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Pharmacology > L8 Lipid Modifying and Antiplatelet Drugs > Flashcards

L8 Lipid Modifying and Antiplatelet Drugs Flashcards

1
Q

Learning Outcomes (for general perusal)

A
  • Understand the mechanisms of actions, therapeutic use and adverse effects of antiplatelet drugs used to prevent future cardiovascular events
  • Understand the role of risk assessment tools to determine 10 year CVD risk to guide the initiation of statin therapy to prevent CVD events
  • Understand the mechanisms of action, value of dose titration and harms and benefits associated with the use of statins for CVD prevention
  • Appreciate the limited role for other classes of lipid lowering drugs for the prevention of CVD
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2
Q

Antiplatelet Drugs

  1. What plays a critical role in the development of arterial thrombi?
  2. What activates platelets?
  3. How do they respond?
  4. What amplifies this process?
  5. Thrombin production via the coagulation cascade is also accelerated. What is thrombus stabilised by?
A
  1. Platelets
  2. Damaged endothelium
  3. respond by adhering and aggregating to the endothelium
  4. Release of thromboxane A2 and adenosine diphosphate (ADP)
  5. conversion of fibrinogen to fibrin
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3
Q

Aspirin

  1. What is it’s mechanism of action? (low dose aspirin - 75mg)?
  2. How does it inactivate the enzyme?
  3. When is most of platelet function recovered by on cessation?
  4. What are reverible inhibitors of COX-1 (and therefore poor antiplatelet agents)?
A
  1. selectively and irreversibly inhibits cyclo-oxygenase (COX-1) which catalyses the production of thromboxanes and prostaglandins (less platelet thromboxane A2)
  2. by acetylation of the serine residue
  3. 4-5days, due to non-linear kinetics
  4. NSAIDs
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4
Q

Aspirin

  1. What is it’s name?
  2. What is it used for?
A
  1. Acetylsalicylic acid
  2. Secondary prevention of transient ischaemic attack (TIA), ischaemic stroke and myocardial infarction

-Prevention of ischaemic events in patients with angina pectoris and Prevention of coronary artery bypass graft (CABG) occlusion => Marginal risk to benefit ratio in primary prevention so not recommended (including diabetes)

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5
Q

Aspirin - Acetylsalicylic Acid

  1. ​What are the drawbacks?
A
  • Risk of gastrointestinal adverse events (ulceration and bleeding) -

Prostaglandins are important in cytoprotection in the stomach. Inhibited by aspiriin.Consistency of mucous layer disrupted. Bicarbonate secretion impaired.

  • Allergic reactions eg aspirin induced asthma
  • Lack of response in some patients (aspirin resistance). This is rare and often related to poor adherence to the drug
  • The irreversible platelet inhibition i.e. continued bleeding risk for some time after stopping the drug
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6
Q

Adenosine diphosphate (ADP) and
platelet function

  1. What is ADP important in producing?
  2. What does ADP interact with?
  3. What happens on binding with P2Y12?
  4. Which drugs act to selectively and irreversibly inhibit ADP-mediated platelet activation and aggregation?
A
  1. platelet activation
  2. Gq - coupled P2Y1 and especially Gi coupled P2Y12 purinergic platelet receptors
  3. ADP inhibits adenylyl cyclase leading to a reduction in cAMP and this promotes platelet activation
  4. thienopyridines, clopidogrel and prasugrel
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7
Q

Clopidogrel

  1. What is it?
  2. What is the prescribed dose?
  3. What is it metabolised and activated by?
  4. What is it’s mechanism of action?
  5. What is it’s secondary action?
  6. Describe the kinetics and what does this mean for inhibition of platelet function upon cessation?
A
  1. An inactive PRODRUG
  2. 75mg/daily
  3. Cytochrome P450 (CYP1A2 and CYP3A4) enzymes in the liver
  4. Blocking the ADP receptor prevents ADP-induced inhibition of adenylyl cyclase and the accompanying reduction of cAMP that causes the activation of platelets. This is the main way the drug prevents platelet activation.
  5. decreases ADP induced activation of the glycoprotein IIb/IIIa receptor.
  6. Linear kinetics so platelet function inhibited for 8 days
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8
Q

Thienopyridines - Clopidogrel

Elaborate on the main drawbacks

  • Prodrug
  • Genetic Variation of Liver P450 enzymes
  • Drug-drug interactions
  • Irreversible inhibition of P2Y12 receptor
A
  • delayed onset of action (steady state platelet inhibition = 5 days) but can be partially overcome by giving loading dose e.g. 300 mg
  • liver enzymes (P450) responsible for metabolism and activation so response varies between individuals
  • e.g. proton pump inhibitors (esp omeprazole) that can influence liver enzymes that metabolise clopidogrel
  • bleeding risk for 7-8 days on stopping drug.
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9
Q

