Month: May 2021 (page 1 of 2)

Folate, folic acid or folinic acid to reduce adverse effects of methotrexate?

May 9, 2021 / / 0 Comments

What is the difference between folate, folic acid, and folinic acid? And how do each of them contribute or are involved in the methotrexate pathway?

Folate is the naturally occurring salt form of vitamin B9. Folic acid is a synthetic water-soluble acid form of vitamin B9. Folate and folic acid are metabolised by dihydrofolate reductase, the enzyme inhibited by methotrexate, to FH2 and then FH4, which in turn is converted to N5, N10-methylene-FH4.

Folinic acid (also known as leucovorin) is N5-formyl-FH4 and can be converted rapidly to N5, N10-methylene-FH4 without the need for dihydrofolate reductase and so bypasses the inhibition of the pathway by methotrexate.

In the treatment of rheumatoid arthritis with methotrexate, adverse effects include nausea and vomiting, mouth and gastrointestinal ulcers, and hair loss are caused by the reduction in N5, N10-methylene-FH4, which is required for the synthesis of amino acids and nucleic acids necessary for cell proliferation.  Folic acid at high enough doses to overcome the methotrexate inhibition of dihydrofolate reductase or folinic acid is therefore used to reduce the adverse effects of methotrexate.

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.

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).

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