s Target of drugs to improve attention in ADHD Image source: http://www.nature.com/nature/journal/v437/n7063/images/nature04284-f2.2.jpg  mother reward movement Dopamine (DA) Parkinson's dystines Pathway Association I tardive Important for “higher order” cognitive Mesocortical functions (motivation, impulse control, emotion) Mesolimbic Reward pathway Nigrostriatal Regulator of movement Tubero- prolactin us Regulation of prolactin infundibular Acetylcholine (ACh) Interact with muscarinic and nicotinic receptors → both excitatory and inhibitory effects ◦ Muscarinic affects smooth muscle a skeletalaffected ◦ Nicotinic affects skeletal muscle ◦ Few drugs are selective for specific receptor Bothsmooth Presynaptic nicotinic receptors: Regulate release of glutamate, 5-HT, GABA, DA, NE in CNS Hydrolyzed through acetylcholinesterase (AChE) ◦ AChE inhibitors: Neostigmine, physostigmine, donepezil to AchW ◦ Many indications: Myasthenia gravis, glaucoma, Alzheimer's, and others  Ach activation DUMBELS Cholinergic Effects/Toxidrome D- Diarrhea Muscarinic: Nicotinic: U- Urination S- Salivation M- Muscle cramps M- Miosis/muscle L- Lacrimation T- Tachycardia weakness U- Urination W- Weakness B- Bronchoconstriction/ D- Defecation T- Twitching bradycardia G- GI cramping F- Fasciculations E- Emesis/excitation of skeletal muscles E- Emesis L- Lacrimation S- Salvation/sweating Image source: Lip inc ott’s Illustrated Reviews: Pharmac ology 4 th edit ion. ACh Effects Organ System Effects Ocular Miosis Negative chronotropy, inotropy, dromotropy though reflex Cardiac sympathetic effects may predominate; decreased peripheral vascular resistance except at high doses Respiratory Bronchoconstriction, increased secretions Increased motility, sphincter relaxation, increased Gastrointestinal secretions Urinary Detrusor muscle contraction, sphincter relaxation Increased secretions (diaphoresis, siallorrhea, Endocrine lacrimation, nasopharyngeal) ANTI cholinergic Effects DUMBELS effects of ACHES Opposite of psychosis Mad as a hatter constipation urinan retention Dry as a bone dryskin Blindas a bat Mydriasis Red at a beet Hotas a hare CNS & Psychiatric Medications Medication Overview Antidepressants Antipsychotics Mood Stabilizers Anxiolytics Antidepressants  Treatment of Major Depressive Disorder (MDD) Somatic Pharmacotherapy Psychotherapy Therapies ECT Combination TMS ECT- electroconvulsive therapy TMS- transcranial magnetic Light stimulation Therapy Pharmacotherapy of MDD Effectiveness generally comparable among antidepressant classes Treatment decisions guided by: ◦ Comorbid medical and psychiatric conditions ◦ Anticipated side effects ◦ Pharmacologic properties of the medications ◦ Half-life, CYP450 activity, drug interactions, metabolites ◦ Previous response to antidepressants ◦ Cost ◦ Patient preference Maximum effect of any antidepressant will not be seen for 4-6 weeks! Black Box Warning All antidepressants carry a black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24) with major depressive disorder and other psychiatric disorders in short-term studies No increased risk for adults > 24 years of age Antidepressants: Overview Selective serotonin reuptake inhibitors (SSRIs) Serotonin/norepinephrine reuptake inhibitors (SNRIs) Atypical antidepressants Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitor (MAOI) Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs MOA: Inhibit presynaptic serotonin reuptake by inhibition of the 5-HT transporter ◦ Increased 5-HT in synaptic cleft SSRIs: Class Adverse Effects Adverse Effect Management GI adverse effects Take with small snack/meal Headache Adjust dose to evening Insomnia/Sedation Adjust dose to morning or evening as necessary Anxiety Slow dose titration to minimize exacerbation Switch to different SSRI, SNRI or non-serotonergic agent (i.e. Sexual dysfunction bupropion) SIADH Discontinue and switch to different antidepressant Slow taper if medication to be discontinued (exception: Discontinuation syndrome fluoxetine) SIADH= syndrome of inappropriate secretion of antidiuretic hormone SSRI Comparison Chart Initial dose Geriatric Renal Hepatic Unique Features Dose-related risk of QT prolongation Citalopram 20 mg daily Avoid: CrCl < Max 20 10-20 mg Max doses for >65 y/o, (Celexa®) Max: 40 mg 20 mL/min mg/day hepatic impairment, or with concomitant 2C19 inhibitors Dose-related risk of QT Escitalopram 10 mg daily Avoid if CrCl < Max 10 5-10 mg prolongation (Lexapro®) Max: 20 mg 20 mL/min mg/day S-enantiomer of citalopram 2D6 inhibitor Fluoxetine 20 mg daily ↓ Dose by Active metabolite 5-40 