AssessmentsAdrenergic antagonists: Alpha blockers
USMLE® Step 2 style questions USMLE
A 50-year-old woman comes to the office because of episodic headaches and palpitations. She says her blood during one of these episodes was 160/98 mm Hg. Currently her temperature is 36.7°C (98°F), pulse is 84/min, respirations are 14/min, and blood pressure is 110/84 mm Hg. A 24-hour urine metanephrine fractionation shows elevated levels of normetanephrine, metanephrine, and norepinephrine. An MRI study of the patient’s abdomen reveals a T2-hyperintense tumor just lateral to the abdominal aorta at the L1 level. Administration of which of the following medications is the most appropriate first step to prepare the patient for surgery?
Alpha blocker and beta blockers are two types of postsynaptic anti-adrenergic medications that prevent their respective receptors from being stimulated by catecholamines, like norepinephrine and epinephrine.
The nervous system is divided into the central nervous system, so the brain and spinal cord; and the peripheral nervous system, which includes all the nerves that connect the central nervous system to the muscles and organs.
The peripheral nervous system can be divided into the somatic nervous system, which controls voluntary movement of our skeletal muscles; and the autonomic nervous system, which is further divided into the sympathetic and the parasympathetic, and controls the involuntary movement of the smooth muscles and glands of our organs.
Now, the autonomic nervous system - which includes both the sympathetic and parasympathetic nervous system - is made up of a relay that includes two neurons.
We’ll focus on just the sympathetic nervous system.
Signals for the autonomic nervous system start in the hypothalamus, at the base of the brain.
Hypothalamic neurons have really long axons that carry signals all the way down to the thoracic and lumbar spinal cord nuclei, where they synapse with preganglionic neuron cell bodies.
From there, the signal goes from the preganglionic neurons down its relatively short axon, exits the spinal cord, and reaches the nearby sympathetic ganglion, which is made up of lots of postganglionic neuron cell bodies.
The postganglionic neurons are also called adrenergic neurons because they release the neurotransmitter norepinephrine, which is also called noradrenalin; and to a much lesser degree, epinephrine, or adrenaline.
These two catecholamines activate the adrenergic receptors on the many different organs, which allow the sympathetic nervous system to trigger the fight or flight response that increases the heart rate and blood pressure, as well as slowing digestion.
All of this maximizes blood flow to the muscles and brain, and can help you either run away from a threat, or fight it, which is why it’s also called the fight or flight response.
Now, there are two main groups of adrenergic receptors: the alpha receptors, and beta receptors.
Let’s focus on alpha receptors, which have two subtypes: alpha-1 and alpha-2. alpha-1 adrenergic receptors are mainly located on the walls of blood vessels, and when stimulated, they cause vasoconstriction, thus decreasing blood flow to tissues.
In the eyes, alpha-1 adrenergic receptors also trigger mydriasis, or pupil dilation.
In the bladder, they cause sphincter constriction and urinary retention, or holding the urine within the bladder.
And in males, they trigger ejaculation.
Now, alpha-2 adrenergic receptors are primarily found on the presynaptic neuron.
So when a presynaptic nerve ending is stimulated to release noradrenaline in the synaptic cleft, some of that norepinephrine turns around and binds to alpha-2 receptors on the presynaptic membrane.
This inhibits further release of norepinephrine and serves as a mechanism of negative feedback control.
Alright, so medications that inhibit peripheral postsynaptic adrenergic neurons are called peripheral postsynaptic anti-adrenergics.
And based on the type of receptors they block, they are divided into two main categories - alpha blockers, and beta blockers.
Now, alpha blockers are subdivided into two groups of their own; non-selective alpha blockers and selective alpha blockers.
Non-selective alpha blockers work on both alpha-1 and alpha-2 adrenergic receptors and include phenoxybenzamine and phentolamine.
By blocking alpha-1 receptors, they cause vasodilation and lower blood pressure.
But what sets these two apart is that phenoxybenzamine is an irreversible, noncompetitive antagonist, while phentolamine is a reversible, competitive antagonist.
So, phenoxybenzamine binds irreversibly, to a different site on the receptor from catecholamines, and changes the shape of the receptor so it can no longer bind to catecholamines.
This effect cannot be overcome, even if the levels of catecholamines increase.
In fact, the only way out is to synthesize new adrenergic receptors, which takes about 24 hours.
This makes phenoxybenzamine perfect for the treatment of pheochromocytoma, a rare tumor of the adrenal medulla, which secretes too much of the catecholamines; adrenaline and noradrenaline.
On the other hand, phentolamine competes with catecholamines for the exact same binding site on the receptor, but is reversible; meaning that it can be kicked off after a while, especially if there’s a lot of catecholamines around.
Now, phentolamine can also be used in pheochromocytoma, but it’s mainly used to treat hypertensive crisis caused by the combination of a Monoamine oxidase inhibitors, or MAOIs for short, and tyramine-rich food and drinks, such as cheese, wine, and beer.
Okay, so since alpha-1 receptor inhibition causes vasodilation, we get side effects like hypotension; headache, due to vasodilation in the brain; and nasal congestion, due to vasodilation of nasal mucosa.
In men, it can cause difficulty in ejaculation, due to alpha-1 receptor inhibition in the seminal tract.
- "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
- "Rang and Dale's Pharmacology" Elsevier (2019)
- "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
- "Anti-tumor activity of phenoxybenzamine and its inhibition of histone deacetylases" PLOS ONE (2018)
- "Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial" The Lancet (2015)
- "Hydralazine and prazosin in the treatment of hypertension." British Journal of Clinical Pharmacology (1983)
- "A Review of the Pharmacological and Clinical Profile of Mirtazapine" CNS Drug Reviews (2006)