What are the classifications and differences of commonly used antifungal drugs?👀

More patients develop deep fungal infections (invasive fungal infections) due to the increased use of immunosuppressive drugs, antibiotics, organ transplants, and medically invasive procedures. Therefore, the use of antifungal drugs is also increasing and the rational use of antifungal drugs has become important.

What are the antifungal drugs for invasive fungal infections?

Antifungal drugs commonly used for invasive fungal infections are systemic antifungal drugs. Among them are:

Echinocandins : Anidulafungin, caspofungin and micafungin.

Polyenes : Amphotericin B and nystatin. Nystatin is mainly used in the treatment of Candida infections of the gastrointestinal tract and its oral absorption is poor.

Triazoles : fluconazole, isavuconazole, itraconazole, posaconazole and voriconazole.

Squalene epoxidase inhibitor : Oral terbinafine is mainly used for superficial fungal infections (such as hair, skin and nails).

Pyrimidines : Flucytosine.

Others : Oral griseofulvin is also mainly used for superficial fungal infections (such as hair, skin and nails).

What is the mechanism of action of antifungal drugs?

1. Fungal cell wall synthesis inhibitor : The main component of fungal cell wall is 1,3-β-gluean. Echinocandin drugs exert antifungal effects mainly by inhibiting the synthesis of 1,3-β-gluean. In addition, since human cells do not have cell walls, the toxicity of echinocandin drugs is relatively low.

2. Membrane Stability Inhibitors : Polyenes bind to ergosterol on fungal cell membranes. It acts as an antifungal agent by causing impaired cell membrane permeability. Damage to the cell membrane is also responsible for the toxicity of amphotericin B. However, it binds to human cell membranes much weaker than to fungal cell membranes.

3. Ergosterol Synthesis Inhibitors : 14-α-sterol demethylase is a microsomal enzyme. It will be inhibited by triazoles to reduce the synthesis of ergosterol and play an antifungal effect. Squalene cyclooxygenase will be inhibited by squalene epoxidase inhibitor to reduce the synthesis of lanosterol (the precursor of ergosterol) and play an antifungal effect.

4. Fungal Nucleic Acid Synthesis Inhibitors : Fungal cells convert pyrimidine antifungals to 5-fluorouracil. It inhibits the nucleic acid synthesis of fungi and thus acts as an antifungal agent.

Which fungal infections can they treat?

Flucytosine has strong antagonism against Candida and Cryptococcus. However, since fungi will rapidly develop drug resistance to flucytosine, flucytosine is mainly used in combination with amphotericin B in the clinical treatment of severe fungal infections.

The following table shows the antibacterial spectrum of commonly used antifungal drugs:

How to choose antifungal drugs?

The clinical selection of antifungal drugs is mainly based on the antifungal drug spectrum, pharmacokinetic characteristics, and the severity of the patient's infection. Fluconazole, flucytosine, and voriconazole cross the blood-brain barrier in patients. More than 80% of the dose of fluconazole and flucytosine will be excreted through the kidneys in their original form. Caspofungin, isavuconazole, itraconazole, micafungin, posaconazole, voriconazole, less than 2% of the dose will be excreted unchanged through the kidneys. 

1. Invasive pulmonary aspergillosis : For patients with invasive pulmonary aspergillosis, voriconazole is the first choice for clinical treatment. Isavuconazole will be used as an alternative drug.

2. Candidal disease : Caspofungin or micafungin are the first choice for the treatment of blood infection candidiasis. Since most of the fluconazole taken will be excreted through the kidneys in its original form, fluconazole is the first choice for the treatment of patients with urinary tract infection candidiasis. Amphotericin B can be used as an alternative treatment drug.

3. Cryptococcal disease : For patients with nonmeningitis infections, fluconazole is the first choice for the treatment. In severe cases, amphotericin B can be used for treatment. However, if the patient has meningitis, a combination of amphotericin B and flucytosine is required. When the patient enters the treatment maintenance period, fluconazole can be used. This is due to the fact that both fluconazole and flucytosine can enter the cerebrospinal fluid.

4. Mucormycosis : Clinically, amphotericin B is the first choice for the treatment of patients with mucormycosis. Isavuconazole can be used as an alternative treatment drug.

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What is the difference between the new hypolipidemic agents alirocumab and evolocumab?😵😵😵

A new type of hypolipidemic agent that is a PCSK9 inhibitor developed in
recent years. It is effective in lowering low-density lipoprotein cholesterol (LDL-C) levels alone or in combination with statins. Alirocumab and evolocumab (both are injections) are two commonly used PCSK9 inhibitors in clinical practice.

How does the body clear LDL-C?

