Neurotransmitters and receptors

Question 1

Adrenergic: Epinephrine (adrenaline) & Norepinephrine (NE or noradrenaline)

Answer 1

Receptors: Alpha 1 and 2, beta 1, 2, &3, G-protein-coupled receptors

Question 2

Serotonergic: Serotonin (5-HT - 5-hydroxytryptamine)

Answer 2

Receptors: G protein-coupled receptors (5-HT1, 5-HT2, 5-HT4, 5-HT7) or ligand-gated ion channels (5-HT3)

Question 3

Dopaminergic: Dopamine (DA) receptors

Answer 3

receptors: D1 to D5; & trace amine-associated receptor (TAAR)

Question 4

GABAergic: Gamma aminobutyric acid (GABA)

Answer 4

inhibitory: GABA-a, GABA-b, GABA-c

Question 5

Glutamatergic: Glutamate

Answer 5

Excitatory: (NMDA: N-methyl-D-aspartate receptor, AMPA, 1 kainate, and omega receptors)

Question 6

Histamine receptors

Answer 6

receptors: H1 to H4

Question 7

Acetylcholine (Ach)

Answer 7

Receptors: cholinergic receptors (mAChRs-Muscarinic (M1 to M5) and nAChRs-Nicotinic (N1 and N2))

Question 8

D2 blockade

Answer 8

• dopamine tracts: mesolimbic: reduction in positive sxs
• Nigrostriata - EPS
• tuberoinfundibulnar: elevation in prolactin
• Mesocortical tract - exacerbate negative sxs

Question 9

H1 blockade effects

Answer 9

• sedation, drowsiness, appetite increase, wt gain, anti-emetic effect, anxiolytic effects

Question 10

M1 blockade

Answer 10

Help with EPS; anticholinergic side effects (dry mouth, dry eyes, blurred vision, constipation, urinary retentions), sinus tachycardia, QRS changes, confusion, worsening cognition, delirium

Question 11

M3 blockade

Answer 11

Reduced insulin release, glucose intolerance, T2DM (beta cell failure)

Question 12

a1 blockage

Answer 12

Postural hypotension, dizziness, reflex tachycardia, sedation

Question 13

a2 blockade

Answer 13

presynaptic receptors enhances serotonergic and noradrenergic transmission; may improve cognitive deficits and have antidepressant activity

Question 14

5-HT1A blockage

Answer 14

antagonism/partial agonism: hypothesized to be related to pro-cognitive, anxiolytic, and antidepressant effects

Question 15

5-HT2A blockade

Answer 15

sedation, dopaminergic actions may stop extrapyramidal symptoms (EPS), improve negative, positive and mood symptoms

Question 16

5-HT2C blockage

Answer 16

increased appetite and weight gain; hypothesized to be associated with pro-cognitive and antidepressant effects

Question 17

5-HT7 blockage

Answer 17

hypothesized to be associated with pro-cognitive, anxiolytic, and antidepressant effects

Question 18

Synthesis of Serotonin and Norepinephrine

Answer 18

5-HT is synthesized from amino acid tryptophan by the tryptophan hydroxylate (TPH). Aromatic L-amino acid decarboxylase converts 5-hydroxytryptophan to serotonin……
- rate limiting step enzymes are regulated by feedback inhibition via auto receptors located presynaptically (first step)

Question 19

What are the 5 areas on a synapse that can regulate serotonin and norepinephrine?

Answer 19

1. tryptophan hydroxylase
2. Sodium/5-HT reuptake transporter
3. MAO degrades 5-HT to 5-hydroxyindole acetaldehyde
4. 5-HT1b receptor (autoreceptor)
5. VMAT

Question 20

MAO inhibitors

Answer 20

• isocarboxazid (Marplan)
• Phenelzine (Nardil)
• Selegiline (Edepryl, Emsam)
• Tranylcypromine (Parnate)

Question 21

MAOi MOA

Answer 21

block deamination of monoamines by inhibiting the functional flavin moiety of MAO; increase the 5-HT and NE available in cytoplasm of presynaptic neurons which leads to increased uptake and storage of 5-HT and NE in synaptic vesicles and leakage into the extracellular space

