Antihypertensive drugs

Updated hypertension classification and drugs used for treat it.

1. ANTIHYPERTENSIVE DRUGS PH 1.27 DR MONICA JAIN

2. Specific Learning objective At the end of session student would able Define hypertension Discuss types of hypertension Enlist drugs used for hypertension Explain mechanism of action and adverse effect of each class of drugs Will be able to choose drug of choice in specific condition Distinguish between emergency and urgency types of hypertension

3. Specific learning objective Describe advantages and disadvantages of each class of drugs Explain the drugs preferred and avoided with justification in hypertension during pregnancy Discuss Hypertension treatment in angina,CHF,diabetes,bronchial asthma,gout,obesity , migraine,osteoporosis

4. Primary or idiopathic or essential hypertension Most adults with hypertension are in this category. It is combination of genetics, diet, lifestyle, and age. Lifestyle factors include smoking, drinking too much alcohol, stress, being overweight, eating too much salt, and not getting enough exercise.

5. Secondary Hypertension Secondary hypertension is when there’s an identifiable— and potentially reversible— cause of your hypertension.   30 percent  of those ages 18 to 40 with hypertension have secondary hypertension. The underlying causes of secondary hypertension include: narrowing of the arteries  that supply blood to your kidneys adrenal gland  disease side effects of some medications, including birth control pills, diet aids, stimulants, antidepressants, and some over-the-counter medications obstructive sleep apnea hormone abnormalities, thyroid abnormalities , constriction of the aorta

6. Difference between urgency and emergency Hypertensive urgency  has no associated target organ damage, whereas  hypertensive emergency  can feature neurologic, aortic, cardiac, renal, hematologic, and/or pregnancy-related damage Hypertensive  urgency is defined as having a systolic blood pressure over 180 mmHg or a diastolic blood pressure over 110 mmHg.  Hypertensive emergency  is defined as elevated blood pressure consistent with  hypertensive  urgency, plus evidence of impending irreversible  hypertension -mediated organ damage (HMOD).

7. Mnenomic 3A- alpha blockers,ACE inhibitors,ARB blockers Beta blockers 2C calcium channel blockers, central sympatholytics 2D diuretics, dialators

8. Non Pharmacological measure

9. Classification CLASSIFICATION 1. Diuretics Thiazides : Hydrochlorothiazide, Chlorthalidone , Indapamide High ceiling :Furosemide , etc. K+ Sparing : Spironolactone , Amiloride 2. ACE inhibitors Captopril , Enalapril , Lisinopril , Perindopril , Ramipril , Fosinopril , etc. 3. Angiotensin (AT1 receptor ) blockers Losartan , Candesartan , Irbesartan , Valsartan , Telmisartan 4. Direct renin inhibitor Aliskiren

10. 5. Calcium channel blockers Verapamil , Diltiazem , Nifedipine , Felodipine , Amlodipine , Nitrendipine , Lacidipine , etc. 6. β Adrenergic blockers Propranolol , Metoprolol , Atenolol , etc 7 . β + α Adrenergic blockers Labetalol , Carvedilol 8 . α Adrenergic blockers Prazosin , Terazosin , Doxazosin Phentolamine , Phenoxybenzamine 9. Central sympatholytics Clonidine , Methyldopa 10. Vasodilators Arteriolar: Hydralazine , Minoxidil , Diazoxide Arteriolar + venous : Sodium nitroprusside

11. ACE inhibitor status in hypertension First line drug Useful for all grades of hypertension Well tolerated Indicated specially as antihypertensives in -hypertension with hypertrophy of heart With DM as they slow development of nephropathy With renal disease slow progression of chronic renal disease Coexisting IHD and post MI Can be combined with other antihypertensives like beta blockers,CCBs,Diuretics

12. Mechanism of action Reduces BP by Reduction in peripheral arterial resistance Inhibition of AngII formation and raised bradykinin levels Fall in aldosterone level Increase in renin activity Suitable for young patient, also patient with gout, PVD, dyslipidemic,with LVH

13. Advantages Free of postural hypotension, electrolyte disturbances, feeling of weakness and CNS effects. • Safety in asthmatics, diabetics and peripheral vascular disease patients. • Long-term ACE inhibitor therapy has the potential to reduce incidence of type 2 diabetes in high risk subjects. • Secondary hyperaldosteronism and K+ loss due to diuretics is prevented. • Renal blood flow is well maintained.

