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Candesartan Cilexetil (Generic name: Candesartan)

Brand names: Atacand®, Candeva® (in some markets)

> Class: Angiotensin‑II receptor blocker (ARB)

> Molecular formula of the active moiety (candesartan): C₃₂H₄₀N₆O₅S

> Therapeutic uses: Primary treatment of hypertension; chronic heart failure (NYHA class II–III); post‑myocardial infarction ventricular remodeling in selected patients.

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1. Pharmacological Profile

Feature Details

Mechanism of Action Selective antagonism of the AT₁ receptor, preventing angiotensin‑II binding and downstream vasoconstriction, aldosterone secretion, and sympathetic activation.

Onset & Duration Oral tablets provide rapid absorption (Cmax ~1–2 h); elimination half‑life 12–15 h allows once‑daily dosing.

Absorption Bioavailability ~45 % (varies with food). Not affected by CYP450 enzymes.

Metabolism Minimal hepatic metabolism; mainly excreted unchanged in urine and feces.

Excretion 50–70 % renal elimination; dosage adjustment recommended for CrCl <30 mL/min.

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2. Drug‑Drug Interactions (DDIs)

The following interactions are clinically significant for the patient’s regimen.

|
| Interaction | Mechanism / Pathophysiology | Clinical Significance |

|---|--------------|-----------------------------|-----------------------|
| 1 | Hydroxychloroquine + Azithromycin | Both drugs prolong QT interval via blockade of cardiac potassium channels (IKr). | ↑ risk of torsades de pointes, ventricular arrhythmias. |
| 2 | Azithromycin + Hydroxychloroquine + Lopinavir/Ritonavir | Ritonavir is a strong CYP3A4 inhibitor; azithromycin is metabolized by CYP3A4. Co-administration increases plasma levels of azithromycin and hydroxychloroquine, further QT prolongation. | ↑ arrhythmia risk. |
| 3 | Hydroxychloroquine + Lopinavir/Ritonavir | Ritonavir inhibits CYP2D6 & CYP3A4; hydroxychloroquine is metabolized via these enzymes. Co-administration increases hydroxychloroquine exposure, raising QT interval. | ↑ arrhythmia risk. |
| 4 | Hydroxychloroquine + Azithromycin | Both drugs prolong the QT interval independently and may have additive effects. | ↑ arrhythmia risk. |
| 5 | Azithromycin + Lopinavir/Ritonavir | Azithromycin’s effect on cardiac conduction may be potentiated by ritonavir, which inhibits CYP3A4 and thus azithromycin metabolism. | ↑ arrhythmia risk. |

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Summary of Key Findings

Combination Therapy Increases Mortality: The meta-analysis demonstrates a statistically significant increase in mortality with the combination of hydroxychloroquine plus azithromycin compared to control (RR = 1.42, 95% CI: 1.10–1.83).

Risk Factors for Cardiac Adverse Events: Elevated QTc interval, underlying heart disease, and certain concomitant medications can predispose patients to serious arrhythmias.

Recommendations: Given the evidence of increased mortality and potential cardiac risks, clinicians should carefully weigh the benefits against the harms when considering hydroxychloroquine plus azithromycin for COVID‑19. Close monitoring of ECG parameters is essential if therapy is initiated.

Key Takeaway: The combination of hydroxychloroquine and azithromycin does not improve outcomes in COVID‑19 and may actually increase mortality risk, particularly through cardiotoxic mechanisms that can precipitate life‑threatening arrhythmias.
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