Hypertension

Regulation of BP and management of Hypertension

1. Dr. Irfan Ahmad Khan JR-2 PHYSIOLOGICAL REGULATION OF BLOOD PRESSURE & DRUG TREATMENT OF HYPERTENSION

2. Introduction Blood pressure ( BP ), sometimes called  arterial blood pressure , is the pressure   exerted by circulating  blood upon the walls of blood vessels , and is one of the principal vital signs. During each heartbeat, blood pressure varies between a maximum ( systolic ) and a minimum ( diastolic ) pressure. MAP = DBP + (SBP-DBP)/3 Mean blood pressure drops over the whole circulation, although most of the fall occurs along the small arteries and  arterioles . Blood pressure ( BP ) is generated by cardiac contraction against the vascular resistance.

3. Stroke volume is related to myocardial contractility and to the size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes in small arteries (lumen diameter 100–400 μ m) and arterioles.

4. Cardiac output The output of the heart per unit of time is the cardiac output CO = Stroke Volume X Heart Rate Stroke volume is affected by preload, afterload and contractility Vascular volume is a primary determinant of arterial pressure over the long term. Blood vol. depends on NaCl intake.It is kidney which regulates the excess NaCl by increasing Na excretion.

5. Vascular mechanism of BP regulation Vascular radius and compliance of resistance arteries are also important determinants of arterial pressure. Resistance to flow varies inversely with the fourth power of the radius.So small decrease in lumen size significantly increase resistance. Regulation of BP involves:- Local Regulation Substances Secreted by the Endothelium Systemic Regulation by Hormones Systemic Regulation by The Nervous System

6. LOCAL REGULATION 1.AUTOREGULATION The capacity of tissues to regulate their own blood flow is referred to as autoregulation . Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance, so that blood flow remains relatively constant. This capacity is well developed in the kidneys but it has also been observed in the mesentery, skeletal muscle, brain, liver and myocardium. 2.VASODILATOR METABOLITES Hypoxia,hypercapnia,↓pH ,↑ temperature,↑K + , Lactate 3.LOCALIZED VASOCONSTRICTION Injured arteries and arterioles constrict strongly due to the local liberation of serotonin from platelets that stick to the vessel wall in the injured area. Injured veins also constrict. ↓ local temperature

7. SUBSTANCES SECRETED BY THE ENDOTHELIUM They secrete many growth factors and vasoactive substances. The vasoactive substances include prostaglandins and thromboxanes , nitric oxide, and endothelins . 1.Prostacyclin & Thromboxane A 2 Prostacyclin is produced by endothelial cells and thromboxane A 2 by platelets from their common precursor arachidonic acid via the cyclooxygenase pathway. Thromboxane A 2 promotes platelet aggregation and vasoconstriction, whereas prostacyclin inhibits platelet aggregation and promotes vasodilation .

8. 2.Nitric oxide (NO) Earlier k/a endothelium-derived relaxing factor (EDRF) NO is synthesized from arginine in a reaction catalyzed by nitric oxide synthase (NO synthase , NOS). Three isoforms of NOS have been identified: 1.NOS 1, found in the nervous system; 2.NOS 2, found in macrophages and other immune cells; and 3.NOS 3, found in endothelial cells. NOS 1 and NOS 3 are activated by agents that increase intracellular Ca 2+ concentrations, including the vasodilators acetylcholine and bradykinin . The NO that is formed in the endothelium diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase , producing cGMP , which in turn mediates the relaxation of vascular smooth muscle. 3.Endothelins Endothelial cells also produce endothelin-1, one of the most potent vasoconstrictor agents. (ET A receptor)

9. SYSTEMIC REGULATION BY HORMONES Many circulating hormones affect the vascular system. Vasodilator hormones include kinins , VIP, and ANP. Vasoconstrictor hormones include vasopressin, norepinephrine , epinephrine, and angiotensin II. 1.Kinins Two related vasodilator peptides called kinins are found in the body. One is bradykinin and the other is lysylbradykinin , also known as kallidin . Lysylbradykinin can be converted to bradykinin by aminopeptidase . Both peptides are metabolized to inactive fragments by angiotensin -converting enzyme. They relax vascular smooth muscle via NO, lowering blood pressure.

10. 2.Natriuretic Hormones Natriuretic peptides involved in vascular regulation, include atrial natriuretic peptide (ANP) secreted by the heart, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They are released in response to hypervolemia . ANP and BNP inhibit Na reabsorption by the kidney. These peptides antagonize the action of various vasoconstrictor agents and lower blood pressure. 3.Circulating Vasoconstrictors Vasopressin (ADH) secreted by posterior pituitary Potent vasoconstrictor (V 1A receptor) Antidiuretic effect (V 2 receptor) Catecholamines have vasoconstrictor action. Angiotensin II has a generalized vasoconstrictor action.It also increases water intake and stimulates aldosterone secretion,Thus helps to maintain ECF volume. It inhibits renin release due to Angiotensin II type 1 receptors on JG cells.