14. Contd • Left ventricular hypertrophy and increased wall-to-lumen ratio of blood vessels that occurs in hypertensive patients is reversed. No hyperuricaemia , no deleterious effect on plasma lipid profile. • No rebound hypertension on withdrawal. • Minimum worsening of quality of life parameters like general wellbeing, work performance sleep, sexual performance

15. Special points Captopril and lisniopril active drug Extensive tissue distribution- ramipril

16. ARB blockers Do not interfere with degradation of bradykinin and so cough is rare. • They result in more complete inhibition of AT1 receptor activation, because responses to Ang II generated via alternative pathways and consequent AT1 receptor activation (which remain intact with ACE inhibitors) are also blocked. • They result in indirect AT2 receptor activation.

17. Contd Due to blockade of AT1 receptor mediated feedback inhibition—more Ang II is produced which acts on AT2 receptors that remain unblocked. • ARBs cause little increase in the level of Ang (1-7) which is raised by ACE inhibitors, since Ang (1-7) is partly degraded by ACE.

18. Advantages No cough Losartan has antiplatelet effect and metabolite of losartan reduces PG synthesis Effective in portal hypertension due to cirrhosis of liver also reduces proliferation of arteriolar intima Except losartan all are longer acting

19. Calcium channel blockers The common property of all three subclasses of CCBs is to inhibit Ca2+ mediated slow channel component of action potential (AP) in smooth/ cardiac muscle cell. The two most important actions of CCBs are: ( i ) Smooth muscle (especially vascular) relaxation . (ii) Negative chronotropic , inotropic and dromotropic action on heart.

20. Classification Three important classes of calcium channel blockers are examplified by: Verapamil —a phenyl alkylamine , hydrophilic papaverine congener. Nifedipine —a dihydropyridine ( lipophilic ). Diltiazem —a hydrophilic benzothiazepine .

21. Dihydropyridines (DHP) Ultra short acting- clevidipine Short acting – nifedipine , nicardipine,nimodipine Intermediate acting- nisoldipine,niterndipine,isradipine,lacidipine , Cilnidipine,lercanidipine Longer acting – felodipine,benidipine and amlodipine

22. Important features Nifedipine – have intrinsic natriuretic effect so does not need diuretic Ankle edema due to dilation and reflex post capillary constriction leading increase hydrostatic pressure Lacidipine cause least ankle edema and slows progression of carotid atherosclerosis, limits development of new metabolic syndrome ,good vasoprotection Nicardipine – more coronary dialator

23. Important features Cilnidipine –more renoprotective Nimodipine –lipid soluble and crosses blood brain barrier , cerbroselective Clevidipine –t1/2 ultra short acting L type CCBwith terminal t1/2 less than 15 min

24. CALCIUM CHANNEL BLOCKERS 1. Do not compromise haemodynamics : no impairment of physical work capacity. 2. No sedation or other CNS effects; cerebral perfusion is maintained. 3.Not contraindicated in asthma, angina (especially variant) and PVD patient: may benefit these conditions. 4. Do not impair renal perfusion. 5. Do not affect male sexual function.

25. Contd 6. No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance. 7. Shown to have no/minimal effect on quality of life. 8. No adverse foetal effects; can be used during pregnancy (but can weaken uterine contractions during labour).

26. Arteriolar vasodialators Include hydralazine,minoxidil,diazoxide and fenoldapam They act by increase in K ion conduction causing hyperpolarization of cell membrane which causes relaxation of vascular smooth muscle Should be combined with beta blockers or diuretics

27. Hydralazine dose 25 to 50mg B.D Needs intact endothelium Activates k channel Generation of nitric oxide and stimulation of cGMP Max response in 30 min to 1 hr Duration 6hrs Prolong use cause DLE as it undergoes N- acetylation Adverse effect due to vasodialation

28. Minoxidil 2.5-5mg daily Orally effective Potent longer acting Converts into active metabolite minoxidil sulphate which opens potassium channel Maximum effect within 1-2 minutes but antihypertensive effect last for 12 to 24 hrs Indicated in severe HT or HT associated with chronic renal failure Typical adverse effect hirsuitism in women as it activates a specific gene that regulates the hair shaft protein

29. Diazoxide Related to thiazide but causes fluid retention Long lasting arteriolar dialatory BP lower in 3-5 min after I.V injection Long term causes hyperuracemia,hyperglycemia and fluid retention Used in treatment of malignant hypertension ,hypertensive encephalopathy and eclampsia

