PHARM: SEDATIVE AND HYPNOTICS

why thiopental can be used during the induction phase of anesthesia

they have a high solubility=fast onset and doesnt last long

barbituates

steep/linear curve

• produces unlimited dose dependnent cns depression progressing rapidly from sedation to surgical anesthesia coma, fetal respiratory depressin

benzodiaphems

capped/plateau curve

• exhibit a therapeutic ceiling witb low maximal cns depression making them unlikely to cause deeo coma or servere respiratory arrest when taken alone

barb efficary

high maximal cns depression used for anesthesia induction

benzo efficancy

high clinical efficacy 4 sleep,anxiety, and seizure,low max depression ceiling

muscle efficacy

effective for relieve skeletal muscle spansm along side sedative actions

barb safety and margin

low safety, narrow therapeutic index= hih risk of fatal respratory depression

benzo safey and margin

high safety wide ti low risk for fatal respiratory arrest aloone

muscle safety and margin

high safety wide range/margin of safety

barb drug interaction

strongly induction hepatic enzymes altering clearance of other drugs, additive with alchol

benzo drug interaction

low enzyme induction metabolized by cyp3a4 (affected by inhibitors/inducers), additive depression with opioids/alchol

muscle drug interaction

shares cyp3a metabolism and additive cns/respiratory depression with other depressants

bard dependence and abuse

high liability for physical dependence, rapid tolerance and abuse potential

benzo dependce and abuse

low abuse/dependence potential for short term use, risk increases with ling term, high dose use

muscle dependence and abuse

low to mmoderate dependnce risk with chronic ise requires gradula tapering

Use the proper pharmacological term that describes how barbiturates and benzodiazepines act on the receptor.

allosteric activators on GABA a receptor

what do benzos do with openings

increase time of pore opening

what do barb do with openings

keep pores open continuously> bad can kill you (body be continououls being sushed)

what can alter a drug duration of action

active metabolites

cyp3a4 inhibitors and inducers

altering a drug duration of action: active metabolites

active metabolites can increase duration→ benzos undergo extensive hepatic metabolism to form pharmacological active intermediates which significantly extends there overall duration of action and their clinical half life.

altering a drug duration of action: cyp3a4 inhibitors

will increase levels of benzi . inhibition of cyp3a4 will prevent benzo from being metabolized thus half life is increased, clearence is decreased and levels of benzo will remain high

altering a drug duration of action: cyp3a4 inducres

will decrease levels of benzo→ increase activity of cyp3a4 will increase metabolism of benzo thus half life is decreased, clearence is increased and levels of benzo will be decreased

diazepam (valium) uses

antiolytic (low dose) sedative (moderate dose) and a hypnotic (high dose)

what is a convient side effect of diazepam (valium)

amnesia

diazepam (valium) onset

rapid

diazepam (valium) effects

Long lasting (effects last for more than 12 hrs).

• Its metabolites are active, and they can accumulate in body fat and are slowly eliminated, thus prolonging the clinical half life to 1-4 days.

diazepam (valium) after anesthesia (IV)

sedation lasts ~45 minutes and the anxiolytic effect lasts much longer.

what is Midazolam used for

Pre-operative anesthetic (i.v.)

• Induces hypnosis and amnesia

• (Dose 10-15 mg)

Midazolam pro

• Rapid onset

• Short acting (effects wear off quickly, leading to a faster recovery)

• (T½ life = 2-5 hrs).

what is Lorazepam (Ativan) used for

Anxiolytic (2-3 mg)

what is Lorazepam (Ativan) used to prevent

anticipatory nausea adjuvant for chemotherapy (inhibits vomiting centers in the brain)

why is lorazepam (ativan) a common benzo used in the elderly

because it is not metabolized in the liver.

• Drug is directly conjugated and excreted.

• Does not have active metabolites

lorazepam (ativan) effects

Moderate acting (effects last for 6-8 hrs)

(T½ = 10-18 hrs)

what is Alprazolam (Xanax) used as

Anxiolytic (Dose: 1.5-3 mg daily)

Alprazolam (Xanax) pros

Rapid onset (1 hr)

short duration (effects last ~ 6 hrs)

(T ½ = 11 hrs)

what does Alprazolam (Xanax) produce

amnesia

benzodiazepines/ Diazepm CNS effects

• Daytime drowsiness (sedation), apathy.

