PCOL LEC midterms - ANTIPSYCHOTIC AGENTS AND LITHIUM

What hypothesis?: Schizophrenia is caused by a relative excess of dopamine in specific neuronal tract in the brain

DOPAMINE HYPOTHESIS

DOPAMINE HYPOTHESIS

1. Antipsychotic drugs blocks _____

2. Dopamine agonist drugs (____) exacerbate schizophrenia

3. _____ density of dopamine receptors detected in certain brain regions of untreated schizophrenic

1. dopamine receptors (D2 receptors)

2. Amphetamine, Levodopa

3. Increased

What hypothesis?

● Discovery of hallucinogens such as lysergic acid diethylamide (LSD) and mescaline that are serotonin agonist lead for the search for endogenous hallucinogen (schizophrenia)

SEROTONIN HYPOTHESIS

What hypothesis?

● 5-HT2a receptor blockage is a key MOA for second generation antipsychotics

SEROTONIN HYPOTHESIS

SEROTONIN HYPOTHESIS

1. Discovery of hallucinogens such as ______ and _____ that are serotonin agonist lead for the search for endogenous hallucinogen (schizophrenia)

2. _____ is a key MOA for second generation antipsychotics

1. lysergic acid diethylamide (LSD) and mescaline

2. 5-HT2a receptor blockage

What hypothesis?

Hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal firing → contributed to schizophrenia

GLUTAMATE HYPOTHESIS

What DOPAMINERGIC PATHWAY?

Controls motor function

(Deficiency can lead to parkinsonian symptoms)

NIGROSTRIATAL

What DOPAMINERGIC PATHWAY?

Hyperactive in schizophrenia

(positive symptoms)

MESOLIMBIC

What DOPAMINERGIC PATHWAY?

Underactive in schizophrenia

(negative symptoms)

MESOCORTICAL

What DOPAMINERGIC PATHWAY?

Controls prolactin secretion

(Dopamine inhibits prolactin release)

TUBEROINFUNDIBULAR

Positive Symptoms of Schizophrenia (HIDES)

● Hallucination

● Illusion

● Delusion

● Excitement

● Suspiciousness

Negative Symptoms of Schizophrenia

(4 Bl An Av An)

● Think of depression

(Blunt affect, anhedonia, avolition, anergia)

What type of Anti-psychotics:

• Can only address the positive symptoms of schizophrenia

TYPICAL ANTIPSYCHOTICS

What type of Anti-psychotics:

• Can be classified into

  High potency (Haloperidol, Trifluoperazine, Fluphenazine) and

  Low potency (Chlorpromazine, Thioridazine)

TYPICAL ANTIPSYCHOTICS

TYPICAL ANTIPSYCHOTICS

• Can be classified into

  1. High potency (3____) and

  2. Low potency (2____)

1. Haloperidol, Trifluoperazine, Fluphenazine

2. Chlorpromazine, Thioridazine

TYPICAL ANTIPSYCHOTICS

1. High potency typical antipsychotics → Higher chances of causing ____

2. Low potency typical antipsychotics → Lower chance of causing EPS more likely to cause ____ and ____

1. extrapyramidal symptoms (EPS)

2. sedation and postural hypotension

What type of Anti-psychotics:

Blocks D2 receptors >> 5-HT2 receptors

TYPICAL ANTIPSYCHOTICS

What type of Anti-psychotics:

Can address both positive and negative symptoms

ATYPICAL ANTIPSYCHOTICS

What type of Anti-psychotics:

Lesser chances of EPS but higher chance to cause metabolic derangements (weight gain, endocrine problems)

ATYPICAL ANTIPSYCHOTICS

What type of Anti-psychotics:

Blocks 5-HT2 receptors >> D2

ATYPICAL ANTIPSYCHOTICS

TOXICITIES OF ANTIPSYCHOTICS:

Mechanism and Manifestation of Autonomic Nervous System

1. Mechanism: Muscarinic Cholinoceptor Blockage (Atropine-like Effect)

   • Manifectation: Loss Of Accommodation, Dry Mouth, Difficulty Urinating, Constipation

2. Alpha-adrenoceptor Blockage

   • Orthostatic Hypotension, Impotence, Failure To Ejaculate

TOXICITIES OF ANTIPSYCHOTICS:

Mechanism and Manifestation of Central Nervous System

1. Mechanism: Super sensitivity To Dopamine Receptors

   • Manifestation: Tardive Dyskenia

2. Mechanism: Muscarinic Blockage

   • Toxic-confusional state

TOXICITIES OF ANTIPSYCHOTICS:

