(4) 29-30: Adrenergic Agonists I and Adrenergic Agonists II

PART 1 — THE FOUNDATION

Sympathetic nervous system (SNS) main function?

Fight or flight.

Sympathetic nervous system (SNS)

Give me all the neurotransmitter and their locations

Location	Neurotransmitter
Preganglionic neuron found in the lumbar and thoracic region of the spinal cord	Acetylcholine (ACh)
Most postganglionic neurons	Norepinephrine (NE)
Renal vascular system	Dopamine
Adrenal medulla	80% epinephrine, 20% NE

What is Adrenergic agonists in nutshell?

• sympathomimetics: Drugs that mimic sympathetic nervous system stimulation.

Adrenergic receptors

Receptor	What happens when activated?	G protein
α1 = SQUEEZE 🩸	vasoconstriction (↑ BP) bladder sphincter contract (urine storage)	Gq
α2 = STOP 🛑	↓ NE release (↓ sympathetic activity) ↓ insulin release	Gi → ↓ cAMP
β1 = 1 HEART ❤	↑ Heart rate and contraction	Gs → ↑ cAMP
β2 = 2 LUNGS 🫁	vasodilation, bronchodilation uterine relaxation	Gs → ↑ cAMP
β3 = PEE 🚽	Bladder detrusor relaxation (urine storage)	Gs → ↑ cAMP

D1	Renal vasodilation → ↑ kidney blood flow

✅ Professor repeatedly emphasized that you can predict most adrenergic drug effects simply by knowing the receptors.

Important definitions

• Positive inotropy =

• Positive chronotropy =

• Vasoconstriction =

• Vasodilation =

• Detrusor muscle =

• Positive inotropy = ↑ force of heart contraction.

• Positive chronotropy = ↑ heart rate.

• Vasoconstriction = vessels narrow → ↑ resistance.

• Vasodilation = vessels widen → ↓ resistance.

• Detrusor muscle = bladder muscle that relaxes during urine storage.

Three types of adrenergic agonists

Type	Mechanism
Direct-acting	Binds adrenergic receptors
Indirect-acting	Increases available NE
Mixed-acting	Both mechanisms

Direct-acting adrenergic agonists: drug classification

• Endogenous catecholamines

• Prototype

Three types of mechanisms for indirect-acting adrenergic agonist

1. ↑ NE release from nerve terminals.

2. Block NE reuptake through NET (uptake-1).

3. Block breakdown by MAO and COMT.

NET = transporter that normally takes NE back into the nerve.

define

Endogenous catecholamines

chemicals naturally produced by your body.

What are the 3 endogenous catecholamines that also act as direct-acting adrenergic agonist drugs?

• Epinephrine

• Norepinephrine

• Dopamine

Receptor comparison — Epinephrine vs NE vs Dopamine

Receptor	Epinephrine	Norepinephrine	Dopamine
α1	✓	✓ (strong)	✓ at high doses
α2	✓	✓
β1	✓	✓	✓
β2	✓	Very little
D1			✓

Endogenous catecholamines

Most important distinction

• Epinephrine: Low-dose β2 vs high-dose α1

• Norepinephrine: Strong ↑ BP → reflex bradycardia

• Dopamine: Dose-dependent receptor effects

Epinephrine (EPI)

topic overview

• What is used during Anaphylaxis?

• Why epinephrine is useful in emergencies?

• Other important facts

Epinephrine (EPI)

What is used during Anaphylaxis?

Epinephrine (drug of choice).

Epinephrine (EPI)

Why epinephrine is useful in emergencies?

Receptor → What it causes	Why we use epinephrine
α1 → vasoconstriction → ↑ BP	Severe hypotension/shock
β2 → bronchodilation → airways open	Breathing difficulties/anaphylaxis
β1 → ↑ HR and force	Supports cardiac activity
α1 → vasoconstriction → ↓ blood flow at injection site	Makes local anesthetic last longer

Epinephrine (EPI)

Other important facts

• Low dose → β2 vasodilation; high dose → α1 vasoconstriction

  • Low-dose EPI → ↑ systolic BP, ↓ diastolic BP.

• metabolic effects:

  • β → ↑ glycogenolysis → ↑ blood glucose.

  • α/β: decrease GIT motility

  • ↓ insulin release (α2), ↑ free fatty acids

• Important side effects: Anxiety, tremor, headache, arrhythmias.

• PK: Ineffective orally; metabolized by MAO/COMT.

Norepinephrine vs dopamine

What they support?

support BP and circulation.

Norepinephrine

α1 → strong vasoconstriction → ↑ BP → baroreceptor reflex → Reflex bradycardia (↓ HR), which is an adverse effect

• Use: Severe hypotension/shock.

