2.2 CVS Pharmacology (1 + 2)

Question 1

What are the aims of CVS drug therapy? (5)

Answer 1

• Enhance systolic function
• Enhance diastolic function
• Ensure optimal cardiac rate and rhythm
• Optimise distribution of fluid within the circulation
• Counteract effects of detrimental neurohormonal activities

Question 2

What cardiac functions can be manipulated pharmacologically?

Answer 2

Heart rate
Heart rhythm
Cardiac muscle contractility

Question 3

What is the effect of noradrenalin on cardiac muscle cells?

Answer 3

Inhibits phosphodiesterase
cAMP not broken down
Increased action of protein kinase A
Increased [Ca2+]i

Question 4

Describe ion handling in cardiac myocytes

Answer 4

• Ca2+ influx balanced by efflux via Ca2+/Na+ exchange
• Na+ extruded in exchange for K+ by the Na+/K+/ATPase
• Changes in [Na+]i affect [Ca2+]i

Question 5

List the targets for drugs acting on cardiac muscle

Answer 5

1) Receptors (e.g. M2, B1 adrenoreceptors)
2) Ion channels (e.g. fast Na+ channels, slow Ca2+ channels, K+ channels)
3)Cardiac muscle cell enzymes (e.g. Na+/K+ ATPase, PDE)

Question 6

What are the effects of a sustained increase in HR?

Answer 6

• Increased myocardial O2 consumption
• Reduced time for ventricular filling
• Reduced time for coronary blood flow

Question 7

List the drugs that slow HR (negative chronotropes)

Answer 7

• Muscarinic (M) receptor agonist
• Drugs that act centrally to increase vagal tone - cardiac glycosides
• 𝛃 adrenoceptors antagonists

Question 8

List the drugs that increase HR (positive chronotropes)

Answer 8

• Muscarinic receptor antagonists
• 𝛃 adrenoceptor agonists

Question 9

Describe the use of B adrenoceptor antagonists as drugs that slow heart rate

Answer 9

Particularly effective in hearts driven by high sympathetic tone

Also reduces the force of contraction of ventricular muscle (which may have negative effects)

Question 10

Describe when B adrenoceptor agonists may be used as drugs that increase heart rate

Answer 10

Non-selective agonists increase heart rate more than B1-selective drugs

Causes vasodilation (particularly in skeletal muscle) B2 effect

Used in emergency of complete (3rd degree) cardiac block

Question 11

Describe when muscarinic receptor antagonists as drugs that increase heart rate might be used

Answer 11

Premedication for anaesthesia and surgery, particularly when vagal stimulationn and slowing of the heart is a potential problem

Treatment of bradycardia (incomplete heart block)

Question 12

What are the actions of the 4 classes of commonly used antidysrhythmic drugs?

Answer 12

Class I: Block voltage-dependant Na+ channels
Class II: Antangonise 𝛃 adrenoceptors
Class III: Unknown mechanism
Class IV: Inhibits Ca2+ channels

Question 13

Describe class I antidysrhythmic drugs

Answer 13

Block voltage-dependant Na+ channels
-Decreased rate and magnitude of depolarisation
-Reduced conduction in non-nodal tissues (e.g. purkinje fibres)

Question 14

Describe class II antidysrhythmic drugs

Answer 14

Antagonise 𝛃 adrenoceptors
-Reduce excessive sympathetic tone that may cause arrhythmias

Question 15

Describe Class III antidysrhythmic drugs

Answer 15

Mechanism not yet understood
-Involves blockade of K+ channels involved in cardiac repolarisation
-Emergency use in vet med

Question 16

Describe class IV antidysrhythmic drugs

Answer 16

Reduce plateau current, shorten action potential, negative isotropic effect

Question 17

List the types of drugs that increase cardiac muscle contractility (positive isotropes)

Answer 17

Cardiac glycosides
Phsophodiesterase (PDE) inhibitors
Benzimidazole derivatives
Sympathomimetric drugs

Question 18

Explain how cardiac glycosides increase muscle contractility

Answer 18

Glycoside inhibits Na+/K+ exchange
Increased [Na+]i
Decreased Na+/Ca2+ exchange
Increased [Ca2+]i
Increased force of contraction

Question 19

Explain how PDE inhibitors increase muscle contractility

Answer 19

PDE inhibited
Increased cAMP
Increased force of contraction

Question 20

Explain how benzimidazole derivatives increase mucle contractility

Answer 20

Increases Ca2+ sensitivity of cardiac myofibrils
Inhibits types III cAMP-phosphodiesterase

Question 21

What is vascular tone maintained by?

