B4. Wk 3. Fibromyalgia, MS, Schizophrenia

FIBROMYALGIA (FMS)
Treatment
– 1. Educate patient
– 2. Exercise program
– 3. Drug monotherapy

Drugs that are FDA-approved for FMS
Pregablin (Lyrica) – GABA agonist
Duloxetine (Cymbalta) – SNRI
Milnacipran (Savalla) -SNRI

Start with a low-dose TCA
NE & 5HT dual reuptake inhibitor
Mostly blocks ACh & histamine
– contributes to ADRs
BBW: Suicide in children
CI: Lethal DDI w MAOIs
– Linezolid, IV methyline, Myocardial Inf
May be limited by ADR profile (esp elderly)

Elavil,
Endep
Amitriptyline
Give 1-3 hours before bed

Norpramine
Desipramine
Give 1-3 hours before bed
Has fewer anticholinergic ADRs

ADRs for TCAs
Anticholinergic ADRs
Cardio: QT prolongation w OD,
– orthstasis,
– tachycadia

Anticholinergic ADRs
dry mouth
blurred vision
constipation
drowsiness
sedation
hallucinations
memory impairment
difficulty urinating
confusion
delirium
decreased sweating
decreased saliva

Alternative to TCA
For mild-moderate symptoms

Flexeril
Cyclobenzaprine
Muscle relaxer
Has similar molecular structure as TCA
with less antidepressant effects

For inadequate response to TCA
(or alternative therapy)
SNRIs,
Anticonvulsants

SELECTIVE NOREPI / SEROTONIN REUPTAKE INHIBITORS (SNRIs)

Note: Venlafaxine is not recommended

For more severe fatigue problems
Take at breakfast
BBW: Suicide in children
CI: Lethal DDI w MAOIs
– Linezolid, IV methyline

Cymbalta
Duloxetine
Preferred if pt also has depression
Take capsule BID
Can decrease FMS pain > 30%
D/C if CrCL < 30

Savalla
Milnacipran
Preferred if pt also has depression
Titrate up over a week
Take tablet BID
ADRs include hot flashes

ADRs for SNRIs come from increased
– Serotonin
– Norepi
Serotinin: N/C, dry mouth, dec appetite, diaphoresis, agitation, sexual issues, bleeding risk if taking
– NSAIDs/ anticoags / ginko
Norepi: C, dilated pupils, inc hr, dry mouth, diaphoresis

ANTI-CONVULSANTS
alpha2-delta Ca2+ channel modulators
aka: alpha2-ligands
These 2 are the only ones for convincing evidence to benefit FMS
May exert analgesic effect by blocking release of various NTs

Lyrica
Pregablin
For more severe sleep problems + pain
Take HS
Controlled substance (C-V)
ADRs: dizziness, peripheral edema, wt gain, blurred vision, mild euphoria
Decrease dose or extend interval if
– CrCL < 60

Neurontin
Gabapentin
Evidence is more limited
Use as alternative to Lyrica if
– cost is an issue
– regulatory requirements are an issue
ADRs: dizziness, peripheral edema, wt gain, blurred vision
Decrease dose or extend interval if
– CrCL < 60

MULTIPLE SCLEROSIS

3 forms of tx (back of card)

1. Disease Modifying Therapy (DMT)
2. Exacerbation Tx
3. Symptom Control Tx

1. DISEASE-MODIFYING THERAPY (DMT)

INJECTABLE DMT’s
Powder for reconstitution have albumin
– increases risk of Creutzfelt-Jacob ds
– some pts are allergic
Do not expel sm air bubble in prefilled syringes (loss of dose)

Avonex & (Avonex Pen),
Rebif & (Refib Rebidose)

Powder for reconstitution &
Pre-filled syringes

Interferon b1a
Avonex: IM Qweekly (low potency)
Rebif: SQ 3x/week (high potency)
MOA: antiviral & antiproliferative effects
– reduces antigen presentation &
– reduces T-cell proliferation
Warning: depression / suicide/ worsening CVD, seizures
ADRs: Flu-like SS (pretx w APAP/ NSAIDs), depression, leukopenia

