Neuropsychopharmacology Flashcards
1
Q
what Is the function of dopamine
A
Dopamine modulates attention and salience
“Salience” refers to the motivational properties of a stimulus, which can cause it to attract attention and drive behavior
2
Q
how is dopamine linked to delusions
A
Dopamine modulates attention and salience
“Salience” refers to the motivational properties of a stimulus, which can cause it to attract attention and drive behavior
Aberrant salience hypothesis:
Abnormal dopamine nuerotransmission
Tendency for irrelevant stimuli to be attributed motivational salience and thus to attract attention and influence behaviour inappropriately - brain thinks everything is important and then the brain gives a meaning for these things - leads to delusions
These are attended to, explored and given meaning – leads to formation of delusions - what meaning is given is dependent to personal circumstances - eg in NI they’ll relate it to paramilitary or psi or mi5 or something but in America it’ll be via or fbi or something like that
3
Q
What causes schizophrenia
A
Genetic risk
first degree relative increases risk to 8-10%
Shared risk with bipolar disorder
Cannabis use in teenage years increases risk x2
Childhood trauma
Social isolation e.g. increased risk in immigrant groups
4
Q
describe Schizophrenia symptoms
A
Positive symptoms:
- Delusions, hallucinations, impaired insight
- Distressing
- Respond well to antipsychotics
Negative symptoms:
- Emotional blunting, social withdrawal, apathy
- Can be very disabling and require long term support
- tend to be more disabling and difficult to treat
Cognitive impairment
- Pattern of impairments
- Drop in IQ
5
Q
describe the dopamine hypothesis in Schizophrenia
A
There are significant abnormalities in dopamine transmission in the striatum
- Elevated pre-synaptic dopamine synthesis and storage
- Increased dopamine release from cells
- Increased density of D2 receptors in striatum
Antipsychotic effectiveness associated with blockade of D2 receptors in striatum
Cannabis – causes increased striatal dopamine release
Other genetic and environmental risk factors associated with abnormalities in dopamine transmission
6
Q
what’s the difference between 1st vs 2nd generation / Typical vs Atypical drugs in Schizophrenia treatment
A
Originally termed ‘atypical’ as not thought to produce Extra Pyramidal Side effects (EPSE) at treatment doses
2nd generation / atypical more likely to produce metabolic side effects
No difference in efficacy
2nd generation have broader receptor profile – not limited to dopamine receptor antagonism
7
Q
describe the pharmacology of antipsychotics
A
Antipsychotics are antagonists at dopamine D2 receptors – this mediates their clinical effect
They improve positive (psychotic) symptoms, but no impact on negative symptoms
Concordance enhanced by DEPOT preparations:
- Haloperidol, zuclopenthixol, risperidone, aripiprazole
Antipsychotics also act at a number of other receptors:
- Serotonin
- Histamine
- Muscarinic
- Alpha adrenergic
Both positive and adverse effects mediated by action at other receptors
8
Q
what are the adverse effects of dopamine antagonism
A
- Nigrostriatal tract - Extra pyramidal side effects (EPSE) (Extrapyramidal side effects: Physical symptoms, including tremor, slurred speech, akathesia, dystonia, anxiety, distress, paranoia, and bradyphrenia, that are primarily associated with improper dosing of or unusual reactions to neuroleptic (antipsychotic) medications.)
- Tuberoinfundibular system – prolactin elevation
9
Q
describe the four Extra pyramidal side effects (EPSE)
A
- Acute dystonia;
- Involuntary muscle spasm
- Occurs within hours of starting antipsychotics
- Torticollis / oculogyric crisis / tongue spasm
- Imbalance between nigrostriatal dopamine / acetylcholine – rapidly respond to IM anticholinergic e.g. procyclidine / benzhexol
- More common in young males / antipsychotic naïve / high potency e.g. haloperidol - Parkinsonism:
- Characteristic signs:
Tremor (“pill-rolling”)
Rigidity (cogwheel)
Bradykinesia
- Develops days to weeks after antipsychotic treatment
- Risk factors: elderly females, first generation antipsychotics
- Nigrostriatal dopamine blockade leads to relative excess of acetylcholine
- Treatment:
Add anticholinergic e.g. procyclidine
Reduce antipsychotic dose
Switch to second generation antipsychotic - Akathisia:
- A subjectively unpleasant state of inner restlessness where there is a strong desire to move:
Foot stamping when seated
Crossing/uncrossing legs
Rocking foot to foot
Pacing up and down
- Associated with increased risk of suicide and aggression
- Pathology less clear
- Occurs in 25% patients, less with 2nd generation (except risperidone and aripiprazole)
- Treatment:
