L10 & L11 Antipsychotics 1&2

Positive symptoms of schizophrenia?

• Hallucinations

• Thought disorder

• Abnormal behavior

• Aggressiveness

Negative symptoms

• Poor hygiene

• Withdrawal

• Avolition

• Alogia

DSM-IV-TR diagnosis

Two or more symptoms with social or occupational dysfunction for >6 months

Alogia

Decrease in the fluency of speech

Avolition

Decrease in the initiation of goal-directed behavior

Dopamine hypothesis of Schizophrenia

Increased and dysregulated levels of DA neurotransmission in the brain

1. D2 receptor antagonists relieves many

   symptoms of schizophrenia

2. Decreased DA level → improvements in schizophrenic symptoms

Mesolimbic System

1. What symptoms?

2. Associated with what?

1. Positive symptoms of schizophrenia

2. Emotions and memory

Mesocortical system

1. What symptoms?

2. Associated with what?

1. Negative symptoms of schizophrenia

2. Attention, planning, and motivated behavior

Glutamate Theory Schizophrenia

Reduced glutamate concentrations and glutamate receptor densities

NMDA receptor antagonists example

Phencyclidine (PCP, angel dust), ketamine and dizocilpine (MK-801)

Serotonin hypothesis

5-HT2C stimulation → Hallucinatory effects

Antipsychotics → 5HT receptor antagonist

Effects on specific areas of the nervous system

• Basal Ganglia

• Limbic System

• Cerebral Cortex

• Hypothalamus and endocrine system

• Basal Ganglia → Reduce motor activity and antagonize the action of dopamine

• Limbic System → mesolimbic and mesocortical

• Cerebral Cortex → dopaminergic projections

  • Hypothalamus and endocrine system → Increased prolactin secretion

  • Reduce the secretion of gonadotropins and sex steroids

  • Amenorrhea in women and sexual dysfunction or infertility in men

Typical antipsychotics

1. What are they also called?

2. What do they block?

3. Describe the ADE

1. First generation antipsychotics - (Neuroleptics)

2. Block dopamine (D2 receptor antagonist), cholinergic, &-adrenergic, and H1-histaminergic receptors

3. Extrapyramidal adverse effects (EPS)

Atypical antipsychotics (Second generation antipsychotics)

1. What are they also called?

2. What do they block?

3. Describe the ADE

1. 2nd generation antipsychotics

2. D1 and D4 antagonists (low affinity for D2 receptors)

3. Fewer adverse effects

***More effective than the typical antipsychotics to treat the negative symptoms of schizophrenia

First generation antipsychotic drugs

• Chlorpromazine

• Fluphenazine

• Haloperidol

• Perphenazine

• Thioridazine

• Thiothixene

• Trifluoperazine

Second generation and Dopamine/5- HT antagonist drugs

• Aripiprazole

• Asenapine

• Clozapine

• Cariprazine

• Brexpiprazole

• Iloperidone

• Lurasidone

• Paliperidone

• Olanzapine

• Quetiapine

• Risperidone

• Ziprasidone

First-generation antipsychotics

• MOA

• Antagonism of what?

• Action

• Therapeutic action

• Block D2 receptors

• Antagonism of mesolimbic system, and mesocortical D2 receptors

• Reduce the positive symptoms of schizophrenia → less effective at controlling the negative symptoms of schizophrenia

• Treat schizophrenia, psychotic disorders, decrease hallucinations

What class is Chlorpromazine and Haloperidol in?

• Phenothiazine – Chlorpromazine

• Butyrophenone- Haloperidol

On target and Off- target Effects

H1→ antihistaminergic (weight gain and sedation)

a1 → orthostatic (postural) hypotension

D2 → parkinsonism

M1 → anticholinergic (dry mouth, constipation, urinary retention, blurred vision)

Name extrapyramidal ADE

Dystonia

Akathisia

Parkinsonian symptoms

Tardive Dyskinesia

Neuroleptic Malignant Syndrome

Prolactin secretion → Hyperprolactemia

Dystonia

• Muscles contract involuntarily- occur within a few hours to days of treatment

• Uncontrollable repetitive or twisting movements

Akathisia

Motor restlessness-occur within days to weeks

Parkinsonian symptoms

• Activate the indirect pathway

• Bradykinesia, rigidity, and tremor

• Treated with nondopaminergic Parkinson’s therapies- amantadine and anticholinergic drugs

