Anti-anxiety Pharmacology

Question 1

What are the barbiturate drugs?

Answer 1

“-barbital; -pental”

Phenobarbital, pentobarbital, thiopental, secobarbital

Question 2

What is the mechanism of barbiturates?

Answer 2

Facilitate GABAa action by increasing duration of Cl- channel opening and thus decreasing neuron firing

(barbiDURATes) = (increase DURATion)

Question 3

Why have barbiturates been phased out of us and benzodiazepines been phased in?

Answer 3

Both work to sedate and lower anxiety, however high amounts of barbiturates can be FATAL, whereas benzodiazepines level off and overdose is not fatal

Question 4

Name the benzodiazepines.

Answer 4

“-am” + clorazepate + chlordiazepoxide (Librium)

“-am” = diazepam (Valium), lorazepam (Ativan), triazolam, temazepam, oxazepam (generic), midazolam (Versed), clonazepam (Klonapin), alprazolam (Xanax)

Question 5

Are benzodiazepines lipophilic or hydrophilic?

Answer 5

They are lipophilic. Benzodiazepines are taken orally, and since they are lipophilic they can cross the blood-brain barrier, as well as cross the placenta and enter breast milk. A mother taking benzodiazepines must be careful.

Question 6

What is the shortest-acting benzodiazepine?

Answer 6

Midazolam with a half-life of 1-7 hours. Its sedation is short.

Midazolam is used during medical or surgical procedures (endoscopy, bronchoscopy) and premedication prior to anesthesia - its full effect occurs in 20-30 minutes, and a few hours later, the effects wear off fully!!

*Be careful because it has higher addictive potential!

Question 7

How do you dose benzodiazepines?

Answer 7

Sparingly! Benzodiazepines reach peak blood levels VERY quickly and last a long time - they have cumulative effects such as increasing drowsiness, so you need to dose them sparingly

Question 8

How are benzos eliminated?

Answer 8

Entirely through hepatic mechanisms! Most common ACTIVE METABOLITE of benzodiazepines is desmethyldiazepam (nordiazepam) with a half-life of >40 hours –> cumulative effects which can really affect the elderly (older livers don’t metabolize/clear well - standard dose in elderly is HALF)

*If people have liver problems, benzos are very problematic because they can accumulate.

Question 9

What is the mechanism of a benzodiazepine?

Answer 9

Facilitates GABAa action by increasing the frequency of Cl- channel opening –> inhibitory

Question 10

Which drugs bind to the GABA receptor?

Answer 10

GABA, benzodiazepines, flumazenil, zolpidem (non-benzo hypnotic), barbiturates

They all bind to different sites on the receptor, so they are all synergistic!!

Question 11

What are the clinical uses of benzodiazepines?

Answer 11

• Anxiety reduction, accompanied by some depressant effects of psychomotor (reaction times) & cognitive functions
• At doses that lower anxiety, BZs can cause disinhibitory effects such as euphoria, impaired judgment and loss of control

Side effect: dose-dependent ANTEROGRADE amnesia - you can’t remember events occurring during drug’s duration of action

Question 12

Which BZs are used for status epilepticus?

Answer 12

Diazepam (Valium) & Lorazepam (Ativan) - smaller dose than that given for anxiety is used to stop a seizure - crazy!

Clonazepam (Klonapin) also has some anticonvulsant effects.

Question 13

Which BZs are used for general anesthesia?

Answer 13

Diazepam (Valium), Lorazepam (Ativan), and Midazolam (Versed)

Question 14

Which BZ is used to stop a muscle spasm?

Answer 14

Diazepam (Valium) - stops the muscle spasm and also relaxes the muscle

Question 15

Tell me about BZs and respiratory depression.

Answer 15

At hypnotic doses in healthy patients, BZs have a comparable effect on respiration to changes that occur during natural sleep. (lower respiration to levels normal for sleep)

However, if patients have compromised lung function (pulm disease or asthmatic), even at therapeutic doses, BZs can produce significant respiratory depression - problem!

Question 16

When is cardiovascular depression present with BZs?