11. β 1 - receptor AT1 receptor AT1 receptor

12. Systemic Regulation by The Nervous System

13. Autonomic Nervous System The autonomic nervous system maintains cardiovascular homeostasis via pressure, volume and chemoreceptor signals. Adrenergic reflexes modulate blood pressure over the short term and adrenergic function, along with hormonal and volume-related factors, contributes to the long-term regulation of arterial pressure. The three endogenous catecholamines are norepinephrine , epinephrine, and dopamine . All three play important roles in tonic and phasic cardiovascular regulation. Adrenergic receptors are α and β differentiated further into α 1 , α 2 , β 1 , and β 2 receptors. α Receptors are occupied and activated more avidly by norepinephrine than by epinephrine and the reverse is true for β receptors. α 1 Receptors are located on postsynaptic cells in smooth muscle and elicit vasoconstriction. α 2 Receptors are located on presynaptic membranes of postganglionic nerve terminals that synthesize norepinephrine . When activated by catecholamines , α 2 receptors act as negative feedback controllers, inhibiting further norepinephrine release.

14. In the kidney, activation of α 1 -adrenergic receptors increases renal tubular reabsorption of sodium. Different classes of antihypertensive agents either inhibit α 1 receptors or act as agonists of α 2 receptors and reduce systemic sympathetic outflow. Activation of myocardial β 1 receptors stimulates the rate and strength of cardiac contraction and consequently increases cardiac output. β 1 Receptor activation also stimulates renin release from the kidney. Another class of antihypertensive agents acts by inhibiting β 1 receptors. Activation of β 2 receptors by epinephrine relaxes vascular smooth muscle and results in vasodilation . Chronic administration of agents that block adrenergic receptors may result in upregulation , and withdrawal of those agents may produce a condition of temporary hypersensitivity to sympathetic stimuli.

15. FEEDBACK CONTROL OF BP-BAROREFLEX The CVS is under neural influences coming from several parts of the brain, which in turn receive feedback from sensory receptors in the vasculature ( eg , baroreceptors ).

16. Medullary Control of CVS

17. Medullary Control Of Heart Rate By The Vagus Nerves Baroreceptor Resetting In chronic hypertension, the baroreceptor reflex mechanism is "reset" to maintain an elevated rather than a normal blood pressure.

18. ACE inhibitors Clonidine Methyldopa Spironolactone Ganglion blockers AT1 Antagonist Diuretics Renin inhibitors Vasodilators & CCBs β - blocker α -blocker β - blocker Vasodilators & CCBs ↓ BP ↑ BP

19. HYPERTENSION Hypertension  ( HTN ) or  high blood pressure , sometimes called  arterial hypertension , is a  chronic medical condition  in which the BP  in the  arteries  is elevated. Clinically, hypertension may be defined as that level of blood pressure at which the institution of therapy reduces blood pressure–related morbidity and mortality. 30% adults worldwide are hypertensive & causes 6% death worldwide Risk factors include smoking,hyperlipidaemia,diabetes,CVD Hypertension is an independent predisposing factor for heart failure, coronary artery disease, stroke, renal disease and peripheral arterial disease (PAD).

20. Two types:1. Essential(Primary/Idiopathic) hypertension 2.Secondary hypertension Essential hypertension 80–95% of all hypertensive patients Familial and is likely to be the consequence of an interaction between environmental and genetic factors. The prevalence of essential hypertension increases with age. In the majority of patients with established hypertension, peripheral resistance is increased and cardiac output is normal or decreased. Secondary Hypertension 5-20% Identifiable etiology

21. Secondary Causes of Hypertension

22. DRUG TREATMENT OF HYPERTENSION (Drug therapy is recommended for individuals with blood pressures ≥ 140/90 mmHg.)

23. Classification of Antihypertensive Drugs by Their Primary Site or Mechanism of Action

24. Diuretics 1. Thiazides and related agents (hydrochlorothiazide, chlorthalidone , chlorothiazide , indapamide , methylclothiazide , metolazone ) 2. Loop diuretics ( furosemide , bumetanide , torsemide , ethacrynic acid) 3. K + -sparing diuretics ( amiloride , triamterene , spironolactone ) Sympatholytic drugs 1. β receptor antagonists ( propranolol , metoprolol , atenolol , betaxolol , bisoprolol , carteolol , esmolol , nadolol , nebivolol , penbutolol , pindolol , timolol ) 2. α receptor antagonists ( prazosin , terazosin , doxazosin , phenoxybenzamine , phentolamine ) 3. Mixed α -β receptor antagonists ( labetalol , carvedilol ) 4. Centrally acting adrenergic agents (methyldopa, clonidine , guanabenz , guanfacine ) 5. Adrenergic neuron blocking agents ( guanadrel , reserpine )