Reduce dose
Switch to 2nd generation antipsychotic
Anticholinergics unhelpful
Propranolol and 5HT2 antagonists e.g. mirtazapine may help but limited evidence - Tardive Dyskinesia:
- Abnormal movements
Lip smacking and chewing
Tongue movements (‘fly catching’)
Choreiform hand movements
Pelvic thrusting
- 5% patients per year of antipsychotic exposure
- More common in elderly women and people who have had early EPSE
- Treatment:
Increasing antipsychotic may improve symptoms initially
Stop anticholinergic
Reduce dose of antipsychotic
Switch to Quetiapine or Clozapine
10
Q
describe Hyperprolactinaemia
A
Dopamine inhibits prolactin release therefore antipsychotics can increase prolactin levels
Olanzapine, aripiprazole, clozapine and quetiapine do not increase prolactin at usual treatment doses
May be asymptomatic
Problems include: sexual dysfunction, breast growth and galactorrhoea (excessive or inappropriate production of milk), reduction in bone mineral density and menstrual disturbances
11
Q
describe the metabolic side effects of antipsychotics
A
More common with 2nd generation antipsychotics
Include
Weight gain
Dyslipidaemia
Type 2 diabetes
Weight gain:
- Mediated by serotonin 5HT2C, 5HT1A and H1 antagonism
- Worst with clozapine and olanzapine
- Likely genetic susceptibility
Dyslipidaemia:
- Increased by lifestyle factors prevalent in individuals with schizophrenia - not eating well, not attending GP as much as they should, not exercising enough
- Also exacerbated by antipsychotics esp Clozapine, Olanzapine and Quetiapine
- Likely associated with weight gain, although precise receptor associations unclear
Type 2 Diabetes:
- Lifestyle factors
- Untreated people with schizophrenia at higher risk
- Overall approx. 13% people with schizophrenia vs 3% general pop
- Mediated by weight gain, but also likely to be direct antipsychotic effect
- Clozapine, olanzapine > Quetiapine > other 2nd gen antipsychotics
12
Q
name the non-metabolic side effects of antipsychotics
A
Sedation (Histamine receptor antagonism)
Dry mouth, constipation (Muscarinic antagonism)
Postural hypotension (Adrenergic receptor antagonism)
Sexual dysfunction (serotonergic antagonism, plus the above)
QTc prolongation
Neuroleptic malignant syndrome
13
Q
describe Neuroleptic malignant syndrome
A
Idiosyncratic response to antipsychotics
Caused by D2 receptor blockade
More likely with 1st generation antipsychotics
Symptom:
- Fever, confusion, muscle rigidity
- Autonomic disturbance
- Rhabdomyolysis (Raised CK) – renal failure
Treatment:
- Stop antipsychotic
- Supportive
- Restart 2nd generation cautiously
14
Q
when Is clozapine used and what are its side effects
A
Reserved for use in treatment resistant schizophrenia
2 trials of antipsychotic, minimum 6 weeks
Side effects:
- Neutropenia→agranulocytosis (deficiency in granulocytes)
- Myocarditis (inflammation of heart)
- Hypersalivation (excessive production of saliva)
- Constipation – potentially severe
- Sedation and weight gain
more effective than any other antipsychotic
but use restricted because it has some severe side effects
most people tolerate it v well
15
Q
when Is aripipazole used and what are its side effects
A
NOT A DOPAMINE ANTAGONIST! – a partial agonist at dopamine D2 receptors
Functionally acts as antagonist in presence of increased dopamine transmission in mesolimbic area
Acts as agonist in mesocortical area
Side effects include akathisia and agitation but no other EPSE, weight gain, sedation or hyperprolactinaemia - not a lot of side effects - no metabolic side effects - not sedative
no evidence that it treats negative symptoms
IF it works - can be very effective because of its side effects profile - difficulty is it doesn’t work for everybody
16
Q
what are the indications for antipsychotics
A
Schizophrenia
Other psychotic disorders:
- Delusional disorder
- Severe depression with psychotic symptoms
- Mania with psychotic symptoms
Non-psychotic disorders:
- Maintenance in bipolar affective disorder
- Adjunctive treatment in depression
- Evidence in OCD, PTSD, ASD
17
Q
what needs to be monitored when you have prescribed antipsychotics
A
Weight Prolactin Blood glucose ECG U&E Blood pressure
18
Q
what is the difference between psychosis and neurosis
A
PSYCHOSIS:
- Characterized by delusions (Fixed false belief out of keeping with a person’s religion and culture), hallucinations (A perception in the absence of a stimulus) and impaired insight (The individual is not aware of the problem – although apparent to others) eg schizophrenia
- E.g:
> Schizophrenia
> Schizoaffective disorder
> Delusional disorder
> Severe depressive disorder and mania may also exhibit psychotic symptoms
NEUROSIS:
- “disorders of sense and emotion”
- No delusions or hallucinations.
