PHA 6115 LEC - CNS Stimulants

A condition has been hypothesized to be based on the balanced relationship between 5-HT, NE and DA neurotransmitters.

Depression

Example of antidepressant drugs

TCAs (Tricyclic antidepressants)

[SNRIs(Serotonin and Norepinephrine Reuptake Inhibitors),

NSRIs (Norepinephrine/Serotonin Reuptake Inhibitors)],

SSRIs (Selective Serotonin Reuptake Inhibitors),

MAOIs (Monoamine Oxidase Inhibitors),

5HT2 (Serotonin receptor) Antagonist/SRM (Serotonin Reuptake Modulators)

Serotonin deficiency results to

anxiety,

panic,

phobia,

obsessive compulsions

Norepinephrine deficiency results to

decreased concentration,

decreased working memory,

decreased information processing fatigue

Dopamine deficiency results to

cognitive slowing,

hypersomnia,

anhedonia

Deficiency in dopamine and norepinephrine results to

decreased attention,

psychomotor retardation

Deficiency in serotonin and dopamine results to

food craving bulimia

Deficiency in serotonin, norepinephrine and dopamine results to

depressed mood

MOA options of antidepressants:

Agonize 5HT receptors,

Agonize NE receptors,

Block 5HT reuptake,

Block NE reuptake,

Block metabolism by MAO, Or any combination

These agents target a transporter protein: SERT, NET, and DAT

TCAs (SNRIs/NSRIs),

SSRIs (Selective Serotonin Reuptake Inhibitors),

NDRI (Norepinephrine/Dopamine Reuptake Inhibitor), and

SARI (Serotonin-2 Antagonist and Reuptake Inhibitors)

MOA TCAs:

blocks transporter_____ preventing inactivation of NTs, allowing NTs to function

proteins

MOA TCAs:

increased levels of _____, _____, and _____ relieves the signs of NT deficiency — antidepressant activity

5-HT (Serotonin), NE (Norepinephrine), DA (Dopamine)

SNRIs stands for

Selective Norepinephrine Reuptake Inhibitors

NSRIs stands for

Norepinephrine/Serotonin Reuptake Inhibitors

MOA SNRIs:

SNRI - selectively blocks _____

NET (norepinephrine transporter)

MOA NSRI:

NSRI - blocks NET and SERT (binding is dependent on _____ potency ratio)

NE:5HT (norepinephrine:serotonin)

TCAs are known to produce _____ like phenothiazines

"anti-HAM" effect

anti-HAM effect

anti-H1 (sedation),

anti-𝛼1 (orthostatic hypotension),

anti-M1 (dry mouth, constipation, blurred vision, urinary retention)

SAR TCA (SNRI and NSRI):

2° N is essential for _____ selectivity

SNRI

SAR TCA (SNRI and NSRI):

C3-X = _____ activity and affinity for NET & SERT

increases

SAR TCA (SNRI and NSRI):

B-ring side chain must be _____ long ending with an amine, branching side chain decreases affinity for NET & SERT

3 Carbons

SAR TCA (SNRI and NSRI):

Replacement of Ring N with propylene =

max potency

SAR TCA (SNRI and NSRI):

C10-C11 double bond = SAR TCA (SNRI and NSRI):

increase activity

SAR TCA (SNRI and NSRI):

_____-replacement in C10-C11 leads to an E/Z mixture resulting to preferential NET/SERT binding

O

METABOLISM TCA (SNRI and NSRI):

N-demethylation (SNRI = inactivation, NSRI = leads to NET inhibitors),

Aromatic hydroxylation (Atomoxetine, Duloxetine), CYP 2D6 hydroxylation (SNRI at C10; Clomipramine at C8),

CYP 2D6 demethylation (Clomipramine, Venlfaxine, Doxepin),

Glucuronidation

Dibenzazepines TCAs suffix

"-pramine"

Dibenzazepine TCA drug:

SNRI agent (2° amine)

Desipramine

Dibenzazepine TCA drug:

NSRI prototype drug (3° amine)

Imipramine

Dibenzazepine TCA drug:

NSRI agent (3° amine; Cl attachment at A3)

Clomipramine

Dibenzocycloheptadiene TCAs suffix

"-trptyline" (except Doxepin)

Dibenzocycloheptadiene TCA drug:

SNRI Agent; has N5-C12 double bond

Nortriptyline

Dibenzocycloheptadiene TCA drug:

SNRI Agent has C10-11 double bond

Protriptyline

Dibenzocycloheptadiene TCA drug:

NSRI Agent has a propylene moiety in the B-ring

Amitriptyline

Dibenzocycloheptadiene TCA drug:

NSRI Agent (E/Z isomers)

Doxepin

Doxepin E selectively inhibits

NET (Norepinephrine Transporter)

Doxepin Z selectively inhibits

SER (Serotonin)

Non-TCA SNRIs / NSRIs drug:

SNRI Agent; R-enantiomer is more active

Atomoxetine

Non-TCA SNRIs / NSRIs drug:

NSRI agents

Duloxetine,

Milnacipran,

Venlafaxine

SSRIs stands for

Selective Serotonin Reuptake Inhibitors

SAR SSRI:

