Foundations in Pharmacology – Familial Hypercholesterolaemia

Foundations in Pharmacology – Familial Hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipid metabolism, characterised by high total cholesterol levels, high low-density lipoprotein cholesterol (LDL-C) levels from birth, tendinous xanthoma which are cholesterol deposits located within tendons that travel along the backs of the hands and arms, tops of the feet or within the Achilles tendon on the heel and an enhanced risk of early onset coronary heart disease (Austin et al. 2004). FH occurs in two forms; heterozygous and homozygous. Kumar & Clark (2012) state homozygous FH is very rare, whereas the heterozygous form occurs in approximately 1 in 500 of the normal population. This assignment, when using the term (FH) will refer to the heterozygous form.

Goldstein & Brown (1973) demonstrated that FH is the result of mutations in the low-density lipoprotein receptor (LDLR) gene; more recently, mutations in the apolipoprotein-B (APOB) gene and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) have been identified as causes of FH (Austin, 2004). Hobbs et al. (1990) proposed four classes of LDLR mutation, and the effects of each class of mutation are shown in Table 1.

Table 1.      LDL Mutations in Familial Hypercholesterolaemia

                                                                                                                         (Hobbs et al.1990)

To facilitate further discussion, it is appropriate to give a very brief overview of lipid metabolism, and the transport proteins involved. Chylomicrons transport dietary fats and cholesterol from the gut through the lymphatic system into the blood. In the capillaries of adipose and muscle tissue, 98% of chylomicrons are taken up for use or storage (Goldberg, 2013). The remaining chylomicrons are returned to the liver for clearance. The liver synthesises lipoproteins to transport fats to systemic sites until they are taken up by the tissues or returned to the liver. Very low density lipoproteins (VLDL) contain apoprotein B-100 (apo B), and transport fats and cholesterol to peripheral tissues. Intermediate density lipoproteins (IDL) result when VLDL is degraded by lipoprotein lipases in the tissues. IDL are either cleared by the liver or metabolised by hepatic lipase into low density lipoproteins (LDL). LDL is the most cholesterol rich of all lipoproteins. Increased levels of LDL are strongly associated with atherosclerosis. High density lipoproteins (HDL) are synthesised both in the liver and in the gut, and are free from cholesterol at the time of synthesis. A principal role of HDL is to transport cholesterol from the tissues to the liver for clearance, thus counterbalancing the role of LDL (Goldberg, 2013).

According to the National Institute of Health and Care Excellence (NICE, 2013), statin therapy is cost effective and delivers optimum health outcomes to patients who are diagnosed with FH. Patients should receive lipid modifying drug treatment with the aim of reducing LDLC concentration by more than 50% from baseline (NICE, 2013). NICE recommend that a statin should be the agent of choice (NICE, 2008a). Atorvastatin has been identified as the most effective drug in this group (Jones et al. 1998 & Smilde et al. 2001). Smilde et al. (2001) compared high dose atorvastatin (80 mg/day) with normal dose simvastatin (40mg/day) in a randomised, double-blind controlled trial with a follow-up of two years. High-dose atorvastatin produced a larger reduction in LDL-C (308 to 149 mg/dL [8 versus 3.9 mmol/L]) than conventional dose simvastatin (321 to 185 mg/dL [8.3 to 4.8 mmol/L]). Further, treatment with high-dose atorvastatin produced a statistically significant reduction in carotid intima media thickness compared to an increase with simvastatin. After treatment with atorvastatin for 2 years, thickness of the carotid intima reduced (-0.031 mm [95% CI -0.007 to -0.055]; p=0.0017), whilst in the simvastatin group it increased (0.036 [0.014-0.058]; p=0.0005). The change was statistically significant between the two groups (p=0.0001).

Statins are competitive antagonists of HMG-CoA as they directly compete with the endogenous substrate for the active site cavity of HMGR. Atorvastatin included, competitively inhibits HMG-CoA reductase (HMGR) which catalyses the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate; the rate limiting step in hepatic cholesterol biosynthesis (Figure 1). HMGR inhibition decreases hepatic synthesis of new cholesterol and increases the expression of LDL-R on hepatocytes. The systemic effect of this is to increase LDL uptake by the hepatocytes, decreasing serum concentration of LDL-C. Atorvastatin, as with other statins, also reduces blood levels of triglycerides and slightly increases levels of HDL cholesterol (Lea & McTavish, 1997).

Fig 1.        The mevalonate pathway

[pic 1]

(British Journal of Anaesthesia, 2009)

Pharmacokinetics

Absorption

Atorvastatin is administered in its active acid form and undergoes extensive first‐pass metabolism mainly by cytochrome P450 3A4 (CYP3A4) in the liver (Chong, et al. 2001). The absolute bioavailabilty of atorvastatin is around 14%, of which 30% is active in the inhibition of HMG-CoA reductase. The drug is absorbed swiftly after oral administration, with maximum plasma concentration reached within 1 to 2 hours, and absorption increases in proportion to dose.

Distribution

The mean volume of distribution of atorvastatin is around 381 litres, and it is approximately 98% bound to plasma proteins (Drugs.com, 2015).

Metabolism

Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, producing two active hydroxy metabolites, ortho‐hydroxy‐atorvastatin (o‐OH‐atorvastatin) and para‐hydroxy‐atorvastatin (p‐OH‐atorvastatin), and three corresponding inactive lactone metabolites (Lins et al. 2003).

Excretion

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