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Pharmacology - Exam 3 > Drugs for Anxiety and Insomnia > Flashcards

Drugs for Anxiety and Insomnia Flashcards

1
Q

What physiologic actions are affected by sedative-hypnotic drugs that place them in a special class as compared to other CNS depressants?

A

Both sedative and hypnotic drugs augment GABA neuronal inhibition.

Both may or may not inhibit glutamate neuronal excitation.

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2
Q

What are the clinical effects of sedative drugs:

A

Decreased activity
Moderated excitement
Calming

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3
Q

What are the clinical effects of hypnotic drugs:

A

Drowsiness
Facilitate the onset and maintenance of sleep
Resembles natural sleep (can still be easily aroused)

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4
Q

Are sedative-hypnotic drugs dose-dependent?

A

Yes! They have a graded dose-response.

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5
Q

Which CNS depressant drug has a non-linear dose-response relationship:
A. Benzodiazepines
B. Barbiturates

A

Benzodiazepines!

think: benzo’s bendover

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6
Q

What is the difference between benzodiazepines and barbiturates that is due to the differences in their respective graded-dose responses (i.e. why do we care that benzo’s bendover)?

A

Barbiturates = linear dose-response.
-As dose increases, CNS effects climb from anesthesia to medullary depression to coma.

Benzodiazapines = nonlinear dose response.
-As dose increases, CNS effects slowly change from general anesthesia to medullary depression.

SO need a much greater dose of benzo’s to reach the level of CNS depression.

SO benzo’s on their own are much safer than barbiturates on their own.

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7
Q

What are the therapeutic effects of both benzo’s and barbiturates BEFORE reaching general anesthesia?

A 
Anti-anxiety
Anticonvulsant
Muscle relaxant
Sedative
Hypnotic

Note that barbiturates require a smaller additional dose to reach the next “tier” of effects: general anesthesia.

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8
Q

What is GABA?

What does it do?

A

The major inhibitory transmitter in the CNS.

When GABA binds to its receptor, an ion channel opens. This allows the eventual Cl- ions to flow through. (but does not directly initiate Cl- current.

When Cl- ions flow through, membrane hyperpolarization results.

Recall that hyperpolarization = poor neuronal excitability potential = low neurotransmission.

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9
Q

How do benzodiazepines affect/interact with GABA?

A

Benzos indirectly increase the GABA effect. They INTENSIFY the effect of GABA.

Therefore, for benzos to have an effect, there must be GABA present. They bind to the channel and make it easier for GABA to bind and open the channel. (benzos bend over to help!)

Increasing GABA binding to the receptor indirectly further diminishes the potential neuronal excitability. (recall: benzos are downers)

Note that benzos only intensify GABA and further hyperpolarization of neurons. They do NOT affect excitatory neurotransmitters.

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10
Q

Why is it important that benzodiazepines do not affect excitatory neurotransmitters?

A

Because they ONLY affect the hyperpolarization of neurons, they can’t induce and maintain surgical anesthesia.

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11
Q

How do barbiturates affect/interact with GABA?

A

At low concentrations, barbs indirectly increase the GABA effect. They PROLONG the effect of GABA.

At high concentrations, barbs directly interact with the GABA receptor - the presence of GABA isn’t necessary at high concentrations!

Barbs therefore aren’t as selective.

  • -> can indirectly increase GABA
  • -> can directly bind with GABA receptor
  • -> also depresses glutamate, an excitatory neurotransmitter
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12
Q

Why is it important that barbiturates can affect excitatory neurotransmitters?

A

Barbs depress glutamate, and excitatory neurotransmitter.

Therefore, they can induce and maintain surgical anesthesia (greater CNS depression)

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13
Q

What are the 5 things that can bind to the GABA receptor-chloride ion channel complex?

A
  1. GABA itself. Its effect is indirectly increased by both benzos (at any concentration) and barbs (at low concentrations)
  2. Benzodiazepines. Bind and indirectly intensify the effect of GABA.
  3. Barbiturates. Directly bind and open channel at high concentations.
  4. Z-drugs. Non-benzos that interact with the benzo binding sites as agonists. Facilitate opening of channel.
  5. Flumazenil. An antagonist to the benzo binding site. Reverses the CNS effects of benzos by preventing their help opening the channel.
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14
Q

What are the 3 Z-drugs?

A
  1. Zolpidem
  2. Eszopiclone
  3. Zaleplon

These all depress the CNS system by binding at the benzo binding site. Also intensify the effects of GABA.

Z-drugs bind to alpha-1 subunits only.

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15
Q

What type of GABA receptors are located in the cortex?

A

Alpha-1 subunits!

