Pharm - Benzos and Hypnotics

Question 1

What are the drugs of choice for anxiety/hypnotics?

Answer 1

BENZODIAZEPINES

They have replaced the original drugs of choice – barbiturates (more prone to abuse, more side effects, lower therapeutic safety margin)

Question 2

Anti-Anxiety : Hypnotic Ratios

Answer 2

Hypnotic effects = drowsiness, delayed rxn times, etc

For Benzos –> Anti-Anxiety : Hypnotic = 1 : 4

Barbs –> Anti-anxiety : Hypnotic = 1 : 2

So, only need to double dose of barbs to get sedation, whereas it takes 4x as much for benzos!

Question 3

Hypnotic : Toxic Dose

Answer 3

For Benzos –> 1 : 30

For Barbs –> 1 : 8

Question 4

ANTI-ANXIETY : TOXIC DOSE

Answer 4

For Benzos = 1 : 120!!!! (takes 120x normal dose aka impossible to OVERDOSE)

For Barbiturates –> Anti-Anxiety : Toxic = 1 :16!!!! (Much easier to OD!)

Question 5

Comparing Benzos and Barbs Safety

Answer 5

Benzos are NOT LETHAL WHEN TAKEN ON THEIR OWN (rarely get past disinhibition stage)

Can lead to CONFUSION, DELIRIUM, ATAXIA, UNCONSCIOUSNESS (but not really severe for any of these)

Barbiturates can KILL: Anesthesia –> Coma –> Death; STRONG respiratory depression +/- Hypotension

BUT! All bets are off when COMBINING WITH ALCOHOL

Benzos become LETHAL when combined –> a synergy occurs (with any two sedatives) that ELIMINATES THE SAFETY MARGIN

Question 6

Therapeutic Dose : DOSE PRODUCING DEPENDENCE

Answer 6

Both drugs can develop dependence, but once again barbiturates require less drug and are thus fare more addictive

Benzos –> 1 : 6-20

Barbs –> 1 : 2-5

So, it is plausible to think that a patient - not thinking the drug is doing much - takes a few extra doses at a time to see more effects – BAM DEPENDENT

Question 7

Tolerance

Answer 7

Barbiturates –> Tolerance in about a week! Fast! Up the dose! Dependence!

Also, NO TOLERANCE DEVELOPS TO THE LETHAL EFFECTS, so the margin of safety is narrowed

Tolerance for BENZOS develops moreso to the HYPNOTIC effects than to the anti-anxiety effects!!!! So they have a VERY LARGE MARGIN

There is NO reason to increase the dose of a benzo for better anxiolytic effects! Won’t do anything

Question 8

Withdrawal

Answer 8

Benzos ONLY see withdrawal with HIGH DOSES FOR MONTHS

Takes about a week of cessation to start experiencing symptoms –> anxiety, tremor, weakness, psychosis, seizures, death

SEIZURES can occur because these drugs essentially inhibit brain function –> so when taken off them there can be over excitation of the brain!!!

Barbiturates develop withdrawal after ONE MONTH –> less than THREE DAYS after cessation will we see the withdrawal effects!

Withdrawal effects can cause patients to SEEK THE DRUGS to avoid them; so for BOTH DRUG CLASSES –> TAPER THE DOSE BEFORE COMPLETE CESSATION

Even benzos have fallen out of favor for LONG TERM use, but if taken appropriately it can be OK

Question 9

Sedatives and Sleep

Answer 9

Barbiturates and Benzos have been used to INDUCE SLEEP

The goal of sleep meds shouldn’t be to knock the person out only, we need to give them a good quality of sleep!

Barbs do NOT give good quality sleep, because they depress the REM state (dreams!)

REM REBOUND –> drug levels drop in the body as we sleep, or even during the day, and as a result, a sort of “withdrawal” occurs in which we enter the REM STATE for a long time! —> High arousal, high anxiety even if technically sleeping –> makes us even MORE TIRED!!!!!! Not enough restful sleep!!!

BENZOS DO NOT SUPPRESS REM SLEEP

Do suppress stage 4, which could be good for suppressing sleep walking and night terrors!

