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PHAR 300 > L10: Benzodiazepines & Cannabinoids > Flashcards

L10: Benzodiazepines & Cannabinoids Flashcards

1
Q

What are the 2 major compounds in marijuana?

A

Tetrahydrocannabinol (THC) and Cannabidiol (CBD).

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2
Q

How can cannabinoids be used for therapy?

A

Therapeutic effects for chronic pain in adults and for chemotherapy induced nausea and vomiting.

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3
Q

What receptors do cannabinoids act on?

A

CB1 and CB2

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4
Q

Where in the body is CB1 found in the highest concentration? What type of receptor is it?

A

Highest concentration: in the brain

Receptor: GPCR

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5
Q

What type of effects are cannabinoids responsible for when they interact with CB1?

A

Psychotropic effects. (action on CNS).

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6
Q

Where in the brain can CB1 be found? What is the function of each brain area?

A
  1. Basal ganglia and cerebellum: movement
  2. Cerebral cortex: higher cognitive function
  3. Hippocampus: learning, memory, stress
  4. Medulla: nausea/vomiting, chemoreceptor trigger zone (inhibitory effect)
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7
Q

Where in the body is CB2 found in the highest concentration?

A

In the immune system.

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8
Q

What are the families of compounds that act on cannabinoid receptors?

A
  1. Endocannabinoids
  2. Phytocannabinoids
  3. Synthetic cannabinoids
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9
Q

What are Endocannabinoids? What are they derived from? Name 2 major compounds of Endocannabinoids.

A

What are they: Compounds made in the body (brain) that are natural ligands for the cannabinoid receptors

Derived from: arachidonic acid

Major compounds: Arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG).

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10
Q

What is arachidonic acid?

A

A constituent of the plasma membrane and is a precursor in the synthesis of many compounds, including Endocannabinoids.

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11
Q

What are Phytocannabinoids derived from? Name 2 major compounds of Phytocannabinoids.

A

Derived from plants

Major compounds: THC and CBD

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12
Q

What are synthetic cannabinoids? Give an example of a synthetic cannabinoid.

A

Synthetic cannabinoids are made in a pharmaceutical lab. The compounds are mimics of THC and other plant derived compounds.
Ex: Nabiolone

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13
Q

What is the main pharmacodynamic mechanism of cannabinoids?

A

Retrograde signalling system: presynaptic inhibition of transmitter release.

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14
Q

Explain the retrograde signalling system of cannabinoids. (F2, L10)

A
  1. AEA or 2-AG are synthesized naturally from a precursor in the post-synaptic neuron and act pre-synaptically at the CB1 receptor. Feedback mechanism.
  2. THC, Dronabinol, and Nabiolone can act on the pre-synaptic CB1 receptor as well.
  3. Activation of the CB1 receptor on the pre-synaptic terminal decreases calcium intake and increases potassium efflux at the pre-synaptic terminal by blocking calcium channels and opening potassium channels.
  4. The change in neuron potential (calcium and potassium levels) hyper-polarizes the cell which decreases the release of neurotransmitters from the pre-synaptic terminal when it receives an action potential. Ca2+ is important in the release of neurotransmitters.

Conclusion: There is less stimulation of the post-synaptic neurotransmitter receptor.

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15
Q

Why are the pharmacodynamic effects of cannabinoids so effective?

A

Because cannabinoid receptors are on multiple cell types and can control the release of many transmitters.
CB1: neurons and astrocytes (regulate transmission of electrical impulses within the brain - can be between 2 neurons)
CB2: microglia (macrophage: 1st immune defense of the CNS)

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16
Q

Describe the absorption of cannabinoids.

A
  1. Lung: by smoking, THC gets into lungs, it is rapidly absorbed and distributed
  2. Intestine: when consumed, absorption is lower than when smoked. First pass metabolism in the liver therefore the blood concentration does not elevate to high levels. However, it is readily absorbed by the intestine and the colon.
  3. Skin: major compounds are lipid soluble and can cross the plasma membrane dermally.
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17
Q

Describe the distribution of cannabinoids.

A

Compounds are distributed in extracellular water and can be stored in fat because they are highly lipid soluble. Some bind to serum proteins.
They can also be passed to the fetus therefore, must be avoided during pregnancy.

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18
Q

Describe the metabolism of cannabinoids.

A

Leads to metabolite formation. Mainly occurs in liver.

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19
Q

Describe the excretion of cannabinoids.

A

Metabolites are secreted in saliva and sweat.
Largely excreted in the urine by kidneys.
Some excreted by the small intestine into the colon: feces.

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20
Q

What are the toxic effects of smoking marijuana? What are the main risks and long term effects?

