Insomnia and Anxiety Pharmacotherapy

Sedatives

- Anxiolytic agents used to reduce anxiety + exert calming effect

- should be given at minimum consistent dose

Hypnotics

- drugs that produce drowsiness + encourage + maintain state of sleep (more CNS depression)

- can be achieved w/ same drugs as as sedatives at higher doses

Benzodiazepines (BZDs)

- GABAa agonist that binds w/ GABA mediated benzo receptors (Alpha 1 and Gama subunits)

- MOA = increased frequency of Cl- channel opening via GABA

- is GABA dependent

- diazepam / chlordiazepoxide / flurazepam...

Barbiturates (BRBs)

- GABAa agonists that w/in w/ barbiturate receptors in GABA mediated Cl- channel

- MOA = prolonged duration of CL-channel opening (allows for more Cl- to pass through

- more powerful + NOT GABA dependent

- Phenobarbital / pentobarbital / secobarbital / meprobamate

Buspirone

- 5-HT1a partial agonist

- used for anti-anxiety

- No anticonvulsant or muscle relaxant properties

- no dependence / rebound anxiety / withdrawal w/ abrupt d/c

Ramelteon

- Meatonin receptore (MT1 or MT2) agonist

- decreases latency of falling asleep w/ no change to sleep architecture

- No dependence / resp. depression / rebound insomnia / withdrawal / next day drowsiness

Suvorexant

- Orexin Receptor antagonist

Flumazenil

- BZD antagonists used to reverse the hypnotic effects Zolpidem / BZDs

- high affinity for BZD binding sites on GABA receptors via competitive antagonism

- Blocks BZDs + ZZEsZ

BZD Metabolism

- Hepatic metabolism + urinary excretion

- Microsomal oxidation (Phase I rxns) --> forms active metabolites that are catalyzed by CYP450

- Metabolite are conjugated (phase II rxns) to form glucuronides

- alternation in hepatic fxn = increase or decrease fxn of BZDs

Duration of Action with BZDs

- elimination T1/2 of parent drug may have little effect on duration of action

- metabolites have same effects of parent drugs

- more likely to have cumulative ADRs w/ rpt dosing

Desmethlydiazpam Duration of Action

- elimination half-life more than 40hrs due to being active metabolite of multiple other BZDs

- active metabolite of chlordiazepoxide / diazepam / prazepma / clorazepate

Alprazolam + Triazolam Duration of Action

- undergo hydroxylation rxn + result in metabolites w/ short T1/2

- short elimination half-life (2-3hrs) favors use as hypnotic

Pros and Cons to Duration of Action w/ BZDs

- No active metabolites w/ Lorazepam / Oxazepam / Temazepma

- Short elimination w/ Traizolam

- Long elimination w/ CLorazepate / Flurazepam / Diazepam

Metabolism of BRBs

- increased aminolaevulinic acid synthetase --> catalyze rate-determining step in porphyrin pathway

Excretion of BZDs and BRBs

- renal excretion

- changes in renal fxn = no marked effect on elimination of parent drug

- Phenobarbital --> elimination can be increased w/ alkalizing urine

Clinical Indications for Sedatives and Hypnotics

- Relief of anxiety

- insomnia

- sedation + amnesia

- Epilepsy + seizure states

- control of withdrawal states

- muscle relaxation

- diagnostics aids for tx in psych

Tolerance w/ BZDs and BRBs

- decreased responsiveness following rpt exposures --> associated w/ down regulation of receptors

- cross tolerance w/ BZDs and Ethanol + BRBs

Dependence w/ BZDs and BRBs

- alterend psychologic stat that requires continuous drug admin to prevent abstinence

- can lead to withdrawal sxs

- Short T1/2 = more withdrawal sxs

OD w/ BZDs

- Alprazolam = more toxic in OD

- early tx = rare to be fatal

- presents w/ resp. depression + CV depression

- Tx w/ Flumazenil +/- dopamine + dialysis

Common ADRs for BZDs and BRBs

- drowsiness / impaired judgement / diminished motor skills

- impact on driving / job / relationships

- Somnambulistic behavior

- impaired learning

- Confusion (MC reversible cause of confusion in elderly)

Drug Interactions with BZDs and BRBs

- Additive effect w/ other CNS depressants

- EtOH / Opioids / Anticonvulsants / Pheothiazines

- Antihistamines / Anti-HTNs / TCAs

Choosing BZDs

- Chlordiazepoxide / Diazepam --> EtOH withdrawal (long T1/2)

- Paraentral Lorazepam --> delirium tremors

- Lorazepam --> seizures

- Diazepam --> MSK relaxant

- General --> manage mania / drug induced hyper-excitability states

Anxiety Treatments

- Acute Panic attack --> Alprazolam

- General Anxiety Disorder --> Buspirone / SSRI / SNRI

Preferred Treatments for Insomnia

- FDA approved --> BZDs / ZZEsZ / Ramelteon / Suvorexant

- have rapid onset + long acting + minimal hangover

BZDs for Insomina

- Decrease latency of falling asleep

- increases Stage 2

- Decreases Stage 4 + REM

- less rebound insomnia

ZZEsZ Drugs

- Zaleplon

- Eszopiclone

- Zolpidem (most prescribed)

Zaleplon

- short T1/2

- decreases latency of falling asleep --> take 30mins before bed

Eszopiclone

- T1/2 of 6hrs

- increases total sleep time

- used for maintaining sleep

ZZEsZ Mechanism of Action

- Binds to GABA a1 subunit

- less effect on cognitive fxn

Key Features of ZZEsZ

- short elimination T1/2

- preferred for insomnia rx

- less anterograde amnesia + tolerance + withdrawal sxs + abuse

Ramelteon ADRs

- no use w/ CYP1A2 (cipro / fluvoxamine / tacrine) and CYP2C9 inhibitors (fluconazole)

- decrease testosterone + increase prolactin

Orexin Receptor Antagonists

- Orexin A and B peptides in hypothalamus involved in wakefulness

- Drugs = Almorexant / Suvorexant / Lemorexant