Betaseron,
Extavia

Powder for reconstitution &
Pre-filled syringes

Interferon b1b (high potency)
SQ QoD
MOA: saa
Warning: depression / suicide/ worsening CVD, seizures
ADRs: Flu-like SS (pretx w APAP/ NSAIDs),
depression, more f injection site rxns

Pelgridy & (Pelgridy Starter Pack)

Pre-filled syringes & pens

Peginterferon b1a
Titrate up – Day 1: 64mcg, Day 15: 94mcg
SQ Q14days (125mcg)
ADRs: Flu-like SS (pretx w APAP/ NSAIDs)

Copaxone,
Glatopa
Glatiramer acetate
20mg SQ QD -or- mg SQ 3x/week
Dosing regimens are NOT interchgable
MOA: unkwn but may induce suppressor T-cells
ADRs: Flushing, diaphoresis, chest pain/ tightness, skin necrosis at inj site
Note: Can be kept at room temp 1 month

ORAL DMT’s

Aubagio
Teriflunomide (active M of leflunomide)
1 tablet PO QD
MOA: Inhibits dihydroorotate dyhydrongenase (mitochondrial enzyme involved in pyrimidine synthesis), may decrease activated lymphocytes in CNS
BBW (2): Hepatotox, Teratogenic (Preg:X)
ADRs: SJS, Liver failure, neutropenia, RTI, activation of TB, alopecia, neuopathy
Note: cholestyramine & charcoal accelerate elimination

Gilenya

FDA issued an alert for PML in 2013
(Progressive Multifocal Leukoencephalopathy)

Fingolimod
1 capsule PO QD
BAD FOR HEART (bradycardia)
– Monitor 6 hrs (ECG) after 1st dose
MOA: Prodrug> Sphingosine 1-R modulator. May may decrease activated lymphocytes in CNS
ADRs: Lymphocytopenia, arthralgia, macular retinal edema (must get eye exam at baseline & Q3-4months)

Tecfidera
Dimethyl fumarate
Delayed Release formulation
Titrate up
– 1 capsule PO BID for 7 days (120mg)
– 1 capsule PO BID (240mg)
MOA: Nicotinic acid R agonist / acitvator of Nuclear factor-like 2 (Nrf2) pathway (cell response to oxidative stress)
Warning: Risk of PML, GI events
ADRs: Flushing (pretx w ASA 30min b4)
– taking w food decreases too
Monitor: CBC b4 /6mo / then Q6-12mo

IV INFUSION DMT’s

Lemtrada
Alemtuzumab
1st course: IV over 4 hrs QD for 5 days
2nd course: saa for 3 days 12 mo later
MOA: CD52-directed cytolytic monoclonal Ab. Causes cell lysis, depleting T & B cells by binding to surface CD52 marker
BBW (4): Fatal autoimmune contision (ITP),
– Fatal infusion rxns
– Increased risk for malignancies
– Only avail via Lemtrada REMS
CI: HIV b/c causes decrease in CD4 count
Notes: only use if fail 2+ MS drugs
– Complete ALL vaccines 6 wks b4
– Pretx w 1g methylprednisolone
– Antiviral PPx – 2 mo or until CD4 >200

Mitoxantrone
Mitoxantrone
12mg/m2 IV Q3mo (life max 140mg/m2)
– max dose due to cardiotox
MOA: Anthracenedione family. Anticancer drug that inbits DNA & RNA synthesis. Also shown to inhibit B & T-cells, macrophages, antigen presentation, secretion of IFN-g, TNF-a, IL-2.
ADRs: BMS, neutropenia, cardiotox, AML, N/V/D

Tysabri
Natalizumab
IV over 1 hour Q4weeks
MOA: Integrin-R antagonist / recombinant humanized IgG4-kappa monoclonal Ab. Prevents transmigration of leukocytes into inflamed tissue / blocks integrin + VCAM-1 interaction / Inhibits continued recruitment
BBW: Fatal PML. Monitor mental changes.
– Risk: anti-JC virus Ab
Only avail via TOUCH REMS program
– Pt / Dr/ Pharmacist all h/t register
ADRs: PMS, depression, fatigue, RTI, arthralgia, IRIS when D/C due to PML
Note: Protect from light during admin

