Alpha Blockers

Question 1

What are α-blockers?

Answer 1

α-blockers are drugs that work as antagonists of α-adrenergic receptors in the SNS, and are used in the tx of essential HTN.

Question 2

What are the 6 α-blocker drugs?

Answer 2

1. Doxazosin 2.Terazosin 3. Prazosin
2. Phenoxybenzamine
3. Phentolamine
4. Yohimbine (not for this module)

Question 3

What are the three principal/primary α-blockers used in the treatment of essential HTN? Why these ones?

Answer 3

the AZOSINS.
1. Doxazosin
2. Terazosin
3. Prazosin
B/c they are relatively α1-specific

Question 4

Which two α-blockers are non-specific and exert their effects on both α1 and α2 receptors? What is the result of this?

Answer 4

1. Phenoxybenzamine 2.Phentolamine
   By virtue of their effects on both α1 and α2 receptors and the subsequent potential for CV stimulation opposing the vasodilatory effect that is intended, these drugs do not see widespread use.

Question 5

What is the α2-specific α-blocker?

Answer 5

Yohimbine this is not important for this module

Question 6

What are the three receptor families of the SNS?

Answer 6

1. α-adrenergic
2. β-adrenergic
3. Dopaminergic

Question 7

Where are α-R’s and β-R’s located and what are there effects when stimulated?

Answer 7

1. α: skin, splanchnic, and skel m blood vessels→ contracts (vasonconstriction)
2. β: a) primarily in the heart (β1 predominantly)→ accelerates HR and increases contractility. b) β2’s in skel m vessels→relaxes (vasodilation)
   Thus, there’s an anatomical difference and physiological purpose difference of alpha and beta receptors

Question 8

What are the two subclasses of α-R’s? Where are they located in synapses? What does their activation result in?

Answer 8

1. α1-R: postsynaptic location; they primarily engage in the downstream signaling (increased DAG and IP3→increased intracellular Ca2+) of the event in the effector organ
2. α2-R: presynaptic location (autoreceptors); inhibit further release of nt (NE) from the terminal

Question 9

a) How does NE affect the BP when administrate alone? b) What if their is pre-tx with an α-blocker prior to giving NE? c) What about pre-tx with a beta-blocker (BB)?

Answer 9

a) NE alone produces an increase in BP as a result of vasconstrictive effect upon α-R’s in the vasculature.
b) Pre-tx w/ an α-blocker almost totally ablates this increase in BP, as it prevents the vasoconstrictive effects of NE mediated thru α-R’s.
c) Pre-tx with non-specific BB has not effect on the vasoconstriction due to NE acting on α-R’s.

Question 10

a) How does E affect the BP when administrate alone? b) What if their is pre-tx with an α-blocker prior to giving E? c) What about pre-tx with a beta-blocker (BB)?

Answer 10

a) E acts on α1and α2-R’s as well as on β2-R’s, which are located in skel m vessels and cause vasodilation when activated (unlike NE which doesnt act on β2’s). The vasodilation opposes the vasoconstrictive effects mediated thru α-R’s, so the rise in BP is not as pronounced, as E alone causes an increase in BP and then a decline back down to normal levels.
b) If pre-tx with an α-blocker, there is no longer the α-mediated vasoconstrictive effect, but E still produces a β2-mediated vasodilation, so BP decreases.
c) In the presence of a BB, α-r activation by E prevails and BP increases.

Question 11

a) How does Isoproterenol affect the BP when administrate alone? b) What if their is pre-tx with an α-blocker prior to giving Isoproterenol? c) What about pre-tx with a beta-blocker (BB)?

Answer 11

a) Isproterenol is non-specific β-agonist with no α-R activity. So, when given alone, it acts upon β2-R’s in skel m producing vasodilation and a decrease in BP.
b) In the presence of an α-blocker, it will still decrease BP, as it does not have any effect/activity on α-receptors
c) In the presence of a BB, the decrease in BP is almost totally ablated

Question 12

At normal clinical, therapeutic doses/levels, which three α-blockers are selective (relative not absolute) for α1-R’s?

