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Clinical Pharmacology, Therapeutics & Principles of Prescribing > Session 3: Cardiac arrhythmias/Lipid and cholesterol metabolism > Flashcards

Session 3: Cardiac arrhythmias/Lipid and cholesterol metabolism Flashcards

1
Q
  • Understand the basis of the heart’s electrophysiological control mechanisms
  • Understand the basic ways in which arrhythmias may occur
  • Be able to describe the targets of drug action on the cardiovascular system
  • Describe the classification of anti-arrhythmic drugs

• For the major classes of anti-arrhythmic drugs, know their:
o Mechanism of action

o Effect on the heart (incl. ECG)

o Common uses

o Common side-effects

• Know the preferred drugs for treating common cardiac arrhythmias

A
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2
Q

• Understand the basis of the heart’s electrophysiological control mechanisms LO

  1. To function efficiently, heart needs to ?
  2. How does relaxation differ in other muscles?
  3. Coordination of heartbeat is a result of a complex, coordinated sequence of changes in?
A
  1. Contract: sequentially (atria, then ventricles) & in synchronicity

Relax: between contractions

  1. Do not relax between contractions

Exhibit TETANY -> contract & hold contraction for certain length of time

  1. membrane potentials & electrical discharges in various heart tissues
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3
Q

Draw a normal ECG wave and label the segments and state what occurs in different parts

A
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4
Q

Arrhythmias

  1. What is an arrhythmia
  2. Tachycardia:
  3. Bradycardia:
  4. Heart condition where disturbances in:
  5. Results in ?
  6. A number of tests can help with diagnosis including?
A
  1. heartbeat is irregular, too fast, or too slow
  2. above 100 beats per minute
  3. below 60 beats per minute
  4. Arrhythmias are due to problems with the electrical conduction system of the heart.

– Pacemaker impulse formation
– Contraction impulse conduction
– Combination of the two

  1. Rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO)
  2. electrocardiogram (ECG) and Holter monito
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5
Q

There are four main types of arrhythmia:

A
  1. Extra beats -> premature atrial contractions, premature ventricular contractions, and premature junctional contractions
  2. Supraventricular tachycardias -> atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia
  3. Ventricular arrhythmias -> ventricular fibrillation & ventricular tachycardia
  4. Bradyarrhythmias
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6
Q

Draw the (ventricular) cardiac action potential

A
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7
Q

What is the effect of drugs Blocking Na channels?

A

Marked slowing conduction in tissue (phase 0)

Minor effects on action potential duration (APD)

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8
Q

Beta blockers

  1. What are they?
  2. Some block activation of all types of β-adrenergic receptorsand others are selective for one of the three known types of beta receptors, designated β1, β2 and β3 receptors.[5] β1-adrenergic receptors are located mainly in the ?

β2-adrenergic receptors are located mainly in the ?

β3-adrenergic receptors are located in ?

A
  1. Competitive antagonists that block the receptor sites for the endogenous catecholamines; adrenaline & noradrenaline on adrenergic beta receptors
  2. heart & kidneys
  3. lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle
  4. fat cells
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9
Q

Effect of beta-blockers of the AP

A

Diminish phase 4 depolarisation and automaticity

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10
Q

Draw the effect of drugs that block K channels on the cardiac AP

A

Increase action potential duration (APD)

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11
Q

Draw the effect of Calcium channel blockers on the cardiac AP

A

decrease inward Ca2+ currents

resulting in a decrease of phase 4 spontaneous depolarization

Effect plateau phase of action potential

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12
Q

Explain the AP in a cardiac myocyte

A
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13
Q

Draw the AP in the SAN

A
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14
Q

Draw the effect of Ca2+ channel blockers on the SAN AP

A
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15
Q
  1. What does automaticity mean?
  2. Draw the effect of drugs affecting automaticity on the SAN AP
A
  1. Automaticity is the cardiac cell’s ability to spontaneously generate an electrical impulse (depolarize). Cells that are dedicated to the purpose of generating an impulse to maintain a heart rate commensurate with the body’s need are called pacemaker cells
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16
Q

State how the SAN generates its own automaticity (session 4 CVS)

A
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17
Q

Describe the AP in the SAN

A
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18
Q

• Understand the basic ways in which arrhythmias may occur LO

State the Mechanisms of Arrhythmogenesis/Abnormal impulse generation: (4)

