[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Pharmacology](https://durgical.com/en/pharmacology/) › [Statins](https://durgical.com/en/pharmacology/classes/statins/) › Simvastatin

[Pharmacology](https://durgical.com/en/pharmacology/) · [Statins](https://durgical.com/en/pharmacology/classes/statins/)

# Simvastatin

An older, widely used statin swallowed as an inactive lactone that the liver turns into the active drug; prone to CYP3A4 interactions.

Updated 2026-11-01

- Class: [Statins](https://durgical.com/en/pharmacology/classes/statins/)
- Enzyme: HMG-CoA reductase
- ATC code: C10AA01
- WHO Model List of Essential Medicines

✂**HMG-CoA reductase**Simvastatin

ⓘ The crystal holds simvastatin acid, the active open-ring form, not the lactone that is swallowed.

**Target in 3D:** HMG-CoA reductase. PDB structure 1HW9 (RCSB PDB, public domain). [View the structure at RCSB PDB](https://www.rcsb.org/structure/1HW9) · Drag to rotate · pinch to zoom

## Mechanism of action

Simvastatin is a lactone prodrug that is hydrolysed to its active beta-hydroxyacid, which competitively inhibits HMG-CoA reductase. Lower intracellular cholesterol raises LDL receptor numbers through SREBP-2, and the liver clears more LDL from the blood. Its label directs once-daily evening dosing.

- The lactone prodrug opens to simvastatin acid in the liver
- The acid blocks HMG-CoA reductase: less mevalonate
- Liver cells add LDL receptors (SREBP-2)
- LDL falls and atherosclerotic events drop

## Pharmacokinetics

**Absorption**
Oral; extensive first-pass extraction by the liver leaves less than 5% in the general circulation.

**Distribution**
About 95% bound to plasma proteins, with the active acid.

**Metabolism**
Hydrolysed to the active acid; metabolized by CYP3A4.

**Elimination**
About 60% in feces and 13% in urine.

## Indications

- High LDL cholesterol and cardiovascular prevention [Atherosclerosis and dyslipidaemia →](https://durgical.com/en/conditions/atherosclerosis-and-dyslipidaemia/)
- Secondary prevention after a myocardial infarction [Myocardial Infarction (Heart Attack) →](https://durgical.com/en/conditions/myocardial-infarction/)
- Secondary prevention after an atherosclerotic ischemic stroke [Ischaemic stroke →](https://durgical.com/en/conditions/ischaemic-stroke/)

## Adverse effects

### Common

- Muscle aches (myalgia)
- Raised liver transaminases
- Constipation, abdominal pain, nausea
- Small rise in new-onset type 2 diabetes in predisposed people

### Serious (rare, important)

- Myopathy and rhabdomyolysis; more likely with higher doses, interacting drugs, age 65 or older, uncontrolled hypothyroidism or kidney impairment
- Liver injury (rare)

## Contraindications

- Strong CYP3A4 inhibitors (azole antifungals, macrolide antibiotics, some antivirals, nefazodone)
- Cyclosporine, danazol or gemfibrozil
- Acute liver failure or decompensated cirrhosis
- Hypersensitivity to simvastatin; it is stopped when pregnancy is recognized

## Key interactions

**Strong CYP3A4 inhibitors (azole antifungals, macrolides such as clarithromycin, HIV protease inhibitors)**
Large rise in simvastatin levels and in the risk of rhabdomyolysis; contraindicated.

**Gemfibrozil, cyclosporine and danazol**
Raise the risk of myopathy; contraindicated.

**Verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine**
Raise simvastatin levels, so lower maximum doses apply.

**Grapefruit juice**
Raises plasma levels and the risk of myopathy; it is avoided.

## What is monitored

- Lipid panel before starting and some weeks later
- Liver enzymes at baseline
- Creatine kinase if there are muscle symptoms

## Memory aid

Simvastatin arrives in disguise, a closed lactone ring the liver unmasks. Anything that blocks CYP3A4 leaves too much of it circulating, and muscle pays the price.

## Test yourself

Think of the answer, then tap the question to see it.

## What does it mean that simvastatin is a prodrug?

It is swallowed as an inactive lactone; hydrolysis, largely in the liver, opens the ring to simvastatin acid, the form that inhibits HMG-CoA reductase.

## Why does so little simvastatin reach the general circulation, and why is that acceptable?

The liver extracts most of it on first pass, leaving less than 5% in the circulation; the liver is where it inhibits cholesterol synthesis.

## Why are simvastatin doses capped in patients who also take amlodipine or amiodarone?

Both drugs raise simvastatin levels by inhibiting its metabolism, which increases the risk of myopathy.

[Add to my cards (3)](https://durgical.app/estudiar/?add=/en/pharmacology/simvastatin/)

## Related drugs

- [Atorvastatin](https://durgical.com/en/pharmacology/atorvastatin/)

## Related conditions

- [Atherosclerosis and dyslipidaemia](https://durgical.com/en/conditions/atherosclerosis-and-dyslipidaemia/)
- [Myocardial Infarction (Heart Attack)](https://durgical.com/en/conditions/myocardial-infarction/)
- [Ischaemic stroke](https://durgical.com/en/conditions/ischaemic-stroke/)

[← Back to the class: Statins](https://durgical.com/en/pharmacology/classes/statins/)

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [Simvastatin: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a692030.html) (MedlinePlus (U.S. National Library of Medicine), 2026); [DailyMed - SIMVASTATIN- simvastatin tablet, film coated](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=751b79c6-bba8-4d29-b69c-a2ac6453fec8) (DailyMed (U.S. National Library of Medicine), 2026); [COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH SIMVASTATIN](https://www.rcsb.org/structure/1HW9) (RCSB Protein Data Bank, 2001); [eEML - Electronic Essential Medicines List](https://list.essentialmeds.org/) (World Health Organization, 2025).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/pharmacology/simvastatin/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/pharmacology/simvastatin/