Answer 12

The three primary agents: Terazosin, Doxazosin, Prazosin

Question 13

What is the specificity for α1 vs α2 of phenoxybenzamine and phentolamine?

Answer 13

They have comparable specificity (not very selective)for α1 and α2. They are considered non-specific.
(Phenoxybenzamine: α1 slightly more than α2)
(Phentolamine: α1=α2)

Question 14

What is the significance of subtypes of α1-R’s?

Answer 14

It helps to explain why certain drugs acting on α1-R’s can show a better spectrum of clinical activity for certain anatomic locations in the body over others. (Not important but for example, α1a drugs have utility in tx’ing urinary/prostatic issues over and above any activity in the CV system)

Question 15

What are the major adverse effects of α-blockers?

Answer 15

1. FIRST-DOSE ORTHOSTATIC HYPOTENSION, especially with PRAZOSIN (so take it before you go to bed)
2. Sinus-TACHYCARDIA (angina, palpitations), syncope, vertigo

Question 16

What α-blocker is most associated 1st-dose orthostatic hypotension?

Answer 16

Firs-dose orthostatic hypotension is most prominent with PRAZOSIN.

Question 17

Why do α-blockers cause sinus tachycardia?

Answer 17

Although the three principal clinically used α-blockers act primarily on α1-R’s, this receptor specificty is never absolute. So, w/ high doses, they can potentially have affect on the presynaptic α2-R’s (autoreceptors).
Inhibition of this feedback mechansim→ increased release of NE across the synapse→increased CV stimulation→tachycardia
This is especially a problem for phenoxybenzamine and phentolamine which have comparable specificities for α1 and α2-R’s.

Question 18

Which of the three primary α-blockers is given less frequently nowadays than the other two? Why?

Answer 18

Prazosin is given less often b/c it has a short half-life and has to given every 8 hrs, which is inconvenient to the patient.
Doxazosin (longest half-life) and Terazosin (longer) are more convenient b/c their longer half-lives require them to be given only once a day.

Question 19

Why is phenoxybenzamine more likely to cause sinus-tach than the three primary α-blockers? How does it differ from the three primary agents?

Answer 19

It acts upon both α1 and α2’s, which can increase CO leading to tachycardia.
It differs from the primary agents b/c it is NON-COMPETITIVE and COVALENTLY binds to the α-R’s, so it has a very long duration of action. It also has some activity against other receptor systems.

Question 20

What are the side effects of phenoxybenzamine associated with?

Answer 20

It has a number of clinical adverse effects based on its affects on α1 and α2’s elsewhere in the body.

Question 21

How is phentolamine similar to and different from phenoxybenzamine?

Answer 21

It acts on both α1 and α2’s, but unlike phenoxybenzamine, it is a SHORT-acting COMPETITIVE antagonist.

Question 22

What are the clinical indications of phenoxybenzamine and phentolamine?

Answer 22

1. Phenoxybenzamine: Rx of sympathetic excess due to pheochromocytoma, Raynauds phenomenon, frostbite, and acrocyanosis
2. Phentolamine: pheochromocytoma and hypertensive (HT emergency)

Question 23

What does the effect phentolamine on BP depend on? How?

Answer 23

There is DOSE-DEPENDENCY in the overall effect of produced by phentolamine.

a) In SMALLER doses: positive inotropic effect predominates, so BP increases (due to antagonism of α2’s increasing circulating NE levels due to loss of neg feedback →increased contractility/CV force)
b) in LARGER doses: peripheral vasodilation predominates (via effects on α1’s) , so BP decreases.

Question 24

What are two adverse effects of phentolamine?

Answer 24

Postural Hypotension
Reflex Tachycardia that precipitates cardiac arrhythmias
These limit its use in the tx of essential HTN

Question 25

Why are phenoxybenzamine and phentolamine not routinely used, unless there is a specific indication?

Answer 25

They both can cause reflex tachycardia, and whenever there is a tachycardic event in a patient, there is the potential risk of cardiac arrhythmias.

Question 26

Why has the use of α-blockers in the tx of HTN decreased?

Answer 26

They have been reported to not have as favorable effects in the prevention of MI’s in comparison to diuretics.