On this episode, I breakdown the sacubitril valsartan pharmacology.
The drug for this week is the combination drug sacubitril/valsartan, also known as Entresto. Entresto has a novel dual mechanism of action to treat HFrEF. Sacubitril, currently, is the only FDA-approved medication that is a neprilysin inhibitor. For background, neprilysin is an enzyme that breaks down natriuretic peptides. The inhibition of neprilysin results in an increase in natriuretic peptides, which causes vasodilation, fluid loss, and a decrease in blood pressure. Valsartan is an angiotensin II receptor blocker; it prevents angiotensin II from binding to AT1 to reduce blood pressure by reducing vasoconstriction, synthesis, and release of aldosterone and ADH, cardiac remodeling, and renal reabsorption of sodium. The unique pharmacology of Entresto makes it advantageous to use in HFrEF and is even now one of the preferred agents.
Common adverse reactions that occur when taking Entresto are related to its dual mechanism pharmacology. The most common adverse reactions of Entresto are hyperkalemia, angioedema, hypotension, and renal impairment. Entresto is contraindicated in pregnancy due to fetotoxicity; it requires a 36 hour washout period when transitioning from an ACE inhibitor due to the increased risk of angioedema.
Entresto is initially dosed at 24/26 mg twice a day if the patient is on a low dose ACE inhibitor/ARB, or if the patient has not taken anything. If a patient is taking over 10 mg of enalapril equivalents a day or 160 mg of valsartan equivalents a day, then the preferred initial dose is 49/51 mg twice a day. Regardless of initial dosing, the target dose is 97/103 mg twice a day. In cases of severe renal impairment, or moderate hepatic impairment, the initial dosing should start at 24/26 twice a day; titration remains the same.
The pharmacology of Entresto leaves room for many potential drug-drug interactions. There’s a risk of duplicate therapy with other ACE inhibitors or ARBs. An exacerbation of adverse drug reactions can also occur when taking medications that can lower blood pressure, like Sinemet, or medications that can increase the risk for hyperkalemia, like trimethoprim, and spironolactone, or medications that can increase the risk of renal impairment, like NSAIDs. Entresto has also been shown to increase the risk of lithium toxicity.
I cover melatonin pharmacology on this episode of the Real Life Pharmacology Podcast.
Melatonin, commonly taken by patients for insomnia, is an endogenous hormone produced by the pineal gland. It is an over-the-counter supplement available in dosage forms such as liquid drops, gummies, and tablets. The pharmacology of melatonin is primarily through the activation of melatonin receptors in the suprachiasmatic nucleus; it is also a derivative of L-tryptophan. The production and secretion of melatonin is stimulated by darkness and is inhibited by light. Melatonin concentrations are also shown to vary with age. Its production primarily begins between months 3-4 post-birth, and it peaks between years 1-3. The production and secretion decrease with age and can play a role in insomnia in adults. The doses of melatonin can vary but is commonly found in 1 mg, 3 mg, 5 mg, and 10 mg. Although it is usually taken in higher doses, doses between 0.1-0.5 mg may be adequate.
Certain things need to be taken into consideration when a patient is taking melatonin. Some of the things that should be taken into consideration are if it works as it’s expected to or if the patient is already on stimulating medications that can cause insomnia. If the patient is taking other medications like zolpidem, trazodone, or mirtazapine, melatonin may not be needed. Other things that should be taken into consideration are if the patient tolerates melatonin well and if a lower dose of melatonin can be used. Melatonin is commonly well-tolerated, but it can occasionally cause CNS issues at higher doses such as oversedation, cognitive impairment. It can even cause hyperprolactinemia that can cause sexual dysfunction, fertility risk, lactation, and is associated with lower bone mineral density.
Common adverse drug reactions associated with the pharmacology of melatonin are headache, CNS depression, irritability, and daytime sedation. With long-term use, melatonin can cause suppression of the hypothalamic-pituitary axis. Melatonin is primarily metabolized by CYP1A2, CYP2C9, and CYP2C19. The concentration and efficacy of melatonin can potentially be impacted by medications that induce or inhibit the CYP enzyme system, such as propranolol, calcium-channel blockers, and others. Interactions of melatonin that are not CYP mediated are additive effects when taken with other sedatives, caffeine, and ethanol that can reduce the efficacy of melatonin, or other medications that can increase the risk of adverse drug reactions.
Melatonin is regulated by the FDA as a dietary supplement, and not as a medication. Toxicology studies are limited.
Show notes provided by Chong Yol G Kim, PharmD Student.
Diphenhydramine is a first generation antihistamine that is highly anticholinergic.
When using medications like diphenhydramine, be sure to watch for side effects like dry eyes, dry mouth, constipation, urinary retention, and CNS changes.
Sedation is a primary effect of diphenhydramine. It can be advantageous in certain situations, and detrimental in others.
Drugs like donepezil, memantine, laxatives, tamsulosin, and artificial tears can be indicators of anticholinergic side effects from diphenhydramine.
Paroxetine (Paxil) is an SSRI that can be used in the management of depression. I discuss more on paroxetine pharmacology in this episode.
Because paroxetine has some modest anticholinergic effects, it does show up on the Beers list as a potentially inappropriate medication.
By inhibiting CYP2D6, paroxetine can have numerous drug interactions. Drugs like atomoxetine, aripiprazole, and metoclopramide can all have their concentrations increased.
Tamoxifen is activated by CYP2D6 and paroxetine can ultimately reduce the effectiveness of the medication.