30. Diuretics Studies shows hydrochlorothiazide is to be used as 12.5 mg and in combination it can be combined with vasodilators or sympatholytics Effective in elderly and with systolic hypertension They reduce calcium excretion so useful in osteoporosis Not effective in chronic kidney disease, metazoline and indapamide effective

31. Fenoldopam dose 0.1 to 1.5 microgms /kg/min Agonist at D1 leading to natriuresis and dilatation of peripheral arteries Rapid onset ,short half life Given I>V infusion for short term management of hypertensive emergencies Urine output, creatinine clearence and Na excretion increases so indicated in hypertensive emergency with renal impairment Concomitant use of beta blocker or diuretic not needed ADR-HYPOKALEMIA,RAISED IOP

32. Sodium N itroprusside Activates guanylyl cyclase either directly or through release of NO Causes increase incGMP -vascular smooth muscle relaxation Powerful,parenterally administered arteriolar veno dialator Onset 30 sec after IV infusion 0.3microgm/kg/min and disaapear in ten min after stopping

33. Contd Indicated in severe HT with acute MI and LVF Aqueous solution of sodium nitroprusside are unstable and sensitive to light so solution freshly made before each administration and bottle covered with black paper Apart from headache nausea and vomiting cynaide and thiocynate accumulation cause toxicity

34. Contd Sodium nitroprusside in erythrocytes to cynaide and in liver convert into thiocynate half life of which is 3 days In renal insufficiency it accumulates causing metabolic acidosis and arrhythmias Thiocynate toxicity manifested as psychosis ,disorientation and convulsion Delayed hypothyroidism may also occur as thiocyanate inhibit iodine uptake Treatment – sodium thiosulfate and hydroxycobalamine

35. Thiazides (hydrochlorothiazide, chlorthalidone ) Chlorthalidone is longer acting (~ 48 hours) than hydrochlorothiazide (< 24 hours) and may have better round-the-clock action

36. Proposed action 1. Initially, the diuresis reduces plasma and e.c.f . volume by 5–15%, and this decreases c.o. 2. Subsequently, compensatory mechanisms operate to almost regain Na+ balance and plasma volume; c.o. is restored, but the fall in BP is maintained by a slowly developing reduction in t.p.r

37. Proposed action Small persistent deficit of Na+ concentration in the vascular smooth muscle may reduce stiffness of vessel wall, increase their compliance and dampen responsiveness to constrictor stimuli (NA, Ang II). Has vasodilator action by opening potassium channel K+ATP Thiazides are mild antihypertensives , average fall in mean arterial pressure is ~10 mm Hg

38. Desirable properties of thiazide diuretics as antihypertensives are: 1. Once a day dosing and flat dose-response curve permitting simple standardized regimens. 2. No fluid retention, no tolerance. 3. Low incidence of postural hypotension and relative freedom from side effects, especially CNS, compared to sympatholytics . 4. Effective in isolated systolic hypertension (ISH). 5. Lessened risk of hip fracture in the elderly due to hypocalciuric action of thiazides . 6. Low cost.

39. Features Thiazides have no effect on capacitance vessels, sympathetic reflexes are not impaired: postural hypotension is rare. In combination, they are useful in any grade of hypertension. They are more effective in the elderly and maximal antihypertensive efficacy is reached at 25 mg/day dose Their antihypertensive action is attenuated by NSAIDs.

40. Indapamide It is a mild diuretic, chemically related to chlorthalidone reduces BP at doses which cause little diuresis . Electrolyte disturbances and K+ loss are minimal at antihypertensive doses. It probably has additional vasodilator action exerted through alteration of ionic fluxes across vascular smooth muscle cell. Indapamide is well absorbed orally, has an elimination t½ of 16 hr. Single daily dose (2.5 mg) is enough

41. High ceiling diuretics Antihypertensive efficacy does not parallel diuretic potency. Furosemide is a weaker antihypertensive than thiazides : fall in BP is entirely dependent on reduction in plasma volume and c.o. The natriuretic action lasting only 4–6 hr after the conventional morning dose is followed by compensatory increase in proximal tubular reabsorption of Na

42. Proposed mechanism They are indicated in hypertension only when it is complicated by: (a) Chronic renal failure: thiazides are ineffective , both as diuretic and as antihypertensive. (b) Coexisting refractory CHF. (c) Resistance to combination regimens containing a thiazide , or marked fluid retention due to use of potent vasodilators.

