Ischaemic Heart Disease Case E

The History Mrs TZ 60yo, takes the following medications on a regular basis. Moduretic 50/5mg (Amiloride/Hydrochlorothiazide) 1 M (commenced 3 weeks ago) Norvasc (Amlodipine) 10mg 1 D Plavix (Clopidogrel) 75mg 1 D

Recent clinical chemistry data: Recent BP readings: 180/95mmHg 185/90mmHg 185/95mmHg Recent clinical chemistry data: TC 7.6mmol/L <5.5 TG 3.3mmol/L <2.0 HDL 0.7mmol/L 0.9-2.0

Estimating LDL Using Friedewald equation: LDL = TC – HDL – TG mmol/L 2.19 = 7.6 – 0.7 – 3.3 Mrs TZ LDL = 5.4 mmol/L LDL > 5 mmol/L excessive even in the absence of risk factors  Foundation of Oz Guidelines: LDL > 3  risk of CVD

Medications which affect lipid levels Antihypertensive medications Thiazide & loop diuretics  VLDL & LDLs  blockers especially Propanolol –  HDL &  total CH/HDL CH ratio Others include: Hepatic microsomal enzyme inducers OCs GCs A lg # of meds can adversely affect serum lipid & lipoprotein [ ]s: Oral contraceptives Oestrogen causes a slight increase in hepatic production of VLDL and HDL, reduces serum LDL levels in post menopausal women Progestogen increases LDL and reduces serum HDL and VLDL Corticosteroids Glucocorticoids shown to increase serum CH and TGs by elevating LDL, and VLDL to a lesser extent more evident in women alternate day dosing can reduce the effect on lipoproteins in some Cyclosporin (immunosuppressant) increases LDL levels, HT and glucose intolerance Usually administered along side glucocorticoids Affects lipid levels in transplant patients Hepatic microsomal enzyme inducers Includes carbamazepine, phenytoin, phenobarbitone, rifampicin and griseofulvin can increase serum HDL levels small increase in LDL and VLDL overall increases HDL to serum LDL ratio Patients treated for epilepsy tend to have a decreased incidence of IHD

Is the effect of thiazide diuretics on lipid levels of clinical sig.? Thiazides tend to  the production of VLDL from the liver Contains  level TGs May cause  in plasma TGs in some Px’s  NOT usually clinically sig. v. few Px marked  TGs  risk vascular problems or pancreatitis Diuretics used manag. of hyperT by ing BP Also shown to prevent: Strokes, MI & CHF

Various types of thiazide diuretics used in high doses showed: Short term studies have shown that high dose diuretics (>50mg/day) may affect lipoprotein profiles Various types of thiazide diuretics used in high doses showed:  T.CH by ~ 4%  sLDL ~10% Lesser effects on VLDL No ∆ in HDL High doses thiazides NOT shown greater benefit Doses >25mg/day of hydrochlorothiazide or  demonstrated rel. flat D-R curve The likelihood of metabolic events such as CHO, e-, & lipid abnormalities may be less with lower doses  aim min effect on lipid levels yet retain anti-hypoT effect Found that indapamide 2.5mg/day is equipotent to 50mg hydrochlorthiazide but has better lipid tolerability

Is it a sustained effect? High dose thiazide diuretics sustained effect Lg scale clinical trial studies show NO effect on lipid levels after 3-5 years of use During 1st yr sCH levels may  sig. However return back to or  baseline after a yr of Tx Long-term Tx w. thiazide diuretics  modest elevation sCH level may occur during the 1st yr but subsides back to or  baseline value after a year of therapy. Thiazide-induced ∆ seem to be D-R & may resolve w. discontinuation of Tx.

Proposed MOA Thiazide-Induced Effect on Lipid Levels The exact mechanism responsible for CH ∆ is uncertain. Many proposed mechanisms: Stim. of catecholamine release in response to vol. depletion Catecholamines stimulate hepatic CH synthesis Hypokalemia proposed as a cause Addition of a K+ sparing diuretic to a thiazide regimen may limit the observed elevation in CH An  in serum glucose or insulin secretion has also been suggested as the aetiology of the TG elevation Thiazide-induced reduction in insulin sensitivity may cause an associated  in hepatic production of CH However, this observation may be more related to the reduction in serum K that may occur w.  dosages of thiazides

Hyperlipidaemia Defined as an elevation in one or more of CH, cholesterol esters, phospholipids, or TG. Can result in premature coronary atherosclerosis, leading to manifestations of IHD.

Classification of Dyslipidemias May be 1° or 2°: 1° forms - genetically determined & classified according to lipoprotein particles raised 2° forms: - consequence of other conditions such as: DM Alcoholism, Nephrotic syndrome CRF

Frederickson/WHO classification of Hyperlipoproteinaemia 1° Dyslipidemias Frederickson/WHO classification of Hyperlipoproteinaemia Type Lipoprotein  CH TG Atherosclerosis Drug Tx I Chylomicrons + +++ NE None IIa LDL ++ High HMG-CoA reductase inhibitors +/- resins IIb LDL+VLDL Fibrates, HMG-CoA reductase inhibitors, nicotinic acid III VLDL Moderate Fibrates IV Fibrates (+/- fish oil) V None (+/- fish oil)

Clinical dyslipidemia assessment Once 2° causes & other medications have been ruled out as a cause of dyslipidemia, the Px’s lipid profile guides therapy (Based on Frederickson’s classification)

Back to the Px…. What should we do? Mrs TZ hyperlipidemia Recommend? Statin Fish oils Non pharmacological Tx Diet   fat intake Exercise Avoid smoking & alcohol