HNS51 Anti-psychotics Flashcards
Antidepressants vs Antipsychotics
NOT interchangeable
Depressive disorders: ↓ NT level
Psychosis: ↑ Dopamine level (or ↑ D2 receptors)
Antidepressant: treat depressive disorder, elevate mood
Antipsychotics: manage psychosis (E.g. Schizophrenia, Bipolar disorder) (delusions, hallucinations, disordered thoughts)
—> Block dopamine action (reward-driven learning)
Psychosis
Mental health problem —> stop person from thinking clearly, telling difference between reality and their imagination and acting in a normal way
- NOT a disease
- Spectrum of symptoms
Symptoms of Psychosis
- Hallucinations (幻覺)
- perceive something not exist in reality
- all 5 senses can occur: sight, touch, taste, small, sound - Delusions (妄想)
- believe things that are not true when examined rationally - Confused and disturbed thought
- rapid and constant speech
- random content of speech (switch topics in the middle of sentence)
- train of thoughts suddenly stop —> abrupt pause in conversation / activity
- difficulty in concentration on activities
- talk to themselves - Lack of insight / self-awareness
- unaware that they are acting strangely / have hallucinations / delusions
- able to recognise behaviours of others but not themselves
- ∴ affected individuals often would not seek medical help themselves, rely on outside to tell them they are abnormal
Positive and Negative symptoms of Psychosis
Positive signs:
- Hallucinations
- Delusions
- Confused and disturbed thought
- Agitation
Negative signs:
- Lack of drive / initiative
- Social withdrawal / Depression
- Apathy
- Lack of emotional response
Causes of Psychosis
- Psychological conditions (e.g. mental illness)
- General medical conditions
- Substance abuse (e.g. alcohol, drugs)
- Others (genetics, brain structural changes, hormonal / sleep pattern)
Psychological conditions
- ***Schizophrenia (repeated episodes of psychosis)
- ***Bipolar disorder (mood swing, depression followed by manic (energetic, impulsive, happy))
- Severe stress / anxiety
- Lack of sleep
- Severe depression (extreme sadness for prolonged period)
General medical conditions
- Metabolic disorders
- Vitamin B deficiency (e.g. Thiamine, B12)
- etc. - Brain diseases
- Stroke
- Tumour
- etc.
Substance abuse
Drugs known to trigger psychotic episodes:
- Cocaine (significantly ↑ dopamine level)
- Amphetamine
- Methamphetamine
- Mephedrone
- MDMA (Ecstasy)
- Cannabis (regular cannabis users 40% more likely to develop psychotic illness)
- LSD
- Psilocybin (magic mushroom)
- Ketamine
Prevalence of Psychosis
- More common than people think
- 1 in 100: >=1 episode of psychosis at some point in life
- Most cases develop during older teens (>15) / during adulthood
- Cases under 15 are rare
- Male > Female
Hong Kong:
- ~200,000 patients
- 1300 new cases each year
Treatment of Psychosis
- Antipsychotics (relieve symptoms of psychosis, but unable to cure)
- Psychological therapy - address underlying cause
- Social support
- Family therapy
- Self-help groups
- Some may need antipsychotics for short period, some life-long
- Severe cases: may need hospital admission / psychiatric unit —> prevent hurting themselves / others
Complications of Psychosis
- More likely to have drug / alcohol problems
- Higher risk of suicide (1 in 25)
- Hurt / Kill others
Antipsychotics formulation
- Oral / Injection
- Slow-release / Rapid-disintegrating
Slow-release:
- long-acting
- one injection every 2-6 weeks
- for patients unable to adhere to daily regimens
Rapid-disintegrating:
- dissolve rapidly in minimal amount of saliva
- avoid swallowing
- for patients suspected of concealing tablets in mouth then disposing —> making non-adherence impossible
***Classification of Antipsychotics
Typical antipsychotics (High affinity for ***D2 receptors):
- ***Chlorpromazine
- ***Haloperidol
- ***Sulpiride
- Perphenazine
- Fluphenazine
- Thioridazine
- Trifluoperazine
Atypical antipsychotics (High affinity for ***Serotonin 5HT2 receptors):
- ***Aripiprazole
- ***Clozapine
- ***Olanzapine
- ***Quetiapine
- ***Risperidone
- Ziprasidone
Both only alleviate symptoms, not cure schizophrenia / bipolar
Typical antipsychotics (1st generation)
- much cheaper
- Effective against ***Positive signs but NOT Negative signs
MOA:
- Block D2 receptors —> block action of Dopamine
(- D1 neuron: stimulate Direct pathway (D1 receptor) —> promote movement
- D2 neuron: inhibit Indirect pathway (D2 receptor) —> promote movement)
(Block D2 receptor in Striatum
—> block action of D2 neuron (Substantia nigra) on Striatum
—> less inhibition of Indirect pathway
—> inhibit movement)
Dopamine hypothesis
Dopamine:
- NT
- associated with how we feel something significant, important, interesting
- **excessive Dopamine —> **interrupt specific pathways responsible for memory, emotion, social behaviour, self-awareness
Hypothesis is based on these observations:
- Many antipsychotic drugs block Dopamine receptors (esp. D2 receptors)
- Dopamine agonists (e.g. Amphetamine, Levodopa) exacerbate psychosis
