CARDIOVASCULAR DISEASE

 Learning objectives:
 Describe the following common forms of cardiovascular disease:
• Hypertension
• Cardiac ischaemia
• Heart failure
• Arrhythmias

 Be able to demonstrate a broad understanding of the

mechanisms which contribute to cardiovascular disease

 Identify drugs used in the treatment of cardiovascular disease

and relate their mechanism of action to their beneficial effects.
SUGGESTED READING
 Rang, Dale, Ritter & Moore
Pharmacology, 5th Edition,
Chapters 17 & 18, Pages 264-304
 CARDIAC CONDUCTION AND
ELECTROPHYSIOLOGY
 In the SA node, pacemaker cells discharge
spontaneously and rhythmically

 Discharge spreads via the AV node and His-

Purkinje systems into the ventricles

 Electrical excitability due to voltage-sensitive

plasma membrane channels for various ions:
• Ca2+
• K+
• Na+
 CARDIAC ACTION POTENTIAL
Phase 0 = rapid depolarisation

Phase 1 = partial repolarisation

50mV Ca2+ Phase 2 = plateau

1 2 Phase 3 = repolarisation

Na+ 0 3 K+ Phase 4 = pacemaker potential

K+

-80mV Effective refractory

period
 CARDIAC CONTRACTION

 Contractility is dependent on the control of

intracellular Ca2+

 voltage-dependent L-type Ca2+ channels

 Ca2+ storage in sarcoplasmic reticulum

 Main factors controlling Ca2+ entry are:

 activity of L-type voltage-dependent Ca2+

channels

 level of intracellular Na+

• Ca2+/ Na+ exchange pump
 CARDIAC CONTRACTION
Volt.-sensitive
Ca2+ channel
Ca2+ Na+ K+
Ca 2+

+
Depol. Ca2+ /Na Na/K

+
Na+ K+

Ca2+ store RyR Free Ca2+

Contraction
Sarcoplasmic reticulum
troponin Ca2+ - troponin
 CARDIAC CONTRACTION

 Initial rapid depolarisation followed by plateau phase

 Influx of Ca2+ via L-type voltage-dependent Ca2+ channels

during plateau phase

 Initial Ca2+ entry acts on ryanodine receptors (RyR) on

sarcoplasmic reticulum

 Results in secondary, larger wave of Ca2+ release from

sarcoplasmic reticulum

 Bind to troponin to cause myofilament contraction

 CARDIAC CONTRACTION
 Ca2+ removed via Ca2+ / Na+ exchange system

 Na+ levels regulated by Na+ /K +

ATPase pump

 Cardiac action potential:

• Increase intracellular Na+
• Reduce intracellular K+

 Na+ pumped out of cell in exchange for K+ via

Na+ / K+ pump

Restore cardiac cell ion equilibrium

 FACTORS THAT REGULATE CARDIAC
CONTRACTILITY
 Cardiac contraction:

 The force with which a myocardial cell

contracts depends on both intrinsic and
extrinsic factors

 Contractility depends on the control of

intracellular Ca2+ and therefore on:

• Ca2+ entry across cell membrane

• Ca2+ storage in the sarcoplasmic reticulum
 FACTORS THAT REGULATE CARDIAC
CONTRACTILITY
 Intrinsic factors:

 Factors that regulate intracellular Ca2+

concentration
 Availability of other biochemical factors within
myocardial cell = ATP

 Regulate myocardial contractility

 Intrinsic factors are sensitive to drugs and

pathological processes
 DRUGS THAT AFFECT CARDIAC FUNCTION
 Drugs that have major action on the heart can be divided
into the following groups:

 drugs that directly affect myocardial cells

• Autonomic neurotransmitters and related drugs
• Cardiac inotropic agents
• Ca2+ channel antagonists

 drugs that indirectly affect cardiac function through

actions elsewhere in the vascular system
• Antianginal agents
• Ca2+ channel antagonists
 AUTONOMIC TRANSMITTERS AND
RELATED DRUGS
 Both SNS and PNS normally exert a tonic effect on the
heart at rest

 SNS:
 Acting through β 1-adrenoreceptors

increasing cAMP formation

activates protein kinase A
phosphorylates α 1-subunits in Ca2+
channels
more Ca2+ channels open in response to
depolarisation
increase in intracellular Ca2+ levels
AUTONOMIC TRANSMITTERS AND
RELATED DRUGS
 increased heart rate (positive chronotropic
effect)
 increased force of contraction (positive
inotropic effect)
 increased automaticity
 increased conduction at AV node
 reduced cardiac efficiency
 AUTONOMIC TRANSMITTERS AND
RELATED DRUGS
 PNS:
 Acting through M2 receptors
inhibits cAMP formation
opens K+ channels
hyperpolerisation

 cardiac slowing and reduced automaticity

 decreased force of contraction
 inhibition of AV conduction
 CONGESTIVE HEART FAILURE
 Congestive heart failure occurs when cardiac output is inadequate to
provide the oxygen needed by the body.

