Pharmacology - Dyslipidaemia & Lipid lowering drugs Flashcards
Atherosclerosis (form of arteriosclerosis)
Atherosclerosis (form of arteriosclerosis): inflammation & dysfunction of the lining of the involved blood vessels & the build up of cholesterol, lipids & cellular debris.
This results in the formation of a plaque (atheroma), obstruction of blood flow & diminished oxygen supply to target organs.
ATHEROSCLEROSIS: SYMPTOMS - 6
- In many cases asymptomatic
- CHD leading to angina, ACS & MI
- Cerebrovascular atherosclerotic disease leading to stroke
- Renovascular disease
- Peripheral artery disease: pain in legs, ulcers, necrosis, impotence & amputations
- Abdominal aortic aneurysm may cause vessel rupture & sudden death
Raised plasma markers of Atherosclerosis - 4
- C-reactive protein (CRP) (pro-inflammatory)
- Homocysteine Homocysteine is a precursor of cysteine (requires vitamin B6) also can be converted to methionine (require vitamin B12). High levels may also signify lack of vitamins B6, B12, folic acid)
- Coagulation factors
- Lipoprotein(a) – an independent CV risk factor
Risk factors for Atherosclerosis - 11
- Dyslipidaemias
- Liver diseases (jaundice)
- Nephrotic syndrome
- Anorexia nervosa
- Hypothyroidism
- Hypertension
- Diabetes mellitus (uncontrolled)
- Smoking
- Alcohol excess
- Lack of exercise
- Obesity
Normal levels of cholesterol & triglycerides in blood plasma
Total Cholesterol (TC):
<5 mmol/L (non-fasting)
Triglycerides (TG):
<2 mmol/L (on a fasting sample)
CHOLESTEROL: Endogenous & Exogenous pathways
- 3
- Endogenous pathway: Healthy liver synthetise cholesterol every day.
- Exogenous pathway: Significant amount used to make bile in the gallbladder to dissolve & facilitate reabsorption of dietary cholesterol. Cholesterol is reabsorbed back in the gut
- Cholesterol travels via lipoproteins in the blood.
LDL (Low-Density Lipoprotein) - Bad Cholesterol - 3
- LDL particles have a hydrophobic core of cholesterol & are surrounded by a hydrophilic phospholipid membrane.
- Contain lipoprotein B-100, which allows interaction with LDL receptors on cells, enabling the uptake of cholesterol.
- Transports cholesterol to cells for normal cellular functions. High levels of LDL can lead to plaque formation in arteries, contributing to atherosclerosis.
HDL (High-Density Lipoprotein) - Good Cholesterol - 3
- HDL has a higher protein-to-cholesterol ratio and more proteins (especially apolipoproteins A1 and A2).
- Involved in reverse cholesterol transport, picking up excess cholesterol from cells & returning it to the liver for excretion or recycling.
- Helps reduce cholesterol buildup in arteries, hence considered protective.
Chylomicrons - 3
- Transport dietary triglycerides & cholesterol from intestines to the bloodstream.
- Transports cholesterol from bile reabsorbed in the gut.
- Produced in enterocytes (intestinal cells).
VLDL (Very Low-Density Lipoprotein) - 2
- Produced by the liver, contains cholesterol esters & triglycerides.
- Transports triglycerides from the liver to cells for energy and stores cholesterol for cell function.
- Can be IDL (intermediate) between VLDL & LDL
CHOLESTEROL: TRANSPORT & TURNOVER
- 9
- Enterocytes absorb cholesterol by Niemann-Pick C1 transporter (target for lipid lowering drugs)
- In hepatocytes is converted to Chylomicrons & excreted.
- Stripped of triglycerides by lipoprotein lipase
- Chylomicron remnants taken up by LDL receptors
- Cholesterol remaining here used to recycle bile, or packed into VLDL
- VLDL secreted by hepatocytes & stripped of tryglyderides.
- VLDL become LDL, release cholesterol for cell needs & reabsorbed
- Excess is HDL, excreted into plasma
- Then scavenged or converted to VLDL/LDL
Normal levels of LDL, HDL cholesterol & TC:HDL-C ratio
LDL-Cholesterol (LDL-C): <3 mmol/L
HDL-Cholesterol (HDL-C): >1 mmol/L (men) >1.2mmol/L (women)
Normal TC:HDL-C ratio<4
High CV risk TC:HDL-C ratio > 6
Lipoprotein(a) bound to Apo(a)
Independent CV risk factor - 3
- Apo(a) is pro thrombotic and pro fibrotic, because level of thrombosis controlled by plasminogen.
- It is endogenous clot buster.
- Low levels of Apo(a) can raise risk of CVD
FORMATION OF AN ATHEROMATOUS PLAGUE - 8
- Damage occurs to endothelial cells (risk factors weaken e.g. smoking)
- Damaged endothelial cells promote migration of LDL from bloodstream into vessel walls & cause the adhesion of other cells, e.g. monocytes.
- LDL oxidized, forming oxidized LDL. Harmful & can be a target for immune cells.
