Pharm II Exam 1

Are Benzodiazepines controlled substances?

Yes, C-IV

Are non-benzodiazapine hypnotics controlled substances?

yes, C-IV

Is suvorexant (Belsomra) a controlled substance?

Yes, C-IV

Is ramelteon (Rozerem) a controlled substance?

no

Is doxepin (Silenor) a controlled substance?

no

Where do benzodiazepines bind on GABA-A receptor? What is the result?

-Benzodiazepines bind to both (nonselective) BZ1 and BZ2 leading to a wide range of actions:
(sedation, hypnosis, antianxiety, anticonvulsant, muscle relaxant)

What is the MOA of benzodiazepines?

-Benzodiazepines are allosteric modulators of GABA-A receptor function. GABA-A receptor is the major inhibitory receptor in the CNS
-BDZs increase the affinity of the GABA-A receptor for GABA and thereby enhance GABA-induced Cl- currents.

Where do non-benzodiazepine hypnotics bind on GABA-A receptor? What is the result?

-non Benzodiazepines (zolpidem, zaleplon, and eszopiclone) activate only BZ1 on the alpha 1 subunit, which may account for their relatively selective hypnotic action and lack of anticonvulsant and muscle relaxant effects.
-nonbenzodiazepine GABA agonists possess only sedative properties

What is the mechanism of GABA-mediated inhibitory neurotransmission?

GABA opens Cl- channels causing hyperpolarization of neuronal membrane--\> inhibition of depolarization

What is the effect of specific BZ1 receptor stimulation?

BZ1 receptor stimulation results in sleep onset and cycle regulation

How do benzodiazepines affect sleep stages (1, 2, 3, 4 and REM)?

Decreases stage 1, 3, 4 and early REM sleep
Increases stage 2 and late REM sleep

How do benzodiazepines affect sleep latency, number and duration of awakenings, and total sleep time?

Decreases sleep latency and number and duration of awakenings
Increases total sleep time

What is the duration of action of flurazepam?

long

What is the duration of action of temazepam?

intermediate

What is the duration of action of triazolam?

short

Which BDZ would be best for treatment of insomnia?

Temazepam

Which BDZ is associated with rebound insomnia and early morning wakening?

Triazolam

Which BDZ, used for sleep, is associated with residual hangover effects?

Flurazepam (long acting)

Which BDZ for insomnia would be safest to use in elderly patients and why?

-Avoid long-acting (long half-life) BDZ (flurazepam, quazepam) in elderly patients due to increased risk of drug accumulation (hangover effect), falls, and confusion
-temazepam is considered to be safer in elderly (\>65 yoa) and those with chronic liver disease because they are metabolized to inactive metabolites

When should benzodiazepine use be avoided?

-pregnancy
-hx of substance abuse
-sleep apnea

What are major limitations of short- acting and long-acting benzodiazepines?

Short acting is associated with rebound insomnia and early morning awakening
Long acting can have hangover effects

Which patient groups are at risk for negative effects of benzodiazepines?

Elderly and liver impairment?

What is anterograde amnesia due to benzodiazepines? Which ones?

-impairment of memory and recall of events occurring after dose was taken
-most likely with short acting

What is the major problem with triazolam?

After abrupt discontinuation, rebound insomnia can occur where there is increased wakefulness for a few nights- need taper

How do Z-hypnotics interact with the GABA-A receptor?

Z-hypnotics\= nonBDZ's
-Only activates BZ1 site on alpha subunit- relatively selective hypnotic action
-lack of anticonvulsant and muscle relaxant properties

Which of the following have limitations on duration of use?
zolpidem IR and ER
zaleplon
eszopiclone
ramelteon
suvorexant

-zolpidem (Ambien) 7-10 days for tartrate;
-Zaleplon 7-10 days;
-Eszopiclone (Lunesta) long term up to 6 months

Which of the following have additive/synergistic drug interactions with other CNS depressants?
zolpidem IR and ER
zaleplon
eszopiclone
ramelteon
suvorexant

zolpidem IR and ER
zaleplon
eszopiclone

Which of the following exhibit withdrawal syndromes similar to barbiturates?
zolpidem IR and ER
zaleplon
eszopiclone
ramelteon
suvorexant

-zolpidem IR and ER
-zaleplon
-eszopiclone

Which of the following are indicated for both decreasing time for sleep onset (stage 1) and increasing total sleep time?
zolpidem IR and ER
zaleplon
eszopiclone
ramelteon
suvorexant

-Zolpidem
-Eszopiclone
-Suvorexant

Which of the non-BDZ hypnotics has the shortest duration of action?