 Highly lethal condition with a 5 year mortality rate of ~50%

 Primary defect due to breakdown of excitation-contraction coupling

machinery of heart

 Also involves many other processes and organs:

• Baroreceptor reflex
• SNS
• Kidneys
• Renin-angiotensin-aldosterone system
• Vasopressin
• Death of cardiac cells
 CONGESTIVE HEART FAILURE
 Positive inotropic agents are commonly used to treat
congestive heart failure
• Cardiac glycosides
∀ β -adrenoreceptor agonists
• Phosphodiesterase (PDE) inhibitors

 Therapy directed at noncardiac targets may be more valuable

in long-term treatment than traditional
• Diuretics
• Angiotensin-converting enzyme (ACE) inhibitors
• vasodilators
 DIRECT-ACTING CARDIAC INOTROPIC
AGENTS
 Sympathomimetrics:
• isoprenaline (β 1 and β 2)
• dobutamine (β 1)

 Mechanism of action:

Mimic effect of NA at β 1 adrenoreceptors

Increases force of cardiac contraction

 Isoprenaline / dobutamine

bind to β 1 adrenoreceptor on myocardial cells

activate adenylate cyclase

cAMP

activation of protein kinase A

increase number of Ca2+ channels open in response

to membrane depolarisation

Ca2+ influx

increase force of cardiac contraction

 INDIRECT-ACTING CARDIAC INOTROPIC
AGENTS
 Cardiac glycosides
• Digoxin

 Extracted from the foxglove plant (Digitalis)

 Mechanism of Action:
• Inhibition of Na+ / K+ ATPase pump

• Results in decreased Na+ / Ca2+ exchange

• Causes secondary rise in Ca2+ accumulation

by sarcoplasmic reticulum

Increase force of cardiac contraction

 Digoxin

Inhibition of Na+ / K+ exchange

intracellular Na+

Decreased Na+ / Ca2+ exchange

intracellular Ca2+

contraction
 MECHANISM OF ACTION OF CARDIAC
GLYCOSIDES
Volt.-sensitive
channel
Ca2+ K+
Na +

_
_ Na /Ca
+ 2+
Na+/K+
Digoxin

Ca2+ Na+

Na+
Ca2+

Sarcoplasmic
reticulum
 CARDIAC GLYCOSIDES
 Administration and dosage:

 Chronic treatment with cardiac glycosides requires careful

attention to pharmacokinetics because of their long half-lives
• Digoxin = 40 hours

 It will take 3 to 4 half-lives to approach steady-state total

body load when given at a constant dosing rate
• Digoxin = 1 week

 Important not to exceed the therapeutic range of plasma

concentration (digoxin = 0.5-1.5ng/ml) therefore a slow
loading regime followed by a maintenance doses is the safest
approach (0.125-0.5mg daily dose)
 CARDIAC GLYCOSIDES
 Drug Interactions:

 At risk of developing serious cardiac arrhythmias is

hypokalemia develops such as in diuretic therapy.

 Quinidine displaces digoxin from tissue binding sites (minor

effect) and depresses renal clearance (major effect)
• Plasma levels of digoxin can double in a matter of days
leading to serious toxic effects

• Similar interaction with other drugs such as NSAIDs and

calcium channel blockers has been reported
 CARDIAC GLYCOSIDES
 Toxicity from cardiac glycosides is common (> 2ng/ml)
• Large multicentre trial 17-27% of patients admitted to
hospital for all medical conditions were taking cardiac
glycosides on admission and 5-25% of this group
demonstrated toxicity effects.

 Visual disturbances
 GI disturbances

 Cardiac arrhythmias
 Depressed automaticity

 Serum digoxin and potassium levels should always be monitored in

patients taking cardiac glycosides.
 INDIRECT-ACTING CARDIAC INOTROPIC
AGENTS
 Phosphodiesterase inhibitors
• amrinone
• milrinone

 Mechanism of action:
• Inhibits heart-specific subtypes of
phosphodiesterase (PDE)

Increase levels of cAMP

Increases number of Ca2+ channels opening in

response to depolarisation

Increase levels of intracellular Ca2+

Increase force of cardiac contraction

 MYOCARDIAL OXYGEN CONSUMPTION
 Relative to its metabolic needs, the heart is one of the most
poorly perfused tissues in the body.