- Insight intact
- Eg mood and anxiety disorders
19
Q
describe mania/hypomania
A
A pathological mood state lasting >= 4 days characterized by:
- Elated or irritiable mood
- Overactivity
- Increased energy
- Grandiosity
- Disinhibition
- Increased libido
- Note mania may be associated with grandiose delusions
20
Q
what is the difference between nicotinic and muscarinic acetylcholine receptors
A
Nicotinic:
- Ionotropic (fast)
- Predominant in PNS
Muscarinic:
- Metabotropic (slow)
- Predominant in CNS
21
Q
Describe in outline how antidepressants are used in the treatment of depression
A
Chronic stress alters neuronal circuits in brain
Antidepressants increase BDNF and stimulate neurogenesis – enhance synaptic plasticity
Moderates limbic system to reduce negative cognitive bias
Increased serotinergic neurotransmission modulates other neurotransmitter systems eg GABA, dopamine
22
Q
describe the mode of action of SSRIs
A
Selective serotonin reuptake inhibitors
Prevents re-uptake and subsequent degradation of the monoamine neurotransmitter serotonin from the synaptic cleft
Overall effect: Prolonged presence of serotonin in the synaptic cleft leads to prolonged neuronal activity – in mood disorders such as depression there are low levels of this neurotransmitter in the brain. SSRIs therefore restore the concentration of serotonin to normal levels.
23
Q
describe some SSRI side effects
A
- Well tolerated
- Relatively safe in overdose
- First line treatment (NICE)
- GI – nausea, vomiting, dyspepsia
- Headache
- Agitation, anxiety
- Sexual dysfunction
- Hyponatraemia
- Increased risk of bleeding
- +/- Insomnia
- NO weight gain
24
Q
what are some interactions of SSRIs
A
Dangerous in combination with other antidepressants and St John’s Wort
CYP enzyme inhibitors – increase levels of antipsychotics, benzodiazepines
Citalopram / Escitalopram – QT prolongation
25
describe the mode of action of SNRIs (Serotonin and Noradrenaline reuptake inhibitors)
Effect: Prevents re-uptake and subsequent degradation of the monoamine neurotransmitters
serotonin and noradrenaline from the synaptic cleft
Overall effect: Prolonged presence of serotonin and noradrenaline in the synaptic cleft leads to prolonged neuronal activity – in mood disorders such as depression there are low levels of these neurotransmitters in the brain. Serotonin/noradrenaline reuptake inhibitors therefore restore the concentration to normal levels.
26
describe some side effects for SNRIs
```
GI – nausea, vomiting, dyspepsia
Headache
Agitation, anxiety,
Sexual dysfunction
Hyponatraemia
Sweating
+/- Insomnia
Elevation of blood pressure at higher doses
NO weight gain,
```
27
what are the interactions of SNRIs
Dangerous in combination with other antidepressants and St John’s Wort
Metabolized by CYP2D6/34A
28
give some examples of SSRIs
Sertraline (Lustral): 50-200mg
Fluoxetine (Prozac): 20-60mg
Citalopram (Cipramil): 20-40mg
Escitalopram (Cipralex): 10-20mg
Paroxetine (Seroxat): 20-50mg
29
give 2 examples of SNRIs
Venlafaxine (Efexor, Vensir): 75 – 375mg
Duloxetine (Cymbalta): 60-120mg
30
name the NASSA (Noradrenergic and Specific Serotonergic antagonists) drug
Mirtazapine (Zispin): 15-45mg
31
describe the mode of action of NASSAs (Noradrenergic and Specific Serotonergic antagonists)
blocks the noradrenaline a2 autoreceptor
this blocks the negative feedback
and causes an increase in release of serotonin and adrenaline in the synaptic cleft
32
describe the mode of action of NASSAs (Noradrenergic and Specific Serotonergic antagonists)
blocks the noradrenaline a2 autoreceptor
this blocks the negative feedback
and causes an increase in release of serotonin and adrenaline in the synaptic cleft
Post synapticly:
- antagonist at 5-HT 1 and 5-HT3 receptors
- enhances 5-HT1 neurotransmission
33
describe the side effects of Mirtazapine
- Drowsiness, sedation
- Increased appetite and weight gain
- Dizziness
- Potential for blood dyscrasia
- Sexual dysfunction uncommon
- Few interactions
- CAN be used in combination with SSRI/SNRI with caution
34
list some Tricycic Antidepressants
Amitriptyline: 50-200mg/day
Clomipramine: 30-250mg/day
Lofepramine: 140-210mg/day
Dosulepin: 75-225mg/day
35
describe the mode of action of Tricycic Antidepressants
Target: Noradrenaline and serotonin reuptake transporters on the pre-synaptic neuronal membrane Action: Inhibitor
Effect: Prevent re-uptake and subsequent degradation of the monoamine neurotransmitters serotonin and noradrenaline from the synaptic cleft
Overall effect: Prolonged presence of serotonin and noradrenaline in the synaptic cleft leads to prolonged neuronal activity – in mood disorders such as depression there are low levels of these neurotransmitters in the brain. TCAs therefore restore the concentration to normal levels.