Thienopyridines - Prasugrel

  1. What is it?
  2. How does it act?
  3. What are the benefits?
  4. What is it used in?
A
  1. PRODRUG, different chemical structure permits conversion to the active metabolite in the liver with less dependence on cytochrome P450 enzymes than clopidogrel (one step oxidation to form active metabolite)
  2. Like clopidogrel, it is an irreversible inhibitor of the platelet P2Y12 receptor
  3. Greater absorption and the higher active metabolite bioavailabilty, Faster onset of action, less individual variation and therefore more predictable response
  4. Used in acute coronary syndromes
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10
Q

Ticagrelor

  1. What is it?
  2. Compare it to Clopidogrel and Prasugrel?
  3. How often is it given?
  4. What is the offset
  5. What is it used for?
A
  1. Is a cyclopentyl-triazolo-pyrimidine that does not bind to the ADP binding site but a separate site on the P2Y12 receptor to inhibit G-protein signalling. Is a reversible inhibitor of the platelet P2Y12 receptor
  2. rapid onset and offset (but may still inhibit platelets infused to pts who are bleeding) of effect (clopidogrel and prasugrel exhibit a slow inset and offset of action by comparison). Not a prodrug and does not require metabolic activation in liver
  3. Given in twice daily dosage (BD dosage)
  4. Offset of action
  5. Used in patients with acute coronary syndrome
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11
Q

Dipyridamole

  1. What type of drug is it?
  2. Outline it’s mechanism of antiplatelet action
  3. What is it’s only therapeutic use?
  4. What are the side effects?
A
  1. Is a pyrimidine derivative - antiplatelet and vasodilating action
  2. (1) inhibition of phosphodiesterase → ↑ cAMP
    (2) potentiation of adenosine

inhibition of platelet function → ↑ cAMP

(3) potentiation and enhanced synthesis of prostacyclin
3. with aspirin for TIA
4. headache, nausea, flushing, chest pain, dizziness, myalgia

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12
Q

Anti-platelet Drugs

  1. What is the most important side effect associated with this group?
  2. When is the risk of bleeding increased?
  3. What are the other common side effects?
  4. These need to be stopped before elective procedures, how long for?
    1. Aspirin
    2. Clopidogrel
    3. Ticagrelor
A
  1. Bleeding
  2. increases with use of drugs that also influence platelet function or haemostasis e.g. warfarin, NSAIDS, SSRIs etc
  3. dyspepsia, altered bowel habit, headache, dizziness
  4. Usually
    1. 5 days
    2. 1 week
    3. 2 days
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13
Q

Anti-platelet Drugs

Therapeutic Use

What is each of the following used for?

  1. Aspirin
  2. Clopidogrel
  3. Prasugrel/Ticagrelor

What are these drugs NOT useful in?

A
  1. secondary prevention e.g. post MI, still widely used for this indication
  2. monotherapy for occlusive vascular events e.g. post stroke, peripheral vascular disease
  3. use limited to acute coronary syndromes (STEMI/NSTEMI)

NOT useful in ATRIAL FIBRILLATION

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14
Q

Lipid Modifying Drugs

  1. What is treatment based upon?
  2. What are Statins effective for?
  3. Outline guidelines for treatment
A
  1. based on calculated CVD risk and not cholesterol levels
  2. Statins are effective for primary and secondary prevention of CVD
  3. UK guidelines set a treatment threshold of 20% ten-year CVD risk

Different CVD risk algorithms (e.g. Framingham, Q-Risk) that require information on age, gender, smoking status, BP, diabetes, lipid profile - further adjusted for family history and ethnicity

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15
Q

Lipid Modification and Cardiovascular Risk

  1. What are the key changes?
  2. What is the first line statin?
    1. What is it’s dose for primary prevention?
    2. Secondary prevention (clinical evidence of CVD)?
  3. What do NICE recommend?
A
  1. CVD risk calculated using QRISK2 risk calculator and 10 year CVD risk (not cholesterol level) at which treatment is offered reduced from 20% to 10%
  2. Atorvastatin
    1. ​20mg​
    2. 80mg
  3. They refer to HDL and non-HDL cholesterol i.e. and suggest a target of 40% reduction in non HDL-cholesterol
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16
Q