Question 10

Effects of Sedatives of the FETUS

Answer 10

Both classes CROSS THE PLACENTA

Benzos –> Concern in the FIRST 6 WEEKS because of birth defects

Both class in the LAST TRIMESTER WILL SEDATE THE FETUS!!!!!! When born, the baby can experience withdrawal! Treat with anti-seizure meds and a benzo to wean them off

Question 11

BENZO MECHANISM OF ACTION

Answer 11

Increase the affinity of GABA for its receptors!
More inhibition

Benzos work INDIRECTLY because they REQUIRE GABA to complete their purpose (NT dependent - important point)

If we take a ton of Benzos and suppress CNS, at some point there will be FEEDBACK INHIBITION on DABA release, blunting the effect of the drug –> also helps to make Benzos a safer drug!

Question 12

BARBITURATES MECHANISM

Answer 12

Non-specifically reduce membrane excitability and suppress glutamate-mediated excitation

NOT A SELF-LIMITING MECHANISM –> Barbiturates can keep depressing excitability with higher and higher doses –> NOT NT DEPENDENT; thus they can kill!!!!!!!

Can also enhance GABA transmission (another minor mechanism)

Question 13

Pharmacokinetics

Answer 13

Can’t just look at half-life to determine a drug’s duration of action –> we also have to consider how long it takes for the drug to be absorbed from the gut

LIPOphilic drugs are more readily absorbed than HYDROphilic drugs

Question 14

OXAZEPAM and Duration of action

Answer 14

This drug is NOT VERY LIPOPHILIC

So despite it getting rapidly metabolized by the plasma, it takes longer to get from the gut to the plasma! Thus it has a LONGER DURATION OF ACTION

Initially it causes a little motor depression, but that increases over the next two hours as the drug is slowly absorbed

OXAZEPAM CAN TAKE UP TO 4 HOURS TO REACH PEAK PLASMA CONCENTRATION

Question 15

DIAZEPAM (Valium)

Answer 15

Very Lipophilic and has a LONG HALF LIFE IN PLASMA!

Gets completely absorbed in less than an hour, so its effects will decrease over time

Question 16

Chordiazepam and Diazepam

Answer 16

Have the EXACT SAME HALF-LIFE because they both have the EXACT SAME ACTIVE METABOLITE (metabolites are doing the work)

Chlordiazepam has a longer time to peak plasma concentration

Question 17

FLURAZEPAM

Answer 17

SHORTEST HALF LIFE itself, but its METABOLITE LASTS THE LONGEST! (47-100 hours!!!)

Question 18

What can affect half life?

Answer 18

Liver Cirrhosis DOUBLES THE HALF LIFE of CHLORDIAZEPAM and DIAZEPAM

OXAZEPAM is NOT AFFECTED because it is NOT METABOLIZED BY THE LIVER

AGE can also increase half life 4-5x

CHRONIC DOSES –> beyond a week, drug and metabolites can accumulate –> active metabolites can actually COMPETITIVELY INHIBIT the parent drugs metabolism –> increasing the half life of a drug like Diazepam from 34-54 hours!

As a result, it may take 6-10 days of CONTINUOUS USE to achieve the desired therapeutic effects

Question 19

Long Acting Benzos

Answer 19

DIAZEPAM

FLURAZEPAM

Question 20

Diazepam and Metabolism

Answer 20

LONG ACTING BENZO

First, it is DESMETHYLATED which yields DESMETHYLDIAZEPAM –> this is the LONGEST LASTING ACTIVE METABOLITE (up to 2 day half life!)

Any drugs that are DESMETHYLATED/DESALKYLATED are going to have a LONG ACTING, ACTIVE METABOLITE

(Desmethyldiazepam is the metabolite of several benzos)

Desmethyl is then ALPHA HYDROXYLATED to OXAZEPAM!! This alpha hydroxyl is essential for RAPID GLUCURONIDATION in the kidney, which inactivates the compound

THUS, OXAZEPAM has a SHORT HALF LIFE

The conversion of desmethyldiazepam to oxazepam is also RATE LIMITING (slowest step, so there is a LOT OF DES and a little OXAZEPAM at all times)

THUS, desmethyldiazepam has the GREATEST IMPACT on the physiological effect of Diazepam*

Question 21

Random reminder of half-life and steady state

Answer 21

As repeated doses of a drug are administered its plasma concentration builds up and reaches what is known as a steady state. This is when the amount of drug in the plasma has built up to a concentration level that is therapeutically effective and as long as regular doses are administered to balance the amount of drug being cleared the drug will continue to be active. The time taken to reach the steady state is about five times the half life of a drug. Drugs like digoxin and warfarin with a long half life will take longer to reach a steady state than drugs with a shorter half life.

