PA 644 - M2 Lectures

Antipsychotic
Pharmacotherapy
Nicole Romstadt, PharmD

Psychiatric Clinical Pharmacy Specialist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Learning Objectives
• Describe the mechanisms of action for first and second generation

antipsychotics. Then, explain how activity at these receptors contributes to
both desirable and undesirable antipsychotic effects.
• Discuss the common and serious adverse effects associated with first and
second generation antipsychotics.
• Describe the role of long-acting injectable antipsychotics in the treatment of
schizophrenia and related disorders.
• Identify monitoring parameters and adverse effects associated with the use
of clozapine.
Common Antipsychotic Target Symptoms
Positive Symptoms Mania Symptoms

• Delusions • Grossly elevated mood
• Hallucinations • Increased energy/decreased sleep
• Auditory, visual, tactile • Racing thoughts
• Disorganized thinking • Grandiosity
• Irritability/agitation
• Example: Schizophrenia, • Impulsivity/risky behaviors
schizoaffective disorder, etc.
• Example: Bipolar disorder
Common Off-Label Uses
Potentially Inappropriate Indications

• Avoid routine use for these indications:
• Insomnia
• Anxiety disorders
• Post-traumatic stress disorder
• Behavioral and psychological symptoms of dementia
• Delirium
• Acute agitation
• If used, must frequently review the appropriateness, safety and need for
continuation
Brief Review of Pathophysiology
Schizophrenia Spectrum and Other Psychotic Disorders

• Exact mechanism is unknown
• Dopamine (DA) hypothesis
• Most recognized theory
• DA hyperfunction in limbic system leads to positive symptoms
• DA hypofunction in prefrontal cortex leads to negative symptoms
• Other implicated neurotransmitters
• Serotonin, glutamate, GABA, acetylcholine
Antipsychotic Mechanism of Action
Class Commonality
• Dopamine antagonism
• Prevents dopamine from acting
at post-synaptic D2 receptors
• Action in mesolimbic pathway
treats positive symptoms
• Requires approximately
60-70% dopamine blockade
• Higher blockade increases risk
for adverse effects
Dopamine Pathways
Dopamine Pathways
Mesolimbic pathway Nigrostriatal pathway

• Controls movement
• Emotional center related to arousal,
• D2-antagonism leads to extrapyramidal
memory, motivation, reward symptoms (EPS)
• Excess DA contributes to psychosis
• D2-antagonism relieves positive Mesocortical pathway
symptoms
• Controls cognition, communication,
executive functioning
Tuberoinfundibular pathway • Decreased DA levels contributes to
negative symptoms
• Innervates pituitary gland • D2-antagonism may worsen negative
• D2-antagonism leads to elevated symptoms
prolactin
Mechanism of Action
Class Variability
• Other receptor involvement
• 5HT2A antagonism is the commonality with SGAs
• May also act as antagonists at ⍺1, H1, M1
• Receptor affinity and activity varies between agents
• May account for either desirable or adverse effects
Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.

Mechanism of Action – Key Receptors
Receptor Mechanism Clinical Effects

D2 Antagonist • Decrease in positive symptoms, mania
• EPS, hyperprolactinemia, cognitive impairment
5HT2A Antagonist • Antidepressant, improvement in negative symptoms
• Reduced EPS
⍺1 Antagonist • Decrease in adrenergic outflow (hyperarousal)
• Orthostasis, reflex tachycardia
H1 Antagonist • Sedation, confusion, falls, weight gain
M1 Antagonist • Decrease in EPS
• Anticholinergic effects (dry eyes, mouth, constipation,
confusion, falls, urinary retention, delirium, etc.)
Pharmacotherapy Overview
Considerations when selecting medications

• Goals of treatment
• Barriers to adherence
• Consequences of non-adherence
• Individual medication properties
• Adverse effect profiles
• Cost and availability
Goals of Treatment
Phase 1 - Acute Stabilization Phase 3- Maintenance and Relapse

• Reduce threat to self and others Prevention
• Reduce acute psychotic symptoms • Achieve symptom control and
• Improve functioning remission
• Improve social and occupational
Phase 2- Stabilization functioning
• Reduce remaining positive, negative • Continue to promote adherence
and cognitive symptoms and address potential barriers to
• Promote adherence adherence
• Minimize and treat adverse effects
Practice Guidelines for the Treatment of Patients With Schizophrenia. American Psychiatric Association, 2004.
Barriers to Adherence
Patient Factors Environmental Factors

• Medication beliefs and biases • Social stigma
• Education regarding mental • Unstable living environment
illness and medication role • Complex healthcare system
• Lack of perceived efficacy • Medication cost and availability
• Intolerable side effects
• Severe symptoms,
disorganization, poor insight
• Forgetfulness
Consequences of Non-Adherence
• Suboptimal response to treatment

• Functional decline and increased risk for relapse
• Develop treatment resistance
• Kindling effect
• Increased hospitalizations and healthcare burden
• Polypharmacy and complex medication regimens
Schizophrenia Treatment Algorithm
DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014

Schizophrenia Treatment Algorithm
DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014

First Generation Antipsychotics
First Generation – “Typical” Class Characteristics

• Chlorpromazine (Thorazine®) • Increased incidence of EPS
• Fluphenazine (Prolixin®) • More potent D2 antagonism
• Haloperidol (Haldol®) • Lower incidence of metabolic ADEs
• Loxapine (Loxitane®) • May worsen negative symptoms
• Perphenazine (Trilafon®) • Result of D2 antagonism in
mesocortical pathway
• Thioridazine (Mellaril®)
• Lack of 5HT2A antagonism
• Thiothixene (Navane®)
• Trifluoperazine (Stelazine®)
FGA D2 Potency Comparison
Low Potency Mild Potency High Potency

Chlorpromazine Loxapine Haloperidol
Thioridazine Perphenazine Fluphenazine
Thiothixene
Trifluoperazine
• Higher doses needed • Lower doses needed for

for antipsychotic effect antipsychotic effect
• Higher incidence of • Higher incidence of
anticholinergic effects, movement-related side
sedation, orthostasis effects
FGA Dosing
Medication Average Typical Max. Daily Special Considerations
Daily Dose Dosing Dose
Chlorpromazine 200-600 mg BID-QID 1000 mg Sedation, anticholinergic, orthostasis
Fluphenazine <20 mg TID-QID 40 mg High incidence EPS
Haloperidol <30 mg BID-TID 100 mg High incidence EPS
Loxapine 20-100 mg BID-QID 250 mg
Perphenazine 8-64 mg BID-QID 64 mg
Thioridazine 50-800 mg BID-QID 800 mg BBW for QTc prolongation
Thiothixene 20-30 mg BID-TID 60 mg
Trifluoperazine 15-20 mg BID 40 mg CI in liver disease
FGA Dosing Considerations
Initiation
• Initiate at low dose and titrate slowly
• Doses are often given 2-4 times per day to improve tolerability
• Less frequent dosing can be trialed once patient is tolerating
• Treatment-naïve patients are at increased risk for adverse effects/EPS
Discontinuation
• Taper over weeks to months to reduce risk for withdrawal and relapse
Black Box Warning
All Antipsychotics
• “Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. [Drug] is not approved for the
treatment of patients with dementia-related psychosis”
Adverse Effects
Extrapyramidal Symptoms (EPS)

• Akathisia
• Dystonia
• Pseudoparkinsonism
• Tardive Dyskinesia
Adverse Effects - EPS
Akathisia
Clinical Presentation • Inability to be still
• Internal restlessness
Mechanism • Unknown
• Related to dopaminergic effects of antipsychotics
Prevention • Initiate at low dose
Management • Discontinue or reduce dose
• Propranolol 30-120 mg/day in divided doses
Acute Dystonic Reaction

Clinical Presentation • Involuntary contraction of skeletal muscle
• Buccal spasms, oculogyric crisis, facial grimacing, trismus
• Onset within days of initiation
Mechanism • Rapid antagonism of D2 receptors in basal ganglia
• Prophylactically initiate anticholinergic or antihistamine
• Avoid IM injections
• Benztropine 1-2 mg IM
• Diphenhydramine 25-50 mg
Pseudoparkinsonism
Clinical Presentation • Slowing of voluntary muscle movements (bradykinesia)
• Muscle rigidity (cogwheel)
• Tremor at rest (pill-rolling)
• Shuffling gait, stooped posture
Mechanism • D2-antagonism in nigrostriatal pathway
• Benztropine 1-5 mg/day
• Trihexyphenidyl 5-15 mg/day
• Diphenhydramine 25-150 mg/day
Tardive Dyskinesia (TD)

Clinical Presentation • Stereotypical, irreversible involuntary movements
• Includes lip smacking, lateral jaw, tongue movements
• Purposeless movements of neck, trunk and/or extremities
• Later symptom onset; may be months-years after initiation
Mechanism • Possible result of DA hypersensitivity
• Secondary to prolonged D2-antagonism
• Thought to be worsened with prolonged anticholinergic use
Prevention • Minimize antipsychotic exposure
• Attempt periodic gradual dose reductions
• Avoid prolonged anticholinergic use
Tardive Dyskinesia (TD)

Management • Discontinue the suspected antipsychotic
• Consider switching to clozapine
• Attempt to reduce anticholinergic
• Provide supportive treatments
• Valbenazine (Ingrezza®) recently approved by FDA
Monitoring • Abnormal Involuntary Movement Scale (AIMS)
• Every 3-6 months with FGA
• Every 6-12 months with SGA
Adverse Effects
Neuroleptic Malignant Syndrome

Clinical Presentation • Muscle rigidity (Elevated CK)
• Autonomic instability (Elevated HR, BP, Temp)
• Altered mental status
• Onset days to weeks after initiation
Prevention • Use minimum dose of antipsychotic
• Avoid neuroleptic polypharmacy
• Minimize use of IM injections (higher risk)
Management • Discontinue all antipsychotics
• Provide supportive care
• Dopamine agonist – bromocriptine, amantadine
• Skeletal muscle relaxant - dantrolene
Adverse Effects
Cardiovascular
• Clinical presentation
• Orthostatic hypotension (⍺1 antagonism)
• Higher incidence with clozapine,
iloperidone, risperidone, quetiapine
• Initiate at low doses, titrate slowly
• QTc interval prolongation
• Torsades de Pointes (TdP)
• Thioridazine has BBW
• Dose-dependent increase
Nielsen J, et al. CNS Drugs. 2011;25:473–490.
Adverse Effects
Cardiovascular
• Monitoring
• ECG at baseline, then annually
• Consider ECG with addition of
QTc-prolonging medications,
dose increases, etc.
• Serum K+, Mg2+ at baseline and
as clinically indicated
Nielsen J, et al. CNS Drugs. 2011;25:473–490.

Adverse Effects
Hyperprolactinemia
• Men: Ejaculatory/erectile dysfunction, galactorrhea, decreased libido
• Women: Amenorrhea, galactorrhea, decreased libido
• Decreased BMD (osteopenia, osteoporosis)
• Increased risk with higher D2 affinity (Includes SGA risperidone)
• Monitoring
• Prolactin level, if clinically indicated
• Not routinely monitored, as prolactin level does not correlate with symptoms
Adverse Effects
Anticholinergic
• Dry mouth, eyes, throat, urinary retention, constipation
• Blurred vision, worsening of glaucoma
• Confusion, delirium, falls (particularly in geriatrics)
Others
• Incidence generally rare and varies between agents
• Transient elevation in LFTs
• Hematologic, Ophthalmologic, Dermatologic reactions
• Lower seizure threshold
FGA Adverse Effect Comparison
Medication Sedation Anticholinergic EPS Hypotension
Chlorpromazine High High Low Moderate
Fluphenazine Low Low Very high Low
Haloperidol Very low Very low Very high Very low
Loxapine Moderate Low Moderate Moderate
Perphenazine Low Low High Low
Thioridazine High High Low High
Thiothixene Low Low High Low
Trifluoperazine Low Low High Low
Second Generation Antipsychotics
Second Generation – “Atypical”

• Aripiprazole (Abilify®) • Paliperidone (Invega®)
• Asenapine (Saphris®) • Quetiapine (Seroquel®)
• Brexpiprazole (Rexulti®) • Risperidone (Risperdal®)
• Cariprazine (Vraylar®) • Ziprasidone (Geodon®)
• Clozapine (Clozaril®)
• Iloperidone (Fanapt®)
• Lurasidone (Latuda®)
• Olanzapine (Zyprexa®)
Second Generation Antipsychotics
Class Characteristics
• Less potent D2 antagonism, shorter duration of receptor occupancy
• Lower incidence of EPS
• 5HT2A antagonism is common mechanism in this class
• Potentially improves negative symptoms (Controversial results)
• Increased incidence of metabolic effects
• Newer agents exhibit D2 partial agonism
• Aripiprazole, brexpiprazole, cariprazine
• Reduces DA neurotransmission, without complete antagonism
• Allows for minimal DA transmission in nigrostriatal, which reduces EPS
SGA Dosing
Aripiprazole 20-30 mg Daily 30 mg Partial D2 agonism
Higher incidence of akathisia
BBW for SI in children-adolescents
Asenapine 10-20 mg BID 20 mg Do not eat or drink within 10 mins
Only available as SL
Brexpiprazole 1-4 mg daily 4 mg Partial D2 agonism
Cariprazine 1.5-6 mg daily 6 mg Partial D2 agonism
Clozapine 300 – 450 mg daily 900 mg REMS program
Iloperidone 12 – 24 mg BID 24 mg Cardiovascular effects

SGA Dosing
Lurasidone 20-120 mg Daily 160 mg Take with 350 calories

Olanzapine 10-15 mg Daily 20 mg BBW for post-injection delirium/
sedation syndrome (PDSS) with LAI
Paliperidone 3-6 mg Daily 12 mg Metabolite of risperidone
Quetiapine 400-800 mg Daily-BID 800 mg BBW for SI in children-adolescents
Risperidone 4-6 mg Daily 16 mg Orthostasis, hyperprolactinemia
Ziprasidone 80-160 mg BID 160 mg Take with 500 calories

Adverse Effects
Overlap with FGAs

• Many FGA adverse effects also occur with SGAs
• Overall less EPS and more metabolic adverse effects with SGAs
Metabolic Effects
• Hyperlipidemia
• Weight gain
• Glucose intolerance, DM2
• Hypertension
Adverse Effects
Metabolic Effects
• Monitoring
• Consensus guidelines from the American Diabetes Association, the American
Psychiatric Association, the American Association of Clinical Endocrinologists,
and the North American Association for the Study of Obesity
American Diabetes Association. Diabetes Care. 2004;27(2):596-601.

Adverse Effect Comparison
Medication Sedation Anticholinergic EPS Weight Glucose Lipid
Gain Intolerance Elevation
Aripiprazole Low Low Low Very low Low Very low
Clozapine High High Very low Very high High High
Lurasidone Low Low Low Very low Low Low
Olanzapine Moderate Moderate Low High High High
Paliperidone Low Low High Moderate Moderate Low
Queitapine High Moderate Very low High High High
Risperidone Low Low High Moderate Moderate Low
Ziprasidone Low Low Low Very low Low Very low
Drug Interactions
Pharmacodynamic
• Additive properties of 2+ medications
• Anticholinergic (cognitive impairment, delirium, constipation, etc.)
• Over-sedation (falls, drowsiness)
• QTc prolongation, etc.
Drug Interactions
Pharmacokinetic
• CYP Interactions (both generations)
• APs are primarily metabolized via CYP1A2, 2D6 and 3A4
• Dose reductions may be required with concomitant CYP inhibitors
• May also be required if patient is known poor metabolizer
• Ex. Aripiprazole, brexpiprazole, iloperidone recommend 50% dose
reduction when combined with CYP2D6 and/or 3A4 inhibitors
• Hydrocarbons produced from smoking cigarettes induce CYP1A2
• May reduce levels of clozapine and olanzapine, requiring dose adjustments
if smoking status changes
Antipsychotic Conversion
Oral Conversion Strategies

• Discontinue old medication and initiate the new one (no-overlap)
• Increased risk for withdrawal symptoms
• Cannot be done with clozapine
• Initiate new medication at full dose, then taper off old medication
• Increased risk for adverse effects while on two treatment doses
• Slowly cross taper by initiating new medication at low dose, while decreasing
old medication
• Reduces risk for withdrawal or adverse effect symptoms
• Taper length (usually 1-2 weeks) varies based on treatment location (inpatient
vs. outpatient), patient tolerability and response
Long-Acting Injectable Antipsychotics (LAIs)
Goals of Treatment
• Improve adherence to antipsychotics
• It’s estimated that 40-50% of patients are non-adherent to antipsychotics,
which may lead to negative outcomes, including:
• Functional decline
• Relapse and treatment resistance
• Psychiatric hospitalizations
• Increased healthcare costs
Role in Treatment
• Chronic mental illness in patients with history of relapse following oral
antipsychotic non-adherence
• Particularly if patient manages medications independently
• Typically not first-line in antipsychotic naïve patients
• Oral formulations more easily titrated and less expensive
• Patients preferring injectable agent versus oral agent
Bartolomeis A, et al. Neuropsychiatr Dis Treat. 2016;12:99-108.

