2.3-Antihypertensive Drugs B pharmacy.pdf

Drug use in treatment of hypertension

1. Chapter 2.3: Anti-hypertensive Agents
Syllabus:
•Betablocker:Timolol
•ACEinhibitors:Captopril,Lisinopril,Enalapril,Benazeprilhydrochloride,Quinapril hydrochloride
•CentrallyActingAdrenergicdrugs:Methyldopatehydrochloride,*Clonidine hydrochloride,
Guanabenzacetate
•Vasodilators:Sodiumnitroprusside,Diazoxide,Minoxidil,Hydralazinehydrochloride
•Others:Guanethidine monosulphate,Reserpine
1Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur

2. HYPERTENSION
2Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
•Abnormallyhighbloodpressureandacombinationofhighpsychologicalstressareknownas
Hypertension.
•Achronicmedicalconditioninwhichtheforceofbloodagainstthearterywallsis
persistentlyelevated,usuallydefinedasBP≥140/90mmHg.

3. HYPERTENSION
3Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
1.Symptoms
Oftencalledthe“silentkiller”becauseitmayhavenosymptomsforyears.
Whenpresent,possiblesymptomsinclude:
•Persistentheadache(especiallyinthemorning)
•Dizzinessorlightheadedness
•Blurredordoublevision
•Shortnessofbreath
•Chestpainortightness
•Nosebleeds(inseverecases)
•Fatigueorconfusion
•Irregularheartbeat

4. HYPERTENSION
4Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
2.Causes
A.Primary(Essential)Hypertension–Noidentifiablesinglecause(90–95%cases);linkedto
genetics,lifestyle,andaging.
B.SecondaryHypertension–Causedbyanotherconditionormedication,e.g.:
•Kidneydisease(chronickidneydisease,glomerulonephritis)
•Endocrinedisorders(hyperthyroidism,Cushing’ssyndrome,pheochromocytoma)
•Certaindrugs(NSAIDs,oralcontraceptives,steroids,decongestants)
•Excessalcohol

5. HYPERTENSION
5Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
3.Types
•Primary(Essential)Hypertension–Gradualonset,nospecificcause.
•SecondaryHypertension–Duetounderlyingdiseaseordrug.
•IsolatedSystolicHypertension–SystolicBP≥140mmHgwithnormaldiastolic(<90mmHg);
commoninelderlyduetoarterialstiffness.
•Malignant(Accelerated)Hypertension–RapidriseinBPwithorgandamage(medical
emergency).
•ResistantHypertension–BPuncontrolledduetouseof≥3antihypertensivesincludinga
diuretic.

6. HYPERTENSION
6Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
4.RiskFactors
Non-modifiable:
•Age(riskincreaseswithage)
•Familyhistoryofhypertension
•Ethnicity(higherprevalenceinAfrican/Asian
populations)
•Malesex(beforeage55)andfemalesex(after
menopause)
Modifiable:
•Highsaltintake
•Lowpotassiumintake
•Obesityandsedentarylifestyle
•Excessalcoholconsumption
•Smoking
•Chronicstress
•Unhealthydiet(highsaturatedfat,processed
food)
•Poorsleepquality

7. HYPERTENSION
7Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
5.Complications
Cardiovascular:
•Coronaryarterydisease(angina,MI)
•Leftventricularhypertrophy(LVH)
•Heartfailure
Cerebrovascular:
•Stroke(ischemic&haemorrhagic)
•Transientischemicattack(TIA)
Renal:
•Chronickidneydisease
•Hypertensivenephrosclerosis
Ocular:
•Hypertensiveretinopathy(visionproblems,blindness)
Other:
•Peripheralarterydisease

8. HYPERTENSION
8Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
6.Prevention
LifestyleMeasures:
•Maintainhealthyweight(BMI18.5–24.9)
•Reducesodiumintake(<5gsalt/day)
•Eatabalanceddietrichinfruits,vegetables,wholegrains
•Increasepotassiumintake(unlesscontraindicated)
•Exerciseregularly(≥150min/weekmoderateactivity)
•Limitalcohol(≤2drinks/daymen,≤1drink/daywomen)
•Avoidtobacco
•Managestress(yoga,meditation,relaxationtechniques)
•Ensureadequatesleep
MedicalCheck-ups:
•RegularBPmonitoring,especially
inhigh-riskindividuals
•Earlydetectionandmanagementof
secondarycauses

9. Anti-hypertensive Agents
9Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
•Antihypertensiveagentsaremedicationsusedtotreathighbloodpressure(hypertension).
•Theyworkbytargetingdifferentmechanismsinthebodytolowerbloodpressure,suchas
reducingfluidvolume,relaxingbloodvessels,orslowingtheheartrate.
•Theseagentsarecrucialinpreventingcardiovascularcomplicationsassociatedwith
hypertension.