This is why for drugs like SSRI, which take a month or so to reach steady state (half life x 4), aren’t effective until then. THEN after that steady state is reached, normal doses will be effective.

Sometimes, boluses or loading doses are given to reach steady state quicker

Question 22

FLURAZEPAM

Answer 22

Also a long-acting benzo

Des-ALKYLATED (same concept as des-methylation) to DESALKYLFLURAZEPAM

This metabolite persists for up to 100 hours!!! So it is VERY LONG ACTING

Question 23

INTERMEDIATE acting benzos (as a class)

Answer 23

Do NOT need to be desalkylated or desmethylated

These drugs can be DIRECTLY alpha-hydroxylated – thus they have a faster metabolism and shorter duration of action

The alpha hydroxylation is still the slow step though, so these drugs last for ~8-20 hours

CLONAZEPAM and LORAZEPAM are in this class

Question 24

Short Acting Benzos

Answer 24

OXAZEPAM!

These drugs do NOT need to be desalkylated or alpha-hydroxylated (already have it!!!!)

Thus, they are ready for DIRECT GLUCURONIDATION!!!!

Very quick clearance, very quick duration of action! 2-8 hours

The short acting agents are BEST USED AS SLEEP AGENTS because they are gone by the time the patient wakes up!!!!!

Question 25

Chronic Daily Dosing

Answer 25

If a drug has active metabolites that persist for a long time, we need to be CAREFUL since they can accumulate and cause side effects

Metabolites can actually interfere with the metabolism of the parent drug which could lead to serious risk of overdose

MORE DRUG = MORE SERIOUS WITHDRAWAL SYMPTOMS

Accumulation of DESMETHYLDIAZEPAM interferes with the metabolism of Diazepam –> this will lead to a buildup of BOTH COMPOUNDS –> stop treatment and DIAZEPAM WILL CLEAR MORE QUICKLY than metabolite

Takes approximately a WEEK to TEN DAYS for the desmethyldiazepam to clear and this is why we DO NOT SEE WITHDRAWAL SYMPTOMS until a WEEK AFTER TREATMENT

Question 26

Anxiety overview

Answer 26

Can categorize it into 3 groups:

ANXIETY TO NOTHING IDENTIFIABLE –> Generalized Anxiety and Panic attacks –>

GENERALIZED = patient can’t identify what causes the anxiety; tends to be PERSISTENT and CHRONIC; can be associated with panic attacks that are usually transient and INTENSE;

Panic attacks are treated with SSRI usually –> composed of TWO FACETS (actual attack - the state of panic, and an ANTICIPATORY anxiety - once a panic attack occurs, hard to do that activity again)

SSRI treat the ATTACKS

BENZOS are good for the ANTICIPATORY effects –> in hopes of preventing attacks!

The other forms of anxiety:
Anxiety to something IDENTIFIABLE (phobias, obssessive compulsive)
Anxiety to a specific traumatic event

Question 27

What makes anxiety a disorder?

Answer 27

IT MUST BE DISABLING!!!!

Has to be SELF DESTRUCTIVE or DESTRUCTIVE TO OTHERS

Question 28

Is anxiety ever good?

Answer 28

YES!!!!

“Optimal anxiety” helps us to function at our best

If we were to treat regular anxiety with a benzo, we would actually HARM the patients’ ability to focus

When we treat a patient with disabling anxiety, the goal is to get them to OPTIMAL ANXIETY, not completely free of it

Question 29

Regions of the brain affected by Benzos?

Answer 29

We see the following effects, IN ORDER –> take a higher dose for muscle relaxation that it does to cause sedation, a higher dose to cause ataxia than anxiolysis

AMYGDALA –> inhibition gives the “taming effect” and “lack of fear”; ANXIOLYSIS is 5HT MEDIATED; increased GABA suppresses 5HT neurons that project from the raphae to the amygdala; essentially same effect as removing the amygdala

CEREBELLUM –> Ataxia, disinhibition applies to movements too

ASCENDING RETICULAR ACTIVATING SYSTEM –> sedation and sleep; depresses firing rates of neurons important for arousal; NE MEDIATED; major concerns with drug-drug interactions (alcohol)

SPINAL CORD –> muscle relaxation; augments GABA-mediated presynaptic inhibition at primary afferent terminals!