Available Agents
• First Generation Antipsychotics
• Fluphenazine decanoate
• Haloperidol decanoate
• Second Generation Antipsychotics
• Risperidone (Risperdal Consta®)
• Paliperidone (Invega Sustenna®, Invega Trinza®)
• Olanzapine (Zyprexa Relprevv®)
• Aripiprazole (Abilify Maintena®, Aristada®)
First Generation LAIs
Medication Dosing Oral Overlap Considerations

Fluphenazine • Starting dose = 1.25x PO • Continue • Deltoid or gluteal
decanoate dose until 2nd LAI IM injection
• Maintenance = 12.5-100 dose • Z-track technique
mg IM every 2-4 weeks
Haloperidol • Starting dose = 10-15x PO • Continue • Deltoid or gluteal

decanoate dose until 2nd LAI IM injection
• 50-200 mg IM every 4 dose • Z-track technique
weeks • Give as two
injections for doses
>100 mg
Second Generation LAIs

Aripiprazole lauroxil • Starting dose based on oral • 21-day oral • Adjust dose for
(Aristada®) • 441 mg, 662 mg, or 882 mg aripiprazole CYP2D6 and/or 3A4
IM q4-6 weeks interactions
• Deltoid or gluteal
Aripiprazole • Standard dose is 400 mg; • 14-day oral • Adjust dose for
monohydrate dose reduced if DDIs aripiprazole CYP2D6 and/or 3A4
(Abilify Maintena®) • 200 mg, 300 mg, 400 mg or other AP interactions
IM qmonth
• Deltoid or gluteal

Olanzapine pamoate • Starting dose based on oral • None • REMS program
(Zyprexa Relprevv®) • 210 mg, 300 mg, 405 mg • Provider, patient
IM q2-4weeks and facility must be
• Gluteal registered
Paliperidone • Loading sequence of • None • Detailed directions

palmitate 234 mg, then 156 mg in package insert
(Invega Sustenna®) • 39 mg, 78 mg, 117 mg, regarding
156 mg, 234 mg IM requirements for
qmonth missed doses
• Deltoid (initial) then either
deltoid or gluteal

Paliperidone • Starting dose based on • N/A • Must be stable on
palmitate current Invega Sustenna® monthly LAI
(Invega Trinza®) maintenance dose formulation for at
• 273 mg, 410 mg, 546 mg, least 4 months,
819 mg IM q3months then transition
• Deltoid or gluteal directly to Trinza®
Risperidone • Starting dose 12.5-25 mg • 21-day oral • Microsphere
microspheres • 12.5 mg, 25 mg, 37.5 mg, risperidone release is delayed
(Risperdal Consta®) 50 mg IM q2weeks or other AP 3-weeks post
• Deltoid or gluteal injection
Clozapine (Clozaril®)
Treatment Resistant Schizophrenia

• Lack of significant symptom improvement despite adequate trials (dose, duration,
adherence) of at least two antipsychotics (at least one SGA)
Clozapine
• Guidelines recommend clozapine for “patient who has had no response or partial
and suboptimal response to two trials of antipsychotic medication or for a patient
with persistent suicidal ideation or behavior that has not responded to other
treatments”
• Evidence has consistently shown clozapine to be superior to other antipsychotics in
this patient population
Practice Guidelines for the Treatment of Patients With Schizophrenia. American Psychiatric Association, 2004.
Mechanism of Action
• Low potency at D2 receptor and high affinity for 5HT2A
• Very low EPS and may improve TD
• Antagonism at ⍺1, H1 and M1 contributes to significant side effect profile
Receptor Mechanism Clinical Effects
⍺1 Antagonist • Decrease in adrenergic outflow (hyperarousal)
• Orthostasis, reflex tachycardia
H1 Antagonist • Sedation, confusion, falls, weight gain
M1 Antagonist • Decrease in EPS
• Anticholinergic effects (dry eyes, mouth, constipation,
confusion, falls, urinary retention, delirium, etc.)
Black Box Warnings

• Dementia-related mortality
• Severe neutropenia
• Orthostatic hypotension
• Myocarditis
• Seizures
Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Mitigating Severe Adverse Effects

• Dose-related effects
• Neutropenia, orthostatic hypotension, bradycardia, syncope, seizures
• Initiating at low doses and slow titration reduces risk
• Titration
• Initial dose of 12.5 mg 1-2 times per day
• Increase total daily dose (TDD) by 25-50 mg per day, as tolerated
• Goal of 300-450 mg divided 2-3 times per day
• Must restart dose titration if interruption in therapy ≥ 2 days
Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Risk Evaluation and Mitigation Strategy (REMS) Program

• Patient, prescriber and pharmacy must be registered
• Outlines absolute neutrophil count (ANC) monitoring requirements
• Once weekly for first 6 months
• Every-other-week after 6-12 months
• Once monthly after 12 months
Clozapine REMS Program website (www.clozapinerems.com)



Other Adverse Effects

• High incidence of metabolic effects and lowest incidence of EPS
• Constipation
• Consider prophylactic bowel regimen
• Sialorrhea
• May require pharmacotherapy if bothersome to patient
• Sublingual anticholinergic - ipratropium nasal spray or atropine eye drops
• Oral anticholinergic - benztropine or oxybutynin
Cost Considerations
Medication Generic Example Average Wholesale
Dosing Price for 30DS
Chlorpromazine Yes 100 mg BID $892
Fluphenazine Yes 5 mg BID $72
Haloperidol Yes 10 mg BID $107

Cost Considerations
Aripiprazole Yes 20 mg daily $1362
Asenapine No 10 mg BID $1316
Brexpiprazole No 3 mg daily $1211
Cariprazine No 4.5 mg daily $1316
Clozapine Yes 100 mg BID $205
Iloperidone No 10 mg BID $2364

Cost Considerations
Lurasidone No 80 mg daily $1336
Olanzapine Yes 10 mg daily $596
Paliperidone Yes 6 mg daily $916
Quetiapine Yes 400 mg BID $1195
Risperidone Yes 4 mg daily $456
Ziprasidone Yes 60 mg BID $645

Antipsychotic DementiaDementia
Pharmacotherapy
Nicole Romstadt, PharmD

Psychiatric Clinical Pharmacy Specialist
Substance Abuse Disorders:
Alcohol,Tobacco, Opiates
Gretchen L. Johnson, Pharm.D., BCPS

Substance Abuse Pharm:
Alcohol
Acute Alcohol Withdrawal
• BZDs are first-line due to cross-tolerance with alcohol
• Symptom triggered BZD treatment is the standard of care to
minimize sx and avoid progression to more severe stages of
withdrawal (seizures, delirium)
– Results in shorter treatment duration and less risk of
oversedation
• All BZDs equally efficacious, but Lorazepam (Ativan) is preferred
due to multiple routes of administration (PO, SL,IV, IM) with
predictable results
– Lorazepam 2mg PO/IM/IV q 1 hour PRN withdrawal sx.
– Sx. assessed via a validated rating scale- Clinical Institute
Withdrawal Alcohol-Revised
• Anticonvulsants are not required to treat alcohol withdrawal sz.
unless progresses to status epilepticus
• Supportive care with IV fluids, thiamine, MVI, electrolytes
– Watch for low K, Mg, PO4
Chronic Alcohol Abuse
• Pharmacologic Management of Alcohol Dependence
– Disulfiram (Antabuse)- Deterrent
– Naltrexone (ReVia)- Anticraving
– Naltrexone IM depot (Vivitrol)- Anticraving
– Acamprosate (Campral)- Anticraving
Disulfiram (Antabuse)
• Deters a pt. from drinking by producing a negative reaction when alcohol
is consumed
• MOA: Inhibits aldehyde dehydrogenase in alcohol metabolism which

results in an accumulation of acetaldehyde. Acetaldehyde causes
disulfiram reaction
– N/V, flushing, throbbing HA, palpitations, CP, weakness, tachycardia,
blurred vision, confusion, hypotension
– Can occur up to 7-14 days after the last dose
– The intensity and duration of symptoms are related to the dose, the
amount of ETOH consumed and individual sensitivity
– Can occur with as little as “ml” of ETOH and last 30 min - 2 hrs.
• Fallen out of favor

– Data is mixed as to effectiveness
– Poorly tolerated
Disulfiram (Antabuse)
• Contraindications:
– CAD, severe cardiac disease
– hepatic disease, cirrhosis
– seizure disorders
– schizophrenia
– Hypersensitivity to rubber (thiuram) derivatives
– concomitant use of ETOH or ETOH-containing products
– Metronidazole- causes acute psychosis and confusion
• Side Effects (Usually transient/dose-related)
– GI upset, sedation, rash, garlicky or metallic taste, flushing
– Hepatotoxic- monitor LFTs
• Drug Interactions: Inhibitor of CYP3A4
– May increase and prolong effects of :warfarin, phenytoin, isoniazid,
rifampin. Metronidazole, theophylline
• Pt education:
– Pt must be abstinent before starting- at least 12 hours since last
drink
– OTC meds alcohol content, including topicals
– Medical alert identification
Naltrexone (ReVia)
• MOA: Opiate antagonist that decreases the reinforcing
effects of alcohol
– Decreases cravings and “buzz”
• Efficacy
– More effective than acamprosate in reducing risk of heavy drinking in
nonabstinent pts.
• Pt. must be opiate-free for 7-10 days
– Verify with urine drug screen
• Contraindications: hepatitis/liver failure; lactation; current
opioid use
• Side Effects : nausea (10%), vomiting, cramps, headache
(7%),dizziness, fatigue, constipation, dose-related reversible
hepatotoxicity
• Hepatotoxic- monitor LFTs
• Pregnancy Category C
• Patient Education:
– Medical alert identification
– DC 24-48 hr prior to procedures where opioids are needed
Naltrexone IM (Vivitrol)
• Once monthly IM naltrexone formulation
• Increases compliance/adherence
• Watch for injection site reactions
– Cellulitis, hematoma, abscess
Acamprosate (Campral)
• MOA: glutamate modulator at the NMDA receptor
resulting in dec. craving
• Efficacy:
– More effective than naltrexone in maintaining abstinence
– Combination of acamprosate + naltrexone appears to be
more efficacious than acamprosate alone
• ADRs: >10% = diarrhea, flatulence, syncope, dizziness,
edema, insomnia, anxiety, headache, nausea
• Precautions:
– Moderate renal impairment
• Dec. dose in renal impariment; Not rec. if Clcr < 30ml/min
– Depression/suicidality
– Pregnancy- Category C
Other Off-label Anticraving Agents
• Topiramate (Topamax)
• Baclofen (Lioresal)
• Varenicline (Chantix)
Substance Abuse Pharm: Tobacco
.
Slides adapted and used with permission from Erin Adams PharmD
What ever happened to Joe Camel?
1991
NONPHARMACOLOGIC METHODS
• Cold turkey: Just do it!  Aversion therapy
• Unassisted tapering (fading)  Acupuncture
– Reduced frequency of use therapy
– Lower nicotine cigarettes
– Special filters or holders  Hypnotherapy
• Assisted tapering  Massage therapy
 Apps
PHARMACOLOGIC METHODS:
FIRST-LINE THERAPIES
Three general classes of FDA-approved
drugs for smoking cessation:
 Nicotine replacement therapy (NRT)
 Nicotine gum, patch, lozenge, nasal spray (Rx),
inhaler (Rx)
 Psychotropics
 Sustained-release bupropion (Zyban) (Rx)
 Partial nicotinic receptor agonist
 Varenicline (Chantix) (Rx)
NRT: RATIONALE for USE
Reduces physical withdrawal from

nicotine
Allows patient to focus on behavioral
and psychological aspects of tobacco
cessation
NRT APPROXIMATELY DOUBLES QUIT RATES.

NRT: PRECAUTIONS
Patients with underlying cardiovascular

disease
– Recent myocardial infarction (within past 2 weeks)
– Serious arrhythmias
– Serious or worsening angina
NICOTINE GUM
Nicorette (GlaxoSmithKline); generics
• Sugar-free chewing gum base

• Contains buffering agents to enhance buccal
absorption of nicotine
• Available: 2 mg, 4 mg; regular, FreshMint,
Fruit Chill, Orange & Cinnamon Surge
NICOTINE GUM: DOSING
Dosage based on current smoking
patterns:
NOTE: dosing difference

NICOTINE GUM:
CHEWING TECHNIQUE SUMMARY
NICOTINE GUM: ADDITIONAL PATIENT EDUCATION
To improve chances of quitting, use at

least nine pieces of gum daily
The effectiveness of nicotine gum may
be reduced by some foods and
beverages:
 Coffee  Juices
 Wine  Soft drinks
Do NOT eat or drink for 15 minutes BEFORE or while

using nicotine gum.
NICOTINE GUM:
ADD’L PATIENT EDUCATION (cont’d)
Chewing gum too rapidly can Side effects of

cause excessive release of nicotine gum include
nicotine, resulting in
– Mouth soreness
– Lightheadedness
– Hiccups
– Nausea/vomiting
– Dyspepsia
– Irritation of throat and mouth
– Jaw muscle ache
– Hiccups
Caution:
– Indigestion
Dental work/aids
Temporomandibula
r Joint (TMJ)
NICOTINE LOZENGE
Commit (GlaxoSmithKline); generics
 Nicotine polacrilex
formulation
– Delivers ~25% more nicotine
than equivalent gum dose
 Sugar-free, mint or cherry
flavor or MINI sized
 Contains buffering agents
to enhance buccal
absorption of nicotine
 Available: 2 mg, 4 mg
– Dissolves
NICOTINE LOZENGE: DOSING
Dosage is based on the “time to first cigarette”
(TTFC) as an indicator of nicotine addiction
NICOTINE LOZENGE:
DOSING (CONT’D)
Recommended Usage Schedule for
Commit Lozenge
Weeks 1–6 Weeks 7–9 Weeks 10–12
1 lozenge 1 lozenge 1 lozenge
q 1–2 h q 2–4 h q 4–8 h
DO NOT USE MORE THAN 24/day
Rotate lozenge
NICOTINE LOZENGE: ADDITIONAL PATIENT EDUCATION
• The effectiveness of the nicotine lozenge

may be reduced by some foods and
beverages:
Wine  Soft drinks

using the nicotine lozenge.
NICOTINE LOZENGE:
Side effects of the nicotine lozenge

include
– Nausea
– Hiccups
– Cough
– Heartburn
– Headache
– Flatulence
– Insomnia
TRANSDERMAL NICOTINE PATCH
Nicoderm CQ (GlaxoSmithKline); generic
 Avoids hepatic first-pass metabolism

 Plasma nicotine levels are lower and
fluctuate less than with smoking
TRANSDERMAL NICOTINE PATCH:
PREPARATION COMPARISON
Product Nicoderm CQ/Generic

Nicotine
24 hours
delivery
Availability OTC
Strengths 7-mg patch
14-mg patch
21-mg patch
TRANSDERMAL NICOTINE PATCH: DOSING
Product Light Smoker Heavy Smoker