A

Triggered rhythms:
Early afterdepolarization
Delayed afterdepolarization

Automatic rhythms:

Ectopic focus -> AP arises from sites other than SA node

Enhanced normal automaticity -> ↑AP from SA node

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19
Q

State the causes of Abnormal conduction: (4)

A

Conduction block (This is when the impulse is not conducted from the atria to the ventricles)

1st degree

2nd degree

3rd degree

Reentry

Circus movement

Reflection

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20
Q

Explain how re-entry occurs

A

1-This pathway is blocked

2-The impulse from this pathway travels in a retrograde fashion (backward)

3-So the cells here will be reexcited (first by the original pathway and the other from the retrograde)

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21
Q

Abnormal anatomic conduction

Label the red arrow

A

Here is an accessory pathway in the heart called Bundle of Kent

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22
Q

What does the Bundle of Kent lead to?

A
  • Present only in small populations
  • Lead to preexcitation -> Wolff-Parkinson-White Syndrome (WPW)
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23
Q
  1. What is Wolff-Parkinson-White Syndrome (WPW)
  2. How does its ECG look?
  3. What does this result in ?
A

1.

2.

  1. Asymptomatic

paroxysmal supraventricular tachycardia

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24
Q

• Be able to describe the targets of drug action on the cardiovascular system LO

Action of drugs

Give a brief description of the drugs you would choose (in terms or mechanism) In case of abnormal generation & In case of abnormal conduction

A

In case of abnormal generation:

  • > Decrease of phase 4 slope (in pacemaker cells)
  • >Raises the threshold

In case of abnormal conduction:

↓conduction velocity (remember phase 0)
↑ERP (so the cell won’t be reexcited again)

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25
Q

Summary

  1. Arrhythmias occur due to:
  2. Drugs work to
A
  1. – Automatic or triggered activity
    – Re-entry due to scar, anatomy of pacemaker/WPW
    • Reduce abnormal impulse generation
      - Slow conduction through tissue
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26
Q
  • *Pharmacologic Rationale & Goals**
    1. Goal:
  1. Antiarrhythmic drugs are used to:
A
    • restore normal sinus rhythm and conduction
      - prevent more serious and possibly lethal arrhythmias from occurring
    • decrease conduction velocity
      - change the duration of ERP
      - suppress abnormal automaticity
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27
Q

• Describe the classification of anti-arrhythmic drugs LO

A

Class Drugs Action

I A. -> Moderate phase 0 -> Quinidine, procainamide

I B. -> No change in phase 0 -> Lidocaine

I C. -> Marked phase 0 -> Flecainide

II -> Beta-adrenergic blockers -> Propranolol, bisoprolol, esmolol

III -> Prolong repolarization -> Amiodarone, Sotalol Dofetalide, ibutilide

IV -> Calcium channel blockers -> Verapamil, diltiazem

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28
Q

• For the major classes of anti-arrhythmic drugs, know their:
o Mechanism of action

o Effect on the heart (incl. ECG)

o Common uses

o Common side-effects LO

Class 1A agents:

  1. Give examples
  2. Absorption and elimination
  3. Effects on cardiac activity
A
  1. Procainamide, quinidine, disopyramide
  2. (oral or iv)
  3. Dec conduction (dec phase 0 of the action potential (Na+))
    Inc refractory period (inc APD (K+) & inc Na inactivation)
    Dec automaticity (dec slope of phase 4, fast potentials)
    Inc increase threshold (Na+)

Quinidine has anticholinergic (atropine like action) to speed AV conduction used with digitalis, β blocker or Ca channel blocker

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29
Q

Class 1A:

  1. Effects on ECG:
  2. Uses

Quinidine:

Procainamide:

  1. Side effects
A
  1. Inc QRS, +/- PR, inc QT
  2. Wide spectrum:

Quinidine: maintain sinus rhythms in atrial fibrillation and flutter & to prevent recurrence, Brugada syndrome

Procainamide: acute IV treatment of supraventricular & ventricular arrhythmias

  1. -Hypotension, reduced cardiac output Proarrhythmia (generation of a new arrhythmia) eg.Torsades de Points (inc QT interval)
    - Dizziness, confusion, insomnia, seizure (high dose)
    - Gastrointestinal effects (common)
    - Lupus-like syndrome (esp. procainamide)
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30
Q

Class 1B agents:

  1. Examples
  2. Absorption and elimination
  3. Effects on cardiac activity
A
  1. Lidocaine, mexiletine,
  2. Lidocaine: iv only

