CNS depressants/sedatives

Positive GABA receptor modulator therapeutic indicators can be used to treat ——, along with many others but this one is our focus

insomnia

Depression / Anxiety (often resolves w/ treatment), Medical Illness, Stress / Emotional Upset, Aging (development of polyphasic sleep pattern), Drug Use (caffeine / alcohol / OTC sleep aids), Sleep Cycle Disruption (e.g., jet lag)

potential causes of insomnia

always want to try to solve insomnia (and lots of other things) with ——- first before introducing pharmacotherapy

behavioral changes

is present throughout the CNS (including spinal cord) and functions as an inhibitory neurotransmitter (suppresses excitatory activity), (Gamma-aminobutryric acid), its primary receptors include A and B

GABA

GABA receptor, ligand-gated ion channel – inhibits fast postsynaptic potentials

GABAa receptor

GABA receptor, G-protein coupled receptor – inhibits slow postsynaptic
potentials

GABAb receptor

GABA binds between the α-β subunits to open the GABA-A receptor and allow ——into the neuron (hyper polarizing it)

Cl- influx

Hyperpolarized because chloride is a

negative ion

Many CNS depressants are bind to allosteric binding sites on GABAAreceptors to produce their effects.
They are —— (PAMs)

positive allosteric modulators

and others all have different binding sites on the GABA-A receptor and are allosteric modulators

barbiturates, benzodiazepines, steroids

Barbiturates and benzodiazepines are positive allosteric modulators of ——(i.e., they improve the ability for GABA to bind and activate the receptor)

GABAa

includes benzodiazepines, neurosteroids, alcohol, gaseous anesthetics, intravenous injections, and barbiturates 

positive allosteric modulators of GABAa

All drugs on the market that bind to GABAA receptors are

positive allosteric modulators

Positive allosteric modulators (PAM) of GABAA enhance GABA binding/increase GABA affinity → ———, Most are anxiolytics, sedatives, muscle relaxants, and reduce seizure risk

decreased neuronal activity

Negative allosteric modulators (NAM) of GABAA inhibit GABA binding/reduce GABA affinity → ——-, Most are excitatory, seizure-inducing, anxiogenic

increased neuronal activity

reverses effects of benzos - antidote, Acts as a competitor, Knocks off the benzos from their binding to GABA receptors

flumazenil

benzodiazepines include:

midazolam, alprazolam, lorazepam, diazepam, clonazepam

therapeutic indications include: Insomnia, Sedation (Anesthetic Adjunct), Seizure Disorders, Anxiety Disorders, Agitation, Muscle Spams, Alcohol Withdrawal

benzodiazepines 

short acting benzodiazepine, (Nayzilam, Versed)- t1/2 = 2 h, lasts about 4-6 hours, Routes of administration for these: IM, IV, oral, intranasal

midazolam

intermediate acting benzodiazepines include: ——-, oral tablet, IM, and IV

alprazolam, lorazepam

intermediate acting benzodiazepine (Xanax) – t1/2 = 12 h, last about a day

alprazolam

intermediate acting benzodiazepine,(Ativan) – t1/2 = 14 h, lasts a little over a day

lorazepam 

long acting benzodiazepines include: 

clonazepam, diazepam 

another long acting benzodiazepine (half life is about a day) is flunitrazepam, also known as

rohypnol

long acting benzodiazepine, (Klonopin) – t1/2 = 23 h, lasts about 2 days

clonazepam

long acting benzodiazepine, (Valium, Diastat, Valtoco) – t1/2 = 43 h, lasts about 4 days

diazepam

are commonly used for seizures but can also be used for long term sedation 

long acting benzodiazepines 

Various formulations (oral, nasal spray, I.M., I.V), Rapid onset of action for all routes of administration, Extensive plasma protein binding, Cross placental barrier, secreted into breast milk

benzodiazepines

benzodiazepines adverse effects:

CNS depression (sedation), amnesia, physical dependence

a therapeutic effect becomes an adverse effect when the drug is not being

taken for that purpose

can also be therapeutic, ex: Amnesia - when not wanting the patient to remember surgery

adverse effects 

Real risk of mixing benzos with other drugs is

respiratory depression

you absolutely cannot mix ——- with benzodiazepines, it will stop your breathing and you will overdose

alcohol, barbiturates, anesthetics, valproic acid (antiepileptic), opioids

what has a black box warning when it comes to benzodiazepines

opioids

cannot give benzodiazepines to anyone who has a history of: 

glaucoma, respiratory complications, pregnancy/lactation, substance abuse 

risk of benzodiazepine abuse increases significantly with a history of —— (regardless of past substance that was abused), can trigger relapse

substance abuse

Neutral modulator at the benzodiazepine binding site on the GABAA receptor complex, Selective antagonist for benzodiazepines and Z drugs, IV only, treatment of benzodiazepine overdose; reversal of sedation by benzodiazepines, can cause seizures or withdrawal if person was on benzos for a long time

flumazenil

don’t bind to all GABA receptors in the brain, So don’t treat as wide of spectrum as benzos, Can induce sleepwalking (amnesia) 

