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Primidone Pharmacology

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On this episode, I discuss primidone pharmacology, adverse effects, and drug interactions.

Primidone, or Mysoline, is an anticonvulsant most commonly used for essential tremors. The primary pharmacological mechanism of action of primidone is similar to other anticonvulsants, like phenobarbital. It causes a reduction in the activity of neurons. Both primidone and its metabolites are potent anticonvulsants. Primidone alters the transmembrane Na/Cl transport channel to reduce the frequency of nerve firing. Phenobarbital, one of primidone’s active metabolites, interacts with GABA-A receptors and chloride channels to reduce nerve excitability.   

Typically B-blockers are used first for essential tremors, then primidone is the next option if B-blockers are ineffective. The dose of primidone can change depending on the use. At lower doses, around 250-700 mg/day (often lower doses than 250 mg will be used), it can indicate that it is being used for essential tremor. When it’s administered at higher doses, up to around 750-1500 mg/day, it can indicate that it is being used for seizures. When used for seizures, it’s important to taper more slowly to not cause seizures with lower minimum effective concentrations. When first dispensing phenytoin, it’s also important to look through a patient’s medication to check that it’s truly essential tremors, and not drug-induced. 

Primidone has common adverse drug reactions of CNS depression, sedation, dizziness, confusion, fatigue, GI issues, ataxia; the adverse drug reactions are similar to alcohol toxicity. Special consideration should be taken in patients with a history of depression; primidone can cause or exacerbate suicidal ideation. It’s important to monitor the blood concentrations of phenobarbital when primidone is taken at higher doses, at lower doses, it’s not as important. Vitamin deficiencies should also be monitored. Primidone can cause a vitamin D deficiency, along with vitamin B12 and folic acid deficiencies. 

Drug-drug interactions of primidone are those that can cause additive effects of CNS depression. For example, other anti-seizure medications, opioids, and first-generation antihistamines. Primidone also has enzymatic interactions. It is metabolized into its active metabolites by CYP2C9, CYP2C19, and CYP2E1. It should be monitored more closely when taken with drugs that can induce, or inhibit, the activity of those enzymes. Primidone, and phenobarbital, also induces CYP3A4 as well as CYP1A2. Certain drugs like apixaban, rivaroxaban, aripiprazole, prednisone, quetiapine, amlodipine, alprazolam, and olanzapine should be monitored more closely. 

The signs of primidone overdose are extensions of its adverse drug reactions. Common signs of an overdose are CNS depression, respiratory depression, lowered reflexes, and hypotension. In cases of severe primidone overdose, removal of the unabsorbed drug with hemoperfusion has been shown to be effective and show improvement in a patient’s clinical condition. In non-severe cases, symptomatic and supportive treatment may be necessary.

Show notes provided by Chong Yol G Kim, PharmD Student.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

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Guide to Drug Food Interactions (Amazon Best Seller)

Drug Interactions In Primary Care (Amazing Resource for Practicing Clinicians)

Perils of Polypharmacy (Great Resource for Those Who Work in Geriatrics)

References

Paragraph 1: taken from episode, information on MOA taken from drugbank (https://go.drugbank.com/drugs/DB00794#mechanism-of-action)

Paragraph 2: taken from episode

Paragraph 3: taken from episode

Paragraph 4: taken from episode, information on metabolism taken from drugbank (https://go.drugbank.com/drugs/DB00794#metabolism)

Paragraph 5: taken from drugbank (https://go.drugbank.com/drugs/DB00794#toxicity)

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Melatonin Pharmacology

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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.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

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Flippin’ Pharmacology Flash Cards

Pharmacology Crossword Puzzle Book (Over 2,000 Clues/Questions!)

NAPLEX Study Materials

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BCMTMS Study Materials

Meded101 Guide to Nursing Pharmacology (Amazon Highly Rated)

Guide to Drug Food Interactions (Amazon Best Seller)

Drug Interactions In Primary Care (Amazing Resource for Practicing Clinicians)

Perils of Polypharmacy (Great Resource for Those Who Work in Geriatrics)

Resources

  1. Information is taken directly from the podcast episode
  2. Light/dark melatonin levels, concentrations with age paragraph 1: 10.1016/s0531-5565(98)00054-0 , podcast
  3. ADRs paragraph 2: Lexicomp, podcast
  4. CYP interactions paragraph 3: Lexicomp
  5. Toxicity paragraph 4: Lexicomp
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Furosemide Pharmacology

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Furosemide is a loop diuretic most commonly recognized by its brand name, Lasix. Pharmacologically, it acts by inhibiting the reabsorption of Na/Cl in the thick ascending limb of the loop of Henle. The inhibition of electrolyte reabsorption results in a loss of fluids causing diuresis. Since it has a diuretic effect, it is commonly used to treat congestive heart failure, general edema, ascites due to cirrhosis, and to aid in fluid elimination. 

