sympathomimetics – PharmaNUS

Category: sympathomimetics

When sympathetic and parasympathetic systems collide: The dominance of excitatory effects

August 30, 2023 / phcdgs / 0 Comments

When the autonomic nervous system ganglia are activated (for example, by low-dose nicotine), both the sympathetic and parasympathetic nervous system innervations of target organs and tissues are simultaneously stimulated. However, the “fright, fight or flight” sympathetic and “rest and digest” parasympathetic nervous systems have opposing effects in most target organs and tissues. So why do the sympathetic and parasympathetic nervous systems not just cancel each other out when activated at the same time?

It is true that in the realm of autonomic nervous system functioning, the sympathetic and parasympathetic systems often represent two sides of the same coin. These systems largely produce opposing effects on the same target organs and tissues. However, what happens when both systems are simultaneously activated? Contrary to intuitive thinking, they don’t simply cancel each other out. Instead, the dominion of activation or excitatory effects takes centre stage.

The Principle of Dominant Excitation: When both the sympathetic and parasympathetic systems are co-activated, it isn’t a zero-sum game. Rather than neutralizing each other, the excitatory effects from each system generally prevail. This principle is observed in a variety of physiological contexts. Continue reading

Brimonidine for glaucoma

If brimonidine is an adrenergic agonist, how and why does it reduce glaucoma?

Brimonidine acts at postsynaptic alpha-2 adrenoreceptors on blood vessels to cause vasoconstriction, reducing aqueous humour production. Long-term, there are also effects on uveoscleral drainage, perhaps secondary to reduced blood flow to the ciliary muscle.

Brimonidine alone is not as potent at reducing intraocular pressure (IOP) as beta-blockers or prostaglandin F2alpha analogues (e.g., latanoprost). The primary reason that brimonidine has come back into use is that it also has a neuroprotective action, reducing the death of retinal ganglion cells through mechanisms that remain poorly understood.

Why is monotherapy with LABAs contraindicated in asthma?

October 5, 2018 / phcdgs / 0 Comments

Why is the chronic use of long-acting beta agonists (LABAs) alone without the concomitant use of an inhaled corticosteroid contraindicated in asthma? What about short-acting beta agonists (SABAs), can they be used without taking an inhaled corticosteroid at the same time?

Activation of β₂-adrenoceptor promotes bronchodilation. β₂-adrenoceptor agonists are the most potent bronchodilators in current clinical use. Inhaled short-acting beta agonists (SABAs), for example salbutamol (known as albuterol in the USA) have a bronchodilator effect that lasts for 4 to 6 hours, while long-acting beta agonists (LABAs), for example salmeterol, have a bronchodilator effect that lasts for 12 to 24 hours (depending upon the drug). SABAs are used to relieve acute bronchoconstriction. Use of a SABA can be a life-saving intervention during an asthma attack. In contrast, LABAs are used chronically to mainain bronchodilation improving airway function and controlling occurance of symptoms.

Chronic use of LABAs causes tolerance due to downregulation of β₂-adrenoceptors. This is associated with an increased risk of mortality in patients with asthma. Therefore the use of LABAs alone is contraindicated. The downregulation of β₂-adrenoceptors by chronic use of LABAs can impair the response to SABAs when they are need for acutre relief of symptoms during an asthma attack.

Clonidine as an analgesic?

April 3, 2018 / phcdgs / 0 Comments

Administration of clonidine can reduce the doses of opioid analgesics required for pain control. Clonidine is also used to counteract symptoms of opioid withdrawal. How does this work?

Clonidine is an alpha-2-adrenoceptor agonist. Clonidine activates presynaptic alpha-2-adrenoceptors serving as autoreceptors on both central and peripheral nervous system noradrenergic nerve terminals. Activation of these autoreceptors reduces release of nordrenaline. Clonidine also activates alpha-2-adrenoceptors on the neurones of the locus coeruleus, the major source of noradrenergic innervation in the brain, to inhibit locus coeruleus neurone firing and further reduce central nervous system noradrenergic neurotransmission. By these mechanisms, clonidine is an indirect sympatholytic agent and has been used as an antihypertensive drug.

