531 Lec 33

What nervous system is dopamine found

Peripheral

Can dopamine cross the BBB

No

What affects does dopamine have in the periphery

Inhibits NE release and acts as a vasodilator in the blood vessels

Increases sodium excretion and urine output in the kidneys

Reduces insulin production in the pancreas

Reduces GI motility and protects intestinal mucosa

Reduces activity of lymphocytes in immune system

Know the enzymes and substrates and transformations of the biosynthetic pathway leading to dopamine production from L-tyrosine.

Know the catabolic pathways (enzymes/substrates/transformations) that break down dopamine into homovanillic acid.

Dopamine receptors are….

G protein coupled receptors

D1 type receptors

D1, D5

D2 type receptors

D2, D3, D4

Understand the dopamine hypothesis and how it relates to Schizophrenia and associated therapeutics

States that overactive dopaminergic transmission in the CNS causes psychosis

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\*No direct evidence for this

positive cognitive symptoms.

Change in thoughts / feelings that add in to a person’s experience

\-Hallucinations

\-Delusions

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(mesolimbic system hyperactivity)

negative cognitive symptoms.

Reflect a decrease in, or loss of, normal functions

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\-Little display/range of emotions (affective flattening)

\-Lowered levels of motivation or drive (avolition)

\-Lack of interest in other people

\-Inability to feel pleasure

\-Inability to speak due to mental confusion (alogia)

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(mesocortical system hyperactivity)

Know the 4 dopamine pathways relevant in Schizophrenia – know how dopamine activity is imbalanced in the mesolimbic and mesocortical areas and what symptoms are associated with each.– you absolutely need to know this and it will appear in some form on a quiz/exam

1)Mesolimbic- increase in DA transmission here causes positive symptoms

2)Mesocortical- decrease in DA transmission here causes negative symptoms

3)Nigrostriatal- Schizophrenia drugs acting here cause EPS

4)Tuberoinfundebulum- Schizophrenia drugs acting here causes hyperprolacteinemia

EPS

extrapyramidal symptoms- involuntary movements, jerkiness, tremors, spasms

Hyperprolactinemia

Higher than normal plasma levels of prolactin, produced by pituitary to stimulate breast milk production 2

Understand how D2 type receptor antagonism helps treat Schizophrenia by altering dopamine action in a specific region of the brain and how this same action in other areas of the brain can exacerbate side effects.

An antagonist binding the D2 receptor blocks DA from binding. NO signaling occurs while the antagonist is bound

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The net effect is less DA transmission in hyperactive and hypoactive areas

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Suppresses hyperactive DA transmission in the Mesolimbic which helps alleviate positive symptoms

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Hypoactive transmission in the Mesocortical is not improved which does not help negative symptoms

D1 Type receptor type impact on adenylate cyclase and cAMP level

Stimulates adenylate cyclase → increase cAMP

D2 Type receptor type impact on adenylate cyclase and cAMP level

Inhibits adenylate cyclase → decreased cAMP

Typical antipsychotics

•Antagonize mesolimbic and mesocortical D2 receptors

•Adverse effects likely mediated by binding to D2 receptors

•EPS side effects associated with >80% occupancy of D2 receptor by drug though this is not an absolute rule

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\*Less commonly used due to side effects

Atypical Antipsychotics

•Generally, show combined antagonist activities at D2 and 5HT2 receptors

•Avoid EPS side effects but may be due to weaker affinity at dopamine receptors

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\*First line for schizophrenia, fewer side effects, more expensive

Know the pharmacophoric model for phenothiazine based, typical neuroleptics.

An electron withdrawing substituent is important to activity (Cl)

Side chain amine is protonated at pH7 (important)

Side chain has a 3 carbon linker often separated by 2 amines (need 3 for antipsychotic activity)

chloropromazine/Thorazine

•First antipsychotic discovered

•Usually administered as an injectable

•Complex metabolism→ 100 metabolites, some active at D2 receptor

•Black box warning for death of elderly with dementia

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**Side effects: Sedative, EPS**

Why are long acting neuroleptics helpful in treating schizophrenia?

→Adherence is a problem especially in this patient population

incorporating long chain fatty acid esters leads to ______acting neuroleptics because…

Long acting because long chain fatty acid esters are released slowly into bloodstream from lipophilic tissue

What physiochemical characteristic of long chain fatty acid esters imparts longer duration of action – be able to put them in order of shortest acting to longest acting.

Longer chain= longer duration of action

Know the pharmacophore of butyrophenone-based typical neuroleptics.

