autonomic pharmacology

Category: autonomic pharmacology (page 1 of 2)

Why are peripheral effects of AChE inhibitors predominantly parasympathomimetic?

Acetylcholinesterase (AChE) inhibitors will prevent the breakdown of acetylcholine (ACh) and so increase ACh levels. Increased ACh levels at autonomic nervous system ganglia should activate both the sympathetic and parasympathetic nervous systems. However, the adverse effects of AChE inhibitors outside of the CNS are mostly parasympathomimetic. Why do AChE inhibitors not stimulate the sympathetic nervous system as well?

Acetylcholinesterase (AChE) inhibitors increase the concentration of acetylcholine (ACh) at synapses by blocking its breakdown. This will activate both the sympathetic and parasympathetic systems, as the preganglionic neurons in both systems release ACh.

However, the impact of AChE inhibitors is more prominent on the parasympathetic nervous system for several reasons:
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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

May 5, 2021 / phcdgs / 0 Comments

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.

Ganglionic blockers versus depolarising NMBAs

May 5, 2021 / phcdgs / 0 Comments

High-dose nicotine induces depolarising blockade and subsequent secondary non-depolarising blockade at autonomic ganglia. Meanwhile, depolarising NMBAs induce depolarising block consisting of Phase I and Phase II. Is it the same thing?

Yes, they are essentially the same mechanisms as far as the nicotinic receptors go. It is primarily a difference in terminology. Although secondary non-depolarising block is a more scientifically descriptive term than Phase II, the depolarising NMBAs are already called “depolarising” to contrast with the non-depolarising NMBAs (direct nicotinic receptor antagonists). It would therefore be confusing to say that depolarising NMBAs have a secondary non-depolarising block. Hence, the common usage of the Phase I and Phase II terminology.

Neostigmine versus pyridostigmine

February 22, 2020 / phcdgs / 0 Comments

What is the preferred oral acetylcholinesterase inhibitor for myasthenia gravis?

Pyridostigmine is often preferred to neostigmine for myasthenia gravis for three reasons:

(1) The onset of the effect of oral pyridostigmine (approximately 45 minutes) is faster than that for neostigmine (approximately 4 hours). The speedier onset allows for more precise adjustment of the dosing schedule around daily living activities to ensure as much muscle function as possible when required.

(2) The half-life of pyridostigmine (approximately 90 to 110 minutes) is longer than that for neostigmine (approximately 50 to 90 minutes). The difference is not great, but when the patient has to take the drug multiple times in a day, it is an advantage that 3 or 4 times per day is often sufficient with pyridostigmine.

(2) Pyridostigmine is about four times less potent than neostigmine. That is right, being less potent is an advantage because it is easier to titrate the dose to a level that controls the motor symptoms without causing too many adverse effects. This is especially important in the early stages of the disease when the motor symptoms are less pronounced.

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.

Why does vagotomy cause diarrhoea?

November 29, 2017 / phcdgs / 0 Comments

Discussing the use of bile salt-binding resins, such as colestyramine (cholestyramine USAN), and somatostatin peptide drugs, such as octreotide, for the treatment of diarrhoea we saw that these drugs are only used for specific types of diarrhoea, such as secretory diarrhoeas. One example given was diarrhoea following vagotomy.

But why does vagotomy cause diarrhoea? Vagotomy is a surgical technique indicated for patients who develop acute complications from peptic ulcer disease or chronic symptoms despite being on maximally tolerated medical therapies. Damage to the vagus nerve can also occur following bariatric surgery, fundoplication, and oesophagal resection. Postvagotomy diarrhoea has been described in up to 30 percent of patients. Many patients have transient watery diarrhoea for three to six months postvagotomy but in some the diarrhoea can be severe and chronic.