A

The carcinogens inhaled are similar to smoking cigarettes because you are burning a leaf and smoking it, thus inhaling the carcinogens.
Main risks: cancers, heart attacks, strokes
Long term effects: unknown.

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21
Q

Why are Cannabinoids addicting?

A

Because they act on the reward pathway in the brain.

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22
Q

What is marijuana’s effect on driving?

A

Impairs driving for a minimum of 5 hours. Can be longer if consumed orally because oral absorption is slower, the effects wear off more slowly. Can also be longer depending on the dose.

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23
Q

What is psychopharmacology?

A

Using drugs to treat mental diseases or disorders.

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24
Q

What is different in the brain of a schizophrenic individual?

A

Increased levels of dopamine.

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25
Q

What was the first effective neuroleptic (antipsychotic) drug? What does it do? What psychotic disease can it be used for? Is it selective?

A

Chlorpromazine. Can be used for schizophrenia.
Blocks D2 dopamine receptor preventing activation by dopamine. Not selective because it blocks things other than the D2 receptor like histamine receptors and 5HT receptors. this causes negative side effects.

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26
Q

What drugs can increase risk of schizophrenia or schizophrenic symptoms? How?

A

Drugs: amphetamine, cocaine

Why? because they block dopamine re-uptake which increases dopamine levels above normal.

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27
Q

What does the effectiveness of antipsychotic drugs (used to treat schizophrenia) correlate with?

A

Effectiveness correlates with their ability to block D2 receptors. The better they block, the more effective they are.

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28
Q

What pathways do antipsychotic drugs affect?

A
  1. Mesolimbic pathway (VTA to nucleus accumbens)

2. Mesocortical pathway (VTA to prefrontal cortex)

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29
Q

What is the effect of increased dopamine in the mesolimbic and mesocortical pathway?

A
  1. Mesolimbic: increased dopamine causes overactivation leading to delusions and hallucinations.
  2. Mesocortical: increased dopamine causes dysfunction which leads to lack of emotions, intellectual impairment and defective cognitive abilities.
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30
Q

What is the main effect of the D2 receptor on a neuron?

A

Mainly inhibitory.

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31
Q

How have antipsychotic drugs been improving over the years?

A

Their selectivity for D2 receptors has been increasing.

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32
Q

What 4 drugs can be used to treat depression? What is their main function?

A
  1. Monoamine Oxidase Inhibitors (MAOIs)
  2. Tricyclic antidepressants
  3. Selective Serotonin Re-uptake Inhibitors (SSRIs)
  4. Atypical noradrenaline 5HT re-uptake inhibitors

they mainly act on the metabolism and uptake of transmitters.

33
Q

Explain how monoamine oxidase inhibitors (MAOIs) work.

A

MOAIs block monoamine oxidase (enzyme) which are found in the pre-synaptic terminal and in the synaptic cleft. Monoamine oxidases act on metabolism by breaking down neurotransmitters (Noradrenaline, dopamine, serotonin). MAOI’s therefore increase the levels of excitatory neurotransmitters in the synapse and at post-synaptic receptors.

34
Q

Explain how tricyclic antidepressants work.

A

They interfere with the re-uptake of neurotransmitters by blocking the 5HT and the noradrenaline re-uptake transporter. Blocking leads to an increase in neurotransmitters (serotonin and noradrenaline) in the synaptic cleft and at the post-synaptic receptors.

35
Q

What are the side effects of tricyclic antidepressants? why?

A

They block adrenergic receptors, histamine receptors, and cholinergic receptors. This affects the vascular system (due to noradrenaline blockage effect on sympathetic nervous system), it produces sedation (due to block of histamine receptors), acts on GI tract and vision (due to blockage of acetylcholine receptors).

36
Q

Why are tricyclic antidepressants used despite their many side effects?

A

It is still used because more specific SSRIs (newer drugs) are not responsive in some patients. Therefore, they use older types of drugs that are less specific but still effective.

37
Q

Explain how Selective Serotonin Re-uptake Inhibitors (SSRIs) work.

A

They are more specific drugs that interfere with the re-uptake of serotonin by blocking the 5HT re-uptake transporters. They DON’T inhibit other transmitter re-uptake. Blocking leads to an increase of serotonin in the synapse and at the post-synaptic receptors.

38
Q

Where are the 5HT receptors found? What type of receptor are they?

A

Found in the smooth muscle, platelets, CNS, PNS, GI tract, blood vessels.
Most are GPCRs.

39
Q

What’s the most effective type of SSRI and why?

A

Fluoxetine (Prozac)
why? it has a high potency of inhibiting the 5HT re-uptake compared to the other antidepressants that have a lower potency of blocking the re-uptake of NA.
Overall, it has the lowest adverse side effects compared to other antidepressants due to their higher selectivity.