mg No change (norfluoxetine) with long (Prozac®) Max: 80 mg 50% half-life (7-9 days), taper not required SSRI Comparison Chart Initial dose Geriatric Renal Hepatic Unique Features Dry mouth, drowsiness, fatigue More anti-cholinergic adverse effects 20 mg daily Max 40 mg if Max 40 Paroxetine (Paxil®) 10-40 mg CrCl < 30 High risk of discontinuation mg/day Max: 50 mg mL/min syndrome with abrupt d/c due to short half-life 2D6 inhibitor GI side effects (diarrhea, nausea, vomiting) common → start with 25 mg daily lower dose and titrate slowly ↓ Dose by Sertraline (Zoloft®) 25-150 mg No change 50% Max: 200 mg Active metabolite N- desmethylsertraline (half-life 60-80 hours) 50 mg daily Potent 1A2 enzyme inhibitor Fluvoxamine No dose Slower 50-300 mg (Luvox®) adjustment titration Max: 300 mg Generally only used in OCD SSRIs: Prescribing Considerations Consider unique features to narrow Medication Consideration selection ◦ Drug-drug interactions Strong anticholinergic ◦ Renal adjustments are generally not necessary effects → may benefit in Paroxetine appetite stimulation and Monitor for response and titrate as weight gain tolerated Sertraline Most GI side effects May require 4-6 weeks for full antidepressant effect Fluoxetine Longest half-life All SSRIs are pregnancy category C ◦ Exception: Paroxetine (cardiac defects) Citalopram/ → Category D May prolong QTc escitalopram Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) SNRIs MOA: Inhibition of the 5HT and NE transporters → increased neurotransmitters in synaptic cleft SNRIs: Clinical Pearls Venlafaxine (Effexor®) ◦ Doses < 150 mg primarily inhibits 5HT-reuptake → higher doses provide dual NE & 5HT blockade ◦ Hypertension (dose-related) ◦ 300 mg/day: Up to 13% Desvenlafaxine (Pristiq®) ◦ Active metabolite of venlafaxine (CYP 2D6) Levomilnacipran (Fetzima®) ◦ NE > 5HT reuptake inhibition Duloxetine (Cymbalta®) ◦ Equal affinity for 5HT & NE reuptake transporters  SNRI Comparison Initial dose Geriatric Renal Hepatic Unique Features 60 mg daily Avoid: CrCl < 30 Duloxetine 20-40mg Avoid Monitor liver function Max: 60 mg mL/min Dose-related increase in IR: 37.5 mg BID IR: 25-225mg blood pressure Max: 225-375 mg CrCl 150 mg required to ER: 75 mg daily ↓ Dose by 50% QID get dual NE & 5HT Max: 225 mg transporter inhibition Active metabolite of 50mg daily venlafaxine CrCl < 30 mL/min: Desvenlafaxine Max: 400 mg (doses 50 mg daily 50 mg every other No change Requires 2D6 for >50 mg show no day metabolism additional benefit) $$$$ BP & HR elevations can 20 mg daily CrCl 5HT reuptake inhibitor SNRIs: Prescribing Considerations Consider unique features to narrow selection of SNRI ◦ All SNRIs are approved for treatment of depression ◦ Venlafaxine is also indicated for panic disorder/anxiety, neuropathic pain ◦ Dose-related increases in blood pressure ◦ Duloxetine has evidence in treatment of anxiety, fibromyalgia, and musculoskeletal pain Non-antidepressant properties may be evident within 1-2 weeks of starting therapy Monitor for response and titrate as tolerated All SNRIs are pregnancy category C Atypical Antidepressants Mirtazapine (Remeron®) Medication Properties Presynaptic α-2 antagonist Mechanism of Action Increases synaptic concentration of 5HT and NE Antagonist at 5HT2 and 5HT3 Dose Initial: 7.5 mg QHS; max: 45 mg/day Increased appetite (17%) Weight gain (7.5%: >7% ↑ in BW) Adverse Effects Constipation (13%) Sedation (54%) Often scheduled at night for sedating and appetite-stimulating Unique Features effects Bupropion (Wellbutrin®) Medication Properties Mechanism of Action NE & DA reuptake blockade with no 5HT effects Dose Differs by formulation (IR, SR, ER) Headache (25-34%) Insomnia (11-20%) Dizziness (6-11%) Adverse Effects Xerostomia (17-26%) Tachycardia (11%) Weight loss (14-23%) Anxiety (5-7%) Activating (useful with fatigue, poor concentration) Unique Features CYP 2B6 (major pathway), strong CYP2D6 inhibitor No sexual dysfunction Bupropion: Adverse Effects Dose-related seizure (0.1-0.4%) ◦ Maximum dose depends on formulation Maximum Single Maximum Daily Formulation Dosing Schedule Dose Dose Immediate release 150 mg 450 mg TID (IR) Sustained release (SR) 200 mg 400 mg BID Extended release (XL) 450 mg 450 mg Once daily Bupropion: Prescribing Considerations Contraindications History of seizures History of anorexia/bulimia Abrupt discontinuation of EtOH, BDZ, barbiturates or antiepileptic drugs AVS malformation in CNS Severe head injury, stroke, CNS tumor Trazodone (Desyrel®) Medication Properties Weak 5HT reuptake inhibitor Mechanism of Action Significantly blocks