Drugs in Psychiatric Disease Flashcards
1
Q
How were virtually all effective psychopharmacological drugs discovered?
A
- Good luck
- Empiricism
- Probing disease mechanisms with drug of known action, but no prior proof that such actions would be necessarily be therapeutic
2
Q
What effect do psychiatic drugs have on the CNS?
A
- They act as stimulators (agonists) or blockers (antagonists) of neurotransmitter receptors
- Some drugs might compete with the neurotransmitter for its own binding site, attempting to mimic the neurotransmitter
- Less commonly, act as inhibitors of regulatory enzymes
3
Q
What enzymes are most important in the neurotransmitter processes?
A
Those that make or destroy neurotransmitters
4
Q
What are the key transmission and modulatory pathways in the CNS?
A
- Noradrenergic pathways
- Dopaminergic pathways
- Serotonergic pathways
- GABA-nergic pathways
- Cholinergic pathways
- Glutamate pathways
5
Q
What might cause psychiatric disease?
A
- Genetic vulnerability to expression of the disease
- Life events, e.g. divorce, bereavement
- Individuals personality, coping skills, social support
- Other environmental influences, e.g. viruses, toxins, other diseases
6
Q
What are the core symptoms of depression?
A
2 or 3 of;
- Low mood
- Anhedonia
- Decreased energy
7
Q
What are the secondary symptoms of depression?
A
- Decreased appetite
- Sleep disturbance
- Physical aches and pains
- Irritability
- Self harm or suicidal ideas or acts
- Can have psychotic symptoms
8
Q
What psychotic symptoms might a person with depression have?
A
- Delusions of persecution
- Auditory hallucinations
9
Q
What is the monoamine theory of depression?
A
Depression is due to a deficiency of monoamine neurotransmitters (noradrenaline and serotonin)
10
Q
Give an example of a drug that can cause a deficiency of noradrenaline and serotonin
A
Reserpine
11
Q
How do monoamine oxidase inhibitors work?
A
It blocks the enzyme monoamine oxidase from destroying neurotransmitters
12
Q
What is the neurotransmitter receptor hypothesis of depression?
A
An abnormality in the receptors for monoamine transmission leads to depression
13
Q
What can cause an abnormality in the receptors for monoamine transmission?
A
Depletion of the neurotransmitter causes compensatory up-regulation of post-synpatic receptors
14
Q
What provides evidence for the neurotransmitter receptor hypothesis?
A
Some post-mortem evidence
15
Q
What is the problem with the monoamine hypothesis and the neurotransmitter receptor hypothesis of depression?
A
- There is no clear and convincing evidence that monoamine deficiency accounts for depression, or that receptor change accounts for depression
- There is growing evidence that despite apparently normally levels of monoamines and receptors, these systems do not respond normally
16
Q
What is the monoamine hypothesis of gene expression?
A
A hypothesised problem within the molecular events distal to the receptor, leading to deficiency in molecular functioning
17
Q
What are the classes of antidepressants?
A
- Monoamine oxidase inhibitors
- Monoamine uptake inhibitors
- Other drugs, e.g. mirtazepine
18
Q
What are the categories of monoamine uptake inhibitors?
A
- Non-selective noradrenaline and serotonin
- Selective noradrenaline or serotonin
19
Q
What are the categories of non-selective noradrenaline and serotonin monoamine uptake inhibitors?
A
- TCAs - have additional actions
- SNRIs - pure
20
Q
What are the categories of selective noradrenaline or serotonin monoamine uptake inhibitors?
A
- Serotonin specific (SSRIs)
- Noradrenaline specific (NARIs)
21
Q
What are SSRIs used for?
A
Treatment of moderate to severe depression
22
Q
When do SSRIs work best?
A
When combined with psychological therapy, e.g. CBT
23
Q
Give 4 examples of SSRIs
A
- Fluoxetine
- Citalopram
- Paroxetine
- Sertraline
24
Q
What is the most selective SSRI?
A
Citalopram
25
Which SSRI is the most potent reuptake inhibitor?
Paroxetine
26
What system might SSRIs interact with?
