Module 1.5.1 (Antipsychotics) Flashcards
What does increase activity in mesolimbic pathway cause?
–Delusions – Hallucinations – Other +ve Sx of schizophrenia.
What does decrease activity in the mesocortical pathway cause?
– Apathy – Withdrawal – Lack of motivation & pleasure – Other –ve Sx of schizophrenia.
What does inhibition of the nigrostriatal pathway cause?
Causes extrapyramidal SE of antipsychotic drugs
What does inhibiton of the tuberoinfundibular pthway cause?
Elevated serum prolactin levels
How do most antipyschotic drugs work?
Most antipsychotic drugs block dopamine receptors
- clinical dose is proportional to D2 receptor blockade
> Single positive electron tomography ligand scans show an increase in D2 receptors in nucleus accumbens of schizophrenia patients
Psychotic symptoms can be induced by drugs that increase dopaminergic activity. What drugs does this?
anti-parkinsonian agents
Drug-indcued parkinsonism is a common adverse effects of FGAs, it usually develops after weeks or months of treatment. What are these symptoms?
- Stooped posture
- Drooling
- Back rigidity
- Flexed elbows and wrists
- Tremors in the legs
- Slight flexed hip and knees
- Shuffling gait
- Reduced arm swing
- Hand tremor
Bradykinesia (slow movements)
Akinesia (immobility) has also been reported
> Usually develops after weeks or months of treatment.
> Usually reversible with anticholinergics
What drugs mimic positive symptoms?
- Amphetamine, methamphetamine (release dopamine & inhibit its reuptake) –> mimic positive symptoms
- Psilocybin, LSD (5-HT2A agonists) mimic positive symptoms
What drugs mimic positive, negative and cognitive symptoms?
Phencyclidine, ketamine (glutamate NMDA receptor antagonists)
What are atypical antispychotics?
(Second Generation Antipsychotics)
What are positive symptoms of schizophrenia? Why does this happpen?
Agitation Delusions Disorganised speech Disorganised thinking Hallucination Insomnia
- Due to excessive neuronal activity in mesolimbic neuronal pathway
What are negative symptoms of schizophrenia? Why does this happpen?
Apathy (avolition) Withdrawal Lack of motivation Lack of pleasure (anhedonia) Limited speech (alogia)
- due to insufficient activity in mesocortical neuronal pathway
What MOA + drug is used to treat negative and cognitive symptoms that results from deficient cortical dopamine activity?
Respond to 5HT2A receptor antagonism produced by SGAs –> increase dopamine release
mesocortical pathway
What MOA + drug is used to treat positive symptoms that results from excessive subcortical dopamine activity?
Respond well to D2 receptor antagonism produced by FGAs & SGAs
mesolimbic pathway
5HT2A antagonists increase dopamine release in the mesocortical pathways but what effects do they have on D2 antagonists?
5HT2A antagonist enhance / complements action of D2 antagonist to reduce positive symptoms
What do neagative and cognitive symyptoms respond to?
respond to 5-HT2A receptor antagonism produced by SGAs
What do positive symptoms respond to?
Positive symptoms respond well to D2 receptor antagonism produced by FGAs & SGAs
Antipsychotics require 1-3 weeks to stabilise the positive symptoms of schizophrenia. What are the three-time dependent changes in dpamine neurotransmission?
- Immediate effects: An increase in dopamine synthesis, release, and metabolism but NO therapeutic effect
- 2Prolonged effects (1-3 weeks): Depolarization blockade –> reduced dopamine release from mesolimbic and nigrostriatal neurons –>alleviate the positive symptoms of schizophrenia while causing EPSE
- Extended prolong effects: Dopamine receptor up-regulation and supersensitivity to dopamine agonists –> may contribute to the development of a delayed type of EPS called tardive dyskinesia
What are examples of first gen antipsychotics (typical)?
clue: CDFHPZ
- Chlorpromazine
- Droperidol
- Flupentixol
- Haloperidol
- Periciazine
- Zuclopenthixol
What are examples of second gen antipsychotics (typical)?
Clozapine
Olanzapine
Quetiapine
Risperidone
Paliperidone
Amisulpride
Aripiprazole
Asenapine (Saphris wafer)
Ziprasidone (Zeldox®)
Lurasidone
Brexipiprazole (new drug)
What are some differences between FGAs and SGAs?
FGA only effective for positive symptoms
SGA can alleviate positive and negative symptoms
- Incidence of extrapyramidal side-effects (less in the SGAs )
- Efficacy in treatment-resistant groups of patients
- Receptor selectivity
- Pharmacological properties
What receptors does FGA have high affinity for?
High affinity for D2 receptors
> chlorpromazine, haloperidol, flupentixol
What receptors does SGA have high affinity for?
high affinity for 5-HT2 receptors
> clozapine, risperidone, sertindole, quetiapine, aripiprazole
What are pharmcokinetic considerations of antipsychotics?
