newer drugs - hypertension

8/6/2019 Newer Drugs - Hypertension

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NEWER DRUGS FORNEWER DRUGS FOR

TREATMENT OFTREATMENT OFHYPERTENSIONHYPERTENSION

Dr.P.SHANKAR.Dr.P.SHANKAR.


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NEWER DRUGS AND MODALITIESNEWER DRUGS AND MODALITIES

DRUGDRUG GROUPGROUP

Azilsartan (Edarbi)Azilsartan (Edarbi) Angiotensin II receptor blockerAngiotensin II receptor blocker

AliskirenAliskiren Renin inhibitorRenin inhibitor

NebivololNebivolol 1 receptor blocker1 receptor blocker

ClevidipineClevidipine Calcium channel blockerCalcium channel blocker

AR9281AR9281 Soluble epoxide hydrolase inhibitorSoluble epoxide hydrolase inhibitor

AzaindoleAzaindole ROCK inhibitorROCK inhibitor

IptakalimIptakalim ATP sensitive K channel openerATP sensitive K channel opener

MelatoninMelatonin

NADPH oxidasesNADPH oxidasesPhophodiesterase 5 inhibitorPhophodiesterase 5 inhibitor

Device based anti hypertensive therapyDevice based anti hypertensive therapy

Carotid baroreceptor activationCarotid baroreceptor activation


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OVER VIEW OF RAAS AXISOVER VIEW OF RAAS AXIS


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AZILSARTANAZILSARTAN Type 1 Angiotensin II receptor blocker(ARB)Type 1 Angiotensin II receptor blocker(ARB)

Possess beneficial antidiabetic and cardioprotective propertiesPossess beneficial antidiabetic and cardioprotective properties

Possess potent antihypertensive effects when used in combinationPossess potent antihypertensive effects when used in combinationwith chlorthalidone and amlodipinewith chlorthalidone and amlodipine

Structurally related to candesartanStructurally related to candesartan------ differentiated by its 5differentiated by its 5--oxooxo--1,2,41,2,4--oxadiazole ring which isoxadiazole ring which is

responsible for its increased lipophilicity and increased oralresponsible for its increased lipophilicity and increased oralbioavailabilitybioavailability

Mechanism of actionMechanism of action

Angiotensin IIAngiotensin IItype 1 ATII receptortype 1 ATII receptor

inhibited by Azilsartaninhibited by AzilsartanGq protein and IP3 signal transduction pathwayGq protein and IP3 signal transduction pathway

(+) vascular smooth muscle contraction(+) vascular smooth muscle contraction


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Actions of Azilsartan:Actions of Azilsartan:

Dilate arteries and veins and thereby reduce arterial pressureDilate arteries and veins and thereby reduce arterial pressure

andand preloadpreload andand afterloadafterload on the heart.on the heart.

Down regulate sympathetic adrenergic activity by blocking theDown regulate sympathetic adrenergic activity by blocking theeffects of angiotensin II on sympathetic nerve release and reuptakeeffects of angiotensin II on sympathetic nerve release and reuptakeof norepinephrine.of norepinephrine.

Promote renal excretion of sodium and waterPromote renal excretion of sodium and water(natriuretic(natriuretic andand diureticdiuretic effects) by blocking the effects ofeffects) by blocking the effects ofangiotensin II in the kidney and by blocking angiotensin IIangiotensin II in the kidney and by blocking angiotensin IIstimulation ofstimulation of aldosteronealdosterone secretion.secretion.

Inhibit cardiac and vascular remodeling associated withInhibit cardiac and vascular remodeling associated withchronicchronic hypertension,hypertension, heart failure, andheart failure, and myocardial infarctionmyocardial infarction

Reduction in TNFReduction in TNF-- productionproduction improved insulin resistanceimproved insulin resistance

Increased expression in adiponectinIncreased expression in adiponectin reduce atheroscleroticreduce atheroscleroticchangeschanges


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Adverse effectsAdverse effects-- dizziness (2.1%)dizziness (2.1%)-- increased creatine phosphokinase (1.1%)increased creatine phosphokinase (1.1%)-- diarrhea (1.0%)diarrhea (1.0%)

Because azilsartan do not inhibit ACE, they do not cause an increase inBecause azilsartan do not inhibit ACE, they do not cause an increase inbradykinin, which contributes to the vasodilation produced by ACEbradykinin, which contributes to the vasodilation produced by ACEinhibitors and also some of the side effects of ACE inhibitors (coughinhibitors and also some of the side effects of ACE inhibitors (coughand angioedema).and angioedema).

