Week 11: Psychopharmacology Flashcards
A 76-year old man is admitted with a urinary tract infection. He is confused but cardiovascularly stable. He becomes increasingly agitated once his family leaves and barricades the fire exit with chairs and equipment. He is shouting and swearing and accusing the nursing staff and other patients of trying to kill him. He appears to be grabbing at things all around him shouting “get the snakes away” repeatedly.
Despite attempts to talk him back to his bed, he refuses, and begins tossing chairs at staff and other patients. He has also opened the fire door and is standing on the stairs.
Outline how you might deal with this situation.
Call for further nursing staff and security if required to help escort back to bed area safely. In this situation the lights should be on and everything done to calm him.
He has been admitted for a UTI so its important to know he has been treated for this as the cause of his delirium.
As a last resort use medication - nursing staff to persuade to take medication for tranquillisation, oral preferred, intramuscular if needed. Nurse on one to one obs in side room to minimise distractions
Medication would be a benzodiazepine (EG Lorazepam 0.5mg-1mg PO or IM) for his agitation and arousal +/- an antipsychotic (EG Haloperidol 2.5mg PO or 1.5mg IM ). Main risks of benzodiazepine would be ataxia and risks of falls, respiratory depression if large doses.
Patient’s obs (BP/Pulse/RR and Alertness) would need to be monitored and patient monitored for ataxia and risks of falls.
Procyclidine (anticholinergic) (5mg PO or 2.5mg IM) may be needed to be administered if the patient is neuroleptic naïve as Haloperidol could cause acute dystonic reaction or extra pyramidal side effects (IE Parkinson like effects due to dopamine blockage).
A 76-year old man is admitted with a urinary tract infection. He is confused but cardiovascularly stable. He becomes increasingly agitated once his family leaves and barricades the fire exit with chairs and equipment. He is shouting and swearing and accusing the nursing staff and other patients of trying to kill him. He appears to be grabbing at things all around him shouting “get the snakes away” repeatedly.
Despite attempts to talk him back to his bed, he refuses, and begins tossing chairs at staff and other patients. He has also opened the fire door and is standing on the stairs.
Consider the underlying reasons for the man’s deterioration.
The most probable diagnosis is delirium causing acute confusion due to a urinary tract infection which is causing systemic complications. Other causes of confusion are numerous and you would need to assess the medical history and undertake a physical exam when able to do so.
EG Co-morbid Infections and dehydration Side effects from medications Dementia Withdrawal from substances (EG alcohol) Stroke leading to confusion Head injury leading to subdural haematoma and confusion Tumour
A 22-year old medical student comes to your GP practice with a several month history of low mood, early morning wakening and occasional suicidal thoughts. She says she has been very depressed since her best friend moved away and her long-term boyfriend separated from her. She has also been struggling with the pressures of exams. She does not feel particularly anxious but sees little joy in her life at present.
Past medical history: 2 bouts of depression in the last couple of years that she did not seek help for. No recreational drug use. Alcohol: 24 units a week recently, previously much less. Otherwise well and examination is unremarkable.
How will you assess the severity of her depression?
Ask about level of activities and functioning.
Ask about sleep, appetite, weight loss, guilt, symptoms of anhedonia (inability to experience pleasure), hopelessness, worthlessness, view of the future. Exclude any psychotic symptoms like delusions or hallucinations.
Ask about any suicidal ideas, plans or intent.
A 22-year old medical student comes to your GP practice with a several month history of low mood, early morning wakening and occasional suicidal thoughts. She says she has been very depressed since her best friend moved away and her long-term boyfriend separated from her. She has also been struggling with the pressures of exams. She does not feel particularly anxious but sees little joy in her life at present.
Past medical history: 2 bouts of depression in the last couple of years that she did not seek help for. No recreational drug use. Alcohol: 24 units a week recently, previously much less. Otherwise well and examination is unremarkable.
Outline a management plan based on current evidence based guidelines? Consider non- pharmacological options as well.