Most antipsychotics have half-lives of 15-30h
Given orally or IM
Considerable individual variation
Dose needs to be individualised
Elderly requires reduction in dose
Depot formulation – long-term therapy
Fluphenazine decanoate – up to 28 days
ncreased risk of EPS with depot formulation
What is responsible for antipsychotic action?
D2 receptor antagonism is essential for antipsychotic action
How does SGA alleviate both positive and negative symptoms?
5HT2A antagonist
Negative symptoms: Inhibits 5HT2A receptors = increases dopamine release
Positive symptoms: HT2A antagonist enhance / complements action of D2 antagonist to reduce positive symptoms
Howe does SGA protect against EPS in SGAs?
preserving nigrostriatal DA activity
> Also alleviate anxiety and insomnia in schizophrenia
what does affinity for D2 receptors cause in FGA?
Affinity for D2 receptors cause of EPS (extrapyramidal sideeffects)
> FGAs are quite ineffective in treating negative & cognitive symptoms and EPS may become intolerable.
Why are SGAs better than FGAs?
- Alleviation of negative & cognitive symptoms as well as positive symptoms
- Lower incidence of EPS and generally better tolerated
- SGAs are superior to FGAs interact with 5-HT2A and D2 receptors
- Antagonism of D3, D4 and other receptors may also contribute to the favourable clinical profile of SGAs
What are the adverse effects of antipsychotics?
- Adverse effects on Dopaminergic pathways
Psychological effects (mesolimbic/mesocortical)
Movement disorders (nigrostriatal)
Neuroendocrine (tuberoinfundibular)
> elevated prolactin
- Blockade of a1 receptors –> Hypotension, reflex tachycardia
- Blockade of histamine H1-receptor –> sedation and weight gain
- Blockade of 5-HT2C & H1 receptors –> weight gain
- Anti-cholinergic effects –> Blurred vision, dry mouth, constipation, urinary retention
- Adverse effects due to immune reaction –> Hypersensitivity reactions, dermatitis, rashes, photosensitivity, urticaria
- Adverse effects due to individual drug –> Clozapine cause agranulocytosis - neutropenia, bone marrow depression
- Idiosyncratic reaction –> neuroleptic malignant syndrome
What are acute EPS effects?
- Acute neurological effects:
acute dystonia, akathisia, parkinsonism
- Early EPS (within days)
- Acute dystonias involuntary muscle spasms
- Parkinsonian-like movements -tremor, rigidity & bradykinesia
What is used to reverse parkinsonian like symptoms? What is the MOA?
Benztropine – anticholinergic – block muscarinic receptors that mediate striatal cholinergic excitation – reduce the excessive cholinergic activity due to D2 blockade by FGAs
What is acute dystonia? What does it include?
Muscle spasm of face, tongue, neck, jaw and/ or hands
Hyperextension of neck & trunk & arching of back.
Can interfere with walking, talking or swallowing
Inlcudes
- Torticollis
- Carpopedal spasm
- Trismus (lock-jaw)
- Perioral spasm
- Oculogyric crisis
What is akathisia (acute eps)? When does it happen?
- Motor restlessness
- Person unable to sit or stand still, feels urgent need to move, pace, rock or tap foot
- Can also present as apprehension, irritability & general uneasiness
- Often confused with worsening agitation*
- More common in females
Usually occurs 2-3 days (up to several weeks) after starting Tx & may subside spontaneously.
What are some chronic EPS effects?
Chronic neurological effects: Tardive dyskinesia, Tardive dystonia
Tardive dyskinesia
- Characterised by abnormal involuntary movements of the mouth, face, tongue and sometimes head, neck, trunk or limbs
- Best approach is prevention / Use SGAs rather than FGAs
Why does Tardive dyskinesia occur? How long does it take to occur?
May be due to a delayed adaptive proliferation of nigrostriatal D2 receptors or neurodegeneration resulting from excessive glutamate release due to chronic antagonism of inhibitory D2 receptors
- usually after 6-24 months of chronic FGA treatment
What are symptoms of neuroleptic malignant snydrome? Which patients does it occur in?
> caused by antipsychotics
- Symptoms include fever, extrapyramidal motor disturbances, muscle rigidity and COMA
Rare but potentially fatal adverse event occurring in patients extremely sensitive to EPS (muscle rigidity & hyperthermia)
what treatment for neuroleptic malignant snydrome?
URGENT treatment required –dantrolene (direct-acting skeletal muscle relaxant) and bromocriptine (dopamine agonist)
What is mnemnic for neuroleptic malginant syndrome features?
FEVER
F - Fever • E - Encephalopathy • V - Vitals unstable • E - Elevated enzymes (elevated CPK) • R - Rigidity of muscles
What are the major drug interactions for the following FGA:
A) Chlorpromazine
B) Fluphenazine
C) Haloperidol
A)
- Additive effects with antiadrenergic, anticholinergic, and CNS depressants.
