L8.2 Ischemic heart disease

Question 1

How is coronary flow increased?

Answer 1

• Prolonged diastole → increases oxygen supply to the heart (coronary blood travels with diastole)
• Dilate coronary A

Question 2

What is O2 demand dependent on?

Answer 2

• CO (workload)
• Preload (compliance)
• Afterload (resistance)

Question 3

Definition of angina?

Answer 3

• Imbalance b/w o2 demand and supply
• Insufficient O2 to meet cardiac demand (due to lack of perfusion)

Question 4

What are the 3 types of angina?

Answer 4

• Stable angina (classic)
  
  • Chest pain with exertion/stress (demands met at rest)
  • Associated with coronary A disease
• Variant angina (vasospastic)
  
  • Coronary vasospasm at rest
  • Mediator unknown
    
    • Cannot treat well
• Unstable angina (crescendo)
  
  • Angina at rest and with effort
  • Potential for thrombus formation

Question 5

Features of stable angina?

Answer 5

• Normally → dilation of A during exercise to increase flow to meet demands
• Angina occurs due to → already dilated at rest, no reserve dilation (due to low compliance) during exercise
  
  • Increase O2 demands not met with increase BF

Question 6

Aims of prevention for stable angina?

Answer 6

• Prevent attacks/relieve symptoms/prevent progression to MI
• Use drugs to increase O2 supply (hard → cannot increase arteriole size) & decrease O2 demand

Question 7

Treating stable angina - by increase O2 supply

Answer 7

• Dilate coronary A
  
  • Hard → may already be maximally dilated and has low compliance
• Reduce HR
  
  • Longer diastole phase → coronary A have longer time to fill

Question 8

Treating stable angina - by decreasing O2 demands

Answer 8

• Decrease CO (ß-adrenoceptor antagonists/Ca channel blockers/ivabradine(targets HR specifically))
  
  • Decrease HR & SV
• Reduce preload (nitrates)
  
  • Dilate veins/reduce venous return
• Reduce afterload (Ca channel blockers)
  
  • Dilate arterioles, decrease resistance for heart to pump against

Question 9

Mechanism of nitrates

Answer 9

Question 10

Features of Nitrate

Answer 10

• Is usually a prodrug
• Mimicks endogenous procress (releasing NO)
  
  • Guanylate cyclase → GTP into cGMP → MLC (myosin light chain) dephosphorylate form (unable to interact with actin) → vascular relaxation
• Nitrates can affect all vessels
  
  • Predominant effect on the veins (decrease preload through vasodilations)

Question 11

GTN

Answer 11

• short acting
• Routes of administration
  
  • Undergo significant first pass metabolism (cannot be taken orally)
  • Taken sublingually → to relieve acute attack
  • Transdermal patch → for prophylaxis (prevention)
  • I.v. → for emergency
• Unstable drug
  
  • Cannot be stored in plastic (absorbed by plastic → decrease activity) and has to be stored in the dark

Question 12

Isosorbide dinitrate

Answer 12

• longer acting
• Used orally for anticipation of effort or prophylaxtically

Question 13

Nitrate SE

Answer 13

• Brief relaxation of gut/airways (not much clin significance)
• Postural hypotension (form venous pooling)
• Headache/flushing - from arterial dilations
• Small reflex tachycardia
  
  • Usually used in combination with b-blockers or Ca channel blockers to minimise effect

Question 14

Nitrate drug interactions

Answer 14

• Viagra is a phosphodiesterase inhibitor
  
  • Phosphodiesterase breaks down cGMP
  • Viagra + GTN → significant cGMP levels → too much venousdilation → may have fatally low VR

Question 15

How does tolerance of nitrates develop

Answer 15

1. Classic mechanism involves depletion of tissue thiols required for NO production from GTN
2. Increase sensitivity of other constrictors (e.g. ANGII/A)
3. Increase endothelial free radical production scavenging NO → reduce NO bioavailability
4. Reduced acitivity of muscle mitochondrial enz → decrease NO production and increase free radicals

Tolerance develops with continuous use

Question 16

How can tolerance with nitrates be prevented/attenuated?

Answer 16

• Need to maximise drug-free period (i.e. remove patch over night/period of non-exercise)

Question 17

Ca channel blockers

Answer 17

• Used prophylactically
• Blocks Ca entry into the heart via L-type channel blocking
  
  • Decrease HR → Increase supply
  • Decrease CO/SV/HR → decreases demands
    
    • Verapamil
• Nifedipine → selective for vasculature
  
  • Leads to arterial dilation → reduce afterload and demands

Question 18

Mechanism of Ca channel blockers

Answer 18

• *MLCK important for phosphorylation of MLC

Question 19

SE of verapamil and nifedipine

Answer 19

Verapamil

• Constipation, flushing/headache/oedema (vasodilation)
• Bradycardia, AV block (acts on heart)
• NEVER taken with ß-blockers

Nifedipine

• Flushing/headache/oedema
• Hypotension (from arteriole dilations)
• Reflextachycardia (from hypotension)

Question 20

B-blockers

Answer 20

• Acts to block the effect of SNS
• Receptors located on the SA, AV nodes → decrease HR/SV/CO
  
  • Decrease workload of heart
  • Increases O2 supply (from decrease HR)
• First-line therapy for prophylaxis
  
  • Atenolol (selective ß1)
  • Propranolol (non-selective)

Question 21

Ivabradine

Answer 21

• Selective for reducing HR (doesn’t have cardio-depressive effects)
• Specific channels within SA node → I-f channel (which causes NA influx into cell)
  
  • Inhibition leads to increase time taken for AP to reach threshold → reduces HR
• Disease-modifying by increasing O2 supply and decrease O2 (from decrease HR)
  
  • Reduces risk of MI, and need for revascularisation
  • No reduction if HR<70bpm

Question 22

Ivabradine SE

Answer 22

• Channels also found in retina → brightness in visual fields
• Conduction abnormalities
• Long-term benefits/risks have been established

Question 23

Overview of the treatment for stable angina

Answer 23

Question 24

Treatment of variant angina

Answer 24

• Treatment: GTN (Short acting)
  
  • To relieve vasospasm
  • Prophylaxis with dihydropyridine Ca channel blocker (i.e. Nifedipine)
  • Contra-indicated with ß-antagonist (potentially increase freq/severity of attacks)

Question 25

Treatment for unstable angina

Answer 25

• Treatment same as classic angina
• Include aspirin for prevention of thrombosis

Question 26

Risk factor reduction and prevention of heart diseases

Answer 26

Stop smoking

Increase physical activity & losing weight

Treat hypertension/dyslipidaemia/diabetes

Question 27

When is revascularisation used

Answer 27

• When other treatments fails:
  
  • Percutaneous coronary intervention
  • Bypass graft