2. EXACERBATION TX
Methylprednisolone IV 3-7 days -or-
Prednisone PO 3-7 days

3. SYMPTOM CONTROL TX

Gait Difficulties
Baclofen (Lioresal) – sk muscle relaxant
Tizanidine (Zanaflex)
BZDs
Dantrolene (Dantrium)
Gabapentin / Pregabalin
Tiagabine (Gabatril)
Botulinum Toxin A (Botox)
Dalfampridine (Ampyra)

Tremor
Propranolol (Innopran, Inderal)
Primidone (Mysoline)
Isoniazid

Sensory Symptoms
(numbness / paresthesia)
Carbamazapine (Tegretol)
Amytriptyline (Elavil)
Gabapentin / Pregabalin
Duloxetine (Cymbalta)

Fatigue
Adamantine (Symmetrel)
ADHD meds / Stimulants
– Methylphenidate (Ritalin)
– Dextroamphetamine (Dexedrine)
– Modafinil (Provigil)
Fluoxetine (Prozac, Sarafem)

Sexual Dysfunction
PDE-5 Inhibitors
– Sildenafil (Viegra)
– Tadalafil (Cialis)
– Vardenafil (Levitra)
Aloprostadil (Caverject)
Intraurethral suppos (MUSE)
Bupropion (if pt has depression too)

Cognition
Stimulants -or-
Cholinesterase inhibitors
– Donepezil (Aricept)
– Galantamine (Razadyne)
– Rivastigmine (Exelon)

Bowel & Bladder – Anticholinergics
Oxybutinin (Ditropan)
Tolterodine (Ditrol)
Propantheline (Pro-Banthine)
Hyoscyamine (Levsin)
Diclomine (Bentyl)

Bowel & Bladder – TCAs
Imipramine (Tofranil)
Amytriptyline (Elavil)

Bowel & Bladder – Antimuscarinics
Trospium (Santura)
Solinfenacin (Vesicare)
Darifenacin (Enablex)
Fesoterodin (Toviaz)

Bowel & Bladder – Alternative (ADH)
Desmopressin (DDAVP)

Bowel & Bladder – if pt has significant sphincter dyssynergia
Prazosin (MiniPress)
Botox

OTHER DRUGS MENTIONED IN GUIDELINES

Cytoxan
Cyclophosphamide
Nitrogen mustard type alkylating anticancer agent
GL: Younger pts may benefit

Trexall,
Rasuvo
Methotrexate
Antirhuematic
GL: May alter ds course favorably

Azasan,
Imuran
Azthioprine
Immunosuppressant used in organ transplantation and autoimmune diseases
GL: May reduce relapse rate

Leustatin
Cladribine
Chemo drug for leukemia
GL: Reduces Gd biomarker for BBB breakdown but does not alter course of ds

Sandimmune
Cyclosporine
Immunosuppressant used in organ transplantation and autoimmune diseases
GL: May be beneficial but ADRs outweigh benefit (esp nephrotox)

Azulfidine
Sulfasalazine
Anti-inflammatory for RA
GL: No benefit for MS

IV Immunoglobulin (IVIg)
GL: Little benefit / bad studies

Plasma exchange
GL: Little to no benefit

SCHIZOPHRENIA
Psychosis – chronic, severe, disabling thought disorder

Increased ventricular size &
Decreased grey matter

Dopaminergic Tracts & Effects of Da Antagonists

Nigrostriatal Da Tract
Function
– Movement & Extrapyramidal system (nerves concerned with motor activity that descend from the cortex to the spine)

Da Antagonist Effect
– Movement disorders

Mesolimbic Da Tract
Function
– Emotional functioning
– Motivational behavior

Da Antagonist Effect
– Relief of psychosis

Mesocortical Da Tract
Function
– Cognition
– Executive fxn

Da Antagonist Effect
– Relief of psychosis
– Relief of akathisia (?)
(state of agitation, distress, and restlessness)

Tuberohypophyseal Da Tract
Function
– Regulates prolactin release

Da Antagonist Effect
– Increased [prolactin]

Diagnostic & Statistical Manual of Mental Disorders (DSM-5)

Diagnostic Criteria

2+ Characteristic SS (for 1 month)
– Delusions / Hallucinations
– Disorganized speech
– Grossly disorganized /catatonic behav.
– Negative Symptoms

Social/Occupational Dysfxn: 1+ major areas of functioning are significantly below level prior to onset
– Work / Interpersonal relationship
– Self-care