Assessing the Risk of CVD

  1. What is the QRISK2 assessment tool used for?
  2. When should it NOT be used?
  3. When might it underestimate value for CVD risk?
A
  1. to assess CVD risk for primary prevention (including type 2 diabetes mellitus) up to age 84
  2. Pre-existing CVD

Type 1 Diabetes Mellitus

Estimated glomerular filtration rate (eGFR)

Familial hypercholesterolaemia

  1. HIV (human immunodeficiency virus)

Drugs (steroids, antipsychotic drugs, immunosuppressants

Systemic lupus erythematosus

People taking antihypertensive or lipid lowering drugs

Severe obesity (BMI >40)

17
Q

Hypercholesterolaemia - Dietary Advice

Outline the key nutrients and their recommended intake per day

A
  • Total fat should be less than <25-35% total cals
  • Cholesterol <300 mg/day
18
Q

Lipid Measurement and Referral

  1. What measurements can be taken?
  2. When should familial hypercholesterolaemia be considered?
  3. If triglycerides > 20mmol/L what should be considered?
  4. If 10-20 mmol/L?
  5. When might CVD risk be underestimated?
A

1.

  • Measure full lipid profile (total cholesterol, HDL-C, non-HDL-cholesterol, triglycerides) non-fasting sample
  • HbA1C , renal function, LFTs, TSH (treat hypothyroidism as the cause if high cholesterol is present)
    2. total cholesterol >7.5mmol/L and family history of CVD
    3. dietary indiscretion, alcohol excess and uncontrolled diabetes
    4. As above, but repeat with a fasting sample
    5. If triglycerides 4.5 - 9.9 mmol/L
19
Q

Statins for the Prevention of CVD

  1. ​How are statins grouped?
  2. What should be carried out before commencing statins?
A
  1. NICE grouped statins into 3 different intensity categories (high, medium, low) based on percentage reduction in low density lipoprotein cholesterol
  2. perform baseline blood tests, clinical assessment, treat comorbidities and secondary causes of dyslipidaemia
20
Q

Statins

  1. What is their mechanism of action?
  2. What does it cause?
  3. What does this then activate?
  4. What is the final effect?
A
  1. hydroxy methylglutaryl CoA (HMG CoA) reductase inhibitors that competitively inhibit the activity of HMG CoA reductase, the rate limiting enzyme in cholesterol synthesis
  2. This causes a transient modest decrease cellular cholesterol concentration
  3. activates sterol regulatory element binding protein (SREBP), a transcription factor, that up-regulates the gene encoding for the LDL-receptor
  4. Increased LDL-receptor expression (70% in hepatocytes) i_ncreases uptake of plasma LDL thus decreasing plasma LDL concentration_
21
Q

Statins - Maintenance Doses

  1. What do both Atorvastatin and Simvastatin interact with?
A
  • Potent CYP3A4 inhibitors (including itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, and HIV protease inhibitors)
  • Ciclosporin*
  • Danazol
  • Verapamil, amiodarone
  • Diltiazem
  • Grapefruit juice
  • Warfarin/courmarins†
  • Fibrates†
  • Ezetimibe†

*Ciclosporin interacts with all statins and is contraindicated with rosuvastatin

†Warfarin/courmarins, fibrates, and ezetimibe are important potential interactions to consider for all statins

22
Q
A
23
Q

Follow-up of Patients on Statins

  1. What are the guidelines?
  2. What if there has been <40% reduction?
  3. What should be measured if there is complaint of muscle pain?
  4. When should LFTs be checked?
A
  1. Measure lipid profile again at 3 months

Aim for 40% or more reduction in non-HDL-cholesterol

  1. check lifestyle, adherence to medication and consider increasing dose
  2. Ask about adverse events and measure creatine kinase (stop if CK> x5 upper limit of normal)
  3. Check LFTs @ baseline, at 3 months and 12 months (stop if ALT > x 3 upper limit of normal)
    1. An alanine aminotransferase (ALT) test measures the amount of this enzyme in the blood. ALT is measured to see if the liver is damaged or diseased. Low levels of ALT are normally found in the blood. But when the liver is damaged or diseased, it releases ALT into the bloodstream, which makes ALT levels go up. Most increases in ALT levels are caused by liver damage.
24
Q

NICE Guidance for Primary Prevention of CVD

What are the guidelines for

  1. The general population?
  2. T1DM?
  3. T2DM?
  4. Chronic Kidney Disease?
A
  1. Lifestyle modification, Atorvastatin 20 mg if ≥ 10% 10 year risk of developing CVD - QRISK2\
  2. Atorvastatin 20mg if ≥ 40 years old, or have had diabetes ≥ 10 years, or have established nephropathy or other CVD risk factors
  3. Atorvastatin 20mg if ≥ 10% year risk of CVD
  4. Atorvastatin 20mg for 1⁰ or 2 ⁰ prevention of CVD

Increase dose if ≤ 40% decrease in non-HDL-C AND eGFR > 30mL/min

25
Q

NICE Guidance for Secondary Prevention
of CVD

​What is the guidance?