Tardive Dyskinesia

• Irreversible

• Repetitive, involuntary, stereotyped movements of the facial musculature, arms and trunk

Neuroleptic Malignant Syndrome (NMS)

• Associated with high affinity for D2 receptors in the hypothalamus (essential for body’s ability to control temperature)

• Rare life-threatening syndrome characterized by catatonia, stupor, fever and autonomic instability

Prolactin secretion (Hyperprolactemia)

Antagonist action at dopamine receptors in the pituitary gland

• Women: osteoporosis, breast swelling, pain and lactation

• Men: Breast swelling, pain and lactation

Adverse effects of Typical agents

Antagonist receptor action at muscarinic and alpha- adrenergic receptors (Off-target)

• Anti-cholinergic: dry mouth, constipation, difficulty urinating

• alpha-adrenergic antagonism: cause orthostatic hypotension and sedation

Extrapyramidal vs. ADE

High potent drugs: higher extrapyramidal effects + less ADE of M1 and alpha adrenergic

Lower potent drugs: fewer extrapyramidal effects + more prominent ADE

Typical antipsychotic drug interactions

Inhibit action of antiparkinsonian drugs —> worsen symptoms

• Potentiate sedative effects on benzodiazepines and antihistamines

• Increase effect of sedatives/analgesics/alcohol/hypnotics/antihistamines/cold remedies

What drugs cause antiemetic action?

• MOA?

• What is the use of this drug?

Haloperidol and Prochlorperazine

• Blocking D2 receptors of the chemoreceptor trigger zone (CTZ) of the medulla

• Treats nausea from chemotherapy

• Haloperidol → delirium/severe agitation in hospice

Azepines

• Clozapine

• Olanzapine

• Quetiapine

Partial DA agonist

Aripiprazole

Benzisoxazole

• Risperidone

• Paliperidone

• (9-hydroxyrisperidone)

Dihydroindolone

Ziprasidone

Affinity to D1 and D2 dopaminergic neurons

Typical antipsychotics have higher D2 affinities

Atypical antipsychotics have higher D1 affinities

Clozapine (Clozaril)

• Action

• ADE

• decreasing suicidality in schizophrenic patients

• agranulocytosis (low white blood cell count)

  • Contraindicated in patients with severe heart disease → myocarditis, orthostatic HoTN, seizures

Olanzapine (Zyprexa)

• Therapeutic action

• ADE

• Anti-psychotic, bipolar disorder

• Anticholinergic symptoms, sedation, weight gain, prolactin secretion

Quetiapine (Seroquel)

• Action

• ADE

• As efficacious as haloperidol in treating positive symptoms + monotherapy for depression

• Risk for cataract development, hypothyroidism and Suicidal thoughts

Risperidone (Risperdal) Action and ADE

Action

• More effective than haloperidol in combating the positive symptoms of schizophrenia

• Preventing relapse of the active phase of the disease

• Bipolar disorder

Higher prolactin secretion

Paliperidone (Invega)

• MOA

• ADE

• Dopamine antagonist and 5-HT2A antagonist

• Higher blood sugar/diabetes → routine blood test in patients with diabetes

  • Increase QT interval

  • Dose dependent prolactin secretion

Ziprasidone (Geodon)

• MOA

• Action

• ADE

• Contraindications

• Inhibition of serotonin and norepinephrine reuptake

• Psychotic disorder, Bipolar disorder

• ADE: Prolongation of the QTc interval

• Contraindication

  • concurrent use of other QTc-prolonging medications

  • MI, heart problems

  • antiarrhythmics

Lurasidone (Latuda)

• Use

• ADE

• Monotherapy, or with lithium/valproate → Bipolar disorder/MDD

• Leukopenia, neutropenia, agranulocytosis

  • Prolactin secretion

Aripiprazole (Abilify)

• MOA

• Action

• ADE

• Dopamine partial agonist and antagonist

  • Reduce dopaminergic activity in mesolimbic pathway

  • Partial D2 agonism (increase dopaminergic activity in mesocortical)

• Treat positive and negative symptoms

  • Psychotic + bipolar disorder

• NMS and high blood sugar

Brexpiprazole (Rexulti)

