anti hypertensive thesis

Antihypertensi ve Agents

IntroductionThe body controls blood pressure by a complex feedback mechanism between baroreceptors and effector nerves, primarily adrenergenic in nature. This system is modulated by a peptide systems (angitensin/renin). Antihypertensive drugs are used in the tretment of high blood pressure (hypertension).hypertension is define conventionally as blood pressure (BP) = 140/90. Hypertension is called the silent killer, because it usually has no symtoms. Called as the silent killer, hypertension is linked with the hardening of the arteries, a condition called Atherosclerosis, and is a factor in 75% of all strokes and heart attacks. When hypertension is not found and treated, it can cause 1. The heart to get larger, which may lead to heart failure. 2. Small bulges to form in blood vesseks. Common location are the main artery from the heart, arteries in the brain, legs,intestines and spleen. 3. Blood vessels in the kidney to narrow, which maycause kidney failure. 4. Arteries throughout the body to ;harden; faster especially those in the heart, brain, kidney and legs. This can cause heart attacks, stroke, kidney failure or amputation of part of the legs. 5. Blood vessels in the eyes to burst or bleed, which may vision changes.

A plethora of substances are normally employed to lower the blood pressure, though their effectmay be transient. A few of them are used for their hypotensive action. An arbitrary definition of normaladult blood pressure afforded by the World Health Organization (WHO)-is a systolic pressure

Department of Pharmaceutical Chemistry, NPC

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equalto or below 140 mm Hg together with a diastolic pressure equal to or below 90 mm Hg.Antihypertensive drugs are invariably employed in the treatment of hypertension, although a fewamongst them, such as : ganglionic blocking drugs, do find their scattered applications in a variety ofother therapeutic, diagnostic and surgical procedures. Interestingly, a few of them are used as hypotensive drugs in nonhypertensive subjects. There exist two major categories of diastolic hypertension, namely : (a) primary hypertension (e.g., essential,idiopathic) ; and (b) secondary hypertension. However, the malignant hypertension is nothing but an acute and rather progressive phase of primary hypertension. It has been revealed that there is absolutely no universal therapy for the control and management of primary hypertension ; and, as such, most individual instances do vary widely in response to various therapeutic agents.In fact, there are several glaring evidences available today that may attribute to certain types ofhypertension previously known as diastolic or essential hypertension, for instances : (a) Renin-angiotensin pathway, (b) Angiotensin II receptor antagonists and (c) Potential-dependent calcium channels. Classification Systolic Blood Pressure (mmHg) Less than 120 and Diastolic Blood

Pressure (mmHg) Less than 80

Normal

Antihypertensi ve Agents Pre-hypertension Stage 1 hypertension Stage 2 hypertension 120-139 140-159 > 160 or or or 80-89 90-99 > 100

Etiology Of AntihypertensionThe various factor which contribute to less or more extent to the state of hypertension can be classified as a) Neural factors b) Hormonal factors c) Electrolyte factors d) Vessels wall factors, and e) Genetic factors

a) Neural increased

factors :- strees or emotion causing excessive cardiac output and eleveted peripheral

sympathetic outflow from the brain may result into an resistance.the over production or incomplete destruction of sympathomimetic amines may further contributed to the eleveted peripheral resistant. The abnormal levels of noradrenaline , adrenaline, dopamine and serotonin may play a peripheral as well as a cental role in activation of Department of Pharmaceutical Chemistry, NPC 3

vasomotor tone. Usually agents which block the effects of sympathomimetic amines are useful to treat hypertension caused by neural factors. b) Hormonal factors :- rennin , a proteolytic enzyme found preliminary in the kidney is released in response to lowered perfusion pressure and low sodium states of lowered perfusion and low sodium states of the circulating blood. It catalyses the conversion of angiotensinogen to angiotensin I (decapeptide). The latter is rapidly converted in the plasma by a chloride activated enzyme (primarily in the lungs) to angiotensin II (octapeptide). Angiotensin II has three fold action. I. It constricts the arterial of catecholamines peripheral resistance. II. It slowly trigger the release of aldosterone which in trun, increases sodium retention and plasma volume. III. It causes an excessive release of catecholamine from adrenal medulla and from peripheral sympathetic nerves, resulting into an increase in cardiac output. The renninangiotensin-aldosterone system thus affects all three primary factor which can cause hypertension, like a) Blood vessels constriction, b) Increased blood volume, and c) Increased cardiac output Though elevated renninangiotensin levels appear to play a critical role

Antihypertensi ve Agents in severe hypertension, other hormones and vasopressor substance may sometimes be important like arachidonic acid metabolite, prostaglandins, corticoids,kinins, vasopressin and some yet unidentified hormones. Prostaglandins (PGA, PGE) for example, cause a fall in blood pressure and renal dilation. They also initiate the release of rennin by a central effect on the vagus.] c) Electrolyte factors :- The inability of the kidney to excreted an adequate daily amount of salt and water retension of salt and water in the blood which causes an increase in the blood volume. The workload on the heart. The blood potassium and blood selenium level may also play an etiological role in hypertension along with other dietary and environmental factor. d) vessel wall factors :- the vascular smooth muscle are highly sensitive to changes in the cardia output. Hence increased perfusion pressure due to increased cardiac output leads to structural changes (like wall thickening and hypertrophy of vasculature) in the blood vessels. The direct acting vasodilators, hence may be of value in this type of hypertension. e) genetic factors :- the increased sensitivity and susceptibility to various etiologic factors (which are mentioned above ) by offsprings of hypertensives underlines the impotance of hereditary factor in hypertension.

Classification of Antihypertensive Agents

1. Peripheral antiadrenergenic drugs


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2. Centrally acting agents 3. Direct vasodilators 4. Ganglionic blocking agents 5. - adrenergic blockers 6. Calcium channel blockers 7. Angiotensin converting enzyme (AEC) inhibitors 8. Angiotensin II antagonists 9. Miscellaneous

1.Peripheral antiadrenergenic drugs

Mechanism :

Antihypertensi ve Agents these drugs lower blood pressure by blocking 1adrenoceptors that subserve vasoconstriction functions. Advantage over other -adrenergenic blockers : These drugs differ from the classic -blocking agents, in that they do not block 2-adrenoreceptors on the adrenergenic nerve terminals, which serve a negative feedback function to limit the release if noradrenaline. Conventional -blockers these receptors and cause an excessive continuing release of noradrenaline, which in the heart gives rise to tachycardia and palpitation. Uses : Used alone in the treatment of mild-to-moderate essential hypertension and with other drugs in severe hypertension.These drugs are useful in the preoperative management of pheochromocytoma.These drugs relax spastic digital arterioles in patients with Raynauds phenomenon.


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Prazosin IUPAC Name :furoyl) piperazine. Sturcture :NH2 H3CO H3CO N N N N CO O

1-(4-Amino-6,7-dimethoxy-2-quinazoliny)-4-(2-

Synthesis :-

Antihypertensi ve AgentsO H3CO NH2 NH2 H3CO O NH N H Quinazollodine HN NH H3CO Piperazine NH2 N N Cl NH3 H3CO Cl N N Cl O POCL3

H3CO

+

NH2CONH2 Urea H3CO

H3CO

H3CO

NH2 H3CO N N

O

COCL2 H3CO

NH2 N N N N CO O

H3CO

Furoyl chloride N NH H3CO

Prazosin

Terazosin IUPAC Name : ylcarbonyl)piperazin-1yl]quinazoli n-4-amine Structure : NH2 H3CO H3CO N N N N CO O

-6,7-dimethoxy-2-[4-(tetrahydrofuran-2-

Synthesis :Department of Pharmaceutical Chemistry, NPC 9

NH2 H3CO N

O

COCL2

NH2 H3CO H3CO N N N N CO O

tetraanhdrofuroyl chloride H3CO N N NH

Dose :It has longer half life (12 hr) and longer duration of action (24 hr) than does.

Trimazosin IUPAC Name :piperazinecarboxili c acid, 2-hydroxy-2-methyl propyl ester. Structure : 4-(4-Amino-6,7,8-trimethoxy-2-quinazolinyl)-1-


NH2 N N N N COOCH2 H CH3 OH CH3

Synthesis : -

NH2 H3CO H3CO N+

CH3

N Cl

+

HN

N

COO

CH2 CH3

OH

OCH3 NH2 N N N N COOCH2 H CH3 OH CH3

Doxazosin IUPAC Name 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl-4-[(2,3-dihdro-


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1,4benzodioxinyl-2y1) carbonyl] piperazine. Structure : NH2 H3CO N N N N CO O+

H3CO

O

+

Synthesis : NH2 H3CO N N Cl O

+

HN

N

CO

H3CO

O

NH2 H3CO N N N N CO O+

H3CO

O

+

Dose :It is a water-soluble analogue of prazosin and terazosin. Doxazosin differs from prazosin in that its long half-life (24 hr) enables once-a-day oral administration.


