Intro to Neuropsychopharmacology Part 1 Flashcards
1
Q
Biogenic Amine Pathways in the Brain:
A
-
Neurons containing norepinephrine are located in the locus coeruleus
- innervate nearly every part of the CNS
-
Neurons containing serotonin are located in two groups of raphe nuclei
- project to most of the brain
- Neurons containing dopamine are located in the substantia nigra and the ventral tegmental area of the midbrain
-
Neurons containing ACh are located in the basal forebrain complex
- includes the septal nuclei and nucleus basalis
- project to the hippocampus and the neocortex
2
Q
Dopamine pathways in the brain include:
A
- Nigrostriatal
- Tubero-infundibular
- Mesolimbic
- Mesocortical
3
Q
- GABA localization:
- Limbic Structures:
A
- GABA Localization: Substantia Nigra, Globus Pallidus, Hippocampus
- Limbic structures: Amygdala, Hypothalamus, Spinal cord
4
Q
AFFECTIVE DISORDERS:
A
- Major Depressive Disorder
- Unipolar
- Bipolar
- Dysthymic Disorder
- Mania
5
Q
Monoamine Theory of Depression
A
Based on pharmacological evidence:
- the ability of known antidepressant drugs (TCAs and MAO inhibitors) to facilitate monaminergic transmission
- drugs such as reserpine that depletes amines to cause depression
- Other pharmacological evidence (ie. delay in onset of effects) fails to support the traditional monoamine hypothesis
- But, pharmacological manipulation of monoamine
transmission remains the most successful approach to treating depression
6
Q
Neurochemical Effects of Tricyclic Antidepressants:
A
-
Blockade of transmitter uptake
- NE and 5–HT
- Receptors and second messengers
7
Q
Drugs Used in the Treatment of Depressive Disorders:
A
- Serotonin Specific Reuptake Inhibitors – SSRIs
- Serotonin – Norepinephrine Reuptake inhibitors – SNRIs
- Atypical Antidepressants – Mirtazapine and Bupropion
- Monoamine Oxidase Inhibitors
8
Q
SSRI:
Pharmacokinetics and metabolism
A
- Most commonly used anti-depressants
- Favored because of side effect profile
- Both long and short half-life compounds available
- Fluoxetine has a long half-life active metabolite
9
Q
**SSRI: **
Pharmacological properties and side effects
A
- Antidepressant actions similar in efficacy and time- course to TCAs
-
Common side effects include:
- Nausea and vomiting
- Insomnia
- Nervousness
- Sexual dysfunction
- Acute toxicity is less than with TCAs and MAO inhibitors ⇒ Less risk of overdose
-
Serotonin reaction can occur in presence of MAO inhibitors
- Includes hyperthermia, muscle rigidity and cardiovascular collapse
- Black box warning for use in teens
- SSRI discontinuation syndrome
10
Q
SSRI Discontinuation Syndrome:
A
- Symptoms occur within 1 to 7 days after stopping an SSRI
- Most common with shorter acting drugs like sertraline and fluvoxamine
- Not with fluoxetine
- Symptoms can include: dizziness, light-headedness, vertigo, anxiety, fatigue, headache, tremor, visual disturbances, etc.
