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PA 644 Module 2 Review Session

Fall 2017

Gretchen L. Johnson, PharmD, BCPS


Exam Content
• Approximately 50-60 multiple choice questions
• 8 questions from all lectures except 4 questions each from
Dementia, Sleep agents, NMBAs, and ADHD
• No doses to memorize
• Will have opiate dose conversions. Table of equianalgesic doses
will be provided, % cross tolerance and % for breakthrough pain
dose to use given and calculator enabled
• MOA/Therapeutic class of all agents
– Mood stabilizers- Lithium is only one to know MOA
Antipsychotic
Pharmacotherapy

Nicole Romstadt, PharmD


Psychiatric Clinical Pharmacy Specialist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Brief Review of Pathophysiology

Schizophrenia Spectrum and Other Psychotic Disorders


• Exact mechanism is unknown
• Dopamine (DA) hypothesis
• Most recognized theory
• DA hyperfunction in mesolimbic system → positive symptoms
• DA hypofunction in prefrontal cortex → negative symptoms
• Other implicated neurotransmitters
• Serotonin, glutamate, GABA, acetylcholine
Antipsychotics MOA

Class Commonality Class Variability


• Dopamine antagonism • Other receptor involvement
• BLOCKS dopamine from • 5HT2A antagonism is the
acting at post-synaptic D2 commonality with SGAs
receptors • May also act as antagonists
• Action in mesolimbic at ⍺1, H1, M1
pathway treats positive • Receptor affinity and
symptoms activity varies between
• Requires approximately agents
60-70% dopamine • May account for either
blockade desirable or adverse
• Higher blockade increases effects
risk for adverse effects
Dopamine Pathways

Mesolimbic pathway Nigrostriatal pathway


• Emotional center related to arousal, • Controls movement
memory, motivation, reward • Nigrostriatal D2-antagonism →
↑extrapyramidal symptoms (EPS)
• ↑DA → ↑psychosis (+ive symptoms)
• Mesolimbic D2-antagonism →
↓positive symptoms Mesocortical pathway
• Controls cognition, communication,
executive functioning
Tuberoinfundibular pathway
• ↓ DA levels → ↑negative symptoms
• Innervates pituitary gland
• Mesocortical D2-antagonism →
• Tuberoinfundibular D2-antagonism → ↑negative symptoms
↑elevated prolactin
Key receptors ANTAGONIZED
Receptor1 Increase Decrease
D2 • ↑ EPS (Nigrostriatal) • ↓ positive symptoms (Mesolimbic)
• ↑ PRL (Tuberoinfundibular) • ↓ mania
• ↓ cognitive fxn (Mesocortical)
5HT2A • ↓ negative symptoms
• ↓ depression
• ↓ EPS
⍺1 • ↑ Orthostasis • ↓ adrenergic outflow (hyperarousal)
• ↑ reflex tachycardia (HR)
H1 • ↑ Sedation
• ↑ confusion
• ↑ falls
• ↑ weight gain
M1 • ↑ Anticholinergic effects • ↓ EPS
• dry eyes/mouth
• Constipation
• Confusion/delirium
• Falls
• urinary retention
.
Schizophrenia Treatment Algorithm Know Stage 1A and Stage 1B

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


1st GEN “TYPICAL” Antipsychotics

• LOW Potency Class Characteristics


• Chlorpromazine (Thorazine®) • More potent D2 antagonism → ↑EPS
• HIGH Potency • ↓metabolic ADR
• Fluphenazine (Prolixin®) • D2 antagonism in mesocortical pathway
• Haloperidol (Haldol®) w/o 5HT2A antagonism → +/- ↑ negative
symptoms

• [LOW potency → ↑anticholinergic (M2),


sedation, orthostatic hypotension (H1)]

• (HIGH potency → ↑EPS)


FGA D2 Potency Comparison

Low Potency Mild Potency High Potency


Chlorpromazine (Thorazine) Loxapine Haloperidol
(Haldol)
Thioridazine Perphenazine Fluphenazine
(Prolixin)
Thiothixene

Trifluoperazine

• Higher doses needed for • Lower doses needed for


antipsychotic effect antipsychotic effect
• ↑ anticholinergic effects, • ↑EPS
sedation, orthostasis
1st GEN AP Dosing
Medication AVG Doses MDD Special Considerations

Chlorpromazine 200-600 BID-QID 1000 mg Sedation, anticholinergic, orthostasis


(Thorazine) mg (M2 and H1)
Fluphenazine <20 mg TID-QID 40 mg High incidence EPS
(Prolixin)
Haloperidol <30 mg BID-TID 100 mg High incidence EPS
(Haldol)
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


Black Box Warning

BBW for ALL Antipsychotics 1st and 2nd GEN!!


• DO ANTIPSYCHOTICS IN Elderly patients with dementia-related psychosis →
↑risk of death.
Extrapyramidal Symptoms (EPS) ADR
(↑ risk w/ Haldol and Prolixin)

Akathisia Dystonia
• (urge to move, restlessness) • (acute onsest when starting,
• Management skeletal mm contractions)
• DC or ↓ dose • Management
• Add Propranolol 30-120mg/day • DC or ↓ dose
in divided doses • Add BDZ 1-2 mg/d IM
• Add Diphenhydramine 25-
50mg/d
Extrapyramidal Symptoms (EPS) ADR
(↑ risk w/ Haldol and Prolixin)

Pseudo-parkinsonism Tardive Dyskinesia


• (slow voluntary mvmt, cogwheel, pill • (late onset mos/yrs, purposless mvmt,
roll, shuffle - reversible) lip smack, lat jaw, tongue, trunk, limbs)
• Management • Prevention
• DC or ↓ dose • ↓ AP exposure via periodic dose ↓
• Add BDZ 1-5 mg/d • Avoid prolonged anticholinergic use
• Triheylphenidyl 5-15 mg/d • Management
• Diphenhydramine 25-150mg/d • DC AP / Consider switch to
Clozapine
• ↓Anticholinergic use
• Supportive tx
• Valbenazine (Ingrezza) new drug
Other ADR