- Oxidized LDL interacts with immune cells, forming cholesterol crystals & accumulate in the walls of blood vessels.
- Macrophages engulf oxidized LDL, & release cytokines & enzymes, causing inflammation.
- Cholesterol crystals trigger release of inflammatory cytokines, contributing immune response.
- Plaque forms, narrowing lumen & reducing blood flow. Can cause angina & reduce 02 supply.
- Plaques weaken from blood flow, & rupture, forming clots. (thrombosis), can block arteries & cause ACS.
Common Familial Hyperlipidaemias (FH) - 7
- Familial Combined Hyperlipidaemia: Elevated cholesterol & triglycerides.
- Familial Primary Hypertriglyceridemia: Characterized by high triglyceride levels.
- Symptoms: lipid deposits in eye, hands, & legs
- Caused by mutations in LDL receptor gene, affecting LDL uptake & leading to high cholesterol levels.
- Mutations in PCSK9 can increase cholesterol levels
Treatment: - Early treatment helps delay atherosclerosis & heart disease.
- Statins used to lower cholesterol, & drugs targeting PCSK9
LIPID-LOWERING DRUGS - 6
- STATINS
- EZETIMIBE
- FIBRATES
- BILE ACID-BINDING RESINS
- NICOTINIC ACID
- OMEGA-3-ACID ETHYL ESTERS (Fish oil derivatives)
Statins MoA - 4
- Statins act as competitive, reversible inhibitors of HMG-CoA reductase, preventing cholesterol synthesis. This acts as a rate limiting step.
- Prevent Mevalonate production, meaning FPP & GGPP are produced less.
- FPP & GGPP used to prenylate proteins such as Ras, a small GTPase.
- Addition of farnesyl or geranylgeranyl groups is required for some protein’s function & membrane localization, impacting cell signalling & growth.
Statins main Lipid lowering effects – 3
- Statins inhibit cholesterol synthesis in the liver, leading hepatocytes to compensate by increasing the surface expression & synthesis of LDL receptors.
- This enhances LDL uptake from the plasma, allowing reuse of cholesterol for cellular functions & bile production.
- Modest increase in HDL due to turnover & exchange between LDL & HDL.
Type 1 Statins (Fungal-derived) - 3
e.g. simvastatin
- These statins share a lactone/open acid moiety & a decalin ring structure, which allows them to interact with HMG-CoA reductase.
- Statins are prodrugs containing an inactive lactone form that is hydrolysed by esterase into an active β-hydroxyacid form.
- Mimics endogenous substrate of HMG-CoA reductase, making statins competitive inhibitors of the enzyme.
Simvastatin Info - 3
- Simvastatin & Lovastatin administered as lactone prodrugs, others in active acid form
- Oral BA of simvastatin & lovastatin is low due to CYP450 first-pass metabolism
- MDR1 (P-gp1 or ABCB1) – Excrete foreign drugs from the cells (liver, intestine). Inhibits Lovastatin, Simvastatin & Atorvastatin.
CYP3A4 inhibitors
(increase statin levels): - 5
CYP3A4 inhibitors
(increase statin levels):
1. Itraconazole (Anti fungal)
2. Erythromycin, Clarithromycin (Antibiotics)
3. Verapamil, diltiazem (CCB)
4. Cyclosporin (Immunosuppressant)
5. grapefruit juice
CYP3A4 inducers reduce statin levels - 2
CYP3A4 inducers reduce statin levels:
1. Rifampicin (antibiotics)
2. Carbamazepine (anticonvulsants)
LIPID-LOWERING DRUGS: THERAPEUTIC USES OF STATINS - 5
- Secondary prevention of CHD
- Primary prevention of CHD in patients with other risk factors:
Chronic Kidney Disease, Diabetes - In familiar hypercholesterolaemia
- Cautions: Liver disease, Hypothyroidism
- Contraindications: In pregnancy
LIPID-LOWERING DRUGS: OTHER CV BENEFITS OF STATINS
- 5
- Improvement of endothelial function
- Anti-inflammatory (inhibition of prenylation of small GTPAses e.g. Rho)
- Anti-thrombotic & antiplatelet effects
- Increase in vasodilatation (inhibition of RhoA-ROCK pathway)
- Increase of neovascularisation of ischaemic tissue
LIPID-LOWERING DRUGS: ADVERSE REACTIONS OF STATINS -
10
- Asthenia (physical weakness)
- Muscle pain (myalgia)
- Nausea, dizziness, headache
- Constipation, diarrhoea
- Flatulence & GI discomfort
- Low platelet count
Rare (likelihood increases with dose) - Myositis (muscle inflammation)
- Rhabdomyolysis (muscle breakdown)
Very rare: - Hepatitis
- Interstitial lung disease
LIPID-LOWERING DRUGS: EZETIMIBE - 5
MoA & 1 disadvantage
- Inhibition of Niemann-Pick C1-like reduces absorption of cholesterol, including both dietary cholesterol & bile cholesterol.
