W8: Intro To Some Centrally Acting Drugs Flashcards
Give some examples of anxiolytics (minor tranquilizers)
Benzodiazepines (BZs)
Aliphatic alcohols
Beta adrenoceptor antagonists
Novel anxiolytics
Give examples of BZs
Diazepam, loprazolam
Describe beta-adrenoceptor antagonists (beta blockers) as anxiolytics
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.
Describe novel anxiolytics as anxiolytics.
E.g, buspirone targeting 5-HT receptor. Work in the brain. Slow to act, reducing anxiety after a week or 2. Mechanism unknown.
Give examples of antidepressants
Monoamine oxidase inhibitors (MAOIs)
Tricyclic antidepressants (TCAs)
Selective serotonin re-uptake inhibitors (SSRIs)
How are benzodiazepines administered?
Orally
What are the therapeutic uses of BZs?
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
What is the mechanism of action of benzodiazepines?
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.
Modulation of GABA’A transmission
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.
What channels are inside the proteins of the GABA’A receptors?
On that protein are binding sites and in it is a chloride channel-ligand gated ion channel.
What happens when BZ binds to the GABA’A receptor?
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.
What is the Monoamine theory of depression?
Depression is due to hypoactivity at monoaminergic synapses in the brain.
What neurotransmitters are monoamines?
Noradrenaline, 5-HT, dopamine
Why does depression not go away quickly with the administration of antidepressants?
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.
How are transmitters made at the monoaminergic synapses?
The neurotransmitter is made in the nerve terminal and packaged into storage vesicles for later release.
What is the reuptake mechanism at monoaminergic synapses?
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).
What are is the enzyme monoamine oxidase associated with?
Mitochondria
What are monoamine oxidase inhibitors?
Inhibiting drugs which block monoamine oxidase
What is the effect of monoamine oxidase inhibitors?
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.
Example of monoamine oxidase inhibitors?
Phenelzine
What do tricyclic antidepressants do?
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.
Examples of tricyclic antidepressants (TCAs)
Imipramine
Are TCAs selective?
TCAs are not selective and will block the uptake of 5-HT and noradrenaline, increasing the activity at both synapses, causing many side effects.
How do selective serotonin reuptake inhibitors work (SSRIs)?
Same mechanism as TCAs but they as selective to 5-HT, preventing its uptake.
Give an example of SSRI
Fluoxetine
Which antidepressant is mostly use in practice?
Selective serotonin re-uptake inhibitors SSRIs
What is schizophrenia?
Severe psychiatric (mental) disorder causing distortion of thoughts and perception and mood. Spectrum meaning people can experience many different symptoms.
What is the difference between type I and type II schizophrenia?
Positive symptoms (type I) = presence of abnormal thoughts and behaviours Negative symptoms (type II) = absence of normal responses/behaviours
What are antipsychotics?
Antischizophrenics = major tranquilliser = neuroleptic
What is the dopamine hypothesis of schizophrenia?
Dopaminergic hyperactivity underlies schizophrenia.
Drugs that increase doperminergic transmission will increase schizo symptoms
How is schizophrenia treated?
Drugs used to treat schizophrenia will block dopamine receptors. Antipsychotic dopamine receptor antagonists.
Describe typical neuroleptics
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
Describe ‘aypical’ neuroleptics
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
What is dopamine transmission needed for?
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.
What are some motor side effects due to dopamine receptor block?
Parkinsonian
Tardive dyskinesia
What is parkinsonian?
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.
What is tardive dyskinesia?
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.
What are the non-dopaminergic side effects of neuroleptic drugs?
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)