Advise to reduce alcohol intake Advise about stress management (EG reduce workload, exercise, postpone exam if needed). If moderate to severe symptoms can consider an SSRI (Selective serotonin reuptake inhibitor) as first line treatment, EG Sertraline 50mg OD. Consider CBT (Cognitive behavioural therapy)
A 22-year old medical student comes to your GP practice with a several month history of low mood, early morning wakening and occasional suicidal thoughts. She says she has been very depressed since her best friend moved away and her long-term boyfriend separated from her. She has also been struggling with the pressures of exams. She does not feel particularly anxious but sees little joy in her life at present.
Past medical history: 2 bouts of depression in the last couple of years that she did not seek help for. No recreational drug use. Alcohol: 24 units a week recently, previously much less. Otherwise well and examination is unremarkable.
What things do you need to discuss with the patient??
Advise to make follow up appointment in 2 weeks for review and make contact if DNA’s. Advise about possible side effects of dry mouth, nausea, diarrhoea, sexual dysfunction. Advise that can take 2 weeks to have an effect. Dose range can be adjusted up at next appointment in steps of 50mg per week upto 150mg and if goes on higher dose advise do not stop as would need to taper down as can have abrupt withdrawal effects – eg GI disturbance, sweating.
Advise about contact details for support if felt suicidal.
A 22-year old medical student comes to your GP practice with a several month history of low mood, early morning wakening and occasional suicidal thoughts. She says she has been very depressed since her best friend moved away and her long-term boyfriend separated from her. She has also been struggling with the pressures of exams. She does not feel particularly anxious but sees little joy in her life at present.
Past medical history: 2 bouts of depression in the last couple of years that she did not seek help for. No recreational drug use. Alcohol: 24 units a week recently, previously much less. Otherwise well and examination is unremarkable.
A few months later, she returns to say she has been feeling a lot happier. She does not know whether to continue with the medication or not.
What will you advise?
Consider continuing as had previous periods of depression, could review in 6 months to a year.
Outline the key severe toxicities of risperidone.
Risperidone – Dystonia due to excess dopamine D2 receptor blockade, sedation, hypotension prolongation of QT interval
A 29-year old man is admitted following an overdose of his medication. He has suffered a recent relapse in his schizophrenia with paranoid delusions and has been plagued by voices insisting he is the “devil” on Earth. His mother said in desperation he took all the tablets he had at home about 3 hours ago and locked himself in the bathroom. By the time the door was broken down he was very drowsy.
He is a chronic schizophrenic on the following medication:
Risperidone 4mg PO BD
Amitriptiline 75mg PO NOCTE
Temezepam 10 mg PO NOCTE as required
On arrival in the ED, he is unwell. He is maintaining his airway, has a respiratory rate of 10 per minute, pulse is 120 sinus rhythm and blood pressure 90/60. His Glasgow Coma Scale is 5.
Outline a management plan. Where relevant discuss specific therapies for each drug individually.
Assess and treat ABC as appropriate (Intubation and nasogastric tube) U&E’s, blood gases and ECG IV fluids for hypotension Call the National Poisons Information Service helpline
Risperidone - Supportive management as above
Amitriptyline – Sodium bicarbonate administration (plasma binding of Amitriptyline increases with more alkaline pH) and direct reduction of QRS prolongation by acting on myocardial contractility
Temazepam – Supportive management as above. Flumazenil (Benzodiazepine antagonist) could be considered but hazardous in mixed overdose such as this
Outline the key severe toxicities of Amitriptiline.
Amitriptyline – Cardiac toxicity by slowing of depolarisation by reducing influx of Na ions (prolonging QRS and PR/QT interval with the potential for arrhythmias), tachycardia (due to inhibition of noradrenaline reuptake and anticholinergic effects)
Treatment of overdose Amitriptyline – Sodium bicarbonate administration (plasma binding of Amitriptyline increases with more alkaline pH) and direct reduction of QRS prolongation by acting on myocardial contractility
Outline the key severe toxicities of Temazepam
Temazepam – Sedation and respiratory depression
Treatment of overdose with Temazepam – Supportive management as above. Flumazenil (Benzodiazepine antagonist) could be considered but hazardous in mixed overdose such as this
6 Key neurotransmission and neuromodulatory
systems important in psychiatry
- Noradrenergic Pathways
- Dopaminergic Pathways
- Serotonergic (5-HT) Pathways
- GABA-ergic Pathways
- Cholinergic Pathways
- Glutamate Pathways
Differentiate unipolar from bipolar affective disorders
Unipolar depression is where the mood swing is always in the same direction.