Drug interactionsDrug interactions LithiumLithium increased lithium concentration and lithium toxicityincreased lithium concentration and lithium toxicity potassiumpotassium--sparing diuretics or potassium supplementssparing diuretics or potassium supplements increaseincrease

the potential for hyperkalemiathe potential for hyperkalemia Nonsteroidal antiNonsteroidal anti--inflammatory drug (NSAID)inflammatory drug (NSAID) deterioration ofdeterioration of

renal functionrenal function

Dosage: 20Dosage: 20--80 mg per day80 mg per day


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ALISKIRENALISKIREN

Renin inhibitorRenin inhibitor

Orally active nonpeptide drugOrally active nonpeptide drug

HalfHalf--life of about 24 hourslife of about 24 hours

DoseDose -- once per dayonce per day

Because of its relatively long halfBecause of its relatively long half--life, it takes about 2 weeks oflife, it takes about 2 weeks ofdosing to achieve a near maximal antihypertensive effectdosing to achieve a near maximal antihypertensive effect

Mechanism of actionMechanism of actionsympathetic activation, hypotension, and decreased sodiumsympathetic activation, hypotension, and decreased sodiumdelivery to the distal renal tubuledelivery to the distal renal tubule

inhibited by aliskireninhibited by aliskiren(+) Renin(+) Renin

enter RAAS systementer RAAS system


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Cardiorenal effects of aliskirenCardiorenal effects of aliskiren VasodilationVasodilation (arterial & venous)(arterial & venous)

-- reduce arterial & venous pressuresreduce arterial & venous pressures-- reduce ventricular afterload & preloadreduce ventricular afterload & preload

Decrease blood volumeDecrease blood volume-- natriureticnatriuretic-- diureticdiuretic

Depress sympathetic activityDepress sympathetic activity

Inhibit cardiac and vascular hypertrophyInhibit cardiac and vascular hypertrophy

Dilate arteries and veins by blocking angiotensin II formation. ThisDilate arteries and veins by blocking angiotensin II formation. Thisvasodilation reduces arterial pressure,preload andvasodilation reduces arterial pressure,preload and afterloadafterload on the heart.on the heart.

Down regulate sympathetic adrenergic activity by blocking the facilitatingDown regulate sympathetic adrenergic activity by blocking the facilitatingeffects of angiotensin II on sympathetic nerve release and reuptake ofeffects of angiotensin II on sympathetic nerve release and reuptake ofnorepinephrine.norepinephrine.

Promote renal excretion of sodium and water (natriureticPromote renal excretion of sodium and water (natriureticandand diureticdiuretic effects) by blocking the effects of angiotensin II in the kidneyeffects) by blocking the effects of angiotensin II in the kidneyand by blocking angiotensin II stimulation of aldosteroneand by blocking angiotensin II stimulation of aldosterone secretion. Thissecretion. Thisreducesreduces blood volume, venous pressure and arterial pressure.blood volume, venous pressure and arterial pressure.

Inhibit cardiac and vascular remodeling associated withInhibit cardiac and vascular remodeling associated with

chronicchronic hypertension,hypertension, heart failure, andheart failure, and myocardial infarctionmyocardial infarction


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Adverse effectsAdverse effects-- GI effectsGI effects ------ diarrhea with higher dosediarrhea with higher dose-- angioedemaangioedema

-- coughcough-- seizuresseizures-- symptomatic hypotensionsymptomatic hypotension-- rash , elevatedrash , elevated uric acid,uric acid, gout and renal stones .gout and renal stones .

Dosage : 150 mg per day, increased upto 300 mg per dayDosage : 150 mg per day, increased upto 300 mg per day

Drug interaction : When aliskiren was given with cyclosporine orDrug interaction : When aliskiren was given with cyclosporine oritraconazole, the blood concentrations of aliskiren were significantlyitraconazole, the blood concentrations of aliskiren were significantlyincreased. Avoid concomitant use of aliskiren with cyclosporine orincreased. Avoid concomitant use of aliskiren with cyclosporine oritraconazole.itraconazole.