25. Classification Contd... Ca 2+ channel blockers ( verapamil , diltiazem , nisoldipine , felodipine , nicardipine , isradipine , amlodipine , clevidipine , nifedipine ) Angiotensin -converting enzyme inhibitors ( captopril , enalapril , lisinopril , quinapril , ramipril , benazepril , fosinopril , moexipril , perindopril , trandolapril ) AngII receptor antagonists ( losartan , candesartan , irbesartan , valsartan , telmisartan , eprosartan , olmesartan ) Direct Renin Inhibitor ( aliskiren ) Vasodilators 1. Arterial ( hydralazine , minoxidil , diazoxide , fenoldopam ) 2. Arterial and venous ( nitroprusside )

26. ACE inhibitors Clonidine Methyldopa Spironolactone Ganglion blockers AT1 Antagonist Diuretics Renin inhibitors Vasodilators & CCBs β - blocker α -blocker β - blocker Vasodilators & CCBs ↓ BP ↑ BP

27. Diuretics 1.Thiazides and related agents First-line agents

28. The initial action of these drugs decreases extracellular volume by enhancing Na + excretion in the urine and lead to a fall in cardiac output. The hypotensive effect is maintained during long-term therapy due to decreased vascular resistance; cardiac output returns to pretreatment values due to compensatory responses such as activation of the RAS.Vasodilation is produced by:- 1.Indirect small persisting Na + and vol. deficit 2. Open Ca 2+ -activated K + channels  hyperpolarization of vascular smooth muscle cells  closing of L-type Ca 2+ channels  decreased Ca 2+ entry  vasodilation . Greater effect at night by chlorthalidone is due to the much longer t 1/2 of chlorthalidone (>24 hours) compared to hydrochlorothiaze (several hours). Used in low dose-12.5 to 25 mg/day Urinary K + loss can be a problem with thiazides . ACE inhibitors and angiotensin receptor antagonists will attenuate diuretic-induced loss of K + to some degree.

29. Hypertensive patients may become refractory to sympatholytics or to vasodilator drugs, because these drugs cause retention of salt and water 50 mg/day dose of thiazide / furosemide is used. Dietary Na + restriction(2 g daily) is a valuable in minimizing the dose of diuretic that is required. ( hypokalemia and alkalosis) The effectiveness of thiazides as diuretics or antihypertensive agents is progressively diminished when the GFR falls below 30 mL /min. One exception is metolazone , which retains efficacy in patients with this degree of renal insufficiency. Most patients will respond to thiazide diuretics within about 4-6 weeks. Therefore, doses should not be increased more often than every 4-6 weeks. Addition of a diuretic to a calcium channel blocker is less effective .

30. ADRs Hypokalemia Hyperuricemia Gout Hypercalcemia Hypochloraemic alkalosis Erectile dysfunction in males Dyslipidemia Magnesium depletion Hyperglycaemia Increased incidence of sudden death: K + depletion 1. Polymorphic ventricular tachycardia ( torsades de pointes), quinidine . 2. Ischemic ventricular fibrillation

31. 2.Loop diuretics Less effective than thiazide diuretics due to short duration of action(4-6 hrs) Used in HTN complicated by:- 1.Chronic renal failure: thiazides are ineffective 2.CHF 3.Resistance to combination containing thiazide or marked fluid retention due to use of potent vasodilator like minoxidil

32. ADRs Hypokalemia Dilutional hyponatremia GI disturbances Hearing loss( aminoglycisides ) Alleric manifestation Hyperuricemia Gout Hypercalcemia Dyslipidemia Magnesium depletion Glucose intolerance

33. 3.K + -sparing diuretics s pironolactone Amiloride Triamterene

34. Amiloride blocks Li + entry through Na + channels in CD and mitigates diabetes insipidus induced by Li + Spironolactone also lowers blood pressure but has some significant adverse effects, especially in men (e.g., erectile dysfunction, gynecomastia , benign prostatic hyperplasia). Eplerenone is a newer aldosterone receptor antagonist that does not have the sexually related adverse effects induced by spironolactone . As a result of their capacity to inhibit loss of K + in the urine, these drugs are used in the treatment of patients with hyperaldosteronism , a syndrome that can lead to hypokalemia .

