Antihypertensives Part 4 – Nitrates

Welcome to today’s episode, where we’re diving into the world of nitrate medications—one of the cornerstone therapies in cardiovascular care. Whether you’re a pharmacist, nurse, med student, or just curious about how medications keep the heart happy, nitrates are fascinating because of their unique mechanism and versatile clinical uses.

Nitrates work by releasing nitric oxide, a powerful molecule that relaxes smooth muscle and dilates blood vessels. This vasodilation primarily reduces venous return to the heart, lowering preload and myocardial oxygen demand, and at higher doses, can also decrease afterload. For patients with angina, this means less chest pain, improved exercise tolerance, and better quality of life.

In this episode, we’ll cover the most commonly used nitrates—from sublingual nitroglycerin for rapid relief of acute angina, to isosorbide dinitrate and mononitrate for chronic management. We’ll discuss how their formulations, onset, and duration of action affect clinical use, and why concepts like tolerance and nitrate-free intervals are critical to understand.

We’ll also explore important drug interactions, including why combining nitrates with PDE5 inhibitors can be dangerous, and highlight practical tips for patient counseling and monitoring. By the end of this episode, you’ll have a clear picture of how and when nitrates are used, and the key pearls every clinician should know to maximize benefit while minimizing risk.

So whether you’re reviewing for boards, prepping for clinical rotations, or just brushing up on cardiovascular pharmacology, stay tuned—we’re about to break down nitrates in a way that’s simple, practical, and memorable.

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Alprazolam Pharmacology

Alprazolam is a short-acting benzodiazepine that enhances the inhibitory effects of gamma-aminobutyric acid (GABA) at the GABA-A receptor. Clinically, this results in anxiolytic, sedative, muscle-relaxant, and anticonvulsant effects.

After oral administration, alprazolam is rapidly absorbed, with onset of action typically within 30–60 minutes. It undergoes extensive hepatic metabolism primarily via CYP3A4 to inactive metabolites, and has an elimination half-life of approximately 11 hours, which may be prolonged in elderly patients or those with hepatic impairment.

Common adverse effects include sedation, dizziness, impaired coordination, and cognitive slowing. More serious risks include respiratory depression, especially when combined with opioids, alcohol, or other CNS depressants.

Clinically, alprazolam should be used at the lowest effective dose for the shortest possible duration. Abrupt discontinuation should be avoided; gradual tapering is essential to reduce withdrawal risk. It is a controlled substance that carries the risk of addiction and dependence.

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Pimavanserin Pharmacology Podcast

Pimavanserin is an atypical antipsychotic approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Unlike traditional antipsychotics, it does not block dopamine receptors, making it a unique option for patients with Parkinson’s disease who are highly sensitive to dopamine antagonism.

Mechanism of Action

Pimavanserin works primarily as a selective serotonin 5-HT2A inverse agonist and antagonist, with minor activity at 5-HT2C receptors. This dopamine-sparing effect is the key reason it does not worsen motor symptoms in Parkinson’s disease.

Adverse Effects

The most commonly reported side effects include peripheral edema, nausea, confusion, and hallucinations. QT interval prolongation is a clinically important concern, especially in patients with existing cardiac risk factors. Somnolence may occur but is generally less prominent compared with dopamine-blocking antipsychotics.

Warnings and Precautions

Pimavanserin carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis, consistent with other antipsychotics. It should not be used in patients with known QT prolongation, a history of ventricular arrhythmias, or in combination with other QT-prolonging agents when possible.

Drug Interactions

Strong CYP3A4 inhibitors, such as ketoconazole or clarithromycin, can significantly increase pimavanserin concentrations and require dose reduction. Strong CYP3A4 inducers, such as rifampin or carbamazepine, may reduce efficacy and should generally be avoided. Additive QT prolongation may occur when combined with other QT-prolonging medications, including certain antiarrhythmics, fluoroquinolones, and macrolide antibiotics.

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Albuterol Pharmacology

On this episode of the Real Life Pharmacology Podcast, I cover albuterol pharmacology, adverse effects, and a rare indication for this classic respiratory medication.