These mediate sedative (sleep), amnestic, and anticonvulsant actions of benzos.

Note: Z-drugs only bind alpha-1 subunits. This is why they increase sleep but have NO axiolysis effects. This is why they are less likely to be abused.

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16
Q

What type of GABA receptors are in the limbic system and brain stem?

A

Alpha-2 and alpha-5!

These mediate motor-impairing, anxiolytic, and ethanol-potentiating effects of benzos.

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17
Q

Which types of receptors do benzos bind?

A

All the alpha receptors (1, 2, 5).

This is why benzos result in sleep AND anxiolysis. So, they might be abused for the relaxing effect they have.

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18
Q

How do benzos or barbs have anticonvulsant effects?

A

Higher dose of barbs
Some benzos

–>inhibit cortical neurons = inhibits seizures.

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19
Q

How do muscle relaxants works?

A

Inhibit spinal cord synaptic reflexes.

Requires high doses, and so also crease significant CNS depression.

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20
Q

Which drugs crease hypnosis?

A

Both benzos and barbs. Need higher doses of benzos to induce sleep.

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21
Q

Benzos aren’t used for anesthesia, but what are they used for in surgical procedures?

A

They are used as adjunts.

Have anxiolytic and amnesia properties.

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22
Q

Is there tolerance to barbs and benzos?

A

Yes.
Both metabolic and pharmacodynamic tolerance is seen.
Occurs rapidly to the sedative and anticonvulsant effect.
Occurs less quickly to the anxiolytic action.

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23
Q

What are the withdrawal symptoms of benzos and barbs?

A

Opposite of a downer!
Decreased appetite, nausea, fatigue, tachycardia, insomnia, depression, weight loss.

Also, anxiety, tremors, hyperreflexia…can become convulsions.

More severe when the drug has a shorter half life.

24
Q

Is there a risk of psychologic and physical dependence in short term benzo use?

A

Nope. This is why they are used.

25
Q

What determines the clinical uses of different benzos?

A

All benzos have similar pharmacodynamic actions.

Their pharmacokinetic properties are different! (Absorption, distribution, excretion)

26
Q

Name the oral-absorbed benzos that we would consider:

A

Diazepam, alprazolam, triazolam all have rapid oral absorption.

take “DAT” by mouth

27
Q

Name the intramuscular benzos that we would consider:

A

Lorazepam has reliable intramuscular absorption.

IV-“L”

28
Q

Does diazepam have good intramuscular reliability?

A

No. Diazepam has poor water solubility. Can be given intramuscularly but doesn’t work well.

29
Q

Do benzos enter the CNS rapidly?

A

Yes! They are all quite lipid soluble.

With an acute, single dose of benzo, it enters the brain rapidly and then redistributes back out of the brain rapidly to terminate.

30
Q

How are benzos excreted?

A

Benzos are lipid soluble, so must be metabolized first.

Drug metabolizing enzymes determine half life = CYP!

Most benzos have CYP450 oxidation, phase 1.

Then, may undergo conjugation with glucoronidation, phase II.

then pee them out!

31
Q

What do we need to know about phase 1 benzo metabolites (after CYP450 oxidation in the liver)?

Recall that in the elderly, phase 1 breaks down.

A

These are active still!
They can have long half lives!
So, they can accumulate and have unwanted effects!

  1. Diazepam has a long lasting phase 1 metabolite.
  2. Triazolam creates an active metabolite, but it is QUICKLY moved into phase 2.
  3. Lorazepam skips the phase 1 and moves directly to phase 2. Shorter half live and fewer side effect. Best to use in elderly!
32
Q

What is the number one enzyme we learned is involved in drug-drug interactions?

Which class of drugs for CNS depression induces it?

A

CYP450!

Note that barbiturates induce CYP450!

Benzos need to be metabolized in phase 1 with CYP450.

Therefore, barbs are very important in drug-drug interactions (and thus why they aren’t used as much anymore).

If benzos are taken with barbs, there can be a drug-drug interaction due to the inducing effect of barbs on CYP450.

33
Q

How toxic are benzo?

A

Not very. Remember, they bend over before reaching the bad CNS depression!

  1. Can result in poor-timed sedation and performance impairment. This is due to accumulation of phase 1 metabolites or high doses or in the elderly.
  2. Can have additive CNS depression with alcohol, opioids, antipsychotics, anticonvulsants, antihistamines, TCADs.
  3. Can result in anterograde amnesia. Common with drugs that enhance GABA. Can be good or for date rape (flunitrazepam = roofies! This is schedule 1)
34
Q

What non-CNS effects can benzos have?

A

Black box warnings: strange sleep behavior.

