Venlafaxine Pharmacology

In this episode, I discuss venlafaxine pharmacology, adverse effect, dose conversion of IR to ER, and drug interactions.

Venlafaxine is notorious for producing withdrawal symptoms when discontinued abruptly. I discuss these in detail on the podcast.

How significant is the interaction of venlafaxine with antiplatelet agents? I discuss that in this episode.

The onset of action is a critical education point that patients must be aware of as it takes some time for venlafaxine to work.

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

Trihexyphenidyl (Artane) Pharmacology

On this episode, I breakdown trihexyphenidyl (Artane) pharmacology, adverse effects, and drug interactions.

Trihexyphenidyl is highly anticholinergic and can cause constipation, dry eyes, dry mouth, and urinary retention.

Dementia medications like donepezil can have their effects blunted by the use of trihexyphenidyl.

Trihexyphenidyl is an older anticholinergic that is rarely used for the management of EPS caused by antipsychotics.

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

Duloxetine Pharmacology

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

Duloxetine is an SNRI that is used for depression, anxiety, and various pain syndromes like neuropathy and fibromyalgia.

Duloxetine can inhibit CYP2D6 which can lead to higher concentrations of clozapine and propranolol and lower activity of tamoxifen.

CYP1A2 inhibitors like ciprofloxacin can raise concentrations of duloxetine leading to an increased potential for adverse effects.

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

Amitriptyline Pharmacology

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

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

Quetiapine Pharmacology

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

Quetiapine (Seroquel) is a medication seen a fair amount particularly in the geriatric population where there is psychosis associated with dementia. It is classified as an antipsychotic. Mechanistically it’s going to block dopamine receptors, specifically D2. It also has some serotonin receptor blockade antagonism. It does have other activity as well from a mechanism of action standpoint. There is alpha-blocking activity potentially as well as an antihistamine/anticholinergic type of activity. Uses of this medication are schizophrenia, bipolar disorder with associated mania, miscellaneous psychotic disorders, and Parkinson’s type disease with psychosis. Off-label you may see it used for OCD, or augmentation for PTSD and depression.

There is a boxed warning of increased risk of mortality in elderly/dementia patients. As a class, antipsychotics have extrapyramidal symptoms, metabolic syndrome, anticholinergic activity, QTC prolongation, sexual dysfunction, hyperprolactinemia, neuroleptic malignant syndrome, sedation, fall risk, and potentially a drop in blood pressure as well. With quetiapine it is important to recognize that antipsychotics can have varying degrees of how much these adverse effects happen and a lot of them are dose-dependent.

There are three important points in comparison to other antipsychotics. Quetiapine is not that great as far as metabolic syndrome risk goes. It’s in the middle of the other antipsychotics. Its extrapyramidal symptoms are better than most, which is why it’s used so often in Parkinson’s. Quetiapine tends to be more sedating than other antipsychotics. This can be helpful when patients are having psychosis worse in the evening or at night.

Metabolic syndrome is something to worry about more in younger patients. The long-term risk of diabetes and hyperlipidemia is going to be a lot higher for them than an 80-year-old using a low dose for dementia-related aggression.

3A4 is a pathway of breakdown for quetiapine drug interactions. With larger food intakes absorption can increase about 15% to 25% and that’s in the area under the curve. This is not something to be very concerned about unless patients change the way they take it. 

Quetiapine’s drug interactions are mostly additive effects. Watch out for other sedative drugs such as alcohol, opioids, and benzodiazepines. The same goes for drugs causing QT prolongation. Quetiapine has alpha-blocking activity and an added effect on patients with borderline low blood pressure or at risk for falls. It also mechanistically has a potential antihistamine burden that can play a role in adding on to anticholinergic effects. Then lastly it is metabolized partly by CYP3A4 so there is some potential there for drug interactions. Classic enzyme inducers are St. John’s Wort and carbamazepine that would lower the concentration of quetiapine.

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

Fluvoxamine Pharmacology

On this episode, I discuss fluvoxamine pharmacology, adverse effects, and most importantly, drug interactions.

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

Zaleplon Pharmacology

On this episode, I discuss the pharmacology of zaleplon including side effects, drug interactions, and important clinical pearls.

Zaleplon is a non-benzodiazepine sleep aide commonly known as Sonata. It is commonly used for sedation and the management of insomnia. Zaleplon is a controlled medication, with a high risk for dependence, and because of that, it is best used to treat short-term insomnia. The pharmacology of zaleplon is similar to other sleep aids like Ambien, and Lunesta; they all have an impact on GABA. Specifically, zaleplon regulates the GABABZ receptor. The GABABZ receptor has been shown to be responsible for the pharmacological properties of benzodiazepines which produce sedative, anxiolytic, relaxant, and anticonvulsive effects. For pharmacokinetics, zaleplon has a general onset of action around 30-60 minutes, because of that it is best dosed closer to bedtime. 