11
Q
SSRIs:
Clinical uses
A
Approved clinical uses include:
- Major depressive disorder
- Obsessive-Compulsive disorder
- Panic disorder
- Social phobia
- PTSD
- Generalized anxiety disorder
- PMS
- Hot flashes associated with menopause
12
Q
SSRI Drugs (2):
A
- Fluoxetine
- Sertraline
13
Q
Fluoxetine:
A
- First SSRI on market
- Effects on drug metabolism
-
Active metabolite with long half-life
- 7 days or more
- Available as sustained released product
- PMS
14
Q
Sertraline:
A
- Similar in action to fluoxetine with less effects on drug metabolism
-
Shorter half-life
- OCD, PTSD, Panic attacks
15
Q
SNRI drugs:
**Duloxetine **(Cymbalta®)
A
- 12-18 hour half-life
- Side effect profile is more SSRI-like than TCA-like
- Use with caution in patients with liver disease
- Also approved for use in fibromyalgia, diabetic neuropathy, back pain, and osteoarthritis pain
16
Q
Atypical antidepressants:
A
- Drugs without typical tricyclic structure or SSRI action
- May or may not block catecholamine uptake
17
Q
Atypical antidepressants drugs (2):
A
- Bupropion
- Mirtazapine
18
Q
Bupropion:
A
- Weakly blocks norepinephrine and dopamine uptake
- Also approved for nicotine withdrawal and seasonal affective disorder
- No weight gain or sexual dysfunction
19
Q
Mirtazapine:
A
- Blocks presynaptic alpha2 receptors in brain
- Increases appetite
- AIDS patients
20
Q
Tricyclic Antidepressants:
A
- First highly effective drugs for the treatment of depression
- Block NE and 5-HT reuptake
- Now used secondarily to SSRIs and other newer compounds
21
Q
Tricyclic Antidepressants:
Pharmacokinetics and Metabolism
A
- Rapidly absorbed after parenteral or oral administration
- Relatively high concentrations are found in the brain and heart
- Imipramine and amitriptyline are demethylated to active metabolites which are used as drugs by themselves
- Long plasma half-life: 8 to 100 hours
22
Q
Tricyclic Antidepressants:
Pharmacological Properties and Side Effects
A
- Produces elevation of mood in depressed patients after about 2 to 3 weeks
- Decreases REM and increases stage 4 sleep
- Prominent anticholinergic effects
- Cardiac abnormalities
- Sedation
- Cardiac abnormalities
- **Overdoses: **acute toxicity
- Symptoms include hyperpyrexia, hyper- or hypotension, seizures, coma and cardiac conduction defects
23
Q
Tricyclic Antidepressants:
Drug interactions
A
- Guanethidine - blocks guanethidine uptake
- Sympathomimetic drugs - particularly indirect acting ones
- Effects on absorption and metabolism of other drugs
24
Q
Tricyclic Antidepressants:
Therapeutic uses
A
-
Treatment of major depression
- replaced by SSRIs as primary treatment
- Enuresis in childhood – Imipramine
- Chronic pain – amitriptyline
- Obsessive-compulsive disorders – clomipramine and SSRIs
- Other tricyclic antidepressants – amoxapine, desipramine, doxepin, nortriptyline
25
**Monoamine Oxidase Inhibitors:**
* Block the oxidative deamination of naturally occurring biogenic amines, such as NE, DA and 5-HT and ingested amines
* Monoamine oxidase is found in the mitochondrial fraction of neurons
* It is also found in liver, lung and other organs
* **Two forms of MAO** - A and B
* Antidepressant action probably due to **inhibition of MAO-A**
26
**Phenelzine:**
**irreversible inhibitor of MAO**
27
**Monoamine Oxidase Inhibitors:**
* **Pharmacological Properties:**
* **Drugs and Food Interaction:**
* **Therapeutic Use:**
* **Pharmacological Properties:**
* Antidepressant action takes about **2 weeks**
* Produces **mood elevation in depressed patients**
* May progress to hypomania, particularly in bipolar disease.
* **Acute toxicity** can produce agitation, hallucinations, hyperpyrexia, convulsions and changes in blood pressure
* **Drugs and Food Interaction:**
* **Tyramine** from food ⇒ can produce
* *hypertensive crisis**
* **Therapeutic Use:**
* ****Major depression
* not drug of first choice
28
**Psychosis:**
* A general term for **major mental disorders characterized by:**
* **derangement of personality**
* **loss of contact with reality**
* **delusions**
* **hallucinations**
* prototype is **Schizophrenia**
29
**Etiology of Schizophrenia:**
* cause(s) of schizophrenia are yet unknown
* **DOPAMINE HYPOTHESIS:**
* ****Schizophrenia results from _hyperactivity of
dopaminergic neurons or their receptors,_
particularly those with terminals in limbic areas
of the brain
30
What do all anti-psychotic drugs interact with?
**dopamine systems**
31
**Dopamine receptors:**
1. **D1 type** (D 1 and D 5) – **Activate adenylyl cyclase**
2. **D2 type** (D 2, D 3, D 4) – **Inhibit adenylyl cyclase**
3. Autoreceptors
32
Which receptors do atypical antipsychotic drugs target?
