Category: MDG5238 (page 1 of 4)

Why are peripheral effects of AChE inhibitors predominantly parasympathomimetic?

August 30, 2023 / / 0 Comments

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 / / 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

PPIs and C. difficile infection

February 1, 2022 / / 0 Comments

Does the use of proton-pump inhibitors (PPIs) increase the risk of Clostridioides difficile infection?

Medical literature has debated whether PPIs increase the risk of C. difficile enteric infections for many years. Analysis of the issue has been complicated because proton-pump inhibitors are often taken together with antibiotics in triple therapy to eradicate Helicobacter pylori. Antibiotics can alter the normal gut microbiota allowing the proliferation of C. difficile. 

While the pathophysiological mechanisms remain unknown, the evidence increasingly supports the conclusion that PPIs increase the risk of C. difficile infection even without antibiotic use (Wolfe et al., 2021). There is a greater risk of C. difficile infection with PPIs than H2 receptor blockers (Kwok et al., 2012; Leonard et al., 2007). Although there is considerable variation among studies, overall PPIs also increase the risk of recurrent C. difficile infection (Kwok et al., 2012; Tariq et al., 2017).
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Dose-dependence of COX-2 selectivity of coxibs

May 9, 2021 / / 0 Comments

Coxibs are pro-thrombotic, but if given at a high dose, there would be COX-1 inhibition resulting in an antiplatelet effect and hence bleeding would occur. Therefore, would the two effects not cancel each other out, or would the prothrombic effect still be the predominant effect?

The pro-thrombotic effect still dominates since, for coxibs, the COX-2 inhibition is always more than the COX-1 inhibition.

Coxibs are selective inhibitors of COX-2. Selective inhibition of COX-2 results in shunting of the precursor arachidonic acid over to the COX-1 pathway. With COX-2 inhibited and COX-1 functional, there is a relative increase in the ratio of the thromboxane A2 (TXA2) produced via COX-1 to prostaglandin I2 (PGI2) or prostacyclin produced via COX-2, and also in some cell types via COX-1. As TXA2 promotes platelet aggregation, while PGI2 inhibits platelet aggregation, the increased ratio of TXA2 over PGI2 favours platelet aggregation, so there is an increased risk of thrombosis.

Although coxibs are selective for COX-2, the selectivity is dose-dependent. Therefore, at higher doses, there will be more inhibition of COX-1. However, in the case of the balance between the risk of thrombosis versus the risk of bleeding, there is little impact because, as the dose increases, there will still be more inhibition of COX-2 than COX-1. So the ratio of TXA2 to PGI2 remains in favour of thrombosis.

Importantly, the dose-dependence of the selectivity for COX-2 is significant with regards to the gastrointestinal adverse effects. A major advantage of the coxibs is that they have a lower risk of upper gastrointestinal tract (GIT) adverse effects as they do not inhibit COX-1 in the stomach. However, if the dose is increased, there is greater inhibition of COX-1 and, therefore, less sparing from upper GIT adverse effects.

Choice of NSAID for closure of patent ductus arteriosus?

May 9, 2021 / / 0 Comments

Why is indometacin a drug of choice for closing the ductus arteriosus post-partum? As the ductus arteriosus is kept open by PGE2, may I know why other NSAIDs or paracetamol are not as ideal for this purpose?

The ductus arteriosus allows blood to bypass the lungs in utero but should close after birth. Cyclo-oxygenase-2 (COX-2) mediated production of prostaglandin E2 (PGE2) is important in keeping the ductus arteriosus open in utero. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2 when administered at analgesic and anti-inflammatory doses. Therefore, the risk of premature closure of the ductus arteriosus is one reason for the contraindication of NSAIDs in the third trimester of pregnancy.

Patent ductus arteriosus (PDA) occurs when the ductus arteriosus fails to close after birth. NSAIDs can help to close the PDA. Older NSAIDs are typically used because there is a longer history of use and so better knowledge of the risks in infants. Either indometacin, also known as indomethacin (USAN), or ibuprofen is usually used. Paracetamol has also been used as it is has been considered safer in young children. It is not as effectively or widely used, but that it works at all shows that paracetamol can in certain situations inhibit COX-2 in vivo outside of the CNS. Newer NSAIDs are typically not preferred as clinical trials rarely include newborn infants, and so their safety in infants is poorly understood.

Route of administration of N-acetylcysteine for paracetamol poisoning

May 9, 2021 / / 0 Comments

In a clinical setting of paracetamol poisoning, how would N-acetylcysteine be administered to the patient? 

It is usually administered intravenously (IV). It is best administered within 8 hrs of paracetamol overdose, and dosing is maintained over the next 20 hrs.

Paracetamol for osteoarthritis or rheumatoid arthritis?

May 9, 2021 / / 0 Comments

Some guidelines say paracetamol is only suitable for osteoarthritis, not rheumatoid arthritis (RA), as it is a poor anti-inflammatory. However, further reading online indicates that paracetamol is still used for other inflammatory rheumatological disorders like gout and RA. May I seek further clarification on this point?

Paracetamol (acetaminophen) is no longer recommended as a first-line for the pain associated with osteoarthritis (OA) as it has only small, non-clinically significant effects on the pain and there are safety concerns over long-term use for osteoarthritis (e.g., Macahdo et al., 2015; Roberts et al., 2016). Previously, paracetamol alone was used for the pain associated with OA if there was no significant inflammation following the damage to the joints. However, paracetamol is rarely sufficient for the pain associated with gout or RA. As there is always inflammation in gout and RA, a drug that is both analgesic and anti-inflammatory, such as a non-steroidal anti-inflammatory drug (NSAID), is usually preferable. So you will typically find paracetamol in evidence-based medicine guidelines for OA but not for RA or gout.