Neuroleptic Malignant Syndrome


• (↑ mm rigidity, autonomic instability,
AMS, acute onset days/weeks)
• Management
• DC ALL APs
• Supportive tx
• Add DA agonist
• (bromocriptine or amantadine)
• Add Skeletal mm relaxer
• (dantrolene)
Cardiovascular ADR

Orthostatic Hypotension Monitoring


• (⍺1 antagonism) • ECG at baseline, then annually
• ↑ incidence with clozapine, • Consider ECG if adding QTc-
iloperidone, risperidone, prolonging meds or ↑ AP
quetiapine
dose
• Initiate at low doses, titrate
slowly • K+, Mg2+ at baseline and PRN

QTc Prolognation • DON’T USE THIORIDAZINE


• Torsades de Pointes (TdP) (MELLARIL) (1ST GEN) OR
• Thioridazine has BBW ZIPRASIDONE (GEODON) (2ND GEN)
• Dose-dependent increase
1st GEN AP – Other ADR

Hyperprolactinemia Anticholinergic
• (Tuberoinfundibular DA antagonism) → ↑ • Clinical presentation
PRL) • Dry mouth, eyes, throat, urinary
• ↑ risk with ↑D2 affinity (2nd gen retention, constipation
Risperidone, AND 1ST GENS) • Blurred vision, worsening of
• Clinical Presentation glaucoma
• Men – Ejaculatory/Erectile dysfunction • Confusion, delirium, falls in elderly
• Women – Amenorrhea
• Both - galactorrhea, ↓ libido
FGA Adverse Effect Comparison – KNOW 1ST THREE IN RED
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
2nd GEN Atypical Antipsychotics

• Aripiprazole (Abilify®) Class Characteristics


• Asenapine (Saphris®)
• Brexpiprazole (Rexulti®) • ↓ potent D2 antagonism dt
• Cariprazine (Vraylar®) shorter duration of receptor
• Clozapine (Clozaril®) occupancy compared to 1st GEN
• Iloperidone (Fanapt®) → ↓ EPS
• Lurasidone (Latuda®)
• Olanzapine (Zyprexa®) • 5HT2A antagonism → may ↓neg
• Paliperidone (Invega®) symptoms
• Quetiapine (Seroquel®) • ↑metabolic ADR
• Risperidone (Risperdal®)
• Ziprasidone (Geodon®)
Medication Special Considerations

Aripiprazole • ↑akathisia
2nd GEN APs (Abilify) • BBW for SI in children-adolescents

Clozapine • REMS program


(Clozaril)

Lurasidone • Take with 350 calories


(Latuda) • BBW for SI in children-adolescents

Olanzapine • BBW for post-injection delirium/sedation syndrome (PDSS)


(Zyprexa) with LAI

Paliperidone • Metabolite of risperidone


(Invega)

Quetiapine • BBW for SI in children-adolescents


(Seroquel)

Risperidone • Orthostasis
(Risperdal) • hyperprolactinemia

Ziprasidone • Take with 500 calories


(Geodon)
2nd GEN AP - ADR

Overlap with ADR of 1st GEN APs


• ↓EPS
• ↑metabolic ADR

Metabolic ADRs
• Clinical presentation
• Hyperlipidemia
• Weight gain
• Glucose intolerance → DM2
• HTN

• GL say to monitor Weight, BP, Lipids, Glucose


Adverse Effects – GL say to monitor Weight, BP, Lipids, Glucose

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.


Medication Sedation Anticholinergic EPS Weight Gain Glucose Intol. ↑Lipid
Aripiprazole Low Low Low Very low Low Very low
Adverse Effect Comparison
(Abilify)
Clozapine High High Very low Very high High High
(Clozaril)
Lurasidone Low Low Low Very low Low Low
(Latuda)
Olanzapine Moderate Moderate Low High High High
(Zyprexa)
Paliperidone Low Low High Moderate Moderate Low
(Invega)
Queitapine High Moderate Very low High High High
(Seroquel)
Risperidone Low Low High Moderate Moderate Low
(Risperdal)
Ziprasidone Low Low Low Very low Low Very low
(Geodon)
Drug Interactions

Pharmacokinetic Pharmacodynamic
• Hydrocarbons produced from • Anticholinergic
smoking cigarettes induce 1A2 • cognitive impairment,
delirium
• ↓levels of clozapine
(Clozaril) and olanzapine • Constipation
(zyprexa)
• dose adjustments if • Over-sedation
smoking status changes • Falls
• ↓if they DC smoking • drowsiness
• ↑ if they start
smoking/are smoker • QTc prolongation
Long-Acting Injectable Antipsychotics (LAIs)

Goals of Treatment
• Improve adherence
• Typically not first-line in antipsychotic naïve patients
• Oral formulations more easily titrated and less expensive
Clozapine (Clozaril®)
Treatment Resistant Schizophrenia Mitigating Severe Adverse Effects
• Lack of significant symptom improvement despite • Dose-related effects
adequate trials (dose, duration, adherence) of at
least two antipsychotics (at least one SGA) • Neutropenia, orthostatic hypotension,
bradycardia, syncope, seizures
Clozapine • Initiating at low doses and slow titration
• “patient who has had no response or partial and reduces risk
suboptimal response to two trials of antipsychotic
medication or for a patient with persistent suicidal Risk Evaluation and Mitigation Strategy (REMS)
ideation or behavior that has not responded to other
treatments” Program
• Patient, prescriber and pharmacy must be
Black Box Warnings registered
• Dementia-related mortality • Outlines absolute neutrophil count (ANC)
monitoring requirements
• Severe neutropenia
• Once weekly for first 6 months
• Orthostatic hypotension
• Every-other-week after 6-12 months
• Myocarditis
• Once monthly after 12 months
• Seizures
Clozapine (Clozaril®)

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.)
Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.
Clozapine (Clozaril®)