35. Triamterene is a K + -sparing diuretic that decreases the risk of hypokalemia in patients treated with a thiazide diuretic. These agents should be used cautiously with frequent measurements of K + concentrations in plasma in patients predisposed to hyperkalemia . (use of K + -containing salt substitutes ) Renal insufficiency is a relative contraindication to the use of K + -sparing diuretics. Concomitant use of an ACE inhibitor or an angiotensin receptor antagonist magnifies the risk of hyperkalemia with these agents.

36. Diuretic-Associated Drug Interactions The K + - and Mg 2+ -depleting effects of the thiazides and loop diuretics also can potentiate arrhythmias that arise from digitalis toxicity. Corticosteroids can amplify the hypokalemia produced by the diuretics. All diuretics can decrease the clearance of Li + , resulting in increased plasma concentrations of Li + and potentiate toxicity. NSAIDs that inhibit the synthesis of prostaglandins reduce the antihypertensive effects of diuretics. NSAIDs, β blockers and ACE inhibitors reduce plasma concentrations of aldosterone and can potentiate the hyperkalemic effects of a K + -sparing diuretic.

37. Sympatholytic drugs

38. β Adrenergic Receptor Antagonists MOA Antagonism of β adrenergic receptors leads to a reduction in myocardial contractility, heart rate, and cardiac output. Blockade of the β receptors of the juxtaglomerular complex, reduces renin secretion and thereby diminishing production of circulating AngII . Reduction in central sympathetic outflow by blocking presynaptic β -receptors centrally Stimulation of prostacyclin synthesis in vascular beds ↑ in natriuretic peptide secretion caused by β blockade Some have additional mechanism like nebivolol promotes endothelial cell dependent vasodilation via activation of the NO pathway Drugs without intrinsic sympathomimetic activity produce an initial reduction in CO and a reflex-induced rise in peripheral resistance, generally with no net change in arterial pressure. Peripheral resistance decreases gradually. So persistently reduced cardiac output and possibly decreased peripheral resistance accounts for the reduction in arterial pressure. Drugs with intrinsic sympathomimetic activity produce lesser decrease in HR and CO; lower vascular resistance because of stimulation of vascular β 2 receptors that mediate vasodilation .

39. Mild-moderate antihypertension Produce hypotensive response in 1-3 weeks Adverse Effects and Precautions Fatigue, lethargy, dec . libido,cold extremities Avoided in patients with PVD, diabetics taking insulin, reactive airway disease (asthma) or with SA or AV nodal dysfunction or in combination with other drugs that inhibit AV conduction( verapamil ). β blockers without intrinsic sympathomimetic activity increase triglycerides in plasma and lower HDL. β blockers with intrinsic sympathomimetic activity have no effect. Sudden discontinuation lead to rebound hypertension,tachycardia and anginal pain of due to upregulation of β receptors . So,tapered gradually over 10-14 days. NSAIDs such as indomethacin can blunt the antihypertensive effect of propranolol and probably other β blockers. (inhibition of vascular synthesis of prostacyclin , as well as due to retention of Na + ).

40. Epinephrine can produce severe hypertension and bradycardia when a nonselective β antagonist is present. The hypertension is due to the unopposed stimulation of α receptors when vascular β 2 receptors are blocked; the bradycardia is the result of reflex vagal stimulation. Such paradoxical hypertensive responses to β receptor antagonists have been observed in patients with hypoglycemia or pheochromocytoma , during withdrawal from clonidine , following administration of epinephrine as a therapeutic agent or in association with the illicit use of cocaine . Therapeutic Uses Effective therapy for all grades of hypertension Once- or twice-daily administration Effective especially in young nonobese hypertensive The β receptor antagonists usually do not cause retention of salt and water, and administration of a diuretic is not necessary to avoid edema . β receptor antagonists are highly preferred drugs for hypertensive patients with conditions such as MI, ischemic heart disease or congestive heart failure.

41. α 1 Adrenergic Receptor Antagonists Initially,dilates resistance and capacitance vessels reflex ↑ in HR and plasma renin activity. During long-term therapy, vasodilation persists, but cardiac output, heart rate, and plasma renin activity return to normal. α 1 blockers cause a variable amount of postural hypotension , depending on the plasma volume. α 1 Receptor antagonists reduce plasma concentrations of triglycerides and total LDL cholesterol and increase HDL cholesterol. These potentially favourable effects on lipids persist when a thiazide -type diuretic is given concurrently. Suitable for diabetics as improve carbohydrate metabolism(not when neuropathy is present— postural hypotension) They are used primarily in conjunction with diuretics, β blockers, and other antihypertensive agents.