Nicoderm CQ 10 cigarettes/day >10 cigarettes/day
Step 2 (14 mg x 6 Step 1 (21 mg x 6
weeks) weeks)
weeks) weeks)
Step 3 (7 mg x 2 weeks)
Generic 10 cigarettes/day >10 cigarettes/day
(formerly Step 2 (14 mg x 6 Step 1 (21 mg x 4
Habitrol) weeks) weeks)
weeks) weeks)
Step 3 (7 mg x 2 weeks)
DIRECTIONS for USE
 Apply adhesive side
– Clean, dry, hairless
and not irritated
– Location
 Rotate
– Press firmly x10 sec
 Wash hands
 Other info:
– OK to shower with patch on
– Do not cut patches
– No more than 24 hours/patch
– Adhesive remaining on skin
– Disposal of used patch
DIRECTIONS for USE (cont’d)
• Side effects to expect in first hour:
– Mild itching
– Burning
– Tingling
• Additional possible side effects:
– Headache
– Vivid dreams or sleep disturbances
• Avoid use in dermatological issues
NICOTINE NASAL SPRAY
Nicotrol NS (Pfizer)
 Aqueous solution of
nicotine in a 10-ml
spray bottle
 Each metered dose
actuation delivers 0.5
mg nicotine
 ~100 doses/bottle
NICOTINE NASAL SPRAY:
DOSING & ADMINISTRATION
• Dose: 1 spray in each nostril

• Start with 1–2 doses per hour
– Maximum : 5 doses/hr or 40 mg daily
• For best results, patients should use at
least 8 doses daily for the first 6–8 weeks
• Termination:
– Gradual tapering over an additional 4–6
weeks
DIRECTIONS FOR USE
• Blow nose (if not clear)

• Prime
– If pump is not used for 24 hours, prime the
pump 1–2 times
• Do not sniff or inhale while spraying

– If nose runs
• Wait 5min
PATIENT EDUCATION
What to expect (first week):

 Hot peppery feeling in back of throat or nose
 Sneezing
 Coughing
 Watery eyes
 Runny nose
Caution
 If side effects do not decrease after a week, contact health care
provider
 Patients with chronic nasal disorders or severe reactive airway
disease should not use the spray
NICOTINE INHALER
Nicotrol Inhaler (Pfizer)
Nicotine inhalation
system consists of
 Mouthpiece
 Cartridge with porous plug
containing 10 mg nicotine
Delivers 4 mg nicotine
vapor
May satisfy hand-to-
mouth ritual of smoking
NICOTINE INHALER
Nicotrol Inhaler (Pfizer)
Nicotine inhalation
system consists of
 Mouthpiece
 Cartridge with porous plug
containing 10 mg nicotine
Delivers 4 mg nicotine
vapor
May satisfy hand-to-
mouth ritual of smoking
NICOTINE INHALER: DOSING
 Start with 6 cartridges/day
 Maximum of 16 cartridges/day
 Use for minimum of 3 weeks, maximum of 12 weeks
 Gradual dosage reduction: if needed over additional 6–12

weeks
NICOTINE INHALER:
NICOTINE INHALER:
DIRECTIONS FOR USE (CONT’D)
• Inhale into back of throat or puff in
short breaths
– Frequent puffing
• Depletion of plug
– Cartridge does not have to be used all at once
– Open cartridge retains potency for 24 hours
NICOTINE INHALER:
ADDITIONAL PATIENT EDUCATION
• Side Effects
– Mild irritation
– Unpleasant taste or cough when first using
the inhaler
• Other (less common) side effects include
– Rhinitis
– Dyspepsia
– Hiccups
– Headache
• Precautions
– Underlying bronchospastic conditions
– Storage
NICOTINE INHALER:
• Effectiveness of the nicotine inhaler

may be reduced by some foods and
beverages
 Wine  Soft drinks

using the nicotine inhaler.
BUPROPION
Zyban (GlaxoSmithKline); Buproban ER
Nonnicotine
cessation aid
Sustained-release
antidepressant
Wellbutrin?
Oral formulation
BUPROPION
• MOA: Atypical antidepressant

thought to affect levels of various
brain neurotransmitters
– Dopamine
– Norepinephrine
• Clinical effects
–  craving for cigarettes
–  symptoms of nicotine withdrawal
BUPROPION:
CONTRAINDICATIONS & WARNINGS
• Contraindications: • Precautions:
– Patients with a seizure – History of seizure/
disorder meds that lower
– Patients taking seizure threshold
• Wellbutrin, Wellbutrin (antipsychotics,
SR, Wellbutrin XL antidep, theophylline,
• MAO inhibitors in systemic steroids
preceding 14 days – Bipolar patients
– Anorexia or bulimia – History of cranial
nervosa trauma
– Abrupt d/c of alcohol or – severe hepatic
sedatives cirrhosis
BUPROPION SR: DOSING
Patients should begin therapy 1 to 2 weeks PRIOR

to their quit date to ensure that therapeutic plasma levels of the
drug are achieved.
Initial treatment
 150 mg po q AM x 3 days
Then…
 150 mg po bid
 Duration, 7–12 weeks
BUPROPION:
ADVERSE EFFECTS
Common side effects:
– Insomnia (avoid bedtime dosing)
– Dry mouth
WARNING: neuropsychiatric symptoms
Less common but reported effects:

– Tremor
– Skin rash
– Suicidal Ideations
VARENICLINE
Chantix (Pfizer)
Nonnicotine
cessation aid
Partial nicotinic
receptor agonist
Oral
formulation
VARENICLINE
• MOA: Binds with high affinity and selectivity at 42
neuronal nicotinic acetylcholine receptors
– Competitively inhibits binding of nicotine

• Clinical effects
–  symptoms of nicotine withdrawal

– Blocks dopaminergic stimulation responsible for
reinforcement & reward associated with smoking
• T1/2 24 hours
VARENICLINE: DOSING
Patients should begin therapy 1 week PRIOR to their

quit date. Can also begin therapy and taper cigarettes in first 12
weeks
Treatment Day Dose
0.5 mg
Day 1 to day 3
Initial qd
dose
0.5 mg
titration Day 4 to day 7
bid
Day 8 to end of treatment* 1 mg bid
* Up to 12 weeks
VARENICLINE:
ADVERSE EFFECTS
• Common: • Post-marketing
– Nausea – Dizziness/falls/loss
– Sleep disturbances (insomnia, of consciousness
abnormal dreams) – Cardiac rhythm
– Constipation disturbances
– Flatulence – Acute MI
– Vomiting – Severe skin
reactions
• Neuropsychiatric symptoms
– Seizures
• Cardiovascular effects – Diabetes
– Spasms
PHARMACOLOGIC METHODS:
Second-line and Future Therapies
Clonidine (Catapres transdermal or

oral)
Nortriptyline (Pamelor oral)
NicVAX Vaccine
Pharmacotherapy Abstinence Rates
Evidence suggests that rates of smoking abstinence

may increase from
• approximately 10% in control groups (placebo or
no pharmacotherapy) to 17% in persons using any
form of NRT
• approximately 11% in control groups (placebo or
no bupropion SR) to 19% in those using bupropion
SR
• approximately 12% in control groups (placebo) to
28% in those using varenicline
COMBINATION PHARMACOTHERAPY
Combination NRT- moderately better than
one NRT product alone
Long-acting formulation (patch)
PLUS
Short-acting formulation (gum, lozenge, inhaler, nasal spray)
Bupropion + NRT- may be better than

Bupropion alone
 Monitor BP
Varenicline + NRT
Varenicline + Bupropion
USE in PREGNANCY
NRT
Category D
Bupropion and
varenicline
Category C
Attempt nondrug
treatment first
Substance Abuse Pharm: Opiates
Methadone Prescribing Laws
• In the treatment of detoxification or maintenance,
methadone can only be used by Opiate Treatment
Programs (OTP) that are accredited by Center for
Substance Abuse Treatment.
• Above is waived if patients are admitted for a life
threatening condition that requires methadone to
stabilize their opioid dependence while in the
hospital
– May prescribe to opioid dependent pt up to 72 hr as
bridge to treatment entry
Office-based opioid treatment
• Evolved after passage of the Drug Addiction Treatment
Act of 2000 (DATA 2000)- Updated with Comprehensive
Addiction and Recovery Act of 2016 (CARA 2016)
• CARA 2016 expanded prescribing for buprenorphine to
PAs and NPs
– Can apply to become waivered to prescribe
buprenorphine for opiate addiction
– Obtain 24 hr training course
– Can treat up to 30 patients in first year with option to
increase to up to 100 patients after 1 year if certain
conditions met
– Defers to state law as to if PA/NP must work with a
physician in a supervisory or collaborative manner
Buprenorphine Pharmacology
• A mu receptor partial-agonist and an antagonist at kappa
receptor
• High affinity for the mu receptor but low efficacy; thus
producing a dose-related response with a ceiling effect
• High affinity for mu may displace other opioids from the
receptor and cause withdrawal sx
– Start in office AFTER pt shows signs of withdrawal
• Partial agonism:
– Does not activate the mu receptor fully, therefore has a ceiling
effect
– Larger doses do NOT lead to greater agonist effect
– 16mg buprenorphine = 60mg methadone
– Methadone is a full agonist and has no ceiling effect
• Greater margin of safety, less respiratory depression
Buprenorphine
• Subutex (buprenorphine): CIII
– Use at beginning of tx to dec. risk of withdrawal
– Available as SL tabs
• Suboxone(buprenorpine/naloxone): CIII
– Use in maintenance management
– Naloxone: added to guard against IV abuse of
buprenorphine
– No effect of naloxone orally or SL - poorly absorbed
– Available as SL tabs and SL film
• Dosed once daily
– Do not chew or swallow- dec. absorption
– Dosage adjustment needed in hepatic impairment
Buprenorphine
• Buprenorphine implant (Probuphine) Schedule III
– New dosage form- 4 subdural rods that are implanted in the inside of
the upper arm every 6 months
• Treatment duration is 12 months
– May address problems with diversion and compliance
– Only for stable patients on <8mg SL buprenorphine daily
– Prescribers must complete a training course in order to prescribe and
implant
– Expensive
Buprenorphine
• Drug interactions:
– Benzodiazepines: potentially fatal interaction- resp
depression
• Avoid use
– Increase effects of buprenorphine (3A4 substrate)
• Antiretrovirals, BZD, fluvoxamine, ketoconzaole, ETOH
– Decrease effects of buprenorphine (3A4 substrate)
• CBZ, phenobarbital, rifampin, phenytoin
• Patient education
– Caution with driving care or operating heavy machinery
– Avoid concomitant alcohol
– Store in a secure area out of reach of children and pets
and avoid theft
Buprenorphine Adverse Effects
• Constipation
• Headache
• N/V
• Sedation
• Hepatotoxicity- get baseline and periodic LFTs
• Precipitate withdrawal
• Pregnancy category C
• Avoid during breastfeeding- passes in to breast milk
Induction, Stabilization, Maintenance
• Generally start with Subutex and give a small supply to pt (usually 2
days)
– If > 1 prescriber with Rx, assume diversion
• Suboxone is preferred for long-term tx
• Determine min amount of buprenorphine required to prevent
withdrawal sx, cravings
• Stabilization lasts 2-3 months at lowest dose
• Length of treatment (maintenance) = at least 6 months but can last
up to 2 yrs.
– Length depends on past instability
– Previous response to tx
Reversal Agents
• Naloxone (Narcan)
– MOA: Opiate receptor antagonist
– Used to reverse opiate effects/overdose
– CARA 2016 expanded use to law enforcement and other first responders
– Some states are now allowing prescribing to third parties to administer in the case of
overdose
– Public health emergency declared in VA- Anyone can get naloxone at a pharmacy for either
themselves or someone else of concern through a standing order from the State Health
Commisioner
– Consider for patients at high risk- on large doses of opiates, opiate plus BZDs, prior h/o
overdose
• Flumazenil (Romazicon)
– MOA: BZD receptor antagonist
– Used to reverse BZD effects/overdose
Attention Deficit/
Hyperactivity
Disorder
Molly Rincavage, PharmD
Objectives
1. Recognize the pharmacology of medications

used to manage ADHD
2. Select a treatment plan for ADHD that
considers patient and agent related
variables
3. Identify an appropriate monitoring plan for
a patient with ADHD, including how to
mitigate adverse effects
Outline
•Review
•Mechanism of Action
•Formulations
•Adverse Effects, Precautions, Contraindications,
Black Box Warnings
•Treatment Guidelines
•Monitoring
•Patient Case
Review
Review
Which of the following is not a core symptom of

ADHD?
A.Inattention
B. Hyperactivity
C. Defiance
D.Impulsivity
Review
True or False: ADHD occurs predominantly

in young, female individuals
Review
Which of the following is not a common comorbidity

in patients with ADHD?
A.Disruptive behavior disorder
B. Hyperthyroidism
C. Mood disorder
D.Anxiety disorder
Mechanism
of
Action
Pharmacologic Classes
Stimulants
• Methylphenidates
• Methylphenidate
• Dexmethylphenidate
• Amphetamines
• Dextroamphetamine
• Levoamphetamine
• Lisdexamfetamine
Non-stimulants
• Selective norepinephrine reuptake inhibitors
• Atomoxetine
• Alpha-2 agonists
• Guanfacine
• Clonidine
Stimulants
• Amphetamines and
methylphenidates
• Block the reuptake of
norepinephrine and
dopamine into the
presynaptic neuron, thus
increasing the
concentrations of these
monoamines in the
extraneural space
Non-stimulants
• Atomoxetine
• Selective norepinephrine
reuptake inhibitor
• Inhibits reuptake of
norepinephrine, thus
increasing concentration in
synaptic cleft
Non-stimulants
• Guanfacine and clonidine

• Alpha 2-adrenergic
receptor agonists
• Increase noradrenergic tone
in prefrontal cortex by
stimulating postsynaptic
alpha-2A receptors
Formulations
Medication Administration at School
ADHD affects a largely pediatric population, which often requires

coverage throughout the school day
There is a stigma associated with taking medication at school
Medication Authorization Form

• Completed by the parent which authorizes the school nurse to
give child medication
• Completed by the practitioner to provide information on the
diagnosis, medication, time, dosage to be dispensed, and
possible side effects
Plasma Concentration Time Profile
Amphetamine Formulations
Formulation Brand Name Available Dosage Duration of Frequency
Forms Action (hours)
Mixed Immediate- Adderall 5, 7.5, 10, 12.5, 15, 4-6 1-3 times daily
release (IR) salts 20, 30 mg tablets
Amphetamine Evekeo 5, 10 mg tablets 4-6 1-3 times daily

sulfate IR
Dextroamphetamine Dexedrine 5, 10 mg tablets 4-6 1-3 times daily
IR
Dextroamphetamine ProCentra 1 mg/ml 4-6 1-3 times daily
IR liquid
Amphetamine Formulations
Formulation Brand Name Available Dosage Forms Duration of Frequency
Action (hours)
Dextroamphetamine Extended- Dexedrine Spansule 5, 10, 15 mg capsules 6-8 Daily
release (ER)
Lisdexamfetamine Vyvanse 20, 30, 40, 50, 60, 70 mg 10-12 Daily
capsules
Mixed Extended-release (XR) Adderall XR 5, 10, 15, 20, 25, 30 mg 10-12 Daily
salts capsules
Amphetamine sulfate XR orally Adzenys-XR- ODT 3.1, 6.3, 9.4, 12.5, 15.7, 12 Daily
disintegrating tablet 18.8 mg tablets
Amphetamine sulfate XR Dyanavel XR 2.5 mg/ml 12 Daily

suspension
Mixed Extended-release (XR) Mydayis 12.5, 25, 37.5, 50 mg 16 Daily
salts capsules
Methylphenidate Formulations
Formulation Brand Name Available Dosage Duration of Frequency

Forms Action (hours)
Immediate-release (IR) Methylin 5, 10, 20 mg tablets 3-6 1-3 times daily
Ritalin
Dexmethylphenidate IR Focalin 2.5, 5, 10 mg tablets 3-6 1-3 times daily
Extended release (ER) Metadate ER 20 mg tablet 6-8 Daily
Sustained release (SR) Ritalin SR 20 mg capsules 6-8 Daily
Long-acting (LA) Ritalin LA 20, 30, 40 mg 6-8 Daily
capsules
Controlled delivery (CD) Metadate CD 10, 20, 30, 40, 50, 60 6-8 Daily
mg capsules
Methylphenidate Formulations
Formulation Brand Name Available Dosage Duration of Action Frequency
Forms (hours)
Dexmethylphenidate XR Focalin XR 5, 10, 15, 20 mg 8-12 Daily
capsules
Transdermal patch Daytrana 10, 15, 20, 30 mg 8-10 Daily
patches
Osmotic release oral system Concerta 18, 27, 36, 54 mg 10-12 Daily
(OROS) capsules
Methylphenidate XR orally Contempa-XR- ODT 8.6, 17.3, 25.9 mg 12 Daily
disintegrating tablet tablets
Extended release multilayer Aptensio XR 10, 15, 20, 30, 40, 12 Daily
bead (MLR) 50, 60 mg capsules
Extended-release (XR) Quillivant XR 5 mg/ml 12 Daily
suspension
Extended-release (ER) Quillichew ER 20, 30, 40 mg 12 Daily
chewable tablet tablets
Non-stimulants
Medication Brand Available Duration of Frequency Notes

