Pharmacology of the CVS

Question 1

Quantitatively describe the effects of angina pectoris

Answer 1

• 2 million sufferers in the UK
• annual risk of death (usually MI) of 4 - 6%
• Quality of life impacted

Question 2

What causes angina pectoris?

Answer 2

Caused by local myocardial Ischaemia

• when oxygen demand exceeds supply
• often precipitated by exertion; reversible at rest

Question 3

Outline the symptoms of Angina Pectoris

Answer 3

• Crushing chest pain (or in jaw, shoulders ,arms)
• Ischaemic products (H+, lactate)
  -> stimulate nociceptive afferents
• may be associated with shortness of breath, sweating
  and nausea

Question 4

What is the risk of angina increased by?

Answer 4

Increased Systolic BP (afterload)
Increased sympathetic nerve activity
Increased Contractility
Increased vasoconstriction

Question 5

Explain how increased afterload increases risk of angina

Answer 5

Heart has to work harder to eject blood; requires more oxygen

Question 6

How does increased sympathetic activity cause angina?

Answer 6

Less diastolic time

Less coronary artery perfusion which only occurs in systole

Question 7

What causes increased contractility?

Answer 7

exercise
emotion
stress
aortic valve stenosis

=> all increase Oxygen demand

Question 8

Give an example of how increased vasoconstriction trigger angina?

Answer 8

e. g.
- Redistribution of blood flow in cold weather
- During large meal blood diverted to GI
etc.

=> vasoconstriction in coronary circulation

Question 9

What are the different types of angina?

Answer 9

Stable Angina
Unstable Angina
Variant (prinzmetal) Angina

Question 10

Describe the pathology of Stable angina

Answer 10

most common form
- exercise induced: predictable can work out how much
exertion induces symptoms

• not able to meet increased oxygen demand due to
  atheroma in coronary arteries
• relieved by rest and medications

Question 11

Describe unstable angina

Answer 11

• induced due to minimal exertion; unpredictable
• rest and medications may not relieve symptoms
• may indicate thrombosis / plaque rupture

Question 12

Outline the features of Variant (prinzmetal) angina

Answer 12

• symptoms at rest
• decreased oxygen supply due to vasospasm
  (uncontrolled vasoconstriction decreasing blood flow)
  downstream of occlusion

Question 13

How are the different forms of angina detected?

Answer 13

All linked to acute coronary syndrome (coronary thrombosis)

- ECG will show STEMI

Question 14

Describe the effect of stable angina during normal activity

Answer 14

In exercise, metabolic vasodilation of arterioles reduces resistance to increase blood flow to meet increased oxygen demand

Question 15

Describe the effects of stable angina during exercise

Answer 15

Stenosis in coronary arteries increases resistance
at rest metabolic vasodilation occurs as normal

However/
during exercise arterioles may attempt further dilation but TPR is still too high - Oxygen demand can’t be met; angina develops

Question 16

What are the aims of angina treatment?

Answer 16

Improve prognosis

• prevent MI + death
• reduce plaque progression - stabilise it
• prevent thrombosis

Minimise symptoms
- improve quality of life

Question 17

What are the approaches to angina treatment?

Answer 17

Vasodilators: Nitrates
Cardiac depressants: Beta Blockers
Both: Ca2+ blockers

Question 18

Explain how ꞵ Blockers aid angina treatment

Answer 18

Reduce action of sympathetic activity (NA and adrenaline) on ꞵ₁ adrenoceptors in the heart causing:

• Slow HR and AV conduction
• Reduced force of Contractility

Question 19

What is the effect of slowed HR and AV conduction?

Answer 19

Increased diastolic time - increases coronary artery perfusion
Both of these factors mean more energy is required and ∴ a greater oxygen demand

Question 20

What is the effect of a reduced force of contractility?

Answer 20

Reduces myocardial work and oxygen consumption

Question 21

Name an example of a ꞵ-blocker drug used to treat high BP

Answer 21

Atenolol

more ꞵ₁ selective - ꞵ₂ found in vasculature & airways

Question 22

Describe the side effects of using atenolol

Answer 22

Bronchospasm
Fatigue
Postural hypotension

Question 23

Evaluate the use of ꞵ₁ selective drugs

Answer 23

Advantage:
ꞵ₁ selective is better as reduces side effects of ꞵ₂ e.g. bronchospasm (but is still not perfect)

Disadvantage:
Blocking ꞵ₁ causes fatigue as heart rate / force of contraction can’t be increased

Question 24

When is the use of ꞵ blockers such as Atenolol contraindicated?

