General pharm – Beta (β) adrenergic drugs

Catecholamines are hormones produced by adrenal medulla – i.e., epinephrine, norepinephrine, and dopamine.

α and β receptors are bound by catecholamines.

They are known as adrenergic receptors because the adrenal medulla hormones bind them.

The cortex produces aldosterone, cortisol, and androgens. These do not bind the adrenergic receptors.

Epinephrine agonizes: α1, α2, β1, β2.

Norepinephrine agonizes: α1, α2, β1.

Dopamine agonizes: α1, α2, β1, β2, D1.

At low-dose dopamine, D1 is bound most strongly (makes sense); as dose increases, β and α receptors are also bound.

If the USMLE Q tells you dopamine is used to increase someone’s BP, choose α1.

Cardiac muscle

Juxtaglomerular cells of the kidney

(Also found in adipose tissue, but don’t need to know that for USMLE)

Dobutamine.

Dobutamine is classically used as “dobutamine-echo” for stress tests in patients who cannot do an exercise stress test. Dobutamine will increase the heart rate, therefore increasing oxygen demand, and then the cardiac function can be evaluated using a transthoracic echo.

↑ chronotropy (heart rate), ↑ inotropy (contractility), ↑ oxygen demand on the heart.

• Dobutamine is classically used as “dobutamine-echo” for stress tests in patients who cannot do an exercise stress test. Dobutamine will increase the heart rate, therefore increasing oxygen demand, and then the cardiac function can be evaluated using a transthoracic echo.

Causes increased renin release from the kidney.

• 22M + runs 10 miles and is dehydrated; which of the following would be expected in this patient? –> answer = “increased sympathetic nerve stimulation at the kidney.” This is because we’d have upregulation of the renin-angiotensin system to help restore blood volume, so ↑ β1 agonism via sympathetic nerve stimulation at JG cells –> increased renin release.

Beta 1-selective blockers: A BEAM of beta-blockers –> Atenolol Bisoprolol, Esmolol, Acebutolol, Metoprolol.

• If it stars with a letter before M in the alphabet and ends in -olol, it’s beta 1-selective.

Beta 1/2 non-selective blockers: everything else –> i.e., Propranolol, Pindolol, Timolol, Nebivolol.

Beta-blockers with mixed alpha-blocking effect (i.e., mostly block beta, but also block alpha to a lesser degree): labetalol, carvedilol.

• Beta-blockers end with -olol. If the ending is not -olol (as with labetalol + carvedilol), that’s how you can remember it’s mixed.

Beta 1-selective blockers: A BEAM of beta-blockers –> Atenolol Bisoprolol, Esmolol, Acebutolol, Metoprolol.

• If it stars with a letter before M in the alphabet and ends in -olol, it’s beta 1-selective.

Beta 1/2 non-selective blockers: everything else –> i.e., Propranolol, Pindolol, Timolol, Nebivolol.

Beta-blockers with mixed alpha-blocking effect (i.e., mostly block beta, but also block alpha to a lesser degree): labetalol, carvedilol.

• Beta-blockers end with -olol. If the ending is not -olol (as with labetalol + carvedilol), that’s how you can remember it’s mixed.

Carvedilol and labetalol.

—

Beta 1-selective blockers: A BEAM of beta-blockers –> Atenolol Bisoprolol, Esmolol, Acebutolol, Metoprolol.

• If it stars with a letter before M in the alphabet and ends in -olol, it’s beta 1-selective.

Beta 1/2 non-selective blockers: everything else –> i.e., Propranolol, Pindolol, Timolol, Nebivolol.

Beta-blockers with mixed alpha-blocking effect (i.e., mostly block beta, but also block alpha to a lesser degree): labetalol, carvedilol.

• Beta-blockers end with -olol. If the ending is not -olol (as with labetalol + carvedilol), that’s how you can remember it’s mixed.

The four beta-blockers that decrease mortality in heart failure: metoprolol XR, bisoprolol, carvedilol, nebivolol.

• USMLE will only ever write “metoprolol.” But some cardiologists on the ward will freak the fuck out if you don’t specify “extended release” as the metoprolol formulation when discussing mortality reduction in heart failure. “Regular” metoprolol is used for atrial fibrillation.

Hierarchy for drugs in heart failure (simplified but HY for USMLE):

• Start with ACE inhibitor or an angiotensin II receptor blocker (ARB) to improve ejection fraction (normal is 55-70%).
• If the patient is fluid overloaded (i.e., peripheral edema or pulmonary edema), attempt to achieve euvolemia by adding furosemide (loop diuretic).
• If insufficient ejection fraction with the ACEi or ARB, add a beta-blocker (metoprolol XR, bisoprolol, carvedilol, or nebivolol).
• If insufficient ejection fraction with ACEi/ARB + beta-blocker, add spironolactone (aldosterone receptor antagonist).
• If insufficient ejection fraction, add the combination of hydralazine + nitrates. Only the combo decreases mortality in HF. It is especially efficacious in African Americans (tend to have stiffer vessels).
• If if insufficient ejection fraction when already on ACEi/ARB + beta-blocker + spironolactone + hydralazine + nitrates, add digoxin.
• If pharmacologic therapy insufficient, use implantable device.

