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BM324: Fundamental Pharmacology > Block E Lecture 2 - Benzodiazepines > Flashcards

Block E Lecture 2 - Benzodiazepines Flashcards

1
Q

What is the general structure which all benzodiazepines follow?

A

They have a 7-membered ring containing 2 nitrogens and 4 main substituent groups, which can vary between molecules

(Slide 4)

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2
Q

What is a substituent group?

A

An atom or group of atoms that replaces a hydrogen atom on a parent molecule

(Slide 4)

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3
Q

When did benzodiazepines come into clinical use and for what purposes?

A

Benzodiazepines have been in clinical use since the early 1960s. They are used as anxiolytics, hypnotics, sedatives, anticonvulsants, and muscle relaxants

(Slide 4)

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4
Q

What is an anxiolytic?

A

A drug used to reduce anxiety

(Slide 4)

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5
Q

What effect do benzodiazepines have?

A

They enhance presynaptic inhibition in the spinal cord

(Slide 5)

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6
Q

What are 2 examples of things which block the effect of benzoiazepines?

A

They’re blocked either by bicuculine or by decreased GABA levels, as their effect requires a normal level of GABA

(Slide 5)

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7
Q

What is the displacement relationship between GABA and benzodiazepines?

A

GABA doesn’t displace benzodiazepines but benzodiazepines also don’t displace GABA

(Slide 6)

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8
Q

What does the location of benzodiazepine binding sites correlate to and where are they localised?

A

They correlate to the presence of glutamic acid decarboxylase (GAD) and they are localised at GABAergic synapses

(Slide 6)

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9
Q

What does benzodiazepine displacement of tritiated ( 3[H]- ) benzodiazepines in the CNS correlate to?

A

Benzodiazepines with the highest capacity to displace tritiated (3[H]-) benzodiazepines in the CNS have the highest clinical efficacy

(Slide 7)

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10
Q

How does benzodiazepine binding (binding sites) correlate to glutamic acid decarboxylase (GAD) distribution?

A

The areas with the most flunitrazepam (a potent benzodiazepine) are the frontal cortex, cerebellum, dentate gyrus (dg).. etc and there areas are associated with GABAergic neurones an a high level of GABA activity (remember GAD synthesises GABA)

(Slide 8)

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11
Q

What does a specific benzodiazepine binding site on the α-subunit of the GABAA receptor complex modulate?

A

The binding of GABA to its site and the opening of the chloride ion channel

(Slide 9)

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12
Q

What do classical benzodiazepines act as at the benzodiazepine binding site at the interface of the α and γ subuits?

A

Positive allosteric modulators which enhance the inhibitory effects of GABA

(Slide 9)

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13
Q

How do benzodiazepines act as positive allosteric moderators and how do they compare to barbiturates?

A

Benzodiazepines: Increase frequency of the activate GABA receptors to open
Don’t change channel conductance or mean duration of opening

Barbiturates: Don’t change frequency of opening or channel conductance but do increase the mean duration the channels are open for

(Slide 10)

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14
Q

What is a GABA shift?

A

When the effect of GABA changes from being inhibitory to excitatory or vice versa
(Slide 12)

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15
Q

How is a GABA shift caused?

A
  1. GABA facilitates benzodiazepine binding to its binding site on the receptor
  2. Benzodiazepines facilitate GABA binding to its binding site on the receptor
  3. This reciprocal relationship is what leads to a GABA shift occurring

(Slide 12)

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16
Q

What are endozepines?

A

Endogenous compounds which have similar effects to benzodiazepines

(Slide 17)

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17
Q

What are 2 examples of endozepines?

A

Diazepam binding inhibitor and oleamide

(Slide 17)

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18
Q
A
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18
Q

What are the properties of diazepam binding inhibitor?

A

It is an acyl-CoA binding protein which binds medium and long chain acyl-CoA esters. It acts as an intracellular carrier of acyl-CoA esters and it displaces benzodiazepines and Z drugs from the GABAA complex

(Slide 17)

19
Q

What are the properties of oleamide?

A

It’s derived from the fatty acid oleic acid and accumulates in the cerebrospinal fluid during sleep deprivation. It induces sleep in animals and also interacts with multiple neurotransmitter systems (e,g cannabinoid)

(Slide 17)

20
Q

What are Z-drugs?

A

The are non-benzodiazepine agonists of the benzodiazepine receptor. They are chemically unrelated to benzodiazepines. Their clinical properties and therapeutic uses are also similar to benzodiazepines

(Slide 19)

21
Q

What characteristic do Z-drugs lack when compared to benzodiazepines?

A

They lack the signature 7-membered ring

(Slide 19)

22
Q

What are benzodiazepine receptor inverse agonists and what effects to they have?

A

They act as negative allosteric modulators for GABA; they reduce GABA mediated inhibitory effects by decreasing GABA affinity for its binding site and GABA-mediated ion channel opening frequency.

They have reversed behavioural effects to benzodiazepines: Anxiogenic (causes anxiety), proconvulsant, and can cause panic attacks

(Slide 20)

23
Q

What is an example of a class of benzodiazepine receptor inverse agonists?

