1) Chlorpromazine

2) Haloperidol

3) Fluphenazine

4) Perphenazine

-     The conventional antipsychotics block the dopamine receptor type 2,3, and 4 (D2, 3, 4), with the major effect being on D2.

-    There is a correlation between the affinity for D2 and the clinical efficacy of the Conventional antipsychotics.
-    The treatment over 2-3 weeks causes a silencing of dopamine (DA) neurons in the substantia nigra (SN) and in the ventral tegmental area (VTA) in the midbrain.
-    This silencing may be responsible for the delay in the onset of the antipsychotic effect of
the drugs.

Important Concepts of Dopaminergic Neurotransmission

What G protein is D1 couples to?

What protein is D2 coupled to?

Name the function of the 4 dopaminergic pathways.

All Dopamine receptors are G-protein coupled receptors

-    D1 (D1, D5)- coupled to Gs
-    D2 (D2, D3, D4)- couples to Gi (autoreceptor)
-    Functions
a.   Nigrostriatal: Extrapyramidal motor function
b.  Mesocorticolimbic: Regulates emotional behavior and cognition
c.   Arcuate-pituitary (Tuberoinfundibular): Inhibits prolactin secretion from pituitary

d. Mesocortical: regulates cognition

Classify the Typical Anti-pyschotics by Potency

Explain main concept about spectrum:

Concept: low potency anti-psychotics are dirtier (have higher affinity at other receptors - ACh, H1, α1); high potency D2 blockers cause more EPS

Typicals in order of potency: 1st most potent at D2

1) Haloperidol & Fluphenazine (<10mg daily)

2) Perphenazine

3) Chlorpromazine (>100mg daily)

-    Primary Psychotic Disorders
-    Schizophrenia
-    Schizoaffective Disorder
-    Delusional Disorder
-    Brief Psychotic Disorder
-    Mood Disorders: Bipolar Disorder and MDD with psychotic features
-    Secondary Psychosis
-    Severe agitation/violent behavior
-    Delirium
-    Tourette’s Disorder/Tics

PharmKinetics of Typicals

Half Lives?

T for dosing?

What kinds of administration?

When is peak plasma conc found?

Special formulations?

-    Half lives range from 10-20 hours

-    Can use once daily dosing
-    Many available in parenteral form
-    Peak plasma concentration 1-4 hours after oral, 30-60 minutes after parenteral
-    Haloperidol & Fluphenazine available in long-acting depot formulation- give every 1-4 wks
(can take 6 mo to reach steady state)

Side Effx of Typicals: Parkinsonism (4)

incidence?

when?

sx?

w/ what drugs?

tx?

•   Occurs in 15% of patients
•   Typically within 5-90 days of treatment initiation
•   Symptoms: Muscle stiffness, cogwheel rigidity, tremor, shuffling gait, stooped posture, drooling, masked facies, bradykinesia
•   High potency antipsychotics carry most risk
•   Treatment: Anticholinergics, DA agonists

Side Effx of Typicals: Acute Dystonia (5)

sx?

when?

more likely w/ which administration?

risk factors (5)?

tx?

•   Sx: Intermittent spasmodic or sustained involuntary contractions of muscles in the face, neck, trunk, pelvis, and extremities 
•   50% occur within 48 hours of initiation of the neuroleptic; 90% within 5 days 
•   Parenteral > Oral
•   Risk factors: family hx, cocaine or alcohol, potent D2 blocker, young, male
•   Treatment: Anticholinergic (benztropine, trihexyphenidyl, diphenhydramine)

Side Effx of Typicals: Akathisia (4)

subjective vs. objective sx?

pathophysiology?

tx (3)?

•   Subjective: feeling of inner restlessness and urge to move
•   Objective: increased motor activity
•   Pathophysiology?
•   Treatment: beta adrenergic antagonists, benzodiazepines,
anticholinergics

 Antidotes to the Dopamine-Related Side Effects

What Txs (3)?

•   Anticholinergic anti-Parkinson’s medications: benztropine and trihexyphenidyl.

  - The anticholinergic medications work, because there is a reciprocal relationship between the effects of dopamine and acetylcholine in the basal ganglia.
•   Antihistaminic diphenhydramine, can also be used.
•   The dopaminergic agonist, amantadine, is sometimes used

Side Effx of Typicals: Tardive Dyskinesia

Cause?

Incidence?

Sx?

More common w/?

Mechanism?

What tx doesn't work long term?

Tx?

§   Caused by chronic use of antipsychotics
§   Incidence= 5%/year
§   Continuous writhing movements of the tongue, mouth, fingers, hands and sometimes feet. 
§   More common with high potency antipsychotics

§   Postulated mechanism: hypersensitivity of the dopaminergic response in the striatum 
§   Increasing dose can temporarily ameliorate TD, but in the long run will worsen the condition. 
§   Treatment: Stopping or switching the antipsychotic

Side Effx of Typicals: Neuroleptic Malignant Syndrome

severity?

when?

motor & behavioral sx?

autonomic sx (4)?

lab findings (4)?