Name Dosage Action
Forms (hours)
Atomoxetine Strattera 10, 18, 25, 12-24 1-2 times Dosed by weight
40, 60, 80, daily Takes 4-6 weeks
and 100 mg to see response
capsules
Clonidine extended- Kapvay 0.1, 0.2 mg 12-24 1-2 times Takes 2-4 weeks
release tablets daily to see response
Guanfacine Intuniv 1, 2, 3, 4 24 Daily Dosed by weight
extended-release mg tablets Takes 2-4 weeks
to see response
Wax Matrix
Formulations:
● Metadate ER
● Ritalin SR
Multilayer Extended Release Bead
Formulations:
● Aptensio
XR
DiffuCaps and SODAS
Formulations:
● Ritalin LA
● Focalin XR
● Adderall XR
● Metadate CD
● Mydayis
Osmotic Release Oral System (OROS)
Formulations:
● Concerta
Prodrug
Formulations:
● Vyvanse
LiquiXR
Formulations:
● Dyanavel
XR-ODT
Formulations:
● Adzenys
● Contempla
Administration Instructions
Immediate release tablets

• May crush
Extended release tablets

• Do not crush or chew
Extended release capsules

• Do not crush or chew. Capsules may be opened and contents
sprinkled on food (ex: applesauce).
Administration Instructions
Patch
• Apply to hip 2 hours before effect is needed and remove up to
9 hours after application. Effects persists for 1-3 hours after
removal.
Suspension
• Shake vigorously for 10 seconds before administration
Orally disintegrating tablet

• Place tablet on top of tongue and allow to dissolve
Adverse Effects,
Precautions,
Contraindications,
Black Box Warnings
Stimulants
Adverse Effects
•Common
•Decreased appetite, delayed growth, insomnia,
headache, irritability
•Rare
•Hypertension, tachycardia, tics, psychosis, mania,
priapism, peripheral vasculopathy
Stimulants
Precautions
•Bipolar disorder, anxiety, seizure disorder
Contraindications
• History of substance abuse, hyperthyroidism,

cardiovascular disease, circulatory disorders,
uncontrolled hypertension, glaucoma, tics, MAOI use
within 14 days
Stimulants
Black Box Warnings

•Use has been associated with serious cardiovascular
events including sudden death in patients with
preexisting structural cardiac abnormalities or other
serious heart problems
•Stimulants have high potential for abuse and
dependence. Administration for prolonged periods may
lead to drug dependence and must be avoided. Assess
the risk of abuse prior to prescribing and monitor for
signs of abuse and dependence while on therapy
Atomoxetine
Adverse effects
• Common
•Headache, nausea, vomiting, dry mouth, insomnia,
somnolence
• Rare
•Tachycardia, hypertension, priapism, hepatotoxicity,
psychosis, mania
Atomoxetine
Precautions
• Bipolar disorder, uncontrolled hypertension, hepatic
impairment
Contraindications
•Severe cardiovascular disease, glaucoma,
pheochromocytoma, MAOI use within 14 days
Black Box Warning
•Atomoxetine increases the risk of suicidal ideation in
studies in children and adolescents with ADHD
Guanfacine and Clonidine
Adverse Effects
• Somnolence, hypotension, bradycardia
• Taper when discontinuing to prevent rebound
hypertension
Precautions
• Hypotension, bradycardia, heart block
• Operating heavy machinery
Drug/Food and Drug/Drug Interactions
High fat meals

• Delay time to peak concentration of extended release
stimulants
Acidic foods
• Decrease absorption and increase excretion of immediate
release stimulants
Acid suppressing medications (PPIs, H2RAs, antacids)
• Increase absorption and decrease excretion of immediate
release stimulants
Drug/Drug Interactions
Monoamine oxidase inhibitors

• Concurrent use with stimulants or atomoxetine can result in
hypertensive crisis
CNS depressants
• May enhance sedative effect of alpha-2 agonists
CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, quinidine)

• May require decreased dose of atomoxetine
Treatment
Guidelines
AAP Treatment Guidelines
Preschool-aged children (4 –5 years of age)

• 1st line
• Behavior therapy
• 2nd line
• Methylphenidate IR
• Off label, but evidence to support its use in
moderate to severe dysfunction if patient fails
behavior therapy
Elementary school-aged children (6-11 years of age)

• 1st line
• Methylphenidate or amphetamine +/- behavior
therapy
• 2nd line
• Atomoxetine, guanfacine ER, or clonidine ER
+/- behavior therapy
Adolescents (12-18 years of age)

• 1st line
• Methylphenidate or amphetamine +/- behavior
therapy
• 2nd line
• Atomoxetine, guanfacine ER, or clonidine ER
+/- behavior therapy
ADHD Treatment in Adults
• Stimulants and atomoxetine are FDA approved

for use in adults
• Weak evidence for guanfacine ER and clonidine
ER
Non-pharmacologic Therapy
Caregiver education
• Structured schedule
• Positive and negative reinforcement
Classroom modifications
• Individualized education plans
• Small classrooms
• Work/test modifications
Social skills training

• Learn teamwork
Medication Selection
Patient related variables

• Patient preferences
• Age
• Comorbidities
• Risk of abuse
• Patient ability to swallow pills
Agent related variables

• Onset, peak, duration
• Frequency of dosing
• Adverse effects
• Expense
Personal or family history of substance abuse

• Vyvanse (prodrug), Concerta (OROS), Daytrana
(patch), atomoxetine, guanfacine, clonidine
Uncontrolled hypertension, structural cardiac

abnormality, cardiomyopathy, heart murmur,
arrhythmia
• Guanfacine, clonidine
Depression
• Stimulants, guanfacine, clonidine
Bipolar disorder, tics

• Guanfacine, clonidine
Difficulty swallowing pills

• Daytrana (patch), Dyanavel (liquid),
Quillichew (chewable), Quillivant (liquid),
Procentra (liquid), Adzenys (ODT), Contempla
(ODT), crush immediate release
Difficulty affording medications

• Immediate release, generics
Dosing
• Start at lowest dose and titrate on a 7-day basis

• Young children have slower metabolism so should
be started at a lower dose that is increased in smaller
increments
• When converting from one formulation to another,
not a 1:1 conversion
Dosing
Atomoxetine
Dosing
Guanfacine ER
Monitoring
Indices of Therapeutic Effect
• Improvement in core symptoms

• Improvement in family and peer relationships
Rating Scales
Conners’ Rating Scale

•Used clinically and in clinical trials
•Parent-rated version (full length 110 items, abbreviated 43 items)
and teacher-rated version (full length 115 items, abbreviated 39
items)
•Items scored 0 (never) to 3 (very often)
•Raw score converted to percentile indicative of ADHD
•Scales for inattentive, hyperactive-impulsive, and combined
subtypes of ADHD
•Screens for oppositional defiant disorder and conduct disorder
Monitoring
Efficacy Safety
• Rating scales • HR • Appetite
• School • BP • Mood
performance • Height • EKG if
• Weight history of
• Sleep cardiac
disease
Managing Adverse Effects
Insomnia
• Take earlier in day, switch to shorter duration, use
medication for sleep
Reduced appetite
• High calorie meals at lowest effect of medication
(early morning, late evening)
Nausea/vomiting
• Take with food, reduce dosage
Rebound symptoms
• Add dose in afternoon,
change time of second dose,
change to longer
formulation
Delayed growth (crosses two

major percentile lines)
• Reduce dosage, drug
holiday, alternative therapy
Cardiovascular (change in BP ≥15 mmHg or HR ≥20 bpm)

• Reduce dosage, alternative therapy
Irritability
• Reduce dosage, assess for comorbidities
Tics
• Reduce dosage, alternative therapy
Psychiatric disorder
• Discontinue medication, alternative therapy
Follow-Up
• A follow-up visit is recommended 1 month after initiation to monitor for

safety and efficacy
• Visits can then occur on a monthly basis until there is a consistent
optimal response, and then every 3 months
• Need for continued use should be assessed every 12 months
•Continue as long as symptoms are present and cause functional
impairment
•If patient is on a stimulant, consider drug holidays during vacations,
weekends, summer
Response
Maximum
Dose?
Titrate to No Yes
maximum Response?
dose
Partial None
Switch to other
Add non-stimulant
stimulant class
If still no
response,
switch to non-
stimulant
Patient Case
Patient Case
Peter is an 8 year old male who was recently

diagnosed with ADHD, with a predominantly
hyperactive-impulsive presentation. His personal
history is unremarkable. He has a family history
of diabetes, MI, and colon cancer. What class of
medications would you recommend as initial
therapy?
Patient Case
Peter arrives to school at 8:00AM. His teachers report his symptoms

affect his ability to complete his work at school. Peter’s parents
state that the symptoms then persist when he does homework after
school, which takes until 4:00PM. Peter’s parents are worried
about being able to afford his medication. Which of the following
therapies would you recommend for Peter?
A. Ritalin (methylphenidate) LA 20 mg every morning

B. Amphetamine salts IR 5 mg in the morning and at lunch
C. Vyvanse (lisdexamphetamine) 20 mg every morning
D. Daytrana (methylphenidate) 10 mg patch daily
Patient Case
Peter is initiated on the recommended

therapy. He returns for a follow up visit in
one month. What pertinent information
would you want to assess as part of your
monitoring plan?
Patient Case
Over the course of 6 months, Peter is titrated to the maximum dose

of Adderall. Peter’s score on the Conners Scale has improved by
25%. His parents feel that Peter’s symptoms have improved, but
still interfere with his ability to complete his schoolwork. What
changes, if any, would you recommend to his regimen?
A. Switch to a methylphenidate product

B. Switch to clonidine ER 0.1 mg daily
C. Add guanfacine ER 1 mg daily
D. No changes are necessary at this time
Questions?
mrincava@su.edu
References
1. Attention-Deficit / Hyperactivity Disorder (ADHD) [Internet]. Centers for Disease Control and Prevention; [updated
18 July 2017; cited 5 Sept 2017]. Available from: https://www.cdc.gov/ncbddd/adhd/index.html
2. Diagnostic and statistical manual of mental disorders: DSM-5. 5th edition. Washington, DC: American Psychiatric
Association; 2013.
3. About ADHD [Internet]. CHADD-The National Resource on ADHD; [cited 7 Sept 2017]. Available from:
http//www.chadd.org
4. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L. Attention Deficit/Hyperactivity Disorder.
Pharmacotherapy: A Pathophysiologic Approach. 9 ed. McGraw-Hill; 2014.
5. Conners CK. Conners 3rd Edition. Toronto, Multi-Health Systems, Inc., 2008.
6. AACAP Workgroup on Quality Issues. Practice Parameter for the Assessment and Treatment of Children and
Adolescents With AttentionDeficit/Hyperactivity Disorder. Journal of the American Academy of Child and Adolescent
Psychiatry. 2007;46(7):894-921.
7. Harstad EB, Weaver AL, Katusic SK, Colligan RC, Kumar S, Chan E, Voigt RG, Barbaresi WJ. ADHD, stimulant
treatment, and growth: a longitudinal study. Pediatrics. 2014;134(4):e935.
8. Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST,
Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA. ADHD drugs and serious cardiovascular events in
children and young adults.N Engl J Med. 2011;365(20):1896.
9. American Academy of Pediatrics. ADHD: clinical practice guidelines for the diagnosis, evaluation, and treatment of
Attention-Deficit/Hyperactivity Disorder in children and adolescents. Pediatrics. 2011;128(5):1007-22.
Pharmacotherapy of Insomnia
Gretchen L. Johnson, PharmD, BCPS

Insomnia
• Defined as difficulty falling asleep, difficulty maintaining sleep
or experiencing nonrestorative sleep.
• Most common complaint in general medical practice
• 40% of pts with chronic insomnia have a psych diagnosis
(depression, anxiety, substance abuse)
• 10-20% self-medicate with OTC meds or alcohol
Insomnia
• Three types of Insomnia
– Transient- lasting 2-3 nights (Ex. jetlag)
– Short-term- lasting < 3 months (Ex. situational)
– Chronic- lasting > 3 months
Common Causes of Insomnia
• Situational
– Work or financial stress, major life events, interpersonal conflicts, jet lag or
shift work
• Medical
– Cardiac: angina, arrhythmias, HF
– Respiratory: asthma, sleep apnea
– Chronic pain
– Endocrine: DM, hyperthyroidism
– GI: GERD, ulcers
– Neurologic: delirium, Parkinson’s, Seizures, RLS
– Pregnancy
Common Causes of Insomnia
• Psychiatric
– Mood disorders: depression, mania
– Anxiety disorders: GAD, OCD
– Substance abuse: alcohol, sedative-hypnotic withdrawal
• Drug-induced Insomnia
– Anticonvulsants
– Central adrenergic blockers
– Stimulants
– SSRIs, Bupropion
– Steroids
– Diuretics
Determining Management
• Determine if transient, short-term, or chronic
• Assess onset, duration and frequency of sx
• Assess effect on daytime functioning
• Assess for underlying causes
• Assess sleep hygiene
• Assess stress
Nonpharmacologic Treatment
• Cognitive behavioral therapy
– May be more effective than drugs in > 55yo
– Stimulus control, good sleep hygiene, cognitive therapy, relaxation
therapy
• Table 72-2 Stimulus Control and Sleep
Hygienehttp://accesspharmacy.mhmedical.com.suproxy.su.ed
u/ViewLarge.aspx?figid=134128156&gbosContainerID=0&gbos
id=0
OTC options
• Antihistamines
– Diphenhydramine (Tylenol PM, Sominex)
– Doxylamine (Unisom)
• Herbal meds
– Melatonin
– Valerian
– Kava Kava
Nonprescription Treatments
• Antihistamines
– Watch for anticholinergic side effects- esp. problematic
in elderly
– Tolerance develops to sedative effects after 1 week
– Diphenhydramine- Pregnancy Category B; Lactation-
may dry up milk
• Herbals
– Little if any evidence of efficacy
• Melatonin may be helpful in jet lag
• Hepatotoxicity reported with Kava Kava and Valerian root
Prescription Treatments
• Benzodiapezines (BZDs)
– Temazepam (Restoril)
– Flurazepam (Dalmane)
– Triazolam (Halcion)
– Estazolam(Prosom)
– Quazepam (Doral)
• Non-BZD GABA-A agonists- “Z- hypnotics”
– Zolpidem (Ambien)
– Zaleplon (Sonata)
– Eszopiclone (Lunesta)
Prescription Treatments (cont’d)
• Melatonin receptor agonist
– Ramelteon (Rozerem)
• Sedating antidepresants
– Amitriptyline (Elavil)
– Doxepin (Silenor)
– Trazodone (Deseryl)
– Mirtazepine (Remeron)
Benzodiazepines
• MOA: GABA-A receptor agonists
• Controlled subtance
Drug Onset Duration T 1/2
Triazolam 30 min 2-4 hrs 2-5 hrs
Temazepam 60-120 min 8-10 hrs 9-12 hrs
Estazolam 60-120 min 8-10 hrs 10-20 hrs
Quazepam 30-60 min 8-10 hrs 40 hrs
Flurazepam 30-60 min 8-20 hrs 40-150 hrs
• Effective in dec. time to fall asleep and inc. total sleep time
Benzodiazepines
• Do not use in:
– Pregnancy
– Substance abuse
– Untreated sleep apnea
• Avoid use with alcohol and other CNS depressants
• Caution with driving or operating heavy machinery
Benzodiazepines
• ADRs: daytime sedation, psychomotor incoordination, decreased
concentration and mental alertness, cognitive deficits,
respiratory depression
• ADRs are dose-related- use lowest effective dose
• Tolerance can develop
• Scheduled substance
– Can be habit forming
• Rebound insomnia can occur with abrupt DC
• Anterograde amnesia, an impairment of memory and recall of
events occurring after the dose is taken, can occur
• Can accumulate in the elderly
– Avoid BZDs with long t1/2- flurazepam and quazepam
– Inc. risk of falls and hip fracture
• Pregnancy Category X- cleft pallette, resp. depression
• Breastfeeding- not recommended
Non-BZD GABA-A agonists
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)
• MOA: selective GABA-A receptor agonist subtype 1

