Adrenergic antagonists: Beta blockers

Alpha blockers 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 controls the involuntary movement of the smooth muscles and glands of our organs; this system is then further divided into the sympathetic and parasympathetic nervous systems.

Now, the autonomic 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 also known as adrenaline. These two catecholamines activate the adrenergic receptors on many different organs, which allows the sympathetic nervous system to trigger the fight or flight response that increases the heart rate and blood pressure, as well as slowing down digestion. This response 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 beta receptors, which have two main subtypes: beta1 (β1) and beta2 (β2). Beta1 adrenergic receptors are mainly located in the heart, where they increase the heart rate and contractility, which helps pump out more blood. Beta1 receptors are also found in the kidney, where they stimulate a very special kind of cell, called juxtaglomerular cells, to release renin. Renin is a part of the renin- angiotensin- aldosterone system, which increases sodium and water retention by the kidneys and helps increase blood pressure.

Moving on to beta2 adrenergic receptors, these are found on smooth muscle cells in the walls of blood vessels supplying skeletal muscles and the brain, which leads to vasodilation and increased blood flow to these tissues. In the lungs, beta2 adrenergic receptors cause bronchodilation, and that increases oxygen delivery to cells. In the gastrointestinal tract, they decrease motility and slow digestion. In the eyes, they act on the ciliary body to promote the secretion of aqueous humor, which provides support and helps to maintain the shape of the eye. Now, in the liver, they cause more glucose to be released into the blood. In the pancreatic islets of Langerhans, they promote the release of insulin. Finally, beta2 receptors stimulate an enzyme found on the surface of the cells lining capillary walls called lipoprotein lipase, which breaks down triglycerides into free fatty acids and glycerol.

Alright, so medications that act on peripheral post-synaptic adrenergic neurons to block adrenergic receptors are called peripheral post-synaptic anti-adrenergics. And based on the type of receptors they block, they are divided into two main categories - alpha blockers and beta blockers.

Now, beta blockers are subdivided into three generations. The first generation of beta blockers are non- selective blockers, meaning that they work as antagonists on both beta1 and beta2 adrenergic receptors. So, here we have propranolol, timolol, nadolol, sotalol, and pindolol. Actually, pindolol is not a pure antagonist, but a partial agonist. This means that, when bound to a beta receptor, it very weakly stimulates it, but at the same time, it prevents binding and stimulation by the more potent catecholamines. This is known as intrinsic sympathomimetic effect. Or more simply, pindolol has the same but weaker effects compared to the other first generation beta blockers.

Now, by blocking beta1 receptors in the heart, these medications decrease the heart rate and contractility, which lets the heart work less hard, and pump less blood out, resulting in a drop in its oxygen and energy demands, as well as a drop in blood pressure. At the same time, beta1 blockade in the juxtaglomerular cells in the kidney decreases renin release, which in turn decreases angiotensin II and aldosterone, letting more sodium and water be lost in the urine and lowering the blood pressure even more. Okay, but by blocking beta2 receptors as well, they also cause some vasoconstriction of blood vessels supplying the skeletal muscles and the brain. This is typically very mild though, and doesn’t have a significant effect on blood pressure. In the brain, in fact, beta2 receptors in blood vessels are only reached by propranolol, which is lipid- soluble enough to penetrate the blood- brain barrier and induce some degree of vasoconstriction.

Now, moving on to the lungs, blocking beta2 receptors causes bronchoconstriction, or narrowing of the respiratory airways, which obstructs airflow, and lets in less oxygen. In the gastrointestinal tract, beta2 blockade speeds up motility. In the eye, aqueous humor production decreases, so intraocular pressure or the pressure within the eye falls. Now in the liver, less glucose gets released in the bloodstream, and the pancreas releases less insulin. And finally, inhibition of lipoprotein lipase leads to the accumulation of triglycerides in the blood.

Alright, so looking at the indications of non- selective beta blockers, they are widely used in the treatment of hypertension; and coronary artery disease, in the form of angina pectoris or a heart attack. It has also been suggested that beta blockers slow down the progression of congestive heart failure, or CHF for short. This remains controversial though, since individuals with heart failure often rely on sympathetic drive to maintain some degree of heart function. So in this situation, beta blockers might actually make things worse, especially in a situation of acute CHF exacerbation. Next, beta blockers can be used to slow down the heart rate in cases of severe tachycardia, like in thyroid storm, which is an acute, life- threatening complication of hyperthyroidism - where the body becomes very sensitive to the effects of excess thyroid hormone. For the same reason, some people use them in cases of severe anxiety, like before giving a speech. Now propranolol in particular, has been also shown to effectively prevent migraines, a type of terrible headache, perhaps by altering blood flow to the brain. And timolol helps reduce the intraocular pressure when applied topically on the eye, which is why it’s been used in the treatment of glaucoma.

Now, side- effects of non- selective beta blockers include bradycardia and hypotension, meaning that the heart rate or blood pressure may fall too low. Note also, that in cases where someone quits taking them all of a sudden, they can lead to severe rebound tachycardia, hypertension, or even arrhythmias, meaning irregular heartbeat. There are also often complaints of fatigue, perhaps due to the reduced blood flow to the muscles, as well as dizziness, depression, insomnia, and nightmares, particularly due to the central nervous system effects of propranolol. since they can cause wheezing, shortness of breath, and chest tightness, they are also strictly contraindicated in both chronic obstructive pulmonary disease, or COPD for short; and asthma. Sometimes diarrhea has also been seen. In other cases, there’s hypertriglyceridemia, or increased blood triglycerides and hypoglycemia, or reduced blood glucose levels. Hypoglycemia is the side effect to watch out for, as it may go unnoticed, since beta blockers blunts the counter- regulatory effects and symptoms of catecholamines, like tachycardia and tremors. That’s particularly dangerous for people with diabetes, who already take a bunch of other hypoglycemic medications like insulin.

Okay, now the second generation of beta blockers are selective for beta1 adrenergic receptors, which is why they are called beta1 selective or cardioselective beta blockers. Examples here include atenolol, metoprolol, bisoprolol, esmolol, and acebutolol. Like pindolol, acebutolol is a partial beta1 receptor agonist, with an intrinsic sympathomimetic activity and weaker beta1 blocking effects.

Now, once again, by blocking beta1 receptors these medications lower blood pressure by decreasing the heart rate and contractility, while in the kidneys they decrease renin release. This makes them suitable for the treatment of hypertension, coronary artery disease, and cases of severe tachycardia, like thyroid storm and anxiety. Their use in congestive heart failure is controversial here too, but metoprolol and bisoprolol have shown fairly good results so they are commonly administered. Due to the absence of the beta2 blockade, they don’t cause bronchoconstriction, so they can be safely used in individuals with COPD and asthma. They also don’t affect blood glucose as much, so they are the preferred beta blockers for those with diabetes. Bear in mind though, that at high enough doses, these medications may also start blocking beta2 receptors, so these individuals should always be carefully monitored.