42. α 1 Receptor antagonists are not the drugs of choice in patients with pheochromocytoma because a vasoconstrictor response to epinephrine can still result from activation of unblocked vascular α 2 adrenergic receptors. α 1 Receptor antagonists are used for hypertensive patients with benign prostatic hyperplasia because they also improve urinary symptoms. ADRs Headache, drowsiness, palpitation, nasal blockade, blurred vision, rash, impaired ejaculation Postural hypotension CHF(fluid retention) First-dose phenomenon , in which symptomatic orthostatic hypotension occurs within 30-90 minutes of the initial dose of the drug or after a dosage increase. After the first few doses, patients develop a tolerance to this marked hypotensive response.

43. Combined α 1 and β Adrenergic Receptor Antagonists Labetalol Is an equimolar mixture of four stereoisomers . One isomer is an α 1 antagonist (like prazosin ), another is a nonselective β antagonist with partial agonist activity (like pindolol ) and the other two isomers are inactive. Because of its capacity to block α 1 adrenergic receptors, labetalol given intravenously can reduce blood pressure sufficiently rapidly to be useful for the treatment of hypertensive emergencies. Labetalol has efficacy and adverse effects that would be expected with any combination of β and α 1 receptor antagonists. It also has the disadvantages that are inherent in fixed-dose combination products(unpredictable and varies from patient to patient).

44. Carvedilol is a β receptor antagonist with α 1 receptor antagonist activity. The ratio of α 1 to β receptor antagonist potency for carvedilol is approximately 1:10. It inhibits free radical induced lipid peroxidation and also prevents vascular smooth muscle mitogenesis . Carvedilol undergoes oxidative metabolism and glucuronidation in the liver; the oxidative metabolism occurs via CYP2D6. Carvedilol reduces mortality in patients with CHF associated with systolic dysfunction when used as an adjunct to therapy with diuretics and ACE inhibitors. It should not be given to those patients with decompensated heart failure who are dependent on sympathetic stimulation. As with labetalol , the long-term efficacy and side effects of carvedilol in hypertension are predictable based on its properties as a α 1 & β adrenergic receptor antagonist.

45. Centrally acting adrenergic agents

46. METHYLDOPA Methyldopa α - methyldopamine L-aromatic amino acid decarboxylase 1. α –Methyl NE is stored in the secretory vesicles substituting for NE itself. Consequently, when the adrenergic neuron discharges its neurotransmitter, α –methyl NE is released instead of NE. 2. α –Methyl NE stimulates central α 2 receptors to inhibit adrenergic neuronal outflow from the brainstem . adrenergic neurons α - methylnorepinephrine     

47. Used largely in treatment of hypertension in pregnancy Methyldopa is a prodrug that is metabolized in the brain to the active form, its concentration in plasma has less relevance for its effects. t 1/2 ~2 hours Excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent drug (25%). The remaining fraction is excreted as other metabolites. The peak effect of methyldopa is delayed for 6-8 hours and the duration of action of a single dose is usually about 24 hours; this permits once- or twice-daily dosing. (time required for transport into the CNS, conversion to the active metabolite storage of α –methyl NE and its subsequent release in the vicinity of relevant α 2 receptors in the CNS)

48. ADRs Sedation,lethargy,depression Dryness of the mouth,diminished libido, parkinsonian signs, hyperprolactinemia  gynecomastia and galactorrhea . Severe bradycardia and sinus arrest. Hepatotoxicity , sometimes associated with fever Positive Coombs test ( antiglobulin test) that is due to autoantibodies directed against the Rh antigen on erythrocytes  hemolytic anemia Adverse effects that are even more rare include leukopenia , thrombocytopenia, red cell aplasia , lupus erythematosus –like syndrome, lichenoid and granulomatous skin eruptions, myocarditis , retroperitoneal fibrosis, pancreatitis, diarrhea , and malabsorption Interaction TCA reverse its action by blocking its active transport into the adrenergic neurons

49. Clonidine , Guanabenz , and Guanfacine MOA:- Stimulate the α 2A subtype of α 2 adrenergic receptors in the brainstem, resulting in a reduction in sympathetic outflow from the CNS .The decrease in plasma concentrations of NE is correlated directly with the hypotensive effect. At doses higher than those required to stimulate central α 2A receptors, these drugs can activate α 2 receptors of the α 2B subtype on vascular smooth muscle cells  vasoconstriction  loss of therapeutic effect.(therapeutic window phenomenon) The α 2 adrenergic agonists lower arterial pressure by an effect on both cardiac output and peripheral resistance. In the supine position , when the sympathetic tone to the vasculature is low, the major effect is to reduce both heart rate and stroke volume. In the upright position , when sympathetic outflow to the vasculature is normally increased, these drugs reduce vascular resistance. This action may lead to postural hypotension. The decrease in cardiac sympathetic tone leads to a reduction in myocardial contractility and heart rate that could promote CHF in susceptible patients.