2.Centrally Acting Anti-Hypertensive DrugsMechanism :These drugs stimulate central 2-adrenergenic receptor in the vasomotor and cardio inhibitory centres, and in spinal cord on preganglionic sympathetic neurons. They also appear to have peripheral action to reduce the release of noradrenaline from sympathetic nerves. They stimulate 2arrenergic receptor on the sympathetic nerve terminals, which feedback negatively to suppress the release of the mediator.


13

Fig :- Mechanism of action of antihypertesive drugs. Clonidine The antihypertensive actions are, in part, due to a central action. However, an observed retardationin the sympathetic activity gives rise to a variety of pharmacological actions, such as : vasodilation,bradycardia and occasional atrioventicular block, and a decrease in the release of renin from the kidney ;besides, an enhancement in the vagal activity also affords bradycardia.Interestingly, the central activity, in part, seem to be the outcome of a specific stimulant action on the 2-adrenergic receptors either located in

Antihypertensi ve Agents the vasomotor and cardioinhibitory centres, or in thespinal cord on the preganglionic sympathetic neurons. Besides, it may also exert a peripheral action toreduce the release of norepinephrine from the sympathetic nerves. It has been found to cause stimulationof the 2-adrenergic receptors on the sympathetic nerve terminals, which stimulation ultimately affordsa feed back almost negatively to put an end to the release of the ensuing mediator\ IUPAC Name Structure : Cl HN N

2-(2,6-Dichloroanilino)-2-imidazoline.

NH Cl

Synthesis : Cl NH2 Cl 2,6 dichloroaniline SCH3 Cl N Cl thiouronium salt NH2 NH2CH2CH2NH2 Cl HN N Cl NH2 Cl S NH2 NH4SCN Cl Thiourea NH CH3I

+

NH2

Cl - NH3

HN N H Cl

Cl

HN N

N

NH

Uses : 1. Primary hypertension. 2. Post-menopausal vasomotor instability, dysmenorrhoea, and in the


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prophylaxis of migraine and cluster headaches.

Methyldopa IUPAC Name Sturcture : NH2 COOH

1-3-(3,4-Dihydroxyphenyl)-2-methlylalanine.

HO OH

H3C

Synthesis : CN H3CO HO COCH3 (1) NH4CN (2) KCL H3CO OH Camphor Sulphonilic acid H3C NH2

L~Isome

Phenyl acetone derivative

Conc. H2SO 4 HO OH H3C

NH2 COOH

Is a potent antihypertensive agent that acts centrally by stimulating adrenergic receptors. It also helps to minimise the tissue concentrations of adrenaline, noradrenaline and serotonin. It is widely employed to treat patients having moderate to severe hypertension by reducing the supineblood pressure as well as the standing blood pressure. The reaction of 4-hydroxy-3-methoxy phenylacetone with ammonium chloride and potassiumcyanide yields the corresponding racemic mixture of -

Antihypertensi ve Agents aminonitrile. The L-isomer is separated by meansof camphorsulphonic acid salt which on treatment with concentrated sulphuric acid affords two processessimultaneously, namely : hydrolysis of the nitrile function to the acid function ; and cleavage of the methyl ether moiety, to yield the official compound in its hydrated form. Dose : Usual, initial dose, oral 250 mg of anhydrous methyldopa 2 or 3 times per day for 2 day: usual maintenance dosage is 0.5 to 2 g of anhydrous methyldopa everyday.

Mechanism of actionNH2 L~ Aromatic amino acid HO OH H3C COOH Decarboxylase HO OH CH3

NH2

H2N CH CH

H

OH HO OH

The drug gets converted to -methylnorepinephrine that eventually helps in displacing norepinephrine, from the storage sites ; and thus, release as


17

a false transmitter by means of the prevailing nervous impulses in the adrenergic nerves. Importantly, the metabolite -methylnorepinephrine shows potent 2-agonist activity, and this perhaps acts summararily to lower the blood pressure almost in the same manner as that of clonidine. However, in the spinal cord and the vasomotor centre, the ultimate results is an observed decrease in the vasomotor outflow, that ultimately is responsible for lowering blood pressure besides decreasing the plasma-renin activity. Methyldopa is metabolite to -methylnorepinephrine and the metabolite acts in the brain to inhibit adrenergic neuronal outflow the brainstem, and this central effect is principally for its anti-hypertensive action.

Uses:Anti-hypertensive drugs also has some usefulness in the treatment of pheochromocytoma and carcinoid tumour.


Guanabenz IUPAC Name Structure:Cl NH N Cl NH . NH2

(2,6-Dichlorobenzylidene) aminoguanidine.

Synthesis:-

Cl NH CHO Cl 2,6~Dichlorobenzaldehyde

Cl NH2 N Cl NH NH . NH2

+H2N

NH .

Hydrazinyl aminoguanidine


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Guanabenz (Wytensin) and guanfacine (Tenex) are two drugs with considerable structural similarity to clonidine. These agents also are central 2-agonists andexhibit an antihypertensive profile similar to that of clonidine. It appears to cut act an 2-adrenergic agonist at presynaptic nerve terminals in the CNS , thus decreasing the release of neuroyransmitter.

3.Direct vasodilatorsDiazoxide IUPAC Name 7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide. Structure :CH3 NH O

N

Cl O

S

Synthesis:-

Antihypertensi ve AgentsNO2 C6H5CH2SH Benzyl mercaptan Cl Cl Cl NO2 Cl2 (O) SCH2C6H5 Cl SO2Cl NO2 NH4OH

2,4~Dichloro nitro benzene

NH2 H2 Reduction Cl SO2NH2 Cl

NO2

SO 2NH2

(CH3CO)2O (or) Ethyl ortho acetate Cl O

N NH O

CH3

S

The drug at therapeutic dose levels, causes vasodepression which is primarily the outcome of arteriolar dilatation, in order that the ensuing orthostatic hypotension is normally minimal. However,certain extent of venous dilatation invariably occurs, which occasionaly is responsible to afford orthostatic hypotension. It has been duly observed that the smooth musclerelaxing effects are usually caused due to the hyper-polarization of vascular smooth muscle by activating ATPase-sensitive K-channels. Hence, it is mostly used in IV as a hypotensive drug in situations arising from acute hypertensive crises. Diazoxide is found to be 90% protein-bound; however, fast and rapid IV administration allows quick-distribution to smooth muscle before it gets bound to protein intimately. Therefore, one may attain a greater and longer-lasting drop in blood pressure through faster rates of IV injection. Interestingly, the drug is found to persist in blood circulation much longer than the corresponding hypotensive effect. The plasma half-life is 20 to 60 hours in subjects having normal renal function, whereas the corresponding hypotensive Department of Pharmaceutical Chemistry, NPC

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effects lasts only 2 to 15 hours. Mechanism of action :Diazoxide hyperpolarrise arterial smooth muscle cells by activating ATP-sensitive K+ channels; this causes relaxation of the vascular smoot muscle. Uses:Used intravenously in acute hypertensive cases. Injection of an IV bolus lowers BP within 30 sec, and a maximum effect is achieved within 3 to 5 min. Dose:0.4 to 1 g per day in 2 or 3 divided doses.

Hydralazine IUPAC Name Structure:1-hydrazinophthalazine.

Antihypertensi ve AgentsHN N N NH2

Synthesis:O COOH

Cl NH N POCl3 N N

+CHO

H2NNH2 Phthalazone HN NH2 N N

NH2NH2

The drug acts on the vascular smooth muscle to afford definite relaxation. Its exact mechanism of action is still not quite vivid and clear. It is found to interfere with Ca2+ entry and Ca2+ release from the prevailing intracellular reserves ; besides, causing a specific activation of guanylate cyclase there by giving rise to an enhanced levels of cGMP. In fact, the concerted effort of all these biochemical events may afford an apparent vasodilation. It gets excreted rapidly through the kidneys, and within a span of 24 hours nearly 75% of the total quantum administered appears in the urine as its metabolites or absolutely unchanged form. The drug invariably undergoes mainly three types of chemical transformations, namely : (a)benzylic oxidation ; (b) glucuronide formation ; and (c) N-acetylation by the microsomal enzymes invariably found in the liver and tissues. It has been


23

observed that acetylation could pose as a main determinant factor of the rate of hepatic removal of the drug from the blood in circulation ; and, hence, of the prevailing systemic availability of the same.* Consequently, the rapid acetylation aids in an extremely high hepatic extraction ratio ensuing from the circulatory blood, which is virtually responsible for the greater portion of the first-pass elimination. Mechanism of action :It causes vasodilatation by stimulating guanylate cyclase in arteriolar smooth muscle; the stimulant appears to be nitric oxide (NO) from the local oxidation of the hydrazine moiety. Nitric oxide is a natural, endothelin-derived relaxing factor. Uses :Treatment of hypertensive emergencies, toxemia of pregnancy, acute congestive heart failure or after myocardial infarction. Dose :Oral, initial, 10 mg 4 times daily for 2 to 4 days, then 25 mg 4 times per day for the rest of the week.