 Angina occurs when the oxygen supply to the myocardium is

insufficient for its needs

 Angina is medical term for chest, arm and/or neck pain due
to coronary artery disease

 Due to coronary arteriosclerosis or myocardial infarction

 MYOCARDIAL INFARCTION
 Occurs after a coronary artery has been blocked by a thrombus.

 This may be fatal and is the commonest cause of death in many

parts of the world

 Cardiac myocytes rely on aerobic metabolism

• If the supply of oxygen remains below a critical level
(myocardial ischemia) a sequence of events leading to cell
death occurs

 Prevention of irreversible ischemic damage following myocardial

infarction is an important therapeutic aim
CONTROL OF VASCULAR SMOOTH MUSCLE
TONE
 Smooth muscle cell contraction initiated by
increase in intracellular Ca2+

activates myosin-light-chain kinase

phosphorylation of myosin

OR by sensitisation of myofilaments to Ca2+ by

inhibition of myosin phosphatase
 VASCULAR SMOOTH MUSCLE
CONTRACTION
 Vascular smooth muscle contraction involved
an increase in intracellular Ca2+ via:

1. Activation of G-protein-coupled receptor

leading to IP3 production. IP3 binds to IP3
receptors on sarcoplasmic reticulum and
releases stored Ca2+

2. Activation of ligand-gated Ca2+ channels

• ATP P2x receptor

1. Voltage-gated Ca2+ channels which open in

response to depolarisation.
 CONTRACTION OF VASCULAR SMOOTH
MUSCLE
Ligand
Ca2+ Ca2+

GPCR + DEPOL

IP3 PI

IP3R Ca2+
SR
calmodulin Ca2+ -calmodulin contraction
MLCK
myosin myosin-P
 VASCULAR SMOOTH MUSCLE
RELAXATION
 Agents that cause relaxation of vascular smooth muscle
act either by reducing intracellular Ca2+ levels or act
directly on contractile machinery:

1. Inhibit Ca2+ entry through voltage-gated Ca2+ channels

• directly or indirectly

1. Activation of receptors coupled to adenylate cyclase or

guanine cyclase
• leads to increased cAMP or cGMP production.
• cAMP acts via PKA and MLCK to inhibit
contraction.
• cGMP opposes agonist-induced increases in
intracellular Ca2+
 ROLE OF VASCULAR ENDOTHELIUM
 Endothelial cells release various vasoactive substances:

• Prostaglandin I2 (vasodilator)
• NO (vasodilator) / endothelium-derived relaxing
factor (EDRF)
• Endothelin (vasoconstrictor)

 Many vasodilator substances (Ach and bradykinin) act

via endothelial NO production

 NO causes smooth muscle relaxation by increasing

cGMP formation
AGENTS USED TO IMPROVE PERFUSION OF
MYOCARDIUM OR REDUCE METABOLIC
DEMAND
 Several therapeutic agents act on the cardiovascular
system to improve perfusion of the myocardium or reduce
metabolic demand:

• Organic nitrates
∀ β -adrenoreceptor antagonists
• Ca2+ channel antagonists
 ORGANIC NITRATES
• Isosorbide mononitrate = oral
• Glyceryl trinitrate = sublingually

 Relax vascular smooth muscle

 Converted to NO

 NO activates guanylate cyclase

Activates cGMP

Activates PKG

vascular smooth muscle relaxation

 Effective by reducing cardiac pre-load and after-load and by dilation of coronary vessels
 ORGANIC NITRATES
 Tolerance to organic nitrates can occur with the longer-
acting drugs (isosorbide mononitrate).

 Unwanted effects:
 Uncommon

• Headache
• Postural hypotension
β -ADRENORECEPTOR ANTAGONISTS
• propranolol (Inderal: β 1 / β 2 antagonist)
• atenolol (Tenormin: β 1 antagonist)
• metoprolol (Toprol: β 1 antagonist)

• Block β 1 receptors

• Inhibit formation of cAMP

Reduce number of Ca2+ channels open in

response to membrane depolarisation

Reduce intracellular Ca2+ levels

• reduce rate and force of cardiac contraction

β -ADRENORECEPTOR ANTAGONISTS
 reduce force of cardiac contraction and heart rate

reduce cardiac output

reduction in blood pressure and reduce

oxygen demand on heart

 Prophylaxis of angina by reducing cardiac oxygen

consumption

 Good choice for patients with concurrent angina or history

of myocardial infarction

 Contraindicated for patients with asthma and diabetes

CALCIUM CHANNEL ANTAGONISTS
• Nifedipine
• Diltiazem

 Block Ca2+ entry by preventing opening of voltage-gated

Ca2+ channels

 Reduce intracellular Ca2+ levels and produce vascular

smooth muscle relaxation

 Effective in angina by reducing after-load (vasodilation of

resistance vessels) and dilating coronary vessels.