- Decreases serum levels of lithium
- Concurrent use of a β-adrenergic receptor antagonist or an antidepressant may increase serum levels of both drugs
B)
- Additive effects with anticholinergic and CNS depressants
- Concurrent use of a β-adrenergic receptor antagonist (beta blocker) or an antidepressant may increase serum levels of both drugs
C)
- Barbiturates and carbamazepine decrease serum levels
- Quinidine increases serum levels
What are the major drug interactions for the SGA:
A) clozapine
B) olanzapine
C) risperidone
A)
Not established; possible interaction with drugs that induce or inhibit cytochrome P450 isozyme CYP1A2.
B)
same as clozapine
C)
Not established; possible interaction with drugs that induce or inhibit cytochrome P450 isozyme CYP2D6.
What are precautions for antispyhcotic drugs?
Parkinson’s disease •
Epilepsy •
Respiratory failure •
Hyperthyroidism •
Shock •
Risk factors for prolonged QT interval •
GI obstruction, urinary retention, myasthenia gravis –> anticholinergic effects exacerbate this
Low WCC or previous blood dyscrasia •
Diabetes –> olanzapine, clozapine, quietapine increases BSL
Elderly –> Associated with increased risk of stroke & death
D2 receptors blockade lead to increased prolactin release, what are the effects of this?
Galactorrhoea Amenorrhoea Gynaemastia Infertility
Pharmacalogy of chlorpromazine (fga)
EPS can become troublesome
Prominent sedation, hypotension & antimuscarinic effects /
Can cause obstructive jaundice and photosensitivity leading to sunburn
Useful when sedation is desired
Administered orally, IV or IM
Pharmacology of haloperidol (fga)
“high potency antipsychotic” /
EPS is a main problem /
Favoured when sedation, hypotension, and antimuscarinic effects are undesirable (elderly patients)
Administered orally or IM
pharmacology of flupentixol decanoate (FGA)
“depot preparation” that can be administered IM every 2-4 weeks /
Minimal sedation & hypotension, but prominent EPS
When should long acting depot antipsychotics such as Flupenthixol decanoate, haloperidol decanoate, risperidone be used?
Should be considered for schizophrenic patients who do not reliably take oral antipsychotic medication
What are the clinical used of FGAs?
Treatment of acute and chronic psychoses
Treatment of acute mania
Management of “organic psychoses”, such as those seen in elderly patients with dementia and dementia-associated agitation (progressive failure of intellectual and cognitive function.)
Severe behavioural disorders on children
Adjunct in psychotic depression
Adjunct in anaesthesia
Adjunct in treatment of alcoholic hallucinosis
Treatment of Gilles de la Tourette and other choreas
Acute treatment of intractable nausea and vomiting (haloperidol, droperidol).
Treatment of intractable hiccough (chlorpromazine).
Pharmacology of clozapine
Highly effective for treating the positive, negative & cognitive symptoms of schizophrenia without producing EPS
Reduces the suicide rate /
Risk of agranulocytosis (1% of patients). Regular monitoring of blood required if prescribed. /
Convulsions can occur /
Other side-effects include: prominent sedation, weight gain, impaired glucose regulation, hypotension and antimuscarinic effects
> Use clozapine in schizophrenics unresponsive to other antipsychotics
Pharmacology of olanzapine
Has a similar therapeutic profile to clozapine. However, it may not be as effective as clozapine in severely impaired schizophrenics.
Does not cause agranulocytosis
Convulsions can occur
Side-effects include: sedation, weight gain, impaired glucose regulation, hypotension and antimuscarinic effects
Olanzapine is a widely prescribed antipsychotic for schizophrenia and other psychoses
Pharmacology of risperidone
Effective for treating positive, negative & cognitive symptoms of schizophrenia.
Above usual therapeutic doses (!4-6 mg/day), it can produce EPS
Does not cause agranulocytosis
Antimuscarinic effects are minimal /
Side-effects include: mild sedation, mild weight gain & impaired glucose regulation, hypotension, hyperprolactinaemia
Risperidone is a widely prescribed antipsychotic for schizophrenia and other psychoses
Pharmacology of Quetiapine
Can treat positive, negative & cognitive symptoms without producing EPS
Does not cause agranulocytosis
Side-effects include sedation, dry mouth, constipation, hypotension, mild weight gain & impaired glucose regulation
Quetiapine is a useful antipsychotic for treating schizophrenia
Pharmacology of aripiprazole
Improve positive symptoms and reduce relapse rates after an acute episode.
Does not cause agranulocytosis
Side-effects include: sedation, weight gain, impaired glucose regulation, hypotension and antimuscarinic effects
precautions
Recent history of MI, unstable heart
Treatment with CYP3A4
Poor metaboliser - CYP2D6
Indicated for schizophrenia and bipolar disorder as monotherapy
What are the clinical used of atypical antipsychotic drugs?
Treatment of acute and chronic psychoses (e.g. schizophrenia)
Acute mania (olanzapine, quetiapine, risperidone)
Organic psychoses (e.g. dementiaassociated agitation)
Severe behavioural disorders in children
