1. VASOACTIVE DRUGS February 2017
VASCULAR SYSTEM
VASOACTIVE DRUGS
February 2017

2. 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)

3. 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:-
Hypertension (systemic and pulmonary)
Heart failure
Shock
Peripheral vascular disease
Raynaud’s disease
NB: the use of vasoactive drugs to treat angina has been discussed (e.g. calcium antagonists)

4. 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:
Total systemic (‘peripheral’) vascular resistance, one of the main determinants of arterial blood pressure
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.
Aortic compliance and pulse wave reflection, which are relevant to the treatment of cardiac failure and angina 2+

5. Introduction
Actions of drugs on the vascular system can be broken down into effects on:…..
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)
Atheroma and thrombosis
New vessel formation (angiogenesis)-important for example, in diabetic retinopathy and in treating malignant disease

6. 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

7. Read on the following: Vascular Structure and Function
Control of Vascular Smooth Muscle Tone
-Two important physiological system regulate vascular tone, namely;-
The vascular endothelium
The renin-angiotensin system

8. VASOACTIVE DRUGS

9. 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 elsewhere.

10. Vasoactive Drugs… Vasoconstrictor Drugs Angiotensin II
Antidiuretic hormone
Endothelin
Vasodilator Drugs
Directly acting vasodilators
Vasodilators with unknown mechanism of action
Indirectly acting Vasodilator drugs

11. 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.

12. Vasoconstrictor Drugs..
Read on:-
Angiotensin II
Antidiuretic hormone
Endothelin

13. 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.

14. 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.
Calcium antagonists
Drugs that activate potassium channels
Drugs that act via cyclic nucleotides

15. 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.

16. 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.

17. 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 .

18. Vasodilator Drugs… 3. Indirectly acting Vasodilator drugs
The two main groups of indirectly acting vasodilator drugs are inhibitors of:
sympathetic vasoconstriction
the renin-angiotensin-aldosterone system.
NB:
Read

19. CLINICAL USES OF VASOACTIVE DRUGS

20. 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.

21. References
Read
Rang & Dale’s Pharmacology-7th Edition Chapter 22.