Mexiletine: oral

  1. Fast binding offset kinetics

No change in phase 0 in normal tissue (no tonic block)

APD slightly decreased (normal tissue)

(Inc) increase threshold (Na+)
(Dec) phase 0 conduction in fast beating or ischaemic tissue,

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31
Q

Class 1B agents:

  1. Effects on ECG
  2. Uses
  3. Side effects
A
  1. None in normal, in fast beating or ischaemic (inc) QRS
  2. acute: VT (esp. during ischaemia)
    Not used in atrial arrhythmias or AV junctional arrhythmias
  3. Less proarrhythmic than Class 1A (less QT effect)

CNS effects: dizziness, drowsiness

Abdominal upset

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32
Q

Class 1C agents:

  1. Give examples
  2. Administration
  3. Effects on cardiac activity
A
  1. Flecainide and propafenone
  2. oral or iv
  3. very slow binding offset kinetics (>10 s)

Substantially decrease decrease phase 0 (Na+) in normal

Decrease automaticity (increase threshold)

Increase APD (K+) and increase refractory period, esp in rapidly depolarizing atrial tissue.

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33
Q

Class 1C agents:

  1. Effects on ECG
  2. Uses
  3. Side effects
A
  1. increase PR, increase QRS, increase QT
  2. Wide spectrum

Used for supraventricular arrhythmias (fibrillation & flutter)
Premature ventricular contractions (caused problems) Wolff-Parkinson-White syndrome

  1. Proarrhythmia and sudden death especially with chronic use (CAST study) and in structural heart disease

increase ventricular response to supraventricular arrhythmias (flutter)

CNS and gastrointestinal effects like other local anesthetics

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34
Q

How is conduction block treated?

A

pacemakers

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35
Q

Class II agents:

  1. Give examples
  2. Absorption and elimination
  3. Cardiac effects
  4. Effects on ECG
A
  1. propranolol, bisoprolol, metoprolol and esmolol
  2. Propranolol:

PO: 10–40 mg 3–4/day

IV: 1 mg, to be given over 1 mi, dose may be repeated if necessary at intervals of 2 mins, maximum 10 mg per course (5 mg in anaesthesia).

Metoprolol 5mg IV, orally too (shorter acting BD or TDS regime)

bisoprolol: oral

Esmolol: iv only (very short acting T½, 9 min)

  1. (inc) APD and refractory period in AV node to slow AV conduction velocity
    (Dec) decrease phase 4 depolarization (catecholamine dependent)
  2. Inc PR, dec HR
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36
Q

Class II (cont.)

  1. Uses:
  2. Side effects:
A

1.treating sinus and catecholamine dependent tachycardia

converting reentrant arrhythmias at AV node

protecting the ventricles from high atrial rates (slow AV conduction)

    • bronchospasm
      - hypotension
      - don’t use in partial AV block or ventricular (heart) failure
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37
Q

Class 1 agents very rarely used

A
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38
Q

Flecainide cannot be used if patients with?

A

CAD/MI etc should not have flecainide Class 1C

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39
Q

Class III agents:

  1. Give examples
  2. Administration
  3. Cardiac effects
  4. Effects on ECG
A
  1. amiodarone, sotalol
  2. Amiodarone - oral or iv (T 1/2 about 3 months)
  3. Inc increase refractory period and inc APD (K+)

Dec phase 0 and conduction (Na+)

Inc threshold

Dec phase 4 (β block and Ca++ block)

Dec speed of AV conduction

  1. Inc PR, inc QRS, inc QT, dec HR
40
Q

Asthma and beta blockers should not be used

41
Q

Amiodarone (cont.)

  1. Uses
  2. Side effects:
A
  1. Very wide spectrum: effective for most arrhythmias
  2. many serious that increase with time

-Pulmonary fibrosis

  • Hepatic injury
  • Increase LDL cholesterol
  • Thyroid disease
  • Photosensitivity optic neuritis (transient blindness) 1/10,000

May need to reduce the dose of digoxin and monitor warfarin more closely

Dronaderone (no iodine) not widley used despite new drug, failed to live up to expectation

42
Q

Sotalol

  1. Administration
  2. Cardiac effects
  3. ECG effects
  4. Uses
  5. Side effects
A
  1. oral
  2. Inc APD and refractory period in atrial and ventricular tissue