10. Classification of Anti-hypertensive Agents
10Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
MajorClassesofAntihypertensiveDrugs:
•Diuretics:Thesedrugshelpthebodyremoveexcessfluid&sodium,reducingbloodvolumeand
pressure.
•Beta-blockers:Thesemedicationsblocktheeffectsofadrenaline,slowingtheheartrateandreducingthe
forceofheartcontractions.
•ACEinhibitors(Angiotensin-ConvertingEnzymeInhibitors):Thesedrugspreventthebodyfrom
producingahormonethatnarrowsbloodvessels,allowingthemtorelaxandwiden.
•ARBs(AngiotensinIIReceptorBlockers):SimilartoACEinhibitors,ARBsblocktheeffectsofa
hormonethatconstrictsbloodvessels.
•Calciumchannelblockers:Thesedrugspreventcalciumfromenteringthemusclecellsoftheheartand
bloodvessels,causingthemtorelaxandwiden.

11. Classification of Anti-hypertensive Agents
11Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
OtherAntihypertensiveAgents:
Renininhibitors:Thesedrugsblocktheenzymerenin,whichplaysaroleinregulatingbloodpressure.
Alpha-adrenergicreceptorblockers:Theseagentsblocktheeffectsofadrenalineoncertainreceptorsin
bloodvessels,causingthemtorelax.
Centrallyactingagents:Thesedrugsaffectthebrain'scontrolofbloodpressure.
Direct-actingvasodilators:Thesemedicationsdirectlyrelaxthesmoothmuscleinbloodvesselwalls,
causingthemtowiden.

12. Classification of Anti-hypertensive Agents
12Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
1.SympatheticInhibitors-
(a)Centrallyacting:Clonidine,Methyldopa.
(b)Ganglionblocking: Pentolinium,Trimethaphan.
(c)Adrenergicneuroneblocking:
(i)InhibitNAstorage:Reserpine
(ii)InhibitNArelease:Guanethidine, Bethanidine.
(d)Adrenergic receptorantagonists:
(i) blockers:Prazosin,Phentolamine,Phenoxybenzamine.
(ii) -blockers: Propranolol,Metoprolol,Atenololetc.
(iii) +:Labetalol.

13. Classification of Anti-hypertensive Agents
13Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
2.DirectVasodilators:Hydralazine,Minoxidil,Diazoxide
3.Diuretics:Thiazides,Furosemide,Spironolactone
4.Angiotensinconvertingenzymeinhibitors:Captopril,Enalapril
5.AngiotensinReceptorBlockers:Losartan,Olmesartan,Telmisartan
6.Calciumchannelblockers:Nifedipine,Diltiazem

14. 14Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
1)BetaBlocker
•SelectivebetablockersAtenolol,Metoprolol,Acebutololmainlyblocktheβ1receptorat
heartandfurtherinhibitthecardiacactivityresultingindecreasetheforceofcontraction,
heartrateandmyocardialoxygendemands.
•NonselectivebetablockerslikePropranolol,Pindolol,Timololblocktheβ1receptoraswell
β2receptorthusitmayslightlyincreasethevascularresistancebutoverall,theydecreasethe
bloodpressureinlongtermusageduetopotentiallyinhibitthecardiacactivity.
•βblockersmainlyusedinhypertensionandanginapectoris.
Medicinal Chemistry of Anti-hypertensive Agents

15. 15Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
A.Timolol
(S)-1-tert-butylamino-3-(4-morpholino-1,2,5-thiadiazol-3-yl-oxy)-propan-2-ol
MOA:
•Non-selectivebetablocker,reducethecardiacactivity,bloodpressure,andincrease thevascular
resistance.
Medicinal Chemistry of Anti-hypertensive Agents
Uses:
•Hypertension
•Angina
•Migraine
•Eyedropsforglaucoma