36
what are some side effects of tricyclics
Not recommended first line
Less well tolerated than other antidepressants
Potentially fatal in overdose
Dangerous in combination with other antidepressants and St John’s Wort
Other indications – eg amitriptyline and pain
- General:
Nausea, vomiting, headache
- Histamine receptor:
Sedation, hangover
- Alpha 1 receptor antagonism:
Postural hypotension, tachycardia, arrhythmia
- Anticholinergic:
Dry mouth, blurred vision, constipation, urinary retention
37
list some MAOIs (Monoamine oxidase inhibitors)
Reversible: Moclobemide
Irreversible: Phenylzine, Tranylcypromine
38
list some MAOIs (Monoamine oxidase inhibitors)
Reversible: Moclobemide
Irreversible: Phenylzine, Tranylcypromine
39
describe the mode of action of MAOIs (Monoamine oxidase inhibitors)
An enzyme called monoamine oxidase is involved in removing the neurotransmitters noradrenaline, serotonin and dopamine from the brain. MAOIs prevent this from happening, which makes more of these brain chemicals available to effect changes in both cells and circuits that have been impacted by depression.
40
list some side effects of MAOIs
Rarely used in clinical practice
Possible role in treatment resistant depression
Dangerous in combination with other antidepressants and St John’s Wort
CHEESE REACTION:
Tyramine is contained in certain foods: aged cheeses, chicken liver, soy products, pickled fish and red wine
Tyramine normally inactivated by MAO in GIT
Patients on MAOIs cannot metabolize tyramine
Tyramine causes release of catecholamines resulting in tachycardia, hypertension, arrhythmias, seizures and stroke
41
list some side effects of MAOIs
Rarely used in clinical practice
Possible role in treatment resistant depression
Dangerous in combination with other antidepressants and St John’s Wort
CHEESE REACTION:
Tyramine is contained in certain foods: aged cheeses, chicken liver, soy products, pickled fish and red wine
Tyramine normally inactivated by MAO in GIT
Patients on MAOIs cannot metabolize tyramine
Tyramine causes release of catecholamines resulting in tachycardia, hypertension, arrhythmias, seizures and stroke
also:
- Postural hypotension
- Drowsiness
- Insomnia
- Headaches
- Anticholinergic effects
- Weight gain
- Parathesia
- Hepatotoxicity
- Leucopenia
- Hypertensive crisis
42
describe the mode of action of vortioxetine
```
Serotonin reuptake(SERT) inhibitor:
- Serotonin reuptake inhibition
```
5HT-1A receptor Agonist:
- Post-synaptic: enhances sertoninergic neurotransmission
- Pre-synaptic: Leads to desensitisation of 5HT1A autoreceptors and enhanced 5HT release
Other serotinergic activity:
- Enhances serotinergic neurotransmission
- Thought to mediate other neurotransmitter systems: Dopamine, GABA, glutamate, acetylcholine
43
list some adverse effects of vortioxetine
Metabolised by p450 system
Common adverse effects: nausea, vomiting, diarrhoea, dry mouth, headaches, abnormal dreams
Less sexual dysfunction
“pro cognitive” effects
44
describe some discontinuation symptoms of antidepressants
Occur on abrupt cessation of antidepressants
Onset within 5 days:
- Irritability
- Nausea
- Sweating
- Paraesthesia, ‘electric shock’ sensations
- Dreaming
- Usually mild and self limiting but can be severe
- Up to 1/3 of patients
- Can occur with ANY antidepressant
- Worst with short half life – paroxetine, venlafaxine
- NOT relapse
- NOT addiction
- Can be avoided by gradual withdrawal of antidepressant
45
describe the NICE guidelines for antidepressant use
Do not routinely treat mild depression with antidepressants
Psychosocial interventions for mild-moderate depression
Antidepressant treatment combined with psychosocial interventions for mod-severe depression
Monitor for suicidality if <30 years old
1. SSRI 1st line
2. If ineffective/intolerable then switch
- Alternative SSRI
- Another class of antidepressant
3. Augment
- Lithium
- Antipsychotic
- Mirtazapine
4. ECT
46
when is electroconvulsive therapy used
Severe depression which is life threatening and rapid response required
OR
Not responded to treatment
More effective than antidepressants, faster response rate
47
describe the neurobiology of manic episodes and depressive episodes in bipolar disorder
Manic episodes:
- Increased DOPAMINE neurotransmission
- Increased GLUTAMATE transmission
- Reduced GABA neurotransmission
- Role for SEROTONIN and NORADRENALINE?