• MOA

• Therapeutic action

• ADE

• Partial agonist activity at 5-HT1A and D2

• Schizophrenia, MDD

• ADE: Extrapyramidal symptoms and akathisia

Asenapine

• Therapeutic action

• ADE

• Brands

• Schizophrenia and bipolar disorder

• ADE: normal ADE

Other brands

• Transdermal formulation (Secuado)

• Sublingual (Saphris)

Cariprazine (Vraylar)

• MOA

• Therapeutic Action

• ADE

• Partial agonist and antagonist (greater affinity for D3 than D2)

• Schizophrenia + bipolar disorder

• ADE: leukopenia, neutropenia, and agranulocytosis

Lumateperone (Caplyta)

• MOA

• Therapeutic Action

• ADE

• Enhance glutamate neurotransmission and serotonin reuptake inhibitor

• Schizophrenia + BP

• Blood dyscrasia (leukopenia, neutropenia and agranulocytosis), weight gain

Pimavanserin (Nuplazid)

• MOA

• USE

• ADE

• Selective inverse agonist of the serotonin 5-HT2A receptor

• Parkinson’s disease psychosis

• CNS depression

Xanomeline and trospium (Cobenfy)

• Role of each drug and why

• Use

• ADE

• Contraindications

Xanomeline - M1 and M4 muscarinic receptors agonist

• Reduce psychotic symptoms

Trospium - muscarinic receptors antagonist

• Do not cross BBB, minimize GI

Effective for positive and negative symptoms

ADE: urinary retention, increased heart rate, decreased gastric movement

Contraindications: liver impairment; gastric retention, untreated narrow-angle glaucoma

Atypical antipsychotics

Higher metabolic side effects

• diabetes, hypercholesterolemia and weight gain

First vs. Second generation

First generation- Neurological side effects

Second generation- Metabolic side effects

Drugs approved for maintenance treatment

• Aripiprazole

• Olanzapine

• Quetiapine

• Risperidone

• Ziprasidone

Which is a positive symptom of schizophrenia?

A. Social withdrawal

B. Hallucination

C. Lack of motivation

D. Reduced speech output

B

The mesocortical pathway is primarily associated with A. Positive symptom

B. Negative symptom

C. Both positive and negative

D. Cognitive symptoms

B

Which of the following best describes the role of the mesolimbic pathway in schizophrenia?

A. It is associated with cognitive deficits and negative symptoms.

B. It is involved in motor coordination and balance.

C. It contributes to positive symptoms due to increased dopamine activity.

D. It regulates circadian rhythms and sleep cycles

C

What is the mechanism of action of atypical antipsychotics?

A. Block D2 receptors

B. Activate D2 receptors

C. Activate glutamate transmission

D. Activate D1 receptors

A

Which of the following receptor blockage induced by antipsychotics cause dry mouth, constipation & urinary retention?

A. Dopamine

B. Glutaminergic

C. Histamine

D. Cholinergic

D

Blockade of this receptor system most likely associated with akathisia side effect of antipsychotic treatment?

A. Muscarinic

B. Adrenergic

C. Serotonin

D. Dopamine

C

High potent typical antipsychotics induce less extrapyramidal adverse effects

True

False

False

A patient treated with a high-potency first-generation antipsychotic develops muscle rigidity, tremors, and bradykinesia. What is the mechanism behind these symptoms?

First-generation antipsychotics, especially high-potency ones like haloperidol, block dopamine D2 receptors in the nigrostriatal pathway, which is involved in motor contel. This leads to extrapyramidal symptoms (EPS) such as rigidity, tremors, and bradykinesia, resembling Parkinsonism.

An adolescent male is newly diagnosed with schizophrenia. Which of the following agents may be a better choice to improve his speech fluency?

A. Chlorpromazine

B. Fluphenazine

C. Risperidone

D. Haloperidol

C

A 33-year-old man with schizophrenia presents to the ambulatory clinic for follow-up. He has been taking haloperidol for years but has been developing extra pyramidal system symptoms recently. The physician decides to switch him to ziprasidone. Which of the following is an adverse effect of ziprasidone?

A. Diarrhea

B. Prolonged QT interval

C. Hallucinations

D. Hypertension

B