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 – ALL very $$$!!
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
Medication Generic Example Average Wholesale
Dosing Price for 30DS

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
Medication Generic Example Average Wholesale
Dosing Price for 30DS

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


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
• Pt education:
– Pt must be abstinent before starting- at least 12 hours since
last drink
– OTC meds alcohol content, including topicals (can induce
reaction)
– Medical alert identification
Naltrexone (ReVia)
• MOA: Opiate antagonist (like naloxone) 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 will precipitate withdrawal
– 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
Substance Abuse Pharm: Tobacco

.
Slides adapted and used with permission from Erin Adams PharmD
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
– MI within past 2 weeks
– Serious arrhythmias
– Serious or worsening angina
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 – History of seizure/
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 (↑seizure risk) 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
VARENICLINE
Chantix (Pfizer)

Nonnicotine
cessation aid
Partial nicotinic
receptor agonist
Oral
formulation
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
– Seizures
symptoms
– Diabetes
• Cardiovascular effects – Spasms
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
YES PAs can prescribe with special waiver
• 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
– 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
• ↑safety for outpatient use dt ↓ respiratory depression
(compared to methadone)
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
• 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- Monitor baseline and periodic LFTs
• Precipitate withdrawal

• Pregnancy category C
• Avoid during breastfeeding- passes in to breast milk
Reversal Agents
• Naloxone (Narcan) • Flumazenil (Romazicon)
– MOA: Opiate receptor antagonist – MOA: BZD receptor antagonist
– Used to reverse opiate effects/overdose – Used to reverse BZD 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 – DON’T NEED AN RX TO GET IT
– 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
Attention Deficit/
Hyperactivity
Disorder
Molly Rincavage, PharmD
Pharmacologic Classes

Stimulants
block NE and DA reuptake Non-stimulants
• Methylphenidates • Selective norepinephrine
• Methylphenidate reuptake inhibitors
• Dexmethylphenidate • Atomoxetine
• Amphetamines • Alpha-2 agonists
• Dextroamphetamine • Guanfacine
• Levoamphetamine • Clonidine
• Lisdexamfetamine
Stimulants MOA

• 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 MOA

• Atomoxetine
• Selective norepinephrine
reuptake inhibitor
• Inhibits reuptake of
norepinephrine, thus
increasing concentration in
synaptic cleft
Non-stimulants MOA

• Guanfacine and clonidine


• Alpha 2-adrenergic
receptor agonists
• Increase noradrenergic tone
in prefrontal cortex by
stimulating postsynaptic
alpha-2A receptors
Stimulants

Adverse Effects vasculopathy


•Common
• ↓appetite delayed growth,
insomnia, headache, irritability
•Rare
•Hypertension, tachycardia,
tics, psychosis, mania,
priapism, peripheral
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 CVD
•glaucoma, pheochromocytoma, MAOI use within 14
days
Black Box Warning
•suicidal ideation in studies in children and adolescents
Guanfacine and Clonidine

Adverse Effects
• Somnolence, hypotension, bradycardia
• Taper when discontinuing to prevent rebound
hypertension

Precautions
• Hypotension, bradycardia, heart block
• Operating heavy machinery
Drug/Drug Interactions

Monoamine oxidase inhibitors


• Concurrent use with stimulants or atomoxetine can result in
hypertensive crisis
Treatment
Guidelines know what
is recommended first
line for different ages
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
AAP Treatment Guidelines

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
Medication Selection

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
Medication Selection

Depression
• Stimulants, guanfacine, clonidine

Bipolar disorder, tics


• Guanfacine, clonidine
Medication Selection

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
Monitoring
Monitoring
Know what should be monitored but don’t need to know how to fix it!

Efficacy Safety
• Rating scales • HR • Appetite
• School • BP • Mood
performance • Height • EKG if
• Weight history of
• Sleep cardiac
disease
Response

Maximum
Dose?
No Yes
Titrate to
maximum Response?
dose

Partial None

Switch to other
Add non-stimulant stimulant class
1st!!

If still no
response,
switch to non-
stimulant
Pharmacotherapy of Insomnia

Gretchen L. Johnson, PharmD, BCPS


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 substance – differences in PKs but these are the most
common
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 ↓.time to fall asleep + ↑ total sleep time


Non-BZD GABA-A agonists (“z-hypnotics)
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)

• MOA: selective GABA-A1 receptor agonist subtype 1


• Controlled substance
Non-BZD GABA-A agonists
• Zolpidem
– Formulations available: IR (Ambien), CR (Ambien CR), lingual
spray (Zolpimist), SL (Edular, Intermezzo)

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
• Sonata can also be used this way
Non-BZD GABA-A agonists
• Zaleplon (Sonata)
– Onset: 30 min Duration: 2 hours
– Useful to initiate sleep or midnight awakenings
• 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)
BZD and Non-BZD GABA-A agonists
• FDA Labeling Changes
• Caution
– Anaphylaxis, facial angioedema
– Complex sleep behaviors- engaging in these activities 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 ↓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
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
November 8, 2016 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D


Clinical Psychiatric Pharmacist
Assistant Professor of Clinical Sciences
Bernard J. Dunn School of Pharmacy
Shenandoah University
ANXIETY DISORDERS AND
THEIR TREATMENT AGENTS
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
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
Generic Name Brand Name

Venlafaxine Effexor®

Desvenlafaxine Pristiq®
(enantiomer of venlafaxine)

Duloxetine Cymbalta®

Milnacipran Savella®

Levomilnacipran ER Fetzima®
(enantiomer of milnacipran)
Benzodiazepines
• Primary site of action: GABAA receptor (a chloride ion channel)
Available Benzodiazepines
Generic Name Brand Name
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
Generic Name Brand Name
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
Generic Name Brand Name

Phenelzine Nardil®

Selegiline Emsam®

Tranylcypromine Parnate®

Isocarboxazid Marplan®

Moclobemide Manerix®
Pregabalin (Lyrica®)
• Could be a first 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)
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
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
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
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)
• Tapers off by itself → ↓ withdrawal symptoms
• Good if they don’t remember to take it every day

