Action of drugs on the cardiovascular

system
LO 1 Describe the types of drugs used to
treat patients with common cardiovascular
disorders
 Cardiovascular drugs are used to treat:
– Arrhythmias
– Heart failure
– Blood clotting disorders
– Ischemic heart diseases
– Hypertension
• Drugs can alter:
– The rate and rhythm of the heart
– The force of myocardial contractility
– Peripheral resistance
– Blood volume
– Coronary arteries blood flow

Some drugs can act at more than one site.

LO 2 Understand how arrhythmias can arise
 Disturbances of cardiac rhythm
(arrhythmias or dysrhythmias)

Abnormality of heart rate or rhythm

• Tachycardia
– Ventricular tachycardia
– Supraventricular tachycardia
• Bradycardia
• Atrial flutter
• Atrial fibrillation
• Ventricular fibrillation
Causes of arrhythmias include:
Ectopic Pacemaker activity
Damaged area of myocardium because depolarised
and spontaneously active.
Latent pacemaker region activated due to ischaemia
Dominate over SA node
After-Depolarisations
Abnormal depolarisations following the action
potential
Thought to be caused by high intracellular Ca2+
Longer AP leads to longer QT interval
Re-entry loop
Conduction delay
Normal spread of excitation disrupted due to
damaged area
Incomplete conduction damage (uni-directional block)
 Re-entrant mechanism for generating
arrythmias
normal spread of excitation
Block of conduction
through damaged
area region

impulses cancel
out at this point

Incomplete conduction damage (unidirectional

block)
- excitation can take a long route to spread the
wrong way through the damaged area, setting
up a circus of excitation
Re-entry loops

It is possible to get several small re-

entry loops in the atria, leading to
atrial fibrillation
LO 3 Describe the classes of anti-arrhythmic drugs
and the principles of their therapeutic use
Drugs affecting the rate and rhythm of the
heart
• There are 4 basic classes of anti-
arrhythmic drugs.
I. Drugs that block voltage-sensitive
sodium channels
II. Antagonists of β- adrenoreceptors
III. Drugs that block potassium
channels
IV. Drugs that block calcium channels
Drugs which block voltage-dependant Na+
channels (class I)
• Typical example is the local anaesthetic lidocaine
• Only blocks voltage gated Na+ channels in open or
inactive state
• Dissociates rapidly in time for next AP
 Lidocaine
• Is sometimes used following MI if patient shows signs
of ventricular tachycardia
– given intravenously

• Damaged areas of myocardium may be depolarised

and fire automatically

• More Na+ channels are open in depolarised tissue

– lidocaine blocks these Na+ channels
– prevents automatic firing of depolarised ventricular tissue
• Not used prophylactically following MI
 β-adrenoreceptor antagonists (class II)

• Examples: propranolol, atenolol

(Beta blockers)
• We have selective and non-
selective β- blockers
• Block sympathetic action
–act at β1-adrenoreceptors in
the heart
 β-blockers

• Used following myocardial infarction

– MI causes increased sympathetic activity

• β-blockers prevent ventricular arrhythmias

– arrhythmias may be due to increased sympathetic
activity

• also reduce O2 demand

– reduce myocardial ischaemia
– beneficial following MI
 Drugs that block K+ channels (class III)
• Class III anti-arrhythmics
• Prolong the action potential
– mainly by blocking K+ channels
• This lengthens the absolute refractory period
• Prevents another AP occurring too soon

Class III
antiarrhythmic

absolute absolute
refractory refractory
period period

0 200 400 600 800 0 200 400

Time (ms)
 Drugs that block K+ channels

• Prolongs the action potential

• Not generally used because they can be also be pro-
arrhythmic

• One exception – amiodarone

• Included as a type III anti-arrhythmic, but has other
actions in addition to blocking K+ channels

• Used to treat tachycardia associated with Wolff-

Parkinson-White syndrome (re-entry loop due to an
extra conduction pathway)
 Drugs that block Ca2+ channels (class IV)

• Example: verapamil
• Decreases slope of pacemaker action potential
at SA node
• Decreases AV nodal conduction
• Decreases force of contraction (negative
inotropy)
– Also cause some coronary and peripheral
vasodilation
– The dihydropyridine Ca2+ channel blockers are not
effective in preventing arrhythmias, but do act on
vascular smooth muscle
 Adenosine

• Produced endogenously
• Acts on A1 receptors at AV node
• Enhances K+ conductance
– hyperpolarises cells of conducting tissue
• Anti-arrhythmic
– Administered intravenously
– Doesn’t belong in any of the classes mentioned
LO 4 Define the term inotropic drug and the
circumstances under which these drugs can be
used
Inotropic drugs are drugs that affect the force
of contraction of the heart.

Negatively inotropic drugs are used in circumstances

where it is beneficial to reduce the workload of the
heart, for example after a myocardial infarction.
This reduces the O2 requirement of the heart and limits
further damage.
-blockers are examples of negative inotropic drugs.

Positive Inotropic drugs are used in circumstances

where the heart needs to beat more strongly, for
example cardiogenic shock or acute but reversible
heart failure (eg following cardiac surgery).
-adrenoceptor agonist, e.g. dobutamine are examples
of positive inotropic drugs.
LO 5 Describe how drugs can be used in the
treatment of heart failure
 Heart Failure

• What is heart failure?