Zaleplon

Which of the non-BDZ hypnotics does not help with sleep maintenance? Why?

Zaleplon due to short half-life (1 hour) - not for reducing nighttime awakening or for increasing total sleep time

Which of the non-BDZ hypnotics is labeled for long-term use for insomnia?

Eszopiclone

What are the warnings for non-benzodiazepine hypnotics?

-risk of CNS depression with

Why can zolpidem cause weight gain?

sleep eating

What is the MOA of suvorexant?

Orexin receptor antagonist- Orexin is a neuropeptide that promotes wakefulness; by blocking the receptors orexin A and orexin B ORAs suppress the wake drive

What is the MOA of ramelteon?

-selective agonists for MT1 and MT2 receptors
-melatonin, the endogenous ligand, promotes sleep and maintenance of the circadian rhythm underlying the normal sleep-wake cycle

Why are orexin receptor antagonists contraindicated in narcolepsy?

there is an absence of orexin in the CSF

What is the effect of fatty food on ramelteon?

-fatty food delays absorption by 45-min; avoid taking with fatty food

How does ramelteon affect sleep onset?

-quicker sleep onset

How does ramelteon affect testosterone and prolactin levels?

increase prolactin in women, decrease free testosterone in men

Explain the abuse potential of ramelteon.

none

What are the ADR's of orexin receptor antagonists?

-cognitive and behavioral changes (somnolence)
-worsening depression, suicidal thoughts (dose-dependent)
-complex behaviors while not fully awake such as sleep driving (parasomnias)
-transient leg weakness and sleep paralysis

Who should avoid using first generation antihistamines in insomnia?

BPH, glaucoma (increased IOP), and elderly (impaired cognition/increased risk of falls)
due to anticholinergic effects

When are first generation antihistamines used for insomnia? What is their major problem?

· Diphenhydramine and doxylamine
-available OTC so easy to access
-problem is tolerance occurs quickly and increasing dose, increases side effects without increasing therapeutic effect

Which tricyclic antidepressants have sedative properties that may be useful for treatment of insomnia?

Doxepin (Silenor), mirtazapine, trazadone

When are tricyclic antidepressants useful for insomnia?

-insomnia secondary to depression
-insomnia secondary to chronic pain
-alternate to a BDZ due to risk of abuse

How do tolerance and physical dependence develop to the barbiturates?

· Two components of tolerance- Induction of P450 enzymes and Adaptive CNS changes compensate for drug effect by increasing neuronal excitability
· Physical and psychological dependence can occur within 1-3 months

Describe barbiturate withdrawal.

o 8-12 hr: anxiety, muscle twitch, tremor, dizziness, insomnia
o 16 hr: convulsions, delirum; may be prolonged- can cause fatality
o Management: control seizures, supportive care

Which drugs interact with barbiturates?

Additive/synergistic CNS depression with other depressants including alcohol and inducers of P450 microsomal drug-metabolizing enzymes (Phenobarbital is the most potent inducing agent and causes numerous drug interactions)

Which of the following are stimulants?
methylphenidate
amphetamine
atomoxetine (Strattera)
clonidine ER (Kapvay)
dextroamphetamine
guanfacine ER (Intuniv)
lisdexamphetamine
methamphetamine

methyphenidate
amphetamine
dextroamphetamine
lisdexamphetamine
methamphetamine

What is first line therapy for ADHD? Why?

Stimulants (amphetamines and methylphenidate)- they are most effective especially in children and adolescence

Compare when amphetamine and methylphenidate are used for ADHD?

-methylphenidate used more than amphetamines due to better safety profile
-amphetamines may be considered first-line in adults as they have shown greater efficacy and acceptable tolerability in adults

How are lisdexamphetamine dimesylate capsules (Vyvanse) extended release?

It is composed of l-lysine bonded to dextroamphetamine, it is hydrolyzed to the active d-amphetamine- it takes time to get activated--\> long lasting properties

How do stimulant medications affect norepinephrine and dopamine neurotransmission?

increases both by blocking presynaptic reuptake

What is the boxed warning for all stimulants?