If a patient has a new prescription of furosemide, it’s important to look for drug-induced causes of edema. Common causes of drug-induced edema are the calcium-channel blockers (amlodipine, nifedipine, diltiazem, verapamil), some anticonvulsants (pregabalin, gabapentin), pioglitazone, and NSAIDs. In times when oral furosemide is not readily available, 40 mg of furosemide is equivalent to roughly 20 mg torsemide, or 1 mg bumetanide. If IV furosemide is desired and the patient is already on an oral formulation, generally, the approximate equivalent IV dose is 50% of the oral dose. Dosing is approximate and based on urine output. Serum creatinine, electrolytes, weight, blood pressure, should generally be monitored due to the pharmacology of furosemide.

Common adverse drug reactions of furosemide associated with its pharmacology are hypokalemia, and its symptoms such as cramping and uncommonly cardiac problems, hypotension, hyponatremia, dehydration, decrease in renal perfusion, uric acid elevation, transient increases in glucose, angioedema and hypersensitivity reactions, ototoxicity, and nephrotoxicity. Drugs that can exacerbate furosemide’s adverse drug reaction profile are ARBs, ACEis, NSAIDs, aminoglycoside, SGLT2 inhibitors, PDE5 inhibitors, a1a blockers. Electrolyte supplementation may be provided to patients on furosemide to counteract any imbalances that may precipitate. 

In cases of overdose, the common symptoms are exacerbations of the adverse drug reactions and mechanism, dehydration, electrolyte imbalances, hypochloremic alkalosis, reduction in blood volume, and hypotension. Supportive treatment of symptoms is necessary to treat furosemide overdoses, fluid and electrolyte replacement is a rational method of treatment. Serum electrolytes, CO2 level, and blood pressure should be monitored in overdose situations. Hemodialysis does not accelerate furosemide elimination.

Show notes provided by Chong Yol G Kim, PharmD Student

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

Support The Podcast and Check Out These Amazing Resources!

Flippin’ Pharmacology Flash Cards

Pharmacology Crossword Puzzle Book (Over 2,000 Clues/Questions!)

NAPLEX Study Materials

BCPS Study Materials

BCACP Study Materials

BCGP Study Materials

BCMTMS Study Materials

Meded101 Guide to Nursing Pharmacology (Amazon Highly Rated)

Guide to Drug Food Interactions (Amazon Best Seller)

Drug Interactions In Primary Care (Amazing Resource for Practicing Clinicians)

Perils of Polypharmacy (Great Resource for Those Who Work in Geriatrics)

Resources

  1. Information taken directly from the podcast episode
  2. Dosing goals diuresis end of paragraph 2: 2013 ACCF/AHA guideline for the management of HF https://doi.org/10.1161/CIR.0b013e31829e8776
  3. Last paragraph on overdose, furosemide FDA label
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Hydroxyzine Pharmacology

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Background: – Hydroxyzine Pharmacology Hydroxyzine, common brands Atarax, and Vistaril, is a first-generation antihistamine. It is a part of the piperazine drug class[1], sharing structural similarities to other antihistamines like Cetirizine, but also drugs of other classes like ranolazine, buspirone, clozapine. Being an H1 blocker, hydroxyzine is commonly used for itching, anxiety, analgesia, urticaria, and insomnia. The main adverse drug reactions associated with hydroxyzine are the anticholinergic effects common with most antihistamines, dry mouth, headache, urinary retention, QTC prolongation, drowsiness[2].

Interactions: Due to hydroxyzine’s pharmacology and mechanism of action, it can exacerbate or worsen gastroparesis by decreasing smooth muscle contraction in the GI tract, and has similar effects on benign prostatic hyperplasia by worsening urinary retention. Hydroxyzine is metabolized into its active drug, cetirizine, by CYP3A4 and CYP3A5[3]. As such, hydroxyzine’s efficacy can be increased with concomitant use of rifampin, carbamazepine, St. John’s Wort; and its efficacy can be decreased with concomitant use of certain azole antifungals, verapamil or diltiazem, or grapefruit juice. The anticholinergic effects can also be compounded when taken with other anticholinergic drugs and can decrease the efficacy of certain dementia medications, like clonidine. Although uncommon, the risk of QTC prolongation, and Torsades de Pointes, can be increased when taken with potassium channel blocking agents like amiodarone or sotalol, or other agents like certain antibiotics and antipsychotics[4][5].