16. 16Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
2)AngiotensinConverting EnzymeInhibitors
Drugs:Captopril, Lisinopril, Enalapril, Benazepril hydrochloride, Quinapril hydrochloride
•ACEIswhichinhibittheangiotensinconvertingenzymewhichresponsiblefortheconversionof
AngiotensinItoAngiotensinII.
•ACEIsreducethebloodpressurebyinhibitingtheAng-IIproduction,Bradykinin(vasodilator)
metabolism,andinlaterenhancetheproductionofAng(1-7)peptide(causethevasodilation).
Uses:
•ACEIsarefrequentlyusedinthetreatmentofhypertension,heartfailure,anginapectoris,diabetic
nephropathy,andchronicrenalfailure.
Medicinal Chemistry of Anti-hypertensive Agents

17. 17Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
2)AngiotensinConverting EnzymeInhibitors
•SulfhydrylContainingACEIs
A)Captopril
1-[(2S)-3-Mercapto-2-methyl-propionyl]-L-proline
•DicarboxylateContainingACEIs
B)Lisinopril
(2S)-1-[(2S)-6-amino-2-{[(1S)-1-carboxy-3-phenylpropyl]amino}hexanoyl]pyrrolidine-2-carboxylic acid
Medicinal Chemistry of Anti-hypertensive Agents

18. 18Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
2)AngiotensinConverting EnzymeInhibitors
•DicarboxylateContainingACEIs
C)Enalapril
1-ethoxy-1-oxo-4-phenyl butan-2-yl] amino]
propanoyl] pyrrolidine-2-carboxylic acid
Medicinal Chemistry of Anti-hypertensive Agents
D)Quinapril
1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,4-
dihydro-1H-isoquinoline-3-carboxylic acid

19. 19Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
2)AngiotensinConverting Enzymeinhibitors
•DicarboxylateContainingACEIs
E)Benazepril
1-ethoxy-1-oxo-4-phenyl butan-2-yl] amino]-2-oxo-4,5-
dihydro-3H-1-benzazepin-1-yl] acetic acid
Medicinal Chemistry of Anti-hypertensive Agents

20. 20Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
3)Centrally Acting Adrenergic drugs
Drugs:Methyldopatehydrochloride*,Clonidinehydrochloride,Guanabenzacetate
ThesearethecentrallyactingadrenergicdrugswhichinhibittheadrenergicactiononCVSbyinhibiting
thereleaseofnor-adrenaline/adrenaline.
Medicinal Chemistry of Anti-hypertensive Agents
A)Methyldopa
3-(3,4-Dihydroxyphenyl)-2-methylalanine ethyl[2-amino-3-(3,4-dihydroxyphenyl)]-2-
methylpropanoate
B) Methyldopate

21. 21Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
3)Centrally Acting Adrenergic drugs
MOA:
•TheyactonAlfa-2adrenoreceptor(autoreceptor)inCNSandreducethesympathetic
outflowtothecardiovascularsystemresultedindecreasecardiacactivityandblood
pressure.
•ApertfromtheAlfa-2adrenoreceptoragonisticactivity,Clonidine,guanabenzand
guanfacinealsoactonimidazolineIIreceptoronCNSandproduceinhibitoryactionCVS
similarasAlfa-2adrenoreceptor.
•CurrentlymoroxydineandtiamenidineweredevelopedasselectiveimidazolineIIreceptor
agonistandhavelessersideeffectsasbradycardia,sedationanddepression.
Medicinal Chemistry of Anti-hypertensive Agents

22. 22Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
3)Centrally Acting Adrenergic drugs
Methyldopa
MOA:
•Methyldopaconvertsintomethylnoradrenaline
whichispotentalfa2receptoragonistandreduce
thesympatheticoutflowtothecardiovascular
systemresultedindecreasecardiacactivityand
bloodpressure
Uses:
•Preferredantihypertensiveagentinpregnancy
Medicinal Chemistry of Anti-hypertensive Agents

