Psychopharmacology Flashcards
What two classes can mental illness be differentiated into?
Psychosis
Neurosis
Characteristics of psychosis
Less common but more serious
Characterised by a radical loss of touch with reality
The patient has no insight into their problem
Characteristic of neurosis
Common mental health problems
Severe forms of normal emotional experiences like depression, anxiety or panic
What are hallucinations?
When someone sees, hears, smells, tastes or feels things that don’t exist outside their mind
What are delusions?
A person has an unshakeable belief in something untrue which cannot be explained by cultural beliefs
Can be persecutory or grandiose
What can the symptoms of psychosis be split into?
Positive - change in behaviour or thoughts; hallucinations or delusions
Negative - withdrawal of lack of social function; reduction in speech or social withdrawal
What are the causes of psychosis?
Psychological causes
General medical causes
Drug induced
Historical methods of treating psychosis
Shock therapy
Psychosurgery
Fever therapy to treat neurosyphilis
Insulin induced coma and convulsion
Electroconvulsive shock therapy
When was the birth of psychopharmacology?
1950s
Describe the development of the first anti-psychotic drug
Promethazine was an anti-histamine causing sedation
Scientists argued that modifying this drug would remove its effect on sedation, but would make positive symptoms decrease since patients were less sensitive to external stimuli
How was Promethazine modified to test its effect as an anti-psychotic?
Chemically altered through addition of chlorine
Make Chlorpromazine
Was Chlorpromazine successful?
Yes
Induced a different type of sedation that made patients less reactive to external stimuli
Decreasing hallucinations and delusions
What is Chlorpromazine an example of?
Class I, typical antipsychotic
Mechanism of action of Chlorpromazine
Binds to dopamine 2 receptor
Blocks dopamine - dopamine antagonist
Causing a sedative-like effect on patients
What is something about the mechanism of action of Chlorpromazine the clinicians did not notice?
Promethazine causes sedation through acting on the histamine 1 receptor
When modifying this compound, the target receptor was also changed
Chlorpromazine was shown to act through the D2 receptor
Describe the dopaminergic hypothesis of psychosis
Hypothesis that believes that dopamine causes psychosis
What are the two main factors relating dopamine to psychosis?
Dopamine antagonists reduce signs and symptoms of psychosis
Drugs that enhance the release of dopamine in the brain can induce hallucination
Example of a drug that induces release of dopamine in the brain
Amphetamine
What did the dopamine hypothesis of psychosis lead to?
The development of receptor antagonists for treatment of psychosis
Especially D2 receptor antagonists
Chlorpromazine, Haloperidol
What is the problem with targeting dopamine as a therapy for psychosis?
Dopamine has actions on a lot of different neural pathways
What are the brain’s main dopaminergic pathways?
Mesolimbic: hyperactive in schizophrenia, leads to the positive symptoms
Mesocortical: hypoactive in schizophrenia, leads to the negative symptoms
Nigrostriatal pathway: extrapyramidal motor control
Hypothalamus-pituitary pathway: hypothalamus inhibits prolactin through dopamine release
What dopaminergic pathway do you want to target in psychosis?
Mesolimbic pathway
Components of the mesolimbic pathway
Dopaminergic neuron originates in the substantia nigra and synapses on the nucleus accumbens
Are dopamine antagonist effects used for psychosis therapy limited to target the mesolimbic pathway?
No
Their effects on other brain pathways lead to unwanted side-effects
What are the non-neurological effects of dopamine antagonists?
Increased prolactin with consequent breast swelling and galactorrhea
Through blockage of the dopaminergic tuberoinfundibular pathway
What are the extrapyramidal effects of dopamine antagonists?
Motor symptoms:
- tremor
- rigidity
- dystonia
- tardive dyskinesia
Ways to control the motor symptoms of dopamine antagonists
The balance between cholinergic and dopamine transmission is important in the extrapyramidal system
Increased acetylcholine in relation to dopamine further worsens the motor side-effect presentation of D2 antagonists
Anticholinergic drugs can reduce the extrapyramidal side effects of D2 antagonists
D2 antagonists have a significant effect on negative symptoms of schizophrenia
TRUE or FALSE
FALSE
D2 antagonists have no significant effect of negative symptoms
Drugs targeting the negative symptoms of psychosis
Second generation of antipsychotics
Atypical antipsychotics
Antagonise the 5HT2A receptors
Example of atypical antipsychotics
Olanzapine
Risperidone
Clozapine
Mechanism of action of Clozapine
5HT2A antagonist
No extrapyrimidal effect
Cause of schizophrenia
No clear cause
There is a significant genetic component (10-15% of first-degree relatives share the condition)
What do PET scans of schizophrenics show?