For sedatives, and other drugs similar to zaleplon, it is generally better to start at lower doses in geriatrics and smaller patients. The commonly accepted dosing is between 5-20 mg, but it is best to use non-pharmacological therapies, instead of pharmacological whenever possible. The most common side effect that may be experienced with zaleplon is next-day sedation, also known as hangover sedation. Loss of mental clarity, dizziness, and confusion may also be present. Serious side effects of taking zaleplon are abnormal sleep behaviors, which it carries a US boxed warning for, and risk of dependence. Zaleplon is also on Beer’s list because of the increased risk of falls, delirium, and increased complications while driving due to sedation and lethargy. 

When a sedative is first prescribed, it’s important to first look at the other medications a patient may be taking to see if that’s what may be causing insomnia. For example, a diuretic administered at night can cause excessive urination that can lead to insomnia. The addition of stimulants too late in the day can also cause that, and similarly, lifestyle changes like increased intake of caffeine can increase the risk for insomnia as well. 

Most of the drug-drug interactions that zaleplon has are due to additive depressive effects. Examples include alcohol, opioids, older antihistamines, trazodone, or any medication that can cause sedation. There is also a smaller risk for CYP3A4 interaction. Concurrent administration of an inducer, like St. John’s Wort, or carbamazepine, can lower the concentrations of zaleplon. Likewise, inhibitors may increase concentrations.

In cases of overdose, the signs and symptoms that will most likely precipitate are exaggerations of zaleplon’s adverse effects. The manifestations of CNS depression can range from drowsiness to coma. More mild cases might have drowsiness, confusion, and lethargy; while more serious cases may have ataxia, hypotonia, hypotension, respiratory depression, coma, and death. To treat a zaleplon overdose, symptomatic and supportive measures are necessary along with gastric lavage. Animal studies suggest that flumazenil is an antidote as an antagonist to zaleplon, but there is no human data. With proper treatment, recoveries have been made with overdoses greater than 200 mg. In instances where the outcome was fatal, it was most often associated with the use of additional CNS depressants.

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!

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

Resources

Paragraph 1: taken from podcast, also taken from https://go.drugbank.com/drugs/DB00962#pharmacodynamics

Paragraph 2: taken from podcast

Paragraph 3: taken from podcast

Paragraph 4: taken from podcast

Paragraph 5: taken from FDA label

Doxylamine Pharmacology

In the podcast this week, I talk about doxylamine pharmacology. Doxylamine is a first-generation antihistamine; it is commonly an active ingredient in night-time medications like Unisom, Nyquil, and Mucinex. The pharmacology of doxylamine is similar to other first-generation antihistamines, it competitively inhibits the binding of histamine at H1 receptors. Its main uses are as sleep aides, in cough-and-cold medications, but doxylamine has also been given with pyridoxine to treat nausea and vomiting during pregnancy.

Doxylamine’s adverse reactions are related to its anticholinergic properties, they include dry eyes, dry mouth, increased fall risk, sedation, urinary retention, constipation, and confusion. Contraindications include concurrent use with a monoamine oxidase inhibitor, known hypersensitivities, concomitant alcohol use, and if the patient has the following conditions: elevated intraocular pressure, narrow-angle glaucoma, asthma, peptic ulcer disease, urinary bladder neck obstruction, or gastric outlet obstruction. It is also a Beer’s list drug due to its anticholinergic effects. The normal dose in adults is 25 mg. In cases of overdosage, the most common manifestation is exacerbations of its anticholinergic effects. The major complications of an overdose include arrhythmia, respiratory failure, seizures, hyperthermia, rhabdomyolysis, and coma. 

When you know a patient is taking doxylamine, it’s important to be cognizant of their occupation, as well as what other conditions they may have. For example, doxylamine should be used with caution in patients that drive heavy machinery due to its sedating properties. You might be able to tell if a patient’s experiencing an adverse reaction exacerbation if they begin having worsening dementia symptoms or increased urinary retention. Other indications include the use of artificial tears, or saliva, or increased complaints of constipation. To monitor for doxylamine, it’s important to monitor the patient’s tolerability. The onset of doxylamine is relatively quick as well, with a peak concentration within 2-4 hours.

For drug-drug interactions, CYP interactions aren’t as concerning as usual. The main interaction to consider when a patient is taking doxylamine is additive anticholinergic effects. Sedative effects can increase when benzodiazepines, skeletal muscle relaxants, opioids, or antihistamines are concurrently taken. Doxylamine can also counteract the usefulness of dementia or BPH medications due to its anticholinergic properties. There is also a risk of increased anticholinergic burden when taken with skeletal muscle relaxants or tricyclic antidepressants. 

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

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

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.

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

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

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

Study Materials For Pharmacists and Students

Useful Books For Any Healthcare Professional

Nursing Professionals

Dietitian Professionals

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)