Answer 21

Balance between opposing actions of neurotransmitters, hormones, and mediators that have vasoconstrictor and vasodilator properties

Question 22

Which mediators have vasoconstrictor properties?

Answer 22

Noradrenaline / Adrenaline (𝛃 adrenoceptors)
Prostacyclin (PGl2)
NO
Atrial natriuretic peptide (ANP)

Question 22

Which mediators have vasoconstrictor properties?

Answer 22

Noradrenaline / Adrenaline (𝛂 adrenoceptors)
ATP
Angiotensin II
Vasopressin (ADH)
Endohelin
TxA2
ADP

Question 23

What mediators have vasodilator properties?

Answer 23

Noradrenaline / Adrenaline (𝛃 adrenoceptors)
Prostacyclin (PGl2)
NO
Atrial natriuretic peptide (ANP)
Adenosine

Question 24

Why is the sympathetic system important in the vasculature?

Answer 24

Can control contraction/dilation of blood vessels Helps contribute to arterial BP control

Question 25

What targets for drugs acting on the vasculature are there?

Answer 25

Membrane receptors Cell membrane ion channels Smooth muscle cell enzymes Enzymes generating or inactivating vasoconstrictors/dilators

Question 26

What do arterial dilators act on? How do these work?

Answer 26

Arterioles Reduce afterload Cause an increase in SV Decreases myocardial O2 consumption Eventually decreases preload

Question 27

What do venodilators act on? How do these work?

Answer 27

Veins Reduce preload by 'trapping' blood in the venous circulation

Question 28

What are the three targets for drugs which interfere with natural vasoconstrictors?

Answer 28

Sympathetic nervous system RAAS Endothelin-I

Question 29

What vasodilator drugs act on the symapthetic system?

Answer 29

α1-selective agrenoreceptor agonists

Question 30

How do α1-selective agrenoreceptor agonists work?

Answer 30

Act on venous and arteriole circulation Best response where sympathetic tone to blood vessels is high Fall in vascular tone is usually short lived

Question 31

What is renin?

Answer 31

Proteolytic enzyme Secreted by specialised cells in the kidney

Question 32

What is the stimulus for renin release?

Answer 32

Renal sympathetic nerve stimulation Reduced pressure in afferent arteriole Reduced [NaCl] in distal tubules

Question 33

What is ACE?

Answer 33

Angiotensin Converting Enzyme Non-specific carboxypeptidase that also breaks down bradykinin

Question 34

Where is ACE found?

Answer 34

Endothelial cells of lung capillaries

Question 35

What is angiotensin II?

Answer 35

One of the most potent vasoconstrictor agent known

Question 36

How does angiotensin II work?

Answer 36

- Enhances salt and water retention (acts via aldosterone) - Acts on cardiac muscle to cause hypertrophy (promotes protein synthesis to make heart grow) - Increases release of norepinephrine from sympathetic nerves

Question 37

At what points can RAAS be influenced by drugs?

Answer 37

Renin release ACE AT1 receptors

Question 38

What drugs affect renin release?

Answer 38

𝛃-antagonists block renin secretion

Question 39

What is the RAAS

Answer 39

Angiotensinogen -(Renin)-> Angiotensin I -(ACE)-> Angiotensin II

Question 40

How is angiotensin production controlled?

Answer 40

By controlling renin release: - reduced glomerular filtration - Reduced [Na] in distal tube - 𝛃 antagonist - 𝛃 agonist ACE inhibitors AT1 antagonists