Slow phase 4 (β blocker)

Slow AV conduction

  1. Inc QT, dec HR
  2. Wide spectrum: supraventricular and ventricular tachycardia
  3. Proarrhythmia, fatigue, insomnia
43
Q

Class IV agents:

  1. Give examples
  2. Administration
  3. Cardiac effects
  4. Effects on ECG
A
  1. verapamil & diltiazem
  2. verapamil: oral or i.v.
    diltiazem: oral

3.slow conduction through AV (Ca++)
Inc refractory period in AV node
Inc slope of phase 4 in SA to slow HR

  1. Inc PR, inc/dec HR (depending of blood pressure response & baroreflex)
44
Q

Class IV (cont.)

  1. Uses
  2. Side effects
A
  1. control ventricles during supraventricular tachycardia convert supraventricular tachycardia (re-entry around AV)
  2. Caution when partial AV block is present.

Can get asystole if β blocker is on board

Caution when hypotension, decreased CO or sick sinus

Some gastrointestinal problems

(Never be used together because you need a pacemaker)

45
Q

Additional antiarrhythmic agents

Adenosine

  1. Administration
  2. Mechanism
  3. Cardiac effects
  4. Uses
A
  1. rapid i.v. bolus, very short T1/2 (seconds)
  2. natural nucleoside that binds A1 receptors and activates K+ currents in AV & SA node dec APD, hyperpolarization → dec HR
    Dec Ca++ currents - inc refractory period in AV node
  3. Slows AV conduction
  4. Convert re-entrant supraventricular arrhythmias hypotension during surgery, diagnosis of CAD
46
Q

Additional antiarrhythmic agents

Vernakalant

  1. Administration
  2. Mechanism
  3. Cardiac effects
  4. Side effects
  5. Uses
A
  1. i.v. bolus over 10 minutes
  2. blocks atrial specific K+ channels (outward channel class 3)
  3. slows atrial conduction

↑ potency with higher heart rates

  1. Hypotension, AV block

sneezing and taste disturbances

  1. convert recent onset atrial fibrillation to normal sinus rhythm
47
Q

Ivabradine

  1. Administration
  2. Mechanism
  3. Cardiac effects
  4. Side effects
  5. Uses
A
  1. orally in 2.5mg bd dosing up to 10mg bd
  2. blocks If ion current highly expressed in sinus node
  3. slows the sinus node but does not affect blood pressure
  4. flashing lights teratogenicity not known (avoid in pregnancy)
  5. reduce inappropriate sinus tachycardia

reduce heart rate in heart failure and angina
(avoiding blood pressure drops)

48
Q

Digoxin (cardiac glycosides)

  1. Mechanism
  2. Uses
A
  1. enhances vagal activity (inc K+ currents, dec Ca++ currents, inc refractory period)

Slows AV conduction and slows HR

  1. treatment to reduce ventricular rates in atrial fibrillation & flutter

Mechanism:

Extended refractory period:
Inhibition of the sodium potassium adenosine triphosphatase (Na+/K+ ATPase),
Inc intracellular Na+
Inactivate Na/Ca2+ exchanger
Inc Ca2+
lengthens phase 4 and phase 0 of the cardiac action potential, which leads to a decrease in heart rate -> AF! Check lecture

Enhances vagal activity para (centrally) at AV node

49
Q

Atropine

  1. Mechanism
  2. Cardiac effects
  3. Uses
A
  1. selective muscarinic antagonist
  2. block vagal activity to speed AV conduction and increase HR
  3. treat vagal bradycardia
50
Q

Which drugs in AF?

A

• Rate control:
– Bisoprolol, verapamil, diltiazem + digoxin

• Rhythm control:
– Sotalol, flecainide with bisoprolol, amiodarone
– (dronedarone hardly used)

51
Q

Which IV drug for VT?

A

Depends on what drugs already prescribed (depends on ectopic or scar)
– Metoprolol

– Lignocaine IV

– amiodarone IV

​

52
Q

Should flecainide be used alone in atrial flutter?

A

• No
– Give AV nodal blocking drugs to reduce ventricular rates in flutter

Want to use a drug visopral vramprimal which blocks the conduction through the AV node so if they do go into flutter

​

53
Q

Best drug for treatment WPW?

A
  • Flecainide (oral or IV if in tachycardia)
  • amiodarone
54
Q

List drugs that could be used in re-entrant SVT?