Tertiary amine four carbons away from phenyl group

Ketone

Most potent analogs have X=F at the 4 position

Piperidine can also be another cyclic amine

haloperidol

Typical neuroleptic- 1st gen antipsychotics

Butyrophenones

>affinity for DA receptors than chlorpromazine

Less weight gain than chlorpromazine

Used for manic phase of bipolar disorder

haloperidol decanoate

Typical neuroleptic- 1st gen antipsychotics

Butyrophenones

Injection (every 4-6 weeks)

Droperidol

Typical neuroleptic- 1st gen antipsychotics

Butyrophenones

Short acting

Use: anesthesia for its sedating and antiemetic effects

Use: psychiatric emergency as a sedative neuroleptic

Know what distinguishes the Atypical/second generation neuroleptics from Typical/first generation neuroleptics

→Additional antipsychotic action at other receptors in addition to or instead of DA D2 receptor antagonism

→ Significant activity at 5HT2 muscarinic, adrenergic alpha1&2 and histamine in addition to DA receptors

→Weaker affinity for D2 receptor compared to first gen

→Difficult to classify agonism/antagonsim

→Fewer extrapyramidal effects compared to first gen neuroleptics

→Better at reating negative and positive symptoms

→Side effect profile and effectiveness against - and + symptoms distinguishes typical vs atypical drugs

Atypical neuroleptic- Second gen antipsychotics

Lumateperone (Caplyta)

Clozapine

Olanzapine

Quetiapine

Loxapine/Amoxapine

Asenapine

Risperidone

Ziprasidone

Apripiprazole

Brexipiprazole

Cariprazine

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Lumateperone (Caplyta)

Atypical neuroleptic- Second gen antipsychotics

Antagonist at D2 receptors and 5HT receptors

Treats positive and negative symptoms of schizophrenia

Oral administration

clozapine

Atypical neuroleptic- Second gen antipsychotics

•5HT2A antagonist, moderate D4 and weak D2 receptor antagonism

•Good for patients who dont respond to 1st gen

•Minimal EPS

•Also treats negative symptoms of schizophrenia

•1-2% patients suffer fatal agranulocytosis

•Incidence of weight gain is high with clozapine

•Orally active, metabolized mostly by CYP1A2

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Drug interaction: Smoking indices CYP1A2 (adjust dose up)

Drug interaction: ciprofloxacin inhibits CYP1A2(adjust dose down)

Olanzapine (Zyprexa)

Atypical neuroleptic- Second gen antipsychotics

•Higher affinity at DA D2 and 5HT2A receptors receptors than clozapine

•Antagonist activity at these receptors

•Similar side effect profile to clozapine

•**agranulocytosis not observed**

•Minimal EPS

•Treats negative and positive symptoms of schizophrenia

•Orally active

•Schizophrenia and bipolar

Amoxapine

Atypical neuroleptic- Second gen antipsychotics

metabolite of loxapin via N dealkylation

•High affinity at D2, 5HT2 and H1 receptors

•Amoxapine has moderate SERT and NET blocking activity which gives it some antidepressanr activity too

•Schizophrenia and bipolar

Risperidone

Atypical neuroleptic- Second gen antipsychotics

•Very high affinity for 5HT2A - antagonist

•High affinity for dopamine D2- antagonist

•High affinity for H1 and alpha1 receptors

•No affinity for muscarinic receptors

•Higher incidence of EPS than other 2nd gen neuroleptics

•Weight gain

•Treats both positive and negative symptoms

Ziprasidone

Atypical neuroleptic- Second gen antipsychotics

•High affinity for 5HT2A, D2, H1, alph1&2- antagonist

•Partial agonist activity at 5HT1a

•Lower incidence of EPS•Blocks reuptake of SERT and NE

•Treats both positive and negative symptoms

Abilify/aripiprazole

Atypical neuroleptic- Second gen antipsychotics

•Partial agonist at D2

•High affinity for D2/D3

•High affinity for 5HT receptors

•Moderate affinity for H1 and alpha1/2

•Lacks affinity for muscarinic receptors

•Low propensity to cause EPS

•Low incidence of hyperprolactinemia

Rexulti/Brexpiprazole

Atypical neuroleptic- Second gen antipsychotics

•Partial agonist at D2

•Used to treat schizophrenia

•Used as adjunct therapy for major depressive disorder

•Less EPS than abilify

Cariprazine/Vraylar.

Atypical neuroleptic- Second gen antipsychotics

•Partial agonist at D2 and D3

•Selectivity at D3>D2

•Used to treat schizophrenia

•Used ad adjunct therapy for Major Depressive Disorder

•Also used for: bipolar mania, bipolar depression

•Negative and posotive sumptoms

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•Longer half life than abilify