H1 and α1 receptors Depression: 150 mg once daily (max 450 mg) Dose Insomnia: 50-100 mg nightly Sedation (46%) Headache (33%) Dizziness (25%) Adverse Effects Fatigue (15%) Dry mouth (25%) Nausea (21%) Constipation (8%) Unique Features Used commonly as sleep aid, rarely as antidepressant Nefazodone (Serzone®) Medication Properties 5HT2A antagonist with moderate inhibition of 5HT Mechanism of Action and NE reuptake Dose Initial: 100 mg BID (Max: 600 mg/day) Dry mouth (25%) Sedation (25%) Adverse Effects Nausea (22%) Dizziness (17%) Blurred vision (16%) Not usually prescribed due to rare incidence of Comments hepatotoxicity Vilazodone (Viibryd®) Medication Properties Inhibition of presynaptic 5HT transporter Mechanism of Action 5HT1A partial agonist 10 mg once daily x1 week 20 mg once daily x1 week Dose Max: 40 mg/day Should be taken with food Diarrhea (28%) Adverse Effects Nausea (23%) Vomiting (5%) Pregnancy Category C Comments $$$$ Vortioxetine (Trintellix®) Medication Properties Inhibition of 5HT reuptake Mechanism of 5HT3 antagonist Action 5HT1A agonist 10 mg daily Dose Max: 20 mg daily Nausea (10-20%) Diarrhea (7-10%) Adverse Effects Dry mouth (6-8%) Sexual dysfunction (males: 16-29%, females: 22-34%) Pregnancy Category C Comments Metabolized by CYP2D6 $$$$ Comparison Chart Initial dose Geriatric Renal Hepatic Unique Features CrCl < 40 7.5-15 mg QHS Sedation, increased Mirtazapine 7.5-45 mg mL/min use Titrate slowly Max: 45mg appetite, weight gain caution IR: 100 mg BID Max: 450 mg in 3 Severe: divided doses IR: max 75 mg daily Risk of seizures SR:150 mg daily May require Bupropion ↓ Dose SR: max 100 Also approved for Max: 400 mg in 2 ↓ dose mg daily smoking cessation divided doses ER: 150mg ER:150 mg daily daily Max: 450 mg 10 mg daily Vilazodone No change No change No change $$$$ Max: 40 mg Concomitant strong 10 mg daily Vortioxetine No change No change No change 2D6 inhibitors reduce Max: 20 mg dose by 50% Atypical Antidepressants: Prescribing Considerations Consider unique features to narrow selection ◦ Mirtazapine supports increased appetite, weight gain, and sedation with possible benefit as an antiemetic ◦ Trazodone is commonly used as a sleep aid, but have increased anticholinergic effects ◦ Newer atypical antidepressants have higher cost with no superior benefit over traditional agents Non-antidepressant effects may be evident within days of starting therapy Monitor for response and titrate as tolerated Tricyclic Antidepressants Tricyclic Antidepressants (TCAs) MOA: Non-selective inhibitors of NE & 5-HT reuptake transporters Different Various affinities Different TCAs choices for NE & prominent within 5HT side class reuptake effects transporter TCA Dosing Comparison Dose Range Generic Name Brand Name Starting Dose (mg/day) Amitriptyline Elavil 25mg TID 50-300 Imipramine Tofranil 25mg TID 50-300 Clomipramine Anafranil 25mg/day 100-250 Doxepin Sinequan 25mg TID 75-300 Nortriptyline Pamelor 25mg TID 50-200 Desipramine Norpramin 25mg TID 50-300 Trimipramine Surmontil 25mg TID 15-90 Protriptyline Vivactil 5mg TID 15-60 Amoxapine Asendin 50mg TID 100-600 Maprotiline Ludiomil 25mg TID 50-300 TCAs: Adverse Effects Significant adverse effects Receptor Blockade Associated Adverse Effect α1 receptor Orthostatic hypotension Dry mouth, blurry vision, confusion, constipation, Muscarinic receptors urinary retention H1 & 5HT2C receptors Weight gain H1 receptor Sedation ◦ Conduction disturbances and EKG changes ◦ Decreases seizure threshold ◦ Toxicity is dose-dependent ◦ May be fatal in overdose QTc Prolongation Doxepin Amoxepine Chlomipra- Nortriptyline Amitriptyline Imipramine mine Structural Properties Tertiary Amines ◦ Ex: imipramine, amitriptyline ◦ Significant side effect profile due to increased α1, H1, and M1 blockade Secondary Amines ◦ Ex: desipramine, nortriptyline ◦ Increased tolerability with minimal α1, H1, and M1 blockade TCAs: Prescribing Considerations Consider unique features to narrow Medication Considerations selection ◦ Tertiary vs. secondary amine May benefit in treatment of ◦ Higher risk of CV and anticholinergic side chronic pain, polyneuropathy, and effects Amitriptyline migraines ◦ Non-antidepressant effects may be evident Additional sedating properties within days of starting therapy ◦ Antidepressant effects superior to SSRIs in May benefit in treatment of context of life-threatening illness with Nortriptyline myofascial pain and neuralgia quicker onset ◦ Monitor for response and titrate as Imipramine, Additional benefit in treatment of tolerated desipramine neuropathic pain May be used