Do mild adverse effects preclude adequate dosing

Structure of the Sceletal Muscle
Sarcolemma: mechanical stability
T-tubules: conductance of electrical stimulation
(R.V. Krstic, mod.)
Statins and adverse effects/ Markus Mohaupt 15
80-90
Lipophilic 3A4 Yes
>99
Lipophilic 2C9 No
>95
Lipophilic 3A4 Yes
43-55
Hydrophilic No Decreased absorption Bedtime
88
Hydrophilic Limited 2C9 No
94-98
Lipophilic 3A4, 3A5 Yes
Statins and adverse effects/ Markus Mohaupt
6
Division of Hypertension, Department of Nephrology/Hypertension
Significant Reduction of CHD
Trial FATS MARS CCAIT SCRIP PLAC I PLAC II REGRESS MAAS 4S Treatment regimen Diet plus resin plus lovastatin Diet plus lovastatin Diet plus lovastatin Diet plus drugs plus lovastatin (36%) Diet plus pravastatin Diet plus pravastatin Diet plus pravastatin Diet plus pravastatin Diet plus simvastatin Duration, [y] 2.5 2 2 4 3 3 2 4 5.4 CHD event reduction, [%] 70 28 22 50* 62* 60 42* 22 34*
Drug-induced SLE
Reduced androgen synthesis?
Interactions:
CYP3A4-metabolisied or activated drugs (e.g. calcineurin inhibitors) reduced clopidogrel activation (Lau et al. Circulation 2003)
Statins and adverse effects/ Markus Mohaupt
3
Division of Hypertension, Department of Nephrology/Hypertension
This talk will cover
1. Why statins are good 2. Why statins might be not so good 3. Should myopathy limit statin use
Do We Really Use Statins Adequately?
Do Mild Adverse Effects Preclude Adequate Dosing?
Markus Mohaupt, Berne, Switzerland
No conflict of interest
Division of Hypertension, Department of Nephrology/Hypertension
4.00 ± 0.12 mmol/l
n.d.
Percentage of damage fibres
1 et al. J Pathol 2006
Statins and adverse effects/ Markus Mohaupt
14
Division of Hypertension, Department of Nephrology/Hypertension
Division of Hypertension, Department of Nephrology/Hypertension
This talk will cover
1. Why statins are good 2. Why statins might be not so good 3. Should myopathy limit statin use
Statins and adverse effects/ Markus Mohaupt
9
Division of Hypertension, Department of Nephrology/Hypertension
Statins Have Side Effects and Interact
Hepatopathy 0,5-3%
(MRC trial et al. Lancet 2002, Charles et al. Am J Med 2005)
Statins and adverse effects/ Markus Mohaupt
10
Division of Hypertension, Department of Nephrology/Hypertension
And the Muscle?
• Asymptomatic damage • General myopathy weakness • Myalgias • Myositis • Rhabdomyolysis
Protein binding, percent
Solubility Cytochrome 450 metabolism and lsozyme Active metabolites Effect of food on absorption of drug Optimal time of administration Renal excretion of absorbed dose, percent
NO, BUT…
Statins and adverse effects/ Markus Mohaupt
2
Division of Hypertension, Department of Nephrology/Hypertension
This talk will cover
1. Why statins are good 2. Why statins might be not so good 3. Should myopathy limit statin use
Statins and adverse effects/ Markus Mohaupt
4
Division of Hypertension, Department of Nephrology/Hypertension
Statins – Mode of Action
Inhibits β-Hydroxy-β-Methylglutaryl-Coenzym A-Reductase
Statins and adverse effects/ Markus Mohaupt
5
Division of Hypertension, Department of Nephrology/Hypertension
Statins – Mode of Action
•Increased LDL receptor expression •Reduced VLDL production •Reduction in LDL (20-60%) •Moderate increase in HDL (5-10%) •Lowered triglycerides (10-33%)
Nephropathy:
Partial Fanconi-Syndrome(Sidaway et al. JASN 2004) Glomerulopathy?(Alsheikh et al. Circulation 2005)
Polyneuropathy OR 3,7 (1,8-7,6)
(Gaist et al. Neurology 2002)
• ...and there might be further benefits beyond cholesterol lowering
Statins and adverse effects/ Markus Mohaupt 7
Division of Hypertension, Department of Nephrology/Hypertension
Division of Hypertension, Department of Nephrology/Hypertension
In Vitro Cholesterol Depletion
caveolin 3 /annexin6
Babiychuk et al. Biochem J 2006
Statins and adverse effects/ Markus Mohaupt 16
8
Division of Hypertension, Department of Nephrology/Hypertension
Statin Pharmacokinetics are Quite Variable
Variable LDL cholesterol reductions (dose range, mg) Elimination half-life, hours Bioavailability, percent Atorvastatin 38-54 % (10-80) 15-30 12 Fluvastatin 17-33 % (20-80) 0.5-2.3 19-29 Lovastatin 29-48 % (20-80) 2.9 5 Pravastatin 19-40 % (10-40) 1.3-2.8 18 Rosuvastatin 52-63 % (10-40) 19 20 Simvastatin 28-48 % (10-80) 2-3 5