Clonidine is also a direct adrenoceptor agonist at presynaptic alpha-2-adrenoceptors serving as heteroreceptors on the primary afferent neurone nerve terminals bringing nociceptive signals into the spinal cord and at postsynaptic alpha-2-adrenoceptors on secondary spinal cord neurones relaying pain information up to the brain. The descending systems gating pain transmission through the spinal cord include noradrenergic neurones releasing noradrenaline to activate the presynaptic alpha-2-adrenoceptor heteroreceptors on the primary afferent neurone nerve terminals preventing them from releasing their neurotransmitters and transmitting their nociceptive signals. Meanwhile, the noradrenergic descending projections also active postsynaptic alpha-2-adrenoceptors on secondary spinal cord neurones, inhibiting these neurones, and preventing them from relaying the nociceptive signals up to the brain. Therefore, clonidine, which activates these alpha-2-adrenoceptors, has analgesic properties.

The descending pain gating systems also activate local engodenous opioid peptide releasing interneurones within the spinal cord. These interneurones inhibit the secondary spinal cord neurones relaying the nociceptive information up to the brain and so further block transmission of nociceptive signals through the spine. There is therefore a good additive effect between clonidine and the opioid analgesics, which produce spinal analgesia by mimicking the action of the endogenous opioid peptides. Administering clonidine can reduce the doses of opioid analgesics required to control pain.

Another use for clonidine is in controlling symptoms of opioid withdrawal. Part of the reason why clonidine helps is that by its non-opioid analgesic mechanisms it controls the pain associated with opioid withdrawal. Opioid receptors also normally inhibit the neurones of the locus coeruleus and opioid withdrawal is also associated with over activation of the locus coeruleus and the brain noradrenergic system. This results in symptoms such as anxiety, agitation, irritability, and mood swings. Clonidine activates alpha-2-adrenoceptors inhibiting the cells of the locus coeruleus and presynaptic alpha-2-adrenoceptor autoreceptors reducing noradrenaline release.

Why does overdose of salbutamol cause tachycardia?

March 14, 2018 / phcdgs / 0 Comments

Salbutamol is beta-2 adrenoceptor agonist used to treat the respiratory symptoms of asthma. We learned that it is beta-2 adrenoceptors in the lungs and beta-1 adrenoceptors in the heart. So why does overdose of salbutamol cause a rapid heart rate?

Activation of beta-2 adrenoceptors in the airways promotes bronchodilation, reduction of airway secretions, and stimulation of mucociliary clearance. Thus beta-2 adrenoceptor agonists are used in treating the symptoms of asthma. Meanwhile, in the heart, beta-1 adrenoceptor activation has inotropic and chronotropic effects, increasing contractile force and heart rate, respectively.

For the treatment of the symptoms of asthma without causing cardiovascular adverse effects, selective beta-2 adrenoceptor agonists would be the preferred. Salbutamol is an example of a selective beta-2 adrenoceptor agonist. However, the beta-2 and beta-1 adrenoceptors are very similar, so salbutamol is not entirely selective. Salbutamol shows dose-dependent selectivity for beta-2 adrenoceptors but does still act as a weak beta-1 agonist. Thus, on overdose, the beta-1 agonist activity of salbutamol can start to cause cardiovascular adverse effects by activating beta-1 adrenoceptors in the heart to increase the force and rate of heart contractions.

Does hyperthyroidism cause constipation or diarrhoea?

March 14, 2018 / phcdgs / 0 Comments

Hyperthyroidism causes sympathetic overactivation such that many of the symptoms of thyroid storm can be alleviated by beta-blockers. The sympathetic nervous system “fright, flight or fight” response opposes the parasympathetic nervous system “rest and digest” response and shuts down gastrointestinal function. So hyperthyroidism causes constipation, correct?

Sorry, not correct. Yes, hyperthyroidism can stimulate overactivation of the sympathetic nervous system. Yes, symptoms of thyroid storm can be treated with sympatholytic beta-blockers. But no, hyperthyroidism does not cause constipation. Hyperthyroidism causes diarrhoea. Conversely, hypothyroidism causes constipation.