Contraindicated in pregnancy due to high fetal and neonatalContraindicated in pregnancy due to high fetal and neonatal

morbidity and mortalitymorbidity and mortality -- hypotension, neonatal skull hypoplasia,hypotension, neonatal skull hypoplasia,anuria, reversible or irreversible renal failure, deathanuria, reversible or irreversible renal failure, death andandoligohydramniosoligohydramnios

Safety in pediatric age groupSafety in pediatric age group -- not established.not established.

Has additive anti hypertensive effect with thiazide diuretics and ARBsHas additive anti hypertensive effect with thiazide diuretics and ARBs


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NEBIVOLOLNEBIVOLOL

1 receptor selective blocker with nitric oxide1 receptor selective blocker with nitric oxide --potentiatingpotentiatingvasodilatory effect used in treatment of hypertension and also forvasodilatory effect used in treatment of hypertension and also forleft ventricular failureleft ventricular failure

Highly cardioselectiveHighly cardioselective

produce fewer adverse effects ( bronchoconstriction) than thoseproduce fewer adverse effects ( bronchoconstriction) than thosedrugs that nondrugs that non--selectively block bothselectively block both 1 and1 and 2 receptor2 receptor

Nebivolol lowers blood pressure by reducing peripheral vascularNebivolol lowers blood pressure by reducing peripheral vascularresistance, and significantly increases stroke volume withresistance, and significantly increases stroke volume withpreservation of cardiac output.preservation of cardiac output.

The net hemodynamic effect of nebivolol is the result of a balanceThe net hemodynamic effect of nebivolol is the result of a balancebetween the depressant effects of betabetween the depressant effects of beta--blockade and an action thatblockade and an action thatmaintains cardiac output.maintains cardiac output.

--


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Adverse drug reactionsAdverse drug reactions

-- HeadacheHeadache-- ParesthesiaParesthesia-- DizzinessDizziness

ContraindicationsContraindications-- Hepatic insufficiencyHepatic insufficiency-- ChildrenChildren-- PregnancyPregnancy-- LactationLactation

Dosage : starting dose 5mg once daily increased upto aDosage : starting dose 5mg once daily increased upto amax of 40 mg once dailymax of 40 mg once daily

As with all beta blockers, nebivolol should not beAs with all beta blockers, nebivolol should not be

abruptly stopped.abruptly stopped.


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CLEVIDIPINECLEVIDIPINE

Dihydropyridine LDihydropyridine L--typetype calcium channelcalcium channel

blockerblocker

Indicated for acute reduction of blood pressure.Indicated for acute reduction of blood pressure.

Highly selective for vascular, as opposed to myocardial, smoothHighly selective for vascular, as opposed to myocardial, smoothmuscle. Has little or no effect on myocardial contractility or cardiacmuscle. Has little or no effect on myocardial contractility or cardiacconduction.conduction.

Reduces mean arterial blood pressure by decreasing systemicReduces mean arterial blood pressure by decreasing systemic

vascular resistancevascular resistance

rapidly metabolized by esterasesrapidly metabolized by esterases elimination is unlikely toelimination is unlikely tobe affected by hepatic or renal dysfunctionbe affected by hepatic or renal dysfunction


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Mechanism of actionMechanism of action


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Dosage and administrationDosage and administration

-- Administered intravenouslyAdministered intravenously

-- Blood pressure and heart rate should be monitoredBlood pressure and heart rate should be monitoredcontinually during infusioncontinually during infusion

-- Should not be dilutedShould not be diluted

-- Once the stopper is punctured, Cleviprex should beOnce the stopper is punctured, Cleviprex should be

used within 4 hoursused within 4 hours

-- An IV infusion at 1An IV infusion at 122 mg/hour is recommended formg/hour is recommended forinitiationinitiation -- should be titrated by doubling the dose everyshould be titrated by doubling the dose every90 seconds90 seconds

-- The maximum infusion rate for Cleviprex is 32The maximum infusion rate for Cleviprex is 32 mg/hour.mg/hour.-- monitored for the possibility of rebound hypertension formonitored for the possibility of rebound hypertension for

at least 8 hours after the infusion is stoppedat least 8 hours after the infusion is stopped


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ContraindicationsContraindications

--in those who are allergic to soybeans, soy products, eggs, orin those who are allergic to soybeans, soy products, eggs, oregg products;egg products;

