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106 > Pharmacology - Dyslipidaemia & Lipid lowering drugs > Flashcards

Pharmacology - Dyslipidaemia & Lipid lowering drugs Flashcards

1
Q

Atherosclerosis (form of arteriosclerosis)

A

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.

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2
Q

ATHEROSCLEROSIS: SYMPTOMS - 6

A
  1. In many cases asymptomatic
  2. CHD leading to angina, ACS & MI
  3. Cerebrovascular atherosclerotic disease leading to stroke
  4. Renovascular disease
  5. Peripheral artery disease: pain in legs, ulcers, necrosis, impotence & amputations
  6. Abdominal aortic aneurysm may cause vessel rupture & sudden death
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3
Q

Raised plasma markers of Atherosclerosis - 4

A
  1. C-reactive protein (CRP) (pro-inflammatory)
  2. 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)
  3. Coagulation factors
  4. Lipoprotein(a) – an independent CV risk factor
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3
Q

Risk factors for Atherosclerosis - 11

A
  1. Dyslipidaemias
  2. Liver diseases (jaundice)
  3. Nephrotic syndrome
  4. Anorexia nervosa
  5. Hypothyroidism
  6. Hypertension
  7. Diabetes mellitus (uncontrolled)
  8. Smoking
  9. Alcohol excess
  10. Lack of exercise
  11. Obesity
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4
Q

Normal levels of cholesterol & triglycerides in blood plasma

A

Total Cholesterol (TC):
<5 mmol/L (non-fasting)

Triglycerides (TG):
<2 mmol/L (on a fasting sample)​

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5
Q

CHOLESTEROL: Endogenous & Exogenous pathways
- 3

A
  1. Endogenous pathway: Healthy liver synthetise cholesterol every day.
  2. 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
  3. Cholesterol travels via lipoproteins in the blood.
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6
Q

LDL (Low-Density Lipoprotein) - Bad Cholesterol - 3

A
  1. LDL particles have a hydrophobic core of cholesterol & are surrounded by a hydrophilic phospholipid membrane.
  2. Contain lipoprotein B-100, which allows interaction with LDL receptors on cells, enabling the uptake of cholesterol.
  3. Transports cholesterol to cells for normal cellular functions. High levels of LDL can lead to plaque formation in arteries, contributing to atherosclerosis.
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7
Q

HDL (High-Density Lipoprotein) - Good Cholesterol - 3

A
  1. HDL has a higher protein-to-cholesterol ratio and more proteins (especially apolipoproteins A1 and A2).
  2. Involved in reverse cholesterol transport, picking up excess cholesterol from cells & returning it to the liver for excretion or recycling.
  3. Helps reduce cholesterol buildup in arteries, hence considered protective.
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8
Q

Chylomicrons - 3

A
  1. Transport dietary triglycerides & cholesterol from intestines to the bloodstream.
  2. Transports cholesterol from bile reabsorbed in the gut.
  3. Produced in enterocytes (intestinal cells).
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9
Q

VLDL (Very Low-Density Lipoprotein) - 2

A
  1. Produced by the liver, contains cholesterol esters & triglycerides.
  2. Transports triglycerides from the liver to cells for energy and stores cholesterol for cell function.
  3. Can be IDL (intermediate) between VLDL & LDL
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10
Q

CHOLESTEROL: TRANSPORT & TURNOVER
- 9

A
  1. Enterocytes absorb cholesterol by Niemann-Pick C1 transporter (target for lipid lowering drugs)
  2. In hepatocytes is converted to Chylomicrons & excreted.
  3. Stripped of triglycerides by lipoprotein lipase
  4. Chylomicron remnants taken up by LDL receptors
  5. Cholesterol remaining here used to recycle bile, or packed into VLDL
  6. VLDL secreted by hepatocytes & stripped of tryglyderides.
  7. VLDL become LDL, release cholesterol for cell needs & reabsorbed
  8. Excess is HDL, excreted into plasma
  9. Then scavenged or converted to VLDL/LDL
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11
Q

Normal levels of LDL, HDL cholesterol & TC:HDL-C ratio

A

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

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12
Q

Lipoprotein(a) bound to Apo(a)
Independent CV risk factor - 3

A
  1. Apo(a) is pro thrombotic and pro fibrotic, because level of thrombosis controlled by plasminogen.
  2. It is endogenous clot buster.
  3. Low levels of Apo(a) can raise risk of CVD
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13
Q