Minoxidil IUPAC Name Structure :. O H2N . NH2

2,6-Diamino-6-piperidinopyrimidine 3-oxide.

N N N

Synthesis :-


25

NH CNCH 2COOC2H5Ethylcyanoacetate

H2N

+

H2N

Guanidine . O . HN OH

.

NH2

C2H5ONa

N N

NH2 POCl3

. O H2N . NH2

H2N

N N Cl

NH2 Peracid

H2N

N N Cl

NH2

N N N

Piperidine

Mechanism of action :It dilates arterioles by opening potassium channels, which causes hyperpolarisation and relaxation of smooth muscle. This lower the total peripheral vascular resistance and hence the BP. Uses :All types of hypertension. Further studies on minoxidil showed that the hair growth stimulation could be obtained in appropriate cases when the drug was administered topically. Consequently, the drug is used topically to restore hair growth in androgenetic alopecia.


4.Ganglionic Blocking AgentsNHCH3 CH2 CH3 CH3 CH3 Mecamylamine


27

O N N

S

+

Trimethaphan

These drug block sympathetic ganglia, interrupting adrenergic control of arterioles and results in vasodilatation, improved peripheral blood flow in some vascular beds and a fall in BP. Uses :Hypertension, vasopastic disorders and peripheral vascular diseases.

Fig:- Antihypertensive drugs affecting sympathetic & cental nervous system.


5.-Adrenergic BlockersThese drug block the -receptor of the heart, slow the heart, reduce the force of contraction and reduce the cardiac output. They also inhibit the secretion of rennin by the juxtaglomerular apparuts of the kidney; hence decrease the plasma levels of Angiotensin-II, a potent vasoconstrictor and sensitizer to the sympathetic nervous activity and stimulant of aldosterone, an antisaluretic.


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Propranolol IUPAC Name propanol. Sturcture :O HO

1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-

NH .

CH3 CH3

Synthesis :O O

HO

+

O ClEpichlorhydrin

H2NCH(CH 3) 2 Isopropylamine

O HO

NH .

CH3 CH3

It is a non-selective -antagonist and used for the treatment of hypertension, arrhythmias, myocardial infarction, phenochromocytoma, angina perctoris and thyrotoxicosis.


Atenolol IUPAC Name Structure :OH H3C NH CH3 NH2 O+

2-[p-[2-hydroxy-3-

(isopropylamino)propoxy]phenyl]acetamide.

H2N

O

Synthesis :-


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HO OH H3C (1) Epichlorhydrin NH2 O p~Hydroxy phenyl acetamide (2) Isopropylamine CH3 NH2 O NH+

H2N

O

It is a selective 1-antantagonist and used for the treatment of hypertension, arrhythmias, myocardial infarction, pheochromocytoma, thyrotoxicosis. angina pectoris, tremors and

Esmolol IUPAC Name methyl 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]benzene propionic acid. Structure :-

Antihypertensi ve AgentsH3C CH3 O H3CO O OH NH

It is a selective 1-receptor antagonist prepared from methyl 4-hydroxy phenyl propionic acid similar to propranolol.

Labetalol IUPAC Name 5-[1-hydroxy-2-[(1-methyl-3phenylpropl)amino]ethyl]salicylamide.


33

Structure :OH NH CH3 CONH2

HO

Synthesis :CH3COCl/AlCl3 HO CONH2 Friedal~crafts acylation HO CONH2 HO CONH2 COCH3 Br 2 COCH2Br

H2N

CH3

O NH CH3 CONH2

4~Phenylbutyl~2~amine

HO

OH H2 Cat. HO CONH2 NH CH3

It

combines

both

non-selective

-and

-antagonist

activity in a ratio of 3 : 1 by the oral and 7 : 1 by the IV routes. It is used in the treatment of hypertension, toxemia of pregnancy, angina pectoris and pheochromocytoma.


Timolol IUPAC Name propanol. Structure:O

1-(teri-Butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3yl)oxy]-2-

N O N N

OH NH CH3 CH3

H3C

Synthesis :-


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Cl CNCONH2

O Cl OH N S N

+

S 2Cl2 N S Cl OH NH2

H3C Tosyl chloride

SOCl2

Cl N S CH3 N

OTs

HO

NH

CH3 CH3 CH3

OH Cl N S O N NH H3C CH3

HN

O

+

Morpholine

O

N O N S N

OH NH CH3 CH3

H3C

It is a non-selective -adrennoreceptor antagonist used for the treatment of hypertension, angina pectoris and glaucoma.

6.Calcium Channel Blockers

Calcium ions (ca+2) play a pivotal role in vascular smooth muscle contraction. Calcium enters cells through specialized pores in the membrane wall called calcium channels, activated by membrane depolarisation (voltageoperated). Calcium channel blocking drugs block voltage-dependent calcium channel, especially the calcium channel in cardiac and smooth muscle. By decreasing calcium influx during action potential in a frequency and voltage-

Antihypertensi ve Agents dependent manner, they reduce systolic intracellular calcium concentration and muscle contractility. Because of this arteriole vasodilatation they decrease blood pressure. Uses :Hypertension, angina pectoris and arrhythmias.

Nifedipine IUPAC Name Dimethyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5pyridine Dicarbox ylate. Department of Pharmaceutical Chemistry, NPC 37

Structure :

NO2 H3COOC COOCH3

H3C

N H

CH3

Synthesis :O NO2 CHO 2~Nitrobenzaldehyde Methylacetoacetate

+

2 H3C

COOCH3

NO2 COOCH3 H3COOC O CH3+

NO2 COOCH3 NH3 -2H2O CH3 H3C N H H3COOC

NO2 COOCH3

H3C

O

CH3

Taludipine

Antihypertensi ve Agents IUPAC Name :Structure :COOC2H5 COOC2H5 NHCH3 H5C2OOC H3C N H

Synthesis :-

+CHO CHO Phthaladehyde

PH3P CH2COOtBuBr -

+

LDA Wittig condensation COOC(CH3)3 CHO

triphenylphosphonium salt

O H3C NH3 COOC2H5 COOtBu H5C2OOC COOC2H5 CH3 Pyridinium Perbromide

H3C

N H

COOC2H5 COOC2H5 H5C2OOC COOC2H5 Br CH3NH2 H5C2OOC H3C N H COOC2H5 NHCH3

H3C

N H


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Other Calcium Channel BlockersStructure :-

Cl Cl H5C2OOC COOCH3 (H3C)2HCOOC

NO2

COOCH2CH2OCH3

H3C

N H

CH3

H3C

N H

CH3

Felodipine

Nimodipine

CF3 EtOOC COOEt

H3C

N

CH3

N

O Floridipine


Verapamil IUPAC Name Structure:5-[3,4-Dimethoxyphenyllethyl)methylamino]-2-(3,4dimethoxyphenyl)- 2- isopropylvaleronitrile.

H3CO CN H3CO H3C CH3

CH3 N OCH3

OCH3

Synthesis:-


41

H3C

NH

OCH3

CH3

+OCH3 Homoveratrylamine

Br

Cl

N

OCH3

1~bromo~3~chloro propane Cl (I)

OCH3

OH3C CN

NaNH2 (CH3)2CHBr

H3CO CN NaOH ( I ) + ( II ) H3C ( II ) CH3

OH3C

H3CO

H3CO CN H3CO H3C CH3

CH3 N OCH3

OCH3

Diltiazem IUPAC Name :- ( + )-cis-3-(acetoxy)-5-[2-(dimethylamino)ethyl]-2,3dihydro-2-(4methoxyphenyl)-1,5-benzothiazepin4-one. Structure :-

Antihypertensi ve AgentsOCH3

S OCOCH3 N O N CH3

CH3

Synthesis :OCH3 SH S

+NO2 Nitrothiophenol H3COOC glycidic ester O

SnCl4 NO2 H3COOC OH

OCH3 NaOH

OCH3 OH ( 1 ) H2 S NO2 HOOC OH OCH3 (2) OCH3 O HN S (1) Cl N

CH3

CH3

( 2 ) (CH3CO) 2O

S OCOCH3 N O N CH3

CH3

7.Angiotensin Converting Enzyme (ACE) inhibitorsDepartment of Pharmaceutical Chemistry, NPC 43

Renin-angiotensin system :-

Angiotensinogen (14 amino acids)

Renin

Angiotensin I (Decapeptide, biologically inactive)

ACE

Angiotensin II (Octapeptide)

Vasoconstriction Na+ retention

Hypertension

Fig :- Renin-Angiotensin System Rennin converts angiotensinogen (a peptide which contains 14 amino acids ) to the decapeptide angiotensin I (which is biologically inactive); ACE acts upon angiotensin I to give the octapeptide angiotensin II, which is responsible for peripheral effects leading to an elevation of BP. Angiotensis converting enzyme inhibitors competitively inhibit ACE and block the conversion of angiotensin I to II, and act as anti-hypertenive agents.


