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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.

Does the 5-aminosalicylic acid metabolite of sulfasalazine play a role in management of rheumatoid arthritis

May 9, 2021 / / 0 Comments

 Sulfasalazine is metabolized by gut microbiota into sulfapyridine, the active metabolite in the treatment of rheumatoid arthritis (RA), and 5-aminosalicylic acid. Does 5-aminosalicylic acid play any significant pharmacological role?

The mechanisms of action of sulfasalazine are not fully understood. However, it is unlikely that 5-aminosalicylic acid plays a role in the treatment of RA. But you will come across 5-aminosalicylic acid in the treatment of inflammatory bowel disease, where it is thought to be the active metabolite of sulfasalazine and is also administered as a drug itself.

Why doesn’t the pro-thrombotic effect of coxibs cancel their impairment of wound healing?

May 9, 2021 / / 0 Comments

Coxibs have both pro-thrombotic and impairment of wound healing effects. So why don’t these cancel each other out?

Thrombosis and impairment of wound healing are not contradictory. Instead, wound healing is a complex process that occurs over days to weeks, and even sometimes months or years, involving the recruitment of a cascade of many cell types.

Haemostasis, which is dependent on COX-1 and platelet aggregation, is only a small component of wound healing that occurs over seconds to minutes when there is bleeding. All the rest of the process over subsequent days and weeks depends on cascades initiated by COX-2-dependent mechanisms. When there is tissue damage without bleeding, all the rest of the COX-2-dependent processes still occur without the need for thrombosis. So even if there is enhanced thrombosis, there can still be impaired wound healing.

Bismuth subsalicylate antacid versus antidiarrhoeal?

May 9, 2021 / / 0 Comments

Bismuth compounds would aid peptic ulcer disease and acute diarrhoea. But bismuth subsalicylate inhibits prostaglandin production, and prostaglandins are cytoprotective, so wouldn’t the inhibition of prostaglandins lead to more mucosal damage?

Both subcitrate and subsalicylate bismuth salts (and also subgallate and subnitrate salts) are used.

Theoretically, the subsalicylate is better for diarrhoea because the salicylate additionally acts as an NSAID to reduce inflammation and reduce prostaglandin-mediated activation of chloride channels reducing chloride and hence water in the lumen of the bowel (the opposite effect to lubiprostone).

Meanwhile, theoretically, the subsalicylate is worse for peptic ulcer as it is hydrolyzed to salicylic acid, which will act as a COX inhibitor preventing the production of the prostaglandins. The prostaglandins have protective actions in the stomach, increasing mucosal blood flow, increasing mucus secretion, increasing bicarbonate secretion and, at high concentrations, reducing acid secretion.

In practice, both subsalicylate and non-subsalicylate bismuth compounds are used clinically for both gastric acid-related disease and diarrhoea, and there is no clear evidence of a difference. However, there have not been large, well-designed clinical trials to compare them directly.

Dopamine receptor antagonists and prolactin levels

May 9, 2021 / / 0 Comments

Why do dopamine receptor antagonists result in elevated prolactin levels?

Because dopamine is an important neurotransmitter in suppressing prolactin release through the tuberoinfundibular pathway.

The tuberoinfundibular pathway comprises dopaminergic projections from the arcuate and periventricular nuclei of the hypothalamus to the infundibular region, also in the hypothalamus or median eminence. Dopamine is released into the portal circulation from the median eminence with the anterior pituitary gland. Dopamine tonically inhibits prolactin release via D2-like receptors, D2 and likely to a lesser extend D4.

Thus, dopamine D2 receptors antagonists increase prolactin release. This explains why antipsychotic drugs and antiemetic drugs acting as antagonists at D2 dopamine receptors can cause hyperprolactinaemia.

Treatment for nausea and vomiting in pregnancy

May 7, 2021 / / 0 Comments

Which is the best antiemetic for nausea and vomiting in pregnancy?

It is best to avoid drugs, if possible, during pregnancy.

Typically, dietary changes and avoidance of triggers are tried first:

  • Take meals and snack when hungry to avoid empty stomach, which can aggravate nausea.
  • Avoid coffee, odorous, high-fat, acidic and/or very sweet foods.
  • Eat meals and snacks slowly and in small amounts every one to two hours to avoid overly full stomach, which can also aggravate nausea.
  • Choose high-protein, salty, low-fat, bland and/or dry foods.
  • Take fluid at least 30 min before solid food. Sip fluid in small amounts. Avoid triggers (e.g., odours, stuffy rooms, etc.).
  • Ginger-containing foods can suppress nausea and vomiting.

If dietary changes and avoidance of triggers do not work, pyridoxine (vitamin B6) supplementation is usually tried next. This can improve nausea, but is usually less effective at preventing vomiting.

If vitamin B6 supplementation does not work, a first-generation antihistamine (muscarinic antagonist and H1 receptor antihistamine) is used. The choice is usually doxylamine, an old antihistamine. Doxylamine is usually still combined with vitamin B6. Older drugs are preferred, as we have greater historical knowledge of use in pregnancy. Newer drugs are generally avoided as clinical trials rarely include pregnant women and so there is little information available on their safety during pregnancy.

If vitamin B6 supplementation and doxylamine do not work, then any of the other older H1/M1 blockers (e.g. diphenhydramine) or D2 blockers (e.g. metoclopramide) is used alone or in combination. Again the older agents are used as there is more accumulated knowledge giving some confidence of safety in pregnancy. Only if none of these approaches work is the newer class of 5-HT3 antagonists tried and the agent chosen is typically either ondansetron or granisetron (older agents within the class for which there is some history of use in pregnancy).

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.

Brimonidine for glaucoma

May 5, 2021 / / 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 / / 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.

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