Anxiolytics

Question 1

Define tolerance.

Answer 1

the capacity of the body to endure or become less responsive to a substance (as a drug) or a physiological insult especially with repeated use or exposure .

Question 2

Define cross-tolerance.

Answer 2

Tolerance or resistance to a drug that develops through continued use of another drug with similar pharmacological action.

Question 3

Define drug dependence as compared to addiction.

Answer 3

Drug dependence means that a person needs a drug to function normally. Abruptly stopping the drug leads to withdrawal symptoms.

Drug addiction is the compulsive use of a substance, despite its negative or dangerous effects.

Question 4

What are the most widely used anxiolytic drugs? What have they replaced and why?

Answer 4

Benzodiazepines.

They have largely replaced barbiturates and meprobamate in the treatment of anxiety, because the benzodiazepines are safer and more effective.

Question 5

Which receptors do benzodiazepiens target?

Answer 5

The targets for benzodiazepine actions are the Gama-amino butyric acid (GABA) receptors. [Note: GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).]

Question 6

Describe the mechanism of action of benzodiazepines.

Answer 6

Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride conductance. Benzodiazepines increase the frequency of channel openings produced by GABA.

The influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing threshold and, thus, inhibits the formation of action potentials.

Question 7

What kind of receptors do benzodiazepines work on? What is the complex they are part of? Define the action of the two different receptors.

Answer 7

Act through BZ receptors

Part of GABA A complex

BZ-1 mediates sedation

BZ-2 mediates antianxiety and impairment of cognitive functions.

Question 8

Considering they work on the GABA complex, do benzodiazepines have GABA mimetic activity? Do they potentiate GABA?

Answer 8

They have no GABA mimetic activity but do potentiate GABA

Question 9

At what dose do benzodiazepines reduce anxiety? What part of the brain do they interact with to do this?

Answer 9

At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by inhibiting neuronal circuits in the limbic system of the brain.

Question 10

At what dose do benzodiazepines have sedative and/or hypnotic effects?

Answer 10

All of the benzodiazepines used to treat anxiety have some sedative properties, and some can produce hypnosis (artificially produced sleep) at higher doses.

Question 11

Do benzodiazepines have antipsychotic effects? Analgesia? Do they affect the autonomic nervous system?

Answer 11

The benzodiazepines have neither antipsychotic activity nor analgesic action and they do not affect the autonomic nervous system.

Question 12

Explain anterograde amnesia caused by BZD.

Answer 12

The temporary impairment of memory with use of the benzodiazepines is also mediated by the GABA receptors. This also impairs a person’s ability to learn and form new memories.

Question 13

Explain the anticonvulsant property of BZD.

Answer 13

Several of the benzodiazepines have anticonvulsant activity and some are used to treat epilepsy and other seizure disorders. This effect is partially, although not completely, mediated by GABA A receptors.

Question 14

Talk about the muscle relaxant property of BZD. What dose is needed?

Answer 14

At high doses, the benzodiazepines relax the spasticity of skeletal muscle.

Question 15

Why should benzodiazepines be reserved for continued severe anxiety and only used for short time periods?

Answer 15

They have high addiciton potential.

Question 16

Which are the longer acting BZD’s and when are they used?

Answer 16

• Clonazepam
• Lorazepam (Ativan)
• Diazepam

These are often used for patients with anxiety that may require treatment for prolonged periods of time.

Question 17

Describe tolerance that builds up for the anxiolytic, sedative and hypnotic effects of benzodiazepines.

Answer 17

Tolerance is the decreased responsiveness to repeated doses of the drug which occurs when used for more than one to two weeks.

The axiolytic effects of benzodiazepines are less subject to tolerance that the sedative and hypnotic effects.

Question 18

Which BZD is used for panic disorders? Is it for short or long term treatment?

Answer 18

Alprazolam

Iti s effective for short and long term treatment. It may cause withdrawal reactions in about thirty percent of people.

Question 19

Which drug is useful in the treatment of skeletal muscle spasms such as in muscle strain, spasticity from degenerative disorders (eg. MS or cerebral palsy)?

Answer 19

Diazepam

Question 20

What is a shorter acting BZD used for medical procedures?

Answer 20

Midazolam ~ Versed

Injectable onlly used for induction of anesthesia

Shorter acting agents are often employed as premedication for anxiety provoking or unpleasant procedures such as endoscopic, bronchoscopy, dental procedures and angioplasty. They also cause a form of conscious sedation, allowing the person to be receptive to instructions during the procedures. The best example is Midazolam.

Question 21

What are the drugs of choice for seizures and epilepsy?

Answer 21

Clonazepam is occasionally used in the treatment of certain types of epilepsy. Diazepam and clonazepam are useful in terminating grand mal epileptic seizures and status epilepticus.

Question 22

Which benzodiazepines are useful in the acute treatment of alcohol withdrawal and reducing the risk of withdrawal related seizures?

Answer 22

• Chlordiazepoxide
• Clorazepate
• Diazepam
• Oxazepam

Question 23

Hypnotic effect means a drug that induces sleep. Not all benzodiazepines are useful as hypnotic agents although all have sedative or calming effects. What are three commonly prescribed BZD’s for sleep disorders? What is their length of efficacy?

