IDT Exam 3 Rx

Alprazolam

Anxiolytic

minor CYP3A4 pathway (10%) >4-hydroxy and alpha-hydroxy

fairly nonpolar with triazole ring on 7 mem

Clonazepam

Anxiolytic

quantified with chromatographic techniques

nitro group off areomatic fused ring > still nonpolar

Diazepam

Anxiolytic

Struc: 7mem lactam ring + fused aeromatic ring + phenyl ; nonpolar

Metab by CYP2C19 + CYP3A4 (to Temazepam)

Lorazepam

Anxiolytic

insoluble, must dissolve in PEG or propylene glycol (ALLERGIES)

more polar bc OH on 7mem ring

Midazolam

Anxiolytic

only water soluble benzo w imidazole off 7 member ring

Temazepam

Anxiolytic

Metabolite of diazepam from CP3A4 - More Polar

Good balance for onset +maint of sleep bc of intermediate duration

Buspirone

(Buspar)  - 

MOA: presynaptic 5-HT1A (partial) agonist located on cell body (NOT an SSRI/ 5-HT uptake); Antagonist at DA autoreceptors - unknown significance;

effects take 2-4 weeks

Place in therapy: •Chronic GAD when SSRI/SNRI not tolerated/preferred, adjunct

•Recent benzodiazepine exposure may be associated with poorer response

-no risk of physical dependency and withdrawal

As effective as Benzodiazepenes as an anxiolytic

Has an ACTIVE METABOLITE (1-PP is an alpha-2 adrenergic receptor antagonist*) and can exacerbate panic attack)

Side Effects: dizziness (10%) – others include tinnitus, blurred vision, chest pain, rash, g.i. distress, nervous*

no sedative, hypnotic, anticonvulsant, muscle   relaxant properties, minimal abuse liability 

Eszopiclone

Sedative

For sleep maintenance

Bicyclic with N

Zolpidem

Sedative

For sleep onset+ and maintenance++

imidazopyridine

CYP3A4 metabolism

Women metabolize slower (HALF Dosage)

Zaleplon

Sedative

For sleep onset

Avoid concurrent CYP3A4 inducers ( rifampicin, carbamazepine, phenobarbital)

though CYP3A4 is normally a minor pathway

Ramelteon

Sedative

MT1/2 melatonin agonist -melatonin drives clock protein gene expression

-niche for onset** of sleep and maintains circadian rhythm short term

-NOT controlled, minimal misuse/dep

-little next day impairment

-CYP interactions (fluvoxamine)

Tasimelteon

Sedative

MT1/2 melatonin agonist - melatonin drives clock protein gene expression

-helps onset of sleep and maintains circadian rhythm

INDIC: non-24H sleep disorder (special syndromes, blind)

Suvorexant

Sedative

Orexin R antag - 1st in class

CYP3A4 metabolism

•Orexins A & B (secretins/hypocretins) are neuropeptides produced by hypothalamus

•Bind:  OX₁R and OX₂R - GPCRs - •Schedule IV

for sleep onset and maintenance

Lemborexant

Sedative

CYP3A4 metabolism

•Orexins A & B (secretins/hypocretins) are neuropeptides produced by hypothalamus

•Bind:  OX₁R and OX₂R - GPCRs - •Schedule IV

for sleep onset and maintenance

Daridorexant

Sedative

CYP3A4 metabolism

•Orexins A & B (secretins/hypocretins) are neuropeptides produced by hypothalamus

•Bind:  OX₁R and OX₂R - GPCRs - •Schedule IV

for sleep onset and maintenance

AE: drowsiness

Flunitrazepam

fast acting benzo

amnesia, abuse

“date rape”

Chloral hydrate

Noctec

older sedative hypnotic BARBITURATE

like GABA-A R effect

Propopfol

Diprivan

rapid acting sedative used for anesthesia

GABA-A R

Gabapentinoids

Pregabalin / Gabapentin

Place in therapy: tx resistant GAD (not 2st line),

-improvement in 1 wk

  inhibit neurotransmitter release through binding to a₂d subunit of presynaptic calcium channel.    “Atypical high voltage calcium channel blocker”

  Disadvantage safety – FDA warning of severe/ fatal breathing   problems especially in combination with opioids and in   patients at risk for decreased lung function; abuse liability

AE: •Sedation, dizziness, edema, renal dosing, wt gain, misuse potential

Hydroxyzine

Place in therapy: short term or intermittent symptom relief (NOT chronic)

-rapid onset

-AE: sedation, anticholinergic

Beta Blockers

(Propranol, Atenolol)

Used for performance and social anxiety

  Only treats physiological symptoms (palpitations,   tremor and gastrointestinal upset, etc.); Acute action (Like benzodiazpenes)