Electronegative (-X) 4-substitution = essential for _____ and _____ for SERT

selectivity and affinity

SAR SSRI:

SSRI _____ significantly affects SERT selectivity

stereochemistry

MOA SSRI:

inhibits _____with high affinity and selectivity for SERT

SERT (Serotonin Transporter)

METABOLISM SSRI:

highly metabolized in the liver by CYP isozymes (especially CYP 2D6),

N-demethylation for N-methyl SSRIs,

MAO and Glucuronidation (Sertraline)

SSRI drug:

S-isomer is more active

Escitalopram

SSRI drug:

R-isomer; metabolite of Escitalopram

Citalopram

SSRI drug:

E-isomer is essential for SERT inhibition

Fluvoxamine

SSRI drug:

R-isomer more potent; S-isomer higher affinity for SERT

Fluoxetine (aka Happy Pill)

SSRI drug:

(-)-3S,4R-isomer is more active for SERT inhibition

Paroxetine

SSRI drug:

1S,4S-isomer is more active for SERT inhibition

Sertraline

MAOIs stands for

Monoamine Oxidase Inhibitors

MAO is an enzyme responsible for deamination of

amines

5-HT is a substrate for MAO-_____

A

Epinephrine, NE, and DA are substrates for MAO-_____ and MAO-_____

A and B

MAOIs may result in _____ (severe headache, tachycardia, diaphoresis, hyperpyrexia) when combined with sympathomimetics or tyramine-containing food.

hypertensive crisis

SAR MAOI:

some has similar structure with _____

amphetamine

SAR MAOI:

presence of electron-withdrawing groups =

increase potency

MOA MAOI:

inhibits metabolism of NE, 5-HT and DA =

increasing conc. in the brain

METABOLISM MAOI:

Oxidation and N-acetylation

MAOI drug:

reversible inhibitor of MAO-A antidepressant w/o hypertensive crisis

Moclobemide

MAOI drug:

resembles amphetamine with 𝛼-methyl condensing with β-carbon

Tranylcypromine

MAOI drug:

irreversible inhibitor of the enzyme

Phenelzine

MAOI drug:

selective irreversible inhibitor of MAO-B

Selegiline

SARIs stands for

Serotonin-2 Antagonist and Receptor Inhibitor

SRMs stands for

Serotonin Reuptake Modulators

SAR SARI/SRM:

All agents are _____ derivatives

phenylpiperazine

MOA SARI/SRM:

antagonizes _____ receptors and/or selectively inhibits SERT

5-HT2

MOA SARI/SRM (Trazodone):

_____ at 5-HT2A receptor = blocks excitation, hypnotic effects

antagonist

MOA SARI/SRM (Vilazodone):

partial _____ at 5-HT1A receptor postsynaptic releases of 5-HT

agonist

MOA SARI/SRM (Vortioxetine):

_____ at 5-HT1A receptor and SERT inhibitor

agonist

MOA SARI/SRM (Aripiprazole):

_____ at 5-HT2A receptor, and partial agonist at 5-HT1A receptor

antagonist

SARI/SRM drug:

5-HT1A agonist and SERT inhibitor

Vortioxetine

SARI/SRM drug:

with phenylpiperazine ring 5-HT2A antagonist

Trazodone

SARI/SRM drug:

partial 5-HT1A agonist

Vilazodone

NDRI stands for

Norepinephrine/Dopamine Reuptake Inhibitor

_____ is a unique compound acting on monoamine receptors useful in the management of depression and smoking cessation

Bupropion

MOA NDRI:

selective inhibition of DAT (dopmine transporter) and NET (norepinephrine transporter) =

increasing NE (norepinephrine)

T or F: MOA NDRI:

induces release of DA and NE

T

METABOLISM NDRI:

CYP 2B6 alkyl hydroxylation resulting to hemiketal forms and reduction resulting to theo and erythro hydrobupropion isomers and hemiketal

NaSSA stands for

Alpha-2-Noradrenrgic/Selective Serotonin Antidepressants

is single representative of NaSSA that has a complex mechanism of action

Mirtazapine

MOA NaSSA:

blocks presynaptic 𝛂2-adrenergic and 5-HT receptors (may lead to orthostatic hypotension) =

increasing NE and 5-HT levels.

MOA NaSSA:

selectively antagonizes _____ and _____ (may lead to sedation)

5-HT2 and 5HT3

METABOLISM NaSSA:

CYP3A4: N-demethylation and N-oxidation,

CYP 2D6: aromatic hydroxylation

TCA Pharmacophore rings responsible for antidepressants activity

Rings A and C

T or F: TCAs are more prescribed than SSRIs

F

Methylxanthines:

Of caffeine, theophylline, and theobromine, which has moderate effect?

Theobromine

Methylxanthines:

Most potent in CNS Stimulation, Respiratory Stimulation, and Skeletal Muscle Stimulation

Caffeine

Methylxanthines:

Most potent in Diuresis, Coronary Dilation, and Cardiac Stimulation

Theophylline

Methylxanthines:

1,3,7-Trimethylxanthine

Caffeine

Methylxanthines:

1,3-Dimethylxanthine

Theophylline

Methylxanthines:

3,7-Dimethyxanthines

Theobromine