• Controlled substance
• Zolpidem
– Formulations available: IR (Ambien), CR (Ambien CR), lingual spray
(Zolpimist), SL (Edular, Intermezzo)
– Both zolpidem CR and eszopiclone are FDA approved for
chronic insomnia and effective for up to 6 months.
Product Onset Duration
Zolpidem IR,Edular SL, Zolpimist 30 min 6 hours
Zolpidem CR 30 min >6 hours
Intermezzo SL 30 min 4-6 hours
– Useful to initiate and maintain sleep; some residual effects

• Intermezzo for middle of the night wakenings- Need 4 hours of sleep left
• Zaleplon (Sonata)
– Onset: 30 min Duration: 2 hours
– Useful to initiate sleep; Can take in middle of night but need 4 hr left in bed; Not for
maintaining sleep unless redosed
– Least likely to cause next-day impairment or anterograde amnesia
• Eszopiclone (Lunesta)
– Onset: 45 min Duration = 5-8 hr
– Useful to initiate sleep and maintain sleep
– No evidence of tolerance after 6 months of use
– ADR: unpleasant/metallic taste (20-33% incidence)
Zolpidem Dosing Change 2013
• FDA Recommends Lower Dose
• Reason:
– Morning blood levels in some pt (females) may be high enough to
impair activities requiring alertness – driving
– Highest risk with ER forms and women eliminate the drug more
slowly than men
• Use 5mg vs. 10mg for IR; Use 6.25mg vs. 12.5mg for CR
• Intermezzo (no change) already at a lower dosage (11/2011)
Eszopiclone Dosing Change 2014
• FDA recommended lower dose
• Reason
– 3mg dose can impair driving ability, coordination, and memory for
over 11 hours
• Start with 1mg for all pts
– Do not exceed 2mg for elderly and 3mg for young pts
• High fat/heavy meal can delay absorption – delays onset
• CYP3A4 inhibitors can increase plasma levels
• Hepatic impairment may require lower doses
• Side effects:
– Headache
– Dizziness
– GI: nausea, dyspepsia
– Anterograde amnesia (high dose zolpidem)
• Withdrawal reactions uncommon but reported
• Pregnancy Category C; Breastfeeding: zolpidem compatible
BZD and Non-BZD GABA-A agonists
• FDA Labeling Changes
• Caution
– Anaphylaxis, facial angioedema
– Complex sleep behaviors- engaging in these activites while not fully awake and
with no recollection afterwards
• Sleep driving
• Sleep eating
• Phone calls
• Risk increased with concurrent alcohol use and doses above maximum recommended
Ramelteon (Rozerem)
• Selective MT1 and MT2 receptor agonist
• Onset: 30 min T1/2= 1-2.6 hours
• Effective for dec. time to fall asleep
• Not effective for maintaining sleep
• ADRs: HA, dizziness, somnolence
• Not a controlled substance
– May be an option in substance abuse pts
• Pregnancy Category C; Breastfeeding- unknown
Sedating Antidepressants
• Alternatives for pt who cannot take BZD or if concommitant
depression
• Improve sleep in depression with stimulating SSRI or bupropion
– Mostly see Trazodone used
• Doses used for insomnia are not effective for treating depression
• Amitriptyline 10-50mg Qhs; Doxepin (Silenor®) 3-6mg Qhs
– Disadvantages
• Anticholinergic side effects, adrenergic blockade
(orthostatic hypotension), cardiac conduction problems,
daytime sedation
• Trazodone 25-150mg QHS
– Watch for orthostatic hypotension, priapism
• Mirtazapine 7.5 – 30mg QHS
– Watch for daytime sedation, weight gain
Suvorexant(Belsomra)
• New class of sleep agent
• MOA: orexin receptor antagonist
– Orexins are involved with promoting wakefulness so antagonising
their effect would cause sedation
• Schedule IV
• Same precautions about combining with alcohol and other
sedating drugs and risk for impairment in driving and other
activities the next day
Treatment of Insomnia
• Stepwise approach to select hypnotic
– ? Type of insomnia
• Difficulty initiating sleep
• Difficulty maintaining sleep/early morning awakening
– ? Duration
– ? Etiologies
• Sleep apnea, psychiatric/medical issues
– ? Sleep habits
– Substance abuse history
 Select agents based on symptoms, kinetic and ADR profile
Clinical Practice Guideline
General Treatment Approach
1. Short-intermediate acting BZD, Non-BZD RA or ramelteon
Ex. Zolpidem, eszoplicone, zaleplon, temazepam
2. Alternate short-intermediate acting BZD, Non-BZD RA or
ramelteon
3. Sedating antidepressant
Ex. Amitriptyline, trazodone, doxepin, mirtazepine
4. Combined BzRA or ramelteon + sedating antidepressant
5. Other sedating agents- with appropriate comorbid
conditions
Ex. Quetiapine, gabapentin
Journal of Clinical Sleep Medicine, Vol. 4, No. 5, 2008

Algorithm
Adapted and Used With Permission from Mitsi Lizer, Pharm.D.
Hypnotic Selection
DFA DMS MNA
Ramelteon, Zolpidem, Zaleplon

triazolam, zaleplon, Eszopiclone,
zolpidem Temazepam Intermezzo
DFA: Difficulty falling asleep; DMS: maintaining sleep: MNA: middle of the night awakening
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)
Lecturer: Teresa Elsobky, Pharm.D., BCPP

Clinical Psychiatric Pharmacist
Shenandoah University
Objectives
• At the end of the presentation, each student should be able to:
• Explain the pharmacology of anti-anxiety agents and antidepressants
• Identify appropriate, guideline-based pharmacological treatment options for anxiety
and depression
• Distinguish the drug properties of the different pharmacological treatment options
• Create a pharmacological treatment plan for a sample patient case
Introducing Our Patient: MG
Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for
acute complaints of rapid onset episodes of palpitations, shortness of breath, sweats,
trembling, and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the
belief that she was having a heart attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology
screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes
occurring at work, at home, and while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the
resolution of the symptoms of each acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps and headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years earlier
• Father –healthy
• Two brothers are healthy
ANXIETY DISORDERS AND
THEIR TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Overview of anxiety
• Anxiety is an emotional state commonly caused by the perception of real or perceived
danger that threatens the security of an individual
• Anxiety may become excessive and/or debilitating
• May present with both physiological and psychological features

• Physiological: tachycardia, diaphoresis, shortness of breath
• Psychological: worry, anticipation of threats
• Individuals may develop an anxiety disorder when feelings of fear and anxiety become
frequent and excessive
Overview continued…
• Anxiety disorders are the most frequent mental illnesses found in clinical practice and are
also the most commonly misdiagnosed
• Anxiety disorders generally develop before the age of 30 years old
• Common risk factors include:

• Sex
• Social issues
• Family history of anxiety or depression
Types of anxiety disorders (not inclusive!)
• Generalized anxiety disorder (GAD)
• Panic disorder (PD)
• Social anxiety disorder (aka social phobia)
• Specific phobias
• Obsessive-compulsive disorder (OCD)
• Posttraumatic stress disorder (PTSD)

Managing anxiety disorders
• GOAL: remission of symptoms ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into two phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into maintenance phase
• Time range: minimum of 4 weeks, up to 12 weeks
• Maintenance phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: minimum of 1 year at adequate dose, up to lifelong therapy
Anxiety Pharmacotherapy:
The Meds (pharmacology
first)!
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Some of these agents are first line options for GAD and PD
• Mechanism of action (MOA):
• Inhibit the reuptake of serotonin back into the presynaptic neuron by inhibiting the activity of the serotonin transporter (SERT)
• This, in turn, keeps the serotonin in the synapse and allows it to exert its actions of regulating mood, emotions, sleep and
appetite
Brief Animation of how SSRIs work
• https://www.youtube.com/watch?v=ocSptPUBbuo
Available SSRI Agents
Generic Name Brand Name
Citalopram Celexa®
Escitalopram Lexapro®
Fluoxetine Prozac®
Fluvoxamine Luvox®
Paroxetine Paxil®
Sertraline Zoloft®
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
• Some of these agents are first line options for GAD and PD
• MOA:
• Inhibit the activity of SERT (like the SSRIs)
• In addition to inhibiting SERT, the SNRIs also inhibit the norepinephrine transporter (NET)
• These mechanisms allow serotonin and norepinephrine to stay in the synapse and exert their actions on postsynaptic receptors
http://brainyinfo.com/antidepressants/snri/
Available SNRI Agents
Venlafaxine Effexor®
Desvenlafaxine Pristiq®
(enantiomer of venlafaxine)
Duloxetine Cymbalta®
Milnacipran Savella®
Levomilnacipran ER Fetzima®
(enantiomer of milnacipran)
Benzodiazepines
• Primary site of action: GABA A receptor (a chloride ion channel)
Available Benzodiazepines
Alprazolam Xanax®
Chlordiazepoxide Librium®
Clonazepam Klonopin®
Clorazepate Tranxene®
Diazepam Valium®
Estazolam Prosom®
Flurazepam Dalmane®
Lorazepam Ativan®
Midazolam Versed®
Oxazepam Serax®
Quazepam Doral®
Temazepam Restoril®
Triazolam Halcion®
Tricyclic Antidepressants (TCAs)
• MOA:
• Similar to SNRis (inhibit reuptake of serotonin and norepinephrine by inhibiting activity of SERT and NET)
• Within this class, these is variability in affinity for SERT vs. NET
• Antagonize postsynaptic receptors, such as H 1 and α, that leads to increased side effects
quizlet.com
Available TCA Agents
Amitriptyline Elavil®
Clomipramine Anafranil®
Desipramine Norpramin®
Doxepin Sinequan®
Imipramine Tofranil®
Nortriptyline Pamelor®
Trimipramine Surmontil®
Amoxapine Asendin®
Protriptyline Vivactil®
Monoamine Oxidase inhibitors (MAOis)
• Found to be a treatment option for treatment-resistant PD
• Mechanism of action:
• Inhibits the activity of monoamine oxidase (degradation of neurotransmitters) in the neuron and increases neurotransmitters
• Some are irreversible, while are others are reversible; some are selective to one form of MAO, while others are nonselective
http://www.neurosoup.com/maoi
s/
Available MAOi Agents
Phenelzine Nardil®
Selegiline Emsam®
Tranylcypromine Parnate®
Isocarboxazid Marplan®
Moclobemide Manerix®
Pregabalin (Lyrica®)
• Could be a second line option for GAD
• MOA:
• Reduces calcium influx by binding to the presynaptic α2-δ subunit of voltage-gated calcium channels
• In trials, it has been shown to produce anxiolytic effects similar to certain benzodiazepines
(lorazepam and alprazolam) and venlafaxine
http://www.apiapollo.com/Pregabalin.html
Buspirone (Buspar®)
• A second line option for GAD
• MOA:
• Does not interact directly with GABA systems
• 5-HT1A agonist on presynaptic neurons (reduces the firing of serotonergic neurons) and acts as a
partial agonist at these receptors on postsynaptic neurons
• Increases the release of norepinephrine and dopamine
google.com
Hydroxyzine (Vistaril®)
• An alternative option for GAD
• MOA:
• Chemical classification: an antihistamine
• In clinical trials, it has been shown to reduce anxiety symptoms
http://www.answers.com/topic/hydroxyzine
Second Generation Antipsychotics (SGAs)
• Some guidelines state that three of these agents (risperidone, olanzapine, and
quetiapine) can be used as augmentation with first and second line therapies for
treatment resistant GAD
Anxiety Pharmacotherapy:
Treatment Guidelines second!
GENERALIZED ANXIETY
DISORDER (TREATMENT
GUIDELINES AND DRUG
PROPERTIES)
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant
WFSBP1 Guidelines Escitalopram* Imipramine Augmentation with:

Paroxetine* Buspirone* Alprazolam
Sertraline Hydroxyzine Diazepam
Venlafaxine XR* Risperidone
Duloxetine* Olanzapine
Pregabalin
IPAP2 Review and SSRI Partial or no response: Assess for co-morbidities

Algorithm SNRI -Increase dose
-Switch to another
Addition of a antidepressant
benzodiazepine if rapid -Augment
response
1World Federation of Societies of Biological Psychiatry *FDA-approved for GAD

2The International Psychopharmacology Algorithm Project
Factors to consider when choosing an agent
• Patient’s history of response
• History of familial response
• Patient’s concurrent medical illnesses and medications
• Presenting symptoms
• Potential for drug-drug interactions
• Side effect profile
• Patient preference
• Drug cost
SSRI Options
Escitalopram Paroxetine Sertraline

Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%
Initial Dosing 10 mg/day 20 mg/day 50 mg/day
Dosing Range 10-20 mg/day 20-50 mg/day 50-200 mg/day
Black Box Suicidal ideation in children, adolescents, and

Warning young adults
Side Effects Insomnia, jitteriness, headache,

nausea/vomiting, diarrhea, weight gain, sexual
dysfunction
Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Escitalopram 80 27-32 5 56 None
Paroxetine 50 24-31 5-7 95 None
Sertraline 36 (increases by 30-40% 27 6-8 99 None

when taken with food)
Why do we care about pharmacokinetics?
• Helps us to understand what the body does to the drug
• Half-life  agents with a long half-life may be beneficial in instances when doses are
missed, for example
• Fluoxetine is the SSRI agent with the longest half-life (4-6 days)
• Active metabolites  if an agent has an active metabolite, this needs to be taken into
consideration because the drug will be acting for a longer period of time in the body
• Fluoxetine is the only SSRI that has an active metabolite
Drug Interactions with the SSRI Options
• Two types of drug-drug interactions:
1. Pharmacokinetic – most common interactions for SSRIs
• **REMEMBER: what the body does to the drug**
• Includes liver enzyme interactions (cannot be inclusive of all drug interactions)
• Example  Paroxetine is a strong CYP2D6 inhibitor; TCAs are CYP2D6 substrates; co-
administration of these agents may lead to elevated drug concentrations of the TCAs
• Citalopram and escitalopram are the two SSRI agents with the least potential of pharmacokinetic
interactions
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme
SSRI Agent 2D6 3A4
Escitalopram + 0
Paroxetine ++++ 0
Sertraline + +
Drug Interactions continued…
2. Pharmacodynamic – what the drug does to the body

• An example – the concomitant administration of two or more
serotonergic agents, leading to serotonin syndrome
• This interaction leads to physiological changes
SNRI Options
Venlafaxine XR Duloxetine
Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%
Initial Dosing 37.5 or 75 mg/day 30 or 60 mg/day

Dosing Range 75-225 mg/day 60-120 mg/day

Side Effects Jitteriness, nausea/vomiting, diarrhea,

headache, sexual dysfunction, elevated blood
pressure, insomnia
Pharmacokinetic Properties of SNRI Options
Agent Bioavailability Half-life Time to Peak Protein Active
(%) (hours) (hours) Binding Metabolites
(%)
Venlafaxine XR 45 5 2 27 Yes (O-
desmethylvenlafaxine
)
Duloxetine 50 12 6 90 None
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents
• Venlafaxine is a substrate, but not an inhibitor, of CYP2D6 and

other CYP enzymes
• Inhibitory Potentials of CYP Liver Enzymes

CYP Liver Enzyme
SNRI Agent 2D6 3A4
Venlafaxine 0/+ 0
Duloxetine +++ 0
• Pharmacodynamic interactions also exist (same instance as SSRIs)

Pregabalin
Mechanism of action Reduces calcium influx by

binding to the alpha2-delta
subunit of the voltage-gated
calcium channels
Initial Dosing 50 mg three times a day
Dosing Range 150-600 mg/day
Side Effects Dizziness, somnolence,

peripheral edema, weight gain
Imipramine: a TCA Option
Mechanism of action Tricyclic antidepressant
Initial Dosing 50 mg/day