Adverse effects of ACE inhibitors :Angiotensin converting enzyme inhibitors not only prevent the conversion of angiotensin I to II, but also prevent ACE-mediated degradation of bradykinin and substance P. because of the elevation of bradykinin and substance P, they cause angioedema and cough.

Captopril IUPAC Name (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2carboxylic acid Structure:-

CH3 N SH O COOH

Synthesis :-


45

CH3 H2C COOH HCl Addition Cl

CH3 COOH SOCl2 Cl

CH3 COOH

Methacrylic acid

HN

NH2 H3C O N COOH NH4SH SH

CH3 N O COOH

HOOC

Enalapril IUPAC Name phenylbutan2-yl]amino}propanoyl]pyrrolidine-2carboxylic acid. Structure :(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-

COOC2H5 O NH H3C HOOC N

Synthesis :-

Antihypertensi ve AgentsH3C COOH NH2 Alanine C6H5CH2OCOCl2 BOC~chloride N~protection H3C COOH NHBOC ( 1 ) Dicychlohexyl cabodiimide ( DCC ) C activation (2)HOOC H N

BOC NH H3C N O HOOC H2/Pd N~Deprotection H3C

NH2 N CH3

H5C2 OOC O

( 1 ) Ethyl 2~oxo~4~phenyl butyrate ( 2 ) Sod.cyanoborohydrate COOH

COOC2H5 O NH H3C HOOC N

Enalapril is a prodrug which is hydrolysed in the liver by a serum esterase to the active parent dicarboxylic acid enalaprilate. Lisinopril IUPAC Name proline Structure :N2-[(1S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-


47

COOH N NH (CH2)4 O NH3 COOH

The replacement of alanine residue of Enalapril by a lysine moiety leads to Lisinopril, which is administered in this case as a free dicarboxylic acid. The synthesis is quite analogous to the one shown for Enalapril.

Fosinopril

Antihypertensi ve Agents IUPAC Name (propanoyloxy)propoxy](4phenylbutyl)phosphoryl}acetyl)pyrrolidine-2carboxylic acid Structure :(2S,4S)-4-cyclohexyl-1-(2-{[2-methyl-1-

O P (CH 2)4 O

O

N COOH

COOC2H5CH3

H3C

Synthesis :-


49

O CH2 (CH2)2 OH Sodium Phosphite O O P (CH 2)4 OH O Cl H3C CH3 o~Alkylation O O C 2H 5(CH 2) 4

P (CH2)4

+

BrCH 2COOCH 2C6H5 AlkylationO O P O O

OH

COOC 2H5CH3

H3C

O

H2 Debenzylation

O (CH 2)4 P O OH

(1) DCC (2)HN

COOC 2H5CH3

H3C

HOOC

O P (CH 2) 4 O

O

N COOH

COOC 2H5CH3

H3C

It is a phosphate containing prodrug cleaved at the ester moiety by hepatic esterases, and transformed into Foosinoprilate.

8.Angiotensin II AntagonistsThese compouds complete with anggionensin II at the receptor site and block the contractile effect of angiotensin II in all vascular smooth muscles. Unlike ACE inhibitors, these drugs do not cause cough and have not been associated with angioneurotic edema. Losartan IUPAC Name :- :yl]methyl}(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-

Antihypertensi ve Agents 1H-imidazol-5yl)methanol Structure :HOH2C N Cl

N N HN N N

H3CH2CH2CH2C

Synthesis :H3C N CH3 NH

+

BrH 2C NC

CH 2CH 2CH 2CH 3 2~Butyl~6~chloro~ 5~hydroxymethyl imidazole

Bromomethyl biphenyl derivative.

HOH 2C N N

Cl NaN 3/HCl Sodium azide NC

CH 2CH 2CH 2CH 3

HOH 2C N

Cl

N N HN N N

H3CH 2CH 2CH 2C

Candesaartan IUPAC Name :- :- 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5yl)phenyl]phenyl}methyl)1H-1,3-benzodiazole-6-


51

carboxylic acid Structure :N NH

N OC2H5 N COOH

N N

Synthesis :-

Antihypertensi ve AgentsNO2 CH3OH H2SO 4 COOH COOH NO2 SOCl2 COOH COOCH3 COCl COOCH3 NO2 NaN3 CON3 COOCH3 NO2

NO2 Curtius rearrangement CH3 HOC(CH3)3 CH3 CH3

NO2 (1) NaH CH3 (2) BrH2C NC

NO2 H3COOC N COOC(CH3)3 (1) H2 (2) C2H5ONa NH H5C2OOC NC CN CH3 CH(C2H5O) 3 Ethyl orthoformate

N OC2H5 N H5C2OOC

NC NaN3/H NaOH+

N OC2H5 N COOH

N N

N NH

Valsartan IUPAC Name :tetrazol-5yl)phenyl]phenyl}methyl)pentanamid o]butanoic Structure :(S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-


53

H3C O H3C N

CH3

COOH

N N

N NH

Synthesis :H3C Alkylation CH3

H3C BrH2C NC

CH3

+H2N COOBz

HN

COOBz CN

Benzyl valine

H3C H3C Valeoryl chloride COCl H3C O

CH3

(1) NaN3/H N COOBz CN

+

(2) H2,Pd/Charcol

H3C O H3C N

CH3

COOH

N N

N NH

9.Miscellaneous :Thiazide and high-ceiling diuretics lower BP of persons with essential hypertension.


Thiazide diuretics :Mechanism of action :-

Na

+

Na

+

ATPCl-

K K

+ +

ThiazidesNa Ca2+ +

Ca

2+ -

Cl

Fig :- Mechanism Of Action Of Thiazide Diuretics. Thiazide diuretics act mainly to block sodium and chloride reabsorption at the first portion of the distal tubules. Thiazides inhibit a Na+ - Cl- symport in the luminal membrane of the epithelial cells in the distal convoluted tubule. Thus, thiazide inhibit NaCl reabsorption in the distal convoluted tubule and may have a small effect on the NaCl reabsorption in the proximal tubule. Thiazides enhance Ca++ reabsorption in the distal convoluted tuble by inhibiting Na+ entry and thus enhancing the activity of Na+-Ca++ exchanger in the basolateral membrane of epithilial cells. Department of Pharmaceutical Chemistry, NPC 55

They also have a mild anti-carbonic anhydrous effect. The resulting diuretics are accompained by increased excretion of potassium, bicarbonates, chloride and water.The anti-hypertensive action of the thiazide is attributable in plasma to factor. 1. Depletion of sodium and subsequent reduction in plasma volume. 2. A decrease in peripheral resistance. Uses :1. As adjunctive therapy in edema associated with congestive heart failure, hepatic cirrosis, renal dysfuntion and corticosteroid and estrongen therapy. 2. Tretment of hypertension. 3. Prevents the formation and recurrence of calcium stones nephrolithiasis in hypercalciuric patients. 4. Nephrogenic diabetes insipidus. Structure Activity Relationship (SAR)R1 N NH O CH3

H2NO2S O

S

1. The position 2 can tolerate the presence of relatively small groups such as CH3. 2. Substituents in the 3-position play a dominant role in determining the potency and duration of action thiazide diuretics. 3. Loss of the carbon-carbon double bond between the 3- and 4- positions of nucleus increases the diuretic potency approximately three to tenfold.

Antihypertensi ve Agents 4. Direct substitution of the 4-, 5- or 8- position with an alkyl group usually result in diminished diuretic activity. 5. Substitution of the 6- position with an activating group is essential for diuretic activity. The best substituents include Cl, Br, CF3 and NO2 groups. 6. The sulphamoyl group in the 7-position is a prerequisite for diuretic activity.