• Anterograde amnesia: Midazolam and diazepam are useful because patients cannot recall the procedure.

• Confusion: As seen in videos after getting wisdom teeth pulled.

• Ataxia, incoordination, dizziness, muscle weakness (probably shouldn’t drive)

benzodiazepines/ Diazepm cardic issues

May cause hypotension. Do not use in patients who are medically unstable (i.e. patients with angina).

benzodiazepines/ Diazepm respiratory problems

Individuals with hypoxemia, hypoventilation, or obstructive sleep apnea. These may worsen with benzodiazepines.

benzodiazepines/ Diazepm in pregnant or breastfeeding people

Benzodiazepines cross the placental barrier and are in breast milk. They have teratogenic effects that can lead to congenital malformations early and CNS depression late term

benzodiazepines/ Diazepm with other CNS depressants

In patients using alcohol, antidepressants, opioids, etc., CNS depression will be exacerbated, and respiratory depression can occur.

benzodiazepines/ diazepem addiction problems

Tolerance and psychological dependence can develop when using long term, thus they need to be tapered off slowly (e.g. Valium).

benzodiazepines/ Diazepm in teens

• For single use such as for a procedure.

• Not the first line therapy for conditions that require long-term treatment.

Other CNS depressants

• Alcohol

• Anesthetics

• Antipsychotics

• Antidepressants

• Opioids (hydrocodone)

• Analgesics

• Anti-histamines

• Other sedative-hypnotics

Identify what would occur if a patient on a CYP3A4 inducer is administered a benzodiazepine

the benzo would be metabolized faster

there would be less benzo levels

the benzo effects wound not last as long

Identify what would occur if a patient on a CYP3A4 inhibitor is administered a benzodiazepine

benzo would be metaboolized slower

there would be higher benzo levels

the benzo effects will be more profound and last linger

what is Flumazenil (Romazicon) used for

Facilitate recovery after benzodiazepine use or toxicity.

what is Flumazenil (Romazicon)

a GABA receptor antagonist

what does Flumazenil (Romazicon) do

competes for the same spot as the benzodiazepine and kicks the benzo off.

why dont we use most benzos in the elderly

because they are metabolized in the liver and in elderly the liver function is lower

what is Zolpidem (Ambien) used for

to quicken asleep onset and improve sleep maintenance.

max dose of Zolpidem (Ambien)

10-12 mg

Zolpidem (Ambien) metabolites

Has inactive metabolites (less daytime drowsiness, T ½ = 5-7 hrs)

what does Zolpidem (Ambien) do to GABA

Potentiates the GABA response.

why is Zolpidem (Ambien) sometimes preferred over benzos

• Does not interact with CYP34A drugs

• Less cognitive side effects.

• No dependence issues.

• Can be used in pregnant women

• No anxiolytic or antiseizure effects

other sleep drugs have what letter in the name

Z

Zolpidem (Ambien) side effects

• Daytime drowsiness

• Dry mouth

• Sleep-related complex behaviors (sorting clothes)

Buspirone (Buspar) mechanism of action

5-HT1A serotonin receptor partial agonist

what is Buspirone (Buspar) used as

an anxiolytic

• (T ½ = 2-4 hrs)

why are Buspirone (Buspar) preeered over benzos

• Not a controlled substance.

• Just as good as diazepam

• Well-tolerated

• Less cognitive side effects:

• Safer

• can be used in pregnant women

why are Buspirone (Buspar) safer than benzos

• No potentiation by CNS depressants

• No dependence properties and lacks potential for abuse

Buspirone (Buspar) cons

Requires multiple doses for the anxiolytic effect. Thus, it doesn’t work for a single time use.

Ramelteon (Rozerem) mechanism of action

Melatonin receptor agonist. This acts just like melatonin.

what is Ramelteon (Rozerem) used for

to Reduce latency to sleep onset. Effects within 30 min

Ramelteon (Rozerem) half life and metabolism

• T ½ = 2-5 hrs)

• Is metabolized via CYP1A2 and 2C9

why is Ramelteon (Rozerem) preferred over benzos

• Not a controlled substance

• Well-tolerated

• Less side effects: No daytime drowsiness

• safer

why is Ramelteon (Rozerem) safer than benzos

same as buspar

• No potentiation by CNS depressants

• No dependence properties and lacks potential for abuse

Ramelteon (Rozerem) cons

• Pregnancy risk: Category C

• Anaphylactic reactions

• Mild cognitive side effects

Suvorexant (Belsomra) (Schedule IV) mechanism of action

Orexin receptor antagonist

what is Suvorexant (Belsomra) (Schedule IV) used for

Reduce latency to sleep onset and improves sleep maintenance.