- Cholesterol can no longer enter hepatocyte to become Chylomicrons
- Preventing Chylomicron remnants being taken up by LDL receptors
- Decreasing cholesterol availability in the body.
Disadvantages: Ezetimbe may block absorption of plant stanols, beneficial components of a cholesterol-lowering diet found in foods like fruits, vegetables, & nuts.
LIPID-LOWERING DRUGS: EZETIMIBE Clinical uses: Hypercholesteremia 2 & S/Es 4
Various hypercholesterolaemia - 2
1. In combination with a statin e.g. Simvastatin
2. Alone (when statins are contraindicated)
Adverse effects - 4
1. Diarrhoea
2. Abdominal pain
3. Headache
4. Myalgia
PPARs as main regulators of energy usage & storage:
PPARα - 3
PPARα:
1.Expression: Liver, skeletal muscles
2. Roles: Lipid catabolism, beta-oxidation of FA (fatty acids), vascular integrity & control of inflammation (via decrease cytokines; decrease NFκB)
3.Therapeutic ligands: Fibrates
PPARs as main regulators of energy usage & storage:
PPARβ/δ: - 3
PPARβ/δ:
1. Expression: Liver, skeletal muscles
2. Role: Insulin sensitivity, glucose uptake & synthesis; vascular integrity.
3. Therapeutic ligands: Thiazolidinediones (glitazones)
PPARs as main regulators of energy usage & storage:
PPARy - 3
PPARy:
1. Expression: Adipocytes
2. Role: Glucose metabolism & lipid storage; increase insulin sensitivity
3.Therapeutic ligands: Thiazolidinediones (glitazones)
Fibrates Mechanism of Action - 5
- Fibrates bind to PPARα, a nuclear transcription factor, activating it.
- Activated PPARα dimerizes with Retinoid X Receptor (RXR), forming a transcription factor.
- Promotes transcription of lipoprotein lipase, facilitating breakdown of triglycerides into fatty acids.
- Breakdown & uptake of fatty acids by cells help lower triglyceride levels.
- Fibrates also increase expression of (Apo-A1 & Apo-A2), components of HDL, increasing in HDL levels.
Fibrates: Main lipid-lowering effects & benefits - 5
- Increase Plasma HDL (due to increased Apo A1/A2 expression)
- Increase Fatty acid uptake & β-oxidation (due to increase LPL activity)
- Decreased Plasma VLDL & decreased TG
- Decreased Plasma LDL (moderate)
- Decreased Inflammation (due to decreased expression of proinflammatory cytokines)
LIPID-LOWERING DRUGS: THERAPEUTIC USES OF FIBRATES
- 3
Clinical use: - 3
1. Mixed dyslipidaemia (cholesterol + triglycerides)
2. High risk of atherosclerosis and low HDL
3. In severe treatment-resistant dyslipidaemia (with statins)
Contraindications: In pregnancy
LIPID-LOWERING DRUGS: ADVERSE EFFECTS OF FIBRATES
- 3
Adverse effects:
1. Abdominal distension;anorexia;diarrhoea;nausea.
Myotoxicity:
2. Myositis (weak muscles)
3. Rhabdomyolysis (when combined with statins)
Myotoxicity can be increased when used in patients with:
- Kidney impairments
- Hypertriglyceridemia (in alcoholic patients)
LIPID-LOWERING DRUGS: BILE ACID-BINDING RESINS:
Clinical use 3 & S/E 3
Clinical use:
1. Patients with liver diseases (where statins not recommended)
2. In dyslipidaemia non-responsive to diet
3. In pregnancy with caution (not absorbed)
S/Es:
1. GI disturbances
2. Constipation
3. Bleeding (Vitamin K deficiency)
LIPID-LOWERING DRUGS: NICOTINIC ACID (NIACIN or VITAMIN B3)
- 3, Use
Lipid-lowering mechanism:
1. Activates the Gi/o coupled HCA2 receptor in adipocytes
2. Decreased triglycerides, leads to decrease VLDL, decreasing LDL
3. Increases apo-A1 levels, leading to increase HDL
Clinical use: Dyslipidaemia
ADRs:
Nausea & vomiting
Severe allergic reaction
Light headedness & syncope
Tachycardia & palpitations
Skin itching or rash
Severe stomach pain
Muscle pain
Flu-like symptoms
Hypertriglyceridaemias:
Hypertriglyceridaemias: high level of VLDL (type IV) or mixed with high levels of TGs+LDL (type IIb) or with high levels of TGs + high TC (type III)
Effect of Anti-PCSK9 on LDL-Receptors - 5
- LDL-C binds to LDL-R on plasma membrane & undergoes endocytosis which causes LDL-C uptake & LDL-R recycling
- PCSK9 & LDL-C bind to LDL-R, PCSK9 causes degradation of LDL-R which increases LDL-C in the circulation.
- Main lipid-lowering effect: Decrease Plasma LDL (due to increase LDL uptake)
- Clinical uses: Primary hypercholesterolaemia, Mixed dyslipidaemia (bad response to statins)
- ADRs: Nausea, Skin reactions
