Other Hypocholesterolemic Drugs
Prior to the introduction of the statins in the mid to late 1980s, the bile acid–sequestering drugs cholestyra-mine (Questran) and colestipol (Colestid) were primary drugs for lowering plasma cholesterol. Today they are second-line drugs that can safely be given with a statin to enhance cholesterol lowering or as an alternative for patients intolerant to a statin or concerned with statin’s potential for toxicity. Alone, the resins can achieve 20 to 25% reductions in LDL cholesterol, but when used with a statin, such as lovastatin, reductions of 50% and more can be seen.
These drugs are basically anion exchange resins that remain in the gut, bind intestinal bile acids, and greatly increase their fecal excretion (mechanism I in Fig. 23.2).
The lowered concentration of bile acids returning to the liver by the enterohepatic circulation results in dere-pression of 7- -hydroxylase, the rate-limiting enzyme for conversion of cholesterol to bile acids. This results in increased use of cholesterol to replace the excreted bile acids and lowering of hepatic cholesterol (mechanism VI in Fig. 23.2). Thus, similar to the statins, the ultimate actions of the bile acid–sequestering resins are up-regulation of transcription of the LDL receptor gene, increased hepatic receptor activity, and lowering of plasma LDL cholesterol (mechanism VII in Fig. 23.2).
The bile acid sequestering resins lower elevated LDL cholesterol and therefore are useful in the treat-ment of type IIa hyperlipoproteinemia. However, be-cause the resins can raise plasma VLDL in some pa-tients, they are not recommended for treatment of combined hyperlipidemias (type IIb) when both LDL cholesterol and VLDL triglycerides are high or in other conditions of elevated triglycerides.
The resins are interesting drugs because they have profound metabolic effects without truly entering the body. Perhaps for this reason they are relatively safe, with constipation being the chief complaint. Because the resins are given as the chloride salt and the chloride is exchanged for the negatively charged bile salt, bile acid resins can lead to hyperchloremic acidosis in vulnerable patients (children and patients with kidney failure).
The principal precaution with use of the bile acid resins is the possibility of impaired absorption of other drugs given orally at the same time. Cholestyramine and colestipol can bind many other drugs, such as digitoxin, phenobarbital, chlorothiazide, and warfarin, and delay or prevent their absorption. For this reason, other drugs should always be taken at least 1 hour before or 4 to 6 hours after the resin. The resins can also decease ab-sorption of fat-soluble vitamins.
Nicotinic acid has three special features as a hypolipi-demic drug: it has multiple beneficial effects on serum lipoproteins, it is the least expensive, and it is the least well tolerated.
Nicotinic acid decreases formation and secretion of VLDL by the liver (mechanism III in Fig. 23.2). This ac-tion appears secondary to its ability to inhibit fatty acid mobilization from adipose tissue. Circulating free fatty acids provide the main source of fatty acids for hepatic triglyceride synthesis, and lowering triglyceride synthe-sis lowers VLDL formation and secretion by the liver. Since plasma VLDL is the source of LDL, lowering VLDL can ultimately lower LDL. In addition, nicotinic acid shifts LDL particles to larger (more buoyant) sizes. The larger LDL particles are thought to be less athero-genic. Nicotinic acid can also significantly increase plasma HDL levels; the mechanism is unknown.
Used alone, nicotinic acid can decrease plasma LDL cholesterol levels by 15 to 30%. It can also be used in combination therapy with the statins or the bile acid– sequestering resins to augment reduction of very high LDL levels. Because nicotinic acid can lower plasma triglycerides by 40% or more, it is useful in treating fa-milial hypertriglyceridemia type IV (Table 23.3), and in combination with the statins it is useful in treating com-bined hyperlipidemia type IIb. As described later with the fibrates, patients with high plasma triglycerides plus low HDL are at increased risk for CHD. Nicotinic acid is useful for treating these patients, since it can both lower triglycerides and raise HDL.
Compliance with nicotinic acid therapy can be poor because the drug can produce an intense cutaneous flush. This can be reduced by beginning the drug in stepped doses of 250 mg twice daily and increasing the dose monthly by 500 to 1000 mg per day to a maximum of 3000 mg per day. Taking nicotinic acid on a full stom-ach (end of meal) and taking aspirin before dosage can reduce the severity of flushing. Time-release forms of nicotinic acid may also decrease cutaneous flushing. Nicotinic acid can cause gastrointestinal (GI) distress, liver dysfunction (especially at high doses), decreased glucose tolerance, hyperglycemia, and hyperuricemia. Thus, it is contraindicated in patients with hepatic dys-function, peptic ulcer, hyperuricemia, or diabetes melli-tus. A paradox associated with nicotinic acid is that it is the most widely available hypolipidemic drug (it is sold over the counter), yet its use requires the closest man-agement by the physician.