Albuterol is a short-acting beta-2 adrenergic agonist (SABA) that works by stimulating beta-2 receptors in the bronchial smooth muscle. This stimulation activates adenylate cyclase, increases cyclic AMP, and leads to relaxation of airway smooth muscle. The end result is rapid bronchodilation, making albuterol effective for quick relief of acute bronchospasm in conditions such as asthma and COPD.

Common adverse effects occur due to both beta-2 and some unintended beta-1 receptor stimulation. Patients may experience tremors, nervousness, headache, or tachycardia. Higher doses or frequent use can lead to hypokalemia because beta-2 stimulation drives potassium into cells. Some individuals may also report palpitations or feelings of anxiety. These effects are generally mild and transient but can be more pronounced in older adults, those with cardiovascular disease, or when albuterol is used excessively.

Albuterol has several clinically relevant drug interactions. Concomitant use with non-selective beta-blockers (such as propranolol) can blunt its bronchodilatory effect and may precipitate bronchospasm in susceptible individuals. Using albuterol with other sympathomimetics can enhance cardiovascular stimulation, increasing the risk of tachycardia or hypertension. Diuretics, especially loop or thiazide types, may compound albuterol-induced hypokalemia. Additionally, monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants can potentiate the effects of albuterol and increase the risk of cardiovascular adverse reactions.

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Glycopyrrolate Pharmacology

Glycopyrrolate is an anticholinergic medication commonly used to reduce excessive secretions, particularly in palliative care, postoperative settings, and certain neurologic conditions. It works by blocking acetylcholine at muscarinic receptors, which decreases salivary and respiratory secretions. Clinically, glycopyrrolate is often used to manage terminal respiratory secretions (“death rattle”).

Adverse effects of glycopyrrolate are primarily related to its anticholinergic properties. These may include dry mouth, constipation, urinary retention, blurred vision, tachycardia, and decreased sweating. While it has fewer central effects than agents like scopolamine, caution is still warranted in patients with glaucoma, gastrointestinal obstruction, or significant urinary retention risk. Monitoring hydration and bowel function is important, especially in elderly or frail patients.

Dosing strategies depend on the clinical need. In palliative care, low doses may be given subcutaneously or intravenously every 4–6 hours as needed, while oral dosing is common for chronic sialorrhea.

Clinicians should consider the patient’s overall medication burden, as cumulative anticholinergic load can worsen cognitive impairment and contribute to falls or constipation. I discuss drug interactions and other commonly used medications that may contribute to anticholinergic burden.

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10 Common Examples of The Prescribing Cascade

One of the most important yet often overlooked concepts in pharmacology is the prescribing cascade. It occurs when a new medication is prescribed to treat a side effect caused by another drug, without realizing that the first medication is the root cause. This leads to a chain reaction of additional prescriptions, unnecessary complexity, and often, new adverse effects.

Prescribing cascades can sneak up on even the most careful clinicians. A patient develops a new symptom after starting a medication—perhaps swelling, dizziness, or urinary changes—and instead of identifying the drug as the culprit, another medication is added to manage the symptom. Over time, this cycle contributes to polypharmacy, drug interactions, and reduced quality of life.

These cascades are particularly concerning in older adults, where multiple comorbidities and high medication counts make it easy for adverse effects to be misinterpreted as new conditions. But they can occur at any age and in any clinical setting.

The key to preventing prescribing cascades is maintaining a critical mindset:

  • Assume any new symptoms could be an adverse effect.
  • Review the timing of medication changes relative to the onset of symptoms.
  • Consider deprescribing or adjusting doses before adding new drugs.
  • Encourage thorough medication reconciliation and communication across providers.

Recognizing and interrupting the prescribing cascade is one of the simplest and most impactful ways we can improve medication safety. In this podcast, I share some of my favorite real-world examples that illustrate just how easily these cascades can happen.

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Cefepime Pharmacology

Cefepime is a fourth-generation cephalosporin antibiotic with broad-spectrum activity against both gram-positive and gram-negative organisms, including Pseudomonas aeruginosa. It works by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins, leading to cell lysis and death.

Clinically, cefepime is commonly used in hospital settings for serious infections such as pneumonia, febrile neutropenia, urinary tract infections, skin infections, and intra-abdominal infections. It’s typically administered intravenously, with doses often ranging from 1 to 2 grams every 8 to 12 hours depending on the indication and renal function.