Duration: at least 6 months & must include 1 month of characteristic SS

Positive Symptoms

Comes from Temporlimbic dysfnx
– Mesocaudate
– Da hyPERactivity

1. Delusions
2. Disorganized Speech
– Association disturbance
3. Hallucinations
4. Disorganized /Catatonic Behavior
– Behavior disturbance
5. Illusions

Negative Symptoms

Comes from Prefrontal Lobe dysfnx
– Prefrontal cortex
– Da hyPOactivity

1. Alogia (poverty of speech)
2. Avolition (lack of interest)
– especially in goal-directed behavior
3. Flattened Affect
– Decreased range of emotions
– Poor eye contact
– Decreased body language
4. Anhedonia (can’t feel pleasure)
5. Social Isolation

Cognitive Dysfunction
1. Impaired attention
2. Decreased working memory
3. Decreased executive function

Executive Function: Mental skills that help you get things done. Controlled in the frontal lobe. Helps you manage time & pay attention

Initial Tx goals in acute psychotic episode
1st 7 days goal of decreasing
– agitation / hostility / combativeness
– anxiety / tension / aggression
– Also, normalization of sleep and eating

If no improvement w/in 3-4 weeks
– switch to alternate antipsychotic

Stabilization Tx goals
Goals over weeks 2-3 are to improve
– socialization / self care / mood

Improvement in mood disorder may take another 6-8 weeks

Continue to titrate dose Q1-2 weeks as needed if there are no ADRs

If SS don’t improve w/in 8-12 weeks, switch to alternate strategy

Maintenance Tx goals
Continue med at lowest effective dose for 12 months after remission

Abrupt D/C of antipsychotics can lead to withdrawal SS (rebound cholinergic outflow) – especially Clozapine

Rebound cholinergic outflow – abrupt withdrawal SS
Insomnia / Nightmares
Headaches / GI symptoms
Restlessness
Increased salivation / Sweating

Tx-Resistant Schizo
Clozapine (if fail 2 antipsychotics)
Augmentation agents
– Lithium
– Valproic acid
– Divalproex
– Carbamazepine
FGA + SNRI to improve negative symptoms

No data for FGA + SGA or combining SGAs

Kinetics (general)
Highly lipophilic
Highly protein-bound
Large Vd
Largely metabolized by liver CYPs
– except Ziprasidone (Geodon)

FIRST GENERATION ANTIPSYCHOTICS (FGA’s)

Typical Antipsychotics

Older agents only treated positive symtoms

ADRs: High risk of EPS, moderate weight gain, seizures, temp dysregulation, allergic rxns, skin / liver / eye /blood effects

Low risk of metabolic effects

MOA:
– High Da: Low 5HT(2) Antagonism

High potency FGAs

Haliperidol,
Fluphenazine,
Trifluoperazine,
Triothixene

Higher risk of EPS
Moderate degree of sedation
Lower risk of
– Orthostatic hypotension
– Tachycardia
– Anticholinergic effects

Mid potency FGAs

Loxapine,
Perphenazine

Low potency FGAs

Chlorpromazine,
Thioridazine

Lower risk of EPS
High degree of sedation
High risk of
– Orthostatic hypotension
– Tachycardia
– Anticholinergic effects

BBW for all antipsychotics
Increase risk of mortality in elderly with dementia (due to increased risk of stroke & infection)

Not helpful for dementia-related outbursts

Haldol

Decanoate (IM)
Lactate (IV)

SAFE IN PREGGERS (the only one)

Haloperidol
High potency & high EPS
Higher drop out rate in 1st episode
Class: Butyrophenone
HUGE QT PROLOGATION RISK
– Have to monitor ECG
Also used for tics & vocal outbursts in Tourette Syndrome

Prolixin
Fluphenazine
High potency
Available in 2-week decanoate formulation

Stelazine
Trifluoperazine
High potency

Navane
Thiothixene
High potency

Loxitane,
Adasuve (inhalation)
Loxapine
Mid potency
Inhalation formulation
– Powder for acute agitation
– Max 10mg /24 hours
– Avail via REMS only b/c brochospasm

