Pharm - Benzos and Hypnotics Flashcards
What are the drugs of choice for anxiety/hypnotics?
BENZODIAZEPINES
They have replaced the original drugs of choice – barbiturates (more prone to abuse, more side effects, lower therapeutic safety margin)
Anti-Anxiety : Hypnotic Ratios
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!
Hypnotic : Toxic Dose
For Benzos –> 1 : 30
For Barbs –> 1 : 8
ANTI-ANXIETY : TOXIC DOSE
For Benzos = 1 : 120!!!! (takes 120x normal dose aka impossible to OVERDOSE)
For Barbiturates –> Anti-Anxiety : Toxic = 1 :16!!!! (Much easier to OD!)
Comparing Benzos and Barbs Safety
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
Therapeutic Dose : DOSE PRODUCING DEPENDENCE
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
Tolerance
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
Withdrawal
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
Sedatives and Sleep
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!
Effects of Sedatives of the FETUS
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
BENZO MECHANISM OF ACTION
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!
BARBITURATES MECHANISM
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)
Pharmacokinetics
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
OXAZEPAM and Duration of action
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
DIAZEPAM (Valium)
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
Chordiazepam and Diazepam
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
FLURAZEPAM
SHORTEST HALF LIFE itself, but its METABOLITE LASTS THE LONGEST! (47-100 hours!!!)
What can affect half life?
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
Long Acting Benzos
DIAZEPAM
FLURAZEPAM
Diazepam and Metabolism
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*
Random reminder of half-life and steady state
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
FLURAZEPAM
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
INTERMEDIATE acting benzos (as a class)
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
Short Acting Benzos
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!!!!!
Chronic Daily Dosing
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
Anxiety overview
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
What makes anxiety a disorder?
IT MUST BE DISABLING!!!!
Has to be SELF DESTRUCTIVE or DESTRUCTIVE TO OTHERS
Is anxiety ever good?
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
Regions of the brain affected by Benzos?
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!
Don’t Benzos work on GABA? Why does 5HT and NE matter?
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!!!!!!
Benzos and Tolerance
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
What is the actual mechanisms of Benzos and their effect on GABA?
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
BUSPIRONE
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
FLUMEANZIL
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
BETA-CARBOLINES
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)
ZOLPIDEM (ambien)
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
Beta Blockers and Anxiety
These are especially useful in cases where autonomic symptoms (tachycardia, hyperventilation) are a major component –> Stage fright!
Antidepressants (Imipramine, MAOI)
Often used for PHOBIC PANIC ATTACKS
What benzo is used for panic attacks?
ALPRAZOLAM
SSRI are NOT good for acute anxiety
Don’t listen to TV ads!
