Dihydralazine + Hydrochlorothiazide + Reserpine

Usage

• This drug combination is primarily prescribed for essential hypertension (high blood pressure). It was also previously used to treat severe agitation in patients with mental disorders, but these uses are much less common. (Note: Reserpine, a component of this combination, is no longer readily available in the US).
• Pharmacological Classification: Antihypertensive (a combination of a vasodilator, thiazide diuretic, and central sympatholytic).
• Mechanism of Action: This combination lowers blood pressure through multiple mechanisms:
  • Dihydralazine: Directly relaxes vascular smooth muscle, causing vasodilation and reducing peripheral vascular resistance.
  • Hydrochlorothiazide: Increases the excretion of sodium and water by the kidneys, reducing blood volume and lowering blood pressure. It also has some direct vasodilatory effects.
  • Reserpine: Depletes norepinephrine stores in peripheral nerve endings, reducing sympathetic nervous system activity, which leads to vasodilation and decreased heart rate.

Alternate Names

• No commonly used alternate generic names exist.
• Brand names (many are discontinued, especially those containing reserpine): Ser-Ap-Es, Serathide, Serpazide, Serpex, Hydrap-ES, Marpres, Unipres, and others.

How It Works

• Pharmacodynamics:
  • Dihydralazine’s primary effect is direct arterial vasodilation. This can lead to reflex tachycardia.
  • Hydrochlorothiazide causes diuresis and has some vasodilatory effects. It can cause electrolyte imbalances (hypokalemia, hyponatremia).
  • Reserpine depletes catecholamines, leading to decreased sympathetic tone, reduced heart rate, and vasodilation. It can cause sedation, depression, and nasal congestion.
• Pharmacokinetics:
  • All three drugs are absorbed orally, but bioavailability varies.
  • Metabolism: Dihydralazine undergoes extensive hepatic metabolism via acetylation (genetic polymorphism influences metabolism); Hydrochlorothiazide is not extensively metabolized; Reserpine undergoes significant hepatic metabolism.
  • Elimination: Metabolites of all three drugs are primarily excreted renally.
• Mode of Action:
  • Dihydralazine likely acts by increasing intracellular cGMP, which leads to smooth muscle relaxation.
  • Hydrochlorothiazide inhibits sodium reabsorption in the distal convoluted tubule of the nephron.
  • Reserpine inhibits the vesicular monoamine transporter (VMAT), which transports norepinephrine into storage vesicles in presynaptic nerve terminals.

Dosage

Standard Dosage

Adults:

• Initial dose: Typically one tablet daily, containing a standard combination like reserpine 0.1 mg, hydralazine 25 mg, and hydrochlorothiazide 15 mg.
• Maintenance dose: Titrated based on patient response up to 2 tablets per day (or equivalent doses of the individual components), divided into two doses. Note: Exceeding 0.25 mg/day of reserpine is not recommended.

Children: No established standard dosing exists for this combination in children; using it in pediatric patients is not routinely recommended.

Special Cases:

• Elderly Patients: Start at lower doses and titrate cautiously due to increased sensitivity to side effects (e.g., dizziness, hypotension).
• Patients with Renal Impairment: Hydrochlorothiazide is less effective with creatinine clearance <25 mL/min. Caution and dose reduction are advised.
• Patients with Hepatic Dysfunction: Caution is advised due to the hepatic metabolism of the drugs. Close monitoring is necessary.
• Patients with Comorbid Conditions: Patients with coronary artery disease, lupus erythematosus, peptic ulcer disease, ulcerative colitis, gout, diabetes mellitus, and asthma need individualized dosage adjustments and careful monitoring.

Clinical Use Cases

This fixed-dose combination is not typically recommended for acute clinical situations such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergencies. Individual agents may be utilized if appropriate.

Dosage Adjustments

Dosage titration is required based on individual blood pressure response. Renal/hepatic dysfunction and other comorbid conditions necessitate specific dose adjustments.

Side Effects

Common Side Effects: Dizziness, headache, drowsiness, fatigue, nasal congestion, nausea, vomiting, diarrhea, depression, nightmares, anxiety.

