drugs acting on the heart

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
— Isohemio heart diseases
— Hypertension


- Drugs can alter:
— The rate and rhythm of the heart
— The force of myocardial oontraotility
— 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
J I Block of conduction
through damaged

As A3

area region

l

k

impulses cancel
out at this point

Incomplete conduction damage (unidirectional
H block)
- excitation can take a long route to spread the
wrong way through the damaged area, setting
A u a circus of excitation
.H. h—
? r


Re-entry loops

69’ It is possible to get several small re-
@@ entry loops in the atria, leading to
atrial fibrillation

@
@


L0 3 Describe the classes ofanti-arrhythmic drugs
and the principles oftheir therapeutic use


Drugs affecting the rate and rhythm of the
hean
- There are 4 basic classes of anti-
arrhythmic drugs.
|. Drugs that block voltage-sensitive
sodium channels
ll. Antagonists of B- adrencreceptcrs
lll. 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
ls sometimes used following Ml 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 Ml


B-adrenoreceptor antagonists (class II)
- Examples: propranolol, atenolol
(Beta blockers)
- We have selective and non-
selective 5- blockers
- Block sympathetic action
—act at B1-adrenoreceptors in
the heart


B-blockers
- Used following myocardial infarction
— Ml causes increased sympathetic activity

- B-blockers prevent ventricular arrhythmias
— arrhythmias may be due to increased sympathetic
activity
- also reduce 02 demand
— reduce myocardial ischaemia
— beneficial following Ml


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
refractory
penod

absolute

O 200 400 600 800 o 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
vasodHa?on
— 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


L0 4 De?ne 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 heat more strongly, for
example cardiogenic shock or acute but reversible
heart failure (eg following cardiac surgery).
B-adrenoceptor agonist, e.g. dobutamine are examples
of positive inotropic drugs.


L0 5 Describe how drugs can be used in the
treatment ofheart 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
— B-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 Nat/K+ ATPase


Action of cardiac glyccsides

- Ca2+ is extruded via
the Nat-Ca2+
exchanger

F
l Na+ 032+ — driven by Na+
exchanger moving down
concentration
N + gradient

a a». - cardiac glycosides

Ca2 5 block Na+/K+

ATPase
- rise in [Nat]iln


Action of cardiac glyccsides

- Rise in intracellular
Na+ leads to decrease
in activity of Nat-Ca2+

F

exchanger

l Na+ - Ca2+
exchanger - Causes increase in
[082+]in
Na+ — more Ca2+ stored in
SR

- Increased force of
contraction


Action of cardiac glycosides

- Block Nat/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
vagalac?v?y
— action via central nervous system
— slows AV conduction
— slows the heart rate


Drugs which increase myocardial
contractility

B — adrenoreceptor agonists
e.g. dobutamine
— acts on [31 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 ( i pre-Ioad )

B—adrenoceptor antagonists ([3-
blockers)


L0 6 Describe how drugs can be used in the
treatment ofAngina


Angina (Myocardial isohaemia)

Occurs when 0 supply to the heart
does not meet its need
lsohemia of heart tissue
—ohest pain
Usually pain with exertion
Due to narrowing of the coronary
arteries


Treating Angina

- Reduce the work load of the heart
— B-adrenoreoeptor blockers
— Ca2+ ohannel antagonists
—organio nitrates
- Improve the blood supply to the heart
—organio nitrates
—Ca2+ Channel antagonists


Action of Organic Nitrates
- Reaction of organic nitrates with thiols (-SH
groups) in vascular smooth muscle causes
N02 to be released
- N02 is reduced to NO (Nitric Oxide)

NO is a powerful
vasodilator

Examples of Organic
Nitrates
glyceryl trinitrate
isosorbide dinitrate


Nitric Oxide causes vasodilation
l vascular smooth muscle cell
guanylate
+ cyclase)

NO

GTP

cGMP —" PKG

l [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 02 demand

SECONDARY ACTION
Action on coronary arteries improves 02 delivery to
the ischaemic myocardium
— acts on collatera arteries rather than arterioles


Action of organic nitrates on collateral

no drug

I

A
l collateral

normal
arteriolar

I

T
arteriolesr/r?j

I T F

fully
dilated

--+

_-:
blood flow to
ischaemic area

arteries

/

J effect of nitrate
\
I collateral dilated
—-

-1?l,
I

blood flow to
ischaemic area
increased


L0 7 Understand the risk ofthrombusformation 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


L0 8 Describe how drugs can be used in the
treatment ofHypertension


Hypertension
- Associated with increases in blood volume.
— Na+ and water retention by the kidneys
- Possible treatments
— diuretics
— ACE-inhibitors
— B-blockers
— Ca2+ channel blockers which act at
vascular smooth muscle
— d1-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
B-blockers
— decrease cardiac output
Ca2+ channel blockers selective for vascular smooth
muscle
— vasodilation
d1 — adrenoceptor antagonist
— vasodilation