A

• Acutely (IV)
– Adenosine
– Verapamil
– flecainide

• Chronic (repeated episodes, orally)
– Bisoprolol, verapamil
– sotalol
– Flecainide, procainamide
– amiodarone

55
Q

Which drugs for ectopic beats?

A
  • Bisoprolol (1st line)
  • Flecainide, sotalol or amiodarone (no ischaemic HD or structural HD)
56
Q

Which drugs to treat sinus tachycardia?

A
  • Ivabradine ((Effects conduction through SAN)
  • Bisoprolol, verapamil

​

57
Q
  • Understand the role of lipids in the pathophysiology of atherosclerosis (path)
  • Recognise the potential for pharmacological manipulation of lipid metabolism
  • Understand role of cholesterol lowering in preventing cardiovascular events
  • Recognise the main drug groups used in reducing LDL cholesterol
  • Recognise the potential for non-drug dietary approaches to lipid lowering
  • Learn how to undertake a CV Risk Assessment

• Understand the key clinical trials & NICE guidance pertaining to lipid-lowering
drug prescribing

58
Q

• Understand the key clinical trials & NICE guidance pertaining to lipid-lowering
drug prescribing LO

What is the The Framingham Study

59
Q

Using this graph and your own knowledge, how can this information help us?

A

10% reduction in total cholesterol results in:
– 15% reduction in CHD mortality (p<0.001)
– 11% reduction in total mortality (p<0.001)

60
Q

What type of cholesterol is the primary target to prevent CHD?

A

LDL cholesterol

61
Q

What are the risk factors for CAD

A

Serum cholesterol -> the highest risk

62
Q

• Understand the role of lipids in the pathophysiology of atherosclerosis (intimal thickness ≥0.5 mm) LO

  1. What are the pro-atherogenic effects of Ox-LDL?
A
  • Inhibits macrophage motility
  • Induces T-cell activation and VSMC division / differentiation
  • Toxic to endothelial cells
  • Enhances platelet aggregation
66
Q

When you increase BMI what fat are you increasing?

A

TAG

Inc conc of cholesterol then plateau

67
Q

What are the Old Classes of Lipid Lowering Drugs

A

● Statins - simvastatin
● Cholesterol lipase inhibitors - ezetimibe
● Nicotinic acid / niacin
● Fibrates – fenofibrate
● Resins - colestyramine
● Omega-3 fatty acids - omacor
● ? Plant sterols

68
Q

How do statins work?

A

Statins
• Inhibit cholesterol synthesis in hepatocytes

  • Increase clearance of IDL and LDL
  • Decrease production of VLDL & LDL

Indications: CV risk Prevention (CVD + DM)

Familial Hypercholesterolaemia

69
Q

Describe how they inhibit cholesterol synthesis

A

Inhibit HMG-CoA reductase

70
Q

Increase clearance of IDL and LDL

A

Increase synthesis of LDL Receptor -> descrease Serum LDL Cholesterol

71
Q
  1. State the adverse drug reactions of statins
A

Increased transaminase levels

  • 0.1%-2.5% of treated patients develop increases of >3 x upper-normal limit, especially at higher doses
  • Rapidly reversible, no evidence of chronic liver disease

Myopathy

  • Diffuse muscle pain and CPK > 10 x upper-normal limit
  • Primarily seen when higher doses of statins are used in combination with cyclosporine, gemfibrozil, and occasionally erythromycin and niacin

Miscellaneous

• Gastrointestinal complaints, arthralgias (joint pain), & headaches

72
Q

Some secondary benefits of Statin treatment

A

● Anti-inflammatory
● Plaque reduction
● Improved endothelial cell function
● Reduced thrombotic risk

​

73
Q

• Learn how to undertake a CV Risk Assessment LO

  1. Statin therapy is recommended as part of the management strategy for the primary prevention of CVD for adults who have a ?
  2. This level of CVD risk should be estimated using?
  3. What does QRISK2 ask?
  4. Treatment involves Lipid Mx (lipid modification). How do we do this?
  5. How do we monitor the patient?
A
  1. 20% or greater 10-year risk of developing CVD
    • risk calculator -> Now use a desktop or internet calculator e.g. Qrisk2
      - or by clinical assessment for people for whom an appropriate risk calculator is not available (for example, older people, people with diabetes or people in high-risk ethnic groups).
  3. Cardiovascular Risk Tables - BNF (look at image)
  4. ● Offer atorvastatin 20 mg for the primary prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD. Estimate the level of risk using the
    * *QRISK2** assessment tool.

