Vasodilators

Vasodilators, Usages, Different Mechanism of Action,

1. Vasodilators (for MD Pharmacology) Dr. Advaitha

2. Usage of Vasodilators Systemic hypertension Heart failure Peripheral vascular disease Raynaud's disease Pulmonary hypertension.

3. Directly acting vasodilators : 1. Calcium channel blockers : Nifedipine , diltiazem , verapamil . 2.K ATP channel activators : M inoxidil and Diazoxide . Newer ones ( coronary vasodilators ) --- - Nicorandil , Pinacidil , cromakalin .

4. Directly acting contd.. 3.Drugs that increase cytoplasmic cyclic nucleotide concentrations by: Increasing adenylyl cyclase activity - prostacyclin ( epoprostenol ). - β 2 - adrenoceptor agonists. -Adenosine.

5. b) Increasing guanylyl cyclase activity -nitrates ( glyceryl trinitrate , nitroprusside ) -Inhibiting phosphodiesterase activity ( sildenafil ) - Natiuretic Peptide analogues ( Nesiritide )

6. Indirectly acting vasodilators : 1.Drugs that interfere with the sympathetic nervous system α 1 - blockers ( Phentolamine , Phenoxybenzamine ). α 2 agonists ( clonidine ) D 1 receptor agonist : Fenoldopam

7. 2.Drugs that block the renin-angiotensin system: Renin inhibitors ( aliskiren ) ACE inhibitors ( ramipril ) AT 1 receptor antagonists ( losartan ).

8. Indirectly acting contd.. 3. Drugs or mediators that stimulate endothelial NO release acetylcholine, bradykinin 4.Drugs that block the endothelin system : Blocks endothelin synthesis – Phosphoramidon (endothelin-1 converting enzyme inhibitor) – not approved Endothelin-1 receptor antagonists ( Bosentan ).

9. Miscellaneous drugs Vasodilators whose mechanism is uncertain -- alcohol, propofol and hydralazine . Drugs in Peripheral vascular disease -- Pentoxifylline , Cilastozole Diuretics : Frusemide ( I.V only )

10. Our focus ! Vasodilator Peptides and related drugs Gaseous vasodilator : Nitric Oxide Direct vasodilators 1. Arteriolar - hydralazine , minoxidil , diazoxide . 2. Venodilator : nitroglycerine 3. Arteriolar + venous – nitroprusside .

11. Gaseous Vasodilator – Nitric oxide NO is now known as a critical endogenous cell-signaling molecule. It has an increasing number of potential therapeutic applications. Endogenous, NO is produced from L- arginine by a enzymes called NO synthases (neural, inducible and endothelial).

12. NO activates the guanylyl cyclase , increasing cellular cyclic GMP . In the vasculature, basal release of NO produced by endothelial cells is a primary determinant of resting vascular tone. NO is also synthesized in response to shear stress or a variety of vasodilating agents

13. Properties : Vasodilation Inhibits platelet aggregation and adhesion. In the immune system , it serves as an effector of macrophage-induced cytotoxicity . Overproduction of NO is a mediator of inflammation .

14. NO has been implicated in mediating central nociceptive pathways

15. Metabolism : NO is rapidly inactivated in the circulation by oxyhaemoglobin . Also, reaction of NO + heme iron = nitrosyl -hemoglobin.

16. Small quantities of methemoglobin are also produced. (These are converted to the ferrous form of heme iron by cytochrome b5 reductase ) The majority of inhaled NO is excreted in the urine in the form of nitrate

17. Therapeutic Uses : Inhaled NO is FDA-approved for only one indication--- persistent pulmonary hypertension of the newborn It is also used in adult and neonatal respiratory distress. Adverse effects : Methaemoglobinaemia Pulmonary toxicity.

18. Vasodilator peptides Natriuretic Peptide Vasoactive intestinal peptide (VIP) Substance P Neurotensin Calcitonin Gene-related Peptide Adrenomedullin

19. Natriuretic Peptide : These are Atrial natriuretic peptide (ANP) B- type natriuretic peptide (BNP) C-type natriuretic peptide (CNP) Urodilatin The inner medullary collecting duct (IMCD) is major site of action of natriuretic peptides.