TCA

relatively slow onset of action

•orthostasis, cardiac toxicity, overdose risk

Place in Therapy: Alt in Panic disorder for tx resistant

MAOi

Place in therapy: refractory panic disorder

delayed onset

-major interactions and dietary restrictions, washout requirements

-requires specialist clinitian

BDZ

bind to GABA_A receptors that contain alpha-1, alpha-2, alpha-3 or alpha-5 subunits (not alpha-4 or alpha-6)

Place in therapy: Short term before 1st line kicks in

Receptors containing the gamma-1 subunit have low affinity for most of the benzodiazepine site ligands

^ potency NOT efficacy of GABA,

•Sedative, hypnotic, muscle relaxants, anticonvulsant and   anxiolytic

•Hypnosis and stupor at high doses

AE: Sedation, psychomotor impairment, dependence, withdrawal, additive CNS/respiratory depression

•Safer than barbiturates - when used alone - (additive depression with opioids, ethanol etc.)

Non-Benzodiazepine (Z-drugs)

specific for receptors containing the alpha-1 subunit; reversed by flumazenil

Receptors containing the gamma-1 subunit have low affinity for most of the benzodiazepine site ligands

Flumazenil

competetive BDZ antagonist

no clinical   effect alone but works to reverse overdose

Clomipramine

for OCD

AE: •anticholinergic effects, orthostasis, cardiac conduction/QT concerns, greater toxicity in overdose- Suicide risk

High dose SSRI Precautions

•Tolerability

•Activation/agitation

•Sexual dysfunction

•Serotonin toxicity risk with interacting medications

Phenobarbital

Barbiturate

for seizures and epilepsy

Metab of Primidone after CYP2C9/19

longer half life

Doxepin

low dose TCA

Best for sleep maintenance with minimal misuse/dependence

-take within 30 min of bedtime, avoid within 3-hr of meal bc prolonged action

-NOT controlled

DORAs

sleep maint **, also sleep onset

Class considerations

•Useful for both sleep onset and sleep maintenance

•Schedule IV

•Somnolence/impaired alertness can occur

•Avoid in narcolepsy

•CYP3A interactions are clinically important

CONTRA: NARCOLEPSY

Z-drugs

•Schedule IV, CNS depression

•Avoid alcohol and other sedatives

•Boxed warning: complex sleep behaviors

•Prior complex sleep behavior with one of these agents is a contraindication

•For zolpidem, recommended initial doses are lower in women because of slower clearance and greater next morning impairment risk.

Trazodone

Desyrel - serotonin modulator

Additionally an H1 histamine and a1 antagonist – Predictable side effects

common but NOT PREFERRED

low dose sedation

-approved for depression

•Adverse effects include morning grogginess/somnolence, dizziness/orthostasis, dry mouth, priapism (rare)

CYP3A4 N Dealkylation > 5HT partial agonist

Mirtazapine

(Remeron) Atypical (tetracyclic) Antidepressant -

–INDIC: sleep and appetite stimulation

•H1 antagonism •Weak NET blocker

•May potentiate NE and 5-HT release by blocking presynaptic autoreceptors (a2 and 5HT1C)

AE: Weight gain, metabolic effects, daytime sedation

•No anticholinergic or sexual side effects

–May be useful for treatment resistant depression and anxiety with depression

Quetiapine

Sedating; often used when psychiatric comorbidity is present

Metabolic effects, orthostasis, anticholinergic burden; very limited insomnia evidence

For Sleep onset insomnia

Ramelteon, zaleplon, zolpidem IR

AVOID: long acting

For Sleep maintenance insomnia

Doxepin, DORAs, zolpidem ER

AVOID: short acting

For fall risk elderly patients

Doxepin, possibly DORA depending on the patient

AVOID: Benzodiazepines, Z-drugs, antihistamines

For substance use concern

Doxepin, ramelteon, selected DORA after individual risk assessment

AVOID: Benzodiazepines, Z-drugs

For no next day impairment

short acting agents

avoid long acting agents

Wake Promoting agents

Modafinil / Armodafinil

INDIC: •Narcolepsy •Residual EDS in treated OSA

•Long track record

•Headache, nausea, insomnia

•Important drug interactions

Solriamfetol

Indic: Narcolepsy, residual EDS in treated OSA

•Dopamine/norepinephrine reuptake inhibitor

•Can increase BP/HR

Pitolisant

INDIC: Narcolepsy

•Histamine H3 inverse agonist

•Not a controlled substance

•QT/drug interaction considerations

Oxybates

•Taken at night, unlike the daytime wake-promoting agents

INDIC: cataplexy + EDS

•Improve disrupted nighttime sleep

•Lumrzy: once nightly formulation

•Xywav: lower sodium burden

•CNS and respiratory depression

•Avoid with alcohol and other sedative-hypnotics

•Misuse potential

•Administration burden can affect treatment choice