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VASCULAR SYSTEM
VASOACTIVE DRUGS
February 2017
THE VASCULAR SYSTEM
Overview
• Concerned with the pharmacology of blood
vessels.
• The walls of arteries, arterioles, venules and
veins contain smooth muscle whose contractile
state is controlled by circulating hormones and
by mediators released locally from sympathetic
nerve terminals (refer to Chemical Mediators & the Autonomic
Nervous system) and endothelial cells.
• These work mainly by regulating Ca2+ in vascular
smooth muscle cells. (refer to How drugs act: cellular
aspects-excitation, contraction and secretion)
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Overview
• This topic will consider the following:
 control of vascular smooth muscle by the
endothelium and by the renin-angiotensin system,
 the actions of vasoconstrictor and vasodilator drugs
 Clinical uses of vasoactive drugs in some important
diseases, namely:1. Hypertension (systemic and pulmonary)
2. Heart failure
3. Shock
4. Peripheral vascular disease
5. Raynaud’s disease
NB: the use of vasoactive drugs to treat angina has been
discussed (e.g. calcium antagonists)
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Introduction
•
Need to understand and describe the structure and
function of the vascular system
• Actions of drugs on the vascular system can be
broken down into effects on:
1. Total systemic (‘peripheral’) vascular resistance, one
of the main determinants2+ of arterial blood pressure
2. The resistance of individual vascular beds, which
determines the local distribution of blood flow to and
within different organs; such effects are relevant to
the drug treatment of angina, Raynauds
phenomenon, pulmonary hypertension and
circulatory shock.
3. Aortic compliance and pulse wave reflection, which
are relevant to the treatment of cardiac failure and
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angina
Introduction
•
Actions of drugs on the vascular system
can be broken down into effects on:…..
4. Venous tone and blood volume (the ‘fullness’
of the circulation), which together determine
the central venous pressure and are relevant
to the treatment of cardiac failure and angina;
diuretics (which reduce blood volume)
5. Atheroma and thrombosis
6. New vessel formation (angiogenesis)important for example, in diabetic retinopathy
and in treating malignant disease
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Introduction…
• Drug effects considered in this topic are caused
by actions on vascular smooth muscle cells
• Like other muscles, vascular smooth muscle
contracts when cytoplasmic Ca2+ ([Ca2+]i) rises
but the coupling between [Ca2+]i and
contraction is less tight than striated or cardiac
muscle.
• Vasoconstrictors and vasodilators act by
increasing or reducing [Ca2+]i and/or by altering
the sensitivity of the contractile machinery to
[Ca2+]i
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Read on the following:
•
Vascular Structure and Function
•
Control of Vascular Smooth Muscle
Tone
-Two important physiological system
regulate vascular tone, namely;1. The vascular endothelium
2. The renin-angiotensin system
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VASOACTIVE DRUGS
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Vasoactive Drugs
•
•
•
•
Drugs can affect vascular smooth muscle by acting
either directly on smooth muscle cells, or indirectly,
for example on endothelial cells, on sympathetic
nerve terminals or on the central nervous system
(CNS)
Mechanisms of directly acting vasoconstrictors and
vasodilators are summarised in Figure 4.10 (p. 61 Rang
& Dale’s 7th edition).
Many indirectly acting drugs are discussed in other
chapters.
We concentrate here on agents that are not covered
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elsewhere.
Vasoactive Drugs…
•
1.
2.
3.
•
1.
2.
Vasoconstrictor Drugs
Angiotensin II
Antidiuretic hormone
Endothelin
Vasodilator Drugs
Directly acting vasodilators
Vasodilators with unknown mechanism of
action
3. Indirectly acting Vasodilator drugs
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Vasoconstrictor Drugs
• The α1-adrenoceptor agonists and drugs that
release noradrenaline from sympathetic nerve
terminals or inhibit its reuptake
(sympathomimetic amines) cause
vasoconstriction (refer to Noradrenergic transmission)
• Some eicosanoids (e.g. thromboxane A2; and
several peptides, notably endothelin,
angiotensin and ADH, are also predominantly
vasoconstrictor.
• Sumatriptan and ergot alkaloids acting on
certain 5-hydroxytryptamine receptors (5-HT2
and 5-HT1D) also cause vasoconstriction. 11
Vasoconstrictor Drugs..
•
1.
2.
3.
Read on:Angiotensin II
Antidiuretic hormone
Endothelin
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Vasodilator Drugs
• Vasodilator drugs may play a major role in the
treatment of common conditions including
hypertension, cardiac failure and angina
pectoris, as well as several less common but
severe diseases including pulmonary
hypertension and Raynaud’s disease.
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Vasodilator Drugs
1. Direct acting Vasodilators
•
Targets on which drugs act to relax vascular
smooth muscle include plasma membrane
voltage-dependent calcium channels,
sarcoplasmic reticulum channels (Ca2+ release
or reuptake), and enzymes that determine
Ca2+ sensitivity of the contractile proteins.
• e.g.
1. Calcium antagonists
2. Drugs that activate potassium channels
3. Drugs that act via cyclic nucleotides
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Vasodilator Drugs…
2. Vasodilators with unknown
mechanism of action
1. Hydralazine
• Hydralazine acts mainly on arteries and
arterioles, causing a fall in blood pressure
accompanied by reflex tachycardia and an
increased cardiac output.
• It interferes with the action of inositol
trisphosphate on Ca2+ release from the
sarcoplasmic reticulum.
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Hydralazine…
• Its original clinical use was in hypertension.
• It is still used for short-term treatment of severe
hypertension in pregnancy but can cause an
immune disorder resembling systemic lupus
erythematosus, so alternative agents are now
usually preferred for long-term treatment of
hypertension.
• Recent evidence has, however, suggested that it
has a place in treating heart failure in patients of
African origin in combination with a long-acting
organic nitrate.
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Vasodilator Drugs…
2. Vasodilators with unknown
mechanism of action…
2. Ethanol
• Ethanol dilates cutaneous vessels,
causing the familiar drunkard's flush.
• Several general anaesthetics (e.g.
propofol) cause vasodilatation as an
unwanted effect .
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Vasodilator Drugs…
3. Indirectly acting Vasodilator drugs
•
The two main groups of indirectly acting
vasodilator drugs are inhibitors of:
1. sympathetic vasoconstriction
2. the renin-angiotensin-aldosterone
system.
NB:
Read
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CLINICAL USES OF
VASOACTIVE DRUGS
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Clinical Uses of Vasoactive
Drugs
• The conditions that can be treated by these
drugs are:
• systemic hypertension
• cardiac failure
• Shock
• Peripheral vascular disease
• Raynaud's disease
• Pulmonary hypertension.
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References
Read
• Rang & Dale’s Pharmacology-7th Edition
Chapter 22.
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