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Pharmacology > Dopaminergic Neurotransmission & Dopaminergic Drugs > Flashcards

Dopaminergic Neurotransmission & Dopaminergic Drugs Flashcards

1
Q

Sites of dopamine in the brain

A

Cells in SN → striatum - nigrostriatal pathway - regulation of motor function

Cells in ventral tegmental area → nucleus accumbens, frontal cortex & amygdala (mesolimbocortical pathway) - REWARD - make actions pleasurable - eating, drinking, procreating, caring for young - dysfunctional in schizophrenia

Cells in ventral hypothalamus → median eminence and pituitary gland (tuberohypophyseal system)

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2
Q

Pathway that’s dysfunctional in schizophrenia

A

Mesolimbocortical pathway

(REWARD)

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3
Q

Synthesis, storage, release, termination, metabolism of dopamine

A
  1. Tyrosine is taken into neuron via carrier mediated transport
  2. Tyrosine is converted to dopamine in 2 steps catalysed by tyrosine hydroxylase and DOPA decarboxylase
  3. Dopamine is actively packaged into vesicles by an amine transporter
  4. Release is via classical Ca2+ mediated exocytosis
  5. Termination is via uptake by a dopamine transporter
  6. Degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase
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4
Q

Degradation of dopamine

A

Monoamine oxidase

Aldehyde dehydrogenase

catechol-o-methyltransferase

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5
Q

Receptor targets of dopamine

A

D1 type receptors

D2 type receptors

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6
Q

D1 type receptors

A

D1 - Gs (AC and increased cAMP)

D5 - Gs (AC and increased cAMP)

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7
Q

D2 type receptors

A

D2, D3, D4 via Gi (AC and decreased cAMP)

OR

Gq (PLC and increased IP3/DAG)

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8
Q

Gs

A

AC and increased cAMP

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9
Q

Gi

A

AC and decreased cAMP

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10
Q

Gq

A

PLC and increased IP3/DAG

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11
Q

Effect of activation of D1 type receptors

A

Causes excitation of post-synaptic neuron

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12
Q

Effect of activation of D2 type receptors

A

Widespread

Located both presynaptically and postsynaptically

Mostly inhibitory effects on presynaptic and postsynaptic neurons e.g. D2 receptors can be presynaptic inhibitory receptors and/or presynaptic inhibitory autoreceptors (on dopamine neurons themselves) suppressing release of dopamine from dopaminergic neurons

Also stimulates or inhibits hormone release

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13
Q

Dopamine is required for

A

Motor control - nigrostriatal pathway

Controls voluntary movement

Mediating effects of rewarding stimuli - mesolimbical pathway

Dopamine mediates the hedonic impact of natural reward (especially nucleus accumbens)

Neuroendocrine function - tuberohypophyseal pathway

dopamine inhibits prolactin and stimulates growth hormone secretion

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14
Q

Side effect of anti-schizophrenic drugs

A

inhibition of prolactin

stimulation of GH secretion

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15
Q

Parkinsons

A

Loss of dopaminergic nigrostriatal neurons and subsequent loss of striatal dopamine is what underlies this disease - dopamine replacement is first line therapy - L-DOPA

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16
Q

Schizophrenia

A

Drugs which release dopamine (e.g. amphetamine) can cause schizophrenia like symptoms

Hyperactivity of mesolimbocortical DAergic pathway has been implicated in schizophrenia

Dopamine antagonists (especially D2 receptor) are used to treat this disorder

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17
Q

Target for anti-scizophrenic drugs

A

D2 receptor dopamine antagonists

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18
Q

MOA amphetamine

A

Release DA

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19
Q

MOA cocaine

A

Block DA reuptake

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20
Q

Symptoms of parkinsons

A

Tremor at rest

Muscle rigidity

Bradykinesia

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21
Q

Prevalence of Parkinsons

A

Affects 1% of population over 65

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22
Q

Pathophysiology of Parkinsons

A

Associated with degeneration of dopaminergic neurons of the nigrostriatal pathway and formation of Lewy bodies (misfolding proteins containing alpha-synuclein)

