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Pharmacology of Antipsychotic Agents Cheat Sheet by

Antips­ychotic Drugs

Used for tx of SZ and for the tx of psychotic sx in manic states, major depres­sion, dementia, delirium, and drug-i­nduced psychoses
Anti­psy­chotic Drug Groups:
➤ 1st generation antips­ychotic agents (Typical)
➤ 2nd generation (Atypical)
Can treat both organic and drug-i­nduced

Protot­ypical 1st Generation (Typical)

Low Potency
Chlo­rpr­oma­zine (1st antips­ychotic discov­ered)
 
Thiori­dazine
Medium Potency
Loxapine
 
Perphe­nazine
High Potency
Halo­per­idol
 
Droperidol
 
Fluphe­nazine
 
Pimozide

Chlorp­rom­azine

Very 1st antips­ychotic drug discovered
Protot­ypic, low-po­tency drug (now, rarely used as an antips­ychotic agent)
Has Low affinity for D2 receptors
Main Side Effects: orthos­tatic hypote­nsion (alpha 1 receptor blockade), sedation (H1), and weight gain (H1 and 5-HT-2A)
LOW incidence of EPS (low affinity for D2)
Dermat­olo­gical reactions (urticaria and photos­ens­itivity resembling sunburn) and LFT abnorm­alities

Questions

What is a measure of a drug's affinity for a receptor?
Ki - determined experi­men­tally and is a measure of the affinity for a drug for a receptor (a measure of strength of the drug-r­eceptor intera­ction)
The lower the Ki value, the ________ (lower or higher) the affinity of the antagonist for the receptor.
Higher - On Exam: Ki values will be provided and we'll need to be able to determine the affinity of the antagonist for the receptor

Halope­ridol

Prototypic high-p­otency antips­ychotic agent
High affinity for D2 receptors
Side Effects: EPS and hyperp­rol­act­inemia

1st Gen (Typical) Antips­ych­otics

30 to 50% of SZ pt's do NOT respond to these drugs
Typical antips­ychotic drugs improve positive sx, but only marginally improve negative sx and cognitive impair­ments of Sz
High incidence of ADRs
2nd gen (atypical) antips­ych­otics have been increa­singly replacing them as the 1st-line tx of SZ

2nd Gen (Atypical) Antips­ych­otics

Clozapine, Olanza­pine, Risper­idone, Palipe­ridone, Zipras­idone, Quetia­pine, Iloper­idone, Asenapine, Lurasidone
Aripip­razole, Braxpi­pra­zole, Caripr­azine (Cons­idered 3rd gen)
More effective than 1st gens in treating negative symptoms and improving cognitive functi­oning
Currently 1st line (except clozapine) due to fewer side effects than typical agents
Atypicals have also been associated with a reduction in the incidence of suic­ide in SZ
There is no uniform definition of the term "­at­ypi­cal­" antips­ych­otic. They are a group of drugs that have at least equal antips­ychotic efficacy compared to 1st gen without producing EPS and increased prolactin levels

MOA of 2nd Gens (Atypical)

Block 5-HT 2A receptors (func­tio­nally, they are 5-HT-2A antago­nists)
Also block D2 receptors ⇨ D2 antagonism is still required to achieve antips­ychotic effects
Also block other receptors (*H1, M1, alpha-1) ⇨ Side effects
Zipra­sidone also inhibits 5-HT and NE uptake
 

1st Generation (Typical) Antips­ychotic Drugs

Chemistry
Struct­ure-Fxn relati­onships that were relied upon in the past have become less important
 
Instead, recept­or-fxn relati­onships and functional assays are more clinically relevant
✽ Classi­fic­ation According to Potency ✽
Low Potency
Chlorp­rom­azine
 
Thiori­dazine
Medium Potency
Loxapine
 
Perphe­nazine
High Potency
Halo­per­idol
 
Droperidol
 
Fluphe­nazine
 
Pimozide
✽ MOA ✽
Block dopamine D2 receptors
D2 receptor binding affinity (but not D1) strongly correlates with clinical potency of typical antips­ychotic agents
Blockade of postsy­naptic D2 receptors
⇨ Reduction of dopami­nergic neurot­ran­smi­ssion
D2 receptor blockade in ALL dopami­nergic pathways
⇨ beneficial in the mesolimbic pathway
 
⇨ alleviates positive sx of SZ
 
⇨ It doesn't do really anything for the negative or cognitive sx
 
Side Effects:
 
• D2 receptor blockade in nigros­triatal pathway ⇨ extr­apy­ramidal sx (EPS)
 
• D2 receptor blockade in the tubero­inf­und­ibular pathway ⇨ incr­eased prolactin release from the anterior pituit­ary
Blocks other receptors:
5-HT2A blockade
Contri­butes to antips­ychotic effects
Other receptor blockade
Numerous additional side effect
✽ SIDE EFFECTS ✽
EPS
Various movement disorders associated with antips­ychotic therapy (occurs mostly with 1st gen)
 
Occurs due to D2 receptor blockade in the nigros­triatal pathway
 
• Akathisia: uncont­rol­lable motor restle­ssness
 
• Dystonias: muscular spasms of the neck, eyes, and tongue
 
• Drug-I­nduced Parkin­son's Syndrome: Resembles Parkin­son's Syndrome
 
• Tardive Dyskinesia (TD): occurs after months or years of tx; may become irre­ver­sib­le; repeti­tive, involu­ntary, purpos­eless movements (typically facial muscles are involved); mech­ani­sm: up-reg­ulation and supers­ens­itivity of D2 receptors (that can become permanent)
Hyperp­rol­act­inemia
D2 receptor blockade in the tubero­inf­und­ibular pathway causes increased plasma prolactin levels (Hype­rpr­ola­cti­nemia)
 
Manifested as: Amenor­rhe­a-g­ala­cto­rrhea in women, gyneco­mastia in men, Infert­ility in both men and women
ADRs caused by Blockade of Non-Do­pamine Receptors
1st generation antips­ychotic drugs also block 5-HT-2, alpha 1 adrene­rgic, muscar­inic, and histamine H-1 receptors ⇨ More Side Effects
Blockade of H1 Receptors
Sedation
Blockade of alpha 1 adrenergic receptors
Orthos­tatic hypote­nsion (could result in falls and injuries)
Blockade of muscarinic receptors
dry mouth, urinary retention, blurred vision, tachyc­ardia, consti­pation, toxic-­con­fus­ional state
Blockade of both H1 and 5-HT-2A receptors
Weight gain
ADDI­TIONAL SIDE EFFECTS
Typical antips­ychotic agents affect hypoth­alamic function
impaired ability to regulate body temper­ature
 
Hypo or Hypert­hermia may result, depending on the ambient temper­ature
Thiori­dazine
Cardiac toxicity: reflected in prolon­gation of QTc interval and abnormal config­uration of ST segment and T wave (corre­lates to increased risk of ventri­cular arrhyt­hmias)
 
Retinal Tox: (pigme­ntary retino­pathy): decreased vision and "­bro­win­ing­" of vision
Neurol­eptic Malignant Syndrome (NMS)
Rare, but life-t­hre­atening reaction to antips­ychotic drugs
 
Symptoms: extreme muscle rigidity (lead pipe), hyperr­efl­ecia, fever, unstable BP, tachyc­ardia, sweating, rapid changes in mental status, confusion, and coma
 
Lab: myoglo­binemia and metabolic acidosis
                                                                                           
 

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