treatments for hypercholesterolaemia, hyperlipidaemia and angina

statins

• end in statin

• competitive inhibitors of HMG-CoA reductase

• eg atorvastatin and simvastatin

mechanism of statins

• feedback inhibition

• stimulate synthesis of LDL receptors

  • recognise ApoB-100, uptake of LDL to liver

• LDL reduced, HDL increased

side effects of statins

• headache

• gi tract

• 10% people get myalgia

• rare is myositis and rhabdomyolysis (muscle breakdown)

  • unhealthy dark urine, myoglobin toxic to kidney

• small inc risk of diabetes

who should take statins

• primary prevention

  • reduce risk of heart attack or stroke

  • reduce non-HDL by 40%

  • QRISK3 of 10% or higher

• secondary prevention

  • reduce risk of further heart attack

  • get non HDL below 2.6mmol/L

  • prescribed routinely

what QRISK score indicates statins are needed

10% of higher

what value does non-HDL need to be below for secondary prevention

2.6

ezetimibe mechanism

• stop dietary absorption of cholesterol in gut lumen enterocytes by NPC1L1

• used for people who cant tolerate statins or used alongside with statins for people with high cholesterol levels

fibrates

• activate PPAR receptor

• worse side effects than statins so have been replaced

• eg fenofibrate and gemfibrozil

GTN glyceryl trinitrate

• short duration of action

• main drug for relieving angina

• prodrug

what is the active form of GTN

nitric oxide

first pass metabolism problems for GTN

• swallowing tablet allows it to be absorbed from GI tract

• transported by hepatic portal vein to liver

• metabolised to the point not reaching systemic circulation

alternative delivery for GTN

• topical

• rectal/vaginal

• injections

• sublingual

isosorbide mononitrate

• can be swallowed as tablet

• longer duration but slower onset than GTN

• used as add on when other drugs not tolerated

mechanism of organic nitrates

• prodrugs broken down to active principle

• activates soluble guanylyl cyclase

• GTP → cGMP

• calcium released

• vasodilation

cardiovascular effects of organic nitrates

• dilation of peripheral capacitance vessels

• dilation of collateral vessels - alt route for blood flow, bypass plaques

• dilation of coronary arteries

side effects of organic nitrates

• headache

• dizzinness

• reflex tachycardia

• flushing

cascade testing

genetic testing used for relatives after genetic variant is found in one family member

third line treatments for familial hypercholesteroaemia

• if LDL persistently high, PCSK9 inhibitors may be tried

• fibrates only used if statins or ezetimibe not tolerated - carry more risk, rhabdomyolysis

lipoprotein apheresis

• 3rd line treatment for familial hypercholesteraemia

• blood is taken, treated with heparin to precipitate LDL, heparin removed and blood returned

• done every 1-2 weeks

3rd line treatments for familial hypercholesteraemia

• if maximum statin and ezetimibe not working

• pcsk9 inhibitors - very expensive

effect of surgical removal of xanthomas

• no effect on LDL levels

• only cosmetic