Suvorexant (Belsomra) (Schedule IV) half life and metabolism

• (T ½ = 12 hrs)

• Is metabolized via CYP3A4

Suvorexant (Belsomra) (Schedule IV) why is it preferred over benzos

• Well-tolerated

• Less side effects: No daytime drowsiness

• safer

why is Suvorexant (Belsomra) (Schedule IV) safer than benzos

• No potentiation by CNS depressants

• No dependence properties and lacks potential for abuse

same as buspar and ramelteon

Suvorexant (Belsomra) (Schedule IV) cons

• Pregnancy risk: Category C

• Anaphylactic reactions

• Mild cognitive side effects

When CNS depressant drugs are used for deep sedation and general anesthesia, the following must be readily available

• suction and monitoring equipment

• emergency drugs

• a means to deliver oxygen under positive pressure

• flumazenil

what would happen if an opiod or alcohol is adminstered wtih a benzo to induce sedation

cns depression will exacerbated

a lower dose will likely exert the target clinical effect

CYP3A4 inducers will

decrease levels of benzodiazepines:

how do CYP3A4 inducers works

• Increased activity of CYP4A will increase metabolism of the benzodiazepine.

• Thus, the half-life is decreased, clearance is increased, and levels of the benzodiazepine will be decreased.

CYP3A4 inducers examples

– Phenytoin

– Phenobarbital

– Rifampicin

– St. John’s Wort

– Glucocorticoids

CYP3A4 inhibitors will

increase levels of benzodiazepines.

how do CYP3A4 inhibitors works

• Inhibition of CYP3A will prevent the benzodiazepine from being metabolized.

• Thus, the half-life is increased, clearance is decreased, and levels of the benzodiazepine will remain high.

CYP3A inhibitors examples

– Erythromycin

– Cimetidine (antihistamine, antacid)

– Verapamil

– Diltiazem

– Itraconazole

– Ketoconazole

– Ritonavir

– grapefruit

— Omeprazole (proton pump inhibitor)

— Antacids

how are Omeprazole (proton pump inhibitor) a CYP3A4 inhibitor

inhibits hepatic metabolism will also increase benzodiazepine levels.

how are Antacids a CYP3A4 inhibitor

which are minimally absorbed) prevent absorption of benzodiazepines if taken at the same time.

What would happen if a patient is elderly with low liver function, and

a benzo is administered to reduce anxiety?

• If the liver isn’t working well, then diazepam will be metabolized slowly.

• It will stay in the system for a really long time and can lead to more profound effects.

• The anxiolytic effect may turn into a sedative or hypnotic effect and last longer

Conscious sedation

• a minimally depressed level of consciousness

• retains the patient’s ability to independently and continuously maintain an airway and respond appropriately to physical stimulation or verbal command

Benzodiazepines - Pharmacokinetics: Mechanism of action

GABA receptor agonist

Benzodiazepines: onset

Lipid solubility determines time of onset.

Benzodiazepines duration

Most undergo extensive metabolism by the liver forming pharmacologically active intermediates, thus determining duration of action (next slide).

Benzodiazepines excretion

in urine

benzo drugs are selected based on

time course of action and desired pharmacological effects.

anxiolytics

Reduces anxiety, but you are still functional

sedative

Makes you really calm and chill, but not fully functional

hypnotics

Helps you fall asleep and/or stay asleep

barbiturates

(1900s). The first sedative drugs with many side effects

including: fatal respiratory depression, high potential for drug abuse, induce hepatic drug-metabolizing enzymes

• benzos replaced these in 1950”s

• benzi like drugs came out in 1990’s

orexin (LH)

WAKE UP signal

Acts on orexin receptors in the Hypothalamic-Ascending Reticular Activating System

GABA receptor agonists can have progressive

dose dependent cns effects

low dose dependent cns effects

anxiolytics: relief of anxiety

low medium dose dependent cns effects

sedatives: produces relaxation, calmness and decreased motor activity without loss of consciousness

medium high dose dependent cns effects

hypnotics: induce drowsiness and a depressed state of consciousness resembling natural sleep, with decreased motor activity and impaired sensory responsiveness