• 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 (Calexa) and escitalopram (Lexapro) are the two SSRI agents with the least potential
of pharmacokinetic interactions
• Calexa - cant use more than 20 mg/d because of QT prolongation
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

Black Box Suicidal ideation in children, adolescents, and


Warning young adults

Side Effects Jitteriness, nausea/vomiting, diarrhea,


headache, sexual dysfunction, elevated blood
pressure, insomnia
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


Dosing Range 75-200 mg/day

Side Effects Jitteriness, anticholinergic


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


Dosing Range 15-60 mg/day

Side Effects Nausea/vomiting, abdominal


pain, drowsiness, dizziness
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


Dosing Range 200-400 mg/day

Side Effects Dry mouth, headache,


somnolence
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


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


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
Phenelzine

Mechanism of action Monoamine oxidase inhibitor


(nonselective)
Initial Dosing 15 mg/day
Dosing Range 30-90 mg/day

Side Effects Jitteriness, hypertensive crisis


in overdose, orthostatic
hypotension
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 2 weeks, initially, and then every
2 months

• SSRIs and SNRIs should work within 4-8 weeks, but


could be up to 12 weeks
• Readdress at 4 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
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:
• Side effect profile
• Safety and tolerability
• Pharmacological properties (half-life, drug interactions)
• Historical response to medications
• Cost
• Patient preference
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
• Initial dose: 25 mg/day; dose range is 50-150 mg/day
• Half-life can reach up to 88 hours, while amitriptyline’s half-life can reach 46 hours
Mixed Serotonergic Agents
Nefazodone Trazodone Vilazodone

Initial Dosing 100 mg/day 50 mg/day 10 mg/day


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,
Bupropion
• Initial dose: 150 mg/day; dose range is 150-450 mg/day

• 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
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


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
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!

Consider for… Avoid or use caution in…

• Psychomotor retardation • Hypertension

• Chronic pain • Agitation or insomnia


Consider this for Bupropion!

Consider for… Avoid or use caution in…

• Sexual dysfunction concern • Seizure disorders

• Smokers • Hypertension

• Psychomotor retardation • Agitation or insomnia

• Fatigue or sleepiness

• Overweight or obese patients


Consider this for Mirtazapine!

Consider for… Avoid or use caution in…

• Agitation • Overweight or obese patients

• Insomnia • Hyperlipidemia

• Underweight patients/low
appetite
Assessing the Adequacy of Antidepressant Interventions

• APA Guidelines
• 4-6 weeks of treatment are 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)
BPD PHARMACOTHERAPY:
THE MEDS (PHARMACOLOGY
FIRST)!
“MOOD STABILIZERS”
• Term used to describe the class of medications used in the
treatment of BPD
• Different medications work better in different episodes of BPD, so
use of term is inaccurate
• Medications that fall into this category:
• Lithium
• Anticonvulsants
• Divalproex sodium/Valproic acid (VPA)
• Lamotrigine
• Carbamazepine
• Oxcarbazepine
• Antipsychotics (both typical and atypical)
“MOOD STABILIZERS”
• Lithium
• 1st line agent for acute mania, acute bipolar depression, and maintenance treatment for bipolar I
and II disorders
• DOC for mania

• Anticonvulsants
• Divalproex sodium/Valproic acid (VPA)
• DOC mixed states
• Lamotrigine (Lamictal)
• Prevention/treatment bipolar depression
• Maintenance
• Carbamazepine (Tegretol)
• 1st line for hypomania
• Oxcarbazepine (Trileptal)
• Less data supporting use

• Antipsychotics (both typical and atypical)


LITHIUM (LI)
• One of the first line options for BPD; drug of choice for manic states
of BPD
• Mechanism of action (MOA):
• Lithium is a monovalent cation, sharing similar properties to sodium
(Na+)
• Hypotheses (first one):
• Li directly inhibits inositol signaling

• Inhibition of the inositol signaling pathway leads to a depletion of


free inositol

• Depletion of free inositol leads to the depletion of other enzymes

• In turn, this pathway modulates energy metabolism, provide


neuroprotection, and increase neuroplasticity
BPD PHARMACOTHERAPY:
THE MEDS (GUIDELINES
SECOND)!
TREATMENT RECOMMENDATIONS
• General recommendations for manic/mixed/hypomanic episodes
• Assess for secondary causes of episode (alcohol or drug use, for example)
• Discontinue antidepressants
• Taper off stimulants and caffeine, if possible
• Treatment substance abuse, if applicable
• Encourage good nutrition, exercise, adequate sleep, stress reduction, and psychosocial
therapy (nonpharmacological treatments)
TREATMENT RECOMMENDATIONS CONTINUED…
Hypomania

1ST - Initiate mood-stabilizing medication: lithium, valproate,


carbamazepine, or an atypical antipsychotic
Benzodiazepine?
Alternative option: OXC

2nd – If response is inadequate after 10-14 days of first-line


treatment(s) at optimized dose(s), consider a 2-medication combo:

a) Lithium + anticonvulsant or an atypical antipsychotic


b) Anticonvulsant + another anticonvulsant or an atypical
antipsychotic
TREATMENT RECOMMENDATIONS CONTINUED…
Mania

1st – Initiate 2- or 3-medication combination:


(Lithium, valproate, or an atypical antipsychotic) plus a
benzodiazepine and/or a typical antipsychotic
Do not combine antipsychotics
3rd – If response is inadequate
Alternative option: CBZ; if no response, consider OXC
after 10-14 days of second-line
treatments at optimized doses,
consider:
a) ECT or
b) Add clozapine
2nd – If response is inadequate after 10-14 days of first-
line treatments at optimized doses, consider a 3-
medication combo:

a) Li + an anticonvulsant + an antipsychotic
b) Anticonvulsant + another anticonvulsant + an
antipsychotic
TREATMENT RECOMMENDATIONS
• General recommendations for acute depressive episodes
• Assess for secondary causes of depression (alcohol or drug use, for example)
• Taper off antipsychotics, benzodiazepines, or sedative-hypnotics, if possible
• Treatment substance abuse, if applicable
• Encourage good nutrition, exercise, adequate sleep, stress reduction, and psychosocial
therapy (nonpharmacological treatments)
TREATMENT RECOMMENDATIONS CONTINUED…
Mild or Moderate Depressive Episode

