Serotonin and dopamine Flashcards
Describe dopamine
Neurotransmitter
Precursor of noradrenaline
Once released it is recaptured by a dopamine transporter at nerve terminals and metabolised by monoamine oxidase (MOA) and catechol-O-methyltransferase (COMT)
Acts both pre and post-synaptically
Describe dopamine synthesis and packaging
(1) Tyrosine is transported into the pre-synaptic dopamine neuron via the tyrosine transporter
(2) Tyrosine is converted to L-DOPA (levodopa) via tyrosine hydroxylase
(3) L-DOPA is converted to dopamine via DOPA decarboxylase
(4) Dopamine is stored in pre-synaptic vesicles vis the vesicular monoamine transporter 2 (VMAT2)
Describe action of dopamine and its metabolism
(1) Dopamine is released from the pre-synaptic terminal into the synapse
(2) Dopamine can now act pre- or post-synaptic dopamine receptors
(3) Dopamine in the synapse can be transported back into the pre-synaptic neuron via the dopamine transporter (DAT) or the noradrenaline transporter (NAT)**.
(4) Dopamine is metabolised by catechol-O-methyltransferase (COMT) in the synapseor is taken back into a pre-synaptic neuron (noradrenaline or dopamine neuron) and metabolised via monoamine oxidase (A or B).
Dopamine is a substrate for both DAT and NAT. Striatal dopamine neurons possess DAT; however, cortical dopamine neurons likely do not. This means that deactivation in cortical dopamine neurons is partly dependent on NAT.
Describe levodopa MoA, indications and clinical uses, side effects,
Levodopa enters the brain and is converted to dopamine. It is broken down in the periphery bydopa decarboxylase and catechol - O - methyltransferase (COMT).
Indications
- Parkinsons Disease
Clincal benefits:
- There is significant benefit and less adverse effects compared with dopamine receptor agonists(particularly in patients over 70 years)
- Over time the effectiveness declines.
- Whilst motor function is improved with levodopa other symptoms such as dysphasia and cognitive decline are not improved.
Unwanted effects:
- involuntary movements (dyskinesia) develop over time.
- ‘on-off’ effect: probably related to the fluctuating plasma levels. Bradykinesia and rigidity will suddenly worsen and then improve (with varying time windows).
- Nausea and vomiting (treated with domperidone which is a dopamine antagonist that works in the chemoreceptor trigger zone but does not access the basal ganglia)
- psychological effects - schizophrenia like syndrome (due to increased dopamine activity in the brain) with hallucinations, confusion, insomnia and nightmares.
- postural hypotension especially in elderly patients.
Note: only available as combination with dopa decarboxylase inhibitor, and sometimes also a COMT, to prevent peripheral conversion to dopamine and therefore also reduce peripheral dopamine adverse effects e.g. nausea, vomiting, hypotension.
Peripherally acting dopa decarboxylase inhibitors e.g. cabidopa reduce the required dose of levodopa and reduce peripheral side effects, but they do not cross BBB, and therefore can’t have an effect once levo is in the brain.
The peripherally acting inhibitors prevent its breakdown by other enzymes e.g. COMT, MAO-B.
Describe receptor agonists
Pramipexole, rotigatine and apomorphine (non-ergot derivatives) bromocriptine and cabergoline
Agonists at dopamine receptors.
Indications:
- Parkinsons Disease (as monotherapy or in combination with levodopa)
- Some are also indicated for restless leg syndrome
Clincal benefits:
Pramipexol is a non-ergot derivative dopamine agonist that is D2 and D3 selective, better tolerated and less fluctuations than levodopa. Does cause somnolence, hallucinations and compulsive behaviours.
Improve bradykinesia and rigidity but less effective than levodopa, with more confusion and hallucinations (especially in the elderly and at high doses)
May be used as monotherapy in early disease (preferred in younger patients) but long term monotherapy is limited due to adverse effects such as impulse control disorders.
Unwanted effects:
- Nausea and vomiting (treated with domperidone which is a dopamine antagonist that works in the chemoreceptor trigger zone but does not access the basal ganglia) and other GI upset
- Impulse control disorders are common and can occur at any time during treatment
- psychiatriceffects - schizophrenia like syndromewith hallucinations, confusion, insomnia and nightmares.