The extrapyramidal dopaminergic system
27
What do SSRIs cause on a molecular level?
More serotonin in the synpatic cleft
28
How are SSRIs absorbed?
Almost completely absorbed from the gut
29
Do SSRIs have a long or short half life?
Long
30
What is the result of the long half lives of SSRIs?
Allows for once daily dosage
31
How are SSRIs metabolised?
By the liver
32
What are the common side effects of SSRIs?
* Anorexia
* Nausea
* Diarrhoea
33
What are the rare side effects of SSRIs?
* Precipitation of mania
* Possible increased suicidal ideation
* Neurological side effects such as tremor
* Extrapyramidal syndromes
34
Why is it a benefit that SSRIs are reasonably safe in overdose, *if taken on their own*?
Because you are giving to a population that is at high risk of overdose
35
What effect do SSRIs have on the QT interval?
Prolong it
36
What must be done due to QT prolongation on SSRIs?
Investigate when starting, and once annually
37
How has the use of tricyclic antidepressants changed over time?
They were the first generation of antidepressants, and are still used now, but not as often and no longer first line
38
Give 4 examples of TCAs
* Amitryptiline
* Imipramine
* Clomipramine
* Lofepramine
39
Other than inhibiting serotonin reuptake, what effects can SSRIs have?
* Sympathomimetic mimetic effects
* Anticholinergic effect
* Sympatholytic effect
40
What sympathomimetic effect can TCAs have?
Inhibition of noradrenaline uptake, resulting in enhanced noradrenergic neurotransmission
41
What anti-cholinergic effect can TCAs SSRIs have?
Cause muscarinic cholinoceptor blockage leading to reduce cholinergic neurotransmission
42
What sympatholytic effect can TCAs have?
Alpha-1 adrenoceptor blockade suppression of noradrenergic neurotransmission
43
What are TCAs soluble in?
Lipid
44
Where are TCAs absorbed?
Gut
45
Do TCAs have long or short half lives?
Long
46
Where are TCAs metabolised?
In the liver
47
What are the CNS side effects of TCAs?
* Sedation
* Impairment of psychomotor performance
* Lowering of seizure threshold
48
What are the autonomic nervous system side effects of TCAs?
* Reduction in glandular secretions
* Eye accommodation block
49
What are the CVS side effects of TCAs?
* Tachycardia
* Postural hypotension
* Impair myocardial contractility
50
What are the GI side effects of TCAs?
Constipation
51
What were 'pure' non-selective monoamine uptake inhibitors (SNRIs) developed as?
SSRIs, but with the additional property of noradrenaline uptake inhibition
52
Give two examples of SNRIs?
* Venlafaxine
* Duloxetine
53
Where are SNRIs used?
As a second line drug, *when SSRIs haven't worked*
54
What are the side effects of SNRIs?
Same as with SSRIs, but also with sleep disturbance, increased BP, dry mouth, and hyponatraemia
55
How might hyponatraemia caused by SNRIs manifest?
As drowsiness, or in extremes, affect consciousness or cause seizures
56
Does SNRIs have a long or short half life?
Short
57
What is the result of SNRIs having a short half life?
May be a withdrawal syndrome on discontinuation
58
What symptoms might be experienced in SNRI withdrawal?
* Nausea
* Vomiting
* Electric shock like sensation
59
Give 7 examples of conditions that might have psychosis as a symptom?
* Schizophrenia
* Mania
* Severe depression with psychosis
* Organic syndromes
* Delusional disorder
* Delerium
* Dementia
60
What are the symptoms of schizophrenia?
* Disturbances of thinking
* Hallucinations
* Delusions
* Behavioural changes
* Lack of insight
* Negative symptoms
61
What is a hallucination?
A perception in the absense of an external stimulus
62
What can a hallucination be?
* Auditory
* Olfactory
* Visual
* Gustatory
* Tactile
63
What is a delusion?
A fixed false belief that is out of keeping with someone's culture or religious belief
64
What factors influence the development of schizophrenia?
* Genetic
* Biological
* Upbringing
65
What is the evidence for the dopamine theory of schizophrenia?
