General pharm – Alpha (α) adrenergic drugs

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HY points followed by a quiz at the end

—

What are α and β receptors?

• 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.

USMLE wants you to know which receptors the catecholamines bind to:

• Epinephrine agonizes: α1, α2, β1, β2.
• Norepinephrine agonizes: α1, α2, β1, but not β2.
• 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 as the answer (discussed below).

α1-receptors

Where are α1 receptors predominantly found?

• Arterioles.
• Internal sphincters (bladder, anal)

What HY α1 agonists do I need to know for USMLE?

• Phenylephrine, Oxymetazoline, Midodrine (POM) are HY α1 agonists.

What are the highest yield points about α1 agonism? (“Cut to the chase. I don’t want superfluous detail.”)

Causes arteriolar vasoconstriction –> increases BP –> reflex bradycardia.

• In other words, epinephrine, norepinephrine, and dopamine binding to α1 receptors on arterioles is how basal blood pressure is maintained.
• Should be noted that cortisol is permissive of the effects of catecholamines. That is, cortisol upregulates α1 receptors and allows catecholamines to do their job.
• 62F + receives intravenous midodrine intraoperatively. What might be expected in this patient? –> answer = ↑ BP; ↓ HR.
• 34F + receives IV phenylephrine; what happens to blood flow through capillary beds? –> answer = decreases.
• 22M jumps into cold water; what happens to central blood volume?  –> answer = increases; we expect α1 agonism to constrict peripheral vessels in order to decrease surface area for heat exchange; this will shift blood toward the core.

Used for nasal decongestion –> α1 agonism causes small vessel constriction in the nasal mucosa –> decreased hydrostatic pressure within vessels –> decreased extravasation of transudate into nasal interstitium –> nasal decongestion.

• 13F + nasal congestion + uses intranasal spray; what’s the most likely agent she used? –> answer = oxymetazoline, phenylephrine, midodrine.
• 16M + viral infection + has been using nasal spray for 5 days straight to treat nasal congestion + stops using the spray and gets rebound nasal congestion; what agent was he using? –> answer = oxymetazoline, phenylephrine, midodrine.
  • Diagnosis is rhinitis medicamentosa –> rebound nasal congestion after continual intranasal use of α1 agonists.
  • Mechanism is tachyphylaxis (tolerance) –> down-regulation of intranasal α1 receptors.
  • Prevention is by not using intranasal α1 agonists for more than 3 days + use as infrequently as possible.

α1 agonists can be used to treat epistaxis –> similar mechanism as for nasal decongestion –> decreased extravasation of blood to mitigate nose bleeding.

• 24M + nose is bleeding in the emergency department; next best step? –> answer = nasal packing (not drugs).
• 24M + nose is bleeding in the emergency department; which of the following drugs may help treat this patient? –> answer = choose the α1 agonist listed –> Phenylephrine, Oxymetazoline, Midodrine (POM).

Should be avoided in patients with Raynaud phenomenon (sounds weirdly specific, but asked on NBME) –> if patient has abnormal peripheral vasoconstriction resulting in Raynaud, then the patient should avoid meds that vasoconstrict.

• 50F + history of dysphagia and pulmonary fibrosis + fingers turn color in the cold; what drug should be avoided in this patient? –> answer = choose the α1 agonist listed –> Phenylephrine, Oxymetazoline, Midodrine (POM).

Constrict internal sphincters (i.e., bladder and anal) –> USMLE wants you to know internal sphincters are under sympathetic control (i.e., catecholamines bind to α1 receptors in order to constrict them; these are not under voluntary control). In contrast, external sphincters are under voluntary (somatic) control (nicotinic receptors binding acetylcholine).

• 34F + pregnant + performing Kegel exercises to strengthen pelvic floor muscles; which muscle is not strengthened by Kegel exercises? –> student says, “Huh wtf? I’m supposed to know Kegel exercises at that level of detail?” –> No. But of the random muscles they list, you’ll notice that “internal anal sphincter” is one of them –> then you say, “Wait, well, internal sphincters aren’t under voluntary control, so it’s impossible that they could be strengthened by a voluntary exercise.” This is a forest for the trees scenario: the USMLE doesn’t expect you to be an obstetrician; they’re just seeing if you know that internal sphincters are sympathetic-controlled.

