Lecture 16: Alpha-Blockers & Adrenergic Neuronal Inibitors

Which drugs are nonselective α1 and α2 blockers?

- phenoxybenzamine

- phentolamine

Which drugs are selective α1 blockers?

- prazosin

- terazosin

- doxazosin

- tamsulosin

What is the general mechanism of action of alpha-adrenergic blockers?

inhibition of vascular and other peripheral α-adrenergic receptors

How do alpha blockers decrease blood pressure?

decrease peripheral vascular resistance by inhibiting α1-mediated arterial vasoconstriction, causing vasodilation

Which alpha blocker causes noncompetitive, irreversible inhibition?

phenoxybenzamine

What are the characteristics of phenoxybenzamine's receptor blockade?

slow onset and irreversible action

(synthesis of new receptors can restore a-adrenergic functions)

What type of receptor inhibition is produced by alpha blockers other than phenoxybenzamine?

competitive, reversible inhibition

(relatively fast onset)

What causes most adverse effects of alpha blockers?

excessive loss of normal α-receptor functions throughout the body

What are the local adverse effects of alpha blockers?

- nasal congestion (due to dilation of vessels in nasal mucosa)

- difficulty with ejaculation

What are the systemic adverse effects of alpha blockers?

- reflex tachycardia

- systemic extracellular fluid retention

- orthostatic hypotensive symptoms

What type of alpha blocker is phenoxybenzamine?

long-acting, irreversible, nonselective α1 and α2 antagonist

What is the primary therapeutic use of phenoxybenzamine?

pheochromocytoma

(prior to surgery or in inoperable patients)

What symptoms of pheochromocytoma are treated with phenoxybenzamine?

sweating and hypertension

Why is phenoxybenzamine preferred over other alpha blockers for pheochromocytoma?

blocks both α receptors and produces irreversible, noncompetitive inhibition

What additional drug class should be used with phenoxybenzamine in pheochromocytoma?

nonselective beta blocker

What is the mechanism of action of phentolamine?

short-acting, reversible antagonist of α1 and α2 receptors

What test has historically been used to diagnose pheochromocytoma?

phentolamine-blocking test

(no replaced by measurement of catecholamines in plasma and urine)

How is phentolamine used during pheochromocytoma surgery?

prevention and management of hypertensive episodes caused by stress or tumor manipulation

(MAIN USE)

Which alpha blocker is used to manage norepinephrine extravasation?

phentolamine

(prevention and treatment of dermal necrosis)

What is the role of phentolamine in local anesthesia?

reverses effects of local anesthesia (helpful in pediatric dental procedures)

What off-label hypertensive condition can phentolamine treat?

hypertensive crisis associated with catecholamine excess

What is the prototype selective α1-adrenergic blocker?

prazosin

What is the primary cardiovascular use of prazosin?

mild to moderate primary hypertension

Is prazosin recommended as monotherapy for hypertension?

no - should be used with diuretics, beta blockers, or other antihypertensive agents

Why may diuretics be useful when combined with prazosin?

help manage fluid retention and edema

In which patients may prazosin be particularly attractive for hypertension?

patients with concurrent benign prostatic hyperplasia

What peripheral vascular condition can prazosin treat off-label?

Raynaud phenomenon

When is prazosin considered for Raynaud phenomenon?

patients resistant to initial treatment with calcium channel blockers

What psychiatric condition can prazosin treat off-label?

PTSD-related nightmares and sleep disruption

(likely due to inhibition of central α1 receptors)

What is the major initial adverse effect of prazosin?

orthostatic hypotension with syncope (first-dose phenomenon)

When should the initial dose of prazosin usually be administered?

at bedtime to avoid syncope reaction

How can orthostatic symptoms associated with prazosin be prevented?

gradual dose titration

What fluid-related adverse effect can prazosin cause?

systemic extracellular fluid retention (when diuretics are not included)

How does prazosin compare with nonselective alpha blockers regarding reflex tachycardia?

causes less reflex tachycardia

what are newer α1 blockers that are almost identical to prazosin regarding MOA, SEs, and uses?

doxazosin and terazosin

how are doxazosin and terazosin different than prazosin?

doxazosin and terazosin have a much longer half life

(may be better for compliance for long-term control of HTN)

What are the therapeutic uses of doxazosin and terazosin?

hypertension and benign prostatic hyperplasia

What additional potential mechanism do doxazosin and terazosin have in the prostate?

induction of apoptosis in prostate smooth muscle cells

(gradually reduces size of prostate)

Is prostate smooth muscle apoptosis caused by α1 receptor antagonism?

no, it is an additional mechanism unrelated to α1 blockade

What structural component is associated with prostate smooth muscle apoptosis from doxazosin and terazosin?

quinazoline moiety

How do α1 blockers improve urinary symptoms in BPH?

relax smooth muscle of the bladder neck and prostatic urethra to alleviate obstructive urinary symptoms

Which long-acting α1 blockers are preferred for BPH?

doxazosin and terazosin

Which α1A subtype-selective antagonists are preferred for BPH?

tamsulosin

Which receptor subtype is primarily found in smooth muscle of the bladder neck and prostate?