● Start statin treatment in people with CVD with atorvastatin 80 mg. Use a lower dose of atorvastatin if any of the following apply: potential drug interactions; high risk of adverse effects; patient preference

● Aim for > 40% reduction in non-HDL cholesterol. If not achieved:

– discuss adherence & timing of dose

– optimise adherence to diet and lifestyle measures

– consider increasing dose if started on less than atorvastatin 80 mg and the person is judged to be at higher risk

  1. Blood plasma cholesterol over 40% reduction

CKP >X10

74
Q

Are all Statins the same ?

A

Cerivastatin -> DO NOT RECOMMEND DRUG TO DRUG INTERACTION

Atorvastatin -> RECOMMEND

75
Q

Fibric Acid Derivatives

  1. Structure
  2. Mechanism of action
  3. How does it effect the levels of cholesterol?
A
  1. Ampipathic carboxylic acids
  2. PPARα (Peroxisome Proliferator-Activated Receptor) agonist -> increases production of lipoprotein lipase
    – Reduces triglyceride production +++
    – Improved postprandial (after dinner/lunch) triglyceridemia?
  3. Reduces TAG

Some reduction (10-20%) in LDL but variable, depending on specific drug

Increase HDL

77
Q

Mechanism of action of fibric acids

A

Increases fatty acid uptake and oxidation

Reduces triglyceride levels

Increases LDL particle size and HDL-C levels

Direct vascular effects

● PPAR α (Peroxisome Proliferator-Activated Receptor) agonist - increases production of
lipoprotein lipase
– Reduces triglyceride production +++
– Improved postprandial triglyceridemia?
● Some reduction (10-20%) in LDL but variable, depending on specific drug

78
Q
  • *Fibric Acid Derivatives**
    1. Indications (used when?):
  1. Efficacy (use results in?):
  2. Side Effects:
  3. Contraindications (reasons you should withhold treatment?):
  4. Intervention Trials:
A
    • Adjunctive therapy to diet
      - Hypertriglyceridemia
      - Combined hyperlipidemia with low HDL who do not respond to NA
  2. Decreases TG 25-50%

LDL decreases, but varible

Increases HDL 15-25% in hypertriglyceridemia

  1. GI upset (8%), cholelithiasis, myositis,

Abnormal LFTs

  1. Hepatic or renal dysfunction

Pre-existing gallbladder disease

  1. Helsinki Heart Study, LOCAT, BECAIT, VAHIT, BIP
79
Q

• Understand the key clinical trials and NICE guidance pertaining to lipid-lowering drug prescribing LO

Describe the results from the Bezafibrate Infarction Prevention Trial (BIP)

80
Q
A

Should decrease outcome ??

81
Q

Nicotinic Acid

  1. Mechanism of action/ efficacy?
  2. Adverse effects
  3. Contraindications (condition or factor that serves as a reason to withhold a certain medical treatment due to the harm that it would cause the patient)
A
  1. • Reduces VLDL and increases HDL at high doses
  • Best agent to raise HDL-C
  • Lipid lowering effect by inhibition of lipoprotein (a) synthesis
  • Reduces coronary events (Coronary Drug Project)
  1. • Flushing, itching, headache ( reduced by immediate-release, Niaspan® or combination with low-dose aspirin)
  • Hepatotoxicity, GI (sustained-release)
  • Activation of peptic ulcer
  • Hyperglycemia and reduced insulin sensitivity
  1. • Active liver disease or unexplained LFT elevations

• Peptic ulcer disease

82
Q

Ezetimibe:

  1. Mechanism of Action
  2. Ezetimibe and its active glucuronidemetabolite circulate enterohepatically, why?
  3. ADRs:
A
  1. • Ezetimibe selectively inhibits intestinal cholesterol absorption
  • ↓ intestinal delivery of cholesterol to the liver
  • ↑ expression of hepatic LDL receptors
  • ↓ cholesterol content of atherogenic particles
  1. • Delivers agent back to the site of action

• Limits systemic exposure

  1. headache, abdominal pain and diarrhoea

Drug of choice when patients cannot tolerate statin therapy i.e adverse reaction rhabdomyolisis

83
Q

What do we mean by combination therapy?