Side Effects Jitteriness, anticholinergic

effects (constipation, dry
mouth, blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
Pharmacokinetic Properties of Imipramine
Bioavailability Half-life Time to Peak Protein Active

(%)
Imipramine 22-77 6-34 1.5-3 63-96 Yes (desipramine)
Drug Interactions with Imipramine
• As stated earlier, TCAs are CYP2D6 substrates
• Combination of CYP2D6 inhibitor and imipramine may result in an increase of imipramine drug
concentration (pharmacokinetic interaction)
• TCAs generally do not induce or inhibit CYP enzymes

• Imipramine has the potential to inhibit CYP2C19, however
• Due to the multiple receptor binding affinities of TCAs, there is an increased risk of side
effects with this class of medications
• Examples of pharmacodynamic interactions:
• Imipramine + Benadryl® = increased risk of antihistamine and anticholinergic side effects
• Imipramine + antihypertensive agents = increased risk of orthostatic hypotension
Buspirone
Initial Dosing 7.5 mg twice daily

Side Effects Nausea/vomiting, abdominal

pain, drowsiness, dizziness
Pharmacokinetic Properties of Buspirone

(%)
Buspirone 4 2.5 (needs to <1 86 Yes
be dosed 2-3
times a day)
Drug Interactions with Buspirone
• Drugs that inhibit CYP3A4 can increase buspirone levels since buspirone is a CYP3A4
substrate
• Likewise, drugs that induce CYP3A4 can decrease buspirone levels
• Both are pharmacokinetic interactions

Hydroxyzine
Mechanism of action Antihistamine
Initial Dosing 25 or 50 mg four times a day

Side Effects Dry mouth, headache,

somnolence
Benzodiazepines
Alprazolam Chlordiazepoxide Clonazepam
Initial IR: 0.75 mg daily 25 mg daily 0.25 mg 1-2

Dosing XR: 1 mg daily times a day
Dosing IR: 0.75-4 mg/day 25-400 mg/day 1-4 mg/day

Range XR: 1-10 mg/day
Benzodiazepines continued…
Clorazepate Diazepam Lorazepam Oxazepam
Initial IR: 0.75 mg daily 0.25 mg 1-2 25 mg daily 30 mg daily

Dosing XR: 1 mg daily times a day
Dosing IR: 0.75-4 mg/day 1-4 mg/day 25-400 mg/day 30-120 mg/day
Range XR: 1-10 mg/day
**only these 7 benzodiazepines have FDA

approval for GAD
Common side effects of benzodiazepines
• Drowsiness, fatigue
• Memory impairment and amnesia
• Respiratory depression
• Potential for dependence
• Withdrawal symptoms may occur

Pharmacokinetic Properties of Benzodiazepine Options
Drug Half-life (hours) Time to Peak (hours) Protein Binding (%) Active Metabolites
Alprazolam 12-15 1-2 80 None
Chlordiazepoxide 5-30 1-4 96 Yes, multiple
Clonazepam 30-40 1-4 85 None
Clorazepate Prodrug 1-2 97 Yes
Diazepam 20-80 0.5-2 98 Yes (oxazepam is

one of them)
Lorazepam 10-20 2-4 85 None
Oxazepam 5-20 2-4 97 None

Drug Interactions with the benzodiazepines:
IMPORTANT interactions to know!
• IMPORTANT: Benzodiazepines may cause CNS depression**
• Simultaneous use of another CNS depressant, such as alcohol, with a

benzodiazepine may result in additive CNS depressant effects
• Other CNS depressants include antihistamines, antipsychotics, and opioids

More drug interactions with benzodiazepines
• Pharmacokinetic interactions
• Drugs that inhibit CYP3A4 (ketoconazole, an antifungal, is an example) can increase blood levels of
alprazolam and diazepam
• Drugs that induce CYP3A4 (carbamazepine is an example) can decrease benzodiazepine blood levels
Tolerance and dependence
• What is tolerance?
• What is dependence?
Benzodiazepine Withdrawal Syndrome
• Need to properly taper down dose
• Frequent withdrawal symptoms:
• Anxiety
• Insomnia
• Irritability
• Muscle aches and tension
• Nausea
• Blurred vision
• Palpitations
• Severe withdrawal symptoms:
• Seizures
• Psychosis
• Delirium and confusion
• Can occur within one day and extend to > 2 weeks, depending on dose
and agent patient was on
Drug properties to consider when predicting a withdrawal
syndrome
• The higher the dose, the more serious the abrupt withdrawal is
• The longer the half-life, the slower the elimination, the fewer and less severe withdrawal
symptoms occur
• The longer the half-life, the later the withdrawal symptoms will occur
Serotonin Syndrome (SS)
• Any antidepressant that increases serotonergic neurotransmission can increase the risk of
developing SS
• Symptoms:
• Mental status changes (agitation)
• Autonomic instability (temperature > 38°C, diaphoresis)
• Neuromuscular abnormalities (tremor, hyperreflexia, spontaneous clonus, muscle rigidity)
• Treatments:
• Lower the dose of the medication and discontinue it
• Benzodiazepines to control agitation and seizures that may occur
• Serotonin-production blocking agents (cyproheptadine is an antihistamine that reduce the
production of serotonin)
How long do we treat for?
• Monitor efficacy every 2 weeks, initially
• Adequate trial of SSRI or SNRI = 4-6 weeks with

adequate dose
• Continue treatment for at least a year once patient

has responded to pharmacotherapy
PANIC DISORDER
(TREATMENT GUIDELINES
AND DRUG PROPERTIES)
Pharmacotherapy Options for PD
Guidelines First Line Second Line Txt-Resistant
WFSBP1 Guidelines SSRI

Venlafaxine XR*
APA2 Guidelines SSRI Partial or no response: MAOi

SNRI -Increase dose
TCA -Switch to another
Benzodiazepine medication
CBT -Augment
1World Federation of Societies of Biological Psychiatry

2 American Psychiatric Association *FDA-approved for PD
Factors to consider when choosing an agent
• Patient’s history of response
• History of familial response
• Patient’s concurrent medical illnesses and medications
• Presenting symptoms
• Potential for drug-drug interactions
• Drug cost
SSRI Options
Citalopram Fluoxetine Fluvoxamine
Efficacy 60-80% response rate
Antipanic effect of SSRIs is delayed for at least 4
weeks (some patients do not respond for 8-12
weeks)
Dosing Range 20-40 mg/day 10-80 mg/day 100-300
mg/day
Side Effects Insomnia, jitteriness, headache,

nausea/vomiting, diarrhea, weight gain, sexual
dysfunction
Pharmacokinetic Properties of SSRI Options
(hours) (%) s
Citalopram >/= 80 33 2-4 80 None
Fluoxetine 95 4-6 days 4-8 94 Yes

(norfluoxetine)
Fluvoxamine 53 15-26 2-8 77 None

Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme
SSRI Agent 2D6 3A4
Citalopram + 0
Fluoxetine ++++ ++
Fluvoxamine 0 +++
Clomipramine: another TCA Option
Mechanism of action Tricyclic antidepressant

Side Effects Jitteriness, anticholinergic

effects (constipation, dry
mouth, blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
Pharmacokinetic Properties of Clomipramine

(%)
Clomipramine 50 12-36 2-6 98 Yes
Phenelzine
Mechanism of action Monoamine oxidase inhibitor

(nonselective)
Side Effects Jitteriness, hypertensive crisis

in overdose, orthostatic
hypotension
Pharmacokinetic Properties of Phenelzine

(%)
Phenelzine Unknown 11 Unknown Unknown None
Drug Interactions with MAOis
• Significant interaction to note:
• When MAOis are taken with certain foods, especially those high in tyramine
• Examples of foods high in tyramine include aged cheeses, sour cream, yogurt, cottage cheese, American
cheese, wine, beer, sardines, canned or processed meats, raisins, liver, soy sauce, coffee, chocolate, licorice
• Result: hypertensive crisis
• Symptoms include occipital headache, stiff neck, nausea, vomiting, sweating, and sharply elevated blood
pressure
• MAOis can also interact with buspirone and other antidepressants

• Increased risk of developing serotonin syndrome
How long do we treat for?
• Monitor efficacy every 1-2 weeks for the first 1-3 months
of pharmacotherapy, and then every 2-4 weeks
• After dose is stabilized and symptoms have decreased,
monitor patient every 2 months
• SSRIs and SNRIs should work within 4-8 weeks, but

could be up to 12 weeks
• Benzodiazepines – effective for acute treatment

• Use short-term for only 2-4 weeks
• Continue treatment for 12-24 months

MAJOR DEPRESSIVE
DISORDER AND ITS
TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Video: What people with depression want you
to know
• https://www.youtube.com/watch?v=IQr1G1OOEEQ
An easy acronym
“SIGE CAPS”
• Sleep increased or depressed
• Interest and/or mood is diminished **
• Guilt or worthless feelings
• Energy is diminished
• Concentration is impaired
• Appetite increased or decreased
• Psychomotor retardation or agitation
• Suicidal thoughts, attempts, or plans
**essential features (must have at least one to hold diagnosis of

MDD)
Assessing Depression: PHQ-9 Scale
Managing MDD
• Euthymia: a patient’s baseline state, no depressive symptoms
• GOAL: remission of symptoms; patient returns to euthymic state ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into three phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into continuation phase
• Time range: 6 – 12 weeks
• Continuation phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: 4 – 9 months
• Maintenance phase
• The time after continuation phase where management involves “watchful waiting” or
treatment is continued at dose that achieved remission of symptoms
• Time range: years – lifelong
Managing MDD continued…
• Relapse – return of depressive symptoms during the acute or

continuation phase
• Recurrence – return of depressive symptoms during the

maintenance phase
Managing MDD:
A depiction
Remission
Relapse Recurrence
Euthymia
Increased
Relapse
severity
Response
Symptoms
Syndrome
Treatment phases Acute Continuation Maintenance

(6 to 12 wk) (4 to 9 mo) (1 y)
Time
Depression Pharmacotherapy:
The Meds (pharmacology
first)!
Mixed Serotonergic Agents
• All these agents are treatment options for MDD
• 3 agents in this class, all with slightly different mechanisms of action
• Trazodone (Desyrel®)
the-medical-dictionary.com
• Nefazodone (Serzone®)
medlibrary.org
• Vilazodone (Viibryd®)
www.medicinescomplete.com
Bupropion (Wellbutrin®)
• Unique agent as it has no effect on serotonin
• MOA:
• Classically known as a NDRI (norepinephrine dopamine reuptake inhibitor)
• Also involved with the presynaptic release of NE (norepinephrine) and DA (dopamine) into the
synaptic cleft
www.pharmacy-and-drugs.com
Mirtazapine (Remeron®)
• Another unique agent that is an option for MDD
• MOA:
• Presynaptic α2 receptor antagonist that, in turn, enhances the presynaptic release of NE and
serotonin
• Antagonizes 5-HT2 and 5-HT3 receptors  leads to lower anxiety levels and GI side effects
• H1 antagonist
dailymed.nlm.nih.gov
Vortioxetine (Trintellix®)
• New medication approved by the FDA in 2013 for the treatment of MDD
• MOA:
• Inhibits the reuptake of serotonin
• 5-HT1A receptor agonist
• Partial 5-HT1B receptor agonist
• 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist
Depression Pharmacotherapy:
Treatment Guidelines second!
How to pick an antidepressant?
• Since the effectiveness of antidepressants is generally comparable between classes and
within classes of medications, the APA (American Psychiatric Association) guidelines state
to:
• Pick an antidepressant based on:
• Safety and tolerability
• Pharmacological properties (half-life, drug interactions)
• Historical response to medications
• Cost
SNRIs not discussed earlier
• Desvenlafaxine (Pristiq®)
• Initial and usual doses are 50 mg/day, with no additional benefit seen with higher doses
• Extended release tablets  dosed once a day
• Half-life is 11 hours and there are no active metabolites
• Relatively new SNRI compared to the others in its class
TCAs not discussed earlier
• Amitriptyline
• Initial dose: 25 mg/day; dose range is 100-300 mg/day
• Nortriptyline
• Amitriptyline’s metabolite
• Half-life can reach up to 88 hours, while amitriptyline’s half-life can reach 46 hours
MAOis not discussed earlier
• Selegiline
• A transdermal patch
• Initial dose is 6 mg/24 hours and the maximum dose is 12 mg/24 hours
• Dose may be increased by 3 mg/day increments every 2 weeks
• Tranylcypromine
• Pharmacokinetic properties are not determined

Mixed Serotonergic Agents
Nefazodone Trazodone Vilazodone

Dosing Range 300-600 150-g00 10-40 mg/day
mg/day mg/day
Note Carries a BBW Place in
for liver failure therapy has
not been
determined yet
Side Effects Orthostatic Orthostatic Diarrhea,
hypotension, hypotension, nausea,
dizziness, sedation, vomiting,
somnolence, dizziness trouble
dry mouth, sleeping
nausea,
Pharmacokinetics of mixed serotonergic agents
(hours) (%) s
Nefazodone 20 2-4 1 99 Yes
Trazodone Unknown 6-11 1-2 92 Yes
Vilazodone 72 25 4-5 > 95 Not determined

Drug Interactions with the mixed serotonergic agents
• Nefazodone is an inhibitor of CYP3A4
• Example: nefazodone can increase triazolam levels, so reduce triazolam dose by 75%
• Trazodone is a substrate of CYP3A4, but does not inhibit or induce it

• Caution when combining with CYP3A4 inducers or inhibitors
• Vilazodone is also a substrate of CYP3A4
• Caution when using with other serotonergic agents due to risk of SS

Bupropion
• Side effects include:

• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold
• Interesting fact: bupropion is actually used as a smoking cessation agent
• Another interesting fact: bupropion could be used to mitigate sexual dysfunction side effects of
SSRI agents
Bupropion continued…
• Pharmacokinetic properties
• Half-life is 10-21 hours
• 3 active metabolites exist for bupropion, so take into consideration when using this medication
• Drug Interactions
• Use with MAOis may increase the risk of hypertensive crisis
• Medications that also lower the seizure threshold (examples: antipsychotics, antihistamines)
• One of bupropion’s metabolites inhibits CYP2D6 (like fluoxetine and paroxetine)
Mirtazapine
• Initial dose is 15 mg/day; dose range is 15-45 mg/day
• Side effects include:

• Somnolence and sedation
• Dry mouth
• Weight gain
• Constipation
• Interesting fact: in clinical practice, mirtazapine is used as an appetite stimulant

Mirtazapine continued…
• Half-life is 20-40 hours
• No active metabolites
• Other serotonergic agents as the risk of SS is increased
• Sedating effects of mirtazapine may be enhanced when given with CNS depressants such as alcohol
or benzodiazepines
• Mirtazapine is a substrate of CYP2D6, CYP3A4, and CYP1A2
• Inhibitors may increase mirtazapine blood levels and inducers may decrease mirtazapine levels
Vortioxetine
• Initial dose: 5 or 10 mg/day; dosing range = 5-20 mg/day
• Side effects:
• Sexual dysfunction
• Nausea/vomiting
• Dizziness
• Dry mouth
• Diarrhea/constipation
Vortioxetine continued…
• Half-life is ~ 66 hours
• No active metabolites
• Other serotonergic agents as the risk of SS is increased
• Vortioxetine is metabolized by CYP2D6
• Inhibitors of CYP2D6 will increase concentration of vortioxetine, while inducers will decrease concentration of
vortioxetine
Consider this for the SSRI Agents!
Consider for… Avoid or use caution in…
• Paroxetine for underweight • Paroxetine for overweight or

patients obese patients
• Paroxetine for insomnia • Citalopram and escitalopram
• Fluoxetine and sertraline for in QTc prolongation or
psychomotor retardation torsades risk
• Fluoxetine for overweight or • Fluoxetine and sertraline in
obese patients agitation or insomnia
• Paroxetine in pregnancy
Consider this for the SNRI Agents!
• Psychomotor retardation • Hypertension
• Chronic pain • Agitation or insomnia