Bipolar affective disorder is characterised by depression and mania at different times in the course of the disease, and is considerably rarer.
Monoamine Hypothesis of Depression.
“Depression is caused by a reduction in monoamine neurotransmitters in the brain, and mania is due to an excess.”
This is a gross simplification but appears to have some pharmacological basis.
The biochemical changes of Monoamine medications take place immediately, but their therapeutic action may take several weeks to occur. This could be due to:
Changes in receptor expression and density
Altered balance of various neurotransmitter systems
Long term adaptive responses – altered gene expression, growth factors etc.
4 main classes of antidepressants
- Tricyclic Antidepressants (TCAs)
- Selective Serotonin Reuptake Inhibitors (SSRIs)
- Selective Serotonin / Noradrenaline Reuptake Inhibitors (SSNRIs)
- Monoamine Oxidase Inhibitors (MAOIs)
Why are SSRIs and SNRIs much more commonly used today than tricyclics and MAOIs?
Nowadays, the vast majority of (new) patients with depression are treated with SSRIs and SSNRIs because of their improved safety profiles. However,
there are still many people on TCAs both for depression and other indications. MAOIs are now rarely prescribed but are important because of their potential for serious drug-drug and drug-food interactions.
Positive Symptoms of Schizophrenia
Hallucinations, delusions, thought disorders,
abnormal behaviour
Negative Symptoms of Schizophrenia
Blunted affect, social withdrawal, poverty of
thought & speech
Cognitive Symptoms of Schizophrenia
Cognitive Symptoms: Selective attention, poor memory, reduced abstract thought
Affective Symptoms of Schizophrenia
Affective Symptoms: Anxiety & depression
Four main dopamine pathways in the CNS
Meso-limbic Pathways
Meso-corticol Pathways
Nigrostriatal Pathways
Tubero-hypophyseal System
Describe the functions associated with the Meso-limbic Dopamine Pathway
emotional response and behaviour, connect to the hippocampal and amygdala areas.
Describe the functions associated with the Meso-cortical Dopamine Pathway
arousal and mood.
Describe the functions associated with the Nigrostriatal Dopamine Pathway
75% of brain dopaminergic pathways.
Neurones span from the substantia nigra to the corpus striatum and is the key pathway damaged in Parkinson’s disease. Dopamine antagonism can thus induce “extra-pyramidal” movement disorders and are relevant to side effects of ant-psychotic drugs.
Describe the functions associated with the Tubero-hypophyseal Dopamine System
small pathways in the hypothalamus and pituitary gland.
Causes of psychosis other than schizophrenia
psychotic symptoms may occur as a result of many conditions (e.g. infections, recreational & other drugs, metabolic abnormalities, severe depression) and in the short term may require similar treatments. However,
these patients may or may not be schizophrenic!
Other examples of illnesses where there may be psychotic symptoms are: • mania • severe depression • organic syndromes • delusional disorder
Typical anti-psychotics: mechanism of side effects
Wide range of pharmacological action, dopamine
receptor blockade, anticholinergic effects, alphaadrenergic blockade, antihistamine effect,
generally older treatments that tend to
have increased dopamine (D2) antagonism producing extra-pyramidal side effects and tardive dyskinesia.