Increased D2 receptors in the nucleus accumbens
Apart from the negative effects of dopamine blockade in the mesolimbic and hypothalamic axes, what neurological side-effects result from blocking the nigrostriatal pathway?
Apathy
Depression
Decreased initiative
Which separate receptors do antipsychotic drugs have effects on?
a-adrenoceptors: hypotension
Muscarinic receptors: urinary retention
H1 receptors: sedation
5-HT receptors: weight gain
Why do antipsychotic drugs have effects on many receptors?
Because their structure targets lots of receptors
What are typical antipsychotics?
Those that inhibit the D2 receptors
Aim to control the positive symptoms
What are atypical antipsychotics?
Those that target the D2 and 5HT2A receptors
Negative symptoms
Why do atypical antipshycotics have less of extrapyramidal effects?
5HT2A inhibits the release of dopamine in parts of the brain that need the neurotransmitter
Inhibiting 5HT2A therefore increases the concentration of dopamine at this site
Drugs which block both 5HT2A and D2 therefore cause less side-effects
Importance of neurosis
Not as serious as psychosis, but has a high social cost due to its prevalence
Why are emotions important in humans?
Represents an important mechanism that makes sure we make correct decisions
What are the two main types of neurosis?
Mod disorders
Anxiety disorders
What is the treatment of neurosis conditions?
Support is the first and main treatment
Pharmacological approaches are second line
What two categories can anxiety disorders be split into?
Specific
Generalised
What are the two types of symptoms of anxiety?
Psychological symptoms
Physical symptoms
Subtypes of specific anxiety disorder
Phobia - patient is fearful of a specific thing
Panic disorder - patient is fearful of death
OCD - patient believes something will happen if they don’t perform a specific task
PTSD - experiences of a severe condition causes false memories leading to stress
What is generalised anxiety disorder?
Not related to a specific fear
Associated with insomnia
What part of the brain is associated with fear?
Fear stems from the amygdala
Hyperactivated in fear
How can the amygdala be targeted in anxiety?
Inhibition of hyperactivation of the amygdala through hyperpolarisation of the cell
Hyperpolarisation achieved through opening of chloride channels
Drug targeting chloride channels of the amygdala
Benzodiazepine
Mechanism of action of Benzodiazepine
Cholinergic GABA channels cause cell hyperpolarisation
Benzodiazepines bind on a separate receptor next to the GABA binding site to increase the affinity of GABAa for its receptor
Other drugs separate to benzodiazepines also causing anxiolytic effects
Serotonin agonists
B-adrenoceptor antagonists
Antihistamines
Barbituates
Which serotonin receptors are targeted in anxiety?
5-HT1a
Where do 5HT1a receptors occur in the brain?
Cerebral cortex
Amygdala
Nature of 5-HT1a receptors
Auto-inhibitory
Result in decreased firing
How are serotonin receptors targeted in anxiety?
5-HT1a agonists
Activate the presynaptic serotonin receptors
Particularly in the dorsal raphe nucleus of the midbrain
How do b-adrenoceptor antagonists help in anxiety?
Reduce some of the peripheral manifestations of anxiety
Mechanism of action of barbituates
Increase channel opening of GABAa beyond that seen with GABA istelf
Use of Barbituates
Clinical use has been severely restricted due to their low TI and dependence
Still used in anaesthesia and epilepsy
What are hypnotics?
Drugs used to treat insomnia
Link between anxiety and insomnia
Both can be treated with CNS depressants
Both can be treated using the same drugs in different concentrations
Disadvantage of benzodiazepines
Due to brain plasticity, tolerance to benzodiazepines develops quickly
Withdrawal from drug leads to worsening symptoms due to the compensatory mechanisms
When are benzodiazepines used?
Short term conditions
- pre-surgery anxiety
- grief reaction
- epilepsy
What is the best therapy for anxiety patients?