Depressive episodes:
- Possible role for DOPAMINE dysregulation in bipolar depression
- Antidepressants can cause a switch to mania
48
what are the general principles for treatment in bipolar disorder
1. Treatment of bipolar depression
2. Treatment of manic episodes
3. Prevention of relapse
49
how would you treat mania in bipolar disorder
STOP ANTIDEPRESSANTS!
Antipsychotic is main treatment:
- Haloperidol, olanzapine, risperidone, quetiapine
- Aripiprazole
- Lithium, valproate - slower than antipsychotics so not given as first line treatment
- If already on long term treatment – optimize dose +/- add on
50
how would you treat depression in bipolar disorder
response to antidepressants is different to normal depression - they barely respond to antidepressants
Quetiapine, Olanzapine (+/- fluoxetine)
Lamotrigine
Lithium – less effective
ECT - for severe bipolar depression
Consider psychological treatments eg CBT
51
describe how you would try to prevent relapse in bipolar disorder
Protect against manic relapse:
- Lithium, Olanzapine, Quetiapine, Risperidone, Valproate
Protect against depressive relapse:
- Lamotrigine, lithium and Quetiapine
Best evidence for long term efficacy – LITHIUM:
- If lithium not tolerated/ineffective then valproate > antipsychotics
52
describe the mode of action of lithium use as a mood stabiliser
reduces presynaptic dopamine - inactivates post synaptic G-proteins - modulates neurotransmission with action on 2nd messenger systems
down regulates NMDA receptor - modulates neurotransmission with action on 2nd messenger systems
facilitates release of GABA - up regulates GABA-B receptor
53
describe the pharmacokinetics of lithium
Absorbtion complete 6-8 hours, peak level 30mins to 2 hours
Distributed in total body water, slow entry to intracellular compartment
No protein binding, Not metabolized
Excreted entirely in urine in similar way to sodium.
Half life 20 hours
54
describe the side effects of lithium
Tends to be very well tolerated - good long term treatment
RENAL:
- Polyuria and polydipsia
- Potentially nephrotoxic
- Check U&E and serum creatinine and eGFR prior to commencing
THYROID:
- Hypothyroidism in up to 20%
- more common in females, FHx
- If hypothyroidism develops - continue lithium and treat with thyroxine.
- TFT’s usually return to normal after stopping lithium.
OTHER SIDE EFFECTS:
- Leukocytosis (most patients)
- Polyuria/polydipsia (30-50%), dry mouth (20-50%)
- Fine hand tremor (45% initially, 10% after 1 year of treatment)
- Minor cognitive effects: verbal learning, memory and creativity
- Muscle weakness (30% initially, 1% after 1 year of treatment)
- Electrocardiographic (ECG) changes (20-30%)
- Nausea, vomiting, diarrhoea (10-30% initially, 1-10% after 1-2 years of treatment)
- Weight gain
55
list some contraindications for lithium
- Pregnancy - relative - can have a mild teratogenic effect
- Breast-feeding
- Renal impairment
- Thyroidopathies
- Sick sinus syndrome
56
describe lithium toxicity symptoms
when a patient has taken too much
MILD:
- Weakness
- Worsening tremor
- Mild ataxia
- Diarrhoea
WORSENING TOXICITY:
- Vomiting
- Coarse tremor
- Slurred speech
- Confusion
SEVERE:
- Seizures →Coma→Death
57
describe the causes of lithium toxicity
Overdose – intentional or accidental
Older patients – more vulnerable to toxicity, and at lower levels
Factors affecting salt/water balance:
- Dehydration, sweating, vomiting
Medications which alter lithium excretion through their effect on the kidneys:
- Thiazide diuretics
- ACE inhibitors
- NSAIDs
- COX-2 inhibitors
58
describe the treatment for mild moderate and severe lithium toxicity
Mild:
- Supportive, stop lithium
Moderate:
- Fluid infusion – saline diuresis
Severe (eg Li >4.0 mmol/L or altered level of consciousness):
- May need haemodialysis
Mortality - <1% of all toxic exposures
59
describe the mode of action of sodium valproate as a mood stabiliser
Mode of action not well understood – enhances GABA neurotransmission
Metabolized in liver by CYP – enzyme INHIBITOR
Increases concentrations of lamotrigine, amitriptyline
Forms: sodium valproate, semi-sodium valproate (Depakote)
60
describe the use of sodium valproate as a mood stabiliser
Used in maintenance treatment, and to treat acute mania
Dose 500-2000mg daily (often as semisodium valproate – ‘Depakote’)
Rapid loading
Reduced need for monitoring and better tolerated than lithium
Check LFT/FBP baseline and 6 months
DO NOT USE IN WOMEN OF CHILDBEARING AGE
61
describe some of the side effects of sodium valproate
```
Common:
Nausea, vomiting
Drowsiness
Dizziness
Weakness
Weight gain
```
```
Uncommon:
Encephalopathy
Liver failure
Pancreatitis
Low platelets – increased bleeding risk
Teratogenic
```
62
describe the mode of action of lamotrigine as a mood stabiliser
Mode of action – acts on pre-synaptic voltage gated sodium channels to reduce glutamate neurotransmission
Metabolism by glucuronic acid conjugation – fewer drug interactions
Level reduced by OCP
Level increased by Valproate
63
describe when lamotrigine is used in bipolar disorder
Use in maintenance particularly to prevent bipolar depression
Limited use in acute mood state – limited by slow titration
Not first line
64
describe some side effects of lamotrigine
- Associated with severe skin reactions – Steven Johnson Syndrome, Toxic epidermal necrolysis
- Risk 0.1%, occurs in 2-8 weeks. Risk reduced by slow titration
- Other side effects: loss of balance and coordination, nausea, dizziness, drowsiness, insomnia, change in menstrual periods, blurred vision
65
describe the symptoms of mild moderate and severe Alzheimer's disease
MILD:
- Memory loss
- Language problems
- Mood and personality problems
- Diminished judgement
MODERATE:
- Behavioural and personality changes
- Unable to learn or recall new information
- Wandering, agitation, aggression or confusion
- Need assistance with daily living
SEVERE:
- Unstable gait, motor disturbances
- Bedridden, incontinence, may be mute
- Unable to attend to ADLs
66
describe the pathophysiology of Alzheimer's disease
Physiologically, Amyloid Precursor Protein (APP) is cleaved by α-secretase to produce soluble Amyloid Precursor Protein (sAPP)
IN Alzheimers, Amyloid Precursor Protein is abnormally cleaved by β-secretase and ɤ-secretase
This forms Beta-amyloid peptide (Aβ)
Beta-amyloid peptide (Aβ) aggregates to form oligomers (amyloid plaques)
Beta-amyloid plaques are toxic:
- Oxidative stress
- Pro-inflammatory
- Altered calcium homeostasis
Tau proteins abnormally phosphorylated to cause neurofibrillary tangle formation leading to cell death
- this leads to depletion of cholinergic neurones
- therefore excessive glutamate release (and impaired re-uptake) leading to excitotoxicity of post synaptic cells
- reduction also in serotinergic and noradrenergic neurones
67
what drug treatments are used in Alzheimer's disease
2 types:
Acetylcholinesterase inhibitors:
- impair the breakdown of acetylcholine in the synaptic cleft by the enzyme acetylcholinesterase and increase availability of acetylcholine
- Donepezil
- Rivastigmine
- Galantamine
NMDA (glutamate receptor) antagonist:
- treats the excessive glutamate release and addresses the excitotoxicity caused by this
- Memantine
68
what are some side effects of acetylcholinesterase inhibitors
related to increased parasympathetic activity
- Nausea, vomiting, diarrhoea
- Bradycardia, syncope, heart block
- Muscle cramps
- Caution: sick sinus/conduction abnormalities, asthma, COPD
69
describe Parkinson's disease
- A neurodegenerative disease resulting from death of dopaminergic cells in the substantia nigra
- The nigrostriatal dopamine pathway projects from the substantia nigra in basal ganglia
- Normally modulates voluntary movement - initiation of movement and inhibition of contradictory movements
- Degeneration of this pathway results in symptoms of parkinsonism
- Parkinsonism is characterised by bradykinesia, rigidity and tremor.
- Idiopathic Parkinson’s disease commonest
Other causes:
- Drug induced parkinsonism
- Post encephalitic parkinsonism
- Toxins e.g. manganese, carbon monoxide
70
describe the symptoms of Parkinson's disease
Motor:
- Resting pill rolling tremor
- Bradykinesia
- Rigidity
- Festinant/shuffling gait
Non Motor:
- Fatigue, depression
- Dysarthria, sialorrhoea
- Micrographia
- Cognitive impairment
71
describe the role of Dopamine and acetylcholine in Parkinsons
Acetylcholine and dopamine are normally in ‘balance’
Acetylcholine release from the striatum is strongly inhibited by dopamine
Acetylcholine excess or dopamine depletion results in parkinsonism
72
name some dopamine enhancing drugs and anticholinergic drugs used in treatment of Parkinson's
Dopamine enhancing drugs:
- Levodopa
- Dopamine agonists
- Apomorphine
- COMT inhibitors
- MAO-B inhibitors
- Amantadine
Anticholinergic drugs:
- Procyclidine
- Orphenadrine
- Benzhexol
73
describe how levodopa is used in the treatment of Parkinson's
Levodopa converted to dopamine by dopa decarboxylase
Dopamine does not cross the blood brain barrier (BBB) but levodopa does cross BBB.
