Adrenergic Agonists

The primary neurotransmitter in the sympathetic nervous system is __________.

norepinephrine

The two main enzymes that terminate NE signaling are __________ and __________.

MAO, COMT

The key mechanism of NE signal termination is __________ into the presynaptic neuron.

reuptake

In contrast to adrenergic signaling, cholinergic signaling is terminated by __________.

acetylcholinesterase

MAO-A preferentially metabolizes __________, __________, and __________.

norepinephrine, epinephrine, serotonin

MAO-B selectively metabolizes __________ and is targeted in __________ disease.

dopamine, Parkinson’s

The selective MAO-B inhibitor used in Parkinson’s disease is __________.

selegiline

MAO-A inhibition requires dietary restrictions to avoid __________ crisis.

hypertensive

The dietary amine degraded by MAO-A is __________.

tyramine

Foods rich in tyramine include __________, __________, and __________.

aged cheeses, cured meats, fermented products

Combining tyramine-rich foods with MAO-A inhibitors can cause excessive __________ release.

norepinephrine

The recommended washout period between MAOIs and SSRIs is approximately __________.

two weeks

Direct agonists bind directly to __________ receptors.

alpha or beta adrenergic

Indirect agonists promote the release or block the reuptake of __________.

norepinephrine

Examples of direct agonists include __________, __________, and __________.

epinephrine, norepinephrine, phenylephrine

Examples of indirect agonists include __________, __________, and __________.

amphetamine, cocaine, tyramine

Direct agonists generally contain a __________ group, making them more polar.

catechol

Indirect agonists lack phenolic OH groups, increasing their __________ and CNS penetration.

lipophilicity

Amphetamine lacks both β-OH and N-methyl groups, making it a potent __________ stimulant.

CNS

Methamphetamine differs from amphetamine by having a __________ group on the nitrogen, enhancing CNS activity.

methyl

Adding bulky groups to the amine (R3) increases __________ receptor selectivity.

beta-2

Removing OH groups increases lipophilicity but reduces binding to __________ receptors.

adrenergic

Substitution at the α-carbon (R2) decreases receptor binding but increases resistance to __________ metabolism.

MAO

The parent structure of all direct adrenergic agonists is __________.

phenethylamine

__________ has 3,4-diOH, no bulky amine, and targets α + β1.

norepinephrine

__________ has 3,4-diOH and a methyl on the amine, activating α, β1, and β2.

epinephrine

__________ has only a 3-OH group and is α-selective.

phenylephrine

__________ has a 3-OH group and a CH₃ at the α-carbon, favoring α selectivity.

Metaraminol

__________ has 3,4-diOH and an i-Pr group, making it β1 + β2 selective.

isoproterenol

__________ has Et at R2 and i-Pr at R3; it is β-selective.

isoetherine

__________ has 3,5-diOH and a t-butyl group, giving it β2 selectivity.

terbutaline

Removing OH groups from catechols reduces __________ and increases __________.

polarity, CNS penetration

Amphetamine and methamphetamine are both basic and are formulated as __________.

salts

Drugs with bulky amines have decreased MAO metabolism and increased __________.

oral availability

Selegiline is metabolized into __________ and __________, which may cause false positives on drug screens.

amphetamine, methamphetamine

Methamphetamine is more __________ than amphetamine, allowing faster CNS entry.

lipophilic

Increased lipophilicity leads to greater __________ potential due to rapid CNS stimulation.

abuse

Methamphetamine has a longer half-life due to resistance to __________ metabolism.

MAO

A general rule: the fewer the __________ groups, the more lipophilic the compound.

hydroxyl (OH)

MAO inhibitors bind irreversibly to the enzyme’s __________ cofactor.

FAD

Once MAO is inhibited, the enzyme must be __________ to restore activity.

resynthesized

The pharmacodynamic effects of MAO inhibitors persist after drug clearance due to __________ inhibition.

irreversible

Drugs like __________ (a PPI) and __________ (a COX inhibitor) are other examples of irreversible inhibitors.

omeprazole; aspirin

COMT inhibitors are used in Parkinson’s disease to prolong the action of __________.

L-DOPA

The COMT inhibitor __________ prevents breakdown of L-DOPA by blocking methylation.

entacapone

Entacapone contains both catechol and __________ groups that make it an electron-withdrawing COMT blocker.

nitro

Lack of a catechol group increases __________ by preventing COMT metabolism.

half-life

When ranking drugs for CNS stimulation, consider lipophilicity. Rank these from most to least CNS penetration:

methamphetamine > amphetamine > pseudoephedrine

In “CAT-BAM,” C stands for __________, which leads to COMT metabolism and short half-life.

catechol

In “CAT-BAM,” A stands for alpha selectivity from a __________ group.

3-OH only

In “CAT-BAM,” T stands for __________ substitution at the amine, favoring β2 activity.

tert-butyl

In “CAT-BAM,” B stands for __________ R2 groups that block MAO metabolism.

bulky

In “CAT-BAM,” M stands for __________, which irreversibly inhibit enzymes and require washout.

MAOIs