23. 23Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
3)Centrally Acting Adrenergic drugs
C)Clonidine
N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
MOA:
•Activates the alfa 2 receptor and imidazoline II receptor and reduce the sympathetic outflow to the
cardiovascular system resulted in decrease cardiac activity and blood pressure.
Uses:
•Hypertension.
•Also used in post-menopausal vasomotor instability, prophylaxis treatment of migraine,
dysmenorrhoea, and cluster headache.
Medicinal Chemistry of Anti-hypertensive Agents

24. 24Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
3)Centrally Acting Adrenergic drugs
D)Guanabenz
2-[(Z)-(2,6-dichloro phenyl) methylideneamino] guanidine
MOA:
•Activatesthealfa2receptorandimidazolineI1receptorandreducethesympatheticoutflowtothe
cardiovascularsystemresultedindecreasecardiacactivityandbloodpressure
Uses:
•Hypertension.
Medicinal Chemistry of Anti-hypertensive Agents

25. 25Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
4)Vasodilators
Drugs:Sodiumnitroprusside,Diazoxide,Minoxidil,Hydralazinehydrochloride
These are the vasodilators which reduce the vascular resistance and cause the reduction of bloodpressure.
A)Sodiumnitroprusside
Na2[Fe(CN)5NO].2H2O
Sodium pentacyanonitrosylferret (III) dihydrate
MOA:
•ItmetabolizedtoNO(nitricoxide)whichactivatestheguanylylcyclaseenzymeandenhancethecGMP
dependentvasodilation.
Uses:
•Itiseffectiveintreatinghypertensiveemergencies,butmustbegivenbycontinuousintravenousinfusion.
Sideeffectsofthisdrugincludesignificanthypotensionandcyanideorthiocyanatetoxicity.
Medicinal Chemistry of Anti-hypertensive Agents

26. 26Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
Potassiumchannelopeners
A)Diazoxide
7-Chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide
MOA:
•It opensthe voltage gatedpotassiumchannelfurthercausesthevasodilation.
Uses:
•In hypertensionandcounterhypoglycaemia.
Medicinal Chemistry of Anti-hypertensive Agents

27. 27Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
Potassiumchannelopeners
B)Minoxidil
2,4-diamino-6-piperidino-pyrimidine-3-oxide
MOA:
•Itopensthe voltagegatedpotassiumchannelfurthercausesthevasodilation.
Uses:
•Topicallyusedinalopeciatoincrease hairgrowthandinhypertension.
Medicinal Chemistry of Anti-hypertensive Agents

28. 28Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
Potassiumchannelopeners
C)HydralazineHydrochloride
1-Hydrazinophthalazine monohydrochloride or Phthalazine
MOA:
•ItinhibittheIP3mediatedcalciumsignalingandrelax theblood vessels
Use:
•Hypertension,heart failure(butnotin usedpresently).
Medicinal Chemistry of Anti-hypertensive Agents

29. 29Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
5)Others
Drugs:Guanethidinemonosulphate,Reserpine
A)Guanethidine
MOA:
•Itreducesthereleaseofcatecholamines,suchas
norepinephrine.
•Itistransportedacrossthesympatheticnervemembraneby
thesamemechanismthattransportsnorepinephrineitself
(NET,uptake1),anduptakeisessentialforthedrug'saction.
•Onceguanethidinehasenteredthenerve,itisconcentratedin
transmittervesicles,whereitreplacesnorepinephrine.
•Itmayalsoinhibitthereleaseofgranulesbydecreasing
norepinephrine.
Medicinal Chemistry of Anti-hypertensive Agents
2-[2-(azocan-1-yl)ethyl]guanidine
Uses:
•Usedinhypertension
•Topically used in openangleglaucoma

30. 30Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur
5)Others
Drugs:Guanethidinemonosulphate,Reserpine
B)Reserpine
MOA:
•Itmodulatetheadrenergicneurotransmissionby
interferingwiththevesicletransportandstorageof
thenoradrenaline.
Uses:
•Usedinhypertensionand psychosis
Medicinal Chemistry of Anti-hypertensive Agents
methyl(1R,15S,17R,18R,19S,20S)-6,18-dimethoxy-17-(3,4,5-
trimethoxybenzoyl)oxy-1,3,11,12,14,15,16,17,18,19,20,21-
dodecahydroyohimban-19-carboxylate

31. 31Dr.Rahul Pawara (M. Pharm., Ph.D.) RCPIOP Shirpur