- Withdrawal syndrome - need to very slowly taper if stopping treatment
Note:
- Useful if PD is severe or if patients can’t or don’t want to swallow to have different modes of possible administration
- topical e.g. patch for rotigatine
- subcutaneous e.g. apomorphine, highly emetogenic, requires pretreatment with dopa antagonist that does not cross BBB
Describe MAOI type B
Monoamine oxidase type B inhibitors - inhibit the breakdown of dopamine
_Rasagiline, selegiline, safinamide_
Irreversibly inhibit monoamine oxidase typeB (MAO‑B); they reduce breakdown of dopamine and may also block dopamine reuptake.
Indications
- Parkinson’s Disease
Clinical benefits
- When used with levodopa, MAO‑B inhibitors may increase dopaminergic adverse effects (eg dyskinesia, hallucinations, nausea, vomiting)
- Often used as an adjunct to levodopa.
Unwanted effects:
Hypotension, dyskinesia, headache, insomnia, vomiting, arthralgia
Non-selective MOAI are used to treat depression an havemore adverse effects.
Describe COMT inhibitors
_Enatacapone_
Inhibits catechol-O‑methyltransferase (COMT), mainly in peripheral tissues; increases the amount of levodopa available to the brain and prolongs the clinical response to levodopa.
Indications:
- Parkinson’s disease as an adjunct to levodopa in patients with motor fluctuations
Clinical benefit
- increases the amount of levodopa available to the brain and prolongs the clinical response to levodopa.
Unwanted effects
- discoloured urine (reddish-brown, nausea, vomiting, dry mouth, diarrhoea, abdominal pain, constipation, hallucination, confusion, paranoia, dyskinesia,skin, hair or nail discolouration, rash, increase in liver enzymes, hepatitis, colitis
Describe amantadine
Increases dopamine release and blocks cholinergic receptors; acts as a N‑methyl-D‑aspartate (NMDA) antagonist in the glutamatergic pathway from subthalamic nucleus to globus pallidus.
An antiviral drug that treats some influenza (more in block 6)
Indications:
- Parkinson’s Disease
- Influenza (limited use)
Clinical benefit
- It is less effective than other treatments, however can reduce dyskinesias induced by levodopa
Unwanted effects:
- nervousness, depression, nightmares, hallucinations, insomnia, hypotension, blurred vision, peripheral oedema, dry mouth, GIT
- There are reports ofimpulse control disordersassociated with amantadine
Broadly describe antipsychotics
Antipsychotic actions are thought to be mediated (at least in part) by blockade of dopaminergic transmission in various parts of the brain
- all effective antipsychotics block D2receptors or are partial agonists at D2receptors(with the exception of pimavanserin, which is not yet available in Australia)
- differential blockade of other dopamine receptors (eg D1) may influence therapeutic and adverse effects
- antagonism of other receptors may influence antipsychotic activity, eg 5HT2Aantagonism with some agents
Describe first and second generation antipsychotics
Typical (first generation):
eg chlorpromazine, haloperidol
- significant motor side efffects via the extrapyramidal system (EPSE)
- only effective against positive symptoms
Atypical (second generation):
eg olanzapine, clozapine, risperidone, quetiapine
- Fewer side effects compared with typical antipsychotics
- More commonly used in practice
- Some are often used in the treatment of depression (i.e., olanzapine + fluoxetine in treatment-resistant depression)
Cautions:
Neurological
- Parkinsons Disease: Antipsychotics aggravate PD as they oppose the action of the dopamine agonists
- Lewy body dementia:Antipsychotics (even low doses) can cause deterioration in cognitive and motor function
Cardiovascular
- Antipsychotics may increase the QT interval, increasing the risk of arrhythmia and sudden death
Elderly
- Use of antipsychotics in older people is associated with an increased risk of stroke and death.