-- defective lipid metabolism such as pathological hyperlipidemiadefective lipid metabolism such as pathological hyperlipidemia-- lipoid nephrosis, or acute pancreatitis if it is accompanied bylipoid nephrosis, or acute pancreatitis if it is accompanied by

hyperlipidemiahyperlipidemia-- and in patients with severe aortic stenosisand in patients with severe aortic stenosis

Adverse drug effectsAdverse drug effects-- Most common adverse reactions (>2%) are headache, nausea,Most common adverse reactions (>2%) are headache, nausea,

and vomitingand vomiting-- Hypotension and reflex tachycardia are potential consequencesHypotension and reflex tachycardia are potential consequences

of rapid upward titration of Cleviprexof rapid upward titration of Cleviprex

-- Negative inotropic effect exacerbate heart failureNegative inotropic effect exacerbate heart failure


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SOLUBLEEPOXIDE HYDROLASE(SOLUBLEEPOXIDE HYDROLASE(sEHsEH))INHIBITORSINHIBITORS

sEH is an enzyme which metabolizessEH is an enzyme which metabolizesepoxyeicosatrienoic acid EET, which is believed toepoxyeicosatrienoic acid EET, which is believed toproduce a variety of beneficial CV effectsproduce a variety of beneficial CV effects

Inhibition of EET metabolism by sEH leading toInhibition of EET metabolism by sEH leading toaccumulation of EET could lead to therapeutic benefit inaccumulation of EET could lead to therapeutic benefit inCV diseases of hypertension, inflammation and organCV diseases of hypertension, inflammation and organprotection.protection.

AR9281, a potent and selective inhibitor of solubleAR9281, a potent and selective inhibitor of solubleepoxide hydrolase (sepoxide hydrolase (s--EH), is in clinical developmentEH), is in clinical developmenttargeting hypertension and type 2 diabetestargeting hypertension and type 2 diabetes


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BradykininBradykinin

acts on bradykinin receptor onacts on bradykinin receptor onendothelial cellsendothelial cells

Nitric oxide synthaseNitric oxide synthase COXCOX CYP450CYP450

NONO ProstaglandinProstaglandin 11,1211,12--Epoxyeicosatrienoic acidEpoxyeicosatrienoic acid

(+) adenyl cyclase(+) adenyl cyclase

cAMP metabolised by sEH which iscAMP metabolised by sEH which isinhibited by sEH inhibitorsinhibited by sEH inhibitors

(+) protein kinase resulting in accumulation(+) protein kinase resulting in accumulationof EETof EET

(+) Ca activated K channel(+) Ca activated K channel

HyperpolarisationHyperpolarisation

Relaxation of vascular smooth muscle cellRelaxation of vascular smooth muscle cell

Soluble epoxide hydrolase actionSoluble epoxide hydrolase action


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ROCK inhibitorsROCK inhibitors ROCK pathwayROCK pathway

-- ROCK1 and ROCK2ROCK1 and ROCK2


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Azaindole 32Azaindole 32

-- Highly potent, cell permeable, selective ATPHighly potent, cell permeable, selective ATPcompetitive inhibitor of ROCK1 and ROCK2 undercompetitive inhibitor of ROCK1 and ROCK2 understudystudy

-- Calcium sensitization of smooth muscleCalcium sensitization of smooth musclemediated by Rho associated protein kinase ismediated by Rho associated protein kinase isinhibited by these agentsinhibited by these agents

which is beneficial in hypertensionwhich is beneficial in hypertension

-- effectively suppresses coronary artery spasm.effectively suppresses coronary artery spasm.useful in vasospastic angina and in exerciseuseful in vasospastic angina and in exercise--inducedinducedmyocardial ischemia in patients with stable angina.myocardial ischemia in patients with stable angina.


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IPTAKALIMIPTAKALIM Adenosine triphosphateAdenosine triphosphate--sensitive potassium (ATP) channel openersensitive potassium (ATP) channel opener

Iptakalim selectively produces arteriolar vasodilation with essentially noIptakalim selectively produces arteriolar vasodilation with essentially noeffect on the capacitance vessels.effect on the capacitance vessels.

Preferentially relax arterioles and small arteries, without affecting largePreferentially relax arterioles and small arteries, without affecting largearteries.arteries.