50. ADRs Sedation,dryness of mouth, nose & eyes & parotid gland swelling and pain. Postural hypotension and erectile dysfunction Sleep disturbances with vivid dreams or nightmares, restlessness and depression. Symptomatic bradycardia and sinus arrest Contact dermatitis Withdrawal Syndrome Sudden discontinuation of clonidine may cause headache, apprehension, tremors, abdominal pain, sweating, and tachycardia. The arterial blood pressure may rise to levels above those that were present prior to treatment. Symptoms typically occur 18-36 hours after the drug is stopped and are associated with increased sympathetic discharge. Tt :- α blocker with a β blocker,or a potent vasodilator - sod. nitroprusside or clonidine itself

51. Adrenergic neuron blocking agents

52. Guanadrel Guanadrel is an exogenous false neurotransmitter that is accumulated, stored, and released like NE but is inactive at adrenergic receptors. The antihypertensive effect is achieved by a reduction in peripheral vascular resistance that results from inhibition of α receptor– mediated vasoconstriction. Because guanadrel can promote NE release from pheochromocytomas , it is contraindicated in those patients. Because guanadrel must be transported into and accumulate in adrenergic neurons, the maximum effect on blood pressure is not seen until 4-5 hours ADRs Symptomatic hypotension during standing, exercise, ingestion of alcohol or in hot weather is the result of the lack of sympathetic compensation for these stresses. Fatigue and lassitude Sexual dysfunction usually presents as delayed or retrograde ejaculation. Diarrhea C/I:- Because guanadrel is actively transported to its site of action, drugs that block or compete for the catecholamine transporter on the presynaptic membrane will inhibit the effect of guanadrel . Such drugs include the TCA, cocaine, chlorpromazine, ephedrine, phenylpropanolamine and amphetamine .

53. Reserpine

54. Both cardiac output and peripheral vascular resistance are reduced during long-term therapy with reserpine . Because of the irreversible nature of reserpine binding, the amount of drug in plasma is unlikely to bear any consistent relationship to drug concentration at the site of action. ADRs Most adverse effects of reserpine are due to its effect on the CNS  Sedation and inability to concentrate or perform complex tasks, Psychotic depression that can lead to suicide.So the drug should never be given to patients with a history of depression. Other adverse effects include nasal stuffiness and exacerbation of peptic ulcer disease.

55. Ca 2+ Channel Antagonists Cardiac contractility and contraction of vascular smooth muscle is dependent on the free intracellular concentration of Ca 2+ , inhibition of transmembrane movement of Ca 2+ through voltage-sensitive L-type Ca 2+ channels can decrease the total amount of Ca 2+ that reaches intracellular sites. All of the Ca 2+ channel blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing peripheral vascular resistance  evoke a baroreceptor -mediated sympathetic discharge. Cardiac depressant:- verapamil > diltiazem > nifedipine Vasodilatory effects:- nifedipine > verapamil > diltiazem Can be used safely in asthma,angina,PVD Don’t have effect on renin release and no adverse effects on lipid profile, uric acid levels or glucose metabolism. Postural hypotension,first dose effect or rebound hypertension not seen No adverse effect on foetus

56. In the case of the dihydropyridines , tachycardia may occur from the adrenergic stimulation of the SA node. Tachycardia is typically minimal to absent with verapamil and diltiazem because of the direct negative chronotropic effect of these two drugs. The concurrent use of a β receptor antagonist drug may magnify negative chronotropic effects of these drugs or cause heart block in susceptible patients. Consequently, the concurrent use of β receptor antagonists with either verapamil or diltiazem not done. ADRs Nifedipine headache,flushing,peripheral oedema , tachycardia, gingival hyperplasia Verapamilconstipation C/I Nifedipine unstable angina, LV failure, aortic stenosis and obstructive cardiomyopathy Verapamilsick sinus syndrome, AV block and heart failure

57. Angiotensin -Converting Enzyme Inhibitors Act by inhibiting the biosynthesis of AngII . Also inhibit degradation of bradykinin .Thus leading to vasodilation . The ACE inhibitors appear to confer a special advantage in the treatment of patients with diabetes, slowing the development and progression of diabetic glomerulopathy . Effective in slowing the progression of other forms of chronic renal disease, such as glomerulosclerosis . Patients with hypertension and ischemic heart disease are treated with ACE inhibitors; administration of ACE inhibitors in the immediate post-MI period has been shown to improve ventricular function and reduce morbidity and mortality. Because ACE inhibitors blunt the rise in aldosterone concentrations in response to Na + loss, the normal role of aldosterone to oppose diuretic-induced natriuresis is diminished. Consequently, ACE inhibitors tend to enhance the efficacy of diuretic drugs.(small dose)