1ST - Initiate or optimize mood-stabilizing medication: lithium,


quetiapine, or lurasidone
Alternative options:
a) Lamotrigine
b) Valproate
c) Fluoxetine/olanzapine combination (Symbyax®)
TREATMENT RECOMMENDATIONS CONTINUED…
Severe Depressive Episode
1st – Initiate or optimize mood-stabilizing medication:
lithium or quetiapine or lurasidone
Alternative options: Symbyax®, lamotrigine, valproate
If psychotic, add an antipsychotic (however, do not
combine antipsychotics) 4th – If response is
inadequate,
consider ECT

2nd – If response is
inadequate, consider CBZ or 3rd – If response is
adding an antidepressant inadequate, consider a 3-
medication combo:

a) Lithium + lamotrigine + an
antidepressant
b) Lithium + quetiapine + an
antidepressant
LITHIUM
• It is a monovalent cation
• Therefore, it is rapidly absorbed, is not protein bound, is not
metabolized, and is excreted unchanged
• 1st line agent for acute mania, acute bipolar depression, and
maintenance treatment for bipolar I and II disorders
LITHIUM CONTINUED…
• Efficacy:
• 78% response rate when aborting an acute manic or hypomanic
episode
• More recently, slower onset of action has been discovered
• In bipolar depression, there is a 6- to 8-week delay in its
antidepressant properties
• Maintenance treatment with Li is more effective in patients with fewer
prior episodes, with a history of good functioning between episodes,
and with a family history of response to Li
• Li has been shown to reduce suicide risk by 8- to 10-fold
• Augmenting Li with CBZ, lamotrigine, or VPA has been shown to
improve treatment response in BPD I
LITHIUM CONTINUED…
• Dosing and administration:
• Initial dosing: 300 mg by mouth twice daily
• Dosing range: 900 – 2400 mg daily in divided doses
• Administer lower dose in renal impairment
• Dosing titration will depend on patient’s response to Li and tolerance to side effects
• Immediate-release and extended-release preparations exist
• Usually would still administer > 1 time per day
• Why?
LITHIUM CONTINUED…
Monitoring parameters for Lithium
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests X X

Metabolic tests X X

Liver function tests

Renal function tests X X

Thyroid function tests X X

Serum Electrolytes X X

Dermatological tests X X
LITHIUM CONTINUED…
• Serum drug monitoring:
• ***NEED TO OBTAIN DRUG BLOOD LEVELS WHEN ON LI***
• Li levels should be considered to be at steady state at day 5
• Blood sample should be obtained about 8-12 hours after the last dose
(around the 5th day of therapy)
• If level is therapeutic and there is a positive response, draw another level
in 2 weeks and then every 3-6 months thereafter
• If level is not therapeutic, there is a partial response, dose has been
changed (increased or decreased), and/or interacting medication(s) have
been initiated, obtain another level in 5 days of stable dose
• Target blood levels/concentrations:
• Maintenance: 0.6 – 1.2 mEq/L
• Acutely manic: may need to go up to 1.5 mEq/L
LITHIUM CONTINUED…
• Lithium toxicity:
• Lithium has a narrow therapeutic index…what does this mean?
• It is an extremely toxic drug
• Risk factors that may predispose a patient to Li toxicity:
• Na+ restriction
• Dehydration
• Vomiting, diarrhea
• Elderly patients
• Drug-drug interactions with those drugs that decrease lithium
clearance
• 3 degrees of Li toxicity and their associated symptoms:
• Mild (1.5-2.0 mEq/L) – nausea, diarrhea, polyuria, blurred vision,
fine resting tremor, confusion, drowsiness
• Moderate (2.0-2.5 mEq/L) – increasing confusion, increased deep
tendon reflexes, myoclonic twitches, increasing restlessness
• Severe (> 2.5 mEq/L) – coma, convulsions, cardiac dysrhythmias,
renal failure
LITHIUM CONTINUED…
• Initial, dose-related side effects:
• GI distress (nausea, vomiting, diarrhea, dyspepsia)
• Muscle weakness and lethargy (develops in about 30% of patients)
• Polydipsia and polyuria
• Fine hand tremor

• Not dose-related (more common with long-term therapy):


• Formation changes in the kidneys (glomerular sclerosis, tubular
atrophy)
• Thyroid changes (hypothyroidism usually occurs after 6-18 months of
therapy)
• Benign and reversible cardiac changes
• Reversible leukocytosis
• Dermatologic changes (acne, exacerbation of psoriasis)
• Weight gain
• Neurologic disturbances (EPS, slurred speech, myasthenia gravis)
LITHIUM CONTINUED…
• Drug-Drug Interactions:
• Thiazide diuretics, NSAIDs, COX-2 inhibitors, and ACEi’s can all
elevate lithium levels
• Elimination of lithium is decreased
• Examples: lithium + ibuprofen; lithium + lisinopril; lithium +
naproxen

• Neurotoxicity can also occur when lithium is combined with Ca2+


channel blockers and carbamazepine
DIVALPROEX SODIUM/ VALPROIC ACID
• FDA-approved for the treatment of acute mania and mixed episodes
• Many different formulations
• Efficacy:
• Has been shown to be as effective as lithium and olanzapine in
patients with pure mania
• More effective than lithium in mixed states and rapid cycling
• Lithium + valproate = added positive effect for treatment-refractory
rapid cycling and mixed states; combo is also efficacious in
maintenance therapy for BPD I
• Combining valproate with other BPD agents (carbamazepine,
lamotrigine, atypical antipsychotics) can be effective
• MONITORING IS KEY!
VPA CONTINUED…
Monitoring parameters for VPA
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests X X

Metabolic tests X X

Liver function tests X X

Renal function tests

Thyroid function tests

Serum Electrolytes

Dermatological tests X X
VPA CONTINUED…
• Side effects:
• Most frequent, dose-related: GI complaints (nausea, vomiting,
indigestion, anorexia, diarrhea, and flatulence)*
• Mild tremor
• Lethargy
• Prolonged bleeding because of inhibition of platelet aggregation
• Transient increases in liver enzymes (this is why we monitor liver
enzymes)
• Weight gain
• Thrombocytopenia (monitor bleeding and bruising)
VPA CONTINUED…
BLACK BOX WARNINGS!!