A

β-carbolines

(Slide 20)

24
Q

What effects do benzodiazepine receptor antagonists have?

A

They block binding of both agonists, and inverse agonists, and also block behavioural effects of both.

They have no intrinsic behavioural effects

(Slide 21)

25
Q

What effects do benzodiazepine receptor partial agonists have?

A

They occupy a lot of receptors, potentially reducing the response of a full agonist. They also provide a restricted behavioural profile, providing a good anxiolytic effect but a poor sedative effect

(Slide 22)

26
Q

Why do benzodiazepine receptor partial agonists provide a good anxiolytic effect but a poor sedative effect?

A

As providing a goo anxiolytic effect requires a low amount of receptors to be occupied whereas a large proportion of the receptors need to be activated to provide a good sedative effect

(Slide 22)

27
Q

What is an example of a benzodiazepine receptor partial agonist?

A

Bretazenil
Abecarnil

(Slide 22)

28
Q

In ascending dose, what effects / side effects do benzodiazepines cause as a CNS depressant?

A

Increase in seizure threshold
Euphoria or intense feelings of pleasure
Anxiety-relief
Relaxation
Sleepiness
Unconsciousness
Death (though rarely as a sole agent)

(Slide 24)

29
Q

What are 5 examples of unwanted effects which benzodiazepine receptor agonists can cause?

A

Answers Include:

Drowsiness

Confusion

Memory Problems

Increased anxiety

Aggressive behaviour

Unpleasant withdrawal syndrome if coming off them

Loss of clinical effect on repeat administration due to tolerance (most on the hypnosis effect)

(Slide 25)

30
Q

What route of administration can you use to induce surgical anaesthesia with benzodiazepines?

A

An intravenous administration of a short-acting compound

(Slide 26)

31
Q

What is the difference between primary and secondary effects of drugs?

A

Primary: These are the direct and intended effects of a substance, action, or treatment

Secondary: These are the indirect or follow-up effects that occur as a result of the primary action or treatment. They can be positive or negative

(Slide 27)

32
Q

What 2 enzymes metabolise benzodiazepines?

A

CYP3A4 and CYP2C19

(Slide 28)

33
Q

Are benzodiazepines inducers of liver enzymes?

A

No

(Slide 28)

34
Q

Many primary metabolites of benzodiazepines are also benzodiazepine agonists. What needs to be done as a result of this?

A

It needs to be factored into the duration of the drug effect

(Slide 28)

35
Q

What reaction may benzodiazepines undergo during metabolism?

A

Glucuronidation

(Slide 28)

36
Q

What is glucuronidation?

A

A process that uses glucose to conjugate compounds with glucuronic acid, making them more water-soluble and easier to excrete in urine and bile

(Slide 28)

37
Q

What are the primary routes of benzodiazepine excretion?

A

Mostly during the kidneys but also in faeces

(Slide 28)

38
Q

How does half-life of benzodiazepines in the blood influence their clinical?

A

Those with long half lives (30-60 hours) use as anticonvulsants

Intermediate half life (10-20 hours) benzodiazepines use as anxiolytics

Short half life (<10 hours) benzodiazepines used as hypnotics. This is done as it minimises daytime sedation (hangover effect).

Very short half life (1-3 hours) benzodiazepines used as type IV anaesthetics

(Slide 30)

39
Q

What are type IV anaesthetics?

A

General anaesthetics that cause loss of consciousness and provide deep sedation for surgeries or procedures that require the patient to be unconscious and immobile

(Slide 32)

40
Q

What is flumazenil?

A

The only benzodiazepine receptor antagonist which is used therapeutically. It is a pure antagonist of benzodiazepines and Z-drugs.

It has a short half life (~1 hour) and is usually administrated intravenously, and repeatedly in order to outlast benzodiazepines.

(Slide 32)

41
Q

How and where is flumazenil used (3 different answers)?

A

It’s used in intensive care to diagnosis a coma of unknown origin (can reveal and then treat benzodiazepine poisoning)

It’s used to reverse anaesthesia or a short sedation caused by a benzodiazepine

It’s used to treat hepatic encephalopathy where abnormal endogenous compounds are acting in the same way as a benzodiazepine agonist

(Slide 32)

42
Q

What is hepatic encephalopathy (HE)?

A

A neuropsychiatric disorder that occurs as a result of liver dysfunction. It is characterized by a decline in brain function due to the liver’s inability to remove toxins

(Slide 32)

43
Q

What are Z-drugs mainly used as?

A

Hypnotics

(Slide 33)

44
Q

How do Z-drugs differ from benzodiazepines?

A

They’re considered more effective as their short half-life minimises daytime sedation (hangover effect)

They’re considered safer, particularly in the elderly

They produce less tolerance

They produce less habitation, resulting in less withdrawal problems

(Slide 33)

45
Q

How do the side-effects profile of Z-drugs compare to benzodiazepines?

A

They are basically the same

(Slide 33)

BM324: Fundamental Pharmacology (15 decks)

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