Briefly describe epses
Extrapyramidal side effects (EPSE): (Dystonia, akathisia, parkinsonism, tardive dyskinesia)
- Much more common with the typical (first generation) antipsychotics
- Incidence is dose related and highest with haloperidol and trifluoperazine
- May require an anticholinergic (eg benzatropine)
Describe dystonias, parkinsonism, akathesia, tardive dyskinesia
Dystonias
Symptoms:
Involuntary movements
- Restlessness
- Muscle spasms
- Protruding tongue
- Fixed upwards gaze
- Neck muscle spasm
Details – onset and treatment
- Commonly occur in the first days to weeks of treatment
- Reversible upon cessation of drug (may be possbile to reintroduce at lower dose or alternative agent)
- Treatment with anticholinergic (eg bezatropine) is effective
Akathisia
Symptoms
Feeling of restlessness (difficult to differentiate from agitation related to psychosis)
Details – onset and treatment
- Occurs 2-3 days (up to several weeks) with increasing cummulative risk and may subside spontaneously
- Improves with dose reduction and worsens with dose increase (opposite to psychosis related agitation)
- Much lower incidence with the “Atypical (2nd generation) agents”
Parkinsonism
Tremor, rigidity, bradykinesia
- Occurs within weeks to months
- Usually reversible although short term symptomatic treatment with anticholinergic (benzatropine) may help
- If persists, may reduce dose or consider alternative antipsychotic
Tardive dyskinesia
Involuntary movements of face and tongue (can also be trunk and limbs)
Tardive dyskinesia is thought to occur from chronic antagonism of D2 receptors leading to upregulation of D2 receptors and, therefore, dopamine hypersensitivity in a pathway in the brain that mediates movement.
- Develops after months or years of treatment, or on sudden cessation
- Often irreversible, although a slow improvement after cessation (in young patient’s identified early)
Describe other side effects
Neuroleptic malignant syndrome
- Potentially fatal
- fever, marked muscle rigidity, altered consciousness and autonomic instability
- Progresses rapidly over 24-72 hours
- Elevated creatine kinase (CK) and leucocytosis often occur
- May occur at any time
- Cessation of therapy and supportive care (cooling, volume replacement etc and occasionally medical treatment with bromocriptine or dantrolene) are required
Endocrine effects
- Antagonising D2 receptors can ↑ prolactin secretion
- Breast swelling, pain and lactation (galactorrhoea) -Can occur in men and women
- ↓ growth hormone secretion
Sexual dysfunction
- ↓ libido and arousal
- Erection and ejaculation difficulties
Metabolic effects
- Weight gain - associated with increased triglycerides, cholesterol and blood glucose
- ↑ risk of diabetes and CVD
- more common with “atypical” agents
- Weight gain associated with H1 and 5HT2Cantagonism
Drowsiness and sedation
- Less common with the atypical antipsychotics
Describe the relevant pathways to psychosis and schizophrenia
(1) Mesolimbic (mesostriatal) pathway - positive symptoms (e.g., delusions, hallucinations, etc.)
- It is hypothesised that increased dopamine transmission (hyperdopaminergia) in the mesolimbic/striatal pathway causes the positive symptoms of schizophrenia
- Therefore, blockade of dopamine in this pathway (via antipsychotics) reduces positive symptoms
(2) Mesocortical pathway - negative symptoms (e.g.,anhedonia, social withdrawal, alogia etc.)
- It is hypothesised that decreased dopamine transmission in the mesocortical pathway mediates the negative symptoms
- Therefore, blockade of dopamine receptors in this pathway canworsennegative symptoms
- This may account for why clozapine works well on negative symptoms, as it has low dopamine blockade
(3) Nigrostriatal pathway - parkinsonism
- Destruction of this pathway occurs in Parkinson’s disease
- Blockade of dopamine receptors in the nigrostriatal pathway, therefore, mimics Parkinson’s disease and leads to similar symptoms.
(4) Tuberoinfundibular pathway -hyperprolactinemia, sexual dysfunction
- Dopamine blockade in the tuberoinfundibular pathway is responsible for increase prolactin and sexual dysfunction/side effects
- Prolactin is produced by lactotrophcells in the pituitary:
- D2 agonism inhibits prolactin release
- 5HT2A stimulates prolactin release
- Therefore, D2 antagonism/partial agonism disinhibits prolactin release (i.e., increases prolactin); however, many atypical antipsychotics are 5HT2A antagonists, which blocks prolactin release (i.e., decreases prolactin). As a result, many atypical antipsychotics have a neutral effect of prolactin release (this is not true for all antipsychotics)
Describe clozapine
- S_uggested to be more effective than all other antipsychotics_
- Reserved for treatment-resistant schizophrenia due to side effects and special monitoring requirements
- Less likely to experience EPSE
- The only antipsychotic to reduce suicide in schizophrenia
- Associated with significant side effects and therefore requires special monitoringfor -neutropenia, agranulocytosis, seizures, cardiomyopathies and potentially life-threatening constipation (paralytic ileus)