20. ANP BNP CNP Site of synthesis Cardiac atrial cells+++, ventricular cells++, central and peripheral neurons Ventricular cells ++++ Vascular endothelium, CNS, kidney Factors stimulating release Atrial stretch, ECF expansion, Heart Failure, Primary aldosteronism Volume expansion Not clear actions Natiuresis , diuresis , decrease in BP (vasodilation) same as ANP Vasodilator, lesser natriuretic and diuretic effects. uses Diagnostic / Prognostic marker in heart failure In CHF

21. ANP A (Receptors) ANP B ANP C Location On the surface of target cells Same as ANP A Vascular endothelium Ligand ANP,BNP CNP ANP, BNP, CNP Mechani-sm Increases cGMP levels, decrease in free Ca2+ conc. -do- not clear function previous table Previous table Removal of ANP, BNP and CNP from circulation. “ clearance receptor”

22. Note on Urodilatin : Is like ANP, synthesised in distal tubule of kidney from ANP precursors. It produces natriuresis , diuresis and vasodilation.

23. Mechanism & Site of action of Natriuretic Peptide: The IMCD is the final site along the nephron where Na + is reabsorbed. There is a cyclic nucleotide gated cation ( CNG) channel in IMCD.

24. This channel is highly selective for cations over anions, has equal permeability for Na + and K + . CNG Channel is inhibited by cGMP , PKG, and atrial natriuretic peptides (ANP). Also, ANP stimulate membrane-bound guanylyl cyclase activity and elevate cellular cGMP

25. This leads to natriuresis at the level collecting duct.

26. Pharmacokinetics of natriuretic peptides : Shorter T-half . metabolized by neutral endopeptidase (NEP-24.11) in kidney, Liver and Lungs and Also removed by ANP C receptor

27. Drugs : Carperitide -Human recombinant ANP, available only in Japan. Nesiritide - Recombinant BNP are currently available therapeutic agents of this class Ularitide ( phase 3 trial )– Synthetic urodilatin

28. Nesiritide : Recombinant BNP. Increases cGMP in vascular smooth muscle resulting in -- Vasodilation and reduction in pulmonary capillary wedge pressure. --- No effect on cardiac contractility. Pharmacokinetics : Half life – 18-23 min Diuretic effect : I.V infusion 60 min.

29. Haemodynamic effect : 2-4 hr ( after I.V bolus) Metabolism : by neutral endopeptidases in brush border of kidney Indication : Acutely decompensated CHF with dyspnoea at rest . Dose : 0.01 mcg/kg/min I.V infusion

30. Adverse effects : Hypotension Raised serum creatinine . Headache.

31. Vasopeptidase inhibitors These inhibits neutral endopeptidases 24.11 and ACE (also). So increases level of ANP and BNP and decreases Angiotensin II. Resulting in enhanced vasodilation with Na+ and water excretion.

32. Drugs : ( None approved ) Omapatrilat , Sampatrilat and fasidotrilat . All improved cardiac function in HF and BP in HTN. But they caused angioedema , cough and dizziness .

33. Direct vasodilators Hydralazine Hydralazine (1-hydrazinophthalazine) was one of the first orally active antihypertensive drugs marketed.

34. Mechanism of Action Hydralazine directly relaxes arteriolar smooth muscle. Molecular targets/mechanisms that explain its capacity to dilate arteries remain uncertain.

35. Evidence shows that Hydralazine inhibits IP 3 -induced release of Ca 2+ from intracellular storage sites in arteries. ultimately fall in intracellular calcium concentrations leading to diminished contraction.

36. Hydralazine promotes arterial dilation by opening high conductance Ca 2+ -activated K + channels. Also, it has nitric oxide–enhancing actions It does not relax venous smooth muscle .

37. Pharmacological Effects It is confined to the cardiovascular system. Involves selective reduction of blood pressure in coronary, cerebral, and renal circulations , with smaller effect in skin and muscle.

38. Postural hypotension is not a common problem (Because of preferential dilation of arterioles over veins) However , vasodilation is associated with baroreceptor -mediated reflexes, to results in Increased heart rate and contractility. Increased plasma renin activity, and fluid retention.

