The vascular system prof. Martínková 2005

1. The vascular system prof. Martínková 2005

2. Vasoactive drugs Vasoconstrictor drugs Vasodilator drugs

3. Vasoconstrictor drugs • alpha1 adrenoceptor agonists - direct acting: • indirect acting drugs that release NORA from sympathetic • nerve terminals or inhibit its reuptake • some eicosanoids - thromboxane A2 • peptides - endothelin, angiotensin and antidiuretic hormone • ergot alkaloids-sumatriptan acting through 5-HT type 2 and • 1D receptors

4. Clinical use of vasoconstrictor drugs • clinical uses are limited mainly • to local applications (nasal decongestion) • coadministration with local anaesthetics • adrenaline in anaphylactic shock and in cardiac arrest • antidiuretic hormone to stop bleeding from oesophageal varices • in patients with portal hypertension caused by liver disease

5. Vasoactive drugs Vasoconstrictor drugs Vasodilator drugs directly acting vasodilators indirectly acting vasodilators

6. Vasodilators act: - to increase local tissue blood flow - to reduce arterial pressure - to reduce central venous pressure Net effect is a reduction of cardiac pre-load (reduced filling pressure) and after-load (reduced vascular resistance) reduction of cardiac work

7. Vasodilator drugs • directly acting vasodilators • block directly voltage-dependent calcium channels • cause hyperpolarisation • block Ca 2+release from sarcoplasmic reticulum • or reuptake into it • Calcium antagonists • Potassium channel activators • Drugs that influence cytoplasmic • concentrations of cyclic nucleotides

8. Vasodilator drugs- directly acting vasodilators Calcium antagonists cause generalised arterial vasodilation, though individual agents exhibit distinct patterns Dihydropyridines-nifedipine act preferentially on vascular smooth muscle rapidly acting …reflex tachycardia as a result of lowering the blood pressure to prevent this adverse action---- formulation with sustained release verapamil acts on the heart diltiazem is intermediate in specificity

9. Vasodilator drugs directly acting vasodilators • Potassium channel activators • Relax smooth muscle by selectively increasing the membrane permeability to K+ hyperpolarisation • Minoxidil • very potent and long-acting vasodilator • causes marked salt and water retention (usually prescribed with a loop diuretic) • reflex tachycardia (a β-adrenoceptor antagonist prevents it) • Usage: a drug of last resort in treating severe hypertension unresponsive to other drugs • more recently developed: cromokalim, lemakalim • nicorandil

10. Vasodilator drugs directly acting vasodilators • Drugs that act via cyclic nucleotides and enzymes • by increasing cAMP or cGMP • NO, nitrates and the natriuretic peptidesact through cGMP • Dopamin increases cAMP by activating adenylate cyclase • Nitroprusside (i.v.) • yields NO, acts equally on arterial and venous smooth muscle • rapidly converted to thiocyanate, t1/2 is only few minutes • must be given as a continuous infusion with • carefulmonitoring to avoid hypotension • Thiocyanate is cleared only slowly (toxicity: weakness, nausea, inhibition of thyroid function) • Usage: in intensive care units for hypertensive crises • to produce controlled hypotension during surgery

11. Vasodilator drugs directly acting vasodilators Phosphodiesterase inhibitors (cAMP accumulates) methylxanthines: theophylline exert their main effects on extravascular smooth muscle papaverine vasodilator of blood vessels Sildenafil (Viagra) inhibits the breakdown of cGMP increases penile erection

12. Vasodilator drugs directly acting vasodilators Nitrates act like endogenous nitric oxide (NO), causing increased cGMP formation See Antianginal drugs

13. Vasodilator drugs- directly acting vasodilators vasodilators with unknown mechanism of action hydralazine acts mainly on arteries and arterioles causing a fall in BP accompanied by reflex tachycardia genetic polymorphism in pharmacokinetics slow acetylators---systemic lupus erythematosus Usage: severe hypertension ethanol dilates cutaneous vessels – familiar flush

14. Vasodilator drugs indirectly acting vasodilators antagonists of sympathetic vasoconstriction α-adrenoceptor antagonists the renin-angiotensin system ACEI- angiotensin-converting enzyme inhibitors captopril, enalapril, ramipril, … Angiotensin II receptor subtype1 antagonists (AT1) losartan

15. Formation of angiotensins I-IV from the N-terminal of the precursor protein angiotensinogen. Renin Aminopetidase N Aminopetidase A ACE Angiotensin III Angiotensin IV C-terminal N-terminal etc. V L L H F P H I Y V R N Angiotensin II Angiotensin I Angiotensinogen (according to Rang HP et al: Pharmacology, 5th ed., 2003)

