Statins are cholesterol lowering drugs widely used for the prevention of cardiovascular disease. They are used for primary prevention in patients with high cholesterol, and secondary prevention in patients with a previous cardiovascular event (stroke, MI).

Mechanism of action

  • HMG-CoA reductase inhibitors
  • HMG-CoA reductase is an enzyme which is involved in the synthesis of cholesterol
  • Inhibition of HMG-CoA reductase in the liver, therefore inhibits the formation of mevalonic  acid (Mevalonic acid pathway)
  • Decreases hepatic cholesterol synthesis and up regulates LDL receptor synthesis
  • Increasing LDL (“Bad Cholesterol”) clearance from the plasma into the liver cells via increasing the expression of hepatic LDL receptors
  • Reduces intracellular cholesterol
  • Overall effect, reduce Total cholesterol, LDL-C, VLDL-C and triglycerides
  • Main biochemical effects of statins are too reduce plasma LDL
  • Also some reduction in triglycerides (TGL) and an increase in HDL (“Good Cholesterol”)

 

Few large randomised placebo controlled trials have shown that the effects of HMG-CoA reductase inhibitors on both morbidity and mortality have been positive.

 

Pharmacokinetics

  • Short acting statins (Simvastatin, Lovastatin, and Pravastatin) are given orally and should be taken at NIGHT. This is due to the reduce the peak cholesterol synthesis in the morning, and also helps reduced the effect of the main side effect; muscle aches, as the patient is asleep!
  • Statins are generally well absorbed and extracted via the liver
  • Possible presystemic metabolism via the CYP P450 and the glucoronidation pathway

 

Side effects

  • Generally well tolerated
  • Mild adverse effects- Myalgia, GI disturbance, raised conc of liver enzymes in the plasma, rash and insomnia
  • Serious adverse effects- Myostitis (can be severe), rhabdomyolisis and angio-oedema
  • Myosistis can be common in patients taking statins. Can occur when taken in combination with other lipid lowering drugs (most commonly FIBRATES). Also can be dose related. More common in patients who have low lean body mass or patients who have uncorrected hypothyroidism.
  • Further side effects can be found in the BNF

 

Cautions

Elderly,      alcohol intake, any history hepatic diseases, hypothyroidism, patients who are at    risk of muscle toxicity, myopathy/ rhabdomyolisis.

Also take into account the patient’s renal function, as there maybe need to be dose adjustments in certain stages of the renal impairment. Consult the BNF for dose adjustments for different statins.

Cautions, Further info

  • MUSCLE EFFECTS- Toxicity. Look at patient’s history of muscle disorders/toxicity and family history.
  • Hypothyroidism

 

Interactions

The list of interactions here are POTENTIALLY SERIOUS in the BNF which is indicated with a black dot and further details of these interactions can be found in the BNF or Stockleys. Furthermore, there are other interactions which are not potentially serious, nevertheless they still should be monitored and clinical judgement should be used by using pharmacodynamics and pharmacokinetic knowledge.

 

  • Anti-arrhythmic: Amiodarone, Dronedarone
  • Antibacterials :Clarithromycin, Erythromycin, Telithromycin, Daptomycin, Fusidic acid
  • Anticoagulants: Coumarins, Phenindione
  • Antiepileptics: Carbamazepine, Eslicarbazepine
  • Antifungals: Ketoconazole, Itraconazole, Posacanzole, Fluconazole, Miconazole, Voriconazole
  • Antivirals: Check the BNF with all antivirals
  • Ca2+ Blockers: Amlodipine, Diltiazem, Verapamil
  • Ciclosporin
  • Clopiodogrel
  • Cobicistat
  • Colchicine
  • Eltrombopag
  • Grapefruit Juice
  • Hormone antagonists: Danazol
  • Lipid-regulating drugs: ALL FIBRATES, Ezetimibe, Lomitapide, Nicotinic acid
  • Ranolazine
  • Teriflunomide
  • Ticagrelor

Contraception: Adequate contraception should be used whilst on statins. And 1 months after it has been discontinued

Pregnancy

  • Avoid in pregnancy
  • Should discontinue 3 months before trying to conceive
  • Congenital abnormalities have been reported
  • Decrease cholesterol synthesis may affect foetal development.