43. Adverse effects • Hypokalaemia —muscle pain, fatigue and loss of energy. Erectile dysfunction in males. • Carbohydrate intolerance: due to inhibition of insulin release (probably secondary to K+ depletion which interferes with conversion of proinsulin to insulin), precipitation of diabetes. • Dyslipidemia : rise in total and LDL cholesterol and triglycerides with lowering of HDL. This could increase atherogenic risk, but no direct evidence has been obtained. • Hyperuricaemia : by inhibiting urate excretion—increased incidence

44. Beta blockers They are mild antihypertensives do not significantly lower BP in normotensives . Used alone they suffice in 30–40% patients—mostly stage I cases Response develop in one to three weeks Nebivolol reduces t.p.r . by generating NO

45. Mechanism of action central inhibition of sympathetic nervous system outflow inhibition of the renin–angiotensin system by decreasing renin release from the juxtaglomerular apparatus decreasing heart rate and myocardial contractility, and a resetting of the baroreceptors Stimulation of prostacyclin synthesis in vascular bed Reduce NA release from sympathetic terminal due to blockade of beta receptor mediated facilitation of release process

46. Cardioselective beta blockers 1. Lower propensity to cause bronchoconstriction . 2. Less interference with carbohydrate metabolism and less inhibition of glycogenolysis during hypoglycaemia—safer in diabetics. However, tachycardia in response to hypoglycaemia is blocked. 3. Lower incidence of cold hands and feet, less chances of precipitating Raynaud’s phenomenon . 4. No/less deleterious effect on blood lipid profile. 5. Ineffective in suppressing essential tremor (it occurs through β2 action on muscle fibres). 6. Less liable to impair exercise capacity

47. Beta blockers Indication 1. Stable heart failure Post MI CAD Suitable for young patient,anxious Low cost therapy

48. β+α ADRENERGIC BLOCKERS- Labetalol It is a combined α and β blocker reduces t.p.r . and acts faster than pure β blockers. It has been used i.v . for rapid BP reduction in hyperadrenergic states, cheese reaction, clonidine withdrawal, eclampsia , etc. Oral labetalol therapy is restricted to moderately severe hypertension not responding to a pure β blocker, because side effects of both α blocker and β blocker occur with it

49. Carvedilol This nonselective β + weak selective α1 blocker produces vasodilatation and has additional antioxidant/free radical scavenging properties. Carvedilol is a frequently selected drug for long-term treatment of CHF, and is approved as an antihypertensive as well. Side effects are similar to labetalol ; liver enzymes may rise in some.

50. α- ADRENERGIC BLOCKERS- Prazosin alpha antagonist dilates both resistance and capacitance vessels; more on resistance little reflex cardiac stimulation and renin release during long-term therapy. postural hypotension and fainting may occur in the beginning—called ‘first dose effect’, and with dose increments so given at bed time with low dose then increased

51. Advantages Does not impair carbohydrate metabolism; suitable for diabetics, but not if neuropathy is present, because postural hypotension is accentuated. • Has a small but favourable effect on lipid profile: lowers LDL cholesterol and triglycerides increases HDL. • Affords symptomatic improvement in coexisting benign prostatic hypertrophy.

52. Adverse effect Headache, drowsiness, dry mouth, weakness, palpitation, nasal blockade, blurred vision and rash. Ejaculation may be impaired in males: especially with higher doses. Fluid retention attending prazosin monotherapy may precipitate CHF. It may be added to a diuretic + β blocker in those not achieving target BP

53. Why Nonselective α blockers ( Phentolamine , Phenoxybenzamine ) is not used as HT because fall in t.p.r . is compensated by increased HR and c.o. They are reserved for special situations like pheochromocytoma , clonidine withdrawal, cheese reaction, etc., where circulating CAs are responsible for the rise in BP

54. CENTRAL SYMPATHOLYTICS Clonidine –dose Dose : Start with 100 µg OD or BD, max. 300 µg TDS, orally or i.m . imidazoline derivative High affinity to alpha2 receptor especially α2A subtype in brainstem and stimulates imidazole receptor present in brain and periphery α2A receptors present mainly postjunctionally in medulla (vasomotor centre). This decreases sympathetic out flow → fall in BP and bradycardia .