The GABA receptor has at least 3 significant sites of binding. List two
- GABA binding site
- Barbiturates and Alcohol binding site
- Benzodiazepines, agonists, antagonists and inverse agonists binding site
List 2 typical anti psychotics
chlorpromazine
flupentixol (depot)
haloperidol
List 2 atypical anti psychotics
risperidone
clozapine
olanzapine
Why is clozapine reserved for treatment resistant schizophrenia?
potential side effects and required monitoring - 1% agranulocytosis
Core symptoms of depression
Core Symptoms – show 2 of 3:
• Low mood
• Anhedonia
• Decreased energy
Secondary symptoms of depression
- Decreased appetite
- Sleep disturbance
- Hopelessness (Depressive Cognitions)
- Reduced concentration
- Irritability
- Self harm or suicidal ideas or acts
- Reduced libido
- Can have psychotic symptoms
More secondary symptoms, more severe disorder.
How do Monoamine oxidase inhibitors (MAOIs) work to treat depression?
Block the enzyme monoamine oxidase from destroying
neurotransmitters, thereby increasing presence of monoamines like serotonin and noradrenaline
Neurotransmitter Receptor
Hypothesis Theory of Depression
• An abnormality in the receptors for monoamine
transmission leads to depression
• Depletion of neurotransmitter
• causes compensatory up regulation of post
synaptic receptors - some post mortem evidence
The Monoamine
Hypothesis of Gene Expression (Theory of Depression)
• Deficiency in molecular functioning
• Hypothesised problem within the molecular
events distal to the receptor
List two reuptake inhibitors for depression
SNRI: Venlafaxine and Duloxetine
SSRI: Fluoxetine, citalopram, paroxetine, sertraline
What type of drug is fluoxetine?
Prozac antidepressant - SSRI
Common side effects of SSRIs
- Anorexia
- Nausea
- diarrhoea
Rare but important side effects of SSRIs
- precipitation of mania (if depression diagnosis wrongly given to bipolar)
- increased suicidal ideation
- neurological side effects such as serotonin syndrome
Give one example of a Tricyclic antidepressants (TCAs)
Amitryptiline, imipramine, clomipramine,
lofepramine
Why are tricyclics not used as first line treatment for depression?
high risk in overdose because it effects multiple pathways (sympathomimetic effects, anticholinergic effects, and sympatholytic effects)
used more often for sleep disturbance and chronic pain than depression
Effects of tricyclic antidepressants
- Inhibition of noradrenalin uptake, resulting in enhanced noradrenergic neurotransmission (sympathomimetic effect)
- Muscarinic cholinoceptor blockade- reduced
cholinergic neurotransmission (anticholinergic effect) - α1-adrenoceptor blockade- suppression of
noradrenergic neurotransmission (sympatholytic
effect)
Side effects and toxicity of tricyclic antidepressants
• CNS: sedation and impairment of psychomotor
performance, lowering of seizure threshold
• Autonomic nervous system: reduction in glandular
secretions, eye accommodation block
• CVS: tachycardia, postural hypotension, impair
myocardial contractility
• GI: constipation
Primarily sympathomimetics
Side effects and toxicity of SNRIs
• As with SSRIs
• Also sleep disturbance, increased BP (contraindicated in CVS patients), dry mouth, hyponatraemia
• Relatively short half-life therefore may be a
withdrawal syndrome on discontinuation.
Define Psychosis
• Psychosis causes people to perceive or interpret things
differently from those around them, they will have a
different perspective on reality
Define Hallucination
a perception in the absence of an external stimulus-auditory, olfactory, visual, gustatory, tactile.
Define delusion
a fixed false belief, not shaken by reasoning
to the contrary, that is out of keeping with someone’s
culture or religious beliefs
What is the difference between hallucinations and delusions?
• Hallucination- a perception in the absence of an
external stimulus-auditory, olfactory, visual,
gustatory, tactile.