Question 30

Don’t Benzos work on GABA? Why does 5HT and NE matter?

Answer 30

Since GABA is the master inhibitory system in the body, its fibers exert inhibition on several NT systems, so enhancement of GABA inhibition will suppress other, NON-GABA NT!!!!!!

Question 31

Benzos and Tolerance

Answer 31

As mentioned above, there is NOT A SIGNIFICANT TOLERANCE THAT DEVELOPS TO ANXIETY REDUCTION if taken chronically

This is because the 5HT neurons DO NOT exhibit tolerance to the increased GABA inhibition and the 5HT neuron is the one responsible for anxiolysis!!!!!!!

There IS tolerance to the NE mediated sedation –> only way to overcome this is to INCREASE THE DOSE

Question 32

What is the actual mechanisms of Benzos and their effect on GABA?

Answer 32

GABA receptor has 5 subunits –> Benzos BIND TO THE ALPHA SITE, whereas GABA binds to the BETA SITE

GABA opens the channel, and benzos AMPLIFY THAT BY KEEPING IT OPEN LONGER!!!!!!

Remember again that the effects of benzos are tied to the action on the GABA channel –> so BLOCKING or REVERSING the effects can be achieved by DEPLETING GABA or ADMINISTERING A GABA RECEPTOR ANTAGONIST

Benzos DO NOT influence the amount of GABA released, synthesized, degraded or reuptaken

Question 33

BUSPIRONE

Answer 33

Cutting out the middle man

NON-BENZO ANXIOLYTIC

Instead of increasing GABA to cut out the 5HT from the raphae nucleus, the drug REDUCES 5HT SECRETION STRAIGHT FROM THE NUCLEUS

Activates auto-receptors in the raphae, essentially tricking it into thinking that it is over producing 5HT!!!!! So it then suppresses firing of 5HT neurons –> anxiolysis

It does this WITHOUT AFFECTING NE NEURON ACTIVITY and thus has NO SEDATION

Not efficacious in everyone, although it is theoretically an extremely good drug

ONLY NON-BENZO ANTI-ANXIETY AGENT ON THE MARKET

Question 34

FLUMEANZIL

Answer 34

This is an ANTAGONIST at the benzodiazepine site

Has the ability to BLOCK all the effects of benzos (anxiolysis, sedation)

LITTLE INTRINSIC ACTIVITY, so it is only useful if there are excess benzos in the body

Clinical Use = REVERSAL POST-ANESTHESIA
and REVERSAL POST OVERDOSE

It will NOT work for barbiturate or alcohol OD

This DOES NOT have a long duration of action –> must be CONSTANTLY RE-ADMINISTERED until the benzos are cleared

Question 35

BETA-CARBOLINES

Answer 35

Inverse agonists at the benzo receptor that DECREASE THE EFFECT OF GABA (i.e. opposite effect of Benzos) –> these drugs cause ANXIETY, PANIC, and SEIZURES – they are not given to humans

These effects would be block by flumenazil (because it is an antagonist)

Question 36

ZOLPIDEM (ambien)

Answer 36

Binds selectively to the ALPHA-1 SUBUNIT OF GABA but does NOT have the same structure as benzos

Work on different receptor subtypes than benzos do, and thus PRODUCES SLIGHTLY DIFFERENT BUT OVERALL SIMILAR EFFECTS

Lunesta, Sonata as well

Question 37

Beta Blockers and Anxiety

Answer 37

These are especially useful in cases where autonomic symptoms (tachycardia, hyperventilation) are a major component –> Stage fright!

Question 38

Antidepressants (Imipramine, MAOI)

Answer 38

Often used for PHOBIC PANIC ATTACKS

Question 39

What benzo is used for panic attacks?

Answer 39

ALPRAZOLAM

Question 40

SSRI are NOT good for acute anxiety

Answer 40

Don’t listen to TV ads!