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Module 8: Neurosciences > Neuropharmacology (8.3) > Flashcards

Neuropharmacology (8.3) Flashcards

1
Q

Outline the metabolism of monoamines

*Draw diagram*

A
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2
Q

Dopamine: Receptor

A

*G-protein coupled receptors - D1 - D5*

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3
Q

Dopamine: Functional associations

A
  • Control of movement (nigrostriatal dopamine)
  • Emotional (mesocorticolimbic dopamine)
  • Reward pathways (mesocorticolimbic dopamine) - link to addiction
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4
Q

Noradrenaline/adrenaline: Receptor

A

NA and Adr act through α- and β-adrenoreceptors - linked to G-proteins, effects via second messengers

The most prominent adrenoreceptor in the forebrain are β-adrenoreceptors (may be targetted by anti-depressants).

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5
Q

Noradrenaline: Functional associations

A
  • Arousal and attention
  • Related to mood and behaviour
  • Role in facilitating the responsiveness of the brain to other neurotransmitters (released simultaneously)
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6
Q

Serotonin: Receptor

A

At least 14 different 5-HT subtypes which are all G-protein linked, apart from 5-HT3

5-HT1 can function as an autoreceptor (pre-synaptic), mediating the effects of serotonergic transmission.

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7
Q

Serotonin: Functional associations

A
  • Mood and pain
    • Diminished transmission has been implicated in depression
  • Released from platelets following activation
  • Released from enterochromaffin cells - stimulates feelings of nausea

Raphe nuclei contains the serotonergic nuclei.

  • Descending fibres: Travel to the spinal cord, inhibit nociceptive pathways
  • Ascending fibres: Travel to the forebrain and cerebral blood vessels
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8
Q

Monoamines: Endogenous regulation of activity

A
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9
Q

Monoamine: Enzymatic degradation pathways

*therapeutic targets*

A
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10
Q

Parkinson’s disease: Definition, symptoms

A

Definition: Characterised by the degeneration of dopaminergic neurones of the substantia nigra. This loss of dopaminergic neurones leads to dopamine depletion

Symptoms:

  • Bradykinesia
  • Resting tremor
  • Muscular rigidity
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11
Q

Parkinson’s disease: Treatment

A

Aim: Restore dopaminergic transmission through increasing dopamine levels

  • Dopamine precursor: L-DOPA (alongside inhibitors of enzymes which convert L-DOPA to its active form (dopa decarboxylase) in the periphery. Acts to increase the concentration available to cross the BBB)
  • Dopamine receptor agonist: Act mainly at D2 (Gi, decrease cAMP) but also at D3
  • Muscarinic receptor antagonist: As Cholinergic overactivity is seen in Parkinson’s disease.
  • MAO-B and COMT inhibitors: Prevent the breakdown of dopamine, increasing availabilty at the synaptic cleft
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12
Q

Parkinson’s disease: Treatment ADRs

A

L-DOPA (dopamine precursor):

  • Motor complications: Dyskinesias, on-off phenomenon
  • GI: Peripheral dopamine antagonists
  • Behavioural: Resultant of the increased levels of dopamine - antipsychotics may be used to combat this

Dopamine receptor agonists:

  • Mental disturbances
  • GI disturbances
  • Fatigue and somnolence

Inhibitors of MAO (MAO-B)

  • Less likely to cause hypertension HOWEVER MAO-A may also be inhibited at high doses which may preciptate a hypertensive crisis(due to peripheral accumulation of noradrenaline - see metabolic pathways)
  • Fatal hyperthermia if + meperidine, cocaine or fluoxetine

L-DOPA + COMT

  • Hyperdopaminergic symptoms
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13
Q

Parkinson’s disease: Therapy of non-motor symptoms

A
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14
Q

Schizophrenia: Definition, symptoms

A

Definition: A type of psychosis (individuals are unable to distinguish their own thoughts and ideas from reality) which changes the way individuals think and behave.

Acute schizophrenia: Patients experience periods when symptoms are particularly severe followed by periods with few or no symptoms.

Symptoms:

Usually classified into positive and negative symptoms.

Positive symptoms: Changes in thought and behaviour, such as hallucinations and delusions

Negative symptoms: Withdrawal or lack of function unexpected of a ‘healthy’ person. Often seen many years prior to the acute schizophrenic episode, referred to as the prodromal period.

  • Hallucinations: Hearing, smelling, tasting seeing or feeling things that are do not exist beyond their own mind. Most commonly voices
  • Delusions: A belief held with complete conviction despite often being based on a mistaken, strange or unrealistic view
  • Thought disorder: Trouble keeping track of thoughts and conversations
  • Changes in behaviour and thoughts
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15
Q

Schizophrenia: Treatment

A

Aim: Decrease signal transmission through dopamine receptors (antagonise). For some patients medications which also act at other receptors types, such as serotonin (5-HT) are required

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16
Q

Depression: Definition, symptoms

A

Definition: Persistent sadness/hopelessness for weeks or months

Symptoms:

  • Loss of interest in activities (anhedonia)
  • Anxiety
  • Loss of appetite
  • Decreased energy/fatiguability
  • Vacillation
  • Psychomotor agitation/psychomotor depression
  • Loss of confidence
17
Q

Depression: Treatment

A

Aim: Depression has been linked to monoamine deficiency. Subsequently, treatment focuses on increasing serotonin and noradrenaline levels