Consequent loss of dopamine from the striatum is what underlies the motor symptoms

Symptoms only manifest after 60% of nigral dopamine neurons have already degenerated and 80% of striatal dopamine has been lost

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23
Q

Main MOA of PD symptom-treating drugs

A

Replace dopamine - L-DOPA

Inhibit dopamine metabolism - COMT inhibitors, MAO inhibitors

Mimic dopamine action - dopamine receptor agonists

Release dopamine

24
Q

Apart from enhancing dopamine transmission, how else is Parkinsons treated

A

Using drugs that block muscarinic ACh receptors

25
Q

Most effective treatment for Parkinsons

A

Dopamine replacement - L-DOPA

Usually given with a DOPA decarboxylase inhibitor that is unable to cross the BBB (carbidopa, benserazide) so that conversion to dopamine only occurs in the brain, thus reducing peripheral side effects

Effectiveness wears off - intact dopamine neurons are at least partially required for its effectiveness

26
Q
A
27
Q

Main side effects of levodopa treatment

A

Dyskinesias

  • Abnormal involuntary movements affecting face and limbs
  • Manifest in the majority of patients within 2 years of starting levodopa therapy
  • Can be reduced by lowering the dose but this causes symptoms to reappear

On-off effects

  • rapid fluctuations in clinical state where symptoms reappear suddenly and can last for mins → hrs
  • Reason is unclear but may relate to changes in plasma levodopa concentrations
28
Q

how is dopamine metabolism inhibited

A

MAO-B inhibitors

COMT inhibitors

29
Q

MAO-B inhibitor

A

Selegiline

30
Q

COMT inhibitor

A

Entacapone

31
Q

Dopamine receptor agonists

A

Non-selective dopamine receptors agonists

Slightly selective D2 receptor agonists

Selective D2 receptor agonists

32
Q

Non-selective dopamine receptors agonist

A

apomorphine

33
Q

Slightly selective D2 receptor agonists

A

Bromocriptine

Pergolide

Cabergoline

34
Q

Selective D2 receptor agonists

A

Pramipexole

Ropinrole

35
Q

Muscarinic cholinergic antagonists

MOA

A

Trihexyphenidyl

Benztropine

Cholinergic interneurons in the striatum oppose the effects of dopamine blocking their actions - partly overcomes the loss of dopamine

36
Q

Prevalence of schizophrenia

When does it manifest

A

1% of population

Men - appears in late teens/early 20s

Women - appears in late 20s/early 30s

37
Q

what type of disorder is schizophrenia

A

Neurodevelopmental in which certain brain structures (especially cerebral cortex) do not develop properly

disease can be

relapsing and remitting

chronic and progressive

38
Q

Clinical symptoms of schizophrenia - POSITIVE SYMPTOMS

A

Delusion

Hallucinations

thought disorder

Abnormal behaviour

(more drugs to treat positive symptoms)

39
Q

Negative symptoms of schizophrenia

A

Withdrawal from society

Flattening of emotional response

Anhedonia

40
Q

Apart from + and -ve symptoms, what are other symptoms of schizophrenia

A

Deficits in cognitive function e.g. attention/memory

anxiety

guilt

depression

self-punishment (up to 50% of suicide attempts)

41
Q

NT systems implicated in schizophrenia

A

Dopaminergic system - most evidence in favour

Glutamatergic system

(drugs came first - neurochemical theory came after)

ALSO

serotonergic system

noradrenergic system

42
Q

Dopamine hypothesis for schizophrenia

A

Overactivity in the dopaminergic system leads to disease

BASED ON 2 OBSERVATIONS

  • All anti-schizophrenic drugs act as antagonists at dopamine receptors and clinical potency correlates with D2 receptor affinity
  • Amphetamine (which releases dopamine from neurons) causes schizophrenia like symptoms in users
43
Q