CNS stimulants have a high potential for abuse and dependence.

What is the boxed warning for amphetamines?

Misuse may cause sudden death and serious cardiovascular events

What is the boxed warning for atomoxetine?

Risk of suicidal ideation; monitor for suicidal thoughts and behavior, worsening mood, or unusual behavior

What cardiovascular effects can occur due to stimulants?

-Severe CV-events and other vascular problems (e.g., priapism, Raynaud's syndrome).
-Primarily *↑HR and BP*; increased risk of serious cardiac events for those with pre-existing cardiac disease
-Avoid in patients with known cardiac abnormalities due to increased risk of sudden death; specifically, some agents are contraindicated in patients with HF, recent MI, arrhythmia, or moderate-severe hypertension

How are cardiovascular effects of stimulants managed?

-lower dose or consider alternative
-Before starting pharmacotherapy for ADHD in *youth or adults*, the clinician should consider a baseline ECG and consultation with a cardiologist if past medical history or family history suggests cardiovascular disease

What psychiatric/behavioral effects can occur due to stimulants?

-Increase suicidality, exacerbate mixed/manic episodes (pre-existing bipolar disorder); can exacerbate any pre-existing psychiatric disorder
-(1) Psychosis, (2) mood disturbance (ie, irritability, lability, or depression), and (3) severe anxiety or panic attacks

How are psychiatric/behavioral effects of stimulants managed?

dose reduction or cessation of therapy and supportive treatment is recommended

What growth effects can occur due to stimulants?

loss of appetite can delay growth trajectory in children

How are growth effects due to stimulants managed?

If symptoms can be managed without medication during weekends or summers, a drug-free trial may be considered every year- give high calorie meal when stimulant effects are low (breakfast or at bedtime), or consider adding cyproheptadine at bedtime

How do stimulants affect serotonin levels?

-can cause serotonin syndrome
-in addition to increasing DA and NE, stimulants can also increase 5HT (serotonin) neurotransmission; increased risk of Serotonin syndrome when used with other serotonergic drugs

How can stimulants affect seizures?

can lower seizure threshold

What is the advantage of Quillivant XR suspension?

long acting

Describe Concerta OROS tablet.

-oral osmotic formulation where outer layer dissolves fast and the rest dissolves slowly
-patients may see ghost tablet in stool
-low abuse potential due to difficulty crushing

What are the application site warnings of Daytrana TD patch.

-loss of skin pigmentation at application site and areas distant from application site, and allergic contact sensitization with local reactions (e.g., edema, papules)

What is Vyvanse a prodrug of?

dextroamphetamine

Why does Vyvanse have a lower abuse potential?

if injected or snorted, the fast effect (rush) is muted due to the need of activation of prodrug

What are 3 advantages of a non-stimulant drug over a stimulant drug to treat ADHD?

no abuse potential, less potential for growth effects, less sleep disturbance

What is the MOA of atomoxetine (Strattera)?

Selective Norepinephrine Reuptake Inhibitor

Compare the onset of action of atomoxetine vs stimulants?

atomoxetine has slower onset of action than stimulants

Why can atomoxetine capsules not be opened?

powder is an irritant

What is the effect of atomoxetine concentration in a poor 2D6 metabolizer?

5-fold increase in plasma concentrations; extends half-life ~22hrs (may have a lower effective dose)

What are the ADR's of atomoxetine?

-hepatotoxicity, (rare); monitor, usually develops within 4-months. Perform LFT at baseline and periodically
-Has less potential for growth suppression compared with stimulants, but it has a greater risk of fatigue, sedation, and dizziness
-Adults less likely to have appetite, but may report urinary hesitation/retention and sexual side effects (decreased libido and erectile disturbances)

What is the MOA guanfacine ER (Intuniv) and clonidine ER (Kapvay)?

(1) stimulate alpha-2A receptors on presynaptic neurons in the CNS to inhibit NE release, (2) also work at postsynaptic receptors to increase blood flow in the prefrontal cortex, which has been shown to enhance working memory and executive functioning

Compare guanfacine ER vs clonidine ER.

guanfacine has greater alpha-2A activity--\> less sedation and dizziness vs clonidine

What are warnings of guanfacine ER and clonidine?