Rare but Serious Side Effects: Heart failure, orthostatic hypotension, bradycardia, syncope, angioedema, blood dyscrasias, lupus-like syndrome, severe depression, suicidal ideation.

Long-Term Effects: Electrolyte imbalances, gout, lupus-like syndrome.

Adverse Drug Reactions (ADR): Allergic reactions (rash, pruritus, angioedema), hepatotoxicity, blood dyscrasias, severe hypotension.

Contraindications

• Hypersensitivity to any component, anuria, depression (especially with reserpine), lupus erythematosus, aortic stenosis, constrictive pericarditis, AV block.

Drug Interactions

• Dihydralazine: Interacts with MAO inhibitors, beta-blockers (can exacerbate heart failure), NSAIDs (reduce antihypertensive effect), nitrates.
• Hydrochlorothiazide: Interacts with other antihypertensives (additive effect), digoxin (hypokalemia increases digoxin toxicity), lithium, corticosteroids (hypokalemia), NSAIDs.
• Reserpine: Interacts with MAO inhibitors (hypertensive crisis), tricyclic antidepressants, digitalis glycosides, sympathomimetics.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (for the combination) Individual agents have different risk profiles.
• Fetal risks: Reserpine has shown teratogenicity in animals. Thiazides can cause fetal thrombocytopenia and electrolyte disturbances. Dihydralazine can cause fetal distress. Use only if benefit clearly outweighs risk.
• Breastfeeding: All three drugs are excreted in breast milk. Reserpine can cause nasal congestion and lethargy in infants. Hydrochlorothiazide can suppress lactation. Use alternative medications if possible.

Drug Profile Summary

• Mechanism of Action: See above.
• Side Effects: See above.
• Contraindications: See above.
• Drug Interactions: See above.
• Pregnancy & Breastfeeding: Not recommended unless absolutely necessary.
• Dosage: See above.
• Monitoring Parameters: Blood pressure, heart rate, electrolytes (sodium, potassium, chloride), renal function, signs of heart failure, mental status (with reserpine).

Popular Combinations

Historically, this fixed-dose combination has been used on its own. However, current practice often favors using individual agents titrated to optimal response.

Precautions

• Monitor for side effects, especially in elderly patients.
• Electrolyte monitoring is important, especially potassium levels.
• Psychiatric monitoring may be necessary with reserpine.
• Caution in patients with heart failure, renal/hepatic impairment, diabetes.
• Avoid abrupt discontinuation.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dihydralazine + Hydrochlorothiazide + Reserpine?

A: Initial: One tablet daily containing a standard combination; titrated up to two tablets per day (or equivalent) based on response. Dosages exceeding 0.25 mg/day of reserpine are not recommended.

Q2: What are the key side effects to watch for?

A: Dizziness, lightheadedness, orthostatic hypotension, depression (with reserpine), electrolyte disturbances.

Q3: Is this combination safe in pregnancy?

A: No, generally not recommended unless the benefits clearly outweigh the risks. Consult a specialist.

Q4: What are the major drug interactions?

A: MAO inhibitors, other antihypertensives, digoxin, lithium, NSAIDs. Reserpine can also interact with TCAs.

Q5: What are the contraindications to this combination?

A: Hypersensitivity, anuria, existing depression, lupus, aortic stenosis.

Q6: Can this drug combination be used in patients with renal impairment?

A: Use with caution and dose adjustments as hydrochlorothiazide can be less effective. Careful monitoring is necessary.

Q7: What monitoring parameters are important for patients on this medication?

A: Blood pressure, heart rate, electrolytes, renal function, signs of heart failure, mental status (especially with reserpine).

Q8: How should this drug be discontinued?

A: Gradually taper the dose to avoid rebound hypertension and other adverse effects. Do not stop abruptly.

Q9: Are there any alternative medications for hypertension?

A: Yes, many other antihypertensive medications exist, including ACE inhibitors, ARBs, beta-blockers, calcium channel blockers. The choice depends on individual patient factors and comorbidities.

Q10: Why is this combination no longer commonly prescribed?

A: Partly due to the availability of newer and more effective antihypertensive medications with fewer side effects and partly due to reserpine no longer being readily available in some countries like the US. It also necessitates careful titration.