So, next, you will ask “What is the mechanism?”. Unfortunately, the mechanism is not known. Recent reviews have speculated that it might be due to beta-2 adrenoceptor-mediated effects on gastrointestinal motility and secretions (Daher et al., 2015; Kyriacou et al., 2015) but the evidence for this is very limited. For example, a case report on one patient has suggested that propranolol can control intractable diarrhoea in hyperthyroidism (Bricker et al., 2001) but another study on ten hyperthyroid patients found no effect of propranolol on the gastrointestinal transit time (Bozzani et al., 1985).

For the moment, as we do not know the underlying mechanism, it is just one of those exceptions that you have to remember. In nearly every other respect, hyperthyroidism has a sympathomimetic effect and hypothyroidism has a sympatholytic effect. But for the gastrointestinal system, it is the opposite.

References:

Bozzani A, Camboni MG, Tidone L, Cesari P, Della Mussia F, Quatrini M, Ghilardi G, Ferrar L, Bianchi PA (1985) Gastrointestinal transit in hyperthyroid patients before and after propranolol treatment. Am J Gastroenterol. 1985 Jul;80(7):550-2.

Bricker LA, Such F, Loehrke ME, Kavanaugh K (2001) Intractable diarrhea in hyperthyroidism: management with beta-adrenergic blockade. Endocr Pract. 2001 Jan-Feb;7(1):28-31.

Daher R, Yazbeck T, Jaoude JB, Abboud B (2009) Consequences of dysthyroidism on the digestive tract and viscera. World J Gastroenterol. 15(23):2834-8.

Kyriacou A, McLaughlin J, Syed AA (2015) Thyroid disorders and gastrointestinal and liver dysfunction: A state of the art review. Eur J Intern Med. 26(8):563-71.

Does nicotine cause sweating?

October 25, 2017 / phcdgs / 0 Comments

The eccrine sweat glands express muscarinic M3 cholinergic receptors. In an exception to the usual rule that the postganglionic neurotransmitter for the sympathetic nervous system is noradrenaline or adrenaline, the sympathetic nervous system innervates the eccrine sweat glands with cholinergic nerve fibres. Thus, sweating associated with the fight-or-flight response is a sympathetic nervous system response mediated by cholinergic activation of M3 receptors.

But does nicotine not also cause sweating? Nicotine can contribute to sweating in a number of ways. The preganglionic nerve fibres of both the sympathetic and parasympathetic nervous system are cholinergic release acetylcholine to activate nicotinic cholinergic receptors on the ganglionic neurones. Thus nicotine can directly activate the ganglionic neurones triggering activation of the cholinergic postganglionic sympathetic nervous system innervation of the eccrine sweat glands.

The nerve terminals innervating the sweat glands also have presynaptic nicotinic receptors. Application of acetylcholine or nicotine to the skin will activate these nerve terminals triggering action potentials to branches of the nerve innervating adjacent sweat glands to release acetylcholine and activate postsynaptic M3 receptors on these sweat glands. This is referred to as the sudomotor axon reflex.

Image credit: http://www.medicavisie.eu/de/technologien/#sudomotor

Note that to acheive activation of nicotinic receptors exposure to nicotine has to be at a low dose and for a short duration. High doses of nicotine or prolonged exposure to nicotine can lead to depolarising and desensitising block of nicotinic receptor neurotransmission.

What does “nonselective” muscarinic receptor antagonist mean?

February 25, 2017 / phcdgs / 0 Comments

In the context of autonomic system pharmacology, you will often come across drugs described as “nonselective muscarinic antagonists” or “nonselective alpha-adrenoceptor antagonists”. What does “nonselective” mean in this context?

The potential confusion here is that you might think that a “nonselective muscarinic antagonist” is a drug that is not selective for muscarinic receptors and so also acts on other types of receptors (for example, adrenoceptors) at therapeutic doses. This is not what is meant when these phrases are used in the context of autonomic nervous system pharmacology.

There are many subtypes of muscarinic acetylcholine receptors: M₁, M₂, M₃, M₄ and M₅ receptors. However, most of the muscarinic cholinergic and anticholinergic drugs in current clinical use are nonselective between the muscarinic receptors subtypes. These drugs are selective for muscarinic receptors over other types of receptor, such as nicotinic acetylcholine receptors or adrenoceptors, but are nonselective between the muscarinic receptor subtypes (M₁, M₂, M₃, M₄ and M₅ receptors). For example, atropine is a nonselective muscarinic acetylcholine receptor antagonist because it blocks all muscarinic receptor subtypes: M₁, M₂, M₃, M₄ and M₅ receptors. But atropine is selective for muscarinic acetylcholine receptors over other classes of receptor, such as nicotinic acetylcholine receptors.