Levodopa is therefore administered with a dopa decarboxylase inhibitor (eg carbidopa, benserazide) to reduce the peripheral metabolism of levodopa to dopamine – reduced side effects
MADOPAR = levodopa + benserazide
74
describe the pharmacokinetics of levodopa (treatment for Parkinson's)
Half life 1-3 hours, peak levels 1 hour - quickly metabolised
metabolized in liver, excreted in bile
Reduced absorption in protein rich meals – Ldopa competes with amino acids
Interaction with pyridoxine (vit B6) – Increases peripheral activity of dopa decarboxylase therefore reduces availability in brain
75
name some adverse effects of levodopa (Parkinson's treatment)
Psychiatric:
- Confusion, anxiety, psychotic symptoms
Peripheral:
- Nausea, vomiting
- Hypotension, arrythmias
- Sweating, discolouration of skin/urine
Long term effects:
- Wearing off
- On/off phenomena
- Freezing
- Involuntary movement (dyskinesias)
76
describe how dopamine agonists work in the treatment of Parkinson's
Act directly on post synaptic dopamine receptors
Longer duration of action than levodopa
Two types:
- Ergot derivatives e.g. Pergolide, Cabergoline - older
- Non-ergot derivatives e.g. Ropinirole, pramipexole, rotigotine - newer
Non ergot derivatives are better tolerated and do not show the fluctations in efficacy shown with levodopa
77
list some adverse effects of dopamine agonists
Peripheral adverse effects:
- Nausea/constipation
- Postural hypotension
- Cardiac arrhythmia
- Peripheral oedema
- Retroperitoneal, pulmonary pericardial fibrosis***
* **associated with ergot derivatives and requires monitoring
Central adverse effects:
- Drowsiness (sudden onset of sleep)
- Hallucinations
- Psychotic reactions
- Impulse control disorders
78
give an example of a dopamine agonist used in treatment of Parkinson's
apomorphine
Potent dopamine agonist
Used in advance disease
Used to treat ‘off’ period with levodopa
Administered subcutaneously
79
describe how COMT inhibitors work in the treatment of Parkinson's
give an example of one
Prevent the peripheral breakdown of levodopa by inhibiting catechol –O-methyltransferase
Reduces variations in plasma levodopa levels
‘continuous dopaminergic stimulation’
e.g. Entacapone, tolcapone
Adverse effects similar to levodopa and tolcapone is hepatotoxic
80
describe how MAO-B inhibitors work in the treatment of Parkinson's
MAO-B breaks down dopamine
Protects dopamine from extra-neuronal degradation, therefore increasing the extent and duration of the response to levodopa
Safety concerns –possible increased mortality on seleginine
Do not cause cheese reaction of non selective monoamine oxidase inhibitors (MAOI – antidepressant)
81
describe the side effects of MAO-B inhibitors
Related to increased dopaminergic effects (cf L-Dopa)
Selegenine metabolized to amphetamine – anxiety, insomnia
82
describe how Anticholinergic drugs could be used to treat Parkinson's
name 2
give some side effects
e.g. Orphenadrine, procyclidine
Suppression of acetylcholine by acetylcholine antagonists (anticholinergics) helps to compensate for the lack of dopamine in Parkinson’s disease
Rarely used in Parkinson’s disease but can be used to treat the parkinsonian side effects of anti-psychotic drugs
SE: cognitive impairment, delirium, blurred vision, dry mouth, urinary retention
83
briefly describe the neurobiology of anxiety
Hyperactivation of “fear network” involving amygdala and hippocampus
Hypoactivation of pre-frontal cortex - part of brain that modulates response to certain stimulus
84
briefly describe generalised anxiety disorder
- Continuous “free floating” anxiety
- May be with or without panic
- Common – up to 5% population, F>M
- Genetic component - neuroticism (tendency to worry)
85
describe treatment for generalised anxiety disorder
- First line pharmacological treatment – SSRI
- May worsen anxiety initially
- 2nd line alternative SSRI or SNRI
- Consider pregabalin
- Benzodiazepines – Not recommended as long term treatment
- Also evidence for Quetiapine and Buspirone
86
briefly describe panic disorder
- Episodes of severe acute anxiety (panic) not related to specific stimulus
- Panic symptoms – highly distressing, often attributed to cardiac arrest
- 2/3 will develop AGORAPHOBIA – fear of situations from which escape difficult or help not available
- Less common than GAD (generalised anxiety disorder)
- May be caused by traumatic events, hereditary component
87
describe treatment for panic disorder
- SSRi first line – may exacerbate symptoms initially
- SSRI/SNRI 2nd line
Also consider:
- Tricyclic antidepressants eg imipramine, clomipramine
- Gabapentin (very rarely used) and sodium valproate
- Benzodiazepines – useful in short term but assoc with worse outcome in longer term
88
briefly describe Obsessive compulsive disorder
Characterized by:
- obsessional thoughts – generate high levels of anxiety