Answer 23

• Flurazepam (long acting)
• Temazepam (intermediate acting)
• Triazolam (short acting)

Question 24

Discuss the pros and cons of using flurazepam in sleep disorders. (Rebound insomnia? How does it help? How long does it maintain effectiveness?)

Answer 24

Pros:

• Significantly reduces sleep induction time and the number of awakenings as well as duration of sleep
• Long acting effect with little rebound insomnia

Cons:

• Half life of 85 hours which may result in daytime sedation and accumulation of the drug
• Maintains its effectiveness for only four weeks with continuous use

Question 25

In what patients would Temazepam be chosen? When should it be taken?

Answer 25

Useful in patients who experience frequent wakening. It can be taken at bedtime to reduce interruptions in sleep.

Peak sedative effect occurs 1-3 hours after oral dose so it should be taken 1-2 hours before bedtime.

Question 26

In what patients would Triazolam be chosen? What are some pros and cons? How should the drug be taken?

Answer 26

Triazolam is usually given to patients who have difficulty in falling asleep.

Pros:

• Can be used to induce sleep
• Short duration of action so no daytime sedation

Cons:

• Tolerance frequently develops within a few days
• Withdrawal often results in rebound insomnia
• Needs to be used intermittently rather than daily

Question 27

How long can hypnotics be prescribed for?

Answer 27

In general hypnotics should be given for only a limited time, usually 2-4 weeks maximum.

Question 28

What is the absorption and distribution of benzodiazepines orally?

Answer 28

They are rapidly and completely absorbed after oral administration and distribute throughout the body.

Question 29

How are BZD’s metabolized in the body? Can they be given during pregnancy or nursing?

Answer 29

Most benzodiazepines (including chlordiazepoxide and diazepam) are metabolized by the hepatic microsomal system (P450 pathway in liver) into compounds that are also active. The half life represents the combined action of the parent drug and metabolites.

All benzodiazepines cross the placental barrier and may depress the CNS of the newborn if given during pregnancy. Nursing infants may also become exposed to the drugs in breast milk. This is not advisable.

Question 30

What are the withdrawal symptoms from BZD’s?

Answer 30

• Agitation
• Anxiety
• Confusion
• Insomnia
• Restlessness
• Rarely, seizures

Question 31

How long do withdrawal symptoms last? How is it affected by short vs long half lives?

Answer 31

Withdrawal symptoms often occur slowly and may last a number of days.

BZD’s with a short elimination half life (eg. triazolam) induce more abrupt and severe withdrawal reacitons while those with logner half lives (eg. flurazepam) are more drawn out but less severe.

Question 32

What are the most common adverse side effects of BZD’s? What are less common but more severe effects that occur at high doses?

Answer 32

Drowsiness and confusion are the most common.

Ataxia may occur at high doses and precludes fine motor coordination (eg. driving).

Cognitive impairment can occur such as decreased long term recall and decreased acquisition of new knowledge.

Question 33

What are some precautions for benzo’s?

Answer 33

• They should be used very cautiously in patients with liver disease.
• They should be avoided in those with acute narrow angle glaucoma
• Overdose is seldom lethal but could be if alcohol or other CNS depressants are taken concurrently as these enhance the sedative hypnotic effects

Question 34

What is a benzodiazepine antagonist that can rapidly reverse the effects of BZD’s? How is it administered and how long does it last? (EXAM)

Answer 34

Flumazenil is a GABA receptor antagonist that rapidly reverses benzodiazepine effects. It is given through intravenous administration only.

The onset is rapid but duration is short with a half life of 1 hour therefore frequent administration may be necessary to maintain reversal of a long acting benzodiazepine.

Question 35

If someone is dependant on benzodiazepines or are using them to control seizure activity what could happen with administration of Flumazenil? (EXAM) What are common side effects of Flumazenil?

Answer 35

Administration may precipitate withdrawal or cause seizures.

Side effects are agitation, dizziness, nausea and vomiting.

Question 36

What is Buspirone and what is it used for? How does it compare to BZD’s?

Answer 36

It is an anxiolytic agent that caues only minimal sedation and lacks the anticonvulsant and muscle relaxant properties of BZD’s. It is useful in teh treatment of generalized anxiety disorder and has an efficacy comparable to BZD’s.

Question 37

What are some adverse side effects of Buspirone? What are some benefits compared to benzodiazepines?

Answer 37

The frequency of adverse effects is low, with the most common effects being dizziness, headache, nervousness.

Sedation, psychomotor and cognitive dysfunction are minimal and dependence is unlikely.

Question 38

What are some unavaoidable changes in hormone that will occur with Buspirone? What is the onset of action?

Answer 38

It will cause an increase in prolactin and growth hormone as well as hypothermia (which seems counterintuitive)

Buspirone has the other disadvantage of a slow onset of action. It takes 1-2 weeks for effects to take place.

Question 39

What is Hydroxyzine? Who is it used for and why? What procedures is it used for?