40
Q

What is seasonal affective disorder (SAD)? Treatment?

A

It is seasonal depression during the winter because the days have less sunlight. Treatment: exposure to light source that emits same wavelength of sun (Light box).

41
Q

What is the main drug family used to treat anxiety?

A

Benzodiazepines.

42
Q

Who are candidates for anti-anxiety drugs?

A

Those who have high levels of anxiety for natural events that occur in life or high anxiety in a short term crisis.

43
Q

What are anxiety states? How can they manifest?

A

They are various combinations of physical (ex: heart pounding, increased BP, shaking) and mental manifestations (ex: sense of dread). They are not attributable to real danger and they occur in either attacks (intermittent) or as a persistent state.

44
Q

What is panic disorder?

A

An extreme state of anxiety. People become non-functional and disoriented.

45
Q

What are some causes of anxiety?

A
  1. Stress
  2. Generalized anxiety disorder
  3. Phobias
  4. secondary anxiety disorder (the person assumes that their original anxiety is itself something dangerous)
  5. Drug induced
46
Q

What are the major effects of benzodiazepines? Where?

A
  1. Antianxiety (hippocampus and amygdala)
  2. Induced sleep (sedative/hypnotic in cerebral cortex)
  3. Anti-convulsant (cerebllum & hippocampus)
  4. Muscle relaxant (spinal cord, cerebellum, and brainstem)
  5. Impairs memory formation (amnesia - cerebral cortex and hippocampus)
  6. Addiction potential (midbrain - dopamine)

There are many different benzodiazepine structures which allows them to be better at managing certain of these effects.

47
Q

What kind of anxiety are benzodiazepines most useful for?

A

Acute, stress related anxiety.

48
Q

Why are benzodiazepines relatively safe?

A

Because their lethal to therapeutic dose ratio is 1000.

49
Q

What was the first widely used drug for anxiety?

A

Diazepam.

50
Q

What is stage fright? What do musicians use to treat it?

A

Stage fright can cause slight tremors and palpitations which can interfere with performance. Instead of using anti-anxiety drugs, because they’re not necessarily anxious, musicians tend to use beta blockers which block beta-receptors in the autonomic nervous system to prevent palpitations.

51
Q

What receptors do benzodiazepines act on? Where are the receptors found?

A

GABA A receptors which are found everywhere in the brain.

52
Q

How do GABA receptors work? What neurotransmitter systems does it effect?

A

When GABA binds to its 2 binding sites on the receptor, the channel opens to allow influx of chloride ions. This leads to a hyperpolarizarion and an inhibitory post synaptic potential across the membrane. GABA has an inhibitor effect on many neurotransmitter systems such as 5-HT, dopamine, and noradrenaline which leads to antianxiety, sedative effects and other effects of benzodiazepines.

53
Q

What is the mechanism of benzodiazepines?

A

The benzodiazepine binding site (BZD binding site) is an allosteric binding site different from the GABA binding site. The binding facilitates the binding of the 2 GABA neurotransmitters to open the chloride channel and causes a larger chloride influx. Therefore, it increases the activity of GABA and facilitates GABAergic inhibition. BINDING BY ITSELF DOES NOTHING.

54
Q

What parts of the synapse are GABA A receptors found? Wha are they responsible for?

A

Subsynaptically and extrasynaptically.
Subsynaptic: responsible for phasic inhibition and the major site of action of banzodiazepines.
Extrasynaptic: For tonic inhibition.

55
Q

What is the first benzodiazepine?

A

Chloridiazepoxide (librium)

56
Q

Whats a commonly used benzodiazepine?

A

DIazepam (Valium)

57
Q

How do benzodiazepines affect the dose response curve of GABA? Why?

A

It shifts the curve to the left because benzodiazepines magnify the ability of GABA to open Cl- channels and hyperpolarize the cell. This leads to a higher effect at lower doses of GABA.

58
Q

What are the differences between benzodiazepines and barbiturates?

A
  • Benzodiazepines affect the frequency and number of opening GABA A channels and has no direct action (needs to bind with GABA to open the Cl- channel). They’re safer and selective. They’re safer because the log dose of benzodiazepines plateau at anesthesia so it is hard to overdose.
  • Barbiturates increase the duration of channel opening and act directly (DOESN’T need GABA) to increase chloride passage through the GABA A channel. They’re not as selective as benzodiazepines, and therefore less safe, an increase in dose can be lethal. Barbiturates log dose curve do not plateau therefore there is a risk of overdose.
59
Q

What are the different units of the GABA A receptor and what are they useful for?