• HEPATOTOXICITY

• PANCREATITIS
VPA CONTINUED…
• Drug-Drug Interactions:
• VPA is highly protein bound (other highly protein bound drugs can displace VPA)
• VPA can inhibit CYP450 enzymes  expect other medications’ metabolism to be affected
• VPA may decrease the clearance of phenobarbital
• Oral contraceptives may increase the clearance of VPA and lower serum levels
• Lamotrigine + VPA = severe dermatologic rash (half the lamotrigine dose)
LAMOTRIGINE
• FDA-approved for the maintenance treatment of BPD; not approved
for bipolar depression, but very effective for the prevention and
treatment of bipolar depression
• Efficacy:
• Possesses both antidepressant and mood-stabilizing effects
• Has a low rate of switching patients to mania
LAMOTRIGINE CONTINUED…
• Dosing and administration:
• Initial dose: 25 mg daily
• Dosing range: 50-400 mg by mouth in divided dose
• Slowly increase dose!!!!!! Slow titration!!!!!
• Example: 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks,
and then increase by 50 mg increments weekly
• Doses of 400 mg daily have shown no advantages
• Need to adjust dose in hepatic and renal impairment
LAMOTRIGINE CONTINUED…
Monitoring parameters for Lamotrigine
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests

Metabolic tests

Liver function tests

Renal function tests

Thyroid function tests

Serum Electrolytes

Dermatological tests X X
LAMOTRIGINE CONTINUED…
• Side effects:
• Common -
• Headache
• Nausea
• Dizziness and drowsiness
• Ataxia
• Tremor
• Rash (self-limiting and resolves eventually)  may progress to life-
threatening conditions!
LAMOTRIGINE CONTINUED…
BLACK BOX WARNING!!

• Serious rash
• Usually accompanied by a fever or sore throat
• May require hospitalization
• Discontinue treatment
• Includes Stevens-Johnson syndrome, toxic epidermal necrolysis (both life
threatening)
• How to avoid?
LAMOTRIGINE CONTINUED…
• Drug-Drug Interactions:
• Lamotrigine + VPA = severe dermatologic rash (half the lamotrigine
dose)
• Lamotrigine + oral contraceptives = reduction in the serum
concentration of lamotrigine
• Lamotrigine + carbamazepine = increase in CNS side effects
• Lamotrigine does not inhibit CYP enzymes and has a low potential for
pharmacokinetic interactions with other drugs
CARBAMAZEPINE
• FDA-approved for the treatment of acute mania and mixed episodes
associated with BPD I
• Many formulations: immediate release and extended release
• Not first line for mania, but its acute antimanic effects are
comparable to lithium
• Combo of carbamazepine with Li, VPA, or antipsychotics is often
used for treatment-resistant patients experiencing a manic episode
• Also reserved for patients who are unable to tolerate or who have an
inadequate response from Li or VPA
CARBAMAZEPINE CONTINUED…
Monitoring parameters for Carbamazepine
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests X X

Metabolic tests

Liver function tests X X

Renal function tests X

Thyroid function tests

Serum Electrolytes X X

Dermatological tests X X
CARBAMAZEPINE CONTINUED…
• Side effects:
• Neurosensory side effects are common (headache, fibromyalgia)
• Nausea
• Hyponatremia (increases with age; need to monitor serum
electrolytes; risk of causing seizures)
• Transient leukopenia
• Bone marrow suppression
CARBAMAZEPINE CONTINUED…
BLACK BOX WARNINGS!!

• Serious dermatologic reactions and HLA-B*1502 allele

• Aplastic anemia/agranulocytosis
CARBAMAZEPINE CONTINUED…
• Drug-Drug Interactions:
• Carbamazepine is an auto-inducer
• What does this mean?
• Induces CYP3A4, and to a lesser degree, 1A2, 2C9/2C10, and 2D6
• Increases the metabolism of many medications, including oral
contraceptives
• Carbamazepine + valproate = displacement from proteins, resulting in
more free CBZ; reduce CBZ dose
• Carbamazepine + clozapine = increased risk of bone marrow
suppression from both agents
• Medications the inhibit CYP enzymes may inhibit the metabolism of
carbamazepine, leading to carbamazepine toxicity
• Examples: diltiazem, verapamil, fluoxetine, fluvoxamine
OXCARBAZEPINE
• Not FDA-approved for BPD
• Currently, there is less data supporting the use of oxcarbazepine over carbamazepine in the
treatment of BPD
• Administer oxcarbazepine if patients have failed other treatments or have experienced
intolerable side effects
• Advantages over CBZ: milder side effects, no autoinduction of liver enzymes, and fewer drug
interactions
OXCARBAZEPINE CONTINUED…
Monitoring parameters for Oxcarbazepine
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests

Metabolic tests

Liver function tests

Renal function tests

Thyroid function tests

Serum Electrolytes X X

Dermatological tests
OXCARBAZEPINE CONTINUED…
• Side effects:
• Dose-related side effects:
• Dizziness and sedation
• Headache
• Ataxia and fatigue
• Vertigo
• Abnormal vision and diplopia
• Vomiting and abdominal pain
• Hyponatremia!
• Occurs more frequently with oxcarbazepine compared to CBZ
• Can be severe (less than 125 mEq/L)
• Occurs more frequently during the first 3 months
• Symptoms: confusion, headache, lethargy, and malaise
• Hypersensitivity reactions
• May occur, especially in patients with a history of CBZ
hypersensitivity
Neurocognitive Disorders
Kimberly Hayashi, PharmD
khayashi@su.edu
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
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
Fong TG et al. Nat Rev Neurol. 2009 5(4):210-20
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
Fong TG et al. Nat Rev Neurol. 2009 5(4):210-20
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
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
Slattum PW, Peron EP, Hill A. Chapter 38. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 9e. 2014
Seeley WW, Miller Bl. Chapter 371. Dementia. In: Harrison’s Principles of Internal Medicine, 18e. 2012.
Treatment
Non-Pharmacologic
● Setting schedules
● Reduce environmental triggers
○ Noises, insecure space, light
● Caregiver support programs
● Adequate sleep, hydration, nutrition
○ Exercise, relaxation techniques
● Occupational therapy
Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Seeley WW, Miller Bl. Chapter 371. Dementia. In: Harrison’s Principles of Internal Medicine, 18e. 2012.
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
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
***
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
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
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
Noncognitive Symptoms

● Psychotic symptoms

● Disruptive/inappropriate behavior

● Depression

Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
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
Noncognitive Symptoms
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!!
Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Noncognitive Symptoms
Depression
SSRIs
● Citalopram (Celexa) or sertraline (Zoloft) - 1st line
○ ADEs- Nausea, agitation, insomnia, sexual
dysfunction
○ May help with behavior symptoms

Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Neuromuscular Blockade in the ICU

Marcia Brackbill, Pharm.D., BCPS


Professor of Pharmacy
BJD School of Pharmacy
Shenandoah University
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?
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 fasciculations 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
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 rocuronium,
pancuronium, or vecuronium only
May allow for use of aminosteroids NMBA agents for
emergency intubations in patients where succinylcholine is
contraindicated
ADRs: Watch for bradycardia & hypersensitivity reactions
Inpatient Acute Pain and Post-Surgical Pain
Management
Kayla R. Joyner, Pharm.D.
Assistant Professor, Pharmacy Practice
Shenandoah University
Non-Opioid Analgesics
Acetaminophen Salicylates NSAIDs
MOA: MOA: MOA:
Central COX inhibitor Irreversibly binds Reversibly binds COX-
COX-1 and COX-2 1 and/or COX-2

Antipyretic/
Antipyretic/
Analgesic/ Anti-
Analgesic inflammatory
Parenteral NSAIDs
Generic Brand Dosing Range
Ketorolac Toradol® 60 mg IM or 30 mg IV x 1,
OR
30 mg IV or IM every 6 hours as needed

MAX: 5 days therapy or 120 mg/d


Ibuprofen Caldolor® 400 to 800 mg IV q6h

MAX: 3200 mg/day


Diclofenac Dyloject® 37.5 mg IV bolus q6h
sodium
MAX: 150 mg/day
Opioid Analgesics
• Mechanism of Action
• mu opioid receptor agonist
• Can work on kappa and delta receptors

• Use
• Standard for acute pain
• Chronic pain refractory to other classes

• Max doses of opioids


Selected Adjuvant (Coanalgesics)
Therapies

• Agents for associated neuropathic pain

• TCAs (desipramine, nortriptyline, amitriptyline)

• SNRIs (Duloxetine, duloxetine, milnacipran)

• Anticonvulsants (gabapentin, pregabalin carbamazepine, oxcarbazepine)


Continuous IV infusion opioid
• Reserved for patients in the ICU
and those that are opioid
tolerant

• Common agents
• Morphine
• Hydromorphone
• Fentanyl
Neuraxial/Intraspinal Opioids
• Intrathecal (Subarachnoid space)
• Epidural (outside dura mater)
• Used postoperatively, L & D,
extreme refractory pain
• Useful in difficult to control pain
states.
• Toleration
• Common agents
• Morphine
• Hydromorphone
• Fentanyl
Patient Controlled Analgesia (PCA)
Routes of
Administration:

Intravenous
Subcutaneous
Epidural
PCAs
• Patients will self administer IV opioid via a pump

• Better pain control

• Fewer side effects (compared to continuous and neuraxial)


PCA orders
Drug name Common Medications

Loading dose

Self-bolus dose • Morphine

Lock-out time • Hydromorphone

Continuous basal dose • Fentanyl


1 or 4-Hour Limit
Multimodal Therapy
• Used to optimize pain therapy and reduce
opioid requirements

• Results in superior analgesia than each agent


alone

• Example: IV opioid + IV NSAID


Hydromorphone + IV
Ketorolac
WHO Pain Ladder
Severe Pain (7-10)
Opioid
+ /– Adjuvant

Moderate Pain (4-6)


Opioid/(NSAID or APAP) Combination products,
Tramadol, Tapentadol
+ /– Adjuvant

Mild Pain (1-3)


Non-opioid (NSAID, APAP)
+ /– Adjuvant
Severe Pain (7-10)
• Start with IV opioids for quick relief

• Moderate dose every 5-15 minutes


• 1-2 mg of Morphine (or equivalent)

• Once response then can reduce frequency to every 4-6 hours

• Consider multimodal options/coanalgesics: IV/PO NSAIDs


Moderate Pain (4-6)
• Manage with combination opioids PO, weak agonist, or high dose
NSAIDs
• Hydrocodone/Acetaminophen
• Oxycodone/Acetaminophen
• Tramadol
• Tapentadol

• Bone/Joint related pain


• Ibuprofen >600 mg Q6H PRN
• Ketorolac >15 mg IV Q6H

• Consider multimodal options/coanalgesics


Mild Pain (1-3)
• Non-opioid analgesics
• NSAIDs or Acetaminophen at over the counter dosing
• Acetaminophen is typically better tolerated
• NSAIDs have inflammatory proprieties