-Abrupt D/C can cause rebound hypertension, nervousness, anxiety; taper upon D/C
-guanfacine - skin rash (rare, but serious, D/C if occurs)

What are drug interactions for guanfacine ER?

-additive sedation and hypotension
-CYP450 inhibitors/inducers

What is the MOA of SSRI's?

-selective and potent inhibition of serotonin (5HT) reuptake - allowing it to be available for binding at synaptic cleft
-minimal to absent effects of NE or DA reuptake

What is the MOA of SNRI's?

-inhibit 5-HT and NE reuptake

What is the MOA of tricyclic antidepressants?

-block reuptake of NE, serotonin, or both
-Tertiary amines prefer serotonin
-Secondary prefer NE

What is the MOA of MAOI's?

-inhibit monoamine oxidase to prevent degradation of biogenic amines (NE, dopamine, and serotonin)

What is the MOA of bupropion?

-inhibits reuptake of dopamine and NE with *no* affect on serotonin

What is the MOA of trazodone?

-inhibits serotonin reuptake
-5HT2A receptor antagonist which is associated with substantial antianxiety, antipsychotic, and antidepressant effects

What is the MOA of nefazodone?

-weak inhibitor of both SERT and NET (serotonin and NE reuptake inhibitor)
-potent antagonist of the postsynaptic 5HT2A receptor

What is the MOA of vortioxetine?

-inhibits serotonin reuptake
-5HT1A receptor agonist
-partial 5HT1B agonist
-antagonist at 5HT receptor subtypes 3, 1D, and 7
-Overall, the actions at these receptors helps stimulate serotonergic activity to relieve symptoms of depression

What is the MOA of vilazodone?

VIIBRYD is brand name
-inhibits serotonin reuptake
-partial agonist at 5HT1A

What is the MOA of mirtazapine?

-blocks central presynaptic alpha-2 receptors--\> increased NE and serotonin
-selectively enhances neurotransmission over 5HT1 receptors
-blocks postsynaptic 5HT 2A, 2C and 3 --\> adverse reactions and sexual dysfunction

Compare the efficacy of antidepressants.

Similar EFFICACY has been shown among the antidepressant classes.

Which drugs are first line for depression? second? last?

-First: SSRI and SNRI's due to best safety profile
-Second: TCA and atypicals
-Last: MAOI's due to undesirable safety profile

Why would you choose one drug over another drug in the same class?

-side effects are not always a class effect
-the first 5 SSRI's did not share any chemical/structural features so one may work better for a patient than another

Which 3 primary receptors are responsible for side effects of antidepressant drugs? What side effect do they cause?

-Muscarinic: anticholinergic- Dry mouth, constipation, urinary retention, mydriasis, blurred vision, tachycardia
-Alpha-1 adrenergic--\> orthostatic hypotension
-Histmaine-1: Sedation

Which antidepressants are most affected by blocking muscarinic, alpha 1 adernergic and histamine-1 receptors?

-TCA's- especially tertiary amines
-Mirtazapine: Blocks histamine H-1 receptors: potent sedation, moderate muscarinic blockade; weak alpha1 blockade

Which SSRI does not necessarily require a taper?

-Fluoxetine due to its very long half-life (2-3 days with active metabolite 7-9 days). Its concentrations in the body declines very slowly after the drug is stopped. This slow decline in concentration reduces the risk of discontinuation syndrome.
-Tapers itself basically

Which patient and drug specific factors need to be assessed before choosing an antidepressant?

-Patient-Specific Factors: History of prior response, Age, Medical/Psych Condition, Cost Patient Preferences, Concurrent disease-states and drug-therapy
-Drug-Specific Factors: Contraindications (including renal and hepatic impairment), Safety in Overdose, Side Effects

What boxed warning is applied to all antidepressants?

-ALL antidepressants increase the risk of *suicidal thoughts & behavior* in children, adolescents, and young adults up to age 24.
-Usually peak risk is 2 weeks after initiation of therapy because they now have energy to act out on thoughts

What are the 3 phases of antidepressant therapy management?

-Acute Phase 4-12 weeks
-Continuation Phase 4-9 months
-Maintenance Phase

What is the acute phase of antidepressant therapy?

• 4-12 weeks
• Goal \= remission of depressive episodes, return to baseline level functioning
• General symptom improvement should begin around 1-2 weeks (e.g., energy, appetite, functioning)