Can exacerbate sleep apnea.

Rare: Can have hypersensitivity, dry mouth, etc with chronic use.

35
Q

How are benzos used in dentistry?

A
  1. Provide conscious sedation.

2. Usually used as alleviation of anxiety

36
Q

When is diazepam use in dentistry? How?

A

Diazepam: IV/IM/PO
Use as adjunt to local anesthesia and anterograde amnesia.
Onset in 30 minutes.
Lasts 30 - 60 minutes.

Use for seizures! (don’t “die”) caused by local anesthesia.

Note that triazolam is similar (PO only).
Has the shortest onset of action.

37
Q

When is midazolam use in dentistry? How?

A

Midazolam: IV/PO

Fast onset, short duration
Anterograde amnesia when used with IV
Carefully monitor!

38
Q

Which neurotransmitter systems are key to modulating anxiety?

A

GABA and serotonin, mainly.

Also norepinephrine (panic) and dopamine (OCD)

39
Q

What are the main origins of anxiety disorders?

A

Medical diseases
Psychiatric disease
Drug induced (can be CNS stimulants or from withdrawal from CNS depressants)
Situational

40
Q

What are the symptoms of anxiety?

A

Motor tension
Autonomic hyperactivity = tachycardia, palpittions, sweating, dry mouth, gI distress
Increase vigilance

Often overlap with depressive symptoms

41
Q

What types of drugs are used for generalized anxiety disorders?

A

SSRIs
SNRIs
Benzos

42
Q

What types of drugs are used for panic disorder?

A 
Strong benzos (alprazolam)
SSRIs
43
Q

What types of drugs are used for social anxiety disorders?

A

SSRIs
SNRIs
beta-blockers
strong benzos

44
Q

What types of drugs are used for obsessive compulsive disorders?

A

SSRIs
SNRIs
Behavioral therapy is best

45
Q

What types of drugs are used with PTSD?

A

SSRIs
SNRIs
Behavioral therapy

46
Q

What class is in general the 1st choice for chronic anxiety?

A

Antidepressants

47
Q

What class is in general the 1st choice for acute anxiety?

A

Benzos
–> Alprazolam!

But, can be abused, so often use SSRIs now.

48
Q

Why are barbituates not used for anxiety?

A 
Fast tolerance
High abuse potential
Dangerous overdose
Excessive sedation
Drug-drug interactions
49
Q

How common is insomnia?

A

38%!

More often in females and elderly

50
Q

What causes insomnia?

A

Medical disorders, psychologic, drugs (like alcohol, nicotine, antihypertensives), miscellaneous

51
Q

How are stages of sleep defined?

A

Based on:

  1. EEG = electrical brain activity
  2. EMG = muscle activity
  3. EOG = eye movements

Result in nonREM or REM - cycle over 90 minutes (4 - 5 stages/night)

Non-REM:
stage 1 = transition, strong EEG
stage 2 = light sleep, weak EEG
stage 3=deep sleep, slowest EEG, night terrors

REM:
Increased bloodpress, pulse, respiration, DREAMS!

52
Q

How do sedative-hypnotic drugs help sleep?

A

Increase onset
Increase stage 2 nonREM

Can:

  • decrease delta sleep (stage 3 and 4)
  • -> barbs especially can do this, Z-drugs are best and decrease it by very little
  • decrease REM duration
  • quick tolerance, >1week
  • ->flurazepam and Z-drugs aren’t as bad.
53
Q

So which class of drugs is safest for treatment of insomnia?

A

Anything that interacts at the benzo receptor on the Cl- ion channel:
Benzos
Z-drugs

Lower abuse, safer, few drug interactions, minimal effect on REM

54
Q

To recap, what drug class and specific drug do we need to know for the treatment of insomnia?

A

Benzos:
Triazolam (I “tri” to sleep!)

Eliminated overnight (shortest duration of action), less "hangover", rapid oral absorption
but can see rebound insomnia due to rapid elimination.

Be careful with elderly!

55
Q

To recap, what drug class and specific drug do we need to know for the treatment of anxiety?

A

Benzos:
Diazepam: anticonvulsant, rapid oral absorption, poor IM absorption, phase 1 metabolite, onset within 30 min, good for acute situational anxiety

Lorazepam: anticonvulsant, IM absorbed, skips phase 1, good for elderly,

Alprazolam: rapid oral absorption, short-lived phase 1 metabolite, onset within 30 min, best for acute anxiety (potent)

Midazolam: ok for IV and PO, fast onset, short duration, anterograde amnesia,

Barbs:
Pentobarbital

Pharmacology - Exam 3 (6 decks)

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