Likewise, there are many subtypes of adrenoceptors: α_1A-, α_1B-, α_1D-, α_2A-, α_2B-, α_2C-, β₁-, β₂– and β₃-adrenoceptors. Many of the adrenergic and antiadrenergic drugs in current clinical use target alpha- or beta-adrenoceptors but are nonselective between the subtypes of alpha or beta receptors. For example, oxymetazoline is selective for alpha-adrenoceptors over beta-adrenoceptors but may be described as a nonselective alpha-adrenoceptor agonist because it is largely nonselective between α_1A-, α_1B-, α_1D-, α_2A-, α_2B– and α_2C-adrenoceptors.

Alpha adrenoceptor agonists and reflex bradycardia

February 25, 2017 / phcdgs / 0 Comments

Phenylephrine and oxymetazoline can increase blood pressure and at the same time cause bradycardia.

Phenylephrine is a selective alpha-1 adrenoceptor agonist while oxymetazoline is a non-selective alpha adrenoceptor agonist. You are likely to most commonly come across phenylephrine and oxymetazoline in their us as nasal decongestants. Acting as agonists at the alpha adrenoceptors on blood vessels, they can vasoconstrict the blood vessels of the nasal mucosa. Phenylephrine can also be administered as eye drops to produce mydriasis (dilation of the pupil) without cycloplegia (paralysis of the ciliary muscle of the eye resulting in loss of accommodation and blurred near vision). In contrast, muscarinic receptor antagonists, such as cyclopentolate, produce both mydriasis and cycloplegia.

The vasoconstriction caused by the alpha adrenoceptor agonists increases blood pressure. In fact, phenylephrine is also used as a vasopressor to treat hypotension. Our baroreceptors constantly monitor blood pressure and trigger reflex bradycardia as a compensatory measure when they detect increases in blood pressure. Thus phenylephrine and oxymetazoline are associated with increases in blood pressure and reflex bradycardia.

When treating hypotension, phenylephrine is most useful as a choice of drug for hypotensive patients who are tachycardic. Other vasopressors that increase the heart rate and force via beta-1 adrenoceptor activation, such as dopamine, adrenaline and noradrenaline, would be more likely used for hypotensive patients with normal heart rates or bradycardia.

Sympathetic cholinergic innervation of blood vessels? Not in humans.

February 7, 2017 / phcdgs / 0 Comments

Exceptions to the general rule that the sympathetic nervous system is adrenergic include cholinergic innervation of sweat glands expressing M3 receptors and dopaminergic innervation of the renal blood vessels expressing D1 receptors. But what about the arteries of skeletal muscle?

Parasympathetic cholinergic fibres innervate some blood vessels. In arterial blood vessels, the release of acetylcholine activates M3 receptors on the vascular endothelium, which are coupled to formation of nitric oxide (NO) that produces vasodilation (1). However, if the synthesis of NO is inhibited, the activation of M3 and M2 receptors can produce vasoconstriction. In contrast, cerebral arteries express M5 receptors, which produce vasodilation in response to acetylcholine (1).

In cats and dogs, some of the arterial blood vessels in skeletal muscle are innervated by sympathetic cholinergic nerves that release acetylcholine, which acts at M3 receptors to produce vasodilation (1). In these species, the sympathetic nervous system innervation of the arterial blood vessel in skeletal muscle appears to play a role in active hyperaemia, increasing blood flow to the muscle at the start of exercise (1).

In contrast to cats and dogs, humans do not have sympathetic cholinergic innervation of arterial blood vessels in skeletal muscle (1).

Reference:
(1) Richard E Klabunde Cardiovascular Physiology Concepts: Adrenergic and Cholinergic Receptors in Blood Vessels http://www.cvphysiology.com/Blood%20Pressure/BP010b [Accessed 7 Feb 2017]