Risk factors (2)?

Mortality rate?

Pathophys & Tx?

§   Life threatening
§   Can occur at ANY time during treatment
§   Motor & Behavior Symptoms: rigidity (not in SS), dystonia, akinesia, mutism, obtundation,
agitation
§   Autonomic Symptoms: fever, sweating, tachycardia, hypertension
§   Lab Findings: increased WBC, creatinine phosphokinase (not in SS), liver enzymes
§   Risk factors: male> female, young> elderly
§   Mortality: can reach 20-30%
§   Pathophysiology not well understood, Tx is supportive

Other SideEffx:

Tuberoinfundibular pathway?

ACh Receptor blockade?

H1 receptor blockade?

Alpha 1 receptor blockade?

Cardiac?

Tuberoinfundibular pathway blockade: Hyperprolactinemia
Blockade of muscarinic/cholinergic receptors: dry mouth, constipation, urinary hesitancy, tachycardia, memory loss, delirium. Can also precipitate an attack in patients with closed angle glaucoma (low potency agents)
Blockade of H1 receptors: sedation, weight gain (low potency agents)
Blockade of α1 receptors: orthostatic hypotension, dizziness, priapism (low potency agents) 
Cardiac: Quinidine-like effects; Can prolong QT interval and cause ventricular arrythymias; associated with sudden death; highest risk probably thioridazine

1) clozapine

2) olanzapine
3) risperidone

4) quetiapine

5) ziprasidone

6) aripiprazole

Atypicals' Mechanisms of Action (2)

for Aripiprazole specifically (2)?

-    Serotonin dopamine antagonists (Block 5HT2A and D2 receptors)
-    D2 antagonists with rapid dissociation
   

Aripiprazole

-    D2 partial agonists (Aripiprazole)
-    Serotonin partial agonists at 5HT1A receptors (Aripiprazole)

Relatinoship of Serotonin and Dopamine in Atypicals' Mechanism of Action

How do 5HT2A receptors usually work (2)?

Overall effect of atypicals on D2 blockade?

-    5HT2A receptors act as a DA brake. When 5HT binds to 5HT2A receptors on postsynaptic DA neurons, this inhibits DA release. Similarly, 5HT binding to 5HT2A receptors on GABA interneurons causes GABA release, which in turn inhibits DA release. When this action is blocked by a 5HT2A antagonist, this leads to an increase in DA release, either by blocking 5HT2A receptors on postsynaptic DA neurons or by blocking 5HT2A receptors on gamma aminobutyric acid (GABA) interneurons.

-    The consequence of this is that dopamine can then compete with the atypical antipsychotic
for the D2 receptor and reverse the inhibition there. As D2 blockade is thereby reversed,
atypical antipsychotics are less likely to cause extrapyramidal symptoms (EPS) or tardive
dyskinesia. 
-    Atypicals have complicated net actions on dopamine activity and th eexact balance of
5HT2A antagonism versus D2 antagonism differs with different drugs in different parts of
the brain, and the ideal balance will be different in individual patients.

Because D2 blockade outside of the mesolimbic pathway is what causes EPS, worsened negative sx, and worsened cognition --> Atypicals should in theory do all the below by reducing D2 blockade in these areas of undesired effects

-    Reduced risk of EPS
-    Reduced risk of hyperprolactinemia
-    Cognitive enhancement
-    Improved adherence
-    Better efficacy for negative symptoms
-    Better long term outcomes

Haloperidol: mostly D2, then alpha 1

Ziprasidone & Risperidone: moslty 5HT2A

Olanzapine: mostly M1, 5HT2A, H1

Clozapine: 5HT2A, H1, alpha 2

Quetiapine: H1, alpha 1, 5HT2A

-    Psychotic Disorders (Schizophrenia, Schizoaffective disorder)
-    Bipolar Disorder
-    MDD with psychotic features
-    Adjunct treatment of MDD (Aripirazole, Quetiapine)
-    Aggression and irritability in children with autism
-    Multiple off-label uses (for better or for worse)

o   More effective than all other antipsychotics
o   Drug of choice for treatment-resistant schizophrenics
o   Relatively low potency as a D2-receptor antagonist
o   Antagonist of 5HT2A (tight binding), D1, D3, D4, H1, M1, α1/2 receptors

o   Side effx: most likely to cause metabolic syndrome and causes agranulocytosis in 2% of people

o   Partial agonist at dopamine D2 receptor and at the 5-HT1A  receptor
o   Antagonist at 5-HT2A  receptors
o   Theoretically better able to modulate dopamine based on ambient dopamine tone
o   Sometimes called 3rd  generation antipsychotic

o   Side effx: Least likely to cause metabolic syndrome

o   At therapeutic doses occupies close to 100% of the 5HT2 receptors but only 65 - 70% of D2 receptors
o   The blockade of D2 is only slightly less than that caused by the conventional neuroleptics
o   Highest risk (of atypicals) of extrapyramidal and other related side effects
o   Use doses < 4 mg/day to avoid EPS
o   Depot form available (Consta)

Adverse Effects of Atypical Antipyschotics:

Metabolic Syndrome

Components (5)?