**DA + 5HT2 receptors**
33
Treatment of schizophrenia:
* **drug treatment** is the most common effective therapy
* **it is not curative**
34
**Actions of Antipsychotic Drugs:**
1. **Decrease in psychotic behavior** - drugs differ only in potency
* All symptoms of schizophrenia are not equally well treated
* exception **Clozapine** and other atypical drugs
2. **Sedation**
3. **Extrapyramidal actions** - result of dopamine receptor blockade
* Include, Dystonias Parkinsonism and Akathisia
* Long-term treatment ⇒ **Tardive dyskinesia** –
* Oral-facial dyskinesias, choreoathetoid movements
4. Neuroendocrine effects - result of dopamine receptor blockade
5. Orthostatic hypotension - alpha adrenergic receptor blockade
6. Weight gain - Diabetes related events are more common with atypicals, particularly olanzapine, risperidone, clozapine and quetiapine.
7. **Neuroleptic malignant syndrome** – Fever, mutism, EPS, possible death
* Treatment includes cooling and hydration,
bromocriptine and dantrolene
35
**Prototype available typical antipsychotic drugs classes (2):**
1. Phenothiazines
2. Butyrophenone Derivative
36
* *Phenothiazines**
* * (3):**
1. **Chlorpromazine**
2. **Thioridazine**
3. **Fluphenazine**
37
* *Chlorpromazine**
* *:**
**aliphatic side chain**
* **low to medium potency**
* sedative
* **pronounced anticholinergic actions**
38
**Thioridazine:**
**piperidine side chain **
* **low potency**
* sedative
* **less extrapyramidal actions**
* anticholinergic
39
**Fluphenazine:**
**piperazine side chain**
* **high potency**
* less sedative
* less anticholinergic
* **more extrapyramidal reactions**
40
**Haloperidol:**
**Butyrophenone Derivative**
* not chemically related to the phenothiazines but is **pharmacologically similar to the high potency piperazine derivatives**
41
**Atypical Antipsychotic Agents (5):**
1. **Clozapine**
2. **Olanzapine**
3. **Risperidone**
4. **Quetiapine**
5. **Aripiprazole**
42
**Atypical Antipsychotic Agents:**
**Uses**
1. **Acute psychotic episodes**
2. **Chronic schizophrenia**
3. Manic episodes, bipolar disorder
* **aripiprazole, olanzapine, quetiapine,** ziprasidone, **risperidone**, asenapine, lurasidone
4. **Augmentation of antidepressant action:**
* **aripiprazole, olanzapine, quetiapine**
5. Tourette’s syndrome
6. Antiemesis – not thioridazine
43
**Clozapine:**
* **Blocks D4 and 5-HT2 receptors**
* Little effect on D2
* **Muscarinic antagonist**
* **Less extrapyramidal symptoms**
* May cause serious **agranulocytosis or other blood dyscrasias** in a small percentage of patients
* Weight gain
* Improves negative symptoms
44
**Olanzapine:**
* Related to clozapine
* **More potent as 5-HT2 antagonist**
* D1 and 2 antagonist, some D4
* **Few extra pyramidal symptoms**
* **No agranulocytosis**
* Weight gain and diabetes risk
* Less seizure incidence than clozapine
* Reports of olanzapine abuse
45
**Risperidone:**
* **Combined dopamine and serotonin receptor antagonist**
* **Has a low incidence of extrapyramidal side effects**
* Greater reduction in negative symptoms
* Less seizure activity and less antimuscarinic than
clozapine
* Paliperidone (Invega®) is the active metabolite of risperidone
* Both are also available as intramuscular depot preparations
46
**Quetiapine:**
* Structurally related to clozapine with **effects on D2 and 5-HT2 receptors **
* Similar to risperidone and olanzapine in effects on schizophrenia symptoms and side effects
* Approved for augmentation in depression
* Has some abuse potential
47
**Aripiprazole (Abilify®): **
* **D2 partial agonist and 5-HT2 antagonist**
* **adjunct in the treatment of depression**