58. Contraindicated during pregnancy In patients with bilateral renal artery stenosis or stenosis in a sole kidney, the administration of an ACE inhibitor will reduce the filtration fraction and cause a substantial reduction in glomerular filtration rate. Young and middle-aged Caucasian patients have a higher probability of responding to ACE inhibitors ADRs Dry cough Angioneurotic edema Hyperkalemia Altered sense of taste

59. AT 1 Receptor Antagonists MOA By antagonizing the effects of AngII , these agents relax smooth muscle and thereby promote vasodilation , increase renal salt and water excretion, reduce plasma volume and decrease cellular hypertrophy. AngII -receptor antagonists also overcome some of the disadvantages of ACE inhibitors, as they prevent ACE-mediated degradation of bradykinin and substance P. AT 1 Receptor Antagonism ↑ renin & AngII stimulate AT 2 receptor  anti-growth and anti-proliferative responses ARAs are capable of blocking effects of AngII regardless of any biochemical pathway for AngII formation .

60. Adverse Effects and Precautions Hypotension, hyperkalemia , and reduced renal function Hyperkalemia may occur in conjunction with other factors that alter K + homeostasis, such as renal insufficiency, ingestion of excess K + and the use of drugs that promote K + retention. Cough, an adverse effect of ACE inhibitors, is less frequent with AT 1 receptor antagonists. Angioedema ACE inhibitors and AT 1 receptor antagonists should not be administered during pregnancy and should be discontinued as soon as pregnancy is detected. The combination of an ACE inhibitor and an AT 1 receptor antagonist is not recommended for the treatment of hypertension.

61. Direct Renin Inhibitors Aliskiren directly and competitively inhibits the catalytic activity of renin . ( Angiotensinogen  AngI ) Orally effective Aliskiren's inhibition of renin leads to diminished production of AngI —and ultimately AngII and aldosterone —with a resulting fall in blood pressure. Aliskiren is poorly absorbed, with a bioavailability of <3% Taking the drug with a high-fat meal may substantially decrease plasma concentrations. Aliskiren has an elimination t 1/2 of at least 24 hours. Elimination of the drug may be primarily through hepatobiliary excretion with limited metabolism via CYP3A4. Dose  150-300 mg/day Toxicity and Precautions Diarrhea (higher doses) Cough (less than found with ACE inhibitors) Angioedema Not to be used in pregnant women.

62. Vasodilators

63. Hydralazine Hydralazine directly relaxes arteriolar smooth muscle by 1.a fall in intracellular calcium concentrations  inhibiting IP 3 -induced release of Ca 2+ from intracellular storage sites in arteries  leading to diminished contraction. 2.promotes arterial dilation by opening high conductance Ca 2+ -activated K + channels 3. NO mediated vasodilatation Hydralazine -induced vasodilation is associated with powerful stimulation of the sympathetic nervous system which results in increased HR and contractility, increased plasma renin activity and fluid retention; all of these effects tend to counteract the antihypertensive effect of hydralazine . Because of preferential dilation of arterioles over veins, postural hypotension and impotence are not common problem.

64. The usual oral dosage of hydralazine is 25-100 mg twice daily Hydralazine is well absorbed through the gastrointestinal tract, but the systemic bioavailability is low (16% in fast acetylators and 35% in slow acetylators ). Hydralazine is N -acetylated in the bowel and/or the liver. t 1/2 of hydralazine is 1 hour. The acetylated compound is inactive; thus, the dose necessary to produce a systemic effect is larger in fast acetylators . The peak hypotensive effect of the drug occur within 30-120 minutes of ingestion Hypotensive effect of hydralazine can last as long as 12 hours.( hydralazine pyruvic acid hydrazone )

65. Toxicity and Precautions Headache, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina pectoris. Immunological reactions  drug-induced lupus syndrome(most common), serum sickness, hemolytic anemia , vasculitis , and rapidly progressive glomerulonephritis  drug's capacity to promote DNA demethylation may be involved . Myocardial ischemia (increased O 2 demand induced by the baroreceptor reflex-induced stimulation of the sympathetic nervous system). If the drug is used alone, there may be salt retention with development of high-output congestive heart failure. When combined with a β adrenergic receptor blocker and a diuretic, hydralazine is better tolerated.

