W8: Intro To Some Centrally Acting Drugs

Question 1

Give some examples of anxiolytics (minor tranquilizers)

Answer 1

Benzodiazepines (BZs)
Aliphatic alcohols
Beta adrenoceptor antagonists
Novel anxiolytics

Question 2

Give examples of BZs

Answer 2

Diazepam, loprazolam

Question 3

Describe beta-adrenoceptor antagonists (beta blockers) as anxiolytics

Answer 3

E.g., propranolol. Used to treat situational phobias. Blocks symptoms of anxiety like tremor, shaky hands, palpitations, sweating etc, since these actions are produced by noradrenaline and adrenaline. Stops the positive feedback loop of thinking you are sweating so getting more anxious etc.

Question 4

Describe novel anxiolytics as anxiolytics.

Answer 4

E.g, buspirone targeting 5-HT receptor. Work in the brain. Slow to act, reducing anxiety after a week or 2. Mechanism unknown.

Question 5

Give examples of antidepressants

Answer 5

Monoamine oxidase inhibitors (MAOIs)
Tricyclic antidepressants (TCAs)
Selective serotonin re-uptake inhibitors (SSRIs)

Question 6

How are benzodiazepines administered?

Answer 6

Orally

Question 7

What are the therapeutic uses of BZs?

Answer 7

Hypnotics (midazolam) - induces sleep
Anxiolytics (diazepam) - calming, increases inhibition to brain and are CNS depression drugs
Sedatives - reduces activity and excitement
Muscle relaxant/anticonvulsants e.g. diazepam

Question 8

What is the mechanism of action of benzodiazepines?

Answer 8

BZs interact with the GABA’A receptor. They bind to the allosteric site on the receptor, causing a conformation change. Act to enhance GABAergic transmission. CNS depressant effect.

Question 9

Modulation of GABA’A transmission

Answer 9

If GABA binds to the agonist binding site it causes a conformational change, allowing chloride ions to pass through the pore, and there is a higher concentration of chloride ions outside the cell than inside, so chloride influxes into the cell, causing hyperpolarisation of the neurone. So much less excitable and less likely to fire an AP.

Question 10

What channels are inside the proteins of the GABA’A receptors?

Answer 10

On that protein are binding sites and in it is a chloride channel-ligand gated ion channel.

Question 11

What happens when BZ binds to the GABA’A receptor?

Answer 11

BZ binding increases affinity of the agonist binding site for GABA, and then when GABA binds it increases the affinity of the BZ site. Synergistic, so increases the likelihood of the channel opening.

Question 12

What is the Monoamine theory of depression?

Answer 12

Depression is due to hypoactivity at monoaminergic synapses in the brain.

Question 13

What neurotransmitters are monoamines?

Answer 13

Noradrenaline, 5-HT, dopamine

Question 14

Why does depression not go away quickly with the administration of antidepressants?

Answer 14

When these drugs are given, the intrasynaptic monoamine levels increase very quickly due to it being a fast neurochemical effect. But it has a slow onset of clinical effects, minimum of 2-3 weeks. Secondary mechanisms are important.

Question 15

How are transmitters made at the monoaminergic synapses?

Answer 15

The neurotransmitter is made in the nerve terminal and packaged into storage vesicles for later release.

Question 16

What is the reuptake mechanism at monoaminergic synapses?

Answer 16

Neurotransmitter is taken back into the nerve terminal, where it can be repackaged or can leak out. Can be broken down by monoamine oxidase (which can break down noradrenaline or 5-HT).

Question 17

What are is the enzyme monoamine oxidase associated with?

Answer 17

Mitochondria

Question 18

What are monoamine oxidase inhibitors?

Answer 18

Inhibiting drugs which block monoamine oxidase

Question 19

What is the effect of monoamine oxidase inhibitors?

Answer 19

The neurotransmitter is released and taken back up, but will not be metabolised so there is an increase in the stores of the neurotransmitter. This could be in vesicles or an unbound store floating around in the nerve terminal (can leak out)
There means there is a higher concentration of intrasynaptic neurotransmitter, so increased receptor stimulation and increased activity at this synapse, so reversing hypoactivity.

Question 20

Example of monoamine oxidase inhibitors?

Answer 20

Phenelzine

Question 21

What do tricyclic antidepressants do?

Answer 21

Block the reuptake of neurotransmitter, so the neurotransmitter will remain in the synapse longer, causing more receptor stimulation and increasing the activity at the synapse.

Question 22

Examples of tricyclic antidepressants (TCAs)

Answer 22

Imipramine

Question 23

Are TCAs selective?

Answer 23

TCAs are not selective and will block the uptake of 5-HT and noradrenaline, increasing the activity at both synapses, causing many side effects.

Question 24

How do selective serotonin reuptake inhibitors work (SSRIs)?

Answer 24

Same mechanism as TCAs but they as selective to 5-HT, preventing its uptake.

Question 25

Give an example of SSRI

Answer 25

Fluoxetine

Question 26

Which antidepressant is mostly use in practice?

Answer 26

Selective serotonin re-uptake inhibitors SSRIs

Question 27

What is schizophrenia?

Answer 27

Severe psychiatric (mental) disorder causing distortion of thoughts and perception and mood. Spectrum meaning people can experience many different symptoms.

Question 28

What is the difference between type I and type II schizophrenia?

Answer 28

Positive symptoms (type I) = presence of abnormal thoughts and behaviours
Negative symptoms (type II) = absence of normal responses/behaviours

Question 29

What are antipsychotics?

Answer 29

Antischizophrenics = major tranquilliser = neuroleptic

Question 30

What is the dopamine hypothesis of schizophrenia?

Answer 30

Dopaminergic hyperactivity underlies schizophrenia.

Drugs that increase doperminergic transmission will increase schizo symptoms

Question 31

How is schizophrenia treated?

Answer 31

Drugs used to treat schizophrenia will block dopamine receptors. Antipsychotic dopamine receptor antagonists.

Question 32

Describe typical neuroleptics

Answer 32

Not selective, they block dopamine (D1 and D2 receptors), ACh muscarinic receptors, histamine H’1 receptors, alpha noradrenaline receptors, 5-HT receptors.
Examples - chlorpromazine, haloperidol

Question 33

Describe ‘aypical’ neuroleptics

Answer 33

Block dopamine receptors.
Fewer motor side effects and/or higher dopamine receptor selectivity compared with the typical neuroleptics, due to greater receptor selectivity.
E.g., sulpiride, clozapine

Question 34

What is dopamine transmission needed for?

Answer 34

Dopamine has an important neurotransmitter system in the brain for normal smooth movement. Dopamine transmission needed for initiation of movement, so if these receptors are blocked then motor side effects are produced.

Question 35

What are some motor side effects due to dopamine receptor block?

Answer 35

Parkinsonian

Tardive dyskinesia

Question 36

What is parkinsonian?

Answer 36

Blocks the receptors which gives the same effect as when the neurones die. Tremor at rest, muscle rigidity, decreased mobility. Developed relatively rapidly but has reversible symptoms if the drugs are stopped.

Question 37

What is tardive dyskinesia?

Answer 37

Severely disabling motor disturbance causing involuntary movements of the face/tongue, limbs, trunk. Slowly developing and generally irreversible. Not produced by all neuroleptics - normal,t by typical and not atypical.

Question 38

What are the non-dopaminergic side effects of neuroleptic drugs?

Answer 38

Anti-muscarinic effects: dry mouth, constipation, visual disturbances etc (peripherally mediated)
Postural hypotension due to alpha-adrenoceptor block (peripherally mediated)
Sedation due to histamine H’1 receptors block (centrally mediates)