PK/PD & toxicity: Hydroxyzine has an onset of action between 15-60 minutes and a duration of action between 4-6 hours[3]. The half-life of hydroxyzine varies with age. On average, it is 7.1 hours in children, 20 hours in adults[6], and 29 hours in the elderly, and should be dosed appropriately[7]. Its volume of distribution is 16±3 L/kg with high concentrations found in the skin than in plasma[3]. Its clearance is 31.1±11.1 mL/min/kg in children and 9.8±3.3 mL/min/kg in adults. The active drug of hydroxyzine is excreted around 70% unchanged in the urine[6]. Overdoses can be characterized by sedation, but can also cause nausea, vomiting, and seizures. General supportive care of the symptoms is needed for treatment. Vomiting should be induced if it has not occurred. Immediate gastric lavage is also recommended[8].

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

Show notes written by Chong Yol G Kim, PharmD Student

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Flippin’ Pharmacology Flash Cards

Pharmacology Crossword Puzzle Book (Over 2,000 Clues/Questions!)

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Meded101 Guide to Nursing Pharmacology (Amazon Highly Rated)

Guide to Drug Food Interactions (Amazon Best Seller)

Drug Interactions In Primary Care (Amazing Resource for Practicing Clinicians)

Perils of Polypharmacy (Great Resource for Those Who Work in Geriatrics)

References

[1] Fifer EK. Drugs Used to Treat Ocular and Nasal Congestion Disorders. In: Roche VF, Zito SW, Lemke TL, Williams DA. Eds. Foye’s Principles of Medicinal Chemistry 8e. Lippincott Williams & Wilkins; Accessed May 15, 2021.

[2] Katzung BG. Histamine, Serotonin, & the Ergot Alkaloids. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw-Hill; Accessed May 15, 2021.

[3] Altamura AC, Moliterno D, Paletta S, Maffini M, Mauri MC, Bareggi S: Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin Drug Metab Toxicol. 2013 Apr;9(4):423-40. doi: 10.1517/17425255.2013.759209. Epub 2013 Jan 21.

[4] Schlit AF, Delaunois A, Colomar A, Claudio B, Cariolato L, Boev R, Valentin JP, Peters C, Sloan VS, Bentz JWG: Risk of QT prolongation and torsade de pointes associated with exposure to hydroxyzine: re-evaluation of an established drug. Pharmacol Res Perspect. 2017 Apr 21;5(3):e00309. doi: 10.1002/prp2.309. eCollection 2017 Jun.

[5] Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3(5):241-253. doi:10.1177/2042098612454283

[6] Paton DM, Webster DR: Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet. 1985 Nov-Dec;10(6):477-97.

[7] Simons KJ, Watson WT, Chen XY, Simons FE: Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther. 1989 Jan;45(1):9-14. doi: 10.1038/clpt.1989.2.

[8] FDA Approved Drug Products: Vistaril (hydroxyzine pamoate)

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Vitamin B12 Pharmacology

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On this episode, I cover clinical tips and practice pearls surrounding vitamin B12 pharmacology.

Vitamin B12 deficiency plays a critical role in the development of macrocytic anemia.

There are medications that you have to be aware that can deplete vitamin B12. Metformin, colchicine, and PPIs are some common examples.

A lack of intrinsic factor can lead to B12 deficiency. Intrinsic factor is necessary for adequate GI absorption of vitamin B12.

I discuss important drug interactions on the podcast, be sure to check out my latest project which is a 200+ page book on managing drug interactions in primary care.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

Support The Podcast and Check Out These Amazing Resources!

Flippin’ Pharmacology Flash Cards

Pharmacology Crossword Puzzle Book (Over 2,000 Clues/Questions!)

NAPLEX Study Materials

BCPS Study Materials

BCACP Study Materials

BCGP Study Materials

BCMTMS Study Materials

Meded101 Guide to Nursing Pharmacology (Amazon Highly Rated)

Guide to Drug Food Interactions (Amazon Best Seller)

Drug Interactions In Primary Care (Amazing Resource for Practicing Clinicians)

Perils of Polypharmacy (Great Resource for Those Who Work in Geriatrics)

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Ketamine Pharmacology

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On this episode, I discuss ketamine pharmacology.

Ketamine is primarily broken down by CYP2B6 which fortunately does not have a lot of common medications that can interfere with its action.

Ketamine can cause psychiatric type adverse effects such as hallucinations, nightmares, and vivid dreams.

At lower to moderate dosages, ketamine does have some mild sympathetic activity which can raise blood pressure and heart rate.

I discuss important drug interactions on the podcast, be sure to check out my latest project which is a 200+ page book on managing drug interactions in primary care.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

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Topiramate Pharmacology

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On this episode of the Real Life Pharmacology Podcast, I cover topiramate pharmacology.

Topiramate is indicated for migraine prevention, seizures, and weight loss which are the most common uses that I see this medication used for.

Topiramate has carbonic anhydrase activity, so rarely, use of this drug may induce metabolic acidosis.