From a pharmacokinetic standpoint, cefepime is primarily renally eliminated, so dose adjustments are required in patients with impaired kidney function. Failure to reduce the dose appropriately can lead to neurotoxicity — one of the key adverse effects associated with cefepime — manifesting as encephalopathy, confusion, myoclonus, or seizures, particularly in elderly or renally impaired patients.

Common side effects include gastrointestinal upset and rash. Cefepime has relatively limited drug interactions, though concurrent nephrotoxic agents can increase the risk of renal injury.

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Midodrine Pharmacology Podcast

Midodrine is an oral alpha-1 agonist most commonly used for the treatment of symptomatic orthostatic hypotension. Its mechanism of action is through peripheral vasoconstriction, which helps increase blood pressure. Because of its short duration of action, it is typically dosed three times daily, with the last dose recommended in the late afternoon to reduce the risk of hypertension at night.

Clinically, midodrine is often considered when non-pharmacologic strategies for orthostatic hypotension (such as increased salt/fluid intake, compression stockings, or physical counter-maneuvers) are not enough. Pharmacists should also be aware of prescribing cascades—such as urinary retention leading to tamsulosin initiation—that can arise when midodrine is used.

Midodrine is generally not metabolized through cytochrome P450 pathways, so significant drug–drug interactions are less common. However, caution should be exercised with other agents that can raise blood pressure (like decongestants) or slow the heart rate (such as beta-blockers). Monitoring parameters include blood pressure, pulse, symptoms of urinary retention, and the patient’s overall response to therapy.

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Piperacillin/Tazobactam Pharmacology

Zosyn (piperacillin/tazobactam) is a broad-spectrum β-lactam/β-lactamase inhibitor combination used widely in hospitals. Piperacillin covers gram-positive, gram-negative, and anaerobic bacteria, while tazobactam helps protect against β-lactamase breakdown. It is commonly used for pneumonia, intra-abdominal infections, skin and soft tissue infections, and febrile neutropenia. An important pharmacology pearl for exams is understanding that Pseudomonas, but it doesn’t cover MRSA.

The drug is renally eliminated, so dosing adjustments are needed in kidney impairment. Many institutions use extended or prolonged infusions to maximize time above the MIC, which can improve efficacy. Standard dosing is 3.375 g to 4.5 g every 6–8 hours, with modifications for dialysis patients.

Adverse effects include hypersensitivity, gastrointestinal upset, electrolyte imbalances like hypokalemia, and blood count changes with prolonged therapy. A key clinical concern is nephrotoxicity risk, especially when used with vancomycin. Monitoring renal function and electrolytes are important.

Methotrexate and probenecid are two medications that can interact with Zosyn. Concentrations of Zosyn can be increased when these medications are used in combination.

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Desmopressin Pharmacology Podcast

Desmopressin is a synthetic analog of vasopressin, also known as antidiuretic hormone (ADH). It works by mimicking the action of natural ADH on the kidneys, primarily increasing water reabsorption in the collecting ducts. This effect reduces urine production and helps concentrate the urine. Because of this mechanism, desmopressin is commonly used in conditions like diabetes insipidus, nocturnal enuresis (bedwetting), and sometimes for nocturia in adults. It also has a role in certain bleeding disorders, such as mild hemophilia A and von Willebrand disease, since it can increase plasma levels of factor VIII and von Willebrand factor. In this podcast, we will explore desmopressin pharmacology and much more.

Desmopressin is available in several dosage forms, including oral tablets, intranasal spray, and injectable formulations. The choice depends on the indication and patient-specific factors such as age, convenience, or the need for rapid effect.

Adverse effects of desmopressin are largely related to water balance. Because it reduces urine output, patients are at risk for water retention and hyponatremia, which can lead to headaches, confusion, seizures, or in severe cases, coma. Monitoring sodium levels is especially important in elderly patients and those taking other medications that can affect fluid or electrolyte balance.

Clinicians also need to be mindful of drug interactions. Medications that increase the risk of hyponatremia, such as SSRIs, carbamazepine, or certain diuretics, may enhance desmopressin’s adverse effects. Conversely, drugs that blunt its activity can reduce effectiveness. Careful monitoring and patient education are key parts of safe use.

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