55. Enhanced vagal tone contributes to bradycardia . Plasma NA declines. Though clonidine is capable of reducing NA release from peripheral adrenergic nerve endings (release inhibitory prejunctional α2 action but not manifest at clinically used doses)

56. Important point Rapid i.v . injection of clonidine raises BP transiently due to activation of peripheral postsynaptic vasoconstrictor α2B receptors at the high concentration At low dose cause because clonidine has lower intrinsic activity on α2B receptors which predominate in vascular smooth muscle Therapeutic window - 0.2–2.0 ng /ml optimum control

57. Adverse effect mouth, nose and eyes (secretion is decreased by central action), constipation ( antisecretory effect on the intestines). • Impotence, salt and water retention, bradycardia . • Postural hypotension occurs, but is mostly asymptomatic.

58. Clonidine withdrawl Features Alarming rise in BP, in excess of pretreatment level, with tachycardia, restlessness, anxiety, sweating, headache, nausea and vomiting occur in some patients when doses of clonidine are missed for 1–2 days. This is due to: (a) Sudden removal of central sympathetic inhibition resulting in release of large quantities of stored CAs. (b) Supersensitivity of peripheral adrenergic structures to CAs that develops due to chronic reduction of sympathetic tone during clonidine therapy.

59. Other uses 1. Opioid withdrawal: Opioid and α2 adrenergic systems converge on the same effectors in many systems; both activate the Gi regulatory protein. Clonidine suppresses sympathetic overactivity of opioid withdrawal syndrome and reduces craving to some extent. Clonidine has also facilitated alcohol withdrawal and smoking cessation. 2. Clonidine has analgesic activity. It has been used to substitute morphine for intrathecal /epidural surgical and postoperative analgesia.

60. Other uses 3. Clonidine attenuates vasomotor symptoms of menopausal syndrome. 4. Clonidine has been used to control loose motions due to diabetic neuropathy. It may be acting by α2 receptor mediated enhancement of salt absorption in gut mucosa

61. Methyldopa – used in pregnancy induced hypertension precursor of dopamine (DA) and NA α methyl-NA (a selective α2 agonist) formed in the brain from methyldopa acts on central α2 receptors to decrease efferent sympathetic activity. Because methyldopa decreases t.p.r . more than HR or c.o., it may be acting on a different population of neurones in the vasomotor centre than clonidine

62. Adverse effect CNS- Sedation, lethargy and reduced mental capacity are common side effects. Cognitive impairment may develop. Dryness of mouth, nasal stuffiness, headache, fluid retention, weight gain, impotence are the other side effects. Postural hypotension is generally mild. Positive Coomb’s test occurs in 1/6 patients, few develop haemolytic anaemia. Fever, rash, hepatitis, ‘flu’ like illness, thrombocytopenia and rarely lupus syndrome occur. Rebound hypertension on sudden withdrawal of methyldopa is mild and less common.

63. Hydralazine – arteriolar dialator dose -25–50 mg OD–TDS; reduces t.p.r . and causes greater decrease in diastolic than in systolic BP. Reflex compensatory mechanisms are evoked which cause tachycardia, increase in c.o. and renin release → increased aldosterone → Na+ and water retention. Cardiac stimulation is due augmentation of NA release hyperdynamic circulatory state is induced—angina may be precipitated

64. contd Tolerance to the hypotensive action develop so other drugs are to added Mechanism of action Interference with Ca2+ release, opening of certain K+ channels and/or NO generation may be involved

65. Important points metabolic pathway is acetylation which exhibits a bimodal distribution in the population: there are slow and fast acetylators . Bioavailability is higher in slow acetylators , but these patients are more prone to develop the lupus syndrome , t½ 1–2 hours. However, hypotensive effect lasts longer (12 hours), probably because of its persistence in the vessel wall.

66. Adverse effect Vasodilatation induce • Facial flushing, conjunctival injection, throbbing headache, dizziness, palpitation, nasal stuffiness, fluid retention, edema , CHF. • Angina and MI may be precipitated in patients with coronary artery disease.

67. Avoided during pregnancy ACE inhibitors, ARBs: Risk of foetal damage, growth retardation. Diuretics: Tend to reduce blood volume— accentuate uteroplacental perfusion deficit (of toxaemia)—increase risk of foetal wastage, placental infarcts, miscarriage, stillbirth. Nonselective β blockers: Propranolol has been implicated to cause low birth weight, decreased placental size, neonatal bradycardia and hypoglycaemia. Sod. nitroprusside : Contraindicated in eclampsia .

68. Safe drugs Hydralazine ,Methyldopa (a positive Coombs’ test occurs, but has no adverse implication). Dihydropyridine CCBs: if used, they should be discontinued before labour as they weaken uterine contractions . Cardioselective β blockers and those with ISA, e.g. atenolol , metoprolol , pindolol , acebutolol : may be used if no other choice. Prazosin and clonidine —provided that postural hypotension can be avoided.