What HY α1 antagonists do I need to know for USMLE?

Phentolamine, phenoxybenzamine, -osins (prazosin, tamsulosin, terazosin).

What are the highest yield points about α1 antagonism?

Causes decreased arteriolar vasoconstriction (not the same as vasodilation) –> decreases BP –> reflex tachycardia. Antagonizing the α1 receptors doesn’t cause an active vasodilation of the arterioles; it merely attenuates the degree of vasoconstriction. The catecholamines only function to increase the tone/constriction of the arterioles.

Phenoxybenzamine is irreversible and non-competitive. It is used for pheochromocytoma (catecholamine-secreting tumor of adrenal medulla). The other agents are reversible and competitive.

• 34M + periodic pounding headaches and palpitations + has history of NF1 + BP of 120/80; what medication might help this patient? –> answer = phenoxybenzamine. Student says, “Wait, how the fuck does the BP of 120/80 make sense?” –> pheochromocytoma causes paroxysmal elevations in BP – i.e., sometimes it will be 220/120; other times it will be 120/80. USMLE Qs like to slam students by giving normal BP in pheochromocytoma vignettes.
• 28F + periodic palpitations and headaches + BP of 180/100 + treated for kidney stone last year; what’s the mechanism of the agent that could treat the BP? –> answer = irreversible α1 antagonism (phenoxybenzamine). Patient has MEN2A (pheochromocytoma, hyperparathyroidism, medullary thyroid cancer). The kidney stone would be from hypercalcemia from the hyperPTH.

Phentolamine is used as the classic USMLE example of an α1 antagonist that’s reversible and competitive. Why they single this one out? –> no fucking idea, but the do. So basically think: “Ok, phenoxybenzamine = irreversible + non-competitive; phentolamine = reversible + competitive.”

Tamsulosin and terazosin = the answers for α1 antagonists used for benign prostatic hyperplasia (BPH).

• 74M + interruption of urinary stream and dribbling; mechanism of agent that is most appropriate for this patient? –> answer = competitive α1 antagonist (i.e., terazosin or tamsulosin). The 5α-reductase inhibitor finasteride can also be used. Irreversible α1 antagonism (phenoxybenzamine) is not correct.

TCAs, anti-psychotics (usually 2nd gen), and first-gen H1 blockers all can cause three types of side-effects: α1 antagonism (orthostatic hypotension + fainting), anti-cholinergic (hot, red, dry patient with a full bladder +/- dry mouth and dry eyes), and anti-H1 (sedation).

• 68F + being treated for depression with new agent + now has full bladder + is hot, red, dry + fainting spells; which agent was she given? –> answer = TCA –> fainting spells = α1 antagonism from the TCA; the urinary retention and anhydrosis are anti-cholinergic side-effects.
• 24F + taking a drug for allergies + has a fainting spell + full bladder; next best step? –> answer = stop anti-cholinergic medications –> diphenhydramine (first-gen H1 blocker) has strong anti-cholinergic effects. Fainting spell due to anti-α1 effects.
• 45M + being treated for schizophrenia with risperidone + fainting spell + suprapubic mass; why is the patient fainting? –> answer = adverse effect of medication.

Any other weird factoids about α1 receptors I should know?

• Lower yield, but rarely they will ask about G-proteins (if you want >260 on Step 1).
• α1 receptors are G-α-q G-proteins, which means that agonism causes ↑ inositol triphosphate (IP3) and antagonism ↓ IP3.
• 72M + started on tamsulosin for BPH; what type of molecular effect does this have? –> answer = ↓ IP3.
• 31F + receives midodrine during surgery; what molecular effect does this have? –> answer = ↑ IP3.