39. Pharmacokinetics : Hydralazine is well absorbed. But the systemic bioavailability is low due to first pass metabolism. (16% in fast acetylators and 35% in slow acetylators ). Hydralazine is N -acetylated in the bowel and the liver.

40. The t 1/2 is 1 hour. Duration of action : 12 hrs (accumulation in artery wall) Peak hypotensive effect : within 30-120 minutes of PO

41. Toxicity and Precautions Headache , nausea, flushing, hypotension. Stimulation of the sympathetic nervous system : Palpitations, tachycardia, dizziness, and angina pectoris. Myocardial ischemia ( baroreceptor reflex-induced ,increased O 2 demand) So I.V Hydralazine is not preferred in HTN with CAD

42. Salt retention + high-output congestive heart failure (if the drug is used alone) So it is better tolerated when combined with beta blocker and diuretic. Drug -induced lupus syndrome ( usually after 6 months).

43. Uses No more first line drugs for essential hypertension. If used, it is with combination diuretics and Beta- blockers. Dose : 25-100 mg twice daily. Max 200mg.

44. Mainly used In hypertensive emergencies : 10–50 mg at 30-min intervals I.V. It is preferred in - preeclampsia.

45. In CHF : It reduces ventricular afterload by reducing pulmonary and systemic vascular resistance. Recently demonstrated, combination therapy with isosorbide dinitrate , reduces CHF mortality.

46. Minoxidil Discovered in 1965. Hypotensive action of minoxidil was a significant advance in the treatment of hypertension. It has proven to be efficacious in patients with the most severe and drug-resistant forms of hypertension.

47. Mechanism of Action : Minoxidil is not active in vitro . It is metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate. Minoxidil sulfate activates the ATP-modulated K + channel in smooth muscle. By opening K + channels , thereby permitting K + efflux , it cause hyperpolarization and relaxation of smooth muscle.

48. Pharmacological Effects Minoxidil produces arteriolar vasodilation with essentially no effect on the capacitance vessels. It increases blood flow to skin, skeletal muscle, the gastrointestinal tract, and the heart more than to the CNS.

49. It is a renal artery vasodilator. Renal function improves in patients who take minoxidil for the treatment of hypertension. (especially if renal dysfunction is secondary to hypertension)

50. Pharmacokinetics : Minoxidil is well absorbed. BA : 90% Initial effect : 1 hour after PO Plasma t 1/2 of 3-4 hours. Duration of action is 2- 5 days. Metabolism : liver , via Glucuronidation

51. Adverse effects Hypertrichosis (80 %) : after extended period (probably a consequence of K + channel activation) Growth of hair occurs on the face, back, arms, and legs. Fluid and salt retention

52. Cardiovascular effects : similar to Hydralzine Abnormal ECG (60%) : Flattened and inverted T, similar to other K+ channel openers. Others : rashes, Stevens-Johnson syndrome

53. Uses Severe hypertension : is best reserved for the treatment that Responds poorly to other antihypertensive medications. HTN with renal insufficiency in male patients.

54. They are concurrently used with a diuretic and beta blockers. Dose : 2.5mg , 10 mg PO Topical solution 2%, 5%: It is used in male pattern baldness and Alopecia Areata .

55. Diazoxide Diazoxide was used in the treatment of hypertensive emergencies. Fell out of favor -risk of marked falls in blood pressure when large bolus doses of the drug were used. Current use : treat patients with hypoglycemia ( inoperable islet cell adenoma). Dose : 50mg/ml oral suspension

56. Nitroglycerine Organic nitrates/ nitrovasodilators / nitric oxide donors : Nitroglycerine etc. They lead to the formation of the reactive gaseous free radical NO and related compounds. The exact mechanism of denitration to liberate NO is an active area of investigation.

57. Mechanism of action : Phosphorylation of the myosin light chain regulates the maintenance of the contractile state in smooth muscle. NO activate guanylyl cyclase , increase the cellular level of cyclic GMP, activate Protein Kinase G (PKG) .