Hepatic Impairment

  • Use with caution in patients with history of liver disease
  • AVOID in patients who actively have liver disease or when there is an increase in serum transaminases which is unexplained

Monitoring tests

  • Before treatment, at least one full lipid profile (non-fasting). Include total TGL, HDL and LDL. Also TSH should be measured before treatment. Furthermore, renal function should be assessed
  • LFT: NICE suggests, liver enzymes should be measured before treatment, and should be repeated within 3-12 months of initiating treatment.
  • Creatine Kinase: Before treatment for anyone who has had generalised, persistent or unexplained muscle pain.
  • Diabetes: Before treatment, patients should have fasting blood glucose and HbA1c Repeated every 3 months

Patient and carer advice

Report any unexplained muscle pain, tenderness or weakness ASAP

Clinical uses of statins

  • 2o prevention of MI and stroke in patients with symptomatic atherosclerotic disease ( e.g. angina, TIA, or following MI/stroke)
  • 1o prevention for patients who are at a high risk of arterial disease. Due to raised serum cholesterol which can lead to atherosclerosis.
  • Use the QRISK2 and JBS3 calculator for CV risk by using a number of parameters.

Atorvastatin

1o hypercholesterolemia/ Combined hyperlipidaemia, in patients who have not responded to diet and other non pharmacological measures.

  • Orally
  • 10mg OD
  • Increase up to 80mg OD if necessary
  • Dose increased at intervals of at least 4 weeks

Heterozygous familial hypercholesterolemia/ Homozygous familial hypercholesterolemia, in patients who have not responded to diet and other non pharmacological measures.

  • Orally
  • 10mg OD for at least 4 weeks
  • Increased to 40mg OD for at least another 4 weeks
  • Increase up to 80mg if necessary

1o prevention of CV events in patients who are at a high risk of a first CV event

  • 20mg OD, dose can be increase if required

2o prevention of CV event

  • 80mg OD

Dose adjustments due to interaction

  • 10mg ON, MAX. Combined, ciclosporin, or tipranavir combined with ritonavir. SEEK SPECIALIST ADVICE
  • 40mg ON, MAX. Combined, anion-exchange resin in patients with heterozygous familial hypercholesterolemia.

Simvastatin

1o hypercholesterolemia/ Combined (mixed) hyperlipidaemia, in patients who have not responded to diet and other non pharmacological measures.

  • Orally
  • 10-20mg ON (DOSE SHOULD BE TAKEN AT NIGHT)
  • Adjust dose at intervals of at least 4 weeks
  • 80mg only for patients with severe hypercholesterolemia + high risk of CV complications

 

Homozygous familial hypercholesterolemia, in patients who have not responded to diet and other non pharmacological measures.

  • Orally
  • Initially 40mg ON (DOSE SHOULD BE TAKEN AT NIGHT)
  • Adjust dose at intervals of at least 4 weeks
  • 80mg only for patients with severe hypercholesterolemia + high risk of CV complications

 

Prevention of CV events in patients with atherosclerotic CV disease or diabetes mellitus

  • Orally
  • 10-20mg ON (DOSE SHOULD BE TAKEN AT NIGHT)
  • Adjust dose at intervals of at least 4 weeks
  • 80mg only for patients with severe hypercholesterolemia + high risk of CV complications

 

Dose adjustment due to interaction

  • 10mg ON, MAX. Alongside bezafibrate / ciprofibrate
  • 20mg ON, MAX. Alongside amiodarone, verapamil, diltiazem, amlodipine and ranolazine
  • 40mg ON, MAX. Alongside lomitapide

 

References

Joint Formulary Committee (2008) British National Formulary. 70th Ed., London: British Medical Association and  Royal Pharmaceutical Society of Great Britain

Rang, HP et al (2012). Rang and Dales Pharmacology. 7th ed. London: Churchill Livingstone, Elsevier. 289-292.

Walker, R and Whittlesea, C (2012). Clinical Pharmacy and Therapeutics. 5th ed. London: Churchill Livingstone, Elsevier. 402-403