69. Hypertensive emergencies and urgencies Emergency – there is high BP Systolic BP > 220 or diastolic BP > 120 mm Hg End organ damage present – is emergency Mean BP should be lowered by no more than 25% over a period of minutes or a few hours and then gradually to not lower than 160/100 mm Hg. Drugs employed are:

70. Sodium nitroprusside predictable, instantaneous, titratable and balanced arteriovenous vasodilatory action which persists without tolerance till infused, nitroprusside (20–300 μg /min) is the drug of choice for most hypertensive emergencies. Continuous monitoring and infusion pump required If MI or LVF then nitroglycerine

71. Glyceryl trinitrate Given by i.v . infusion (5–20 μg /min) GTN also acts within 2–5 min and has brief titrat able action, but is a less potent hypotensive . Its predominant venodilator action makes it particularly suitable for lowering BP after cardiac surgery and in acute LVF, MI, unstable angina, but not in other conditions. Tolerance starts developing after 18–24 hours of continuous infusion

72. Hydralazine 10–20 mg i.m . or slow i.v . injection; acts in 20–30 min and keeps BP low for 4–8 hours, but is less predictable, and not a first line drug. It has been especially used in eclampsia . It causes tachycardia and should be avoided in patients with myocardial ischaemia or aortic dissection.

73. Esmolol This β blocker given as 0.5 mg/kg bolus followed by slow i.v . injection (50–100 μg /kg/min) acts in 1–2 min; action lasts for 10–20 min. It is particularly useful when cardiac contractility and work is to be reduced, such as in aortic dissection. Nitroprusside is given concurrently, because the BP lowering action is weaker. It is a useful hypotensive and bradycardiac drug during and after anesthesia . Excess bradycardia is to be guarded

74. Phentolamine This nonselective α1 + α2 blocker is the drug of choice for hyperadrenergic states, e.g. hypertensive episodes in pheochromocytoma , cheese reaction or clonidine withdrawal. Injected i.v . (5–10 mg) it acts in 2 min and action lasts 5–15 min.

75. labetalol Injected i.v ., it is an alternative to an α blocker + a β blocker combination for lowering BP in pheochromocytoma , etc. but has only weak α blocking action. It has been used to lower BP in MI, unstable angina, eclampsia as well. It is also good for patients with altered consciousness, because it does not cause sedation or increase intracranial pressure.

76. Hypertensive emergencies Mean BP should fall up to 25% over few minutes or hour to gradually 160/100mmHg If reduce too quickly then perfusion of vital organs Vasodilators and adrenergic blockers will serve the purpose

77. Drugs Nicardipine – DHP most popular drug for variety of hypertensive emergencies replacing nitroprusside Highly Vasoselective Dilates arteriolar Reflex tachycardia can be blocked beta blocker can be added Target BP reaches in an hour

78. Nicardipine Fall in BP is predictable and dose related Elimination half life 45 minutes effect last for 3-4 hrs Beneficial in both haemorrhagic stroke and ischaemic , arotic dissection,acute heart failure and preclamsia Less toxic than sodium nitroprusside Dose -5mg/hr also used hypertension attending cardiac surgery and neurosurgeryas well as to facilitate percutaneous coronary intervention

79. Sodium nitroprusside Instantaneous Potent Combined arterio and venodialator Main indication in arotic dissection along with esmolol In acute hypertensive heart failure can be combined with loop diuretic Rapid acting so used precise infusion pump And BP monitoring , it produce cyanide and thiocyanate

80. Glyceryl trinitrate Infused IV 5-20mg microgram /min act in 2to 5min but not a potent hypotensive Venodialtoe useful in patient associated with MI or ACS Needs to be combined with labetalol or nicardipine If used continuously greater than 12 hours tolerance develop

81. Labetalol This alpha and beta blocker Used in pheochromocytoma , cheese reaction and cocaine abuse Also in arotic dissection, MI,ACS and preeclampsia Good for patient with altered mental function as it does not cause sedation Dose 20 to 40 mg i.v . every ten minutes till response or increase up to 20mg/hr

82. Esmolol Ultra short acting beta blocker given in dose of 0.5mg/kg bolus i.v followed by 50 to 200microgram /kg/min acts in 1-2 min and last for 10 -20min Useful cardiac contractility and heart rate need to be reduce use in combination of nicardipine or nitroprusside as BP lowering action low