Dr Suryawan bin Tasref Department of Anaesthesiology & Intensive Care HSNZ

1. VASODILATORS Dr Suryawan bin Tasref Department of Anaesthesiology & Intensive Care HSNZ

2. CONTENT • Introduction • Classifications • Conclusion

3. INTRODUCTION • vasodilator = drugs that relax the smooth muscle in blood vessels, which causes the vessels to dilate. • Dilation of arterial (resistance) vessels leads to a reduction in systemic vascular resistance, which leads to a fall in arterial blood pressure. • Dilation of venous (capacitance ) vessels decreases venous blood pressure 3

4. CLASSIFICATION • Based on their site of action (arterial vs venous) • Arterial dilators--primarily dilate resistance vessels (e.g., hydralazine) • Venous dilators--primarily affect venous capacitance vessels ( e.g., nitroglycerine). • Mixed arterial and venous dilator properties ( e.g., alpha-adrenoceptor antagonists, angiotensin converting enzyme inhibitors)

5. INTRO-CLINICAL USE • Vasodilators are used to treat hypertension, heart failure and angina • Arterial dilators that act primarily on resistance vessels are used for hypertension and heart failure, but not for angina because of reflex cardiac stimulation. • Venous dilators are very effective for angina, and sometimes used for heart failure, but are not used as primary therapy for hypertension. • Most vasodilator drugs are mixed (or balanced) vasodilators in that they dilate both arteries and veins; • there are some drugs that are highly selective for arterial or venous vasculature

6. CLASSIFICATION • By mechanism of action • 1. Antiadrenergic Agents • 2. Vasodilators • 3. Renin-Angiotensin System Inhibitors • 4. Calcium Channel Blocker • 5. Phosphodiesterase inhibitor • 6. Beta adrenoceptor agonist

7. 1. Antiadrenergic Agents • Alpha-1 Receptors • Prazosin • Phenoxybenzamine • Phentolamine • Beta Receptors • Propanolol, Metoprolol, Atenolol, Esmolol • Alpha-Beta receptors • Labetolol

8. 1. Antiadrenergic Agents • Central Nervous System • Clonidine • Methyldopa • Autonomic Ganglia • Trimetaphan • Nerve endings • Reserpine

9. 2. Vasodilators • Vascular Smooth Muscle • Hydralazine • Minoxidil • Diazoxide • Nitroprusside

10. 3. Calcium Channel Blocker • Vascular Smooth Muscle • Verapamil • Nifedipine • Diltiazem

11. 4. Renin-Angiotensin System • Angiotensin Converting Enzyme Inhibitors • Captopril • Enalapril • Lisinopril • Angiotensin II Receptor Antagonists • Losartan

12. 1. Antiadrenergic Agents • A number of drugs that inhibit the adrenergic nervous system are available, including some that act • centrally on vasomotor center activity • peripherally on neuronal catecholamine discharge • by blocking alpha- and/or beta-adrenergic receptors

13. Simplified schematic view of the adrenergic nerve ending showing that norepinephrine (NE) is released from its storage granules when the nerve is stimulated and enters the synaptic cleft to bind to alpha1 and beta receptors on the effector cell (postsynaptic). In addition, a short feedback loop exists, in which NE binds to alpha2 and beta receptors on the neuron (presynaptic), to inhibit or to stimulate further release, respectively

15. 1. Antiadrenergic Agents • Alpha-1 Receptors • Prazosin • Phenoxybenzamine • Phentolamine • Beta Receptors • Propanolol, Metoprolol, Atenolol, Esmolol • Alpha-Beta Receptors • Labetolol

16. PRAZOSIN • quinazoline derivative • produces peripheral vasodilation; vascular tone in both resistance(arterioles) and capacitance(veins) vessels is reduced • resulting in decreased VR, CO and BP • not assd with reflex tachycardia (presyn alpha-2) • selective and competitive postsynaptic alpha-1 receptor blockade (5000 affinity than alpha-2 receptor)