Mechanism and Manifestation of Endocrine System

1. Mechanism: Dopamine-receptor blockage resulting to hyperprolactinemia

   • Manifestation: Amenorrhea-galact orrhea, infertility, Impotence

TOXICITIES OF ANTIPSYCHOTICS:

Mechanism and Manifestation of OTHERS

1. Mechanism: Possibly combined H1 and 5-HT2 blockage

   • Manifestation: Weight gain

TYPICAL ANTIPSYCHOTICS (3)

1. PHENOTHIAZINE

2. PIPERIDINE

3. BUTYROPHENONE

PHENOTHIAZINE examples (4)

Chlorpromazine, Levomepromazine, Prochlorperazine, Promethazine

Chlor,Levo,Pro,Pro

PIPERIDINE examples (3)

Thioridazine, Fluphenazine, Trifluoperazine

Thi,Flu,Tri

BUTYROPHENONE examples (3)

Haloperidol, Droperidol

MOA of what antipsychotic drug:

● Blocks D2 receptor >> 5-HT2 receptors

TYPICAL ANTIPSYCHOTICS

USES of a typical antipsychotic:

• Schizophrenia and other psychotic disorders, Manic phase of bipolar disorder

• Anti-emetics (Promethazine and Prochlorperazine)

PHENOTHIAZINE (Chlorpromazine, Levomepromazine, Prochlorperazine, Promethazine)

SE/AE of a typical antipsychotic:

● Postural hypotension, failure of ejaculation, contact dermatitis

● Sedation

● Extrapyramidal symptoms, Tardive dyskinesia, Hyperprolactinemia

● Corneal and lens deposit

● Neuroleptic malignant syndrome

PHENOTHIAZINE (Chlorpromazine, Levomepromazine, Prochlorperazine, Promethazine)

PHENOTHIAZINE notes: Prototype of all antipsychotics?

Chlorpromazine

• Stooped posture

• Shuffling gait

• Rigidity

• Bradykinesia

• Tremors at rest

• Pill-rolling motion of the hand

Pseudoparkinsonism

• Restless

• Trouble standing still

• Paces the floor

• Feet in constant motion, rocking back and forth

Akathisia

• Facial grimacing

• Involuntary upward eye movement

• Muscle spasms of the tongue, face, neck and back (back muscle spasms cause trunk to arch forward)

• Laryngeal spasms

Acute dystonia

• Protrusion and rolling of the tongue

• Sucking and smacking movements of the lips

• Chewing motion

• Facial dyskinesia

• Involuntary movements of the body and extremities

Tardive dykinesia

a life threatening reaction to antipsychotics characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction.

Neuroleptic Malignant Syndrome

USES of a typical antipsychotic:

• Schizophrenia and other psychotic disorders

PIPERIDINE (Thioridazine, Fluphenazine, Perphenazine, Trifluoperazine)

SE/AE of a typical antipsychotic:

● Postural hypotension, failure of ejaculation, contact dermatitis

● Sedation

● Extrapyramidal symptoms, Tardive dyskinesia, Hyperprolactinemia

● Retinal deposits (Thioridazine)

● Cardiotoxicity – QT prolongation arrhythmia (Thioridazine)

● Decrease seizure threshold

PIPERIDINE (Thioridazine, Fluphenazine, Perphenazine, Trifluoperazine)

USES of a typical antipsychotic:

● Schizophrenia and other psychotic disorders

● Bipolar disorder (Manic Phase)

● Tourette's syndrome

BUTYROPHENONE (Haloperidol, Droperidol)

SE/AE of a typical antipsychotic:

● Extrapyramidal symptoms, Tardive dyskinesia, Hyperprolactinemia

● Neuroleptic malignant syndrome

BUTYROPHENONE (Haloperidol, Droperidol)

NOTES: Less sedating among typical antipsychotics

BUTYROPHENONE (Haloperidol, Droperidol)

ATYPICAL ANTIPSYCHOTICS examples (7)

Clozapine,

Olanzapine,

Quetiapine,

Resperidone,

Paiperidone,

Ziprasidone,

Aripiprazole

MOA of an antipsychotic drug:

Blocks 5-HT2 receptors >> D2 receptors

ATYPICAL ANTIPSYCHOTICS

USES of an Atypical antipsychotic:

Schizophrenia (DOC for refractory and suicidal schizophrenia)