• 68M + shortness of breath on exertion + peripheral edema + JVD + echo shows EF of 35%; what drug should be initiated to improve EF? –> answer = ACEi or ARB; beta-blocker is the wrong answer on USMLE.

Hierarchy for drugs in heart failure (simplified but HY for USMLE):

• Start with ACE inhibitor or an angiotensin II receptor blocker (ARB) to improve ejection fraction (normal is 55-70%).
• If the patient is fluid overloaded (i.e., peripheral edema or pulmonary edema), attempt to achieve euvolemia by adding furosemide (loop diuretic).
• If insufficient ejection fraction with the ACEi or ARB, add a beta-blocker (metoprolol XR, bisoprolol, carvedilol, or nebivolol).
• If insufficient ejection fraction with ACEi/ARB + beta-blocker, add spironolactone (aldosterone receptor antagonist).
• If insufficient ejection fraction, add the combination of hydralazine + nitrates. Only the combo decreases mortality in HF. It is especially efficacious in African Americans (tend to have stiffer vessels).
• If if insufficient ejection fraction when already on ACEi/ARB + beta-blocker + spironolactone + hydralazine + nitrates, add digoxin.
• If pharmacologic therapy insufficient, use implantable device.

• 68M + shortness of breath on exertion + peripheral edema + JVD + echo shows EF of 35%; what drug should be initiated to improve EF? –> answer = ACEi or ARB; beta-blocker is the wrong answer on USMLE.

HY contraindications to beta-blockers:

• Hx of depression (beta-blockers can cause depression).
• Diabetes –> epinephrine is responsible for symptoms of hypoglycemia; with beta-blockade, symptoms can be masked. Diabetics on beta-blockers require diligent monitoring.
• COPD.
• Asthma (can use beta 1-selective, but cannot use non-selective; propranolol is non-selective) –> should be noted that a Q on one of the 2CK psych forms has benzo as the answer for social phobia, over propranolol, in a patient with simple asthma, so for USMLE purposes, asthma period, equals no beta-blocker).
• 2nd or 3rd-degree heart block.
• Unstable heart failure resulting in hemodynamic instability.
• Peripheral vascular disease no longer a contraindication.

Propranolol has many HY uses for USMLE:

• Can be used to treat essential or idiopathic tremors.
  • 22F + bilateral resting tremor + mom also has tremor + self-medicates with alcohol to decrease tremor; Tx? –> answer = propranolol.
  • Essential tremor is a bilateral resting tremor; it’s autosomal dominant; patients frequently self-medicate with alcohol, which decreases tremor.
• Tachycardia in hyperthyroidism.
  • Beta-blockade decreases the conversion of T4 to T3.
• Prophylaxis for esophageal varices.
  • 59M + alcoholic + vomits copious bright red blood that requires banding; what could be given to help prevent future episodes? –> answer = “beta blockade” (propranolol).
• Hypertrophic obstructive cardiomyopathy (HOCM).
  • 20F + 2/6 mid-systolic murmur in upper chest + murmur worsens with Valsalva; what could be given to this patient to reduce risk of death? –> answer = propranolol.
• Akathisia secondary to anti-psychotic use.
  • 39M + schizophrenia + started taking olanzapine a week ago + feels constantly restless; Tx? –> answer = propranolol.
• Social phobia.
  • 29M + needs to speak in front of large audience in upcoming presentation for work; Tx? –> propranolol.
  • 2CK psych form gives two near-identical Qs – one mentions Hx of asthma; the other doesn’t – if patient has asthma, use benzo instead of beta-blocker for social phobia.
  • Atenolol can be used for stage fright instead of propranolol (both are correct).
• Migraine prophylaxis
  • 40F + high BP after lifestyle modification + Hx of migraines; which new medication do we start? –> answer = “beta blockade” (propranolol). This is on one of the 2CK FM forms.
  • Treatment for migraines is NSAIDs followed by -triptans; prophylaxis is beta-blocker.
  • Cluster headache prophylaxis is verapamil; beta-blocker is the wrong answer for cluster (low-30s%-correct Q in Qbank IIRC).

Propranolol.

• Essential tremor is a bilateral resting tremor; it’s autosomal dominant; patients frequently self-medicate with alcohol, which decreases tremor.

Propranolol.

Beta-blockade decreases the conversion of T4 to T3.

Propranolol is used as prophylaxis for esophageal varices.–> decreases portal blood flow and, therefore, pressure.

Treatment is banding and sometimes octreotide. But prophylaxis for a bleed is propranolol.

Propranolol can be used to decrease risk of sudden cardiac death in hypertrophic obstructive cardiomyopathy (HOCM).