- Increased density of dopamine receptors detected in certain brain regions in untreated schizophrenics
Hypothesis not perfect:
- antipsychotics only effective in most patients but not all
- some drugs have higher affinity for other receptors e.g. 5HT2 receptor than D2 receptors
Dopamine receptors
5 different dopamine receptors identified (D1-D5)
D1, D5: Activation of adenylate cyclase —> ↑ cAMP production (—> ↑ downstream signals)
D2, D3, D4: Inhibition of adenylate cyclase —> ↓ cAMP production (—> ↓ downstream signals)
D2 most concentrated in:
- Cortex
- Corpus striatum (Caudate nucleus, Putamen)
- Limbic system
- Basal ganglia
- Pituitary gland
- Hypothalamus
***3 Major Dopamine pathways in brain
**1. Mesolimbic and Mesocortical pathways
(VTA —> Nucleus Accumbens, Amygdala + Hippocampus, Prefrontal cortex)
- **Mental activity + Mood —> blockage of D2 receptors associated with antipsychotic efficacy
- memory
- motivation and emotional response
- reward and desire
- addiction
- hallucinations and schizophrenia
- Nigrostriatal pathway (Substantia nigra —> Striatum)
- motor control
- Parkinson’s disease - Tuberoinfundibular pathway (Hypothalamus —> Pituitary gland)
(e. g. Dopamine from Hypothalamus inhibit Prolactin release from Pituitary gland)
- hormonal regulation
- maternal behaviour, pregnancy
- sensory processes
***Adverse effects of blockage of D2 receptors
Nigrostriatal pathway (Basal ganglia)
- responsible for Extrapyramidal function (motor system)
- blockage —> Extrapyramidal symptoms —> tend to develop after several years of antipsychotic therapy (but can appear as early as 6 months)
- Acute dystonia (扭麻花)
- hyperkinetic movement disorder, intermittent, uncoordinated involuntary contractions of muscle of face, tongue, neck, trunk, extremities
- painful - Akathisia
- motor restlessness, inability to stay still - Parkinsonism
- rigidity, tremor
- cognitive impairment - Tardive dyskinesia
- repetitive movement of Orofacial structure: tongue protrusion, lip smacking, involuntary repetitive body movements
- painless
Tuberoinfundibular pathway
- Dopamine: released from Hypothalamus —> inhibition of prolactin release from Pituitary
- blockage —> Hyperprolactinemia in both male and female —> Pseudopregancy (False pregnancy)
- Hyperprolactinemia
- Gynecomastia
- Galactorrhea
- Loss of libido
- Sexual dysfunction (no ovulation and menstruation) - Inhibition of GnRH due to prolactin
- ↓ FSH, LH release —> Hypogonadism, Infertility
Summary of SE of Typical antipsychotic
- Extrapyramidal symptoms
- Hyperprolactinemia symptoms
- Drowsiness
-
**Neuroleptic malignant syndrome (NMS)
- medical emergency
- **temperature regulation centre fail by drug
- body temperature ↑ >40oC
- 1 in 500
- develop over 1-3 days of drug use
- e.g. rigidity, muscle breakdown, tachycardia, elevated BP, dilation of pupil, sweating
Atypical antipsychotic (2nd generation)
- Treat **Positive + **Negative signs of psychosis
MOA:
- Block 5HT2 receptors
- Affinity for 5HT2 > D2 (quickly dissociate from D2 —> ↓ extrapyramidal, hyperprolactinemia SE)
Adverse effects of Atypical antipsychotics
- **Metabolic SE (combined H1 + 5HT2 blockage):
1. ↑ Risk of high glucose
2. ↑ Lipids, cholesterol
3. ↑ Diabetes risk
4. Severe weight gain
5. Hypertension, Atherosclerosis
(5HT2 regulate energy intake and expenditure, 5HT2c ↑ appetite)
- **D2 blockage:
6. Extrapyramidal effects
7. Hyperprolactinemia
8. Neuroleptic malignant syndrome
9. Sudden death - **α1 adrenergic receptor blockage (α1: Vasoconstriction):
10. Reflex tachycardia
11. Postural hypotension - **Muscarinic receptor blockage (Anticholinergic symptoms):
12. Dry mouth
13. Constipation
14. Urinary retention
15. Mydriasis
16. Tachycardia
17. Hyperthermia - **Histaminergic receptors blockage:
18. Sedation
19. Slowness
Choice of Atypical antipsychotic drugs
Prevent Sedation: Aripiprazole
Prevent Weight gain: Aripiprazole
Prevent EPS: Clozapine
Withdrawal problems
- Gradual dose reduction when switching to another drug / discontinuation
- Blockage of Dopaminergic receptor by antipsychotics
—> ***↑ number and sensitivity of Dopamine receptors
—> Super-sensitivity psychosis (when withdrawing drug) - Withdrawal symptoms:
1. Psychosis (relapse of underlying disorder)
2. Tardive dyskinesia
3. Nausea
4. Emesis
5. Anorexia
6. Anxiety
7. Agitation
8. Restlessness
9. Insomnia
Antipsychotic prescribing indication
Original target population:
- Schizophrenia
- Bipolar disorder
—> relatively small population
Newer target population:
- Severe depression (use in combination with antidepressants)
- Mild mood disorder, Everyday anxiety, Insomnia, Mild emotional discomfort
Off-label use of antipsychotics
Non-psychotic disorders:
- agitation
- various headache conditions
- anxiety disorder (limited controlled trials, no effect / inconsistent results, no approved use yet)
- suppress hiccups
- Alzheimer’s disease
- depression
- dementia
- involuntary motor disorder (Tourette syndrome, Huntington chorea)
- Autism spectrum disorders (Risperidone approved for treatment of irritability in children and adolescents with autism)