Answer 16

At levels higher than that necessary for sleep (more than hypnotic dose)

*NOTE: in patients with hypovolemic states, heart failure, and other diseases that impair CV function, even normal doses can –> cardiovascular depression

Question 17

What is the drug that instantly reverses BZ effects?

Answer 17

Flumazenil (competitive inhibitor of BZ that binds directly to BZ site on GABAa receptor)

Flumazenil antagonizes actions of BZs and the newer hypnotics zolpidem, zaleplon, and eszopiclone, but NOT the barbiturates.

*Flumazenil has short half-life, about 1 hr, so sedation commonly occurs bc BZs still working (half life about 10 hours) - must give repeated doses of flumazenil!

Question 18

Although BZs are better for short-term use, some of them have long-term uses for __ and ___.

Name the BZs used for long-term management.

Answer 18

GAD (generalized anxiety disorder) & panic disorders.

• Alprazolam (Xanax) - GAD, panic disorder, agoraphobia
• Lorazepam (Ativan) - panic disorder
• Clonazepam (Klonopin) - GAD and social phobia

Question 19

What are the advantages of BZs?

Answer 19

• Rapid onset
• Relatively high therapeutic index & availability of flumazenil for treatment of overdose
• Low risk of drug interactions based on liver enzyme induction
• Minimal effects on cardiovascular and autonomic functions

Question 20

Disadvantages of BZs?

Answer 20

• Risk of dependence
• Depression of CNS functions (additive when administered with other drugs, including antihistamines, anticholinergics, and ethanol)
• Amnesic effects

Question 21

BZs are used to treat alcohol withdrawal to prevent what from occurring? Which BZs are used in this regard?

Answer 21

Delirium tremens is the harmful phenomenon which occurs during severe alcohol withdrawal.

The following BZs are used:

• Diazepam (Valium) - longer-acting, administered in progressively decreasing doses
• Lorazepam (Ativan) - parenteral use to suppress DTs

Question 22

How can you tell when a patient is coming close to toxic levels of benzodiazepines?

Answer 22

Toxicity will present as severe lethargy, not responding, moving very slowly, and very confused - similar to gross symptoms of ethanol intoxication (behavioral disinhibition)

Question 23

Abrupt cessation of benzos can precipitate withdrawal symptoms. What are the withdrawal symptoms?

Answer 23

States of increased anxiety, headaches, insomnia, and CNS excitability that may progress to convulsions.

*Short half-life BZs cause more severe withdrawal signs than longer half-life BZs, which are eliminated more slowly and achieve gradual withdrawal.

Question 24

What is BuSpar?

Answer 24

Buspirone (BuSpar) is a newer, non-GABAergic anxiolytic drug - it has selective anxiolytic effects without causing marked sedative, hypnotic, or euphoric effects

Question 25

What is the mechanism of BuSpar/Buspirone?

Answer 25

Partial agonist at brain 5-HT1a receptors, though also has affinity at brain dopamine D2 receptors

Question 26

When is BuSpar/buspirone used?

Answer 26

BuSpar is used in generalized anxiety states (and doesn’t have amnesic effects like BZs), but less effective in panic disorders.

Anxiolytic effects of BuSpar may take > 1 week to show, making drug unsuitable for acute anxiety states.

BuSpar isn’t effective in blocking acute withdrawal syndrome resulting from abrupt cessation of BZs bc it doesn’t act through GABA

BuSpar patients show no rebound anxiety or withdrawal signs on abrupt discontinuation - yay!

Question 27

Differentiate the drug interactions of Benzodiazepines and BuSpar.

Answer 27

Benzodiazepines - no drug interactions!!

BuSpar - inhibitor of CYP3A4 - but therapeutic window is so short and useful that you can deal with that

Question 28

How are beta-blockers used in anxiety & which ones in particular are used?

Answer 28

Beta-blockers are used to control the physical symptoms of anxiety (trembling and sweating).

Particularly useful in short periods of time when patient is facing anxiety-producing event (social phobia, giving speech, attending a meeting).

Propranolol and atenolol are the beta-blockers used.