– Failure of the heart to provide sufficient output to
meet the body’s requirements or demand

• Features
– Reduced force of contraction
– Reduced cardiac output
– Reduced tissue perfusion
– Oedema
 Drugs used in the treatment of heart
failure
• Positive inotropic , increase cardiac output
– cardiac glycosides
– β-adrenergic agonists
• Dobutamine
• Dopamine
• Isoprenaline

• Drugs which reduce work load of the heart

– reduce afterload and preload
 Drugs which increase the force of
contraction of the heart

• Cardiac glycosides
– Have been used to treat heart failure for over 200
years
– improves symptoms but not long term outcome
• Digoxin is the prototype
– Extracted from leaves of the foxglove digitalis
purpurea or digitalis lanata
– Blocks Na+/K+ ATPase
 Action of cardiac glycosides

• Ca2+ is extruded via

the Na+-Ca2+
exchanger
Na+ - Ca2+ Na+ – driven by Na+
exchanger [Na+] moving down
K+ concentration
gradient
Na+
Na+ - K+ • cardiac glycosides
ATPase block Na+/K+
Ca2+ ATPase
• rise in [Na+]in
 Action of cardiac glycosides

• Rise in intracellular
Na+ leads to decrease
in activity of Na+-Ca2+
exchanger
Na+ - Ca2+ Na+
exchanger [Na+] • Causes increase in
K+ [Ca2+]in
Na+ – more Ca2+ stored in
Na+ - K+ SR
[Ca2+] ATPase
Ca2+
• Increased force of
contraction
 Action of cardiac glycosides

• Block Na+/K+ ATPase

• Increase in Na+ concentration inside the cells
leads to an inhibition of the Na+/ Ca2+
exchanger
• Increase Ca2+ concentration inside cardiac
myocytes
– Positive inotropic effect
– Increased force of contraction
Action of cardiac glycosides on heart rate

• cardiac glycosides also cause increased

vagal activity
– action via central nervous system
– slows AV conduction
– slows the heart rate
 Drugs which increase myocardial
contractility

β – adrenoreceptor agonists
e.g. dobutamine
– acts on β1 receptors

Uses:
– Cardiogenic shock
– Acute but reversible heart failure (e.g. following
cardiac surgery)
 Drugs which reduce the workload of the
heart: ACE-inhibitors

• Drugs which inhibit the action of angiotensin

converting enzyme are important in the
treatment of heart failure
• Prevent the conversion of angiotensin I to
angiotensin II
• Angiotensin II acts on the kidneys to increase
Na+ and water re-absorption
• Angiotensin II is also a vasoconstrictor
 ACE-inhibitors

• Decrease vasomotor tone (blood

pressure)
• Reduce afterload of the heart
• Decrease fluid retention (blood
volume)
• Reduce preload of the heart
• Reduce work load of the heart
 Drugs which reduce the work
load of the heart

• Diuretics ( ↓ pre-load )

• β–adrenoceptor antagonists (β-

blockers)
LO 6 Describe how drugs can be used in the
treatment of Angina
 Angina (Myocardial ischaemia)

• Occurs when O2 supply to the heart

does not meet its need
• Ischemia of heart tissue
– chest pain
• Usually pain with exertion
• Due to narrowing of the coronary
arteries
 Treating Angina

• Reduce the work load of the heart

– β-adrenoreceptor blockers
– Ca2+ channel antagonists
– organic nitrates
• Improve the blood supply to the heart
– organic nitrates
– Ca2+ channel antagonists
 Action of Organic Nitrates
• Reaction of organic nitrates with thiols (-SH
groups) in vascular smooth muscle causes
NO2- to be released

• NO2- is reduced to NO (Nitric Oxide)

Examples of Organic
NO is a powerful Nitrates
vasodilator glyceryl trinitrate
isosorbide dinitrate
Nitric Oxide causes vasodilation
vascular smooth muscle cell
guanylate
+ cyclase
NO
GTP
cGMP PKG
[Ca2+]in

• NO activates guanylate cyclase

• increases cGMP
• lowers intracellular [Ca2+]
• causes relaxation of vascular smooth muscle
How does this help alleviate symptoms?

PRIMARY ACTION
• action on venous system venodilation lowers preload
– Reduces work load of the heart
– Heart fills less therefore force of contraction reduced
(Starling’s Law)
– This lowers O2 demand

SECONDARY ACTION
Action on coronary arteries improves O2 delivery to
the ischaemic myocardium
– acts on collateral arteries rather than arterioles
 Action of organic nitrates on collateral
arteries

no drug atheromatous
effect of nitrate
plaque

collateral collateral dilated

normal fully
arteriolar dilated
tone arterioles

blood flow to
ischaemic area
increased

blood flow to
ischaemic area
LO 7 Understand the risk of thrombus formation with
certain cardiovascular conditions and understand how to
treat this
 Anti-thrombotic drugs
Certain heart conditions carry an
increased risk of thrombus
formation
–Atrial fibrillation
–Acute myocardial infarction
–Mechanical prosthetic heart
valves
 Anti-thrombotic drugs
• Anticoagulants
– Heparin (given intravenously)
• inhibits thrombin
• used acutely for short term action
– Fractionated heparin (subcutaneous injection)
– Warfarin (given orally)
• antagonises action of vitamin K
• can be used long term
• Anti-platelet drugs
– Aspirin , dipyridamol and globidogrel
• following acute MI or high risk of MI
LO 8 Describe how drugs can be used in the
treatment of Hypertension
 Hypertension
• Associated with increases in blood volume.
– Na+ and water retention by the kidneys
• Possible treatments
– diuretics
– ACE-inhibitors
– β-blockers
– Ca2+ channel blockers which act at
vascular smooth muscle
– α1-adrenoceptor antagonists
 Hypertension
• Diuretics
– decrease Na+ and water retention by kidney
• decrease blood volume
• ACE-inhibitors
– decrease Na+ and water retention by kidney
– decrease total peripheral resistance - vasodilation
• β-blockers
– decrease cardiac output
• Ca2+ channel blockers selective for vascular smooth
muscle
– vasodilation
• α1 – adrenoceptor antagonist
– vasodilation