Question 22

drugs in MAOi class

Answer 22

-Hydraxines (Phenelzine) - irreversible MAOi
-Non-hydraxines (Tranylcypromine) - irreversible MAOi
- Isocarboxazid - reversible MAOi
- Selegiline (transdermal patch, less tyramine toxicity

Question 23

MAOi Adverse Effects

Answer 23

• systemic tyramine toxicity from foods, wines, etc. leads to uncontrolled catecholamine release, can induce hypertensive crisis

Question 24

MAOi contraindications

Answer 24

concomitant use of: sympathomimetic drugs, other MAOis, L-DOPA, L-trypophan, phenylalanine, bupropion, excessive coffee, chocolate intake, high tyramine containing foods, heart failure, general anesthesia, local anesthesia with vasoconstrictors, liver disease

Question 25

MAOi: Dietary restrictions

Answer 25

Tyramine - cured meat, aged cheese, aged and fermented food and drink

Question 26

Tricyclic Antidepressant (TCA) MOA

Answer 26

-Desipramine - alpha1 adrenoceptors and desensitize alpha2 autoreceptors --> equilibration of NE system

Question 27

TCA moa, clinical application, AE, CI

Answer 27

MOA: inhibit reuptake of 5-HT and NE from synaptic cleft by blocking 5-HT and NE reuptake transporters, thereby enhancing postsynaptic responses Clin. App: Depression second-line treatment AE: heart block (abnormal heart rhythm), cardiac arrhythmia, ORTHOSTATIC HYPOTENSION CI: concomitant use of MAOIs, cardiac conduction system defects, patients recovering from myocardial infarction

Question 28

Muscarinic Adverse Events

Answer 28

- blurred vision - dry mouth - impaired memory - constipation - urinary retention

Question 29

Dopaminergic D2 AE

Answer 29

- extrapyramidal movement disorders - prolactinemia - sexual dysfunction

Question 30

a1-adrenergic AE

Answer 30

- postural hypotension - dizziness - reflex tachycardia

Question 31

Histaminergic H1 AE

Answer 31

- sedation - drowsiness - weight gain - hypotension

Question 32

SSRI - Selective Serotonin Reuptake Inhibitors MOA

Answer 32

first line treatment for depression MOA: selectively inhibit reuptake of serotonin and thereby increase synaptic serotonin levels; also cause increased 5-HT receptor activation and enhanced postsynaptic responses -- well absorbed orally; food intake may alter absorption of some SSRIs w/o affecting clinical efficacy

Question 33

SSRI drugs

Answer 33

**Fluoxetine** Fluvoxamine Paroxetine Sertraline Citalopram Escitalopram

Question 34

SSRI clinical applications

Answer 34

depression, anxiety, OCD, PTSD, panic disorders, bulimia nervosa (<-- Fluoxetine)

Question 35

SSRI AE, CI

Answer 35

AE: decreased effects and less toxicity in overdose compared to MAOIs and TCA; sexual dysfunction; GI distress; vasospasm; sweating; anxiety; somnolence; nausea; diarrhea; agitation -----> Serotonin syndrome from concomitant use of MAOIs; hyperthermia, muscle rigidity, myoclonus, rapid fluctuation in mental status and vital signs. Can lead to mania in bipolar patients CI: concomitant use of MAOI

Question 36

Serotonin-Norepinephrine Reuptake inhibitors (SNRI) drugs in class

Answer 36

**Duloxetine** Venlafaxine Desvenlafaxine Milnacipran Levomilnacipran (FETZIMA)-newer SNRI

Question 37

SNRI moa, clin. app., AE, CI

Answer 37

MOA: blocks 5-HT reuptake transporter and NE reuptake transporter in a concentration dependent manner Clin. App.: depression, anxiety, panic disorder w/ or w/o agoraphobia, pain syndromes, fibromyalgia AE: may exacerbate mania or depression in susceptible patients CI: Concomitant use of monoamine oxidase inhibitors

Question 38

Norepinephrine and Dopamine Retake Inhibitor (NDRI) drugs

Answer 38

**Buproprion** - aminoketone antidepressant that is selective inhibitor of the norepinephrine and dopamine uptake