Synthesis :Method ACl NH2 ClClSO 3H Chlorosulphonic acid 3~chloroaniline

NH2

ClNH 4OH

NH2

ClO2S HCHO

SO2Cl

H2NO2S

SO2NH2 HCOOH

Cl2CHCHO Dichloro acetaldehyde

Cl H N NH O

H N NH

Cl

N NH O

Cl

CHCl2

H2NO2S O

S

H2NO2S O OChlorothiazide

S

H2NO2S O

S

Hydrochlorthiazide

Trichlormethiazide

Method B


57

Cl

NH2

+

C6H5CH2SCH2CHO

NaOH

Cl

N NH

CH2SCH2C6H5

H2NO2S

SO2NH2

H2NO2S O

S

O

Benzthiazide CHO

CHO H N NH O

Cl

H N NH O

Cl

H2NO2S O

S

H2NO2S O

S

Cyclothiazide

Cyclopenthiazide

Method CF 3C NH2 (1) ClSO3H (2) NH4OH F 3C NH2 HCHO F 3C N NH O

H2NO2S

SO 2NH2

H2NO2S O

S

Hydroflumethiazide CHO

Phenyl acetaldehyde

F 3C

H N NH

CH2C6H5

H2NO2S O

S

O

Bendroflumethiazide


Method DO Cl NH2 Cl H N NH H2NO2S O H N N O CH3 O CH2Cl S O Cl H N N CH3 O O

H2N

NH2

CH3I

H2NO2S

SO2NH2

H2NO2S O

S

NaOH Hydrolysis

Cl

NH2

Cl ClCH2CHO H2NO2S O

H2NO2S

SO 2NHCH3

S

Methylclothiazide

CF3CH2SCH2CHO CH3OH

Cl

H N N O

CH2SCH2CF3

H2NO2S O

S

CH3

Polythiazide

Loop Diuretics Uses :1. Acute pulmonary edema. 2. Chronic congestive heart failure when diminution of extracellular fluid volume is desirable to reduce venous and pulmonary edema. 3. Treatment of hyperkalemia in combination when patients do not response satisfactorily to thiazide diuretics and anti-hypertensive drugs. 4. Hypercalcemia. 5. Treatment of hyperkalemia in combination with isotonic NaCl administration. Department of Pharmaceutical Chemistry, NPC 59

6. Used in acute renal failure to increase the urine flow and K+ secretion. 7. Treatment of toxic ingestions of bromide, fluoride and iodide (with simultaneous saline administration). Mechanism of action :+

Na + K 2C l-

+

Na

ATP K K+ + +

Loop D iuretics

K

+

Na

+

C lCl

-

FIG :- Mechanism Of Action Of Loop Diuretics. Loop diuretics inhibit reabsorption of NaCl and KCl by inhibiting the Na+-K+-2Cl- symport in the luminal membrane of the thick ascending limb (TAL) of loop of Henle. As TAL is responsible for the reabsorption of 35% of filtered sodium and there are no significant downstream compensatory reabsorption mechanisms, loop diuretics are thus called high-ceiling diuretics. As the Na+-K+-2Cl- symport and sodium pump together generate a positive lumen potential that drives the reabsorption of Ca++ and Mg++, inhibitors of the Na+-K+-2Cl- symport also inhibit reabsorption of Ca++ and Mg++

. By unknown mechanisms (possibly prostaglandin-mediated), loop

Antihypertensi ve Agents diuretics also have direct effect on vasculature including increase in renal blood flow, and increase in in systemic venous capacitance.

Bumetanide IUPAC Name Structure :3-(butylamino)-4-phenoxy-5-sulphamoylbenzoic acid.


61

COOH

H2NO2S O

NH(CH2)3CH3

Synthesis:COOH HNO3 Cl2OS Cl 4~cloro~5~(chlorosulphonyl) benzoic acid COOH COOH H2SO 4 Cl2OS CH3 NO2

COOH NH3 H2NO2S

COOH HO NaOH

NO2 Cl

[H] H2NO2S O NO2 H2NO2S O NH2

(1) CH3(CH2)2CHO (2) H2/Pd Reductive coupling

COOH

H2NO2S O

NH(CH2)3CH3

Antihypertensi ve Agents Ethacrynic acid IUPAC Name acid. Structure :H3C CH2 COOH CO Cl Cl O

[2,3-dichloro-4-(2-methylenebutyryl)phenoxyl] acetic

Synthesis :COOH O Cl Cl (1) CH3CH2CH2COCl (2) AlCl3 Friedel~craft acylation H3C COOH CO Cl Cl O

CH3 H3C HCHO/(CH3)2NH Mannich reaction CO Cl Cl N CH3 O -(CH3)2NH COOH

H3C

CH2 COOH CO Cl Cl O


63

Furosemide IUPAC Name Structure :COOH NH

4-chloro-N-furfuryl-5-sulphamoylanthranilic acid.

H2NO2S Cl O

Synthesis :COOH Cl ClSO3H Cl2OS Cl Cl Cl NH3 H2NO2S Cl COOH Cl COOH NH2 Furfuryl amine H2NO2S Cl O NH

COOH

O


Recent & Relevant ReviewHypertension Is relatively uncommon in children and adolescents, with an incidence of approximately 1% in the general pediatric population. In contrast, hypertension is a common finding in chronically ill children with diabetes, bronchopulmonary dysplasia and underlying renal disorders. In these children, controlling blood pressure is of critical importance. Hypertension in children is defined as systolic blood pressure (SBP) or diastolic blood pressure (DBP) that exceeds the 95th percentile for age, sex and height. As such, the goal of treatment in these children is to reduce blood pressure to a level below the 95th percentile. Treatment strategies for pediatric hypertension include both nonpharmacologic and pharmacologic interventions. Weight loss in the obese child, increased physical activity and dietary restriction of sodium and potassium intake may be useful in reducing blood pressure, particularly in overweight adolescents with essential hypertension. Children with secondary or severe hypertension, however, often require additional treatment with pharmacologic therapy. Several classes of drugs are currently available for clinical use in infants and children. These include the angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics and sympatholytic agents. ACE Inhibitors/ Angiotensin II Receptor Antagonists:ACE is a membrane-bound, circulating enzyme that catalyzes the Department of Pharmaceutical Chemistry, NPC

65

conversion of angiotensin I to angiotensin II. Angiotensin II increases blood pressure via both direct (e.g., vasoconstriction of the arterial vasculature) and indirect (e.g., aldosterone-mediated salt and water retention) mechanisms. The ACE inhibitors are effective when used either alone or in combination with other antihypertensive agents, particularly in children with underlying renal disease. As a class, ACE inhibitors are well tolerated and few patients discontinue therapy because of adverse reactions. Of the numerous ACE inhibitors currently available, only captopril and enalapril have been systematically evaluated in the pediatric population. The angiotensin II receptor antagonists are selective inhibitors of angiotensin II type 1 (AT1) receptors. The anti-hypertensive effect of these agents is similar to that observed with the ACE inhibitors. In general, these agents are well tolerated and have a side effect profile similar to that of placebo. Although several studies are reportedly in progress, published reports of the angiotensin II receptor antagonists in pediatric hypertension are currently lacking. Calcium channel blockers:Calcium channel blockers (CCB) exert their anti-hypertensive effect via inhibition of voltage- dependent calcium channels and subsequent vascular smooth muscle relaxation and cardiac muscle contraction inhibition (negative inotropic effect). The dihydropyridines (e.g., amlodipine) are used extensively for their blood-pressure lowering effects due to their vascular smooth muscle selectivity and minimal effect on cardiac conduction. In contrast, the phenylalkylamine (e.g. verapamil) and benzothiazepine (e.g., diltiazem) CCBs demonstrate a depressive effect on cardiac conduction and are used primarily for their anti-arrhythmic effects. Successful long-term control of blood pressure in children has been achieved with agents such as felodipine, isradipine and amlodipine. Of these, the latter is particularly advantageous for use in children

Antihypertensi ve Agents because it can be dissolved into a liquid preparation and has a long elimination half-life, allowing for once-daily dosing. Diuretics:Diuretics interfere with the renal tubular mechanisms of salt and water reabsorption and are beneficial in treating hypertension as monotherapy or in combination with other antihypertensive agents. Initially, diuretics decrease extracellular fluid volume and, in turn, cardiac output. Over time, compensatory mechanisms return cardiac output to normal; however, the decrease in peripheral vascular resistance persists. Thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide) are the most common and effective diuretics used for hypertension. These agents inhibit the luminal sodiumchloride transporter in the distal tubule. At maximal therapeutic doses, all thiazides are approximately equal in their diuretic effect. Furosemide, bumetanide and torsemide are loop diuretics that inhibit the luminal sodiumpotassium- chloride transporter in the ascending loop of Henle. Because of the potential for adverse effects (e.g., ototoxicity, electrolyte abnormalities) the loop diuretics are usually reserved as an adjuvant to other antihypertensive agents in children with reduced renal function.

