Benzodiazopines (Sedatives and Anti-Epileptics)

Question 1

What is the difference between a “sedative” and a “hypnotic”?

Answer 1

Sedatives are anxiolytics, which calm or reduce anxiety. Hypnotics induce sleep, and as such have a greater effect on the CNS than anxiolytics.

Question 2

What are the mild moderate and severe dose dependent toxicities of sedatives or hypnotics?

Answer 2

At first, they both cause sedation. At higher doses, they produce hypnosis. And even higher doses, anasthesia, respiratory and cv depression, possible coma and death

Question 3

Besides anxiolytics, anasthetics and hypnotics, what else can the sedative-hypnotics be used for?

Answer 3

Withdrawal symptoms from ethanol and other sedative hypnotics (there is cross reactivity). Also management of mania, and occasional diagnostic aids in neurology and psychology. We can use it for Sedation/amnesia.

Question 4

PK of sedatives-hypnotics?

Answer 4

Lipid soluble (to variable degrees) and as a result crosses other lipid barriers as well, such as crossing the placenta and being in breast milk. CYP metabolized and conjugated, then renally eliminated. Renal dose adjustments unnecessary (w/ exceptions). Liver diseases however is possible if patient has hepatic failure.

Question 5

What is the general target of Benzos and Barbiturates?

Answer 5

The target is the GABA-A receptor.

Question 6

How do Benzo’s and Barbiturates differ in their MOA?

Answer 6

The idea is to perpetuate the effects of the GABA receptor by increasing the frequency of the opening of Cl- channels (Benzo). Barbiturates would increase the duration of the Cl- channels to be open and in fact at high doses it acts like a GABA mimetic (no GABA would be needed to induce effect). Barbiturates also inhibit glutamate AMPA receptors.

Question 7

What’s special about the drug “Flumazenil?”

Answer 7

It is an antagonist for benzo’s and BZ1’s, and thus can be administered as an antidote.

Question 8

What are Benzodiazepines used for? What is one of the main concerns of using Benzo’s long term?

Answer 8

Rapid control of panic attacks, long term management of generalized anxiety disorders and panic disorders. While effective, there is an increased risk of tolerance the longer the drug is used.

Question 9

What effects do benzo’s have on sleep?

Answer 9

Fall asleep faster, increased 2 NREM sleep, decreased duration of REM sleep and stage 4 NREM sleep. End result: patient falls asleep faster and wakes up more refreshed.

Question 10

How long does it take for people to develop tolerance to sedatives/hypnotics?

Answer 10

If used greater than 1-2 weeks, and there is cross tolerance between these drugs and ethanol.

Question 11

Why are these drugs (Benzo’s) abused? What are the withdrawal effects?

Answer 11

They induce anxiety relief, euphoria, disinhibition and sleep, which people want and thus abuse. Withdrawal symptoms are anxiety, insomnia, CNS excitability leading to convulsions. Higher the dose the greater the withdrawal, the longer the half life the less the withdrawal effects are felt.

Question 12

What are the sedative-hypnotics adverse effects?

Answer 12

CNS (and RESPIRATORY) depression, drowsiness, disinhibition, diminished motor skills, impaired judgment, lethargy, ethanol like symptoms, antrograde amnesia (dose dependent), hangover. Also paradoxical reactions like anxiety agression and psychosis.

Question 13

What are the resp and CV adverse effects of sedatives-hypnotics?

Answer 13

Resp depression and impaired CV function that is dose dependent, increased risk in patients with pulmonary and CV problems to begin with. Depression of the respiratory and vasomotor centers of the medulla.

Question 14

Preg and hypnotics-sedatives?

Answer 14

No baby can present with withdrawal symptoms and “Floppy baby syndrome.”

Question 15

What are some drug drug interactions among the hypnotics sedative class?

Answer 15

Alcohol, opoids, anti-epileptics, anti-psychotics, TCA, antihistamines and herbal products.

Question 16

CYP interactions and Benzo’s?

Answer 16

Substrates of 3A4, also 2C19 for Diazepam.

Question 17

Name 8 Benzodiazepines

Answer 17

Alprazolam, Chlordiazepoxide, DIAZEPAM, Flurazepam, LORAZEPAM, Oxazepam, Temazepam and Triazolam.

Question 18

Which Benzo’s do NOT have any CYP metabolism?

Answer 18

Temazepam, oxazepam, lorazepam are all glucorinodated without CYP metabolism.

Question 19

Which of the Benzo’s are short acting drugs with half lives less than 6 hrs?

Answer 19

Midazolam, Triazolam.

Question 20

Which of the Benzo’s have an intermediate half life (6-24 hrs)?

