Folic Acid Pharmacology

folic acid pharmacology

Folic acid is a water-soluble vitamin; compared to fat-soluble vitamins, accumulation is not as much of an issue. It is responsible for the formation of coenzymes, DNA synthesis, erythropoiesis, and certain metabolic processes. Due to the mechanism of folic acid, if there is a deficiency present, anemia can manifest. Although the recommended dietary intake is 0.2 mg, supplementation may be necessary. Some situations where supplementation may be desired are prevention of neural tube defects in pregnancy, patients suffering from alcohol abuse disorder, bariatric surgery patients, and certain types of GI disorders where malabsorption may be present. If a patient is taking certain medications folic acid supplementation may be necessary as well. Notable drugs where a patient may require folic acid include methotrexate and phenytoin. 

The dosages used most often when supplementing folic acid are in the 1-5 mg range, and most of the time it will be 1 mg. Folic acid has a relatively safe adverse drug reaction profile. Some possible adverse drug reactions are flushing, malaise, erythema, skin rash, and hypersensitivity reactions. Although uncommon, the chance for an adverse drug reaction occurring increases as the dose increases. For monitoring folic acid, the normal levels can vary between 2-20 ng/mL, but they can vary based upon the lab. A type of anemia that can manifest with a folic acid deficiency is megaloblastic anemia. When assessing megaloblastic anemia, vitamin B12 levels should also be assessed. 

Folic acid levels can be impacted by phenytoin, methotrexate, trimethoprim and sulfamethoxazole, sulfasalazine, triamterene, and alcohol. When a patient is only taking trimethoprim and sulfamethoxazole for acute treatment of a UTI, folic acid levels aren’t as concerning. Whenever it changes from acute treatment to prophylaxis, folic acid levels should be monitored more closely. Theoretically, folic acid can lower concentrations of phenytoin, and phenobarbital, so closer monitoring may be warranted.  

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

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Insulin Glargine Pharmacology

On this episode, I discuss insulin glargine pharmacology. Insulin glargine is a long-acting insulin that has the common brand names Lantus, Basaglar, and Toujeo. Due to the pharmacology of insulin glargine, it provides a baseline coverage of insulin. It cannot manage acute elevations in blood glucose like target-specific meals. Instead, insulin glargine is used to decrease blood sugar throughout the day. 

It is normally dosed once a day, and sometimes a patient will have another type of insulin that’s rapid-acting, like Humalog. The daily insulin dose will vary, but it’s frequently a 50/50 split between long-acting, and rapid-acting. Dosing of insulin glargine in Type 2 diabetes is usually started at 10 units, but that can vary based on the patient or pertinent clinical data. Whenever doses need to be changed, it’s typically done in the range of 3-7 day intervals. Generally, when dose increases are desired, and the risk for hypoglycemia is low, a 10-20% increase is mostly what’s done. When converting between different types of insulin, the majority are 80% to 1:1 equivalent. Clinical monitoring is vital with any conversion.

Insulin glargine is best suited in long-acting situations due to its formulation. Its solubility varies at different levels of acidity. The pH of the injected solution is 4, where insulin glargine is completely soluble. When the solution is at physiological pH, around 7.4, micro-precipitations can form causing small amounts of insulin glargine to be released over 24 hours. The onset of action of insulin glargine is roughly 3-4 hours, and hypoglycemia is not an immediate concern because of this. If a medication error occurs with insulin glargine, it likely wouldn’t be noticed immediately due to its kinetics. For rapid-acting insulin like Humalog, it would be noticed more quickly.

Monitoring for insulin glargine is individualized, but it’s generally done through measuring A1c levels. Serum potassium levels can also be monitored, but with longer-acting insulins, it is less of a concern. The most common adverse reactions of insulin glargine are hypoglycemia, weight gain, peripheral edema, and immunological reactions. Drug-drug interactions aren’t a large concern with insulins, due to the amount of monitoring of patients on them. There are risks of potentiation of hypoglycemia or masking of the signs and symptoms of hypoglycemia. With diabetic patients, the compounded risk of hypoglycemia might be greater if they’re taking other medications like metformin, GLP-1 agonists, sulfonylureas, SGLT2 inhibitors, etc. Some other drugs that can increase the risk of hypoglycemia are quinolone antibiotics, B-blockers, or thiazide diuretics. The efficacy of insulin glargine can also be decreased by corticosteroids, stimulants, antipsychotics, or transplant medications.

In cases of overdose, because of the pharmacology of insulin glargine, hypoglycemia is common. The milder cases of hypoglycemia can be treated with oral carbohydrates, and simply adjusting the dose, meal patterns, or exercise may suffice. In severe cases of hypoglycemia, coma, seizure, or neurologic impairment may occur. Symptoms of severe hypoglycemia can be treated with glucagon or glucose and these patients typically need to be hospitalized. Once an overdosed patient recovers from hypoglycemia, clinical observation, and carbohydrate intake may be necessary to avoid recurrence.

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

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Paragraph 1: taken from podcast

Paragraph 2: taken from podcast

Paragraph 3: pH solubility (https://go.drugbank.com/drugs/DB00047#mechanism-of-action), medication error taken from podcast

Paragraph 4: taken from podcast, ADRs taken from Lexicomp

Paragraph 5: overdose information (“FDA Approved Drug Products: Lantus (Insulin glargine) for subcutaneous injection”)

Primidone Pharmacology

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.

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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)

Melatonin Pharmacology

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.

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  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

Furosemide Pharmacology

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

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  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

Hydroxyzine Pharmacology

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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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)

Vitamin B12 Pharmacology

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.

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Ketamine Pharmacology

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!

Topiramate Pharmacology

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.

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Colchicine Pharmacology

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.

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