Which 2 drugs cuase the most wght gain?

How do they do this?

What drug is most likely to cuase MS?

Least likely?

o   Components: visceral obesity, hypertension, insulin resistance, high triglycerides, low
HDL cholesterol
o   All antipsychotics can cause this syndrome but some worse than others
o   2-3 x increased mortality from all causes
o   H1 receptor blockade associated with some of the weight gain
o   Clozapine and olanzapine cause excessive weight gain also by also blocking 5HT2C receptors in the hypothalamus
o   Cases of diabetic ketoacidosis (DKA) reported

o   Regular metabolic monitoring recommended

Clozapine>olanzapine>quetiapine>risperidone>ziprazidone>Aripiprazole

Other Adverse Effects of Atypical Antipyschotics: Which Drugs?

Prolonged QT?

Myocarditis?

Sedation (3)?

EPS & hyperprolactinemia?

Anticholinergic sx (2)?

Seizures & Sialorrhea?

Also affect what receptor, causing what sx?

-    Cardiac 
      o   Prolonged QTc (ziprasidone)
      o   Myocarditis (clozapine)
-    Sedation (olanzapine, quetiapine, clozapine)
-    Extrapyramidal symptoms & Hyperprolactinemia (risperidone)
-    Anticholinergic symptoms (clozapine, olanzapine)
-    Seizures & Sialorrhea (clozapine)

-    α1 blockade: Orthostatic hypotension, dizziness

 Clozapine and Agranulocytosis

prevalence?

acute or chronic?

when?

contraindications (3)?

o   Agranulocytosis in 0.5-2% of patients (ANC < 500/mm3)

o   Potentially fatal

o   Can appear precipitously or gradually; not dose related

o   Most often develops in 1st 6 months of treatment  o   Must enroll in national clozapine registry

o   Initiate gradually, in increments of 25 mg every 2-3 days

o   Usual dose is 350-400 mg/day, maximal dose is 900 mg/day

o   Check CBC: weekly x 6mo, biweekly x 6 mo, then q4weeks

o   Contraindications: those with WBC< 3500, history bone marrow disorder, or history of clozapine-induced agranulocytosis

Safety issues in the elderly

Is this seen with FDA approved use?

What are the causes of increased mortality (3)?

o   Antipsychotics sometimes used to treat behavioral disturbances and psychosis associated with dementia in the elderly

o   This is OFF LABEL USE 

o   Conventional antipsychotics --> akathisia and other EPS, anticholinergic delirium, orthostatic hypotension  o   Both high and low potency conventional antipsychotics will cause falls.

o   2008 FDA warning: increased mortality with typical and atypical antipsychotic use in elderly patients treated for dementia-related psychosis (cardiac & infectious causes)

How to choose anti-pyschotic:

What factors should you consider (2)?

1) The effectiveness of most antipsychotics depends on the condition treated.
- Atypicals may be more effective for treatment of negative symptoms
- The success rate of using haloperidol to reduce agitation in medically sick or intoxicated patient is much higher (in the order of 80%) than in schizophrenia.

2) The choice of antipsychotics depends on both the efficacy and the profile of side effects.
- Often start with atypical antipsychotics

- Beware metabolic syndrome in patients with risk factors; regular metabolic monitoring in everyone
- May choose a drug for sedating or energizing effects

 Are atypicals better drugs?

(CATIE trial)

Are they more effective than typicals?

Which is first line and why?

Which 2 drugs are second line despite their superior effectiveness? why?

-    Typical Antipsychotics
o   Reasonable effectiveness, but not a cure 
o   Extrapyramidal side effects difficult to tolerate
o   Most serious major risks are tardive dyskinesia and NMS
-    Atypical Antipsychotics
o   Mostly similar to the conventional antipsychotics in effectiveness
o   Cause less EPS and Tardive dyskinesia
o   But induce the metabolic syndrome
o   First line 
-    Clozapine and Olanzapine
o   Have an edge in effectiveness
o   Cause improvements in refractory patients 
o   Improve cognition, patients have more of a social life
o   However, are much more likely to induce the metabolic syndrome
o   2nd line

A.  NMDA receptors may be pathologically hypofunctional in untreated schizophrenia
B.  Normally, glutamate, via the NMDA receptor regulates (inhibits) mesolimbic dopamine pathway. 
C.  Hypofunction of the NMDA receptor may lead to abnormal dopamine activity in critical brain pathways 
D.  Research into glutamate drugs for schizophrenia has focused on compounds that can enhance NMDA receptor function as well as those that can increase glutamate release. 
E.  In 2007, a specific agonist of the so-called group II metabotropic glutamate receptors, mGlurR2 and mGluR3, was found to be effective in a small study of schizophrenic patients.