Alpha Blockers Flashcards
What are α-blockers?
α-blockers are drugs that work as antagonists of α-adrenergic receptors in the SNS, and are used in the tx of essential HTN.
What are the 6 α-blocker drugs?
- Doxazosin 2.Terazosin 3. Prazosin
- Phenoxybenzamine
- Phentolamine
- Yohimbine (not for this module)
What are the three principal/primary α-blockers used in the treatment of essential HTN? Why these ones?
the AZOSINS. 1. Doxazosin 2. Terazosin 3. Prazosin B/c they are relatively α1-specific
Which two α-blockers are non-specific and exert their effects on both α1 and α2 receptors? What is the result of this?
- 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.
What is the α2-specific α-blocker?
Yohimbine this is not important for this module
What are the three receptor families of the SNS?
- α-adrenergic
- β-adrenergic
- Dopaminergic
Where are α-R’s and β-R’s located and what are there effects when stimulated?
- α: skin, splanchnic, and skel m blood vessels→ contracts (vasonconstriction)
- 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
What are the two subclasses of α-R’s? Where are they located in synapses? What does their activation result in?
- 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
- α2-R: presynaptic location (autoreceptors); inhibit further release of nt (NE) from the terminal
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)?
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.
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)?
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.
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)?
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
At normal clinical, therapeutic doses/levels, which three α-blockers are selective (relative not absolute) for α1-R’s?
The three primary agents: Terazosin, Doxazosin, Prazosin
What is the specificity for α1 vs α2 of phenoxybenzamine and phentolamine?
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)
What is the significance of subtypes of α1-R’s?
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)
What are the major adverse effects of α-blockers?
- FIRST-DOSE ORTHOSTATIC HYPOTENSION, especially with PRAZOSIN (so take it before you go to bed)
- Sinus-TACHYCARDIA (angina, palpitations), syncope, vertigo
What α-blocker is most associated 1st-dose orthostatic hypotension?
Firs-dose orthostatic hypotension is most prominent with PRAZOSIN.
Why do α-blockers cause sinus tachycardia?
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.
Which of the three primary α-blockers is given less frequently nowadays than the other two? Why?
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.
Why is phenoxybenzamine more likely to cause sinus-tach than the three primary α-blockers? How does it differ from the three primary agents?
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.
What are the side effects of phenoxybenzamine associated with?
It has a number of clinical adverse effects based on its affects on α1 and α2’s elsewhere in the body.
How is phentolamine similar to and different from phenoxybenzamine?
It acts on both α1 and α2’s, but unlike phenoxybenzamine, it is a SHORT-acting COMPETITIVE antagonist.
What are the clinical indications of phenoxybenzamine and phentolamine?
- Phenoxybenzamine: Rx of sympathetic excess due to pheochromocytoma, Raynauds phenomenon, frostbite, and acrocyanosis
- Phentolamine: pheochromocytoma and hypertensive (HT emergency)
What does the effect phentolamine on BP depend on? How?
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.
What are two adverse effects of phentolamine?
Postural Hypotension
Reflex Tachycardia that precipitates cardiac arrhythmias
These limit its use in the tx of essential HTN