α1A receptor

What is the mechanism of action of tamsulosin?

selective blockade of α1A receptors

What is the primary therapeutic use of tamsulosin?

benign prostatic hyperplasia

How does tamsulosin compare with other α1 blockers regarding systemic adverse effects?

less frequent and/or less severe systemic adverse effects

(little effect on BP)

Which α1 blocker may be preferred for a patient with BPH but no hypertension?

tamsulosin

Do tamsulosin and silodosin require dose titration?

no

What is the major adverse effect of tamsulosin?

abnormal/retrograde ejaculation

(due to block fo alpha-1A receptors in vas deferens)

Which drugs are centrally acting adrenergic neuronal inhibitors?

- methyldopa

- clonidine

- guanfacine

What is the mechanism of action of centrally acting adrenergic neuronal inhibitors?

agonism of α2 receptors in the CNS

(more prominent effects at CNS sites rather than peripheral)

How do centrally acting α2 agonists affect sympathetic nervous system activity?

decrease sympathetic activity

Where do centrally acting α2 agonists act to reduce sympathetic outflow?

vasomotor centers in the CNS

(decreasing sympathetic outflow to peripheral organs)

How do centrally acting α2 agonists affect normal reflex-mediated changes in sympathetic outflow?

little interference

What is the mechanism of action of methyldopa?

prodrug converted to α-methylnorepinephrine, which acts as a central α2 adrenergic agonist

Which enzymes convert methyldopa to α-methylnorepinephrine?

enzymes involved in the conversion of DOPA to dopamine and norepinephrine

How is α-methylnorepinephrine handled after its formation?

stored similarly to norepinephrine in the vesicles

How does methyldopa affect sympathetic nerve activity?

decreases sympathetic outflow to peripheral cardiovascular tissues

What cardiovascular and renal effects result from methyldopa?

- decreased renin release

- decreased heart rate

- decreased cardiac output

- decreased peripheral resistance

What is the primary clinical use of methyldopa?

hypertension during pregnancy

What common adverse effects of methyldopa are shared with other central α2 agonists?

- peripheral fluid retention

- dry mouth

- sedation

What autoimmune laboratory abnormality can methyldopa cause?

positive Coombs test (strop drug if this occurs)

What hepatic abnormalities can methyldopa cause?

abnormal liver function tests

(rarely severe hepatic necrosis)

What is the mechanism of action of clonidine?

direct α2 adrenergic agonist

How does clonidine lower blood pressure?

decreases sympathetic outflow from CNS vasomotor centers

What is the primary cardiovascular use of clonidine?

primary hypertension

(not recommended as initial treatment)

What formulations of clonidine are available?

immediate-release oral tablet and transdermal patch

Why is clonidine transdermal patch preferred?

smoother blood pressure control and less sedation

What are the most common adverse effects of clonidine?

dry mouth and sedation

(may diminish in intensity with time)

What sexual adverse effect can clonidine cause?

sexual dysfunction, including erectile dysfunction in men

What can happen if clonidine is abruptly discontinued?

rebound hypertension

Does methyldopa produce the same rebound hypertension associated with abrupt clonidine withdrawal?

no because it is incorporated in the vesicles

What neurodevelopmental condition can clonidine treat?

ADHD (last choice)

How is clonidine used in pain management?

epidural administration to inhibit release of NT in afferent pain fibers

What substance withdrawal condition can clonidine treat off-label?

opioid withdrawal

What menopausal symptoms can clonidine treat off-label?

vasomotor symptoms

Which formulation of clonidine is used to reduce postsurgical intraocular pressure?

apraclonidine eye drops

(has little or no systemic effects)

What are the clinical uses of guanfacine?

primary hypertension and ADHD

How does guanfacine's antihypertensive mechanism compare with clonidine?

similar central α2 agonist effects

(slightly less sedation and less tendancy toward rebound syndrome)

Is guanfacine recommended as initial therapy for hypertension?

no

In which ADHD patients is guanfacine generally reserved?

children/adolescents who respond poorly to or experience adverse effects from stimulants or atomoxetine