58. Activated PKG and leads to dephosphorylation of the myosin light chain. This promotes vasorelaxation .

59. Pharmacological action : Low concentrations of nitroglycerin preferentially dilate veins more than arterioles. Decreased venous return, leads to fall in left and right ventricular chamber size and end-diastolic pressures.

60. Systemic arterial pressure may fall slightly. Heart rate is unchanged or may increase slightly in response to a decrease in blood pressure.

61. Pulmonary vascular resistance and cardiac output are slightly reduced. Very low Doses , (that do not alter systemic arterial pressure) may still produce arteriolar dilation in the face and neck. This result in a facial flush , or dilation of meningeal arterial vessels, cause headache .

62. Basis for the differential response of arterial versus venous tissues remains unclear. However , at Higher doses , there is further venous pooling and may decrease arteriolar resistance as well. This decreases SBP , DBP and CO

63. Coronary vessel : Nitrates preferrentially relax bigger conducting coronary arteries than arterioles and resistance vessels. So has favourable redistribution to ischemic areas in angina patients Heart : No direct stimulant or depressant action on heart.

64. Uses : Angina (including prinzmetal’s ): An initial dose of 0.3 mg nitroglycerin often relieves pain within 3 minutes. MI : To relieve ischemic pain and pulmonary congestion. Intravenous 5–200 mcg/min CHF/ LVF : To decrease preload. Biliary colic & Esophageal spasm : to relieve pain.

65. Post operative Hypertension : ( drug of choice ) Cyanide Poisoning : methaemoglobin generated by nitrates has greater affinity for cyanide. Used along with Sod. Thiosulphate .

66. Adverse effects : Headache is common . Transient episodes of dizziness, weakness, postural hypotension. Drug rash. Tolerance

67. Sodium Nitroprusside Mechanism of Action It is a nitrovasodilator that acts by releasing NO. NO activates the guanylyl cyclase – cyclic GMP– PKG pathway, leading to vasodilation. So It mimicks the production of NO by vascular endothelial cells, which is impaired in many hypertensive patients .

68. Tolerance develops to nitroglycerin but not to nitroprusside .

69. Pharmacological Effects Nitroprusside dilates both arterioles and venules . So causes : venous pooling and reduced arterial impedance. In normal subjects , venous pooling affects cardiac output (more than does the reduction of afterload ) so here, cardiac output tends to fall.

70. In contrast , in patients with severely impaired left ventricular function and diastolic ventricular distention the reduction of arterial impedance is the predominant effect , leading to a rise in cardiac output.

71. It is a nonselective vasodilator, and regional distribution of blood flow is little affected by the drug. Renal blood flow and glomerular filtration are maintained. Unlike , other arteriolar vasodilators, Only a modest increase in heart rate and an overall reduction in myocardial O 2 demand .

72. Pharmacokinetics : The drug must be protected from light and given by continuous intravenous infusion to be effective. Onset of action is within 30 seconds. Peak hypotensive effect : 2 minutes The effect disappears within 3 minutes when the infusion is stopped.

73. Metabolized in Blood (100%). Ferrous ion in nitroprusside reacts with sulphydryl compounds in RBCs . This releases Cyanide . Cyanide is further metabolized by rhodanase in liver to form thiocyanate . It is eliminated almost entirely in the urine.

74. Uses It is used primarily to treat hypertensive emergencies. Dose : 2–4 mcg/kg/min; maximum 10 mcg/kg/min for 10 min Acute aortic dissection (to lower blood pressure )

75. To improve cardiac output in CHF , especially in hypertensive patients with pulmonary edema. To induce controlled hypotension during anesthesia to reduce bleeding in surgical procedures.

76. Adverse effects Common ones : Hypotension, bradyarrhythmia , tachyarrhythmia . Headache, restlesness . Injection site irritation.

77. Serious ones : Cyanide poisoning : Management - concomitant administration of sodium thiosulfate can prevent accumulation of cyanide. Thiocynate toxicity : (seen in renal failure) anorexia, nausea, fatigue, disorientation, and toxic psychosis Management - Haemodialysis Raised intracranial pressure

78. Thank you References : Rang and Dale Goodman & Gilman HL Sharma and KK Sharma KD Tripathi Harrison’s principles of Internal medicine