Dyslipidaemias

Question 1

Statins

Answer 1

IND: - all forms of hypercholesterolaemia

• hypertriglyceridaemia (certain types)
• combined hyperlipidaemia

MOA: competitive inhibition of HMG-CoA reductase (CSE)
= rate-limiting step in hepatic cholesterol biosynthesis
→ decreased cholesterol synthesis + higher expression of LDL receptors on hepatocytes
→ higher LDL uptake by the hepatocytes → lower LDL conc. in the blood

ADR: a) insulin sensitivity
b) statin-induced myalgia (10 – 15 % of all patients)
1. myopathy: muscle soreness/pain + weakness
2. rhabdomyolysis: breakdown of skeletal muscles
→ acute renal failure due to increase of myoglobin
+ alles was im Muskel ist = ist jetzt im Blut und erhöht
→ electrolyte imbalances, cardiac arrythmias

Erz. falls richtig angewendet: deutlich gesenkte Mortality (stroke risk, etc) → lowering of LDL-C by 40 mg/dl reduces risk of cardiovascular events by 20 %!

Aufpassen, falls andere Drugs CYPs inducen:
Pravastatin is the only statin that is no subject to CYP metabolism = safest statin in polymedication patients

Question 2

Fibrates

Answer 2

Treatment of Dyslipidaemia
Bsp: bezafibrate, fenofibrate, gemfibrozile

MOA: activation of PPAR-α in hepatocytes
→ increased expression of Apo AI + Apo AII → higher HDL
+
→ increased expression of LPL → lower VLDL + LDL

Do not combine statins + fibrates! → higher risk of rhabdomyolysis and mortality!

Question 3

Ezetimibe

Answer 3

Treatment of Dyslipidaemia, alternative to statins

MOA: antagonism of the NPC 1L1 protein in GI tract epithelial cell (= critical mediator of cholesterol absorption) → inhibition of cholesterol absorption from small intestine

No effect on mortality, low effect on morbidity → highly debatable

Question 4

PSCK9-targeted antibodies

Answer 4

Bsp: Alirocumab, Evolocumab
3rd line therapy for Dyslipidaemia

• has to be injected s.c. (1-2x/month)

MOA:
- normal: PCSK9 binds to the LDL-receptor on hepatocytes → LDLR wird degraded → less LDL being removed from the circulation
- Antibodies: PCSK9 blocked: more LDLRs are recycled and present on the cell surface to remove LDL from the circulation
→ blocking PCSK9 lowers blood concentration of LDL

Question 5

Cholestyramine

Answer 5

MOA:
bile acid sequestrant (complex builder) that prevents bile acids from being reabsorbed (anion exchange resin → exchange of chloride with anionic bile acids) → more plasma cholesterol is converted to bile acids → lower LDL

rather poor efficacy + interaction with many other drugs (via unspecific absorption)

Question 6

Pleiotropic effects of Statins

Answer 6

“lipid-independent effects“ = effects that are independent of LDL-cholesterol lowering

a) anti-thrombotic activities: higher NO release → higher fibrinolytic activity und less endothelia-1
b) antioxidant activities: more eNOS → more glutathione → less ROS → less lipid per oxidation
c) anti-inflammtory activities:
less pro-inflam. cytokines, less CRP

→ lower risk for blood clotting (stroke) and lower RR
→ eventuell preventiv for Osteoporosis + vascular dementia + Multiple Sklerose