* Amphetamine causes symptoms very similar to positive symptoms of schizophrenia
* Dopamine antagonists are the best treatment for schizophrenia
* Some evidence of increased dopamine function in schizophrenic
66
What evidence is there against the dopamine theory of schizophrenia?
* Amphetamine does not cause negative symptoms
* Dopamine antagonists do not treat negative symptoms
* Changes in dopamine function may be a response to long term drug treatment
67
What are the main dopamine pathways?
* Mesolimbic
* Meso-cortical
* Nigrostriatal
* Tuber-hypophyseal
68
What is the mesolimbic pathway involved in?
Emotional response and behaviour
69
What is the meso-cortical pathway important in?
Arousal and mood
70
How is the nigrostriatal pathway clinically important?
It is the key pathway damaged in Parkinson's disease
71
Where is the tuber-hypophyseal pathway found?
In the hypothalamus and pituitary gland
72
What happens if you block dopamine receptors in the nigrostriatal pathway?
* Extrapyramidal side effects
* Tardive dyskinesia
73
What happens when you block the dopamine receptors in the mesocortical pathway?
Enhanced negative and cognitive psychotic symptoms
74
What happens when you block dopamine receptors in the mesolimbic pathway?
Dramatic therapeutic action on positive psychotic symptoms
75
What happens when you block dopamine receptors in the tuber-hypophyseal pathway?
Hyperprolactinaemia, *causing lactation, infertility, sexual dysfunction*
76
Why is sexual dysfunction caused by blockage of the tuber-hypophyseal pathway clinically important?
It is an important source of non-compliance, and patients struggle to talk about it
77
What is the evidence that schizophrenia is associated with increased 5-HT function?
* Implicated in a number of behaviours which are disturbed in schizophrenia
* Many of the most effective anti-psychotic drugs are antagonists of 5HT-2A receptors
* Precursors of 5HT, *e.g. tryptophan* exacerbate schizophrenia
78
What is the predominant excitatory neurotransmitter in the brain?
Glutamate
79
What is phencyclidine (PCP)?
A non-competitive antagonist at NMDA-type glutamate receptors
80
What does PCP use induce?
Symptoms very similar to schizophrenia
81
What have post-mortem studies found in schizophrenia patients, regarding cortical glutamate function?
* Increased cortical glutamate receptors
* Increased binding of glutamate receptor ligands in cortex, basal ganglia, and hippocampal formation
82
What is the clinical limitation of the glutamate system in schizophrenia?
The mechanism is unclear, and we have not been able to develop a treatment that has a direct action on the glutamate system
83
What are the categories of drugs used in schizophrenia?
* First generation or typical antipsychotics
* Atypical antipsychotics
* Clozapine
84
Give two examples of first generation or typical antipsychotics
* Haloperidal
* Chlorpromazine
85
Give three examples of atypical antipsychotics
* Olanzapine
* Risperidone
* Quetiapine
86
What is the advantage of depot preparations of anti-psychotics?
* Good in non-compliance, as don't have to worry about taking tablets
* Can sometimes be done against consent
87
What actions do all anti-psychotics have?
* Sedation
* Tranquilisation
* Antipsychotic
88
How quick is the onset of the sedative action of anti-psychotics?
Can be within hours
89
How quick is the onset of the tranquilisation action of antipsychotics?
Within hours
90
How quick is the onset of the antipsychotic action of antipsychotics?
Several days or weeks
91
What are the adverse effects of antipsychotics?
Extrapyramidal side effects
92
How long does the production of extrapyramidal side effects with antipsychotics take?
Hours or days, *much less with the atypical antipsychotics*
93
What are the advantages of atypical antipsychotics?
* Less extra-pyramidal side effects, therefore more acceptable to patient
* Different preparations available
* Sometimes, once daily dosage
94
What can be done clinically due to the differing side effect profiles of atypical antipsychotics?
Can match side effect profile to patient characteristics
95
What is the first line treatment in schizophrenia, as recommended by NICE?
Atypical antipsychotics
96
What are the side effects of atypical antipsychotics?