LDL-C is transported from surrounding tissues to the liver by high-density lipoprotein cholesterol (HDL-C). After they reach the liver, they will bind to the LDL receptors on the liver cells and be transported into the liver cells. LDL-C is degraded and metabolized in liver cells.

What is PCSK9?

Proprotein Convertase Subtilisin/Kexin Type 9 is the full name of PCSK9. It degrades LDL receptors by binding to LDL receptors on the surface of liver cells. It reduces the number of LDL receptors on the surface of liver cells and prevents the removal of LDL-C from the blood.

How do PCSK9 inhibitors lower blood lipids?

PCSK9 is specifically bound by PCSK9 inhibitors so that it cannot bind to LDL receptors. Thus, the degradation of LDL receptor caused by PCSK9 is inhibited. This can increase the number of LDL receptors on the surface of liver cells and enhance the effect of clearing LDL-C in the blood.

What is the approximate strength of lipid-lowering effect of PCSK9 inhibitors?

PCSK9 inhibitors such as alirocumab and evolocumab have strong cholesterol-lowering effects. LDL-C can be lowered by about 50 to 70% by them. Several commonly used lipid-lowering regimens and their magnitude of lowering LDL-C:

• Ezetimibe: It lowers LDL-C by about 20% on average.
• Moderate-strength statins (such as simvastatin and pravastatin): They lower LDL-C by about 30% on average.
• High-intensity statins (such as atorvastatin and rosuvastatin): They lower LDL-C by about 50% on average.
• Monotherapy with PCSK9 inhibitors: They reduce LDL-C by about 60% on average.
• High-intensity statin + Ezetimibe: They reduce LDL-C by about 65% on average.
• High-intensity statin + PCSK9 inhibitor: They reduce LDL-C by about 75% on average.
• High-intensity statin + PCSK9 inhibitor + Ezetimibe: They reduce LDL-C by about 85% on average.

Usage and dosage of PCSK9 inhibitors.

Both alirocumab and evolocumab are given subcutaneously. Alirocumab is injected every 2 weeks and evolocumab is injected monthly. 

	Alirocumab	Evolocumab
Common dosage forms	Single-dose prefilled injection pen
	75mg/1ml/pen 150mg/1ml/pen	140mg/1ml/pen
Dosage	Subcutaneous injection: Upper arms, abdomen or thighs.
	1 time every 2 weeks, 75 to 150mg each time.	1 time per month, 420mg each time.
Storage	Store away from light at 2 to 8oC. They should not be refrigerated and shaken. Return to room temperature for at least 30 minutes before use. It can be stored at room temperature (25 oC) for up to 30 days when the patient travels.

What are their side effects?

1. Common adverse reactions of PCSK9 inhibitors include: 

Influenza, nasopharyngitis, upper respiratory infection, back pain. In addition, there may be pain, erythema and bruising at the injection site.

2. Specific adverse reactions of PCSK9 inhibitors are:

PCSK9 inhibitors, like other therapeutic protein drugs, may cause immune reactions. Clinical studies have pointed out that in patients with neutralizing antibodies, the long-term lipid-lowering effect of the drug will not be affected. However, they have an increased incidence of local injection reactions.

What is the difference between the adverse effects of PCSK9 inhibitors and statins?

Muscle toxicity: PCSK9 inhibitors did not increase the incidence of muscle-related adverse reactions in the current clinical research performance. They have the opportunity to become a new option for lipid-lowering therapy in patients with muscle-related adverse events on statins.

Hepatotoxicity: PCSK9 inhibitors did not significantly increase liver function damage compared with placebo in the current clinical research performance. Therefore, no dosage adjustment is required for their use in patients with mild or moderate hepatic impairment.

Blood glucose changes in patients: PCSK9 inhibitors did not accelerate the transformation of prediabetic patients to diabetes in current clinical studies. They also did not affect fasting blood glucose and glycated hemoglobin levels in non-diabetic patients. The incidence of dysglycemic events was not increased by the use of PCSK9 inhibitors.

What are the clinical applications of PCSK9 inhibitors?

For patients who are intolerant to statins or have contraindications, PCSK9 inhibitors can be used alone or in combination with other lipid-lowering drugs.

PCSK9 inhibitors combined with maximally tolerated doses of statins can further reduce the risk of cardiovascular events in patients with atherosclerotic cardiovascular disease.

If after four to six weeks of treatment with statins combined with ezetimibe in patients with ultra-high-risk atherosclerotic cardiovascular disease, the patient's LDL-C does not reach the treatment target (LDL-C<1.4mmol/L), it is recommended to add PCSK9 Inhibitors.

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