16. Control of renin release and formation and action of angiotensin II. Renal perfusion pressure + + Renal sympathetic nerve activity + Glomerular filtration + + Atrial natriuretic peptide -Agonists PGl2 + - Renin release Angiotensinogen Angiotensin I Angiotensin II - ACE inhibitors ACE Angiotensin II AT1 subtype receptor antagonists AT1 receptors - Salt retention: 1. Aldosterone secretion 2. Tubular Na+ reabsorption Vascular growth: 1. Hyperplasia 2. Hypertrophy • Vasoconstriction: • 1. Direct • 2. Via increased • noradrenaline • release from • sympathetic • nerves (according to Rang HP et al: Pharmacology, 5th ed., 2003)

17. Clinical use of vasoactive drugs: • hypertension(see Drugs to treat hypertension) • cardiac failure • angina pectoris • shock • peripheral vascular disease • Raynaud´s disease

18. Clinical use of vasoactive drugs: • hypertension • cardiac failure • angina pectoris • shock • peripheral vascular disease • Raynaud´s disease

19. Simplified scheme showing the pathogenesis of heart failure, and the sites of action of some of the drugs used to treat it. - - - - - - Pathological factors Pre-load After-load Heart disease + + Cardiac output Vasodilator drugs Positive inotropes - + Tissue perfusion Renal blood flow Central venous pressure - Renin release + Formation of angiotensin II ACE inhibitors Release of aldosterone + Na+/water retention Diuretics Oedema (according to Rang HP et al: Pharmacology, 5th ed., 2003)

20. Clinical use of vasoactive drugs: • hypertension • cardiac failure • angina pectoris • shock • peripheral vascular disease • Raynaud´s disease

21. Antianginal drugs

22. Angina occurs when the oxygen supply to the myocardium is insufficient for its needs. The pain has a characteristic distribution in the chest, arm and neck and is brought on by exertion or excitement. Three kinds of angina are recognised clinically. Stable a.: Predictable pain on exertion, produced by an increased demand on the heart and is caused by a fixed narrowing of the coronary vessels, almost always by atheroma. Unstable a.: Pain that occurs with less and less exertion, culminating in pain at rest. The pathology is basically the same, but without complete occlusion of the vessel. The risk of MI is substantial. Variant a.: occurs at rest and is caused by coronary artery spasm, again in association with atheromatous disease.

23. Therapy: Stable a. Organic nitrates β-adrenoceptor antagonists Calcium antagonists Unstable a. To reduce the risk of MI: Aspirin and platelet glycoprotein receptor antagonists, β-adrenoceptor antagonists Variant a. Vasodilators: Organic nitrates Calcium antagonists

24. Myocardial infarction • occurs after a coronary artery has been blocked by thrombus. This may be fatal and is the commonest cause of death in many parts of the world, usually as a result of mechanical failure of the ventricle or from dysrhythmia. • If the supply of oxygen remains below a critical value, a sequence of events leading to cell death (by necrosis or apoptosis) ensues. • Therapy: • Thrombolytic and antiplatelet drug to open the blocked artery • oxygen • opioids to prevent pain and reduce excessive sympathetic • activity • beta-adrenoceptor antagonists • ACEI

25. Beta-adrenoceptor antagonists have an important longer-term benefit during chronic treatment in reducing dysrhythmic deaths ACEI improve survival if given to patients shortly after MI, especially if there is even a modest degree of myocardial dysfunction In contrast: A large randomised controlled trial (ISIS-4) showed that organic nitrates do not improve outcome in patients with MI, although they are useful in preventing or treating anginal pain Calcium antagonists have been dissapointing, and several clinical trials of short-acting dihydropyridines (nifedipine) were halted when adverse trends were evident

26. Angina is managed by using drugs that : • improve perfusion of myocardium • reduce its metabolic demand • organic nitrates and calcium antagonists • are vasodilators and produce both of these effects • beta-adrenoceptor antagonists reduce metabolic demand

27. organic nitrates • relax vascular and some extravascular smooth muscles • venorelaxation with a consequent reduction in central venous pressure (reduced pre-load) • Venous pooling occurs on standing and can cause postural hypotension and dizziness. • resistance arteries and arterioles dilate, coronary flow is increased via coronary vasodilation. Redistribution of coronary flow towards ischaemic areas via collaterals • myocardial oxygen consumption is reduced because of the reduction both in cardiac pre-load and after-load • a large íncrease in the oxygen content of coronary sinus blood • pain relief