Sympatholytic agents:Blockade of -adrenergic receptors with -adrenergic receptor antagonists decrease blood pressure via multiple proposed mechanisms. These include decreased cardiac output and renal and aldosterone secretion, alterations in CNS sympathetic output and potentiation of natriuretic peptides. In children, adrenergic receptor antagonists are used in cardiac disease, migraine prevention and hypertension. The centrally acting agents (e.g., clonidine, Department of Pharmaceutical Chemistry, NPC 67

guanabenz and guanfacine) stimulate 2-adrenergic receptors in the brainstem and decrease sympathetic outflow, which in turn decreases cardiac output and vascular resistance. In adolescents with essential hypertension, clonidine and guanabenz have demonstrated a beneficial effect. Discontinuation of centrally acting agents should be gradual because abrupt withdrawal can result in symptoms such as agitation, headache and most importantly, rebound hypertension. Alpha1- adrenergic receptor antagonists (e.g., prazosin, doxazosin) and ganglionic blockers (e.g., reserpine) are rarely used in pediatrics because of the high incidence of side effects (e.g. hypotension, weakness, dizziness). Selection of the most appropriate anti-hypertensive regimen in children is best approached using an individualized stepped-care approach. In children, the trend is to use CCBs or ACE inhibitors as the initial agent because of their effectiveness and favorable safety profile. In adolescents with essential hypertension and no indication for a specific drug, a diuretic or -blocker continues to be recommended as initial drug therapy. The initial drug choice should be based on the presumed etiology and severity of hypertension, concomitant diseases and therapies, availability of appropriate formulations, and pediatric safety and efficacy data. A low dose of the initial drug is then prescribed and slowly titrated upward based on the blood pressure response of adverse effects. If no response or significant side effects are observed, an alternate anti-hypertensive agent can be substituted. If the response is inadequate but well tolerated then a second agent may be added.


Current Clinical ResearchPhase II pharmacokinetic studies of linezolid (a new antibiotic) in neonates and children 3 mo-6 years years, MK826 (a new carbapenem) in children 2-23 months , FK463 (a new antifungal) in neonates, levofloxacin 3 mo-17 years, and fexofenadine 3 mo-2yrs are being conducted. If you are caring for a patient that may be eligible for enrollment, please contact Clinical Pharmacology (234-3059) or you may page Mike Venneman, RN (821-9911).

Market preparation of antihypertensive drugs :LOWEST TIER Preferred generic medications MIDDLE TIER Preferred brand-name medications HIGHEST TIER Non-preferred brand and generic medications


69

DIURETICS Thiazide chlorothiazide chlorthalidone hydrochlorothiazide (hctz) indapamide methyclothiazide metolazone polythiazide Diuril (chlorothiazide) HydroDIURIL (hctz) Lozol (indapamide) Microzide (hctz) Mykrox (metolazone) Renese (polythiazide) Zaroxolyn (metolazone)

No products available in this category

Loop bumetadine furosemide torsemide No products available in this category Bumex (bumetanide) Demadex (torsemide) Lasix (furosemide)

amiloride triamterene

Potassium-sparing No products available in this category

Dyrenium (triamterene) Midamor (amiloride)

spironolactone

Aldosterone receptor blockers No products available in this category BETA BLOCKERS

Aldactone (spironolactone) Inspra (eplerenone) FE

Acebutolol pindolol

BETA-BLOCKER WITH INTRINSIC SYMPATHOMIMETIC (ISA) ACTIVITY No products available in

Cartrol (carteolol) FE Levatol (penbutolol) FE Sectral (acebutolol)

Antihypertensi ve Agents this category

atenolol betaxolol bisoprolol metoprolol nadolol propranolol propranolol long-acting timolol

Non-ISA beta-blockers No products available in this category

Blocadren (timolol) Corgard (nadolol) Inderal (propranolol) Inderal LA (propranolol long-acting) Kerlone (betaxolol) FE Lopressor (metoprolol) Tenormin (atenolol) Toprol XL (metoprolol extended release) FE

labetalol

Combined alpha-and beta-blockers Coreg (carvedilol)

Normodyne (labetalol) Trandate (labetalol)

ACE INHIBITORS (ACEls ) benazepril captopril enalapril fosinopril lisinopril moexipril quinapril Altace (ramipril) Accupril (quinapril) FE Aceon (perindopril) FE Capoten (captopril) ST, FE Lotensin (benazepril) ST, FE Mavik (trandolapril) FE Monopril (fosinopril) ST, FE Prinivil (lisinopril) ST, FE Univasc (moexipril) Vasotec (enalapril) ST, FE Zestril (lisinopril) ST, FE


71

ANGIOTENSIN ll ANTAGONISTS No generic products available in this category Cozaar (losartan) QL Diovan (valsartan) QL Atacand (candesartan) QL, ST, FE Avapro (irbesartan) QL, ST, FE Benicar (olmesartan) QL, FE Micardis (telmisartan) QL, FE Teveten (eprosartan) QL, FE

ALPHA 1-BLOCKERS

clonidine clonidine patch methyldopa reserpine guanfacine

No products available in this category

Aldomet (methyldopa) Catapres (clonidine) Catapres-TTS (clonidine patch)

Uppercase = Brand-name medication lowercase = Generic medication FE = Formulary-excluded medication ST = Step-therapy applies under most plans QL = Quantity limits apply under most plans


LOWEST TIER Preferred generic medications

MIDDLE TIER Preferred brand-name medications

HIGHEST TIER Non-preferred brand and generic medications

CALCIUM CHANNEL BLOCKERS (CCBs) Non-dihyrdopyridines cartia XT QL diltia XT QL diltiazem CD/CR/ER/XT QL taztia XT QL verapamil CR/ER/SR QL No products available in this category Calan (verapamil) ST, FE Calan SR (verapamil) ST, QL, FE Cardizem (diltiazem) ST Cardizem CD (diltiazem CD) ST, QL Cardizal LA (diltiazem LA) ST, QL Dilacor (diltiazem) ST Dilacor SR (diltiazem SR) ST, QL Covera HS (verapamilCoer) QL, FE Isoptin (verapamil) ST, FE Isoptin SR (verapamil SR) ST, QL, FE Tiazac (diltiazem) ST, QL Tiamate (diltiazem) ST, QL Vascor (bepridil) FE Verelan PM


73

(verapamil-Coer) QL, FE Adalat (nifedipine) ST Adalat CC (nifedipine longacting) ST, QL Cardene SR (nicardipine sustained release) ST, FE Dynacirc (isradipine) FE Dynacirc CR (isradipine SR) FE Plendil (felodipine) QL, FE Procardia (nifedipine) ST Procardia XL (nifedipine longacting) ST, QL Sular (nisoldipine) QL, FE

nicardipine nifedipine nifedipine CR/ER QL

Dihydropyridines Norvasc (amlodipine besylate) QL

CENTRAL ALPHA2-AGONISTS AND OTHER CENTRALLY ACTING doxazosin prazosin terazosin No products available in this category DIRECT VASODILATORS Hydralazine minoxidil No products available in this category COMBINATION DRUGS ACEIs and CCBs Lotrel (amlodipine/benzapril hydrochloride) Lexxel (enalapril maleate/felodipine) FE Tarka (trandolapril/verapamil) FE Accuretic (quinapril/hctz) ST, FE Capozide (captopril/hctz) Lotensin HCT (benazepril/hctz) FE Monopril HCT (fosinopril/hctz) FE Prinzide (lisinopril/hctz) ST, FE Uniretic (moexipril HCl/hctz) FE Vaseretic (enalapril/hctz) Zestoretic (lisinopril/hctz) Apresoline (hydralazine) Loniten (minoxidil) Cardura (doxazsoin) Hytrin (terazosin) Minipress (prazosin)

No generics available in this category

benazepril/hctz captopril/hctz enalapril/hctz fosinopril/hctz lisinopril/hctz quinapril/hctz

ACEIs and diuretics No products available in this category

Antihypertensi ve AgentsAtacand HCT (candesartan cilexetil/hctz) ST, QL, FE Avalide (irbesartan/hctz) ST, QL, FE Benicar HCT (olmesartan/hctz) QL, FE Micardis HCT (telmisartan/hctz) QL, FE Teveten HCT (eprosartan mesylate/hctz) QL, FE Corzide (nadolol/bendroflumethiazide) FE Inderide (propranolol LA/hctz) Lopressor HCT (metoprolol tartrate/hctz) FE Tenoretic (atenolol/hctz) Timolide (timolol maleate/hctz) FE Ziac (bisoprolol fumarate/hctz) Aldoril (methyldopa/hctz) Diurpres (reserpine/chlorothiazide) Hydropres (reserpine/hctz) Aldactone (spironolactone/hctz) Dyazide (triamterene/hctz) Maxzide (triamterene/hctz) Moduretic (amiloride hcl/hctz)