α2-receptors

• Sort of the “odd one out” in that they serve a negative-feedback function on presynaptic terminals.
• In other words, if a catecholamine binds to an α2 receptor, then the result is decreased release of additional catecholamine from that presynaptic terminal. That is:
• ↑ α2 agonism = ↓ catecholamine release = ↓ BP.
• ↑ α2 antagonism = ↑ catecholamine release = ↑ BP.

What HY α2 agonists do I need to know for USMLE?

Methyldopa, clonidine.

• Methyldopa is used to treat hypertension during pregnancy.
  • It’s frequent that I’ll ask students, “What’s methyldopa?” And they say it’s for Parkinson disease. Completely unrelated. What you’re thinking of is carbidopa/levodopa.
• Clonidine can be used to treat HTN, but is notably used as a psych drug where it has utility in treating Tourette syndrome.

What HY α2 antagonists do I need to know for USMLE?

Mirtazapine.

• Stimulates appetite. Used to treat patients with anorexia who also have depression.

Any other weird factoids about α2 receptors I should know?

• α2 receptors are G-α-i G-proteins, which means that agonism causes ↓ cAMP and antagonism ↑ cAMP.
• 34F + receives methyldopa during pregnancy; what molecular effect does this have? –> answer = ↓ cAMP.
• 17F + BMI of 14 + depression + receives mirtazapine; what molecular effect does this have? –> answer = ↑ cAMP.

—

1. What kinds of hormones bind to α and β receptors? (select all that apply)

 Bound by hormones of the adrenal cortex

 Bound by hormones of the adrenal medulla

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.

2. Epinephrine binds to which of the following? (select all that apply)

 Alpha 1

 Alpha 2

 Beta 1

 Beta 2

Epinephrine agonizes: α1, α2, β1, β2.

3. Norepinephrine binds to which of the following? (select all that apply)

 Alpha 1

 Alpha 2

 Beta 1

 Beta 2

Norepinephrine agonizes: α1, α2, β1.

4. Dopamine binds to which of the following? (select all that apply)

 Alpha 1

 Alpha 2

 Beta 1

 Beta 2

 Dopamine 1

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 as the answer.

5. Where are α1 receptors predominantly found?

Arterioles

Internal sphincters

6. Name three HY alpha-1 agonists. (excluding catecholamines)

Phenylephrine, Oxymetazoline, Midodrine (POM) are HY α1 agonists.

7. Alpha 1 agonism will cause which of the following? (select all that apply)

 ↑ BP

 ↓ BP

 ↑ HR

 ↓ HR

Alpha 1 agonism causes arteriolar vasoconstriction –> increases BP –> reflex bradycardia.

8. A patient’s dose of phenylephrine is decreased. Compared to the prior dosing, what type of shift would be seen in the patient’s cardiovascular parameters?  (select all that apply)

 ↑ BP

 ↓ BP

 ↑ HR

 ↓ HR

Alpha 1 agonism causes arteriolar vasoconstriction –> increases BP –> reflex bradycardia.

Phenylephrine is an alpha 1 agonist.

Therefore if the dose is decreased, compared to at a higher dose, the effect will be a lessening of BP, as well as a lessening of the degree of reflex bradycardia (meaning HR goes up compared to before).

9. 32F + Hx of SLE managed with prednisone + has surgery + BP falls to 80/40 during surgery.

a) Why did the BP fall?

b) After IV saline is given, what drug is notably given to help?

a)

Cortisol is permissive of the effects of catecholamines (i.e., norepinephrine and epinephrine).