Trilafon
Perphenazine
Mid potency

Thorazine
Chlorpromazine
Low potency
Most wt gain of FGA’s

Mellaril
Thioridazine
Low potency
BBW: Significant QT Prolongation

SECOND GENERATION ANTIPSYCHOTICS (SGA’s)

Atypical Antipsychotics

Effect negative, cognitive and positive symptoms

ADRs: Less EPS symptoms but more metabolic changes (weight gain, lipid & glucose abnormalities)

MOA:
– Mod-High Da: High 5HT Antagonism

Abilify,
Maintena (IM Qmonthly)
Aristada (IM Q4-6weeks)
Aripriprazole (take QAM)
Tablets, ODT, IM (acute agitation)
MOA: Unique b/c it’s a partial agonist
ADRs: Akathisia, anxiety, insomnia (take QAM), Constipation
LESS WEIGHT GAIN / Metabolic effects
Also approved for autism irritability

Saphris
Asenapine
Sublingual only (ODT)
-Eat/drink w/in 10 min reduces F
ADRs: Somnolence, tounge/mouth numbness, EPS, QT prologation
LESS METABOLIC CHANGES

Fanapt
Iloperidone
Caution: CYP2D6 poor metabolizers
ADRs: Somnolence, dizziness, orthostasis, tachycardia, QT prologation
Titrate slowly!!!

Latuda
Lurasidone
ADRs: Somnolence, EPS, dystonias, nausea, agitation, akathisia
LESS METABOLIC CHANGES (NEARLY NEUTRAL)
Take with food >/= 350 Kcal

Zyprexa,
Zydis ODT,
Relprevv IM
Olanzapine (Take QHS)
IM Injection for acute agitation
Relprevv suspension lasts 2-4 weeks
– Only via REMS program
BBW: Sedation (coma), delirium after Zyprexa Relprevv (must monitor for 3 hours post injection)
ADRs: Somnolence, EPS, QT prolongation (lower risk)
Avoid in 1st episode b/c of wt gain
MOST WEIGHT GAIN / METABOLIC CHGS
Smoking reduces drug levels

Invega,
Invega Sustenna (IM Qmonthly)
Invega Trinza (IM Q3months)
Paliperidone
Active metabolite of Risperidone
OROS delivery
– enables QD dosing
– get ‘ghost tab’ in poo
ADRs: Increased prolactin (sexual dysfxn), EPS (higher doses), QT prolongation
MODERATE METABOLIC CHANGES
F is increased when taken w food

Seroquel (& XR)

IR: BID (+/-food)
XR: take QHS (no food)

Quetiapine
ADRs: Somnolence, orthostasis, QT prolongation (less risk)
LITTLE RISK OF EPS (use for Parkinson’s)
HIGH METABOLIC CHANGES
XR – take w/o food or light meal (<300cal)

Risperdal,
Risperdal M-Tab ODT
Risperdal Consta (2 wk injection)

Do not mix oral soln with tea or soda

Risperidone
ADRs: Somnolence, ESP (high doses), increased prolactin (sexual dysfxn), orthostasis, QT prolongation.
MODERATE METABOLIC CHANGES
Also approved for autism irritability
Note: > 6mg increases risk for increased prolactin & EPS

Geodon,
Geodon injection

Has active metabolites and is the only one not metabolized by CYPs

Ziprasidone
BID or acute agitation injection (IM)
CI: QT prologation / QT risk
ADRs: Somnolence, RTIs, H/N/dizziness
LESS METABOLIC CHANGES
HIGHEST RISK: QT PROLOGATION
Take with food
Weird that is it metabolized via aldehyde oxidase (not CYPs like all others)

Clozaril,
FazaClo ODT,
Versacloz suspension

3rd line: only take if have failed 2 antipsychotics or had significant ADRs
(1 has t/b an SGA)

Clozapine
MOA: Low Da: High 5HT Antagonism
DECREASED RISK FOR EPS
HIGH METABOLIC CHANGES
BBW (4): Fatal agranulocytosis, Tachycardia /cardiomyopathy, Increased mortality in elderly, Seizures (start at 12.5mg & titrate up slowly)
Therapeutic [serum]=350ng/mL
Check plasma level b4 exceeding 600 mg
ADRs: Sialorrhea (drooling), metabolic changes, QT prolongation
REMS PROGRAM (Clozaril Registry)
In order to begin taking
– WBC >/= 3500 &
– ANC >/= 2000
Monitor: Qwk for 6 mo, then Q2wks for 6 mo, then Qmonthly
Smoking reduces drug levels