MOA of all anti-schizophrenic/antipsychotic drugs

A

Antagonists of dopamine D2 receptors

may also affect noradrenergic, histaminergic, cholinergic, serotonergic systems (hence side effects)

44
Q

5-HT receptors and anti-psychotic drugs

A

Can act as antagonists at 5-HT2A receptors

agonists at 5-HT1A receptors

provides clinical benefit or a reduced side effect profile

45
Q

MOA of anti-schizophrenic drugs - acute

A

Blocking the effects of dopamine released from the mesolimbic pathway accounts for antipsychotic effects - reduced positive symptoms

Blocking the effects of dopamine released from nigrostriatal pathways accounts for the side effects

clinical efficacy correlates strongly with affinity for D2 receptor

Antipsychotic effects require 80% block of D2 receptors

46
Q

Proportion of D2 receptors that must be blocked in order to see antipsychotic effects

A

80%

47
Q

MOA of anti-schizophrenic drugs - chronic

A

clinical effects take weeks to develop => acute pharmacological effects cannot account for their antipsychotic activity

antipsychotic drugs initially transiently increase the activity of dopaminergic neurons

their longer term effect is to decrease the activity of DAergic neurons

48
Q

Anti-schizophrenic drug - chronic

A

Haloperidol

49
Q

Synonyms for anti-schizophrenic drugs

A

Antipsychotic drugs, neuroleptic drugs and major tranquillisers

50
Q

Effectiveness of antipsychotic drugs

what do they treat in schizophrenia

A

only effective in 70% of patients - 30% are treatment resistant

They can only control the positive symptoms of schizophrenia

they do not control the negative symptoms - while occurence of delusions/hallucinations can be suppressed, schizophrenia patients remain withdrawn and emotionally flattened

51
Q

Classical/typical antipsychotics

A

Chlorpromazine

Haloperidol

Thioradazine

Flupenthixol

52
Q

Recently developed/atypical antipsychotics

A

Sulpiride

Clozapine

Risperidone

Sertindole

Quetiapine

53
Q

Distinction between typical and atypical schizophrenia

A

incidence of side effects - atypical < typical

efficacy in treatment resistant patients - atypical > typical

Efficacy against negative symptoms - atypical > typical

Receptor profile (atypical more selective for dopamine D2 receptor)

54
Q

Side effects of anti-schizophrenic drugs

A

Blocking the effects of striatal dopamine from nigrostriatal pathway leads to motor disturbances (extrapyramidal)

Acute dystonia

parkinsons like syndrome with involuntary movements

common in first few weeks of treatment - acute

reversible on stopping treatment

Tardive dyskinesia

Severe disabling involuntary movements affecting face and limbs

occur after months or years of treatment (tardive)

often gets worse on stopping treatment

→ the occurence of motor side effects is less frequent with the newer atypical anti-psychotics

55
Q

Consequences of blockage of tuberohypophyseal pathway

A

Leads to hormonal imbalances

Increase in plasma prolactin conc

dopamine via D2 receptor is responsible for inhibiting prolactin secretion

blocking these receptors causes an increase in plasma prolactin conc

causes breast swelling, pain and even lactation (gynecomastia) in men and women

56
Q

receptors, apart from dopamine, affected by neuroleptics

A

Histamine

Cholinergic muscarinic

α adrenoceptors

57
Q

Side effects of neuroleptics

A
  • Sedation - H1 block - causes daytime drowsiness and difficulty in concentrating
  • Anticholinergic effects - muscarinic block - dry mouth, constipation, blurred vision, urinary retention
  • Postural hypotension - α adrenoceptor block
  • Neuroleptic malignant syndrome - muscle rigidity, fever, autonomic instability, delerium
  • Miscellaneous reactions - jaundice, urticaria (hives), leucopenia/agranulocytosis (reduction in WBCs), antipsychotic malignant syndrome

Pharmacology (23 decks)

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