A

Statin plus:
• Fibrate (not gemfibrozil)
• Nicotinic acid
• Ezetimibe
• Omega-3 FAs
• (Resins)

Consider:
• Benefit (CV risk reduction)
• Cost
• ADRs

84
Q

Give an example of a PPAR-α Agonists

85
Q

Clinical significance of using fibrates as an adjuvant drug with stations for combination therapy

A

PPAR-α Agonists (Fibrates) and Statins

● Combination fibrate and statin therapy may significantly improve triglyceride, LDL-C, and HDL-C levels

● BUT… Fibrates plus statins are associated with increased risk for myopathy & rhabdomyolysis
– Not thought due to cytochrome P450 drug interaction

– Gemfibrozil may impair glucuronidation of statins (with cerivastatin being more susceptible than other statins such as simvastatin and atorvastatin)

– Fenofibrate appears to have less potential for impairment of statin metabolism, and thus this may account for the reduced reports

86
Q

Complete the name of the drug used to lower cholesterol

? Inhibitor

A

PCSK9 inhibitors

87
Q

Explain how PCSK9 inhibitors work

88
Q

• Understand the key clinical trials and NICE guidance pertaining to lipid-lowering drug prescribing LO

● Evolocumab (Repatha, Amgen) is a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).

● Evolocumab has a marketing authorisation in the UK for treating adults with primary hypercholesterolaemia (heterozygous-familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet.

● The annual cost of treatment per patient is about £4,422.60 for 140 mg every 2 weeks

89
Q

• Recognise the potential for non-drug dietary approaches to lipid lowering LO

If the patient does not want to take tablets what can they take/ do to reduce their cholesterol? (7)

A

Plant sterols -> pro- active

Other dietary factors:
● Positive:
– Fish oils
– Fibre
– Vitamin C / E
– Alcohol (HDL)
● Negative:
– Dietary cholesterol / fat
– Alcohol (TG)

91
Q

What you should know
● Mechanism of action, indication and ADRs of major classes of lipid lowering drugs
● Some of the evidence base supporting the use of this treatment in CV disease
● An appreciation of the new NICE guidance and how this might impact on current medical practice
● The information that you would give a patient to support their decision to consider this
treatment

92
Q

What are the principle difference between cardiac muscle, vascular smooth muscle and voluntary muscle regarding dependency on Ca for contraction?

A

Cardiac: extracellular (more important) and intracellular if you got low calcium in terms of cardiac muscle more imp as have a high dependence on external Ca2+ -> Action potentials
Skeletal: intracellular sarcoplasmic
Smooth: intracellular mito

93
Q

Case History - Arrhythmias A 55-year old woman with known mild mitral valve disease is admitted via A&E having collapsed in Tescos while shopping. She is found to have a pulse rate of 150 beats per minute, which is irregularly irregular. Blood pressure is 120/65. She is otherwise quite comfortable. Blood tests performed are normal except for a raised serum creatinine of 150 mmol/l (normal < 120 mmol/l)
1. What is the most likely cause of her arrhythmia?

  1. How would you confirm the diagnosis?
  2. What drug treatments would you consider, what are their mechanisms of action and how can they be administered?
    You decide to give her digoxin
  3. How would you administer it and how would decide on a dosing regimen?
  4. What are the potential hazards of the use of digoxin in this patient and what precautions would you take?
A
  1. AF -> irregularly irregular
  2. ECG
  3. • Rate control:
    – Bisoprolol, verapamil, diltiazem + digoxin
    • Rhythm control:
    – Sotalol, flecainide with bisoprolol, amiodarone
    – (dronedarone hardly used)

Only do one
Even if you give beta blocker still be in AF just lower HR not treating rhythms
Risk factor for strokes
Need to check co-morbidities

  1. IV- severe
    oral - ok
    -combination of drugs

Loading dose 50% initially -> dose at which you would actually get a therapeutic response
Monitor [K+]

  1. RAISED CREATININE -> NARROW THERAPUETIC WINDOW -> seeing yellow -> toxicity
    Palpitations
    Nausea
    Vomiting
    Diarrhoea
94
Q

Give some reasons for using lipid-lowering therapy and list the drugs relevant to that indication?

A

Reduce CVD outcome
More effective then diet modifying

95
Q

What factors lead to an increased risk of this ADR?

A

Taking other drugs ALSO metabolised by the cytochrome P450
Past history of myopathy

Clinical Pharmacology, Therapeutics & Principles of Prescribing (19 decks)

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