By far, the most common patient complaint I get with the use of topiramate is that it causes cognitive slowing or impairment.

I discuss important drug interactions on the podcast, be sure to check out my latest project which is a 200+ page book on managing drug interactions in primary care.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

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Colchicine Pharmacology

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On this episode I discuss colchicine pharmacology, adverse effects, drug interactions, and pharmacokinetics.

Colchicine ultimately works by reducing the activity of neutrophils that help contribute to pain and inflammation associated with gout.

Colchicine does have some drug interactions with medications and grapefruit juice via CYP3A4.

The most common dose limiting side effect of colchicine is diarrhea.

Colchicine can be used as a potential alternative to NSAIDs or corticosteroids in the management of a gout flare.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

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Fexofenadine Pharmacology

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Fexofenadine is a 2nd generation antihistamine that is primarily used for allergic rhinitis. I cover fexofenadine pharmacology on this podcast episode.

Fruit juices can actually impair the absorption of fexofenadine and increase the risk of treatment failure.

Fexofenadine is mildly anticholinergic but overall has low to no CNS penetration.

Because fexofenadine has low CNS penetration, the risk for sedation and dizziness is much lower than older antihistamines like diphenhydramine.

I discuss important drug interactions on the podcast, be sure to check out my latest project which is a 200+ page book on managing drug interactions in primary care.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

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Empagliflozin Pharmacology

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On this episode I discuss empagliflozin pharmacology and how this medication lowers blood sugar.

In this episode, I talk about empagliflozin pharmacology. Empagliflozin is more commonly known by the brand name Jardiance and is in the class of sodium-glucose co-transporter-2 inhibitors or SGLT2 inhibitors. Jardiance use has definitely escalated over the last few years in the management of type 2 diabetes, but this has been changing a little bit as well due to recent evidence for the cardiovascular benefits from this medication.

The sodium-glucose co-transporter-2 is found in the kidney and is responsible for helping the body reabsorb glucose back into the bloodstream. The way empagliflozin works is by inhibiting this transporter, more glucose is excreted into the urine and ultimately lowering the blood sugar since it is not being reabsorbed. Empagliflozin has additional benefits outside of blood sugar reductions. Studies found that patients with or without diabetes receive cardiovascular protective effects from this medication, including a reduction in heart failure hospitalizations and reducing the risk of death in patients with ASCVD. Additionally, empagliflozin has shown some benefits in protecting renal function over time in patients with and without chronic kidney disease (CKD).

Dosing is pretty straightforward for this medication. Empagliflozin is taken once daily and is an oral medication, which is nice for patients who do not want injectable therapy. Dosing starts at 10 mg once daily and may be increased up to 25 mg daily if tolerated. This increase is typically done after about 4 weeks to see if it is needed. In patients with renal dysfunction and an eGFR less than 45 mL/min, FDA labeling states that empagliflozin should not be initiated, although there is a gray area in the 30-45 mL/min range that needs further study.

When thinking about the side effects of empagliflozin, it is helpful to keep the mechanism of action in mind, where we are increasing the urinary glucose. This can also lead to more fluid being excreted with the glucose, causing a decrease in blood pressure and dehydration risks. This is important to keep in mind for patients who are more prone to hypotension, including elderly patients. Empagliflozin also causes increased genitourinary fungal infections and UTIs due to the increase in sugar in the urine. Other rare adverse effects include ketoacidosis, necrotizing fasciitis risk, bone fracture, and lower limb amputation, however, this one has more controversial evidence.

For monitoring parameters, assessing A1c reduction and blood sugars is definitely important in our patients with diabetes. Patients on empagliflozin should also have their renal function monitored, as well as any blood pressure lowering. It is also important to keep an eye on any prescribing of antifungals, the incidence of UTIs, and assessing for signs of ketoacidosis.

The most important and common drug interactions are typically associated with additive effects with empagliflozin. Diuretic use can increase the risk for dehydration and hypotension. Additive blood sugar-lowering effects when empagliflozin is used with other agents such as insulin and sulfonylureas and can increase the patient’s risk for hypoglycemic episodes. Finally, blood pressure medication dosages may need to be reduced if empagliflozin is causing hypotension. Since empagliflozin is not hepatically metabolized, CYP450 drug interactions are not a problem.

I discuss important drug interactions on the podcast, be sure to check out my latest project which is a 200+ page book on managing drug interactions in primary care.

Be sure to check out our free Top 200 study guide – a 31 page PDF that is yours for FREE!

Resources: 

Empagliflozin. Micromedex DrugDex. IBM Micromedex. Accessed July 29, 2021.Yusuf T, Raji YR, Lasisi TJ, et al. Predictors of taste dysfunction and its severity among patients with chronic kidney disease. Ear Nose Throat J. Published online July 19, 2021. doi:10.1177/01455613211019708.