CLOZAPINE

SE/AE of an Atypical antipsychotic:

● Extrapyramidal symptoms, Tardive dyskinesia, Hyperprolactinemia (less), Postural hypotension

● Weight gain, Hyperglycemia, Hyperlipidemia

● Agranulocytosis

CLOZAPINE and OLANZAPINE

CLOZAPINE notes:

1. ____ and ____ has the highest tendency to cause weight gain

2. Because of the risk of agranulocytosis, patients receiving clozapine must have a weekly blood count for ___

1. Clozapine and Olanzapine

2. 6 week

USES of an Atypical antipsychotic:

● Schizophrenia

● Bipolar disorder, Anorexia nervosa, and Depression

OLANZAPINE

NOTES from an atypical antipsychotic

1. ___and ___ has the highest tendency to cause weight gain

2. Safe in pregnancy

1. Clozapine and Olanzapine

2. Olanzapine

USES of an Atypical antipsychotic:

1. Schizophrenia, Bipolar disorder

2. Sleep promotion and maintenance

QUETIAPINE

SE/AE of an Atypical antipsychotic:

● Extrapyramidal symptoms, Tardive dyskinesia, Hyperprolactinemia (less), Postural hypotension

● Weight gain, Hyperglycemia, Hyperlipidemia (less)

● Somnolence, Fatigue, Sleep paralysis, Hypnagogic hallucinations

● Cataracts, Priapism

● QT prolongation arrhythmia

QUETIAPINE

NOTES of an atypical antipsychotic

● ___ and ___ are amongst the atypicals that is least likely to cause tardive dyskinesia

Quetiapine and Clozapine

USES of an Atypical antipsychotic:

Schizophrenia Bipolar disorder, Tourette syndrome, Depression, Intractable hiccups

RISPERIDONE

SE/AE of an Atypical antipsychotic:

● Extrapyramidal symptoms, Tardive dyskinesia, postural hypotension(less)

● Hyperprolactinemia (marked)

● Weight gain, Hyperglycemia, Hyperlipidemia (less)

RISPERIDONE

NOTES of an Atypical antipsychotic:
● Highest propensity to cause hyperprolactinemia (amenorrhea, galactorrhea)

● Only antipsychotic approved for schizophrenia in the youth

RISPERIDONE

USES of an Atypical antipsychotic:

● Schizophrenia

● Bipolar disorder (Acute mania)

ZIPRASIDONE

SE/AE of an Atypical antipsychotic:

● Extrapyramidal symptoms, postural hypotension(less)

● QT prolongation arrhythmia

ZIPRASIDONE

NOTES of an Atypical antipsychotic:

Little to no tendency to cause hyperglycemia, hyperprolactinemia, or weight gain

ZIPRASIDONE

USES of an Atypical antipsychotic:

● Schizophrenia

● Bipolar disorder (Acute mania), Major depressive disorder, Autism

● Cocaine dependence

ARIPIPRAZOLE

SE/AE of an Atypical antipsychotic:

● Extrapyramidal symptoms, postural hypotension, Tremors

● GIT upset

● Hypersensitivity

ARIPIPRAZOLE

NOTES of an Atypical antipsychotic:

Less sedating and no atropine-like effects

ARIPIPRAZOLE

What antipsychotic drug?

Mood stabilizer

LITHIUM

MOA:

● Uncertain

○ Suppresses inositol signaling and inhibits glycogen synthase kinase 3 (GSK-3)

LITHIUM

Lithium: Suppresses _____ and inhibits ____

inositol signaling; glycogen synthase kinase 3 (GSK-3)

USES:

● Bipolar disorder (DOC)

● Recurrent depression

● Schizoaffective disorders

LITHIUM

SE/AE of this drug:

● Tremors (most common), Ataxia, Aphasia

● Thyroid enlargement and subclinical hypothyroidism, Teratogen (Ebstein anomaly), Diabetes Insipidus

● LITHIUM (Low Thyroid hormone, Heart (Ebstein anomaly), Insipidus, Unintentional Movement (tremors)

LITHIUM

Side effects of lithium

mnemonic: LITHIUM

1. Low Thyroid hormone,

2. Heart (Ebstein anomaly),

3. Insipidus,

4. Unintentional Movement (tremors)

Notes of this drug:

● Narrow therapeutic window → Overdose is treated with hemodialysis

LITHIUM

LITHIUM:

Narrow therapeutic window → Overdose is treated with _____

hemodialysis