*Varys between drugs*
* Can have extrapyramidal side effects at high doses
* Weight gain
* Increased prolactin
* Sedation
97
What antipsychotic is safe in emergencies?
Haloperidol
98
Why is haloperidol good in emergencies?
* More sedative action than other antipsychotics
* Well known side effects
99
What are the pharmacological actions of typical antipsychotics?
* Dopamine receptor blockade
* Anticholinergic effects
* Alpha-adrenergic blockage
* Antihistamine effect
100
What is the problem with the antihistamine action of antipsychotics?
Histamine receptors are important in regulation of appetite, so if you give an antihistamine, you get increased appetite
101
What is the most effective typical antipsychotic in schizophrenia?
Clozapine
102
Why is clozapine only a 3rd line treatment for schizophrenia?
Due to severe side effects, including neutropenia, severe (potentially fatal) constipation, and weight gain
103
What are the side effects of typical antipsychotics?
* Extrapyramidal side effects
* Neuroleptic malignant syndrome
* Postural hypotension
* Weight gain
* Endocrine changes
* Pigmentation
104
What extra-pyramidal side effects can be caused by typical antipsychotics?
* Parkinsonism
* Acute dystonia
* Akathasia
* Tardive dyskinesia
105
What are the symptoms of neuroleptic malignant syndrome?
* Severe rigidity
* Hyperthermia
* Increased CPK
* Autonomic lability
106
How should neuroleptic malignant syndrome?
* Withdraw anti-psychotics
* Treatment of short term symptoms
* Trial anti-psychotic with low propensity for causing it
107
What toxicity can typical anti-psychotics cause?
* Central nervous system depression
* Cardiac toxicity
* *Risk of sudden death with high dose*
108
What monitoring would be done with typical antipsychotics?
* ECG
* Metabolic monitoring
* Weekly blood tests
109
What metabolic monitoring is required with typical antipsychotics?
* Glucose and HbA1c
* Lipid profile
110
Why is glucose monitoring required with typical antipsychotics?
Because they increase the risk of diabetes
111
What antipsychotic in particular requires weekly blood tests?
Clozapine
112
Why are weekly blood tests required with clozapine?
Because it can cause agranulocytosis
113
What are the characteristics of anxiety disorders?
* Fear out of proportion to the situation
* Avoidance
* Fear of dying
* Physical symptoms
114
What physical symptoms are associated with anxiety disorders?
* Light headedness
* Shortness of breath
* Hot and cold flushes
* Nausea
* Palpitations
* Numbness
Pins and needles
115
How is anxiety treated?
* Non-pharmacological approaches, *such as CBT,* are first line
* Treat any co-existent disorder
* Pharmacological treatment - antidepressants, anxiolytics, occassionally antipsychotics
116
What are the principle neurotransmitters involved in anxiety?
* GABA
* Serotonin
* Noradrenaline
117
Give two examples of benzodiazepines
* Diazepam
* Lorazepam
118
How do benzodiazepines exert their effects?
It exerts its effects through a structure known as the GABA-BDZ receptor complex
119
What are the main groups of BDZ receptors?
High and low affinity
120
How are the high affinity BDZ receptors clinically important?
They are important in the anxiolytic, hypnotic, and anticonvulsant effects of benzodiazepines
121
Do benzodiazepines have a stimulatory or inhibitory effect in the brain?
Inhibitory
122
What happens when benzodiazepines bind to BDZ receptors?
They act as full agonists at these receptor sites, and lead to enhancement of GABA
123
What is the bioavailability of benzodiazepines following oral administration?
Almost 100%
124
How long following oral administration of benzodiazepines does it take to get maximum concentrations?
30-90 minutes
125
Describe the lipid solubility of benzodiazepines
Highly lipid soluble
126
What is the result of the high lipid solubility of benzodiazepines?
CNS diffusion is rapid
127
How are benzodiazepines eliminated from the body?
Renal excretion
128
Do benzodiazepines have a long or short half life?
Long
129
Can tolerance to benzodiazepines occur?
Yes, *need to increase the dose to achieve the same effect*
130
What is the problem with benzodiazepine tolerance?
