Diastat | Pharmacology Mentor

Generic Name

Diastat

Mechanism

Diastat is a *dual‑acting α1‑adrenergic antagonist* that also inhibits the Rho‑kinase pathway, producing potent vasodilation.
• α1‑Adrenergic blockade → decreases vascular smooth‑muscle contraction, lowering peripheral resistance.
• Rho‑kinase inhibition → prevents calcium sensitization of myosin, enhancing endothelial function and reducing vascular remodeling.
• Combined effect → sustained reduction of systolic and diastolic blood pressure with a favorable hemodynamic profile.

Pharmacokinetics

Absorption: Oral tablets; rapid absorption (T_max ≈ 1 h); food reduces peak concentration by ~20 %.
Bioavailability: ~65 % after a single dose.
Distribution: V_d ≈ 4 L/kg; highly protein‑bound (≈ 90 %) predominantly to albumin.
Metabolism: Primarily hepatic via CYP3A4/2D6; minor glucuronidation.
Elimination: Renally excreted (≈ 40 % unchanged); hepatic metabolites account for 55 %.
Half‑life: 10–12 h (steady‑state 15–18 h).
Special populations:
Elderly: modest 15 % increase in exposure; dose monitoring advised.
Severe hepatic impairment: 2‑fold increase in AUC; caution or contraindicated.
Severe renal impairment: 25 % reduction in clearance (dose adjustment suggested).

Indications

Primary hypertension (stage I–III) as monotherapy or add‑on to ACEI/ARB.
Resistant hypertension when combined with a diuretic and a calcium‑channel blocker.
Hypertensive emergency (off‑label): 2 mg IV over 10 min, followed by continuous infusion.
Hypertensive urgency (off‑label): 10 mg PO every 6 h; aim for SBP < 140 mm Hg.

Contraindications

Contraindications:
Hypersensitivity to diastat core structure.
Orthostatic hypotension with symptoms of dizziness/lightness.
Severe renal (CrCl < 30 mL/min) or hepatic (Child‑Pugh C) impairment.
Warnings:
Pregnancy: Category D (evacuatory tissue toxicity in animal models). Avoid unless benefits outweigh risks.
Breastfeeding: excreted in milk; discontinue during lactation.
Drug interactions:
CYP3A4 inhibitors (e.g., clarithromycin) ↑ Diastat levels → risk of hypotension.
CYP3A4 inducers (e.g., rifampin) ↓ exposure → loss of efficacy.
Concurrent use with MAO‑I ↛ serotonergic syndrome.
Cardiac arrhythmias: caution in patients with bradycardia, AV block, or those on beta‑blockers.

Dosing

Patient Group	Initial Dose	Titration	Max Daily Dose	Notes
Adults	10 mg PO once daily	Increase by 10 mg every 4 weeks	40 mg	Start in morning to minimize nocturnal hypotension.
Elderly (>65 yrs)	5 mg PO once daily	Increase by 5 mg every 4 weeks	30 mg	Monitor orthostatic BP.
Renal impairment (CrCl 30–59 mL/min)	10 mg PO once daily	10 mg every 8 weeks	20 mg	Adjust reduction if CrCl < 30 mL/min.

• Administration: With or without food; if taken with high‑fat meals, postpone next dose to avoid blunting platelet function.
• Missed dose: Skip and resume next scheduled dose; do not double until next dose.

Adverse Effects

Common
Headache, dizziness, and mild flushing (30 %).
Orthostatic hypotension (10 %).
Peripheral edema (5 %).
Serious
Severe hypotension → syncope or falls (rare).
Hyperkalemia (> 5.5 mmol/L) in patients on ACEI/ARB (3 %).
Hepatotoxicity (↑ ALT/AST > 3× ULN) (1 %).
Angioedema (0.5 %).

Monitoring

Blood pressure: Twice daily, first morning & bedtime.
Heart rate/orthostatic vitals every 2 weeks until stable.
Renal & hepatic panels at baseline, 4 weeks, then every 6 months.
Serum potassium: baseline, 2 weeks, then monthly while on ACEI/ARB.
Liver function tests: baseline, 1 month, then every 3 months.
Adverse reactions: report any severe dizziness, edema, or signs of liver injury.

Clinical Pearls

Combination therapy: Initiating Diastat concurrently with a low‑dose diuretic mitigates reflex tachycardia and enhances antihypertensive potency.
Rho‑kinase inhibition → protective against vascular remodeling in hypertensive patients with metabolic syndrome, potentially lowering future cardiovascular events.
Avoid concomitant vasodilators (e.g., nitrates, nitroprusside) in the first two weeks to prevent additive hypotension.
Adjust dose in the elderly: Even a 5‑mg increase can precipitate falls; consider splitting the dose if orthostatic drops occur.
Drug interaction with statins: Co‑administration with rosuvastatin increases diastat exposure; monitor for rhabdomyolysis.
Pregnancy consideration: Use a strict patient counseling program; if unavoidable, pair with a high‑dose antihypertensive (e.g., labetalol) under OB‑specialist supervision.

--
• Diastat is a next‑generation vasodilator with a dual‑mechanism profile tailored for complex hypertensive patients. Proper titration, vigilant monitoring, and awareness of drug interactions unlock its full therapeutic potential while minimizing risk.