No generics available in this category

Angiotensin ll Antagonists and diuretics Diovan HCT (valsartan/ hydrochlorothiazide) QL Hyzaar (losartan potassium/ hydrochlorothiazide) QL

atenolol/hctz bisoprolol fumarate/hctz metoprolol tartrate/hctz nadolol/bendroflumethiazide propranolol LA/hctz timolol maleate/hctz

Beta-blockers and diuretics No products available in this category

methyldopa/hctz reserpine/chlorothiazide reserpine/hctz amiloride hcl/hctz spironolactone/hctz triamterene/hctz

Centrally acting drug and diuretic No products available in this category Diuretic and diuretic No products available in this category

Anti-hypertensive Combinations ACE inhibitors & diuretics Angiotensin-II receptor antagonists & diuretics Beta blockers & diuretics Calcium channel blockers & ACE inhibitors Diuretic combinations / Other Department of Pharmaceutical Chemistry, NPC 75

ACE inhibitors & diuretics Benazepril (HTN) range: 10-80 mg qd (Initial: 10mg po qd). HCTZ (Range): 12.5-50 mg per day. Lotensin HCT 10/12.5 or Lotensin HCT 20/12.5. The HCTZ dose should generally not be increased until 2-3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily HCTZ, but who experience significant potassium loss with this regimen, may achieve similar blood-pressure control without electrolyte disturbance if they are switched to Lotensin HCT 5/6.25. Supplied: (5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg) Adult (usual) Hypertension (HTN): initial, 1 tab (captopril 25 mg/HCTZ 15 mg) orally once daily. HTN: titration, allow 6-8 wk to achieve optimum antihypertensive effect - may administer daily dose in divided doses. HTN: maximum dose: 150 mg captopril and 50 mg HCTZ per day. Supplied: (25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg) Enalapril (Usual range): 10 to 40 mg per day administered in a single or two divided dose. HCTZ (range): 12.5 to 50 mg daily. A patient whose blood pressure is not adequately controlled with either enalapril or HCTZ monotherapy may be given Vaseretic 5-12.5 or Vaseretic 10-25. The HCTZ dose should generally not be increased until 2-3 weeks have elapsed. In general, patients do not require doses in excess of 20 mg of enalapril or 50 mg of HCTZ. The daily dosage should not exceed four tablets of Vaseretic 5-12.5 or two tablets of Vaseretic 1025. Supplied: (5 mg/12.5 mg, 10 mg/25 mg) Hypertension - Initial dose: 10/12.5 or 20/12.5. Further

Benazepril & HCTZ (Lotensin HCT )

Captopril & HCTZ (Capozide )

Enalapril & HCTZ (Vaseretic )

Lisinopril & HCTZ

Antihypertensi ve Agents increases of either or both components could depend on clinical response. The HCTZ dose should generally not be increased until 2-3 weeks have elapsed. Maximum dose: 80/50 mg orally once daily. Patients whose blood pressures are adequately controlled with 25 mg of daily HCTZ, but who experience significant potassium loss with this regimen, may achieve similar or greater blood pressure control with less potassium loss if they are switched to 10/12.5. Dosage higher than lisinopril 80 mg and HCTZ 50 mg should not be used. Supplied: (10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg) Moexipril (range) 7.5 to 30 mg daily- administered in a single or two divided doses. HCTZ (range): 12.5 to 50 mg daily. Initial dose: (7.5 mg /12.5 mg) or (15 mg /12.5 mg) or (15 mg /25 mg) one hour before a meal. Titrate: q2-3 weeks. Total daily doses above 30 mg /50 mg a day have not been studied in hypertensive patients. Patients whose blood pressures are adequately controlled with 25 mg of HCTZ daily, but who experience significant potassium loss with this regimen, may achieve blood pressure control without electrolyte disturbance if they are switched to moexipril 3.75 mg/HCTZ 6.25 mg (onehalf 7.5 mg /12.5 mg tablet). For patients who experience an excessive reduction in blood pressure with 7.5 mg /12.5 mg, the physician may consider prescribing moexipril 3.75 mg/HCTZ 6.25 mg. Supplied: (7.5 mg/12.5 mg, 15mg/12.5 mg, 15 mg/25 mg)

(Prinzide )

(Zestoretic )

Moexipril & HCTZ (Uniretic )

Angiotensin-II receptor antagonists & diuretics Adult (usual) Hypertension (HTN): initial, 1 tab (50 mg losartan/12.5 mg HCTZ) po qd. HTN: titration, allow 3 wk to achieve optimum antihypertensive effect. HTN: titrate to maintenance, may increase to MAX dose of 100/50 mg orally once daily. Supplied: (50 mg/12.5 mg, 100 mg/25 mg)

Losartan & HCTZ (Hyzaar )


77

Valsartan & HCTZ (Diovan HCT )

Adult (usual) Hypertension: initial, 12.5 HCTZ/80 mg valsartan orally once daily. Hypertension: maintenance 12.5/80 mg to 25/160 mg po qd. Titrate at intervals of 3-4 wekks. MAX 25/160 mg daily. Supplied: (80 mg/12.5 mg, 160 mg/12.5 mg, 160mg/25 mg)

Beta blockers & diuretics Dosage, Adult (usual): Hypertension (HTN): initial, 1 tab (50/25 mg) po qd. HTN: titration, allow 1-2 wk to achieve optimum antihypertensive effect. HTN: maintenance, may increase to 1 tab (100/25 mg) orally once daily. Supplied: (50 mg/25 mg, 100 mg/25 mg) Hypertension: initial, 1 tab (2.5/6.25 mg) orally once daily. Titration - allow 1-2 wk to achieve optimum antihypertensive effect. May increase to MAX dose of 20/12.5 mg orally once daily. Supplied: (2.5 mg/6.25 mg, 5 mg/6.25 mg, 10 mg/6.5 mg) [ HCTZ (range): 12.5 to 50 mg per day. The usual initial dosage of Lopressor is 100 mg daily in single or divided doses. The effective dosage range is 100 to 450 mg per day. ] The following dosage schedule may be used to administer from 100 to 200 mg of Lopressor per day and from 25 to 50 mg of HCTZ per day: Lopressor HCT Dosage Tablets of 50/25 - 2 tablets per day in single or divided doses. Tablets of 100/25 - 1 to 2 tablets per day in single or divided doses. Tablets of 100/50 - 1 tablet per day in single or divided doses. Dosing regimens that exceed 50 mg of HCTZ per day are not recommended. Supplied: (50 mg/25 mg, 100 mg/25 mg, 100 mg/50 mg)

Atenolol & chlorthalidone (Tenoretic)

Bisoprolol & HCTZ (Ziac)

Metoprolol & HCTZ (Lopressor HCT)

Antihypertensi ve Agents Initial dose: 40 mg/5 mg tablet once daily. When the antihypertensive response is not satisfactory, the dose may be increased by administering the 80 mg/5 mg tablet once daily. When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure. Supplied: (40 mg/5 mg, 80 mg/5 mg) HCTZ (range): 12.5 to 50 mg per day. The initial dose of propranolol is 80 mg daily. The usual effective dose when used alone is 160 to 480 mg per day. One Inderide tablet twice daily can be used to administer up to 160 mg of propranolol and 50 mg of HCTZ. For doses of propranolol greater than 160 mg the combination products are not appropriate, because their use would lead to an excessive dose of the thiazide component. Supplied: (40 mg/25 mg, 80 mg/25 mg). (Inderide LA ) : (80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg) Initial dose (HTN): 1 tablet twice a day or 2 tablets once a day. HCTZ (range): 12.5 to 50 mg per day when used alone. If the antihypertensive response is not satisfactory, another nondiuretic antihypertensive agent may be added. Supplied: (10 mg/25 mg) Calcium channel blockers & ACE inhibitors Amlodipine & benazepril (Lotrel ) Adult (usual)- Hypertension: initial 2.5/10 mg orally once daily - may increase to 5/10 mg or 5/20 mg orally once daily. Amlodipine is an effective treatment of hypertension in oncedaily doses of 2.5-10 mg while benazepril is effective in doses of 10-80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5-10 mg and benazepril doses of 10-20 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.