as sleep aid at low Doxepin doses Monoamine Oxidase Inhibitors (MAOIs) MAOIs Mechanism of action: Non- specific irreversible inhibition of monoamine oxidase MAO is responsible for metabolism of 5HT, NE, and DA MAOIs Agent Dose Max (mg/day) Comments Phenelzine (Nardil) 15 mg TID 90 mg Diet restriction required Tranylcypromine 30 mg/day 60 mg Diet restriction required (Parnate) (BID/TID) Isocarboxazid 20 mg/day 60 mg Diet restriction required (Marplan) (divided) Tyramine-diet restriction unnecessary unless daily dose > 6 mg Selegiline patch 6 mg/24 hours 12 mg Two active metabolites: amphetamine/ (Emsam) methamphetamine→ urine tox may be (+) MAOIs Adverse Effects Sedation Insomnia Weight Gain Changes in blood pressure MAOI Diet Recommendations Foods to avoid ◦ Aged cheeses, dried meats, red wine, tap beers, sauerkraut, raw yeast, legumes Foods to limit ◦ Caffeinated beverages, chocolate, figs, meat tenderizers, raisins Very important to counsel patients on how to successfully follow low tyramine diet! Hypertensive Crisis Resulting from significant tyramine levels Usually develops 20-60 minutes after ingestion of the interacting food or drug Can lead to cardiovascular event or death Clinical Presentation: nausea, vomiting, sweating, headache, stiff neck, chest pain, hypertension, palpitations Serotonin Syndrome Image source: NEJM. 2005, 352(11). Serotonin Syndrome May result from over activation of central serotonin receptors Rare, but can occur with the combination of serotonergic medications May be life-threatening Altered Muscular Life- Mild Tremor/ Clonus Clonus Hyper- Akathisia mental hyper- threatening Symptoms GI distress (inducible) (sustained) thermia status tonicity toxicity Image source: NEJM. 2005, 352(11). Serotonin Syndrome Abdominal pain, diarrhea, sweating, fever, tachycardia, delirium, hyperreflexia, clonus, irritability Presentation Discontinue suspected causative agent(s), provide supportive therapy (symptoms often resolve within 24 hours of discontinuation) Treatment SSRIs (other than fluoxetine)  MAOIs: 2 week washout Fluoxetine  MAOIs: 5 week washout Prevention MAOI  SSRI: 2 week washout MAOIs: Prescribing Considerations Not commonly used as first-line agent for treatment of depression Many drug-drug and drug-food interactions Central Nervous System Medications ELIZABETH COHE N, PHARMD BCPS Objectives Review the mechanisms of action and adverse effects of commonly used CNS agents Identify important counseling points for patients prescribed CNS agents Develop an optimal psychotropic regimen considering patient and medication specific characteristics Summarize clinically significant drug interactions, key monitoring parameters and contraindications for CNS agents Audience Question Which of the following is a major inhibitory neurotransmitter? A. Serotonin B. Glutamate C. Acetylcholine D. GABA  GABA & Glycine Major INHIBITORY neurotransmitters in CNS GABA Glycine Glycine Present in spinal cord & brainstem GABA Present throughout CNS GABA= Gamma-Aminobutyric Acid  Glutamate Major EXCITATORY neurotransmitter in CNS Glutamate Interacts with several receptors: AMPA (all neurons), KA (hippocampus, cerebellum, spinal cord), NMDA (all neurons in CNS) Most important pharmacological target of glutamate NMDA receptors NMDA= N-methyl-D-aspartate KA= kainic acid AMPA= α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid Serotonin Receptors Acetylcholine (ACh) Interact with muscarinic and nicotinic receptors → both excitatory and inhibitory effects ◦ Muscarinic affects smooth muscle ◦ Nicotinic affects skeletal muscle ◦ Few drugs are selective for specific receptor Presynaptic nicotinic receptors: Regulate release of glutamate, 5-HT, GABA, DA, NE in CNS Hydrolyzed through acetylcholinesterase (AChE) ◦ AChE inhibitors: Neostigmine, physostigmine, donepezil ◦ Many indications: Myasthenia gravis, glaucoma, Alzheimer's, and others Audience Question Which of the following is an effect of cholinergic activation? A. Diarrhea B. Dry skin C. Mydriasis D. Psychosis Cholinergic Effects/Toxidrome D- Diarrhea Muscarinic: Nicotinic: U- Urination S- Salivation M- Muscle cramps M- Miosis/muscle L- Lacrimation T- Tachycardia weakness U- Urination W- Weakness B- Bronchoconstriction/ D- Defecation T- Twitching bradycardia G- GI cramping F- Fasciculations E- Emesis/excitation of skeletal muscles E- Emesis L- Lacrimation S- Salvation/sweating Image source: Lip inc ott’s Illustrated Reviews: Pharmac ology 4 th edit ion. Audience Question Which of the following patients would you be concerned for increased risk of suicidal