• Consider NSAIDs over APAP for bone pain


Opioid Conversion
• Calculate the 24 hour dose (All opioids received)

• Assess the patients pain

• Choose agent and convert

• Adjust for cross-tolerance (TDD decrease by 0-75%)- You will be told


what % to use for calculation. (50%)

• Give a agent for breakthrough pain (10-20%) You will be told what % to
use for calculation. (10%)
Patient case IV to PO
• AW is post-op day 2 from exploratory laparotomy
his medication administration record is shown
below. Design a regimen for the patient to
convert the IV morphine to PO oxycodone.
0714 0900 1135 1621 2045 0200 0600
Morphine 2 2 mg 2 mg 2 mg 2 mg 2 mg
mg IV q4h
PRN
Morphine 4 4 mg 4 mg 4 mg 4 mg
mg IV q4h
PRN
Converting Between Opioids
Drug Parenteral (mg) Oral (mg)
Morphine 10 30
Buprenorphine 0.3 0.4
Codeine 100 200
Fentanyl 0.1 N/A
Hydrocodone N/A 30
Hydromorphone 1.5 7.5
Meperidine 100 300
Oxycodone 10 20
Oxymorphone 1 10
Tramadol 100 120
Conversion
• Set up conversion
26 mg IV Morphine 10 mg IV Morphine
x mg PO Oxycodone
= 20 mg PO Oxycodone
• Cross multiply
(26 x 20)=10x
x=52mg PO Oxycodone

• Adjust for Cross-Tolerance (Relatively well


controlled. Use 50% dose reduction)
• 52 x 50%= 26 mg PO Oxycodone
• Oxycodone ER 15mg po BID
Conversion
• Breakthrough dose ~10-20% of TDD (3 -6 mg)
• TDD=30mg/day 10-20% of 30mg= 3-6mg
• Oxycodone IR 5mg po q 4hours PRN
Patient Case- PO to PO
• KH is a 50yo M who has pancreatic cancer. His
pain is controlled on Oxycodone/APAP 10/325mg
2 tablets every 4 hours. You decide to change him
to PO Morphine to minimize the APAP dose.
Converting Between Opioids
Drug Parenteral (mg) Oral (mg)
Morphine 10 30
Buprenorphine 0.3 0.4
Codeine 100 200
Fentanyl 0.1 N/A
Hydrocodone N/A 30
Hydromorphone 1.5 7.5
Meperidine 100 300
Oxycodone 10 20
Oxymorphone 1 10
Tramadol 100 120
Conversion
• Set up conversion
120 mg PO Oxycodone 20 mg PO Oxycodone
x mg PO Morphine
= 30 mg PO Morphine
• Cross multiply
(120 x 30)=20x
x=180mg PO Morphine

• Adjust for Cross-Tolerance (Relatively well


controlled. Use 50% dose reduction)
• 180 x 50%= 90mg/d PO Morphine
• Morphine ER 45mg po q 12 hours
Conversion
• Breakthrough dose ~10-20% of TDD= Use 10%
 TDD=90mg/day 10% of 90mg= 9mg
 Morphine IR 10mg po q 4hours PRN
Safety: Acetaminophen Side Effects
• Nausea
• Vomiting
• Decreased appetite
• Upper quadrant pain
• Jaundice
• Elevated LFT (don’t check HEPATOTOXICITY!!
unless there is clinical
suspicion of liver dysfunction)
Safety: NSAID Side Effects
MORE COX-1 Ketorolac (Toradol®)
SELECTIVE Ketoprofen (Orudis®)
• GI side effects Indomethacin (Indocin®)
Aspirin (Bayer Aspirin®)
• Renal Toxicity
Nabumetone (Relafen®)
Sulindac (Clinoril®)
• Bleeding
Naproxen (Advil®, Anaprox
®)
• Hyperkalemia NON- Piroxicam (Feldene®)
SELECTIVE Ibuprofen
• Rash Meloxicam (Mobic®)
Diclofenac (Voltaren®)
• Edema
Celecoxib (Celebrex®)
MORE COX- Etodolac (Lodine®)
• CV Effects
2 Rofecoxib (Vioxx®)
SELECTIVE
Managing Constipation
Place in
Classes Agents Max Dosage Therapy
Stool Softener + Docusate + Senna Docusate: 360mg/day
Stimulant laxative Senna: 68.8mg/day
Stimulant laxative Senna, Bisacodyl Senna: 68.8 mg/day
1st
Bisacodyl:
15mg/day(PO)
;10mg/day(rectal)
Stool Softener Docusate 360 mg/day

Osmotic Laxative Polyethylene glycol, Poly gly: 34g/day


Mag. Hydroxide, Mag Mag: 300 mL/day 2nd
citrate
Synthetic Lactulose ~40 g/day
disaccharide
Peripherally-acting Methylnaltrexone Relistor: 12 mg/day (SQ)
OP 3 (mu-)opioid (Relistor) 450mg/day(PO)
Nausea and Vomiting
• Occurs in approximately 25% of opioid treated patients
• Tolerance usually develops,
Suggested antiemetic Dose
Antihistamines
Meclizine (Antivert) Oral: 25 to 100 mg daily
Scopolamine (Transderm-scop) Transdermal: 1 patch applied Q 72
Promethazine (Phenergan) hours
IV: 12.5-25 mg Q 4-6 hours PRN
5HT3 (Serotonin) antagonist
Ondansetron (Zofran) IV: 4-8 mg Q 8 hours PRN
SL tablet: 4 mg Q 8 hours PRN
Dopamine antagonists
Prochlorperazine (Compazine) IV: 2.5-10 mg Q 3-4 hours PRN
Pruritus
• Probability is greater if using epidural or intra-spinal route

• Antihistamines
• Diphenhydramine 12.5-25 mg IV/PO q4h PRN
• Hydroxyzine 25-50 mg PO q4h PRN
• Consider cool compress and moisturizers

• Try synthetic opioid if occurring with morphine or codeine