Nadolol & bendroflumethazide (Corzide )

Propranolol & HCTZ (Inderide )

Timolol & HCTZ (Timolide )


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Supplied: (2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg) Felodipine & enalapril (Lexxel ) Adult (usual) Hypertension: initial, 5mg/5mg tab po qd, may titrate to two 5mg/5mg tab po qd, then four 5mg/2.5 mg tab po qd. Supplied: (5mg/2.5 mg, 5 mg/5 mg) Adult (usual) - 1 tablet po qd. Hypertension: 1-4 mg trandolapril/120-480 mg verapamil po qd or in 2 divided doses. The recommended usual dosage range of trandolapril for hypertension is 1 to 4 mg per day administered in a single dose or two divided doses. The recommended usual dosage range of Isoptin-SR for hypertension is 120 to 480 mg per day administered in a single dose or two divided doses. Supplied: (180 mg/2 mg, 240 mg/1 mg, 240 mg/2 mg, 240 mg/4 mg). Diuretic combinations / Other Give with food. The usual starting dosage is 1 tablet a day. The dosage may be increased to 2 tablets a day, if necessary. More than 2 tablets of Moduretic daily usually are not needed and there is no controlled experience with such doses. HCTZ (range): 12.5 to 50 mg per day. Supplied: (5 mg/50 mg) CHF, hepatic cirrhosis, or nephrotic syndrome: The usual maintenance dose of Aldactazide is 100 mg each of spironolactone and HCTZ daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. Hypertension: many patients will be found to have an optimal response to 50 mg to 100 mg each of spironolactone and HCTZ daily, given in a single dose or in divided doses. Supplied: (25 mg/50 mg, 50 mg/50 mg)

Verapamil & trandolapril (Tarka )

Amiloride & HCTZ (Moduretic )

Spironolactone & HCTZ (Aldactazide )

Triamterene & Adult (usual) Hypertension (HTN): initial, 1 tab/cap (25 mg HCTZ HCTZ/37.5 mg triamterene) po qd. HTN: titration, allow 2-3 (Dyazide , Maxzide ) wk to achieve optimum antihypertensive effect. HTN: titrate to maintenance, may increase to maximum dose of 50/75 mg po qd. Supplied: (37.5 mg/25 mg capsule and tablet, 75 mg/50 mg

Antihypertensi ve Agents tablet) Clonidine & chlorthalidone (Combipres ) Hydralazine & HCTZ (Apresazide ) Adult (usual) Hypertension: 15 mg/0.1 mg, 15 mg/0.2 mg, or 15 mg/0.3 mg po qd - bid. maximum dose of 30 mg/0.6 mg per day. Supplied: (0.1 mg/15 mg, 0.2 mg/15 mg, 0.3 mg/15 mg) Usual Dosage: One capsule twice daily. Supplied: (25 mg/25 mg, 50 mg/50 mg, 100 mg/50 mg) Usual starting dose: (250 mg/15 mg) two or three times a day or one tablet of (250 mg/25 mg) - two times a day. Alternatively, one tablet of 500 mg/30 mg or 500 mg/50 mg once daily may be used. HCTZ (range): 12.5 to 50 mg per day. methyldopa daily range: 500 mg to 2 g. The maximum recommended daily dose of methyldopa is 3 g. Supplied: (250 mg/15 mg, 250 mg/25 mg, 500 mg/30 mg, 500 mg/50 mg) Usual - Adults: Oral: 1 capsule 2-3 times/day. Supplied: (1 mg/0.5 mg, 2 mg/0.5 mg, 5 mg/0.5 mg)

Methyldopa & HCTZ (Aldoril )

Prazosin & polythiazide (Minizide )


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References :1. MeSH Antihypertensive+Agents 2. Nelson MR, McNeil JJ, Peeters A et al. (Jun 4 2001). "PBS/RPBS cost implications of trends and guideline recommendations in the pharmacological management of hypertension in Australia, 19941998". Med J Aust 174 (11): 5658. PMID 11453328. 3. Chobanian AV et al. (2003). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". JAMA 289: 256072. doi:10.1001/jama.289.19.2560. PMID 12748199. http://jama.amaassn.org/cgi/content/full/289.19.2560v1. 4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (Dec 18 2002). "Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)". JAMA 288 (23): 298197. doi:10.1001/jama.288.23.2981. PMID 12479763. http://jama.amaassn.org/cgi/content/full/288/23/2981. 5. Wing LM, Reid CM, Ryan P et al. (Feb 13 2003). "A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly". NEJM 348 (7): 58392. doi:10.1056/NEJMoa021716. PMID 12584366. 6. Wang TJ, Ausiello JC, Stafford RS (20 Apr 1999). "Trends in Antihypertensive Drug Advertising, 19851996". Circulation 99 (15): 20552057. PMID 10209012.

Antihypertensi ve Agents http://circ.ahajournals.org/cgi/content/full/99/15/2055. 7. "Hypertension: management of hypertension in adults in primary care" (PDF). National Institute for Health and Clinical Excellence. http://www.nice.org.uk/download.aspx?o=CG034quickrefguide. Retrieved on 2006-09-30. 8. Sheetal Ladva (2006-06-28). "NICE and BHS launch updated hypertension guideline". National Institute for Health and Clinical Excellence. http://www.nelm.nhs.uk/Record %20Viewing/viewRecord.aspx?id=567178. Retrieved on 2006-09-30. 9. Lindholm LH, Carlberg B, Samuelsson O (Oct 29-Nov 4 2005). "Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis". Lancet 366 (9496): 154553. doi:10.1016/S0140-6736(05)67573-3. PMID 16257341. 10. Carlberg B, Samuelsson O, Lindholm LH (Nov 6-12 2004). "Atenolol in hypertension: is it a wise choice?". Lancet 364 (9446): 16849. doi:10.1016/S0140-6736(04)17355-8. PMID 15530629. 11. Freemantle N, Cleland J, Young P et al. (Jun 26 1999). "Beta Blockade after myocardial infarction: systematic review and meta regression analysis". BMJ 318 (7200): 17307. PMID 10381708. http://bmj.bmjjournals.com/cgi/content/full/318/7200/1730. 12. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (September 2003). "Diuretic Versus alpha-Blocker as First-Step Antihypertensive Therapy". Hypertension 42 (3): 23946. doi:10.1161/01.HYP.0000086521.95630.5A. PMID 12925554. http://hyper.ahajournals.org/cgi/content/full/42/3/239.


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13. Jennifer Chu. Taking a Shot at Hypertension. Technology Review. 12 March 2008 14. Discontinuing the offending agent will usually normalize blood pressure but when continuation is necessary, antihypertensive drugs are required. 15. Secondary hypertension due to drugs and toxins by Gyamlani, Geeta; Geraci, Stephen A. / Southern Medical Journal 16. Pickering doesn't recommend antihypertensive drugs for people with white-coat hypertension. 17. White-Coat Hypertension by FACKELMANN, KATHLEEN / Science News 18. nbsp;(ACE) inhibitor, has proven effective in preventing progression to stages IV and V Calcium channel blockers, another class of antihypertensive drugs, also show promise. 19. Kidney disease of diabetes by Pamphlet by: National Institute of Diabetes & Digestive & Kidney Diseases 20. Medicinal chemistry by D. Sriram & P. Yogeeswari PEARSON Education. 21. Essentials of Medical pharmacology by KD Tripathi.JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD. 22. Principles of Medicinal chemistry volume II by S.S.Kadam, K.R.Mahadik, K.G.Bothara. NIRALI PRAKASHAN. 23. Medicinal chemistry volume I by Dr. Anees Ahmad Siddiqui, Seemi Siddiqui, Dr.R.Rajesh. BIRLA PUBLICATION PVT LTD. 24. Medicinal chemistry (Synthesis & Biochemical approch) [vol II ] by

Antihypertensi ve Agents Surendra N. pandeya. SG PUBLISHER, VARANASI. 25. Source: Sandoz product information sheet 26. Bahl VK, Jadhav UM, Thacker HP (2009). "Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG prospective, observational, multicenter study". Am J Cardiovasc Drugs 9 (3): 135 42. DOI 10.2165/00129784-200909030-00001. PMID 19463019 27. J. Luka, D. Josi, M Kremser, Z. Kopitar, S. Milutinovi: Pharmacokinetic behaviour of (R)-(+)- and (S)-()-amlodipine after single enantiomer administration, Journal of Chromatography B: Biomedical Sciences and Applications 703 (1997) 185193, doi:10.1016/S0378-4347(97)00394-0. 28. J. Luka, D. Josi, B. Furlan, M. Kremser: Semi-preparative chromatographic purification of the enantiomers (S)-()-amlodipine and (R)-(+)-amlodipine, Journal of Chromatography B: Biomedical Sciences and Applications 693 (1997) 367375, doi:10.1016/S03784347(97)00069-8. ^ Kennedy, Val Brickates (2007-03-22). "Pfizer loses court ruling on Norvasc patent". MarketWatch. http://www.marketwatch.com/news/story/pfizer-loses-court-rulingnorvasc/story.aspx?guid=%7B9819D67E-B76B-431D-835CFB8D6D8327B7%7D. 29. www.osun.org, anti-hypertensive agents , drugs class. 30. www.wikipedia.com.


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anti hypertensive thesis

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