Answer 39

It is an antihistamine with antiemetic activity. It has a low tendency for habituation and is therefore useful for patients with anxiety and a history of drug abuse.

It is also often used for sedation prior to dental procedures or surgery.

Drowsiness is an obvious possible adverse effect.

Question 40

When should antidepressants be considered as first line agents for anxiety?

Answer 40

Patients who have depression as a comorbidity or who have addiction or dependence to other substances in their history. Many antidepressants have proven efficacy in managing the long term symptoms of chronic anxiety disorders.

Question 41

What is Flunitrazepam? What form does it come in?

Answer 41

Also known as Rohypnol or Roofies it is a benzodiazepine used to treat severe insomnia and assist with anesthesia. It is a tasteless odorless tablet that can be crushed and dissolved in liquid.

Question 42

How does Flunitrazepam work? What other BZD is it similar to? How long will the effects last? Why is it called the “date rape” drug?

Answer 42

It is a CNS depressant and is similar to diazepam (Valium) but is 10 times more potent. One small tablet can produce effects for 8-12 hours.

When it is mixed with alcohol its effects cause a person to not resist sexual assault. It can also produce a form of amnesia so the person may not remember what happened to them.

Question 43

Barbiturates were formerly the mainstay of treatment to sedate a patient or induce and maintain sleep. Why have they largely been replaced by benzodiazepines?

Answer 43

They induce tolerance, physical dependence and are associated with very severe withdrawal symptoms. They are liable to cause a coma in toxic doses.

Question 44

What is the mechanism of action of barbiturates?

Answer 44

Barbiturates interact with the GABA A receptors which potentiates the action of GABA on chloride entry into the neuron by prolonging chloride channel openings. This has inhibitory effects on nerve transmission. In addition they block excitatory glutamate receptors.

Question 45

Both barbiturates and benzos bind to GABA A recptors. Do they have the same binding site?

Answer 45

No, the binding sites are distinct.

Question 46

In addition to normal barbiturate activity what additional effects does pentobarbital have at anesthetic concentrations?

Answer 46

It also blocks high frequency sodium channels, again leading to decreased neuronal activity.

Question 47

Barbiturates are classified according to their duration of action. Name and describe a very short acting and a very long acting barbiturate. What are their different uses?

Answer 47

Thiopental acts within seconds and has a duration of about 30 minutes. it is used in the IV induction of anesthesia.

Phenobarbital has a duration of action greater than a day and is useful in the treatment of seizures.

Question 48

Name three short acting barbiturates which are effective as sedative and hypnotic but not anxiolytic agents.

Answer 48

• Amobarbital
• Pentobarbital
• Secobarbital

Question 49

What are the CNS depressant effects of barbiturates at low doses and higher doses?

Answer 49

At low doses the barbiturates have sedative effects, calming and reducing excitement.

At higher doses they can induce hypnosis (sleep), followed by anesthesia (loss of feeling or sensation) and finally coma and death.

Question 50

Barbiturates have anesthetic effects at higher doses. Do they then also have analgesic properties?

Answer 50

No. They do not raise the pain threshold and have no analgesic properties. They may even exacerbate pain. Chronic use leads to tolerance.

Question 51

How do barbiturates cause respiratory depression?

Answer 51

They supress the hypoxic response to CO2 which is why overdose is followed by respiratory depression and death.

Question 52

What effect do barbiturates have on the liver and drug metabolism?

Answer 52

They induce enzymes in the liver (speed up P450 microsomal enzymes) which means they can diminish the action of many drugs that are dependent on P450 metabolism by clearing them quickly.

Question 53

Anesthesia vs Anticonvulsant… which barbiturates would be chosen?

Answer 53

The ultra short acting barbiturates like thiopental are chosen to induce anesthesia intravenously.

The long acting barbiturates are more likely to be used for anticonvulsant properties. Phenobarbital is used in long term management of tonic clonic seizures, staus epilepticus and eclampsia. It is the drug of choice for young children with recurrent febrile seizures, although it can depress cognitive performance and should be used cautiously.

Question 54

When barbiturates are used as hypnotics which sleep stage is suppressed most?

Answer 54

REM

Question 55

How are barbiturates absorbed and distributed? Can they cross the placenta?

Answer 55

After being absorbed orally (or through IV) they distribute widely from brain to splanchnic area, then skeletal muscle and finally adipose tissue.

Yes they readily cross the placenta and can depress the fetus.

Question 56

Describe the “drug hangover” of barbiturates?

Answer 56

Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. This drug hangover may lead to impaired ability to function normally for many hours after waking. Occasionally nausea and dizziness occur.

Question 57

How severe is the withdrawal from barbiturates? (Compare to benzodiazepines and opiates.)

Answer 57

It is very severe, much more so than for benzos or opiates and can result in death. It may cause anxiety, cardiac arrest, delirium, weakness, nausea, vomiting, seizures, and of course coma and death.

Question 58

Why are antihistamines with sedating properties not typically used for treating insomnia?

Answer 58

They are usually ineffective for all but the milder forms of situational insomnia. They also have numerous undesirable anticholinergic side effects that make them less useful than benzos.