17. Pharmacokinetics Prazosin • administered orally (2 to 40mg/day) in divided bd doses • 60% bioavailability • protein binding 90% • nearly completely metabolized by the liver • elimination half-time is about 3 hours (prolonged by cardiac failure)

18. Side Effects Prazosin • vertigo • fluid retention • orthostatic hypotension • ‘first dose phenomenon’ ; dizziness, faintness, syncope soon after the administration of the first dose • dryness of the mouth, nasal congestion, nightmares, urinary frequency, lethargy, and sexual dysfunction

19. PHENOXYBENZAMINE • non-competitive and irreversible blocker • 100x affinity for alpha-1 • active metabolites which actually binds to the receptor; slow onset • poorly absorbed; 20-30%, dosage 40-60mg/day • elimination half-life; 24hours • indications; pre-operative preparation or long term Mx in phaechromocytoma

20. PHENTOLAMINE • competitive antagonism • less selective alpha blocker (3-5x alpha-1) • also acts at histamine and Ach receptors • administered intravenously • as a diagnostic test for phaechromocytoma; risk of CVS collapse • to ctrl HPT during surgical removal of phaechromocytoma

21. 1. Antiadrenergic Agents (cont) • Alpha-1 Receptors • Prazosin • Phenoxybenzamine • Phentolamine • Beta Receptors • Propanolol, Metoprolol, Atenolol • Alpha-Beta Receptors • Labetolol

22. Mechanism of Action • competitive antagonist • binding is reversible • chronic administration is associated with an increase in the number of beta-adrenergic receptors (up-regulation) • produces some degree of membrane stabilization in the heart

23. Classification • selective and nonselective for beta-1 and beta-2 receptors • partial or pure antagonists on the basis of the presence or absence of intrinsic sympathomimetic activity(ISA) • antagonists with ISA cause less direct myocardial depression and heart rate slowing (better tolerated in patients with poor LV function)

24. CLASSIFICATION

25. Clinical Effect • negative inotropic and chronotropic effects • conduction speed (AVN) is slowed • decreased the rate of spontaneous phase 4 depolarization • antidysrhythmic effect

26. Side Effects • increased airway resistance • unmask the signs of hypoglycaemia • precipitate cardiac failure • PVD and Raynaud’s phenomenon • hyperkalaemia • memory loss and mental depression • withdrawal hypersensitivity; up-regulation

27. PROPANOLOL • non-selective blocker • lacks of ISA; pure antagonist • equal antagonism at beta-1 and beta-2 • the first beta-antagonist introduced • the standard drug to which all other beta antagonists are compared

28. Pharmacokinetics Propanolol • rapidly and almost completely GIT absorption • extensive hepatic first-pass metabolism (70%); poor bioavailability • extensively bound to plasma proteins (90% to 95%) • clearance is by hepatic metabolism to active metabolite, 4-hydroxypropranolol (equivalent in activity to propanolol)

29. Pharmacokinetics Propanolol • elimination half-time is 2 to 3 hours, • elimination reduced when hepatic blood flow decreases • alterations in hepatic enzyme activity may also influence the rate of hepatic metabolism

30. ESMOLOL • selective beta-1 blocker; lacks of ISA • rapid-onset and ultra short-acting • preventing or treating haemodynamic instability intraoperatively in response to noxious stimulation, e.g. during intubation

31. Pharmacokinetics Esmolol • rapid metabolism in blood by hydrolysis of the methyl ester • inactive acid metabolites • elimination half-time 10 minutes • poor lipid solubility; limits transfer into the CNS or across the placenta • dosage: (peri-operative)= 0.5 to 1mg/kg over 15-30sec • infusion 50-300mcg/kg/min

32. 1. Antiadrenergic Agents (cont) • Alpha Receptors • Prazosin • Terazosin • Beta Receptors • Propanolol, Metoprolol, Atenolol • Alpha-Beta receptors • Labetolol