Beta-blockade slows heart rate –> increases time for diastolic filling –> lessens chance of low preload state where the murmur (LV outflow tract obstruction) worsens.

Propranolol can be used to treat akathisia secondary to anti-psychotic use.

Propranolol or atenolol.

Social phobia is managed first-line with beta-blockers.

• 29M + needs to speak in front of large audience in upcoming presentation for work; Tx? –> propranolol.
• 2CK psych form gives two near-identical Qs – one mentions Hx of asthma; the other doesn’t – if patient has asthma, use benzo (clonazepam) instead of beta-blocker for social phobia.
• Atenolol can be used for stage fright instead of propranolol (both are correct).

Benzo (e.g., clonazepam).

Social phobia is managed first-line with beta-blockers, however, if the patient has asthma, benzo is the answer.

• 29M + needs to speak in front of large audience in upcoming presentation for work; Tx? –> propranolol.
• 2CK psych form gives two near-identical Qs – one mentions Hx of asthma; the other doesn’t – if patient has asthma, use benzo (clonazepam) instead of beta-blocker for social phobia.
• Atenolol can be used for stage fright instead of propranolol (both are correct).

Propranolol is used for migraine prophylaxis.

40F + high BP after lifestyle modification + Hx of migraines; which new medication do we start? –> answer = “beta blockade” (propranolol). This is on one of the 2CK FM forms.

Treatment for migraines is NSAIDs followed by -triptans; prophylaxis is beta-blocker.

Cluster headache prophylaxis is verapamil; beta-blocker is the wrong answer for cluster (low-30s%-correct Q in Qbank IIRC).

Topical timolol can be used for glaucoma.

• Beta-blockade decreases aqueous humor production.
• USMLE just wants you to know that beta-blockade, in general, can be used for glaucoma and reduces aqueous humor production.
• Propranolol is not used for glaucoma.

Any other weird factoids about β1 receptors I should know?

• Lower yield, but rarely they will ask about G-proteins (if you want >260 on Step 1).
• β1 receptors are G-α-s G-proteins, which means that agonism causes ↑ cAMP and antagonism ↓ cAMP.
• 34M + long Hx of migraines + started on new drug for HTN; what’s the molecular effect of this agent? –> answer = ↓ cAMP (propranolol).

Bronchiole smooth muscle (cause dilation).

Peripheral arterioles (cause dilation).

Uterus (cause relaxation).

What HY β2 agonists do I need to know for USMLE?

Beta 2-selective agonists: Albuterol, Salmeterol, Ritodrine.

Beta 2 non-selective agonists: Terbutaline, Isoproterenol.

What HY β2 agonists do I need to know for USMLE?

Beta 2-selective agonists: Albuterol, Salmeterol, Ritodrine.

Beta 2 non-selective agonists: Terbutaline, Isoproterenol.

Dilates bronchioles.

Dilates peripheral arterioles.

Can be used for tocolysis (cause relaxation of the uterus).

a) Albuterol

b) Salmeterol

Answers: Drug X = epinephrine. Drug Y = phentolamine.

• Selective β2 agonists can decrease BP in theory, but are not used for this purpose.
• If epinephrine is administered alone, BP will go up. However BP will decrease with epinephrine if alpha 1 is blocked first.
• “What do you mean? That’s confusing.” I know. Chill the fuck out. I’ll explain:
• If we give epinephrine (which agonizes α1, α2, β1, and β2), the strong vasoconstrictive effect of α1 on arterioles overpowers the peripheral vasodilatory effect of β2, so BP goes up with epinephrine administration alone.
• That is: effect of α1 outpowers β2, where effect of constriction > dilation, so BP goes up.
• But if we first block alpha 1 with phentolamine, then give epinephrine, the effect on β2 is no longer countered by α1, so we get dilation and BP decreases.
• “But Michael, how does the USMLE actually assess that?”
  • Scientist is running an animal model experiment. Drug X is given and BP goes up. He then performs the experiment a second time. In this case, Drug Y is administered before drug X. BP goes down slightly with Drug Y. It then decreases further with Drug X. What are Drug X and Y? –> Answers: Drug X = epinephrine. Drug Y = phentolamine.

Ritodrine.

Beta 2 agonists be used for tocolysis (cause relaxation of the uterus).

Tocolytic agents (i.e., ritodrine) delay labor and buy the expectant mother time in certain delivery situations.

β3 agonist used for urge incontinence (yes, beta 3). Weird MOA, but you need to know it for USMLE.

Classic Tx for urge incontinence (overactive detrusor muscle) is oxybutynin, a muscarinic receptor antagonist. But mirabegron has been showing up on students’ USMLEs and shelf exams as well.

So I want you to say: “Treatment for urge incontinence is almost always oxybutynin, a muscarinic receptor antagonist. But mirabegron is a beta 3 agonist that is newer and now shows up on the USMLE.”