- Compulsive behaviour performed to reduce anxiety levels - eg they do the behaviour in response to the thought - by doing the behaviour it rationalises the irrational thought
- Distinguish from obsessional personality - two different things
89
describe treatment for OCD
1st line SSRI
- titrate to maximum tolerated dose
- May need 8-12 weeks
2nd line another SSRI or Clomipramine
Treatment resistance common
- Augment with antipsychotic
- Possible role for anti-glutamatergic drugs – memantine, lamotrigine
90
briefly describe Post traumatic stress disorder (PTSD)
- follows highly traumatic event
- Persistent anxiety, intrusive memories, hypervigilance following highly traumatic event
- High prevalence in NI vs rest of the world. (troubles) May be chronic and difficult to treat
- Increased by nature of trauma, underlying neuroticism and previous MH problems
- Often comorbid depression and substance misuse
91
describe treatment for PTSD
1st line – sertraline, paroxetine (?any SSRI) and venlafaxine
2nd line – as above
Treatment resistance common
- Add antipsychotic – risperidone and olanzapine
- Prazocin
92
describe treatment for simple phobias
Best evidence is for exposure therapy
Some evidence to suggest SSRIs helpful
No evidence for other pharmacological interventons
93
how do benzodiazepines work when treating short term anxiety
Target: Benzodiazepine (BDZ) receptor on GABA-BDZ receptor complex
Action: Agonist
Effect: Increase affinity of the inhibitory neurotransmitter GABA for the GABAA receptor – this causes post-synaptic chloride ion channels to open
Overall effect: Increased flow of negative chloride ions into the neurone leading to hyperpolarisation of the membrane – this prevents further excitation
94
list some side effects of benzodiazepines
Common:
- Amnesia, ataxia (especially elderly); confusion; dependence, drowsiness and dizziness the next day (hang-over effect)
- Psychomotor impairment
Important:
- Ataxia leading to increased risk of falls in the elderly
- Physical and psychological dependence
- Respiratory depression
- Tolerance
Also:
Interaction with alcohol at GABA receptor
95
describe how diazepam works in treating short term severe anxiety
Target: Benzodiazepine (BDZ) receptor on GABA-BDZ receptor complex
Action: Agonist
Effect: Increase affinity of the inhibitory neurotransmitter GABA for the GABAA receptor – this causes post-synaptic chloride ion channels to open
Overall effect: Increased flow of negative chloride ions into the neurone leading to hyperpolarisation of the membrane – this prevents further excitation
96
when is diazepam used in psychiatry
Short term use to manage anxiety / agitation
- Crises
- Specific situations
- Psychosis / mania when sedation and anxiolytic effect required
May be used to terminate seizures – PR/IV
Long term use best avoided – limited efficacy and concerns re tolerance
Indicated for alcohol withdrawal syndrome (or chlordiazepoxide – Librium)
Note frequently misused “yellows, roches”
97
describe Z-drugs (Zolpidem, zopiclone)
Non-benzodiazepines (different chemical structure)
Bind to benzodiazepine site at GABA-A receptor
Short onset of action
Specific to α-1 subtype – Hypnotic
Anticonvulsant and muscle relaxant only at high doses
Side effects otherwise similar to benzodiaepines
98
compare benzodiazepines vs barbiturates
Benzodiazepines:
- When bound, benzodiazepines increase affinity of receptor for GABA, increasing frequency of opening of chloride channel
Barbituates:
- Bind to different site than benzodiazepines – synergistic effect possible
- increase duration of opening of chloride channel, and may act in absence of GABA at high doses, increasing risk of toxicity
99
when is flumazenil used and describe how it works
treatment of benzodiazepine overdose
- Competitive antagonist in benzodiazepine binding site
- Displaces Benzodiazepines – can treat OD
- Rapid onset of action, short half life (needs repeated doses)
- No effect on barbituates
- Should not be used when benzos are used to treat epilepsy
- Metabolised in liver
100
when is pregabalin used and describe how it works
Anticonvulsant (mostly used for this), anxiolytic and neuropathic pain
Structural derivative of GABA – however does NOT bind to GABA receptors
Inhibitory action at presynaptic voltage gated calcium channels – modulates release of excitatory neurotransmitters inc glutamate and noradrenaline
Licence for GAD
Negligible metabolism – excreted largely unchanged in urine
Limited by potential for misuse (“buds”) - can give you a high
101
when is bus-irons used and how does it work
Agonist at presynaptic 5HT-1A receptors, partial agonist at postsynaptic 5HT-1A receptors
No action at GABA receptors
Supresses serotinergic neurotransmission
Presynaptic dopamine antagonist D2/D3 receptors
No sedation / anticonvulsant activity
Efficacy = diazepam in GAD, Adjunct to SSRIs in depression
Mode of action unclear