33. LABETOLOL • Both alpha & beta (ratio1:7) • selective alpha-1 antagonist (1/5 to 1/10 as potent as phentolamine); presynaptic alpha-2 receptors are spared • nonselective beta-1 and beta-2 antagonist (1/4 to 1/3 as potent as propranolol) • useful in Mx of PIH

34. Pharmacokinetics Labetolol • extensive first pass metabolism • 30-40% bioavailability • metabolism is by conjugation to glucuronic acid • < than 5% excreted unchanged in the urine • elimination half-time is 5 to 8 hours (prolonged in liver disease and unchanged in renal dysfunction)

35. Dosage and Administration Labetolol • oral dose of 100-400mg per day • severe HPT • multiple bolus dose 20-40mg every 10-15 mins (up to 300mg) • continous infusion 2mg/min (up to 150mg) • intraop/postop HPT or induced hypotension during anaesthesia • lower starting multiple bolus dose of 5-10mg

36. Side Effects Labetolol • orthostatic hypotension (most common) • beta-antagonists effects (bronchospasm, congestive heart failure, heart block, fatigue, mental depression • fluid retention

37. 1. Antiadrenergic Agents • Central Nervous System • Clonidine • Methyldopa • Autonomic Ganglia • Trimetaphan • Nerve endings • Reserpine

38. CLONIDINE • centrally acting alpha-2 agonist • stimulates alpha-2 inhibitory neurons in the medullary vasomotor center • resulting in reduction of SNS outflow from the CNS to peripheral tissues • manifested as decreases in BP, HR and CO

39. Pharmacokinetics Clonidine • well absorbed after oral administration • daily adult dose is 0.2 to 0.3 mg orally (bd) • 60% of the drug excreted unchanged in the urine • duration of action; 8 hours • elimination half-time; 8.5 hours

40. Side Effects Clonidine • dry mouth • sedation • withdrawal syndrome; hyperadrenergic states resembling phaechromocytoma • retention of Na + and water • skin rashes • constipation

41. METHYLDOPA • serves as an alternative substrate to dopa • decarboxylated to methyldopamine and beta-hydroxylated to alpha methylnorepinephrine • inhibits SNS from the vasomotor center to the periphery • resulting in decrease SVR and BP

42. Pharmacokinetics Methyldopa • daily adult dose is 250 to 2000mg (bd) • incomplete absorption (25-50%) • low protein binding 15% • maximal effect within 4 to 6 hrs after an oral dose and persists for as long as 24 hrs

43. Side Effects Methyldopa • Sedation • Hepatic dysfunction, necrosis; maybe fatal • Positive Coombs' test (10-20%) • Rebound hypertension • Retention of Na + and water • Sexual dysfunction • Bradycardia

44. 1. Antiadrenergic Agents • Central Nervous System • Clonidine • Methyldopa • Autonomic Ganglia • Trimetaphan • Nerve endings • Reserpine • Guanethidine

45. TRIMETAPHAN • peripheral vasodilator and adrenergic ganglionic blocker • directly relaxes capacitance vessels and blocks autonomic nervous system reflexes • decreases CO and SVR; hence lowering BP • increases in HR; most likely reflect PNS ganglionic blockade

46. Side effects Trimetaphan • Mydriasis • Reduced gastrointestinal activity; ileus • Urinary retention • Histamine release

47. 1. Antiadrenergic Agents • Central Nervous System • Clonidine • Methyldopa • Autonomic Ganglia • Trimetaphan • Nerve endings • Reserpine

48. RESERPINE • interferes with the cathecholamines uptake into the storage vesicles • depletes stores of catecholamines • decreased CO and bradycardia leading to hypotension

49. Side Effects Reserpine • Orthostatic hypotension (prominent) • Sedation and drowsiness • Mental depression • Signs of PNS predominance include bradycardia, nasal stuffiness, xerostomia, increased gastric H+ secretion, and exaggerated gastrointestinal motility (abdominal cramps and diarrhea)

50. 2. Vasodilators • Vascular Smooth Muscle • Hydralazine • Nitroprusside