thinking and behavior when treating with an antidepressant based on the Black Box Warning? A. 32 year old with MDD and anxiety B. 18 year old with MDD and current smoker C. 65 year old with MDD after the loss of a spouse D. 42 year old with MDD who lost their job Black Box Warning All antidepressants carry a black box warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24) with major depressive disorder and other psychiatric disorders in short-term studies No increased risk for adults > 24 years of age Audience Question Which of the following medications are you most concerned about discontinuation syndrome? A. Venlafaxine (Effexor) B. Fluoxetine (Prozac) C. Paroxetine (Paxil) D. Bupropion (Wellbutrin) SSRI Comparison Chart Initial dose Geriatric Renal Hepatic Unique Features Dry mouth, drowsiness, fatigue More anti-cholinergic adverse effects 20 mg daily Max 40 mg if Max 40 Paroxetine (Paxil®) 10-40 mg CrCl < 30 High risk of discontinuation mg/day Max: 50 mg mL/min syndrome with abrupt d/c due to short half-life 2D6 inhibitor GI side effects (diarrhea, nausea, vomiting) common → start with 25 mg daily lower dose and titrate slowly ↓ Dose by Sertraline (Zoloft®) 25-150 mg No change 50% Max: 200 mg Active metabolite N- desmethylsertraline (half-life 60-80 hours) 50 mg daily Potent 1A2 enzyme inhibitor Fluvoxamine No dose Slower 50-300 mg (Luvox®) adjustment titration Max: 300 mg Generally only used in OCD Audience Question Which agent may be most beneficial in a patient with MDD and a history of anxiety? A. Venlafaxine (Effexor) B. Bupropion (Wellbutrin) C. Escitalopram (Lexapro) D. Trazadone (Desyrel) SNRIs: Prescribing Considerations Consider unique features to narrow selection of SNRI ◦ All SNRIs are approved for treatment of depression ◦ Venlafaxine is also indicated for panic disorder/anxiety, neuropathic pain ◦ Dose-related increases in blood pressure ◦ Duloxetine has evidence in treatment of anxiety, fibromyalgia, and musculoskeletal pain Non-antidepressant properties may be evident within 1-2 weeks of starting therapy Monitor for response and titrate as tolerated All SNRIs are pregnancy category C Audience Question Due to its 5HT3 receptor blockade, mirtazapine lacks which of the following adverse effects? A. Constipation B. Nausea and vomiting C. Sedation D. Weight gain Mirtazapine (Remeron®) Medication Properties Presynaptic α-2 antagonist Mechanism of Action Increases synaptic concentration of 5HT and NE Antagonist at 5HT2 and 5HT3 Dose Initial: 7.5 mg QHS; max: 45 mg/day Increased appetite (17%) Weight gain (7.5%: >7% ↑ in BW) Adverse Effects Constipation (13%) Sedation (54%) Often scheduled at night for sedating and appetite-stimulating Unique Features effects Assessment Question For which of the following patients would bupropion be an acceptable option to treat MDD? A. 36 y/o with comorbid cocaine use disorder and borderline personality disorder B. 24 y/o with PMH of anorexia nervosa C. 47 y/o with comorbid panic disorder, generalized anxiety disorder, and GERD D. 29 y/o with PMH of epilepsy and comorbid multiple sclerosis Bupropion (Wellbutrin®) Medication Properties Mechanism of Action NE & DA reuptake blockade with no 5HT effects Dose Differs by formulation (IR, SR, ER) Headache (25-34%) Insomnia (11-20%) Dizziness (6-11%) Adverse Effects Xerostomia (17-26%) Tachycardia (11%) Weight loss (14-23%) Anxiety (5-7%) Activating (useful with fatigue, poor concentration) Unique Features CYP 2B6 (major pathway), strong CYP2D6 inhibitor No sexual dysfunction Audience Question What class of antidepressants may be most beneficial in patients with severe, life-threatening illness? A. SSRIs/SNRIs B. Atypical C. MAOIs D. TCAs TCAs: Prescribing Considerations Consider unique features to narrow Medication Considerations selection ◦ Tertiary vs. secondary amine May benefit in treatment of ◦ Higher risk of CV and anticholinergic side chronic pain, polyneuropathy, and effects Amitriptyline migraines ◦ Non-antidepressant effects may be evident Additional sedating properties within days of starting therapy ◦ Antidepressant effects superior to SSRIs in May benefit in treatment of context of life-threatening illness with Nortriptyline myofascial pain and neuralgia quicker onset ◦ Monitor for response and titrate as Imipramine, Additional benefit in treatment of tolerated desipramine neuropathic pain May be used as sleep aid at low Doxepin doses Antipsychotics Dopamine Pathways in the Brain Dopamine Related Dopamine Receptor Dopamine Receptor Agonist Pathway Antagonist Mesocortical Worsening negative symptoms