A
  1. Alpha 1 units: useful for sedation

2. Alpha 2 units: useful for anxiety

60
Q

What is a benzodiazepine antagonist? What can it be used for?

A

It’s a drug that can be used if someone is very heavily sedated by benzodiazepines. Increasing amounts can wake a person.

61
Q

What is the shift of the dose response curve of benzodiazepine agonist? antagonist? inverse agonist?

A

Agonist: to the left
antagonist: to the right
inverse agonist: even more to the right

62
Q

What are beta-carbolines? what are their effects?

A

They are inverse-agonists (blocks the agonist AND causes the opposite effect of the agonist) of benzodiazepines.
Effects: opposite of benzodiazepines- increases anxiety.

63
Q

Where do Benzodiazepines, benzodiazepine agonists, benzodiazepine antagonists and reverse agonists bind?

A

they all bind to the BZD binding site.

64
Q

What are the effects of benzodiazepine agonists, benzodiazepine antagonists and reverse agonists on the GABA A receptor (at the binding site of BZD)?

A
  1. GABA alone = normal response
  2. GABA + benzodiazepine agonist = increased effect of GABA
  3. GABA + inverse agonist = reduced effect of GABA
  4. GABA + benzodiazepine antagonist = no effect on GABA
65
Q

What is zolpidem?

A

A drug acting on GABA A receptors at a different site than benzodiazepines. It has a range of side effects.

66
Q

What can drugs that act on GABA B receptors do? where are GABA B receptors found?

A

Found in spinal cord.

Drugs can cause muscle relaxation.

67
Q

Describe the absorption of benzodiazepines?

A
  1. Well absorbed orally
  2. Highly lipid soluble
  3. Gets to the brain quickly - quick relief
  4. Peaks in 1 hour
68
Q

Describe the distribution of benzodiazepines?

A
  1. Widely distributed
  2. Variable protein binding
  3. Rapidly enters brain
69
Q

Describe the metabolism of benzodiazepines?

A
  1. Benzodiazepines are metabolized by CYP3A and CYP2C19 into intermediates.
  2. Many drugs from this family have multiple active intermediates with long half-lives. It is therefore important to consider the effect of the parent drug and the intermediate drug.
  3. Geriatric populations have slower metabolisms therefore the use of anti-anxiety drugs must be closely monitored for accumulation and overdose.
  4. Accumulation of active metabolites can cause side effects and takes time to get back to normal.
70
Q

Describe the excretion of benzodiazepines?

A

Excreted into the urine by the kindeys.

71
Q

What is diazepam metabolized into? What is the half life of the first metabolite?

A

First metabolite: nordiazepam with a 60 hour half-life.

Nordiazepam is further metabolized into Oxazepam.

72
Q

What are the side effects of benzodiazepines?

A
  1. Amnesia: Cognitive impairment, chronic high blood level
  2. Sedation: do not combine with other CNS depressants
  3. Muscle relaxation, ataxia: don’t drive, especially with drugs with high half life
  4. Tolerance may develop; differential, pharmacodynamic tolerance
  5. Dependence liability
  6. Withdrawal seizures may occur

Some of the side effects are “just” side effects but some have some clinical relevance

73
Q

What is the toxicity of benzodiazepines?

A
  1. When taken alone its a low toxicity

2. In combination it can be fatal especially with CNS depressants

74
Q

How can you treat overdose of benzodiazepines?

A
  1. Stomach pump
  2. Activated charcoal
  3. Hemodialysis
  4. Flumazenil: a benzodiazepine antagonist that can be used to block its adverse effects.
75
Q

What are the types of tolerance that can develop against benzodiazepines?

A
  1. Differential: different targets of drugs do not develop tolerance at the same speed and to the same degree.
  2. Pharmacodynamic
76
Q

What pharmacodynamic changes makes the brain tolerant to benzodiazepines?

A

Changes in re-uptake of GABA receptors.

77
Q

What are the withdrawal symptoms of taking high doses benzodiazepines for a long time?

A

Anxiety, hallucinations, loss of coordination, restless leg syndrome, more severe seizures, coma, death.

78
Q

What can be used to treat insomnia? Side effects?

A

Benzodiazepines with short half-lives. When you stop taking the drug, there may be a rebound of hyper-dreaming if you have been taking the drug for a long time. Since benzodiazepines suppresses REM sleep there is REM rebound when in withdrawal which causes people to have nightmares.

79
Q

What are non-benzodiazepine sedative hypnotics? Give an example.

A

They act on GABA A receptors. They are selective for certain subtypes of the receptor so there are fewer side effects.
Zolpidem is a non-benzodiazepine that only binds alpha 1. This treats insomnia without altering REM sleep. It binds next to the BZD site.

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