Answer 24

Asthma
- don’t want to block ꞵ₁ as will cause bronchospasm

Heart blockage:

• already poor perfusion between atria and ventricles
• don’t want to block AV conduction further via AV node

Question 25

Explain how Ca2+ channel blockers provide anti-anginal effects

Answer 25

Reduces contractility by reducing Ca2+ entry into cardiac myocytes / vascular smooth muscle cells

Question 26

Describe the effects on the CVS of Ca2+ channel blockers

Answer 26

Direct coronary vasodilation ∴ more coronary blood flow

Reduced TPR/BP/afterload ∴ heart works less hard to eject blood

Reduced force of contraction ∴less oxygen consumption

Question 27

What are the 3 different sub types of Ca2+ channel blockers?

Answer 27

Vascular
- dihydropyridines e.g; amplodipine, nifedipine

Cardiac
- Benzothiazepines e.g; Verapamil

Both
- Diphenylalkyamines e.g; Diltiazem

Question 28

What are the side effects of dihydropyridines?

Answer 28

lower limb oedema due to increased Pc
Flushing and headaches due to vasodilation
Reflex tachycardia

Question 29

How do dihydropyridines cause reflex tachycardia?

Answer 29

Dihydropyridine induced vasodilation causes increased sympathetic activity (baroreflex) HR/Contractility - negative in angina

Question 30

What is a major caution of using Ca2+ channel blockers in the heart?

Answer 30

Blocking Ca2+ channels in the heart may alter electrical conduction and contractility

Question 31

How is NO produced / donated in the body?

Answer 31

1. ENOS - endothelium NO synthesis
   
   • conversion of L-arginine -> NO
2. NO donors cause dilation of smooth muscles
3. NO -> cGMP -> PKG / GMP via PDE5

Question 32

What is NO production / donation stimulated?

Answer 32

Shear stress
ACh
Histamine
Bradykinin

Question 33

Describe some essential features of NO gas

Answer 33

Lipophilic, soluble gas
Continually produced and released
Diffusible endothelium -> surrounding vascular smooth myocytes

Question 34

What is the effect of Protein Kinase G (PKG) produced from NO on CVS?

Answer 34

PKG reduces smooth muscle tone:
- via myosin light chain dephosphorylation
- increased Ca2+ uptake by SR, decreasing cytoplasmic
levels
- activates K+ channel s causing hyperpolarisation ->
closing VGCCs

Question 35

Where does vasodilation occur?

Answer 35

Coronary artery and veins

Question 36

What is the effect of coronary artery dilation?

Answer 36

Coronary artery dilation:

• reduces TPR
• decreasing afterload
• increases collateral arteriole dilation
• shunts blood from areas of good perfusion

Question 37

What is the effect of venodilation?

Answer 37

Decreases intraventricular pressure to decrease cardiac preload

Question 38

Give examples of drugs used to cause vasodilation

Answer 38

GTN (glyceryl trinitrate)
- spray, sublingual tablets

Isosorbide mononitrate

• oral, longer acting
• high oral dose (1st pass metabolism by liver)

Question 39

Name other anti-anginal drugs

Answer 39

Nicorandil
Ivabradine
Ranolazine

Question 40

Explain the effects of Nicorandil

Answer 40

K+ channel activator
causes hyperpolarisation; decreased VGCCs and Ca2+ entry -> coronary vasodilation
Has nitrate moiety ∴ has venodilation action via NO production

Question 41

Describe the effects of Ivabradine

Answer 41

Specific If current inhibitor in SAN - slows HR

• Decreases pacemaker potential frequency
• Decreases HR reducing myocardial oxygen demand

Question 42

Explain the effects of anti-anginal drug, Ranolazine

Answer 42

Late Na+ current inhibitor 
reduces Ca2+ in ischaemic myocardiocytes
reduces Oxygen demand 
reduces compression of small intra-myocardial vessels 
-> improves myocardial perfusion

Question 43

Name some prophylactic angina drugs

Answer 43

Aspirin
Clopidogrel
Statins

Question 44

Explain the effects of Aspirin on Angina

Answer 44

Inhibits COX

Decreases Thromboxane A2 and platelet aggregation (GpIIb/IIIa) expression

Question 45

How does Clopidogrel prevent angina?

Answer 45

Inhibits ADP receptor on platelets, reducing aggregation

Question 46

Why are Aspirin and Clopidogrel often used together?

Answer 46

Both reduce thrombosis and can be used together as they have entirely different mechanisms

Question 47

What is the effect of Statins?

Answer 47

HMG-CoA Reductase inhibitor - decreases cholesterol levels