NEW AGENTS:
Rexulti & Vraylar
Brexpiprazole (Rexulti)
Cariprazine (Vraylar)
Partial agonists
Much lower ADR
Very little or not orthostasis
Very little metabolic changes
Lower QT prologation (none for Vraylar)

DEPOT MEDS: HOW TO START
For non-adherant patients
Long-acting injectable IM antipyschotics are not 1st line
1st: stabilize pt on oral dosage of same agent (at least short trial of 3-7 days) to make sure pt is tolerant

Fluphenazine Decanoate
Give 1.2x PO daily dose for stable pts
– Round to nearest 12.5mg interval
– 1st 4-6 wks Z-track IM method Qweekly
Then Q2-3weeks
Overlap w PO for 1 week

Note: Give 1.6x PO daily dose for more acutely ill pts

Haloperidol (Haldol Decanoate)
Give 10-15x PO daily dose
– Round to nearest 50mg interval
– Z-track IM method Qmonthly
Overlap w PO for 1 month

OR: 20x PO daily dose; divided into 100-200mg dose Q3-7days until entire amount given (no PO overlap)

Paliperidone Palmitate (Invega Sustenna)
Day 1: 234mg IM (deltoid or gluteal)
Day 8: 156mg IM
Then Qmonthly
No PO overlap
Titrate monthly doses btwn 39-234mg

NEW: Paliperidone (Invega Trinza)
Q3months
Have to be on Sustenna for 4 months before can use this

Risperidone (Risperdal Consta)
1st dose: 25mg deep IM + PO
Then 25-50mg deep IM Q2weeks
Give PO at least 3 weeks concurantly
Dose adjust no more than Q4weeks

Olanzapine Pamoate (Zyprexa Relprevv)
Gluteal injection Q2-4 weeks
BBW: post-injection sedation /delirium
REMS: must give in registered HC facility & be observed for 3 hours

IM FORMULATIONS USED TO CALM AGITATED PATIENTS
Aripiprazole (Abilify)
Haloperidol (Haldol)
Olanzapine (Zypreza)
Ziprasidone (Geodon)

Lorazapam (2mg IM PRN)

Note: DO NOT GIVE THIS COMBO due to hypotention /CNS depression /respiratory depression /death
– Injectable Lorazapam + Olanzapine or Clozapine

Polymorphic Metabolism susceptibility

Metabolized via CYP2D6
– some are poor metabolizers of this

FGAs
– Fluphenazine (Prolixin, Permitil)
– Perphenazine (Trilafon)

SGA
– Risperidone (Risperdal)

ADVERSE EFFECT DETAIL & TX

AUTONOMIC NERVOUS SYSTEM
Impaired memory, Dry mouth, Constipation, Tachycardia, Blurred vision, Ejaculation inhibition, Urinary retention

Tx of dry mouth
Increase fluids / oral lubricants / ice chips
Sugarless gum / hard candy

Tx of constipation
Increase exercise / fluids / fiber

CENTRAL NERVOUS SYSTEM
Extrapyramidal Symptoms (EPS)
– Dystonia
– Akathisia
– Pseudoparkinsonism
– Tardive dyskinesia
Sedation
Seizures
Hyperpyrexia / Hypothermia
Neuroleptic Malignant Syndrome (MNS)
– A medical emergency

Dystonia
Abnormal tonicity / severe muscle spasm
Tx: IM /IV anticholinergics or BZDs
– Benzotropine
– Benedryl
– Diazapam
– Lorazapam

Akathisia
Inability to sit still
Tx: reduce dose / switch to different med
– Anticholinergics, BNZs
– BBs (propranolol / nadolol / metoprolol)

Lowest risk: Clozapine / Quetiapine

Psuedoparkinsonism
Too much Da blockade in nigrostriatum
Tx: Anticholinergics & Amantadine
– Benzotropine
– Benedryl
– Trihexyphenidyl