• Alpha-1 agonism causes arteriolar vasoconstriction and an increase in BP.
• Norepinephrine and epinephrine bind to alpha-1 receptors on arteriole endothelium.
• Cortisol helps maintain blood pressure, not by binding to cortisol receptor where that directly increases BP; instead, cortisol upregulates alpha-1 receptors on peripheral arterioles.
• Norepinephrine and epinephrine can now do their job.
• Without cortisol present, there is decreased expression of alpha-1 receptors on vascular endothelium, so even if NE and E are floating around, there is insufficient alpha-1 receptor expression and BP cannot be maintained.
• USMLE wants you to know the phrase: “cortisol is permissive of the effects of catecholamines,” where cortisol permits NE and E to do their job.

b)

• 32F + SLE + has surgery + intraoperatively her BP falls to 80/40; IV fluids are administered; what drug should be given? –> answer = hydrocortisone. Students always get this wrong. Patients with autoimmune disease (i.e., SLE, IBD, RA) managed with chronic corticosteroids (prednisone) will have suppression of the zona fasciculata and a decreased ability to mount a cortisol stress response during surgery or trauma –> corticosteroid in the blood is consumed –> NE and E can’t do their job –> BP falls –> give hydrocortisone (cortisol analogue) to restore alpha-1 receptor expression.

10. 62F + receives intravenous midodrine intraoperatively. What might be expected in this patient? (select all that apply)

 ↑ BP

 ↓ BP

 ↑ HR

 ↓ HR

Phenylephrine, Oxymetazoline, Midodrine (POM) are HY α1 agonists.

Cause arteriolar vasoconstriction –> increase BP –> reflex bradycardia.

11. 34F + receives IV phenylephrine; what happens to blood flow through capillary beds?

 Decreases

 Increases

Phenylephrine, Oxymetazoline, Midodrine (POM) are HY α1 agonists.

Cause arteriolar vasoconstriction –> lead to decreased blood flow distally because of the vascular constriction (but increased blood proximally, which is why BP goes up with alpha 1 agonism).

12. 22M jumps into cold water; what happens to central blood volume?

 Decreases

 Increases

We expect α1 agonism to constrict peripheral vessels in order to decrease surface area for heat exchange; this will shift blood toward the core.

13. 13F + nasal congestion + uses intranasal spray; what pharmacologic agent in the nasal spray functions to decrease her nasal congestion?

Phenylephrine, Oxymetazoline, Midodrine (POM) are HY α1 agonists.

α1 agonism causes small vessel constriction in the nasal mucosa –> decreased hydrostatic pressure within vessels –> decreased extravasation of transudate into nasal interstitium –> nasal decongestion.

14. 16M + viral infection + has been using nasal spray for 5 days straight to treat nasal congestion + stops using the spray and gets rebound nasal congestion

a) Name one of three agents that could have been in the nasal spray.

b) What’s the diagnosis?

c) What’s the mechanism?

d) How to prevent this?

a) Phenylephrine, Oxymetazoline, Midodrine (POM) are HY α1 agonists.

b) Diagnosis is rhinitis medicamentosa –> rebound nasal congestion after continual intranasal use of α1 agonists.

c) Mechanism is tachyphylaxis (tolerance) –> down-regulation of intranasal α1 receptors.

d) Prevention is by not using intranasal α1 agonists for more than 3 days + use as infrequently as possible.

15. 24M + nose is bleeding in the emergency department; next best step?

 Intranasal alpha 1 agonist alone

 Nasal packing alone

 Nasal packing moistened with alpha 1 agonist

α1 agonists can be used to treat epistaxis –> similar mechanism as for nasal decongestion –> decreased extravasation of blood to mitigate nose bleeding.

24M + nose is bleeding in the emergency department; next best step? –> answer = nasal packing (not drugs).

24M + nose is bleeding in the emergency department; which of the following drugs may help treat this patient? –> answer = choose the α1 agonist listed –> Phenylephrine, Oxymetazoline, Midodrine (POM).

16. 50F + history of dysphagia and pulmonary fibrosis + fingers turn color in the cold; which drug should be avoided in this patient?

 Oxymetazoline

 Phentolamine

Alpha 1 agonists should be avoided in patients with Raynaud phenomenon (sounds weirdly specific, but asked on NBME) –> if patient has abnormal peripheral vasoconstriction resulting in Raynaud, then the patient should avoid meds that vasoconstrict.

• 50F + history of dysphagia and pulmonary fibrosis + fingers turn color in the cold; what drug should be avoided in this patient? –> answer = choose the α1 agonist listed –> Phenylephrine, Oxymetazoline, Midodrine (POM).