Z drugs 

Only effective for treatment of insomnia, Bind to same binding site as benzodiazepines, but chemically distinct from them, Selective for GABAA receptors containing α1 subunit(subset of GABAA receptors in brain), Less effective than benzodiazepines at seizure control, muscle relaxation, anxiolysis, Largely replaced benzodiazepines for treatment of insomnia

Z drugs

Z drugs favor and bind to the GABAa receptors in the brain responsible for —-

sedation

Z drugs (nonbenzodiazepine agonists) include:

zolpidem

Z drug, (Ambien, Edluar, and more) – t1/2 = 1 hr

zolpidem 

Z drug adverse effects: ——, as well as abnormal taste, abnormal dreams
increased risk of infection, small risk of skin irritation/rash, Risk of abuse/physical dependence with long-term use

morning sedation, amnesia, headaches

cannot give Z drugs to pregnant people because it causes an increased risk of —-

respiratory depression and withdrawal in neonates

Older sedative-hypnotic agents, Largely replaced by benzodiazepines (except for few specialized uses), Tend to have greater risk of serious adverse effects

barbiturates

barbiturates have a therapeutic indication for 

anesthesia, seizure disorders 

barbiturates include:

methohexital, pentobarbital, phenobarbital

ultra short acting barbiturate, (Brevital Sodium) – t1/2 = 4 hr (~ 6 min duration due to redistribution)

methohexital

short to intermediate acting barbiturate, (Nembutal) – t1/2 = 15-50 hr

pentobarbital

long acting barbiturate, (Luminal) – t1/2 = 80-120 hr

phenobarbital 

Water-soluble salt formulations (available oral and IV), High lipid solubility – rapidly and well absorbed, Inactivation mainly by redistribution / metabolism, Metabolism occurs in liver and barbiturates induce own hepatic enzymes, metabolites excreted by kidney

barbiturates

barbiturates adverse effects:

CNS depression, respiratory depression, physical dependence

barbiturates contraindicated for

pregnancy/lactation, pulmonary insufficiency, porphryia 

benzodiazepines cannot directly open GABAa receptors while —— can directly activate them = making benzodiazepines safer

barbiturates 

are metabolized by the liver, Increases metabolism of other things in the body, ex: Oral contraceptives, Because they have their own hepatic enzymes

barbiturates

have a ceiling to where they won’t decrease respirations but if taken with other drugs that ceiling goes away

benzodiazepines

Will depend upon CNS Depressant + polypharmacy, Sedation, Coma, Decreased Respiration, Decreased Cardiovascular Function (↓ BP, ↓ CO), Memory Loss

toxicity/overdose presentation

Treatment: Depends upon the —-

CNS depressant 

treatment for overdose on a barbiturate

life support

treatment for overdose on a benzodiazepine or Z drug

flumazenil, life support

physical dependence/withdrawal symptoms of CNS depressants = (“Hangover”-like Effects), Anxiety, agitation, increased sensitivity to light/sound, paresthesia (burning/prickling sensation), muscle cramps, myoclonic jerks, sleep disturbance, dizziness

moderate dose usage

physical dependence/withdrawal symptoms of CNS depressants = Seizure, delirium, Might require months-long dose tapering due to withdrawal symptoms, If substance abuse: might require long-term rehabilitation program after detox

high dose usage 

other sedatives and hypnotics MOA include:

H1 receptor antagonists, melatonin congeners, orexin receptor antagonists

1st generation H1 histamine receptor antagonists, Produce sedation by inhibition of CNS histamine receptors

H1 receptor antagonist

MT1 / MT2 melatonin receptor agonists, Drugs that mimic effects of melatonin and influence natural circadian rhythm to promote sleep

melatonin congeners

OX1 / OX2 orexin receptor antagonists, Blocks wake-promoting effects of hypocretin/orexin system

orexin receptor antagonist 

H1 receptor antagonist, t1/2 = 9 h, Therapeutic Indications: insomnia, allergies, motion sickness, PONV, cough suppression OTC and Rx, AE could be = sedation and antimuscarinic effects (anti-SLUDE), Zzzquil

diphenhydramine

natural circadian signaling molecule, Role in regulating biological rhythms. Available as OTC sleep aid, MOA: MT1 / MT2 receptor agonists

melatonin

melatonin congener, (Rozerem) – t1/2 = 2 hr (active metabolite ~ 4 h), synthetic analog of melatonin; treatment of sleep onset disorder, Adverse Effects:sleepiness, shouldn’t take if pregnant/lactating 

ramelteon 

orexin receptor antagonist, (Belsomra) – t1/2 = 12 h, uOX1 / OX2 orexin receptor antagonists, Attenuates wake-promoting effects of hypocretin/orexin system, Therapeutic Indications: sleep onset / sleep maintenance disorder, No risk of amnesia, AE:daytime sleepiness, headache,abnormal dreams;

suvorexant