Cognitive behaviour therapy
What are the two types of mood disorders?
Unipolar depression
Bipolar depression
Characteristics of depression
Low mood
No pleasure, appetite or sexual drive
Longer than 2 months
Subtypes of depression
Seasonal depression - related to season
Postpartum depression
Endogenous depression - nothing is wrong, but don’t know why
Neurological basis behind depression
Poorly understood
Monoamine theory explains that depression is caused by a functional deficit of noradrenaline and 5-HT in the forebrain
Evidence backing the monamine theory of depression
Inhibition of NA or 5-HT reuptake improves mood
Inhibition of MAO improves mood
Drugs which deplete monoamine stores cause depression
Evidence against the monamine theory of depression
Some drugs have antidepressant effect without affecting NA/5-HT transmission
There is a 2-4 week delay in the clinical action of antidepressants despite immediate effects on neurotransmission
Which part of the brain contains serotonin receptors important for mood?
Raphe nucleus
What are the 3 main types of antidepressants?
Those that inhibit the reuptake of monoamines
MAO inhibitors
Atypical
Targets for preventing the uptake of serotonin
Uptake 1 transporter
Selective serotonin transporter
Targets for preventing the uptake of noradrenaline
Uptake 1 transporter
Drugs that target the uptake 1 transporter
Tricyclic antidepressants
Drugs that target the selective serotonin transporters
Selective serotonin receptor inhibitors
What is the advantage of SSRIs over TCADs?
SSRIs specifically target serotonin
Not many side-effects, whereas people can overdose on TCADs
Also works for anxiety disorders
Less side-effects due to fewer effects on off-target receptors
What is the goal of drugs inhibiting the reuptake of serotonin and noradrenaline?
Increases the concentration of these transmitters in the synaptic cleft
Increases stimulation of postsynaptic transmission
What is the goal of MAO inhibitors?
Increase the concentration of serotonin and noradrenaline in the synaptic cleft
Through oxidation
What is the major side-effect of MAO inhibitors?
Cheese reaction
Explain what is meant by the cheese reaction
Tyramine is a naturally occuring amine which causes hypertension
The liver contains a lot of MAO to destroy tyramine
When taking MAO inhibitors, this is inhibited too
Patients with MAO inhibitors cannot consume wine or cheese, because they will develop hypertension
What is the difference between older and newer MAO inhbitors?
Older MAOIs bind covalently and therefore have a longer duration of action
Newer MAOIs are more selective to MAO-A and therefore have fewer side effects
What are atypical antidepressants?
Combine actions of MAOIs and reuptake inhibitors
Less well characterised mechanism of action
What is the main drug used to treat bipolar depression?
Lithium
Prophylaxis
Describe the discovery of lithium chloride as a therapy for bipolar depression
Hypertension was a big issue in the mid-1900s
Scientists wanted to replace salt with Lithium Chloride
They noticed that upon consumption, people looked seemed relaxed
They tried to see its effect on bipolar through an injection
This was shown to be effective at reducing episodes of mania
Mechanism of action of lithium chloride
Inhibits the formation of IP3
Modifies the membrane potential an ionic balance
Why must administration of lithium chloride be carefully controlled?
Patients can overdose
Increased incidence of diabetes in individuals
Examples of psychomotor stimulants
Amphetamines
MDMA
Cocaine
Mechanisms of action of amphetamines and cocaine
Raise the synaptic concentrations of NA, DA and 5-HT
Through:
- stimulation of release into synaptic cleft
- inhibition of neuronal uptake
- inhibition of MAO
- inhibition of vesicular uptake
Actions of amphetamines and cocaine
Euphoria
Elation
Improved concentration
Appetite suppression
Inhibition of REM sleep
Are the physical withdrawal symptoms of cocaine and amphetamines pronounced?
No
What pathway is particularly involved in the action of amphetamines and cocaine
Dopamine pathways
Mechanisms of action of methylxanthines
Inhibits PDE, increasing the concentration of cAMP
Potentiates responses mediated by b-adrenoceptors and D1 receptors
What causes the behavioural effects of methylxanthines?
Antagonism on adenosine receptors
What is a unique feature of caffeine?
On top of inhibiting PDE, it also enhances release of NTs by blocking presynaptic receptors
Uses of methylxanthines
Asthma