Phentolamine is an alpha 1 antagonist.

17. 34F + pregnant + performing Kegel exercises to strengthen pelvic floor muscles; which muscle is not strengthened by Kegel exercises?

 Pubococcygeus

 Puborectalis

 Iliococcygeus

 Internal anal sphincter

 External anal sphincter

Student says, “Huh wtf? I’m supposed to know Kegel exercises at that level of detail?” –> No. But of the random muscles they list, you’ll notice that “internal anal sphincter” is one of them –> then you say, “Wait, well, internal sphincters aren’t under voluntary control, so it’s impossible that they could be strengthened by a voluntary exercise.” This is a forest for the trees scenario: the USMLE doesn’t expect you to be an obstetrician; they’re just seeing if you know that internal sphincters are sympathetic-controlled.

Alpha 1 agonism constricts internal sphincters.

18. Name five alpha 1 antagonists.

Phentolamine, phenoxybenzamine, -osins (prazosin, tamsulosin, terazosin).

19. Which of the following occur(s) with alpha 1 antagonism? (select all that apply)

 ↑ BP

 ↓ BP

 ↑ HR

 ↓ HR

Alpha 1 agonism causes arteriolar vasoconstriction –> increases BP –> reflex bradycardia.

So alpha 1 antagonism has the opposite effect –> less arteriolar vasoconstriction (different from dilation) –> decreases BP –> reflex tachycardia.

20. Phenoxybenzamine is: (select all that apply)

 Reversible

 Irreversible

 Competitive

 Non-competitive

 Alpha 1 agonist

 Alpha 1 antagonist

Phenoxybenzamine is an irreversible and non-competitive alpha-1 antagonist. It is used for pheochromocytoma (catecholamine-secreting tumor of adrenal medulla). The other alpha 1 blockers are reversible and competitive.

21. 34M + periodic pounding headaches and palpitations + has history of NF1 + BP of 120/80; what medication might help this patient?

Phenoxybenzamine is irreversible and non-competitive. It is used for pheochromocytoma (catecholamine-secreting tumor of adrenal medulla). The other agents are reversible and competitive.

Student says, “Wait, how the fuck does the BP of 120/80 make sense?” –> pheochromocytoma causes paroxysmal elevations in BP – i.e., sometimes it will be 220/120; other times it will be 120/80. USMLE Qs like to slam students by giving normal BP in pheochromocytoma vignettes.

22. 28F + periodic palpitations and headaches + BP of 180/100 + treated for kidney stone last year.

a) What’s the mechanism of the agent that could treat the BP?

b) What’s the diagnosis?

a)

Phenoxybenzamine is an irreversible and non-competitive alpha-1 blocker. It is used for pheochromocytoma (catecholamine-secreting tumor of adrenal medulla).

b)

Patient has MEN2A (pheochromocytoma, hyperparathyroidism, medullary thyroid cancer). The kidney stone would be from hypercalcemia from the hyperPTH.

23. 74M + interruption of urinary stream and dribbling. Name two agents with distinct MOAs that could be used to treat this patient.

1) Competitive α1 antagonist (i.e., terazosin or tamsulosin). Irreversible α1 antagonism (phenoxybenzamine) is not correct.

2) The 5α-reductase inhibitor finasteride can also be used.

24. 68F + being treated for depression with new agent + now has full bladder + is hot, red, dry + fainting spells; which agent was she given?

TCA –> fainting spells = α1 antagonism from the TCA; the urinary retention and anhydrosis are anti-cholinergic side-effects.

TCAs, anti-psychotics (usually 2nd gen), and first-gen H1 blockers all can cause three types of side-effects: α1 antagonism (orthostatic hypotension + fainting), anti-cholinergic (hot, red, dry patient with a full bladder +/- dry mouth and dry eyes), and anti-H1 (sedation).

25. 24F + taking a drug for allergies + has a fainting spell + full bladder; next best step?

Stop anti-cholinergic medications –> diphenhydramine (first-gen H1 blocker) has strong anti-cholinergic effects. Fainting spell due to anti-α1 effects.