FORMATION OF AN ATHEROMATOUS PLAGUE - 8

A
  1. Damage occurs to endothelial cells (risk factors weaken e.g. smoking)
  2. Damaged endothelial cells promote migration of LDL from bloodstream into vessel walls & cause the adhesion of other cells, e.g. monocytes.
  3. LDL oxidized, forming oxidized LDL. Harmful & can be a target for immune cells.
  4. Oxidized LDL interacts with immune cells, forming cholesterol crystals & accumulate in the walls of blood vessels.
  5. Macrophages engulf oxidized LDL, & release cytokines & enzymes, causing inflammation.
  6. Cholesterol crystals trigger release of inflammatory cytokines, contributing immune response.
  7. Plaque forms, narrowing lumen & reducing blood flow. Can cause angina & reduce 02 supply.
  8. Plaques weaken from blood flow, & rupture, forming clots. (thrombosis), can block arteries & cause ACS.
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14
Q

Common Familial Hyperlipidaemias (FH) - 7

A
  1. Familial Combined Hyperlipidaemia: Elevated cholesterol & triglycerides.
  2. Familial Primary Hypertriglyceridemia: Characterized by high triglyceride levels.
  3. Symptoms: lipid deposits in eye, hands, & legs
  4. Caused by mutations in LDL receptor gene, affecting LDL uptake & leading to high cholesterol levels.
  5. Mutations in PCSK9 can increase cholesterol levels
    Treatment:
  6. Early treatment helps delay atherosclerosis & heart disease.
  7. Statins used to lower cholesterol, & drugs targeting PCSK9
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15
Q

LIPID-LOWERING DRUGS - 6

A
  1. STATINS
  2. EZETIMIBE
  3. FIBRATES
  4. BILE ACID-BINDING RESINS
  5. NICOTINIC ACID
  6. OMEGA-3-ACID ETHYL ESTERS (Fish oil derivatives)
16
Q

Statins MoA - 4

A
  1. Statins act as competitive, reversible inhibitors of HMG-CoA reductase, preventing cholesterol synthesis. This acts as a rate limiting step.
  2. Prevent Mevalonate production, meaning FPP & GGPP are produced less.
  3. FPP & GGPP used to prenylate proteins such as Ras, a small GTPase.
  4. Addition of farnesyl or geranylgeranyl groups is required for some protein’s function & membrane localization, impacting cell signalling & growth.
17
Q

Statins main Lipid lowering effects – 3

A
  1. Statins inhibit cholesterol synthesis in the liver, leading hepatocytes to compensate by increasing the surface expression & synthesis of LDL receptors.
  2. This enhances LDL uptake from the plasma, allowing reuse of cholesterol for cellular functions & bile production.
  3. Modest increase in HDL due to turnover & exchange between LDL & HDL.
18
Q

Type 1 Statins (Fungal-derived) - 3
e.g. simvastatin

A
  1. These statins share a lactone/open acid moiety & a decalin ring structure, which allows them to interact with HMG-CoA reductase.
  2. Statins are prodrugs containing an inactive lactone form that is hydrolysed by esterase into an active β-hydroxyacid form.
  3. Mimics endogenous substrate of HMG-CoA reductase, making statins competitive inhibitors of the enzyme.
19
Q

Simvastatin Info - 3

A
  1. Simvastatin & Lovastatin administered as lactone prodrugs, others in active acid form
  2. Oral BA of simvastatin & lovastatin is low due to CYP450 first-pass metabolism
  3. MDR1 (P-gp1 or ABCB1) – Excrete foreign drugs from the cells (liver, intestine). Inhibits Lovastatin, Simvastatin & Atorvastatin.
20
Q

CYP3A4 inhibitors
(increase statin levels): - 5

A

CYP3A4 inhibitors
(increase statin levels):
1. Itraconazole (Anti fungal)
2. Erythromycin, Clarithromycin (Antibiotics)
3. Verapamil, diltiazem (CCB)
4. Cyclosporin (Immunosuppressant)
5. grapefruit juice

21
Q

CYP3A4 inducers reduce statin levels - 2

A

CYP3A4 inducers reduce statin levels:
1. Rifampicin (antibiotics)
2. Carbamazepine (anticonvulsants)

22
Q

LIPID-LOWERING DRUGS: THERAPEUTIC USES OF STATINS - 5

A
  1. Secondary prevention of CHD
  2. Primary prevention of CHD in patients with other risk factors:
    Chronic Kidney Disease, Diabetes
  3. In familiar hypercholesterolaemia
  4. Cautions: Liver disease, Hypothyroidism
  5. Contraindications: In pregnancy
23
Q

