15 - Drugs to treat hyperlipidaemia and angina

What is the rate limiting step for cholesterol synthesis?

HMG-CoA -> mevalonate

Which enzyme is the target of the most common class of drugs used to treat hypercholesterolaemia?

HMG-CoA reductase

Why is HMG-CoA reductase the target for the most common class of drugs used to treat hypercholesterolaemia?

Because it catalyses the rate limiting step of cholesterol synthesis

How does statins reduce cholesterol synthesis in liver?

By competitively inhibiting HMG-CoA reductase

How is the production of bile acids maintained when patient is under statins and therefore has reduced cholesterol synthesis?

Liver removes cholesterol from bloodstream by increasing number of LDL receptors on surface of hepatocytes.

Other than reduction in LDL, what other benefits do patients get from statins?

Small increase in serum HDL / reducing TG / anti-inflammatory effects

What do all statin drug names end in?

-statin

What are some named examples of statin drugs?

Atorvastatin / simvastatin

What are all the possible side effects of statins?

Headache /GI problem / myalgia

What is myalgia?

Muscle pain

What is the rate of myalgia in patients on statins?

10%

What is myalgia caused by and what further complications can this lead to?

Muscle inflammation (myositis) / can process to rhabdomyolysis

What is rhabdomyolysis?

When muscle begin to break down / life threatening if not treated as breakdown of muscle releases myoglobin into circulation.

Why is the release of myoglobin into circulation life threatening?

Myoglobin is toxic to kidney / can lead to acute kidney failure

What does the prescription of statins for primary prevention dependent of?

QRISK3 score

Would the dose for secondary prevention be higher or lower than primary?

Usually higher

What transporter allows intake of cholesterol from diet?

NPC1L1 transporter

How does cholesterol from diet end up in the bloodstream?

Transported into enterocytes via NPC1L1 / produce chylomicron particles / chylomicrons are secreted into lymph and pass to bloodstream.

What does the drug Ezetimibe do?

Block absorption of dietary cholesterol by blocking NPC1L1

Compare the effectiveness between statins and ezetimibe drugs.

Ezetimibe is less effective on its own than statins

How is the drug ezetimibe often given with?

Statins

What type of patients is the dual approach of statins + ezetimibe effective for?

Whose non-HDL lvl cannot be adequately controlled with statins alone / familial hypercholesterolaemia

What do Fibrate drugs do?

Activate nuclear hormone receptors (PPARs) / modulate a range of genes involved in lipid metabolism.

What benefits/results do fibrate drugs produce?

Raised HDL / lowered TG / small effect of LDL

What is a high risk if fibrates are combined with statins?

High risk of rhabdomyolysis.

What does GTN stand for?

Glyceryl trinitrate

How is explosive prevented when using GTN as a medication?

In a dilute solution / formulated with stabilisers

Why must GTNs be formulated with stabilisers?

So doesnt explode.

What is a prodrug?

Inactive / weakly active compound that is metabolised in body to produce a active drug

How is GTN a prodrug?

Must be converted to active form nitric oxide (NO) before it can act

Why is GTN ineffective if taken as a tablet?

Bc it is subject to extensive first-pass metabolism

What is the term for the fraction of drug that makes it into the system circulation?

Bioavailability

What is bioavailability?

The fraction of drug that makes it into the system circulation

Why are many drugs metabolised before they even enter bloodstream?

Cell lining the GI have array of enzymes whose purpose is to detoxify foreign substances

What are the advantages of tablet mediation (not considering bioavaliability)?

Precisely measured dose / easy to transport / convenient for patient to take

What are 4 ways of drug intake that can avoid first-pass metabolism?

Rectal ointment / intravenous injection / sublingual tablet or spray / Transdermal patches

What are rectal ointment used for?

Anal fissures

How does sublingual tablets / sprays work?

Sprayed under the tongue or a tablet is placed there / drug absorbed through mucous membranes in mouth and pass into circulation.

Is isosorbide mononitrate subject to first pass metabolism?

No

Compare the use of isosorbide mononitrate to GTNs

Slower onset action compared to GTN / not suitable for relieving acute angina attacks

What does ‘sustained release formulation’ mean?

That the tablet is designed so drug is released slowly over long period of time

Are all organic nitrates prodrugs?

Yes

What type of signalling molecule is nitric oxide?

Endogenous intracellular

What enzyme does nitric oxide activate?

Soluble guanylyl cyclase

What does the enzyme, guanylyl cyclase, do?

Convert GTP to cyclic GMP (cGMP)

How does nitric oxide relieve angina attacks?

Nitric oxide activates guanylyl cyclase / which convert GTP → cGMP / cGMP activates PKG / PKG phosphorylate target protein / reduction in intracellular calcium / vasodilation.

What does PKG stand for?

Protein kinase G

What are all the CV effects of organic nitrates?

Dilation of: collateral vessels / coronary artery / peripheral capacitance vessels & artery & arterioles

What are the side effects of organic nitrates?

Headache / hypotension / flushing

What can hypotension lead to?

Dizziness / reflex tachycardia

Why is GTN not routinely used as a maintenance drug for angina attacks, despite being a 1st-line treatment?

Patient can rapidly develop tolerance to organic nitrates

What are some surgical options for treatment angina?

Coronary artery angioplasty / coronary artery bypass graft

What does CABG stand for?

Coronary artery bypass graft

What does PCI stand for?

Percutaneous coronary intervention

What is another name for the procedure: Coronary artery angioplasty?

Percutaneous coronary intervention / PCI

How does coronary artery bypass graft work?

Involve removing non-essential vessel from another part of the body to use to restore blood flow to compromised part of the heart.

What are some common vessels used in CABG?

Internal mammary artery (chest) / great saphenous vein (leg)

When would CABG need to be used?

When resistant to drug / location of blockage where PCI cannot be used

How can the CABG procedure lead to a myocardial infarction / stroke?

Due to emboli and debris from surgery entering the cirulation.