TCAs, anti-psychotics (usually 2nd gen), and first-gen H1 blockers all can cause three types of side-effects: α1 antagonism (orthostatic hypotension + fainting), anti-cholinergic (hot, red, dry patient with a full bladder +/- dry mouth and dry eyes), and anti-H1 (sedation).

26. 45M + being treated for schizophrenia with risperidone + fainting spell + suprapubic mass; why is the patient fainting?

Anti-psychotic –> fainting spells = α1 antagonism; the urinary retention and anhydrosis are anti-cholinergic side-effects.

TCAs, anti-psychotics (usually 2nd gen), and first-gen H1 blockers all can cause three types of side-effects: α1 antagonism (orthostatic hypotension + fainting), anti-cholinergic (hot, red, dry patient with a full bladder +/- dry mouth and dry eyes), and anti-H1 (sedation).

27. What do alpha 2 receptors do?

Sort of the “odd one out” in that they serve a negative-feedback function on presynaptic terminals.

In other words, if a catecholamine binds to an α2 receptor, then the result is decreased release of additional catecholamine from that presynaptic terminal. That is:

↑ α2 agonism = ↓ catecholamine release = ↓ BP.

↑ α2 antagonism = ↑ catecholamine release = ↑ BP.

28. Alpha 2 agonism will cause which of the following? (select all that apply)

 ↑ catecholamine release

 ↓ catecholamine release

 ↑ BP

 ↓ BP

Sort of the “odd one out” in that they serve a negative-feedback function on presynaptic terminals.

In other words, if a catecholamine binds to an α2 receptor, then the result is decreased release of additional catecholamine from that presynaptic terminal. That is:

↑ α2 agonism = ↓ catecholamine release = ↓ BP.

↑ α2 antagonism = ↑ catecholamine release = ↑ BP.

29. What is:

a) methyldopa

b) carbidopa/levodopa

a) Methyldopa is used to treat hypertension during pregnancy.

b) Drugs for Parkinson disease.

30. What’s clonidine?

Clonidine is an alpha-2 agonist that can be used to treat HTN, but is notably used as a psych drug where it has utility in treating Tourette syndrome.

31. What’s mirtazapine?

Alpha 2 antagonist. Stimulates appetite. Used to treat patients with anorexia who also have depression.

32. What’s the MOA of phenoxybenzamine? Be specific.

Alpha 1 blocker. Irreversible. Non-competitive.

33. What’s the MOA of phentolamine?

Alpha 1 blocker. Reversible. Competitive.

34. a) What adrenergic drug can be used in those who have both anorexia and depression?

b) What’s its MOA?

a) Mirtazapine

b) Alpha-2 antagonist

• Stimulates appetite. Used to treat patients with anorexia who also have depression.

35. 72M + started on tamsulosin for BPH; what type of molecular effect does this have?

 ↑ IP3

 ↓ IP3

 ↑ cAMP

 ↓ cAMP

 ↑ cGMP

 ↓ cGMP

Any other weird factoids about α1 receptors I should know?

• Lower yield, but rarely they will ask about G-proteins (if you want >260 on Step 1).
• α1 receptors are G-α-q G-proteins, which means that agonism causes ↑ inositol triphosphate (IP3) and antagonism ↓ IP3.

36. 34F + receives methyldopa during pregnancy; what molecular effect does this have?

 ↑ IP3

 ↓ IP3

 ↑ cAMP

 ↓ cAMP

 ↑ cGMP

 ↓ cGMP

α2 receptors are G-α-i G-proteins, which means that agonism causes ↓ cAMP and antagonism ↑ cAMP.

37. 17F + BMI of 14 + depression + receives mirtazapine; what molecular effect does this have?

 ↑ IP3

 ↓ IP3

 ↑ cAMP

 ↓ cAMP

 ↑ cGMP

 ↓ cGMP

α2 receptors are G-α-i G-proteins, which means that agonism causes ↓ cAMP and antagonism ↑ cAMP.

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