Dopamine

Dopamine

• D1 → renal vasodilation → ↑ blood flow.

• β1 at low dose→ ↑ HR + force → ↑ cardiac output.

• α1 at high doses → vasoconstriction → ↑ BP.

Use: Low cardiac output/hypotension in critical care.

Direct-acting drug prototypes - CHART

Drug	Receptor → effect	Main use	Key adverse effect
Phenylephrine 🩸 PHENYL = Pressure	α1 → vasoconstriction → ↑ BP	Hypotension/decongestion	Reflex bradycardia
Clonidine 😴 CLON = Calm	α2 → ↓ NE → ↓ BP	HTN, ADHD	Sedation
Isoproterenol ❤ ISO = Both β's	β1 → ↑ HR; β2 → vasodilation	Severe bradycardia	Tachycardia
Dobutamine ❤ DO-BUT = Do Better Pumping	β1 → ↑ heart contraction force	Weak cardiac contraction	Arrhythmias
Metaproterenol 🫁 META = Momentary	β2 → short bronchodilation	Acute bronchospasm	Tremor, tachycardia
Salmeterol 🫁 SAL = Stays A Long time	β2 → long bronchodilation	Maintenance inhaler	Paradoxical bronchospasm
Mirabegron 🚽 MIRA = More room	β3 → detrusor relaxes	Overactive bladder	Hypertension

Direct-acting drug prototypes

SABA vs LABA

• SABA: Metaproterenol, albuterol, levalbuterol, terbutaline → short-acting bronchodilation.

• LABA: Salmeterol, formoterol → longer-acting bronchodilation.

Direct-acting drug prototypes

Salmeterol

• is not appropriate alone for acute rescue because its onset is slow.

Direct-acting drug prototypes

Mirabegron

• advantage in older adults because it avoids characteristic antimuscarinic adverse effects.

Indirect-Acting Adrenergic Agonists

• Releasing agents → Amphetamine

• Reuptake inhibitors → TCAs, SNRIs, NRIs

• Metabolism inhibitors → MAOIs, COMT inhibitors

Indirect-Acting Adrenergic Agonists

Amphetamine

1. MOA

   • An indirect drug that increases available catecholamines.

   • Three mechanisms:

     • Releases stored catecholamines.

     • Blocks NET and DAT reuptake.

     • Weakly inhibits MAO.

2. Uses

   • ADHD and sleep-wake disorders.

3. Key side effects

   • Insomnia, euphoria

   • tachycardia, hypertension

   • anorexia, weight loss.

4. Counseling

   • Take early enough in the day to avoid insomnia.

Indirect-Acting Adrenergic Agonists

Reuptake inhibitors

Group	What to know
TCAs	Inhibit neurotransmitter reuptake
SNRIs	Inhibit NE + serotonin reuptake
NRIs	Inhibit NE reuptake

Indirect-Acting Adrenergic Agonists

Metabolism inhibitors

Group	What to know
MAO-A	Metabolizes NE, serotonin, dopamine
MAO-B	Preferentially metabolizes dopamine
COMT	Breaks down catecholamines

Indirect-Acting Adrenergic Agonists

Metabolism inhibitors - Examples to recognize: comeback

• Phenelzine/tranylcypromine (MAOIs)

• selegiline/rasagiline (MAO-B inhibitors)

• entacapone/tolcapone (COMT inhibitors)

Indirect-Acting Adrenergic Agonists

problem that can occur?

Nonselective MAOI + tyramine-rich food → hypertensive crisis.

Mixed-Acting Adrenergic

• Ephedrine

• Pseudoephedrine

Ephedrine

1. MOA

   • mixed-acting agonist that works in two ways.

     • Direct

       • α1 → vasoconstriction

       • β1 → ↑ cardiac activity

       • β2 → bronchodilation.

     • Indirect: Releases stored NE.

2. Use

   • Raises BP during spinal anesthesia-related hypotension.

3. Side effects

   • Insomnia

   • tachycardia, arrhythmias.

4. Interaction

   • Avoid with MAOIs used within the past 14 days.

Which drug combinations or situations can cause problems?

1. Direct: PROTOTYPE

   1. Salmeterol alone for acute bronchospasm - Not appropriate

2. In-Direct

   1. Amphetamine taken late - Insomnia

   2. Clonidine + TCA - TCA can oppose clonidine

   3. MAOI + tyramine-rich food -Hypertensive crisis

3. Mixed

   1. Ephedrine + recent MAOI - Avoid within 14 days

4. More

   1. Hypertension + OTC vasoconstricting decongestant - BP can rise dangerously