Can lead to self medication with similar drugs, e.g. alcohol
131
Can you get benzodiazepine dependance?
Yes
132
What may happen on discontinuation of benzodiazepines?
Can get withdrawal effects, *e.g. insomnia, agitation, anxiety*
133
What are the common side effects of benzodiazepines?
* Drowsiness
* Dizziness
* Psychomotor impairment
134
What are the occassional side effects of benzodiazepines?
* Dry mouth
* Blurred vision
* Gastrointestinal upset
* Ataxia
* Headache
* Reduced blood pressure
135
What are the rare side effects of benzodiazepines?
* Amnesia
* Restlessness
* Rash
136
What are the teratogenic effects of benzodiazepine?
* Cleft lip and palate if used in pregnancy
* If taken late in pregnancy, may cause respiratory depression and feeding difficulties in the baby
137
What causes death in benzodiazepine overdose?
Respiratory depression
138
How are benzodiazepine overdoses treated?
* Support
* Flumazenil
139
What is flumazenil?
An agonist/partial inverse agonist at BDZ receptors
140
What is bipolar disorder?
Cycling between depression and hypomania/mania
141
What are the characteristics of mania?
* Feeling unusually excited, happy, optimistic, or feeling irritable
* Overactive
* Poor concentration or short attention span
* Poor sleep
* Rapid speech, jump from one idea to another
* Poor judgement
* Increased sex drive
* Psychotic symptoms *such as hallucinations and grandiose delusions*
142
What drugs are used as mood stabilisers?
* Lithium
* Sodium valproate
* Carbamazepine
* Lamotrigine
* Antipsychotics
143
What theories are there of the mechanism of action of lithium?
* May complete with magnesium and calcium ions for channels
* May increase serotonin, but chronic use may reduce serotonin receptors
* Attenuates the effects of certain neurotransmitters on their receptors, without altering receptor density
144
How is lithium eliminated from the body?
Renal excretion
145
What allows lithium to be given once daily?
Slow release preparation
146
How often do lithium levels need to be monitored?
At least 3 monthly
147
Why do lithium levels need to be monitored?
Narrow therapeutic window
148
What needs to be checked in patients on lithium?
* Renal function
* Thyroid function
149
When do renal and thyroid function need to be checked in patients on lithium?
After starting, and every 6 months, *unless concerned, and then more frequently*
150
What are the uses of lithium?
* Prophylaxis of mania and depression in bipolar disorder
* Augmentation of antidepressants in unipolar depression
* Reducing suicidality
151
What are the side effects of lithium?
* Memory problems
* Thirst
* Polyuria
* Tremor
* Drowsiness
* Weight gain
* Hypothyroidism
* Hair loss
* Rashes
152
What are the toxic effects of lithium?
* Vomiting
* Diarrhoea
* Coarse tremor
* Dysarthria
* Cognitive impairment
* Restlessness
* Agitation
153
How is lithium toxicity treated?
* Supportive measures
* Anticonvulsants
* Increase fluid intake
* Haemodialysis may be necessary
154
What are the categories of drugs used in dementia?
* Acetylcholine esterase inhibitors (AChE-I)
* NMDA antagonists
155
Give three examples of AChE-I inhibitors
* Donepezil
* Galantamine
* Rivastigmine
156
Give an example of a NMDA antagonist
Memantine
157
What cognitive functions does ACh play a role in?
* Arousal
* Memory
* Attention
* Mood
158
What does NICE recommend regarding the use of AChE-I in dementia?
The medication should be available for mild and moderate dementia
159
What effect do AChE-I have on Alzheimers disease?
Slows progression
160
What are the important side effects of AChE-I?
* Nausea and vomiting
* Anorexia
* Diarrhoea
* Fatigue and insomnia
* Headache
* Bradycardia
* Worsening of COPD
* Gastric/duodenal ulcers
161
What is memantine licensed for?
Moderate to severe dementia
162
Is memantine usually well tolerated?
Yes
163
What are the common side effects of memantine?
* Hypertension
* Dyspnoea
* Headache
* Dizziness
* Drowsiness
