Professional Documents
Culture Documents
Fall 2017
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
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
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
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
Adverse Effects - EPS
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
Prevention • Initiate at low dose
Management • Discontinue or reduce dose
• Benztropine 1-5 mg/day
• Trihexyphenidyl 5-15 mg/day
• Diphenhydramine 25-150 mg/day
Adverse Effects - EPS
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
Hyperprolactinemia
• Clinical presentation
• 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
• Clinical presentation
• 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
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
Medication Average Typical Max. Daily Special Considerations
Daily Dose Dosing Dose
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
BBW for SI in children-adolescents
Cariprazine 1.5-6 mg daily 6 mg Partial D2 agonism
Metabolic Effects
• Clinical presentation
• 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
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
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
Long-Acting Injectable Antipsychotics (LAIs)
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
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®)
Clozapine (Clozaril®)
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.
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®)
Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Clozapine (Clozaril®)
Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Clozapine (Clozaril®)
.
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
Initial treatment
n 150 mg po q AM x 3 days
Then…
n 150 mg po bid
n Duration, 7–12 weeks
VARENICLINE
Chantix (Pfizer)
nNonnicotine
cessation aid
nPartial nicotinic
receptor agonist
nOral
formulation
VARENICLINE: DOSING
* 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
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
• 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
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
Pharmacologic Classes
Stimulants
• Methylphenidates
• Methylphenidate
• Dexmethylphenidate
• Amphetamines
• Dextroamphetamine
• Levoamphetamine
• Lisdexamfetamine
Non-stimulants
• Selective norepinephrine reuptake inhibitors
• Atomoxetine
• Alpha-2 agonists
• Guanfacine
• Clonidine
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
Adverse Effects
•Common
•Decreased appetite, delayed growth, insomnia,
headache, irritability
•Rare
•Hypertension, tachycardia, tics, psychosis, mania,
priapism, peripheral vasculopathy
Stimulants
Precautions
Contraindications
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/Drug Interactions
CNS depressants
• May enhance sedative effect of alpha-2 agonists
• 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
Depression
• Stimulants, guanfacine, clonidine
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
If still no
response,
switch to non-
stimulant
Pharmacotherapy of Insomnia
• Effective in dec. time to fall asleep and inc. total sleep time
Non-BZD GABA-A agonists
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)
Hypnotic Selection
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)
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 H1 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
• Presenting symptoms
• Patient preference
• Drug cost
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant
• Half-life à 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 à 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 à 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
Escitalopram + 0
Paroxetine ++++ 0
Sertraline + +
Drug Interactions continued…
Venlafaxine 0/+ 0
Duloxetine +++ 0
• 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
• Respiratory depression
• 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?
• Presenting symptoms
• Patient preference
• Drug cost
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme
Citalopram + 0
Fluoxetine ++++ ++
Fluvoxamine 0 +++
Phenelzine
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 à 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 à 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
• 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:
• Sexual dysfunction
• Nausea/vomiting
• Dizziness
• Dry mouth
• Diarrhea/constipation
Consider this for the SSRI Agents!
• Smokers • Hypertension
• Fatigue or sleepiness
• 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)
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
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
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
Hematologic tests X X
Metabolic 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
Hematologic tests X X
Metabolic tests X X
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 à 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
Hematologic tests
Metabolic 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) à 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
Hematologic tests X X
Metabolic 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!!
• 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
Hematologic tests
Metabolic 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
● 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
● 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
● 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
causes MCD
cisatracurium 2-3 min 40-60 Hoffman can be used in MOF
pancuronium 4-6 min 120-180 renal causes MCD
vagolytic é HR , BP
rocuronium 1-2 min 30-40 hepatic facilitates intubation
é 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
• Use
• Standard for acute pain
• Chronic pain refractory to other classes
• 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
Loading dose
• 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
• Antihistamines
• Diphenhydramine 12.5-25 mg IV/PO q4h PRN
• Hydroxyzine 25-50 mg PO q4h PRN
• Consider cool compress and moisturizers