Iptakalim strongly lowers the blood pressure of hypertensive humans butIptakalim strongly lowers the blood pressure of hypertensive humans buthas little effect on normotensives.has little effect on normotensives.

Selective antihypertensive action is not observed with pinacidil orSelective antihypertensive action is not observed with pinacidil ordiazoxide may be due to the high selectivity of iptakalim for thediazoxide may be due to the high selectivity of iptakalim for theSUR2B/Kir6.1 subtype of K(ATP) channels, as well as its selectiveSUR2B/Kir6.1 subtype of K(ATP) channels, as well as its selectiverelaxation of resistance vesselsrelaxation of resistance vessels

Has renoprotective effect in hypertensive patientsHas renoprotective effect in hypertensive patients


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MELATONINMELATONIN Hormone secreted by the pineal gland in the brainHormone secreted by the pineal gland in the brain

Maintains the body's circadian rhythmMaintains the body's circadian rhythm

Has strong antioxidant effectsHas strong antioxidant effects

Role in hypertensionRole in hypertension--The nighttime production of melatonin is reduced inThe nighttime production of melatonin is reduced in

hypertensive individuals.hypertensive individuals.-- melatonin decreased BP in several animal models ofmelatonin decreased BP in several animal models of

hypertension, in healthy men and women, and in patientshypertension, in healthy men and women, and in patientswith arterial hypertensionwith arterial hypertension

-- Most promising results were achieved in patientsMost promising results were achieved in patientswith nonwith non--dipping nighttime pressure, in which the circadiandipping nighttime pressure, in which the circadianrhythm of BP variation is disturbed.rhythm of BP variation is disturbed.


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Potential mechanisms of BP reduction by MelatoninPotential mechanisms of BP reduction by Melatonin

-- Melatonin can, via its scavenging and antioxidant nature,Melatonin can, via its scavenging and antioxidant nature,improve endothelial function with increased availability of nitricimprove endothelial function with increased availability of nitricoxide exerting vasodilatory and hypotensive effectsoxide exerting vasodilatory and hypotensive effects

-- Melatonin seems to interfere with peripheral and centralMelatonin seems to interfere with peripheral and centralautonomic system, with a subsequent decrease in the tone of theautonomic system, with a subsequent decrease in the tone of theadrenergic system and an increase of the cholinergic system.adrenergic system and an increase of the cholinergic system.

-- Melatonin may act on BP also via specific melatonin receptorsMelatonin may act on BP also via specific melatonin receptorslocalized in peripheral vessels or in parts of central nervous systemlocalized in peripheral vessels or in parts of central nervous systemparticipating in BP control.participating in BP control.


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NADPH OXIDASESNADPH OXIDASES

Reactive oxygen species (ROS) play an important role inReactive oxygen species (ROS) play an important role inthe development of cardiovascular disease, includingthe development of cardiovascular disease, includinghypertension and atherosclerosishypertension and atherosclerosis

ROS are produced by all vascular cell types, includingROS are produced by all vascular cell types, includingendothelial, smooth muscle and adventitial cells.endothelial, smooth muscle and adventitial cells.

NADPH oxidase is a multiNADPH oxidase is a multi--subunit enzyme that catalyzessubunit enzyme that catalyzes

ROS production by the electron reduction of O2 usingROS production by the electron reduction of O2 usingNADPHNADPH


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DEVICE THERAPYDEVICE THERAPY

The first implantable device being developed to treatThe first implantable device being developed to treatpatients with refractory hypertensionpatients with refractory hypertension -- Rheos BaroreflexRheos BaroreflexHypertension TherapyHypertension Therapy

Works by electrically activating the baroreflex, theWorks by electrically activating the baroreflex, the

system that regulates blood pressuresystem that regulates blood pressure Signals are sent to the central nervous system that areSignals are sent to the central nervous system that are

interpreted as an excessive rise in blood pressure, andinterpreted as an excessive rise in blood pressure, andthis perceived rise is counteracted by a reduction inthis perceived rise is counteracted by a reduction inheart rate and decreased efferent outflow.heart rate and decreased efferent outflow.

European and US feasibility clinical trials are evaluatingEuropean and US feasibility clinical trials are evaluatingthe Rheos System in hypertensive patientsthe Rheos System in hypertensive patients


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newer drugs - hypertension

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