LIPID-LOWERING DRUGS: OTHER CV BENEFITS OF STATINS
- 5

A
  1. Improvement of endothelial function
  2. Anti-inflammatory (inhibition of prenylation of small GTPAses e.g. Rho)
  3. Anti-thrombotic & antiplatelet effects
  4. Increase in vasodilatation (inhibition of RhoA-ROCK pathway)
  5. Increase of neovascularisation of ischaemic tissue
24
Q

LIPID-LOWERING DRUGS: ADVERSE REACTIONS OF STATINS -
10

A
  1. Asthenia (physical weakness)
  2. Muscle pain (myalgia)
  3. Nausea, dizziness, headache
  4. Constipation, diarrhoea
  5. Flatulence & GI discomfort
  6. Low platelet count
    Rare (likelihood increases with dose)
  7. Myositis (muscle inflammation)
  8. Rhabdomyolysis (muscle breakdown)
    Very rare:
  9. Hepatitis
  10. Interstitial lung disease
25
Q

LIPID-LOWERING DRUGS: EZETIMIBE - 5
MoA & 1 disadvantage

A
  1. Inhibition of Niemann-Pick C1-like reduces absorption of cholesterol, including both dietary cholesterol & bile cholesterol.
  2. Cholesterol can no longer enter hepatocyte to become Chylomicrons
  3. Preventing Chylomicron remnants being taken up by LDL receptors
  4. 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.

26
Q

LIPID-LOWERING DRUGS: EZETIMIBE Clinical uses: Hypercholesteremia 2 & S/Es 4

A

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

27
Q

PPARs as main regulators of energy usage & storage:
PPARα - 3

A

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

28
Q

PPARs as main regulators of energy usage & storage:
PPARβ/δ: - 3

A

PPARβ/δ:
1. Expression: Liver, skeletal muscles
2. Role: Insulin sensitivity, glucose uptake & synthesis; vascular integrity.
3. Therapeutic ligands: Thiazolidinediones (glitazones)

29
Q

PPARs as main regulators of energy usage & storage:
PPARy - 3

A

PPARy:
1. Expression: Adipocytes
2. Role: Glucose metabolism & lipid storage; increase insulin sensitivity
3.Therapeutic ligands: Thiazolidinediones (glitazones)

30
Q

Fibrates Mechanism of Action - 5

A
  1. Fibrates bind to PPARα, a nuclear transcription factor, activating it.
  2. Activated PPARα dimerizes with Retinoid X Receptor (RXR), forming a transcription factor.
  3. Promotes transcription of lipoprotein lipase, facilitating breakdown of triglycerides into fatty acids.
  4. Breakdown & uptake of fatty acids by cells help lower triglyceride levels.
  5. Fibrates also increase expression of (Apo-A1 & Apo-A2), components of HDL, increasing in HDL levels.
31
Q

Fibrates: Main lipid-lowering effects & benefits - 5

A
  1. Increase Plasma HDL (due to increased Apo A1/A2 expression)
  2. Increase Fatty acid uptake & β-oxidation (due to increase LPL activity)
  3. Decreased Plasma VLDL & decreased TG
  4. Decreased Plasma LDL (moderate)
  5. Decreased Inflammation (due to decreased expression of proinflammatory cytokines)
32
Q

LIPID-LOWERING DRUGS: THERAPEUTIC USES OF FIBRATES
- 3

A

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

33
Q

LIPID-LOWERING DRUGS: ADVERSE EFFECTS OF FIBRATES
- 3

A

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)

34
Q

LIPID-LOWERING DRUGS: BILE ACID-BINDING RESINS:
Clinical use 3 & S/E 3

A

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)

34
Q

LIPID-LOWERING DRUGS: NICOTINIC ACID (NIACIN or VITAMIN B3)
- 3, Use

A

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

35
Q

Hypertriglyceridaemias:

A

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)

36
Q

Effect of Anti-PCSK9 on LDL-Receptors - 5

A
  1. LDL-C binds to LDL-R on plasma membrane & undergoes endocytosis which causes LDL-C uptake & LDL-R recycling
  2. PCSK9 & LDL-C bind to LDL-R, PCSK9 causes degradation of LDL-R which increases LDL-C in the circulation.
  3. Main lipid-lowering effect: Decrease Plasma LDL (due to increase LDL uptake)
  4. Clinical uses: Primary hypercholesterolaemia, Mixed dyslipidaemia (bad response to statins)
  5. ADRs: Nausea, Skin reactions

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