• Delusion- a fixed false belief, not shaken by reasoning
to the contrary, that is out of keeping with someone’s
culture or religious beliefs
Diagnostic criteria for schizophrenia
One of:
oThought echo, insertion, withdrawal or broadcast
oDelusions of control or passivity; delusional perception
oRunning commentary or voices discussing the patient between themselves
oPersistent delusions
Or two of: oPersistent hallucinations in any modality oThought disorder oCatatonic behaviour oNegative symptoms • Negative symptoms
Cause of schizophrenia
• Multifactorial
• Neurodevelopmental disorder
oExcess of obstetric complications
oMotor and cognitive problems precede onset
oBrain abnormalities are present at first
presentation
- Gene environment interactions
- Cannabis
- Trauma
Dopamine Theory of Schizophrenia - what is the evidence for this?
schizophrenia results from excessive dopamine transmission in the mesolimbic pathway
• Amphetamine increases dopamine release and
causes symptoms very similar to positive symptoms
of schizophrenia
• Dopamine antagonists treat schizophrenia
• Some evidence of increased dopamine function in
schizophrenics
What are the limitations of the dopamine theory of schizophrenia?
• Dopamine antagonists do not treat negative
symptoms
• Changes in dopamine function may be a response to long term drug treatment
Use the main dopamine pathways to explain the major side effects of Dopamine Antagonists
D2 antagonists act on all 4 pathways. For schizophrenia treatment, aim is to target mesolimbic pathway - dramatic action on reduction of psychotic symptoms.
They also have off target effects:
Nigrostriatal pathway: extrapyramidal side effects and tardive dyskinesia
Mesocortical pathway: enhanced negative and cognitive psychotic symptoms
Tuberoinfundibular: hyperprolactinemia (lactation, infertility, sexual dysfunction)
Antagonism at which dopamine pathway results in extrapyramidal side effects and tardive dyskinesia?
Nigrostriatal pathway
Antagonism at which dopamine pathway results in enhanced negative and cognitive psychotic symptoms?
Mesocortical pathway:
Antagonism at which dopamine pathway results in hyperprolactinemia (lactation, infertility, sexual dysfunction) ?
Tuberoinfundibular dopamine systems
Evidence that schizophrenia is associated with
increased 5-HT function
• 5-HT has been implicated in a number of behaviours
which are disturbed in schizophrenia (e.g. perception,
attention, mood, aggression, sexual drive, appetite,
motor behaviour, sleep)
• Many of the most effective antipsychotic drugs are
antagonists at 5-HT-2A receptors. (Clozapine)
• Precursors of 5-HT (e.g. tryptophan) exacerbate
schizophrenia
Action of all antipsychotics
• Sedation- within hours
• Tranquilisation- within hours
• Antipsychotic- several days or weeks
• Production of extrapyramidal side effects- hours or
days. Much less with the atypical antipsychotics
• Longer term side effects include tardive dyskinesia
(typicals) and metabolic syndrome (atypicals)
Side effects and Toxicity of Typical anti-psychotics
• Extrapyramidal side-effects- Parkinsonism, acute
dystonia, akathasia, tardive dyskinesia
• Neuroleptic malignant syndrome- severe rigidity,
hyperthermia, increased CPK, autonomic lability
• Postural hypotension
• Weight gain
• Endocrine changes e.g. prolactinaemia
• Pigmentation
Why might viagra be prescribes alongside typical anti psychotics?
side effect of prolactinaemia - gynacomastia and erectile dysfunction
Atypical antipsychotics advantages
• Less EPSE side effects therefore more acceptable to
patient
• Different preparations e.g. dissolvable
• Some once daily dosage
• Differing side effect profiles can be matched to
patient characteristics
• First line treatment in schizophrenia now as
recommended by NICE
Side Effects of Atypical antipsychotics
• Vary between drugs • Can have extrapyramidal side effects at high doses • Weight gain- e.g. olanzapine • Increased prolactin e.g. risperidone • Sedation
Toxicity of Clozapine
• Requires regular blood tests due to risk of agranulocytosis • Central nervous system depression • Cardiac toxicity • Risk of sudden death with high dose
Benzodiazepines exert effects through which structure?
GABABDZ
receptor complex
• Benzodiazepines only bind to BDZ receptor of which
there are 2 main groups- high and low affinity
• High affinity group- important in anxiolytic, hypnotic
and anticonvulsant effects of BDZs
• Inhibitory effects in brain
Action of
benzodiazepines
• Act as full agonists at GABA receptor sites - Lead to enhancement of GABA
Differentiate between tolerance and dependence on benzodiazepines
• Tolerance can occur i.e. need to increase the dose to
achieve the same effect.