Theorized improvement in (prefrontal cortex) (anhedonia) negative symptoms Mesolimbic Relief of positive symptoms Reward pathway (addiction), (basal ganglia) (hallucinations) psychosis Target of action for relief of Nigrostriatal (substantia Extrapyramidal Symptoms movement disorders in nigra) Parkinson’s Tuberoinfundibular Increase prolactin release Decrease in prolactin release (hypothalamus)  TraditionalAntipsychotics First Generation Antipsychotics (FGAs) MOA: Blockade of post-synaptic D2 receptors in brain ◦ Other receptors may be affected, which accounts for differences in side effects ◦ Ex: Histaminergic, muscarinic, adrenergic AllSES  reallygooddopamineantag LOTSAEs psych Haloperidol good Chlorpromazine notgoodforpsychosis but BE FGAs: Overview Max Equiv. Dose range Generic Name Trade Name Potency dose Class Dose (mg) (mg/d) X (mg/d) Aliphatic Chlorpromazine Thorazine LOW 100 100-800 2000 Phenothiazine Mesoridazine Serentil LOW 50 50-400 500 Piperidine Thioridazine Mellaril LOW 100 100-800 800 Phenothiazines 9H Loxapine Loxitane MID 10 10-80 250 Dibenzoxapine Molindone Moban MID 10 10-100 225 Dihydroindolone fan Perphenazine Trilafon MID 10 10-64 64 two Fluphenazine Prolixin HIGH 2 2-20 40 Piperazine FGACI Phenothiazines Trifluoperazine Stelazine HIGH 5 5-40 80 Thiothixene Navane HIGH 4 4-40 60 Thioxanthenes Haloperidol Haldol HIGH 2 2-20 100 Butyrophenone *This card is meant as a general guide for dosing. Please refer to medication databases for patient specific dosing information. FGAs: Overview Blockade of D2 receptors in other areas lead to variety of adverse effects ◦ Nigrostriatal → movement disorders ◦ Tuberoinfundibular → hyperprolactinemia ◦ Mesocortical → worsening negative symptoms Black Box Warning Black Box Warning for ALL Antipsychotics ◦ Increased death associated with treatment in patients with dementia-related psychosis Bcnotreally treating if using antipsychotics dementia  FGA Potencyinvenetosedation Potency sedationAntichol FGAs: Adverse Effects TEPS Serrill Potency Sedation EPS Anticholinergic Cardiovascular Chlorpromazine Low High Low High High Thioridazine Low High Low High Mod Perphenazine Mid Low High Low Low Loxapine Mid Mod Mod Low Low Trifluoperazine High Low High Low Low Fluphenazine High Low High Low Low Haloperidol High Low High Low Low Thiothixene High Low High Low Low  FGA Prescribing Considerations Monitor for symptoms of EPS May require use of anticholinergic agent as adjunct to minimize movement side effects a ◦ Ex: benztropine (Cogentin) 0.5 mg BID Parkinson's balanceDog Generic availability so relatively inexpensive cholinergicactivity EPS: extrapyramidal symptoms  canhave Extrapyramidal Symptoms 5 main EPS only 1 Group of potentially serious adverse effects associated with It maybe antipsychotic medications or metoclopramide NIV of unaware ◦ Antagonize D2 receptors in nigrostriatal pathway (substantia nigra) EPS Symptom Description Repetitive, involuntary, purposeless body or facial movements Dyskinesia Ex: Lip smacking, tongue movements, finger movements Tardive Occurs after longer duration of use, may be permanent dyskinesia Extreme form of internal or external restlessness, inability to sit still, Akathisia urge to move constantly Muscle tension disorder → strong muscle contractions, unusualtorsion Dystonia twisting of parts of body especially neck or wo W pain Mask-like facies, resting tremor, cogwheel rigidity, shuffling gait, Parkinsonism bradykinesia FGA Prescribing Considerations Immediate acting injections (haloperidol, fluphenazine, and chlorpromazine) → option for hospitalized agitated patients ◦ May be ordered as a cocktail: “B52” ◦ Haloperidol 5 mg po/IM/IV ◦ Lorazepam 2 mg po/IM/IV LESSCOMMON BC r ICUDELIRIUM ◦ Diphenhydramine 50 mg po/IM/IV only last resort High-potency agents require addition of anticholinergic medication to reduce risk of developing EPS Low potency agents do not require additional meds ◦ Ex: A patient treated with chlorpromazine does NOT need adjunctive anticholinergic medication or lorazepam ◦ Highly sedating itself & highly anticholinergic  SGAI NOTBETTERTHAN a massivemarketing FGAs in the Marketplace FGAs campaign Second Generation Antipsychotics (SGAs) MOA: Post-synaptic D2 and 5HT2A blockade SGAs: Overview Generic Name Trade Name Dosage Range (mg/d) Schedule Aripiprazole Abilify 10-30 Once daily Brexpiprazole Rexulti® 2-4 Once daily Cariprazine Vraylar® 1.5-6 Once daily Clozapine Clozaril 12.5-900 BID Olanzapine Zyprexa 5-20 Once daily Quetiapine Seroquel 50-800 BID Risperidone Risperdal 2-16 Once daily – BID Paliperidone Invega 