Tardive Dyskinesia
Abnormal involuntary movements

Prevention: regular neurologic exams
– baseline & quarterly
– Or use Clozapine

Most sedating antipsychotics
Chlorpromazine (Thorazine)
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Quetiapone (Seroquel)
Thioridazine

Seizures
All have high risk but highest risk
– Chlorpromazine & Clozapine

Lowest risk
– Fluphenazine (Prolixin, Permitil)
– Haloperidol (Haldol)
– Pimozide (Orap)
– Thioridazine
– Trifluperazine (Stalazine)
– Risperidone (Risperdal)

Neuroleptic Malignant Syndrome (NMS)

Most important CNS ADR
A medical emergency

0.5-1% of patients
Increased risk in FGAs
Decreased risk in SGAs
SS develop quickly over 24-72 hours
Fever (100.4 / 38) /altered consciousness
Autonomic dysfxn / rigidity
Labs: Leukocytosis, Increased SCr/ liver enzymes/lactate/myoglubulinuria.
Have to D/C drug immediately!!! & provide supportive care

Tx: Bromocriptine (reduce rigidity & fever)
– Amantadine
– Dantroline (sk muscle relaxant)

ENDOCRINE SYSTEM
Hyperprolactinemia (Da antagonism)
– Galactorrhea / menstral irregularities
Weight gain (5HT antagonism)
Hyperglycemia / DM

Lowest risk of weight gain
Aripiprazole (Abilify)
Asenapine (Saphris)
Lurasidone (Latuda)
Ziprasidone (Geodon)

Highest risk of weight gain
Olanzapine (Zyprexa)
(Also Clozapine & Quetiapine)

Highest risk of new onset DM
Clozapine (Clozaril)
Olanzapine (Zyrexa)

Tx
Weigh reducing agents,
Dietary restriction,
Exercise &/or
Behavior modification programs

CARDIOVASCULAR SYSTEM
Orthostatic hypotension
ECG changes
– QT prolongation
Sudden cardiac death

Highest risk of orthostatic hypotension

To reduce, titrate up over several days very slowly

Clozapine (Clozaril)
Iloperidone (Fanapt)
Quetiapine (Seroquel)
Risperidone (Risperdal)

Highest risk of ECG changes
Clozapine (Clozaril)
Haloperidol (Haldol)
– BBW for QT prologation w high IV dose)
Iloperidone (Fanapt)
– Can have polymorphic metabolism (M)
– Increased risk in CYP2D6 poor M
Thioridazine
– BBW for QT prologation
Ziprasodone (Geodon)

Also women are at higher risk

LIPID CHANGES
Elevated TGs & cholesterol
Metabolic syndrome
– TG > 150
– Low HDL
– Fasting blood glucose > 100
– HTN
– Waist circumference
– Men > 40, Women > 35

Lower risk of elevated TGs & cholesterol
Aripiprazole (Abilify)
Asenapine (Saphris)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Risperidone (Risperdal)
Ziprasidone (Geodon)

GENITOURINARY SYSTEM
Urinary hesitancy / retention
Urinary incontenence (esp clozapine)
Sexual dysfunction

Urinary hesitancy / retention
Secondary to anticholinergic effects & alpha blockade

Higher risk with FGAs & Clozapine

Sexual dysfunction
From Da blockade & hyperprolactinemia

Higher risk with FGAs & Risperidone

HEMATOLOGIC SYSTEM
Leukemia (transient)
Agranulocytosis

Leukemia (transient)
Higher risk with (D/C if WBC < 3000) - Chlorpromazine (Thorazine) - Clozapine (Clozaril) - Olanzapine (Zyprexa)

Agranulocytosis
Higher risk with FGAs &
– Chlorpromazine (Thorazine)
– Thioridazine

Usually seen w/in 8 weeks
SS: local infection, sore throat, leukopenia, erythema, pharynx ulcers

DERMATOLOGIC SYSTEM
Allergic rxns (rare)
Contact dermatitis
Photosensitivity
Discoloration of skin exposed to sun
– mostly with ‘phenothiazines’ b/c they absorb UV light

Chlorpromazine – blue/gray/purple skin coloration in areas exposed to sun

PREGNANCY / LACTATION
FDA Safety Announement 2011: Increased risk of neonatal EPS & withdrawal symptoms if exposed to FGAs in 3rd trimester

Also, these meds appear in breastmilk

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