However, paracetamol will still cause analgesia. Therefore, you will still find it used sometimes as a safer option in cases when the pain is mild or as an addon between doses of ibuprofen (which happens to have a similar dosing interval) to provide additional analgesia. In addition, for patients for whom NSAIDs are contraindicated, you will often find paracetamol used.

References:
Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, Doherty M, Zhang W, Birrell F, Porcheret M, Dziedzic K, Bernstein I, Wise E, Conaghan PG. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552.

Mechanism of action of lubiprostone

May 7, 2021 / / 0 Comments

What is the exact mechanism of action of lubiprostone in increasing intestinal motility?

Lubiprostone is a bicyclic fatty acid derived from a metabolite of prostaglandin E1 (PGE1). It is used primarily to treat chronic idiopathic constipation in adults and constipation-predominant irritable bowel syndrome in women. Lubiprostone acts via chloride channels to increase chloride levels in the lumen of the bowel. Water osmotically follows the chloride. The increase in fluid both softens the bowel contents and increases the bulk of the bowel contents stimulating peristalsis.

The peristaltic reflex triggers the peristalsis. The bulk of the bolus in the lumen of the gut mechanically stimulates enterochromaffin (EC) cells to release 5-HT, which activates intrinsic primary afferent neurons (IPANs). The IPANs, in turn activate the myenteric plexus to engage retrograde and anterograde cholinergic pathways. The retrograde pathway releases substance P and acetylcholine to contract the smooth muscle behind the bolus. The anterograde pathway releases nitric oxide and vasoactive intestinal peptide to relax the smooth muscle in front of the bolus. This allows peristalsis to move the bolus forward along the intestinal tract.

However, there is some controversy in the scientific literature over the exact mechanism by which lubiprostone acts on chloride transport (for review, see Wilson and Schey, 2015). It was initially identified as an activator of type 2 chloride channels (ClC-2) on the apical surface of the intestinal epithelium stimulating chloride-rich secretions. However, it has also been shown that lubiprostone likely activates prostaglandin E2 receptor 4 (EP4) to activate the cystic fibrosis transmembrane conductance regulator (CFTR), another major epithelial cell membrane chloride channel. Yet, lubiprostone still appears to be effective in treating constipation in patients with cystic fibrosis, suggesting that other mechanisms are also important. Meanwhile, other evidence emerged that ClC-2 is localised on the basolateral membranes of the jejunal and colonic epithelium and is involved primarily in absorption rather than secretion of chloride. It has been reported that lubiprostone leads to internalisation of basolateral ClC-2 with concomitant trafficking of CFTR and the chloride/ hydrogen carbonate exchanger PAT-1 to the apical membrane. Thus, lubiprostone may result in reduced absorption of chloride via ClC-2 on the basolateral membranes at the same time as increased secretion of chloride via CFTR and PAT-1 on the apical membranes.

Although the exact mechanisms of the effect on chloride remain incompletely understood, it is clear that lubiprostone increases chloride in the lumen of the bowel.

Reference:

Wilson, N. and Schey, R. (2015) Ther Adv Chronic Dis. Mar; 6(2): 40–50.

NSAIDs increase risk of gastritis and gastric ulcers

May 7, 2021 / / 0 Comments

What is the mechanism for NSAIDs leading to gastric ulcer formation? Can it also cause gastritis?

With high levels of acidity and digestive enzymes, and food movement, the stomach is an aggressive environment for the tissues lining the stomach wall. Prostaglandins mediate endogenous protective mechanisms, including (1) increased mucosal blood flow; (2) increased mucus secretion; (3) increased bicarbonate secretion; and, at high concentrations, (4) reduced acid secretion.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) enzyme. COX is involved in the production of prostanoids, including classical prostaglandins. In the stomach, COX-1 is essential for the production of the protective prostaglandins. Therefore, inhibition of COX by NSAIDs increases the risk of gastritis (the general term for conditions involving inflammation of the lining of the stomach), including gastric ulcers.

How does ageing impact on drug dosing

May 5, 2021 / / 0 Comments

Physiological changes associated with ageing can impact the appropriate dosing for many drugs. General principles to keep in mind include:

Absorption:

  • Absorption usually does not change with normal ageing.

Distribution:

  • Concentrations of water-soluble drugs are usually higher as there is less water and so a lower volume of distribution.
  • Concentrations of free or active (unbound) drug are usually higher due to lower serum proteins.

Metabolism:

  • The half-life of lipophilic drugs is usually higher due to more fat resulting in an increased volume of distribution and prolonged duration of action.
  • There is slower Phase I metabolism (e.g., oxidation, reduction and dealkylation) due to cytochrome P450 pathways resulting in higher levels of drugs dependent on these pathways for metabolism (e.g., warfarin).
  • However, Phase II reactions (e.g., conjugation, acetylation, and methylation) are usually unchanged in normal ageing.
  • There is a greater risk of drug-drug interactions in metabolism due to increased numbers of drugs for multiple medical problems.

Excretion:

  • Hepatic excretion may be impaired.
  • Renal clearance may be impaired, and serum creatinine may not be an accurate reflection of renal clearance in elderly patients due to decreased lean body mass (muscle mass).
  • Active drug metabolites can accumulate, resulting in prolonged therapeutic actions and a greater risk of adverse effects.

There is also increased susceptibility to adverse effects. Older adults are also more likely to have multiple chronic medical problems, and disease states can result in physiological changes:

  • Cardiac disease can result in impaired cardiac output resulting in impaired ADME and greater susceptibility to cardiac adverse effects.
  • Liver or kidney disease can decrease metabolism and excretion, reducing drug clearance.
  • Neurological diseases result in greater sensitivity to neurological adverse effects due to diminished neurotransmitter levels and/or impaired cerebral blood flow.

 

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