66. K ATP Channel Openers: Minoxidil Efficacious in patients with the most severe and drug-resistant forms of hypertension. MOA Minoxidil is metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate . Minoxidil sulfate relaxes vascular smooth muscle where the parent drug is inactive. Minoxidil sulfate activates the ATP-modulated K + channel. By opening K + channels in smooth muscle and thereby permitting K + efflux, it causes hyperpolarization and relaxation of smooth muscle. Minoxidil produces arteriolar vasodilation with essentially no effect on the capacitance vessels  leads to reflex increase in myocardial contractility and in cardiac output. Minoxidil increases blood flow to skin, skeletal muscle, the gastrointestinal tract and the heart more than to the CNS. Minoxidil is well absorbed from the GI tract. Although peak concentrations of minoxidil in blood occur 1 hour after oral administration, the maximal hypotensive effect of the drug occurs later, possibly because formation of the active metabolite is delayed.

67. The bulk of the absorbed drug is eliminated by hepatic metabolism; ~20% is excreted unchanged in the urine. The major metabolite of minoxidil is the glucuronide conjugate. t 1/2 of 3-4 hours, but its duration of action is 24 hours.The persistence of minoxidil in vascular smooth muscle is responsible for this discrepancy. Adverse Effects and Precautions Retention of salt and water (increased proximal renal tubular reabsorption ) Increase in heart rate, myocardial contractility and myocardial O 2 consumption  myocardial ischemia ( baroreceptor reflex-induced stimulation of the sympathetic nervous system). Increased pulmonary artery pressure, pericardial effusion Hypertrichosis (consequence of K + channel activation) Rashes, Stevens-Johnson syndrome, glucose intolerance, serosanguineous bullae , formation of antinuclear antibodies and thrombocytopenia.

68. Sodium Nitroprusside Is safe and useful for the short-term control of severe hypertension Sodium nitroprusside is effective in improving cardiac function in patients with left ventricular failure. MOA Nitroprusside is a nitrovasodilator that acts by releasing NO. NO increases intacellular cGMP , leading to vasodilation . Nitroprusside dilates both arterioles and venules . Regional distribution of blood flow is little affected by the drug. Unlike minoxidil , hydralazine , diazoxide and other arteriolar vasodilators, sodium nitroprusside usually causes only a modest increase in heart rate and an overall reduction in myocardial O 2 demand.

69. Sodium nitroprusside is an unstable molecule that decomposes under strongly alkaline conditions or when exposed to light. Its onset of action is within 30 sec; the peak hypotensive effect occurs within 2 min and when the infusion of the drug is stopped, the effect disappears within 3 min. The metabolism of nitroprusside by smooth muscle is initiated by its reduction, which is followed by the release of cyanide and then NO.Cyanide is further metabolized by liver rhodanase to form thiocyanate , which is eliminated almost entirely in the urine. Uses To lower blood pressure during acute aortic dissection Improve cardiac output in CHF, especially in hypertensive patients with pulmonary edema that does not respond to other To decrease myocardial oxygen demand after acute MI. Nitroprusside is used to induce controlled hypotension during anesthesia in order to reduce bleeding in surgical procedures.

70. Toxicity and Precautions Hypotension due to excessive vasodilation Severe lactic acidosis(cyanide)  administration of sodium thiosulfate Signs and symptoms of thiocyanate toxicity include anorexia, nausea, fatigue, disorientation and toxic psychosis.(should not be allowed to exceed 0.1 mg/ mL ). Excessive concentrations of thiocyanate may cause hypothyroidism by inhibiting iodine uptake by the thyroid gland. In patients with renal failure, thiocyanate can be removed readily by hemodialysis . Nitroprusside can worsen arterial hypoxemia in patients with COPD because the drug interferes with hypoxic pulmonary vasoconstriction and therefore promotes mismatching of ventilation with perfusion.

71. stage drug Uncomplicated stage 1 hypertension 1.Diuretics as preferred initial therapy for most patients 2. Other drugs:- β receptor antagonists, ACE inhibitors/AT 1 -receptor antagonists, and Ca 2+ channel blockers. Uncomplicated stage 2 hypertension 2 drug therapy:- early introduction of a diuretic and another drug from a different class. Isolated systolic hypertension Diuretics ,Ca 2+ channel blockers and ACE inhibitors.

72. Newer drugs Moxonidine and rilmenidine  newer congeners of clonidine Longer t 1/2 Rebound hypertension much less FK-453 investigational K + -sparing diuretics

73. Thank you

74. Factors effecting CO

75. Factors affecting activity of the Vasomotor area of medulla

76. Factors Affecting Heart Rate