• Dependence-on discontinuation of treatment can get
withdrawal effects e.g insomnia, agitation, anxiety
Side effects of benzodiazepines
• Common- drowsiness, dizziness, psychomotor
impairment
• Occasional- dry mouth, blurred vision,
gastrointestinal upset, ataxia, headache, reduced
blood pressure
• Rare- amnesia, restlessness, rash
Toxicity of benzodiazepines
• ?cleft lip and palate if used in pregnancy
• If taken late in pregnancy may cause respiratory
depression and feeding difficulties in baby
Treatment of Benzodiazepine Overdose
• Deaths are rare – respiratory depression
• Support
• Flumazenil an antagonist/partial inverse agonist at
BDZ receptors may be useful in reversing effects
Symptoms of mania
o Feeling unusually excited, happy, optimistic or feeling
irritable
o Overactive
o Poor concentration and short attention span
o Poor sleep
o Rapid speech, jump from one idea to another
o Poor judgement (overspending)
o Increased interest in sex
o Psychotic symptoms- hallucinations, grandiose delusions
List 2 Mood stabilisers
- Lithium
- Sodium valproate
- Carbamazepine
- Lamotrigine
- Antipsychotics
Theories of why lithium treats bipolar
- Electrolytes and channels- may compete with
magnesium and calcium ions - Neurotransmitters - Li increases 5-HT, chronic Li may
reduce 5-HT receptor sites - Second messenger systems- lithium attenuates the
effects of certain neurotransmitters on their
receptors without altering receptor density
Side effects of lithium
- Memory problems- 52%
- Thirst- 42%
- Polyuria-38%
- Tremor- 34%
- Drowsiness-24%
- Weight gain- 18%
- Effect on kidneys
- Endocrine changes- hypothyroidism
- Hair loss
- Rashes
Your patient has a history of bipolar disorder and is treated with lithium. The patients call to make an appointment to discuss a tremor they have developed. What is the significance of the type of tremor?
fine tremor - lithium side effect
coarse tremor - lithium toxicity, medical emergency
Toxic effects of lithium
- Need to monitor blood levels closely
- Vomiting
- Diarrhoea
- Coarse tremor
- Dysarthria
- Cognitive impairment
- Restlessness
- Agitation
Treatment of Lithium Toxicity
- Supportive measures
- Anticonvulsants
- Increase fluid intake / IV Fluids etc
- Haemodialysis may be necessary
Two categories of dementia medication
Acetylcholinesterase Inhibitors, e.g.
o Donepezil
o Galantamine
o Rivastigmine
NMDA antagonist e.g. Memantine
Acetylcholinesterase Inhibitors (AchE-I) in dementia
Acetylcholine plays a role in arousal, memory, attention and
mood.
Slows down progression of Alzheimers Disease
Side effects of Acetylcholinesterase Inhibitors (AchE-I)
o Nausea, vomiting, anorexia, diarrhoea o Fatigue insomnia, headache o Bradycardia o Worsening of COPD o Gastric/duodenal ulcers
Memantine for dementia: mechanism and side effects
NMDA antagonist used in treatment of dementia
• Licensed for moderate to severe dementia
• Usually well tolerated
• Common side effects include: hypertension,
dyspnoea, headache, dizziness, drowsiness
How might you treatment overdose with Amitriptyline?
Toxicity – Cardiac toxicity by slowing of depolarisation by reducing influx of Na ions (prolonging QRS and PR/QT interval with the potential for arrhythmias), tachycardia (due to inhibition of noradrenaline reuptake and anticholinergic effects)
Treatment of overdose Amitriptyline – Sodium bicarbonate administration (plasma binding of Amitriptyline increases with more alkaline pH) and direct reduction of QRS prolongation by acting on myocardial contractility
How might you treatment overdose with ?
Temazepam – Sedation and respiratory depression
Treatment of overdose with Temazepam – Supportive management as above. Flumazenil (Benzodiazepine antagonist) could be considered but hazardous in mixed overdose such as this