Reuptake inhibitors

  • TCA: Inhibit reuptake of serotonin and noradrenaline, through inhibition of SERT and NET of the pre-synpatic membrane
  • SSRI: Inhibit the reuptake of serotonin, through inhibition of SERT
  • SNRI: Inhibit reuptake of serotonin and noradrenaline, through inhibition of SERT and NET of the pre-synpatic membrane
  • NRI: Block the reuptake of noradrenaline (NET)

Atypical antidepressants:

  • MOA-A inhibitors: Prevent metabolism of noradrenaline and serotonin
  • Increasing release of neurotransmitters
  • Ketamine/LSD: Act on NMDA
18
Q

Depression: Treatment ADRs

A
19
Q

Glutamate: Sources and synthesis

A

Sources: Glutamate can be obtained from the diet but may also be synthesised from α-ketoglutarate or glutamine.

Synthesis: Synthesised from α-ketoglutarate or glutamine and then packaged into synaptic vesicles ready for release following an action potential.

20
Q

Glutamate: Action

A

99 % of transmission is excitatory. Mainly acts through inotropic receptors, AMPA and NMDA.

The receptors are composed of 4 subunits, with an integral ion channel.

Permeabilty:

AMPA: Na+ and K+

NMDA: Ca2+, Na+ and K+

NMDA receptors have a Mg2+ blockade, preventing their activation. The receptors can only be activated following cell depolarisation through the repeated activation of AMPA receptors. The depolarisation of the neuron ‘drives’ Mg2+ out of the channel, allowing for the entry of Ca2+. This provides the basis for long-term potentiation - which allows for learning and memory (creates reinforcement), as the Ca2+ influx allows for the generation of secondary messengers implicated in this process.

21
Q

Glutamate: Reuptake

A

2 possible mechanisms:

Glutamate → reuptake into glutaminergic neurones via pre-synaptic transporters → repackaged into vesicles and used again

Glutamate → reuptake by glial cells → converted to glutamine (inactive) → travels to glutaminergic neurone → converted to glutamate → repackaged

22
Q

Glutamate: Functional assoications

A

Involved in fast excitatory neurotransmission in the CNS

Extremely important for learning and memory, via LTP. Acetylcholine is also implicated.

CAUTION: Tonic excitation may result in some cases, leading to the death of neuronal cells.

Mechanism: Excessive excitation of AMPA and NMDA leads to a large influx of Ca2+. Reuptake of glutamate is impaired, due to the vast quantity released. As glutamate remains within the synpatic cleft there is excessive stimulation of the receptors, leading to excitotoxic neuronal cell death. Antagonists may be used to avoid this.

23
Q

GABA: Souces and synthesis

A

Sources: Synthesised from glutamate

Synthesis: Synthesised from glutamate in GABAergic neurones. GABA is then packaged into synaptic vesicles and released following action potential propagation.

24
Q

GABA: Action

A

Role in arousal/attention, memory formation, anxiety, sleep and muscle tone.

GABA activation is inhibitory, causing neuronal cells to become less excitatory (resting membrane potential is decreased and so are less likely to reach the activation threshold).

Main action is through GABAA iontropic receptors, which have a central Cl- channel.

25
Q

GABA: Reuptake

A

2 possible mechanisms:

GABA → reuptake into GABAergic neurones via pre-synaptic transporters→ repackaged into vesicles and used again

GABA → reuptake by glial cells → converted to glutamate → converted to glutamine → travels to glutaminergic neurone → converted to glutamate → converted to GABA → repackaged

26
Q

GABA: Functional associations

A

Extremely important for the modulation of neuronal excitability. Also important in the motor system.

GABA receptors are important pharmacological targets:

  1. anxiolytic medications (anti-anxiety)
  2. General anaesthetics - Stabilise the GABA receptor in the open position, causing constant inhibition of neuronal signalling
27
Q

Epilepsy: Treatment

A

Anticonvulsant drugs provide an effective treatment. There are several possible modes of action, including modulation of GABA and glutamate transmission. It has been noted that GABA levels are reduced in epileptic patients.

Generally, these medications aim to increase GABAergic signalling and/or decrease glutaminergic signalling

Examples: *M.O.A.s not certain*

  • Phenytoin - Inhibits Na+ channels
  • Gabapenin - Inhibits Ca2+ channels and glutamate release
  • Carbamazepine - Inhibits Na+ channels
  • Sodium valporate - Inhibits Na+ channels
    • Caution in women of child bearing age - TERATOGENIC. Pregnancy prevention programme
  • Lamotrigine - Inhibits Na+ channels and glutamate release
28
Q

Epilepsy: Treatment common ADRs and possible interactions

A
  • Nausea
  • Vomiting
  • Diarrhoea
  • Weight gain
  • Hepatotoxicity
  • Rashes
  • Headache
  • Dizziness
  • Ataxia

Possible interactions:

Other medications may change the metabolism of anticolvulsants.

Anticonvulsants also affect CytP450, causing changes in metabolism of other medications.

29
Q

Anxiety disorders: Changes in neurotransmitter release

A
30
Q

Anxiety disorders: Treatment

A

Benzodiazapines: Faciliate the opening of GABA channels

Barbiturates: Faciliate GABA and inhibit AMPA (glutamate) receptors

Module 8: Neurosciences (19 decks)

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