Consider this for Bupropion!
• Sexual dysfunction concern • Seizure disorders
• Smokers • Hypertension
• Psychomotor retardation • Agitation or insomnia
• Fatigue or sleepiness
• Overweight or obese patients

Consider this for Mirtazapine!
• Agitation • Overweight or obese patients
• Insomnia • Hyperlipidemia
• Underweight patients/low
appetite
Initial Treatment
Severity Level PHQ-9 Score Initial Treatment
Strategies
Mild 10-14 Evidence-based
monotherapy:
psychotherapy or
pharmacotherapy
Moderate 15-19 Evidence-based

monotherapy:
psychotherapy or
pharmacotherapy
Severe >/= 20 Combination of

psychotherapy and
pharmacotherapy
STAR*D Trial
• STAR*D Trial
• Sequenced Treatment Alternatives to Relieve Depression
• Funded by the National Institute of Mental Health
• Largest and longest study ever conducted to evaluate
depression treatment
• Goal: to assess the effectiveness of depression treatments in
patients diagnosed with MDD
• 4 levels in the study
• Those participants who did not reach remission in one level could
proceed to the next level of treatment
STAR*D Trial continued…
• Who participated?
• 7-year period, study enrolled 4,041 outpatients
• Ages 18-75 years old
• 1,165 excluded, so 2,876 participants were actually evaluated
• Treatment Levels
• Level 1: Citalopram was given to participants for 12-14 weeks
• Level 2: Switch to sertraline, bupropion SR, venlafaxine XR or psychotherapy, or
add bupropion SR, buspirone, or psychotherapy to citalopram from level 1
• Level 3: Switch to mirtazapine or nortriptyline, or add lithium or triiodothyronine
(T3) to their current regimen
• Level 4: Switch to tranylcypromine or combination of venlafaxine XR with
mirtazapine
• Results
• Outcome measure in this trial was remission of symptoms, not response
• In level 1, ~33% reached remission and another 10-15% responded
• It took approximately 7 weeks to reach remission
• In level 2, in the switch group, ~25% reached remission, and in the add-on
group, ~33% reached remission
• In level 3, in the switch group, 12-20% reached remission, and in the add-on
group, ~20% reached remission
• In level 4, 7-10% reached remission
• Investigators conclude: ~50% of participants reached remission after 2
treatment levels, and over the course of all 4 levels, almost 70% of those
who did not withdraw reached remission
• What can we take away from this trial?
• If a patient fails one SSRI, it does not mean that he/she will fail another
• Monoamine oxidase inhibitors are limited because of their tolerability
profiles
• Patients with difficult-to-treat depression can get well after trying different
treatment strategies, but the odds of reaching remission lessen with every
additional treatment strategy needed
• Those who reach remission have a better chance of remaining symptom-
free compared with those who just experience symptom response
• Provide medications at optimal doses, maintain diligent monitoring, and try
different treatment choices
Assessing the Adequacy of Antidepressant Interventions
• APA Guidelines
• 4-6 weeks of treatment at target dose is needed before
concluding that a patient is unresponsive or partially
responsive to a specific therapy
• If patient has not reached remission, may consider
switching a patient to an agent within the same class or
to an agent from a different class
• Augmenting the first therapy with a non-MAOi
antidepressant from a different class or augmenting with
a non-antidepressant therapy (lithium, T3, second-
generation antipsychotic) are also second-line options
Assessing the Adequacy of Therapeutic Interventions
continued…
• After 7-10 days
• Improved sleep
• Reduced anxiety
• After 7-21 days
• Improved self-care
• Improved thinking, concentration
• Increased energy, activity level
• Appetite impairments resolve
• After 2-4 weeks
• Improved mood
• Reduced suicidal ideation (SI)
Back to our patient: MG
Recap of Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for acute complaints of rapid onset
episodes of palpitations, shortness of breath, sweats, trembling, and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the belief that she was having a heart
attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes occurring at work, at home, and
while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the resolution of the symptoms of each
acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps and headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years earlier
• Father –healthy
• Two brothers are healthy
In Conclusion
• Anxiety is a normal human emotion, that when excessive, may result in an
anxiety disorder
• Anxiety disorders are frequently misdiagnosed
• Major depressive disorder is a DSM-5 diagnosable condition Treatment
guidelines help healthcare professionals make treatment recommendations
and choices
• There is overlap between the agents that can be used to treat anxiety disorders
(especially the two discussed in this presentation) and MDD
Valuable MDD Resources
• VA/DoD Clinical Practice Guidelines for the Management
of Major Depressive Disorder (2016):
https://www.healthquality.va.gov/guidelines/MH/mdd/VA
DoDMDDCPGFINAL82916.pdf
• APA Practice Guideline for the Treatment of Patients

With Major Depressive Disorder (2010):
http://psychiatryonline.org/pb/assets/raw/sitewide/practic
e_guidelines/guidelines/mdd.pdf
Questions??
Thank you for your time and attention!
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)
Lecturer: Teresa Elsobky, Pharm.D., BCPP

Clinical Psychiatric Pharmacist
Neurocognitive Disorders
Kimberly Hayashi, PharmD
khayashi@su.edu
Objectives
1. Describe the differences in dementia and delirium
2. Identify common medication causes of delirium
3. Identify the MOA, doses, and common side effects of
dementia medications
4. Given a patient case, determine the reversible causes of
dementia and identify a treatment plan
5. Given a patient case, recognize non-cognitive symptoms
of dementia and identify appropriate treatment options
Case
An 95 yo male Aemon Targaryen was Medication List:
admitted to the hospital after a fall. He has a
Lisinopril/HCTZ 12.5/25 1 tab daily
past medical history of HTN, anxiety, Amlodipine 5 mg 1 tab daily
dementia, hypercholesterolemia, and type 2 Atorvastatin 40 mg 1 tab daily
diabetes mellitus. Alprazolam 1 mg 1 tab prn
Zolpidem 5 mg 1 tab nightly
Metformin 1000 mg 1 tab BID
DSM V
● Delirium ● Dementia
○ Causes ○ Minor vs Major
○ Presentation ○ Presentation
○ Management ○ Treatment
Fong TG. Nat Rev Neurol. 2009 5(4):210-20

APA Delirium Clinical Practice Guidelines 2010.
DSM V
Delirium
● Presentation
○ Hypoactive
○ Hyperactive
○ Mixed
● Duration
○ Acute
○ Persistent
Fong TG. Nat Rev Neurol. 2009 5(4):210-20
APA Delirium Clinical Practice Guidelines 2010.
Delirium
Common Causes
Potentially Modifiable Non modifiable
Medications
● Sensory Impairment ● Dementia
● Medications ● Age (>65) Anticholinergic
Benzodiazepines
● Infection ● Hx of delirium
Hypnotics
● Metabolic (dehydration) ● Multimorbidity Opioids
● Surgery ● Chronic renal, hepatic Corticosteroids
● Pain disease Herbals
● Sleep
● EtOH or illicit drug
withdrawal
Fong TG et al. Nat Rev Neurol. 2009 5(4):210-20
Delirium
Medications Hypnotics
Anticholinergic ● Zolpidem (Ambien),
● TCA’s ● Eszopiclone (Lunesta),
○ Amitriptyline (Elavil) ● Zaleplon (Sonata)
● Diphenhydramine (Benadryl) Opioids
● Oxybutynin (Ditropan, ● Tramadol (Ultram),
Oxytrol) ● Hydrocodone, Oxycodone
Benzodiazepines Herbals/OTC
● Alprazolam (Xanax), ● St. John’s Wort
● Diazepam (Valium), ● Valerian root
● Lorazepam (Ativan), ● Loperamide (Imodium)
● Temazepam (Restoril) Fong TG et al. Nat Rev Neurol. 2009 5(4):210-20
Khawaja, IS. et al Psychiatric Services, 50(7), pp. 969a–970
Delirium
Presentation
Characteristic Delirium
Onset Sudden
Course Fluctuating
Cognition Disordered
Attention Disordered
Consciousness Reduced
Delusions Fleeting
Arnold E. Nursing. 2004:34(6);36-42
Speech Often Incoherent Inouye et al. Ann intern Med.1990;113:941
http://nursing.advanceweb.com/
Delirium
Management
● Prevention Is Key!
○ 30-40% of delirium cases are preventable
● Non-pharmacologic strategies are First Line
○ Reorientation, appropriate environment (sleep, no
restraints, family)
● Pharmacologic treatment only if delirium might
compromise safety Arnold E. Nursing. 2004:34(6);36-42
APA Clinical Practice Guidelines; 2010
Treatment
Pharmacologic
1st Generation Antipsychotics (Typical)
● Haloperidol (Haldol)
● EKG, sedation, pseudoparkinsonism, prolactin levels
2nd Generation Antipsychotics (Atypical)
● Quetiapine (Seroquel), Olanzapine (Zyprexa), Risperidone
(Risperdal), Ziprasidone (Geodon)
● More anticholinergic SE, Orthostatic hypotension, weight
gain APA Clinical Practice Guidelines; 2010
Case
An 95 yo male Aemon Targaryen was Medication List:
admitted to the hospital after a fall. He has a
past medical history of HTN, anxiety, Amlodipine 5 mg 1 tab daily
dementia, hypercholesterolemia, and type 2 Atorvastatin 40 mg 1 tab daily
diabetes mellitus. He has been admitted for Alprazolam 1 mg 1 tab prn
4 days, and at morning rounds he is Zolpidem 5 mg 1 tab nightly
withdrawn and slow to respond. Later in the Metformin 1000 mg 1 tab BID
afternoon when the nurse comes to bring
medications, Aemon was very agitated,
restless and had difficulty following
conversations with his nurse.
Case
1. How would you characterize Aemon’s delirium?
2. What are his nonmodifiable risk factors for developing delirium?
3. What are his modifiable risk factors?
4. How would you manage these causes?

DSM V
Dementia
● Minor Neurocognitive Disorder
○ Alzheimer’s Dementia, Lewy Body Dementia, Vascular Dementia,
Frontotemporal Dementia
○ With or without behavioral disturbances
● Major Neurocognitive Disorder

○ Alzheimer’s Dementia, Lewy Body Dementia, Vascular Dementia,
Frontotemporal Dementia American Psychiatric Association: Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association, 2013
Simpson JR. J Am Acad Psychiatry Law 42:159 – 64, 2014
Dementia
Types of Dementia
● Alzheimer’s Dementia
○ Most Common - 50-60% of diagnosed dementias
● Vascular Dementia
● Lewy Body Dementia
● Frontotemporal Dementia (Pick’s Disease)

Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s
● Reversible causes of Dementia Disease. In: Pharmacotherapy: A Pathophysiologic

Approach, 10e. 2017
Reversible Causes
Diagnosis of Exclusion
● Drugs
Drugs
● Emotional illness (depression)
Anticholinergic
● Metabolic/endocrine disorders Benzodiazepines
Hypnotics
Opioids
● Eye (visual problems)/Ear (hearing) Antipsychotics
Anticonvulsants
● Nutrition/neurologic problems
● Tumors; trauma; toxins

Dementia
Medications
Anticholinergic Antipsychotics
● Haloperidol (Haldol),
Benzodiazepines ● Risperidone (Risperdal),
● Olanzapine (Zyprexa),
● Ziprasidone (Geodon)
Hypnotics Anticonvulsants
● Phenytoin (Dilantin),
Opioids ● Valproate (Valproic Acid),
● Carbamazepine (Tegretol)
Herbals ● Levetiracetam (Keppra)
● Monitor for drug interactions
Dementia
Presentation
Characteristic Dementia Delirium
Onset Gradual Sudden
Course Stable Fluctuating

Cognition Impaired Disordered
Attention Usually normal Disordered

Consciousness Clear Reduced
Speech Word finding difficulties and Often incoherent
perseveration
Arnold E. Nursing. 2004:34(6);36-42
Dementia
Prevention
● Cognitive Stimulation
● Diet
● Exercise
● Smoking cessation
Seeley WW, Miller Bl. Chapter 371. Dementia. In: Harrison’s Principles of Internal Medicine, 18e. 2012.
Alzheimer's Disease
Neurotransmitter Dysfunction
● Pathology ● Neurotransmitter depletion
○ Neurofibrillary tangles (NFTs) ○ Acetylcholine
and β-amyloid plaques ○ Norepinephrine
○ Degeneration of neurons ○ Serotonin
○ Cortical atrophy ○ Dopamine→ metabolized to
MAO-B
● Dysregulation
○ Glutamate
Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Treatment
Goals
● Support quality of life for both patient and caregiver
● Preserve function for as long as possible
● Minimize psychiatric/ behavioral symptoms
● Palliative care approach
Cannot cure or reverse disease process
Treatment
Non-Pharmacologic
● Setting schedules
● Reduce environmental triggers
○ Noises, insecure space, light
● Caregiver support programs
● Adequate sleep, hydration, nutrition
○ Exercise, relaxation techniques
● Occupational therapy
Treatment
Pharmacologic
● Acetylcholinesterase Inhibitors
○ Donepezil (Aricept)
○ Rivastigmine (Exelon)
○ Galantamine (Razadyne)
● N-Methyl D-Aspartate Receptor Antagonist

○ Memantine (Namenda)
Treatment
AChE Inhibitors
● MOA: Reversibly inhibits
AChE to prevent the
degradation of ACh
● AChE Inhibitor
○ Donepezil (Aricept®)
○ Rivastigmine(Exelon®)
○ Galantamine (Razadyne®)
http://peaknootropics.com/acetylcholinesterase-memory-problems/
Donepezil (Aricept®)
AChE Inhibitor
Indication Mild- Severe Alzheimer's Dementia
SLOW Titration!
Dosing Mild/Mod- 5 mg once daily →
Recommended 10 mg once daily 5mg→ 10mg
Mod/Sev- 5mg once daily → Max 23mg after 4-6 weeks
once daily
10mg→ 23 mg
Dosage Tablets/ODT- 5 mg, 10 mg After ≥ 3 mos
Form Film coated tabs- 23mg
Adjustments No Adjustments necessary
Donepezil (Aricept®)
AChE Inhibitor
Adverse Dose related:N/V/D, Anorexia, weight loss
Effects Non-Dose related: insomnia, abnormal
dreams, accidental injury,bradycardia,
dizziness, syncope, QTc prolongation Benefit:
3-6 Months
New Warning Rhabdomyolysis, Neuroleptic Malignant
Syndrome (NMS)
Drug Anticholinergics, Antipsychotics (EPS),
Interaction Succinylcholine, QTc Prolonging
Monitoring Mood, Behavior, Cognition, Functional Ability,
Bowel/Bladder Function, Pulse, QTc
Rivastigmine (Exelon®)
AChE Inhibitor
Indication Mild- Mod Alzheimer’s Dementia (PO) SLOW
Mild- Severe Alzheimer’s Dementia (Patch) Titration!
Mild-Mod Parkinson’s related Dementia (Both)
PO: Q 2
Dosing Mild/Mod: PO- 1.5 mg BID → Max 6 mg BID weeks
*with meals Patch- 4.6 mg/24 hr→ 9.5mg/24 hrs
Mod/Severe: PO- Same as above Patch: Q 4
Patch - Increase to 13.3 mg/24hr Weeks
Adjustments Weight <50 kg: consider lower maintenance

dose
Hepatic Impairment: Patch 4.6mg/24hr (MAX)
AChE Inhibitor
***
Adverse GI (dose): N/V/D, anorexia, weight loss
Diarrhea
Effects CNS: Dizziness, HA, agitation, falling
Other: tremor, site reaction (patch) Urination
Miosis
Drug Nicotine, Anticholinergics,
Bronchospasm/
Interaction Antipsychotics (EPS), Succinylcholine
Bradycardia
Monitoring Cognition, Cholinergic Crisis*, CBC (GI Excitability
bleed risk), GI Tolerance, Pulse
Lacrimation
Salivation/
If therapy is interrupted, restart titration at lowest dose
Sweating
AChE Inhibitor
Galantamine (Razadyne®)
AChE Inhibitor
Indication Mild- Mod Alzheimer's Dementia
Dosing IR/Solution: 4 mg BID (range: 16-24 mg SLOW
*with meals divided) Titration!
ER: 8 mg once daily (range: 16-24 mg daily)
Must wait at
Adjustments Renal Impairment: least 4 weeks
Mod (CrCl 9-59): Max dose 16 mg/day to increase
Sev (CrCl < 9 ml/min) Do not use
Hepatic Impairment:
Mod (Class B): Max dose 16 mg/day
Sev(Class C): Do not use
Galantamine (Razadyne®)
AChE Inhibitor
Adverse GI: Nausea(25%), Vomiting(13%), diarrhea, anorexia,
Effects weight loss
CNS:Dizziness, HA, depression, fatigue, insomnia,
Other: UTI (8%), Bradycardia, Rash
Drug Anticholinergics, Antipsychotics (EPS), Succinylcholine,
Interaction QTc Prolonging agents
Monitoring Cognition, Cholinergic Crisis*, Weight, GI tolerance, Pulse
If therapy is interrupted, restart titration at lowest dose