28. Comparison of the effects of organic nitrates and an arteriolar vasodilator (dipyridamole) on the coronary circulation. Control (no drug) in a patient with CAD Atheromatous plaque Effect of dipyridamole Effect of nitrate Collateral Fully dilated arterioles Normal arteriolar tone Collateral not dilated Collateral dilated Blood flow to normal area of myocardium Blood flow to ischaemic area of myocardium Blood flow to ischaemic area INCREASED Blood flow to normal area INCREASED Blood flow to ischaemic area REDUCED A: Control. B: Nitrates dilate the collateral vessel, thus allowing more blood through to the underperfused region (mostly by diversion from the adequately perfused area). C: Dipyridamole dilates arterioles, increasing flow through the normal area at the expense of the ischaemic area (in which the arterioles are anyway fully dilated). (CAD, coronary artery disease). (according to Rang HP et al: Pharmacology, 5th ed., 2003)

29. Mechanisms of action: Organic nitrates are metabolised with release of NO guanylate cyclase protein kinase G cGMP a cascade of effects in smooth muscle culminating in dephosphorylation of myosin light chains and sequestration of intracellular Ca2+ ------relaxation

30. Short acting drugs • amyl nitrate • glyceryl trinitrate (nitroglycerin) • well absorbed from the mouth and is taken as a tablet under the tongue or as a sublingual spray, producing its effects within a few minutes …. lasting for 30min : acute pain relief • slow-release transdermal patches : prophylaxis • undergoes the first pass effect • Longer acting drugs • Isosorbide mononitrate: - tabl for oral use: twice a day • for prophylaxis (usually in the morning and at lunch, to allow a nitrate-free period during the night…. to avoid tolerance) • - in slow-release form for once daily use in the morning

31. Adverse reactions: • postural hypotension • headache • tolerance (long-acting usage) • „Monday morning sickness“ (the headache) among workers in explosive factories. Tolerance to this effect develops quite quickly but wears off after a brief nitrate-free interval (which is why the symptoms appeared on Monday and not late in the week) • formation of methemoglobin –an oxidation product of hemoglobin that is ineffective as an oxygen carrier

32. Clinical use: • Stable angina • - prevention (e.g. regular isosorbide mononitrate or glyceryl trinitrate sublingually immediately before exertion) • therapy(sublingual glyceryl trinitrate) • Unstable angina: i.v.glyceryl trinitrate

33. Clinical use of vasoactive drugs: • hypertension • cardiac failure • angina pectoris • shock and hypotensive states • peripheral vascular disease • Raynaud´s disease

34. Shock is a medical emergency characterised by inadequate perfusion of vital organs, usually because of a very low arterial blood pressure S. can be caused by various insults: haemorrhage, burns, bacterial infections, anaphylaxis, MI. The physiological response to this is complex: vasodilation in a vital organ (brain, heart, kidney) favours perfusion of that organs´but at the expense of a further reduction in blood pressure, which leads to reduced perfusion of other organs. Tissue hypoxia produces secondary effects in the latter the patients with established shock have profound and inappropriate vasodilation in non-essential organs. Mediators promoting vasodilation: Hi, 5-HT,bradykinin, PGs, TNF, NO… capillary dilation and leakiness

35. Simplified scheme showing the pathogenesis of hypovolaemic shock. Circulating volume + Haemorrhage Transfusion (fluid replacement) Myocardial damage - Cardiac output Dobutamine Adrenaline Arterial pressure Renal blood flow Adrenaline +/- Vasoconstriction Renin release Renal failure Prostacyclin (epoprostenol) - Acidosis Tissue hypoxia DEATH  - Arteriolar and capillary dilatation and leakiness Release of mediators Corticosteroids Adrenaline Allergen Bacterial endotoxin Burns, trauma (according to Rang HP et al: Pharmacology, 5th ed., 2003)

36. Clinical use of vasoactive drugs: • hypertension • cardiac failure • angina pectoris • shock • peripheral vascular disease • Raynaud´s disease

37. Peripheral vascular disease When atheroma involves peripheral arteries, the commonest symptom is pain in the leg on walking claudication Treatment is often surgical: surgical reconstruction or angioplasty (disruption of atheroma by inflation of a ballon surrounding the tip of a catheter) Antiplatelet drugs- aspirin and clopidogrel, ACEI: ramipril statin: simvastatin To reduce the excess risk of ischemic coronary events

38. Clinical use of vasoactive drugs: • hypertension • cardiac failure • angina pectoris • shock • peripheral vascular disease • Raynaud´s disease

39. Inappropriate vasoconstriction of small arteries and arterioles gives rise to Rf (blanching of the fingers during vasoconstriction, followed by blueness owing to deoxygenation of the static load and redness from reactive hyperemia following return of blood flow. Prevention: stop smoking and avoiding cold Therapy: vasodilators beta-blockers are contraindicated

40. References: Rang HP, Dale MM, Ritter JM, Moore PK: Pharmacology, 5th edition, Churchill Livingstone, Edinburgh, London, New York, 2003.