6-12 Once daily Lurasidone Latuda 20-160 Once daily Iloperidone Fanapt 1-24 Twice daily Asenapine Saphris 5-20 Twice daily  SGAs: CYP450 Primary Pathway moreDisthanFGAS.SGADIV PEI.ME 2D6 1A2 3A4 Aripiprazole Asenapine Aripiprazole please Iloperidone Clozapine Lurasidone metalices Risperidone (converted to Olanzapine Quetiapine gergfesting active metabolite paliperidone) Ziprasidone* Cigarettes metabtheseSGAC toofast *Two-thirds of ziprasidone metabolism occurs via aldehyde oxidase and one-third by CYP450 system (3A4)  Psych & CYP450 System 1A2 ◦ Smoking induces this enzyme by 20-30% ◦ May need to adjust dose if changes in smoking status ◦ Watch for 1A2 inhibitors like fluvoxamine 2D6 ◦ Genetic variations between PM, UM, RM ◦ 2D6 inhibitors: paroxetine, fluoxetine, and bupropion ◦ If patient is taking risperidone + 2D6 inhibitor may not get full effect of antipsychotic 3A4 ◦ Many medications are metabolized through this enzyme ◦ Watch for strong inhibitors such as azole class of antifungals PM= poor metabolizer RM= rapid metabolizer UM= ultra metabolizer SGAs: Class Adverse Effects CV risk worsethanFGA hyperlipid a Dm ◦ Metabolic abnormalities (lipids & glucose) induces ◦ Weight gain ◦ QTc prolongation ◦ Prolactin elevation ◦ Sedation bi still antihistamine ◦ Akathisia ◦ Anticholinergic effect ◦ Orthostatic hypotension SGA Adverse Effects H1 & 5HT2C Weight Gain blockade Prolactin D2 blockade in tuberoinfundibul Elevation ar pathway Anticholinergi Muscarinic c blockade D2 blockade in EPS nigrostriatal pathway Adverse Effect Rankings I Weight Clozapine Quetiapine Risperidone AripiprazoleL urasidone Gain Olanzapine Iloperidone Paliperidone Ziprasidone Most likely to cause Less likely to cause *This is meant as a general guide for dosing. Please refer to medication databases for patient specific information. Adverse Effect Rankings bestblockade pop desamine leastblockade Prolactin Risperidone Lurasidone Iloperidone Olanzapine Quetiapine Elevation Paliperidone Ziprasidone Asenapine Aripiprazole Most likely to cause Less likely to cause *This is meant as a general guide for dosing. Please refer to medication databases for patient specific information. Adverse Effect Rankings Olanzapine Asenapine Aripiprazole Sedation Clozapine Quetiapine Risperidone Iloperidone Ziprasidone Lurasidone Paliperidone Most likely to cause Less likely to cause *This is meant as a general guide for dosing. Please refer to medication databases for patient specific information.  Antipsychotics & QTc Prolongation Paliperidone Olanzapine So Aripiprazole Quetiapine Ziprasidone Thioridazine Haloperidol Risperidone Lurasidone Iloperidone Worsening QTC *All above are oral formulations for QTc prolongation SGA Prescribing Considerations Risperidone clinical max of 6-8 mg ◦ >8 mg begins acting similar to typical antipsychotics→ haloperidol Paliperidone ◦ Dose adjustment required when CrCl 2 adequate trials of antipsychotics Requires patient, pharmacy, and physician registration with Clozapine REMS program* Prior to initiation and throughout time on clozapine blood draws are required due to risk of neutropenia 5 black box warnings (BBW) associated with clozapine. *1 universal REMS program replaced registry in October 2015 Clozapine: BBW & Adverse Effects Bloodwork: weeklytesting ANC > 1500 (general pop) Agranulocytosis ANC > 1000 (BEN)* MOH IM SEVERE 5 Black SEVERE Orthostatic monitor Myocarditis Box Hypotension Troponins Most cases Warnings for SLOWLY titrate generally occur in first Clozapine dose to Death in minimize 8 weeks dementia- Seizure related psychosis all APs *BEN = benign ethnic neutropenia  Clozapine: Adverse Effects Highly anti-cholinergic medicationDrying ◦ Tachycardia ◦ Constipation ◦ Prescribe sufficient bowel regimen! Cholinergic agonist at M4 receptors in mouth 4 ◦ Excessive salivation Strong histaminergic effect ◦ Sedating Weight gain Clozapine: Prescribing Considerations Consider in patients that have failed adequate doses and trials of other agents. May not be appropriate in patients with adherence issues ◦ Dose will need to be re-titrated from initial 25 mg QHS if patient missed > 48 hours of dose Patient will need to travel for blood work ◦ Weekly for 1st 6 months ◦ Biweekly for 2nd 6 months ◦ Then monthly for life EPS Rankings High Risk Medium Risk Low Risk Haloperidol Perphenazine FGA Thiothixene Chlorpromazine Loxapine Fluphenazine Aripiprazole Brexpiprazole Asenapine Clozapine Paliperidone SGA Cariprazine Iloperidone Risperidone Lurasidone Olanzapine Quetiapine Ziprasidone EPS Treatment General treatment: ◦ Diphenhydramine (Benadryl): 25-50 mg po or IM (prn or scheduled) ◦ Benztropine (Cogentin): 0.5 – 4 mg po ◦ Typically divided into BID dosing ◦ Propranolol may help with treatment of akathisia Anticholinergics may worsen Parkinsonian symptoms or tardive dyskinesia Tardive Dyskinesia Long term usage may be permanent Repetitive, involuntary neurological movement disorder cause by DA blockade Oral, Facial, Lingual Dyskinesia Limbs and Trunk Abnormal movements of the Twisting, spreading of fingers tongue Foot tapping Facial grimacing Dyskinesia of neck Lip puckering, smacking, Shoulder shrugging pouting Rocking/swaying Bulging of cheeks Tremor (rare) Chewing movements Tardive Dyskinesia Treatment No standard treatment approach has been established: Discontinue medication e ◦ Low response rate Switch to less potent dopamine antagonist ◦ FGA → SGA Adjunctive agents ◦ Clonazepam, gingko biloba, amantadine ◦ VMAT2 inhibitors? i MEYER JM. FORGOTTEN BUT NOT GONE: NEW DEVELOPMENTS IN THE UNDERSTANDING AND TREATMENT OF TARDIVE DYSKINESIA. CNS SPECTR. 2016 DEC;21(S1):13-24 Valbenazine (Ingrezza®)VMATZinhibitor for TD Medication Properties notsuper Class Vesicular monoamine transporter 2 (VMAT2) inhibitor FDA indications Tardive dyskinesia effective Reversibly inhibits VMAT2 transporter → regulates uptake of Mechanism of monoamine from cytoplasm to synaptic vesicle for storage/release Action (↓ monoamine levels in synapse) 40 mg po daily x 1 week then increase to 80 mg daily Dosing CrCl 1.2 mEq/L ◦ GI disturbances, tremor ◦ Mental status changes ◦ Coma/seizures/death can occur at toxic doses even 1 am Eg L Monitoring: may followLotexcreted in les ◦ Levels ◦ Insipidus (Diabetes insipidus) be a NatsoH2O ◦ TSH (hypo/hyperthyroidism), Tremor Li retention if dehydrated ◦ Hydration status (hyponatremia→ increased Li levels) Lithium: Overview Lithium concentration Lithium concentration Thiazide diuretics Sodium Sodium bicarbonate Furosemide antacids ACE inhibitors Theophylline ARBs Verapamil NSAIDs Osmotic Diuretics Reduced sodium Caffeine intake Discussion Questions What labs would you want to check prior to starting lithium? NaoCreatinineBNPfor k fan TSH How would you monitor lithium levels? When would you check a lithium level? 4 5 d steady state 4 or 5 dose troughbefore 4 51 again Δ after if dose K 6M Δ then spread out from if meets weekly many as stabilize Anxiolytics  GABA to shutdown hyperactive signaling Benzodiazepines (BDZs) anxiety's by ability GABAto bind MOA: Bind to the gamma subunit of the GABAA receptor → allosteric modification of receptor → GABA binds→ increased 2Wh frequency of channel opening→ increase in chloride ion for conductance and inhibition of the action potential term long depend Gd end 1 hk few every Ix PM dayscausing not10nsFacs Benzodiazepines good for Four categories based on elimination half-life mantresthesia Category Half-life (t ½) Examples Ultra-short acting T ½ 24 hours Flurazepam, diazepam, quazepam, clonazepam affine BDZs: Prescribing Considerations 0 Elimination half-life Slow taper to avoid potential for seizures Generally safe when used alone ◦ Present a fall risk for elderly patients! Potential for physiological and psychological dependence slowwaimental mold ◦ Reserve for short-term therapy not Preferred agents in elderly or with poor hepatic function: lorazepam, oxazepam, temazepam to b CYP metabinese arent due LOT as reliant on Cyp LOT  Alternative Anxiolytics very few effective Medication MOA Dose ADRs Binds to H1 receptors Hydroxyzine for skeletal muscle 25-100 mg 3-4 Xerostomia, somnolence (Atarax®) relaxing, antihistamine, times daily antiemetic effects it muscletension cantsleep Structurally related to Sleepiness (25%), dizziness 300-2400 mg daily Gabapentin GABA, does not bind to (23%), ataxia (20%), nystagmus, (divided) (Neurontin®) GABAA or GABAB headache, fatigue, peripheral Max: 3600 mg receptors edema p Not completely Weight gain, peripheral edema, Pregabalin understood 150-600 mg daily constipation, xerostomia, ataxia, (Lyrica®) GABA analog → binds to (divided) dizziness, headache, fatigue, alpha2-delta site disturbance in thinking/SI Unknown, high affinity 20-30 mg daily Better long term lessAos Buspirone for 5-HT1A receptors and Nausea, dizziness, somnolence, (divided) (Buspar®) moderate affinity for D2 headache Max: 60 mg Summary: Pharmacotherapy Considerations Sedation Appetite Type of pain Onset of action Comorbid conditions Renal/hepatic function Half-life of medication Drug-drug interactions Drug-food interactions Central Nervous System Medications ELIZABETH COHE N, PHARMD BCPS