Answer 20

Temazepam and Lorazepam (both of these also have no CYP metabolism).

Question 21

Long acting benzos (greater than 24 hrs)? Which one is greater than 50 hrs and which is greater than 100 hrs?

Answer 21

Diazepam, Flurazepam and Quazepam, the active form of diazepam (nordiazepam) and flurozepam (N-desalkylflurazepam) have half lives over 50 and 100 hrs respectively.

Question 22

What is the MOA of Benzo’s?

Answer 22

Allosterically binds to GABA-A receptor, enhances the inhibitory effects of GABA. Also increases the frequency of channel opening. It increases the effect of GABA without directly opening the GABA-A receptor or opening their associated channels, and its effect is dependent on the pre-synaptic release of GABA. Dose response curve B, meaning at dose increase the effect will increase up to a point, and then flatten.

Question 23

Peripheral effects of Benzos?

Answer 23

With IV, there is coronary vasodilation and with very high doses there is neuromuscular block. (in overdose).

Question 24

CV effects of Benzo’s pre anesthesia and overdose?

Answer 24

Preanesthesia you will decrease BP and increase HR, toxic dose will lead to depression of vasomotor centers in the medulla, vasodilation and decreased cardiac output –> circulatory collapse.

Question 25

What are the respiratory effects of Benzo’s pre-anasthesia? Overdose?

Answer 25

Pre anesthesia there is slight depression of alveolar ventillation leading to hypoxia induced acidosis. OD depresses the medullary respiratory centers.

Question 26

When is Benzo’s cautioned in its use?

Answer 26

Patients with previous pulmonary and CV problems, obstructive sleep apnea,

Question 27

When would we use what Benzo’s? When would we use the short and long half life benzo’s?

Answer 27

All Benzo’s are equally efficacious, but have to consider the state of the patient, i.e. CYP considerations, liver, lung or CV impairment, etc. Short half life for sleep disorders, long for anxiety disorders.

Question 28

Alcoholics are prescribed these two benzo’s to taper off the alcohol, which two are they and why?

Answer 28

Chlordiazeopxide and dizazepam, they are used first at relatively high doses and tapered off and they generally have a relatively long half life.

Question 29

In the event of a Benzo overdose, what drug can be used and how does it work?

Answer 29

Can use the antidote “Flumazenil,” which works as a competetive antagonist to Benzo’s (binds at the same binding site at GABA-A as Benzo’s). Also can be used for Z compound antidote.

Question 30

How is the antidote to Benzo’s administered?

Answer 30

IV, it is rapid onset and short duration so might require repeat dosing.

Question 31

What are the 2 considerations to keep in mind when using the antidote to Benzos?

Answer 31

It can trigger withdrawal symptoms of Benzo’s in chronic BZ users, and concomitent TCA overdose can precipitate seizures and arrythmias.

Question 32

Describe the Vd of Diazepam and why this is important? Metabolism?

Answer 32

It is highly lipophilic so goes straight to the brain immediately, however this property makes it leak into other body tissues too so it leaks OUT of the brain just as quickly. Result: stays in the brain about 30 mins but stays in the body for a long time in other tissues, thus only useful for status epilepticus in that 20-30 mins. 2C19 and 3A4 metabolism.

Question 33

How does Lorazepam relate to Diazepam? Metabolism of Lorazopam?

Answer 33

While the onset of action is shorter for Lorazepam (about 5 mins, compared to almost immediately for diazepam), it stays in the brain for longer. Metabolized by hepatic glucoronidation.

Question 34

Tx use of Clonezapam? Metabolism?

Answer 34

It is a benzo that is oral only and used for chronic tx. 3A4 metabolism.

Question 35

Why are Benzo’s generally used only for acute seizures?

Answer 35

Benzo’s develop tolerance to the anti convulsant effects (except for myoclonic seizures).

Question 36

Why can barbiturate overdose lead to death and why doesn’t Benzo’s?

Answer 36

It increased dosage, the barbs overcome their need to have GABA present in order for it to work, it mimics GABA and opens the GABA receptors on its own repeatedly, causing death. Benzo’s on the other hand cannot act as GABA mimetics so GABA must be present.

Question 37

What is the importance of Diazepam Rectal Gel?

Answer 37

Used in refractory seizures in pt’s already on stable AED’s. Common in children esp with mental retardation.

Question 38

When would we use Clonazepam?

Answer 38

Monotherapy or adjunt for Lennox-Gastaut syndrome, petit mal variant, akinetic and myoclonic seizures.

Question 39

When would we use Chlorazepate?

Answer 39

Alternative, adjunct partial seizure disorder.