Treatment
NMDA Receptor Antagonist
● MOA: Uncompetitive binding to Mg2+ site on the NMDA
receptors → blocks excessive stimulation
● Memantine (Namenda®)
http://glaucoma-today.blogspot.com
Memantine (Namenda ®)
Indication Mod- Severe Alzheimer's Dementia

Dosing IR Soln: (10mg/5mL) 5 mg daily → target dose 10 mg BID
ER cap: 7 mg daily → Max: 28 mg daily
--Can titrate weekly--
Adjustments Renal Impairment = CrCl 5-29 mL/min:
IR:Max 5 mg BID; ER: 14 mg daily
Memantine (Namenda ®)
Adverse CV: hypertension, hypotension
effects CNS: dizziness, confusion, HA, anxiety, depression,
GI: constipation, diarrhea Other: cataract
Drug Bupropion, Trimethoprim
Interaction
Monitoring Cognition, hypertension, constipation, CNS changes, rash
Clinical Pearls
Acetylcholinesterase Inhibitors
● Benefit in 3-6 months
● Donepezil best tolerated oral AChE Inh
● Transdermal rivastigmine has least GI ADEs
● Remember goals of therapy-
○ Discontinue medications if no benefit
○ Taper Cholinesterase Inhibitors
■ Ex. Donepezil 10 mg → 5 mg for one month→ Then
discontinue
Clinical Pearls
NMDA Receptor Antagonists
● Over all well tolerated
● No clinical difference between XR and IR
● When added to Acetylcholinesterase Inhibitors likely

no clinically significant benefit
Alternative Treatments
Treatment Evidence Concerns
Vitamin E No clinical benefit in dementia Higher bleed risk

treatment and toxicity
Ginkgo biloba RCT show no protection in Interaction: anticoagulants,
developing dementia antiplatelets
Omega-3 Fatty Acids No clinical benefit in Alzheimer's Antiplatelet activity
Huperzine A Limited clinical benefit GI, insomnia
Prevagen No peer-review research in HA, Dizziness, confusion

humans or animals
Noncognitive Symptoms
● Psychotic symptoms
● Disruptive/inappropriate behavior
● Depression
Non-Cognitive Sx
Management
● Nonpharmacologic treatment
○ Redirection, animal therapy, multisensory stimulation, emotion
oriented therapy
○ Occupational Therapy
● Pharmacologic
○ Initiate when symptoms pose a risk to patient or caregiver
○ Patient in severe distress
Risk vs Benefits
VA-ESP Project #50-225, 2011
American Association for Geriatric Psychiatry Position Statement, 2006
Psychosis
Antipsychotics - haloperidol, risperidone, olanzapine, quetiapine
● May help with aggression and agitation
● BBW- Elderly patients with dementia → increased risk of
death
● ADE- somnolence, EPS, worsening cognition, hypotension,
abnormal gait, metabolic effects, cerebrovascular events
● Do no use > 12 weeks
● Drug Interactions!!
Disruptive/Inappropriate Behavior
● AChE Inh - may reduce use of antipsychotics
● Antipsychotics - agitation with psychosis, sexual
aggression, impulse control in men
● Benzodiazepines- PRN for infrequent agitation
○ ADEs- impaired cognition, worsening of breathing
disorders, increased fall risk
● Mood stabilizers- Carbamazepine, valproic acid
○ Evidence conflicting
Depression
SSRIs
● Citalopram (Celexa) or sertraline (Zoloft) - 1st line
○ ADEs- Nausea, agitation, insomnia, sexual
dysfunction
○ May help with behavior symptoms
Clinical Pearls
● Consider the symptoms you are treating and if the
benefits outweigh the risks
● Use lowest effective dose
● Offer oral before parenteral
○ If IM use single drug: lorazepam, haloperidol, or

olanzapine
Future Directions
World of Possibilities
● Citalopram
○ Reduction in amyloid-β in healthy patients and AD mice
● Vitamin D
○ Correlation b/w low serum Vit D levels and incidence of cognitive decline
● Amyloid-β monoclonal Antibodies
● Inflammation studies Sci Transl Med. 2014 May 14; 6(236): 236re4
Geriatr Psychol Neuropsychiatr Vieil. 2016 Sep 1;14(3):265-73.
Curr Alzheimer Res. 2016 Sep 30.
Budur K. etal. Alzheimer's and Dementia. 2014. 10(4):809-810
Patient Case
An 95 yo male Aemon is following up with Medication list:
his primary care provider, as winter is
coming. He has a past medical history of Amlodipine 5 mg 1 tab daily
HTN, moderate dementia, anxiety, Atorvastatin 40 mg 1 tab daily
hypercholesterolemia, and type 2 diabetes Metformin 1000 mg 1 tab BID
mellitus. The PCP would like your input on
what to start for this patient’s dementia.
Case
1. What would you like to start this patient on (drug/dose/frequency) and why?
2. What are the common side effects you would monitor for with your treatment
regimen?
Take Aways
Delirium Dementia
● Hypoactive vs Hyperactive vs Mixed ● Screen for reversible causes
(medications)
● Medical Emergency ● Treatment goals
○ Palliative in nature
● Modifiable and non-modifiable ○ QOL of patient and caretaker
causes ● Acetylcholinesterase Inhibitors
● NMDA Receptor Antagonists
● Prevention is key! ● Noncognitive Symptom
management
● Antipsychotics are used only if safety ○ Leading cause of nursing
is compromised. home placement
Kimberly Hayashi, PharmD
khayashi@su.edu
Neuromuscular Blockade in the ICU
Marcia Brackbill, Pharm.D., BCPS

Professor of Pharmacy
BJD School of Pharmacy
Objectives
Explain the mechanism of action of neuromuscular
blocking agents used in the ICU/ED
Discuss the indications and clinical effects of
neuromuscular blockade
Identify concomitant medication(s) which are necessary
when a patient is on a neuromuscular blocker
Contrast the medications within each pharmacologic class
with regards to MOA, indication, pharmacokinetic
parameters (type of elimination), adverse effects and
precautions and/or contraindications
Identify appropriate therapeutic options to reverse
neuromuscular blockade
Normal Neuromuscular
Transmission
Image source: http://www.frca.co.uk/images/acetylcholine.jpg

Normal Neuromuscular
Transmission
Image source:
http://archive.ispub.com/journal/the-internet-journal-of-orthopedic-surgery/volume-7-number-2/orthopaedic-surgery-implications-of-a-
novel-encapsulation-process-that-improves-neuromuscular-blockade-and-reversal.html#sthash.uVggnUzg.dpbs
MOA
Work on skeletal muscles postsynaptic nicotinic acetylcholine
(ACh) receptor
Two categories (same clinical result – Paralysis)
Depolarizing – works by binding to Ach receptors and
causes persistent depolarization of the neuromuscular
endplate, causing sustained contraction
Succinylcholine is structurally similar to acetylcholine (2 ACh
molecules bonded together)
Non-depolarizing – bind to alpha subunits of intra-junctional
ACh receptor on the postsynaptic membrane leading to
inhibition of current through receptor
What do you need to be sure the patient is receiving when

you administer a NMBA?
Inhibited Transmission
Image source:
NMBA’s
Depolarizing – Just one agent!
Succinylcholine (Anectin)
Very quick onset and short duration of action
Onset < 1 min
Duration: 5-10 min
Produces initial muscle fasciculation followed by
a flaccid paralysis
Frequently use for intubations
Not indicated for prolonged (i.e. continuous
infusion) use b/c of SE’s: release of histamine,
rising potassium levels, risk of malignant
hyperthermia, elevated intragastric and
elevated intraocular pressures
NMBA’s
Non-Depolarizing
Chemical class: benzylisoquinoline
Atracurium (Tracrium)
Cisatracurium (Nimbex)
Chemical class: aminosteroid
Pancuronium (Pavulon)
Rocuronium (Zemuron)
Vecuronium (Norcuron)
Indications for NMBA’s
Facilitate endotracheal intubation
Assist with mechanical ventilation (after sedation and

analgesia have been optimized)
ARDS (PaO2/FiO2 is < 150)
Immobilization for selected procedures
Increased intracranial pressures

Traumatic Brain Injury (TBI)
Prevention of shivering during implementation of cardiac

hypothermia protocols
Treat life threatening agitation refractory to aggressive

sedation and analgesic therapy
Contraindications of
NMBA’s
Inability to obtain a secure airway
Patient not on analgesia and sedation
Unstable bone fractures
Relative contraindications include burns,
hemiplegia, hemiparesis, and peripheral
neuropathy
Receptors may be resistant to NMBAs and lead
to excessive doses
Factors to Consider When Selecting
a NMBA
Duration of procedure - (duration of action)
Need for quick endotracheal intubation (onset of action)
Adverse effect profile (hemodynamic instability,
histamine release)
PK/route of elimination (especially in patients with renal
or hepatic insufficiency)
Concurrent medications/drug interaction
Cost/Availability/Formulary Agents
Comparison of NMBAs
Agent Onset of Action DOA Metab Comments
atracurium 2-4 min 30-40 Hoffman can be used in MOF;
causes MCD
cisatracurium 2-3 min 40-60 Hoffman can be used in MOF
pancuronium 4-6 min 120-180 renal causes MCD
vagolytic  HR , BP
rocuronium 1-2 min 30-40 hepatic facilitates intubation
 HR
vecuronium 2-4 min 30-40 hepatic no MCD/ histamine
MOF = multiple organ failure
release
MCD = mast cell degranulation and histamine release
Factors Which May Prolong
the Action of NMBA
Paralysis
Medications
Antibiotics (aminoglycosides, clindamycin, tetracycline,
polymyxin B, vancomycin), beta blockers, Ca channel
blockers, corticosteroids, local anesthetics, lidocaine
Clinical Conditions
Acidosis, renal/ hepatic failure, severe electrolyte toxicity
(i.e. hypermagnesemia), hypothermia, neuromuscular
disease (Myasthenia Gravis, Muscular Dystrophy), renal
failure
Factors Which May Prevent
Desired Levels of Paralysis
Medications
Anticholinesterase agents, carbamazepine
(Tegretol), phenytoin (Dilantin), ranitidine
(Zantac)
Clinical Conditions
Alkalosis, demyelinating lesions, diabetes,
peripheral neuropathies
Reversal
Image source:
Reversal Agents
MOA: acetylcholinesterase inhibitors
Prevent breakdown of acetylcholine in synaptic
cleft to overcome the NMBA
Neostigmine (Bloxiverz)
0.03mg/kg for rocuronium & shorter duration
agents
0.07mg/kg for vecuronium and pancuronium due to
longer duration of action
Edrophonium (Enlon) -less commonly used
10mg may repeat every 5-10min up to 40mg
Reversal Agents (cont.)
MOA: Selective Relaxant Binding Agent (SRBA)
Selectively forms a tight complex with aminosteroid
NMBAs and removes them from the NMJ into the
plasma for removal
Sugammadex (Bridion)
Approved by the FDA December 2015
Potential advantage: provide more rapid reversal
of aminosteroid NMBAs
May allow for use of aminosteroids NMBA agents for
emergency intubations in patients where succinylcholine is
contraindicated
ADRs: Watch for bradycardia & hypersensitivity reactions

Complications With
Difficulty in clinical
NMBAs
DVT
assessment of certain
pathologies Pressure ulcers
Acute abdomen, angina,
neurologic alterations
Corneal ulcers
Increased protein Prolonged paralysis

catabolism may be due to
1. accumulation of the
Tachyphylaxis drug
2. acute myopathy (AKA
Myositis ossificans acute quadraplegic
(calcification of the myopathy syndrome –
muscle) most serious side effect
and may occur with
Peripheral nerve damage infusions of 1-2 days)
Monitoring NMBAs
Critical: Always verify patient is receiving Image source:

http://www.bge.com.b
r/img%20banner/01x.j
sedation/analgesia !! pg
Train-of-Four (TOF)
Peripheral nerve stimulator –used to intermittently
monitor neuromuscular transmission during long-
term administration of muscle relaxants in the ICU
TOF – Electrode Placement
TOF – Procedure and Goals
Electrical stimuli (4) used to evoke a
"twitch" responses from the patient which may be
observed (tactile and visual observation) by the clinician
Goal - 1 twitch (out of 4 ) - which correlates to 90%
blockade
Decreases likelihood of prolonged paralysis/myopathy
When do you perform TOF monitoring?
Baseline
15 minutes after bolus dose (or change in infusion rate) titrate
to clinical endpoint every 15 minutes
When patient is clinical stable (at clinical endpoint), monitor
every 4 hours
Questions?

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Antipsychotic

Nicole Romstadt, PharmD

• Describe the mechanisms of action for first and second generation

Positive Symptoms Mania Symptoms

Potentially Inappropriate Indications

Schizophrenia Spectrum and Other Psychotic Disorders

Mesolimbic pathway Nigrostriatal pathway

Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.

Receptor Mechanism Clinical Effects

Considerations when selecting medications

Phase 1 - Acute Stabilization Phase 3- Maintenance and Relapse

Patient Factors Environmental Factors

• Suboptimal response to treatment

DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014

DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014

First Generation – “Typical” Class Characteristics

Low Potency Mild Potency High Potency

• Higher doses needed • Lower doses needed for

Extrapyramidal Symptoms (EPS)

Acute Dystonic Reaction

Tardive Dyskinesia (TD)

Tardive Dyskinesia (TD)

Neuroleptic Malignant Syndrome

Nielsen J, et al. CNS Drugs. 2011;25:473–490.

Second Generation – “Atypical”

Clozapine 300 – 450 mg daily 900 mg REMS program

Iloperidone 12 – 24 mg BID 24 mg Cardiovascular effects

Lurasidone 20-120 mg Daily 160 mg Take with 350 calories

Quetiapine 400-800 mg Daily-BID 800 mg BBW for SI in children-adolescents

Risperidone 4-6 mg Daily 16 mg Orthostasis, hyperprolactinemia

Ziprasidone 80-160 mg BID 160 mg Take with 500 calories

Overlap with FGAs

American Diabetes Association. Diabetes Care. 2004;27(2):596-601.

Oral Conversion Strategies

Bartolomeis A, et al. Neuropsychiatr Dis Treat. 2016;12:99-108.

Medication Dosing Oral Overlap Considerations

Haloperidol • Starting dose = 10-15x PO • Continue • Deltoid or gluteal

Medication Dosing Oral Overlap Considerations

Medication Dosing Oral Overlap Considerations

Paliperidone • Loading sequence of • None • Detailed directions

Medication Dosing Oral Overlap Considerations

Treatment Resistant Schizophrenia

Black Box Warnings

Mitigating Severe Adverse Effects

Risk Evaluation and Mitigation Strategy (REMS) Program

Clozapine REMS Program website (www.clozapinerems.com)

Clozapine REMS Program website (www.clozapinerems.com)

Clozapine REMS Program website (www.clozapinerems.com)

Other Adverse Effects

Chlorpromazine Yes 100 mg BID $892

Fluphenazine Yes 5 mg BID $72

Haloperidol Yes 10 mg BID $107

Aripiprazole Yes 20 mg daily $1362

Asenapine No 10 mg BID $1316

Brexpiprazole No 3 mg daily $1211

Cariprazine No 4.5 mg daily $1316

Clozapine Yes 100 mg BID $205

Iloperidone No 10 mg BID $2364

Lurasidone No 80 mg daily $1336

Olanzapine Yes 10 mg daily $596

Paliperidone Yes 6 mg daily $916

Quetiapine Yes 400 mg BID $1195

Risperidone Yes 4 mg daily $456