A

Lifestyle modification

Atorvastatin 80mg for secondary prevention of CV…..but

Use lower dose if potential drug interactions or high risk of adverse events

26
Q

Non-Cardiovascular Harms of Statins

What can statins cause?

A

Muscle Pain

Rhabdomyolysis - CK > x40 ULN associated with renal failure

Myositis - CK > x10 ULN

Myalgia - muscle pain with normal CK

27
Q

Summary of Trial Evidence for Muscle Pain

  1. What did the trial show?
  2. What are the weaknessess of the trial?
A
  1. Modest increase in risk of myositis/rhabdomyolysis - not myalgia

Usually higher dose statins or with concurrent use of drugs that increase drug levels

  1. Intolerant patients excluded from trials

Patients with CKD excluded from trials

However with rechallenge studies show the majority of patients can tolerate on the statin on rechallenge

28
Q

Non-Cardiovascular Harm

Outline some of the possible non-CV adverse effects

A
  • Diabetes - modest increase in incidence especially higher intensity statins
  • Liver - modest increase in ALT, asymptomatic, reversible and more common with high intensity statins
  • Cataracts - no robust evidence but “healthy participant” and prescription bias i.e. these patients more likely to take statins and less likely to develop medical problems (confounding)
  • Cognition - memory loss no robust evidence
  • AKI - association may be due to confounding by indication i.e. sicker patients receive the high dose statins
  • OTHERS: Possible link with COPD, pulmonary fibrosis, pancreatitis, fatigue, erectile dysfunction, cancer (evidence not robust)
  • SUMMARY: Benefits of statins outweigh harms
29
Q

Ezetimibe

  1. Outline it’s mechanism of action?
  2. What is it’s overall effect?
  3. When is it used?
  4. What are some side effects?
A
  • Scavenger receptor B1 inhibitor - influences intracellular cholesterol translocation
    • Initially developed as - Acyl-coenzyme A: cholesterol acyltransferase inhibitor then considered Neimann-Pick C1 receptor inhibitor - inhibit gut cholesterol absorption then considered
  • lowers LDL-cholesterol but has potential “off-target” effects that may negate benefit in reducing CVD events
    • To date no definite CVD benefit demonstrated with 10 mg daily
  • Monotherapy if statins contraindicated and/or truly intolerant to the drugs

In combination with statins if cholesterol insufficiently lowered by statins alone

  • Gastrointestinal disturbance, headache, fatigue, myalgia
30
Q

Other Lipid Lowering Drugs

What do NICE advise?

A

do not routinely offer fibrates, and

do not offer nicotinic acids, bile acid sequestrants or omega-3-fatty acids alone or in combination with statins

31
Q

Other Lipid Lowering Drugs - Fibrates

  1. What is their primary mode of action?
  2. What does this result in?
  3. What other effect does it have?
  4. What is the overall effect?
A
  1. by activating the nuclear transcription factor PPARα especially in liver and muscle
  2. Modulation of target genes increases activity of lipoprotein lipase and decreased synthesis of apo C-111 → ↓ VLDL and ↓ triglycerides
  3. ↓ liver fatty acid oxidation (↓ VLDL) and promote shift in density of LDL to more buoyant particle (less atherogenic)
    1. ↓ triglycerides 30-50%
  5. ↑high density lipoprotein 5-15%
32
Q

Other Lipid Lowering Drugs - Fibrates

  1. When are they used?
  2. What are they often used in combination with?
  3. What do they come as? How often are they taken?How?
  4. What are the side effects?
A
  1. As a 1st line therapy of triglycerides > 10 mmol/l
  2. often used in combination with statins in patients with diabetes and hypertriglyceridemia - but evidence of additional CVD protection is minimal
  3. Fenofibrate preparations (160-267mg) taken orally once daily
  4. Increased risk of myositis when combined with statin risk increases with renal impairment (reduce dose)
    * Gastrointestinal disturbance, cholestasis, headache, dizziness, weight gain*
33
Q

For general perusal

A

**STATINS are important, know these in detail**

Only others are ezetamibe and fibrins

Pharmacology (26 decks)

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