M.

Pharm (Pharmaceutical Analysis)

Introduction

introduction introduction
1.1 INTRODUCTION TO HYPERTENSION
Hypertension is a chemical condition in which the blood pressure is elevated .it is also referred to as high blood pressureor shortened to HT ,HTN or HPN . the word hypertension , by itself ,normally refers to systemic , arterial hypertension .(1) Hypertension can be classified as either essential (primary ) or secondary .Essential or primary means that no medical causes can be found to explain the raised blood pressure and represents about 90-95% of hypertension cases. (2-5) .secondary hypertension indicates that the high blood pressure is a result of (i.e. , secondary to) another conditions , such as kidney diseases or tumors (adrenal adenoma or pheochromocytoma) . Pertsistent hypertension is one of the risk factor for strokes ,heart attack ,heart failure abd arterial aneurysm and is a leading cause of chronic renal failure. (6) .even moderates elevation of arterial blood pressure leads to shortened life expectancy .at severely high pressures ,defined as mean arterial pressures 50% or more above average , a person can expext to live no more than a few years unless appropriately treated(7) . beginning at a systolic pressure (which is peak pressure in the arteries ,which occurs near the end of the cardiac cycle when the ventricles are contracting ) of 115 mmHG and diastolic pressure (which is minimum pressure in the arteries ,which occurs near the beginning of the cardiac cycle when the ventricles are filled with blood ) of 75mmHG ( commonly written as 115/75mmHG), cardiovascular disease (CVD) risk doubles for each increment of 20/10mmHG.(8) Signs and Symtoms Accelerated hypertension is associated with Headache Somnolence

 Confusion

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Visual disturbances Vomiting Chronic hypertension is associated with Centripetal obesity Abdominal striate Diabetes Glucocorticoid excess Cushings syndrome Hypertension Hypothyroidism 1.1.1 PREVENTION AND TREATMENT

Introduction

The process of managing hypertension according the guidelines of the British hypertension society suggest that non-pharmacological options should be explored in all patients who are hypertension or pre-hypertensive . The measures include Weight reduction abd regulary aerobic exercise(9) (e.g walking) . Reducing dietary suger intake Reducing sodium (salt) in the diet may be effective .it decreases blood pressure in about 33% people .many people use a salt subsitiute to reduce their salt intake .(10) Increase in dietary potassium ,which offset of sodium has been shown to lower blood pressure . Discontinuing tobacco use and alcohol consumption has been shown to lower blood pressure. The exact mechanism are not fully understood ,but blood pressure (especially systolic ) always transiently increases following alcohol or nicotine consumption .besides ,abstention from cigarette smoking is important for people with

hypertension because it reduces the risk of many dangerous outcomes of hypertension ,such as stroke and heart attack. Note that coeffe drinking (caffeine

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Introduction

ingestion ) also increases blod pressure transiently but does not produce chronic hypertension .. Resucing stress,for example with relaxation therpy ,such as meditation and other mindbosy relaxation techniques.(12)

1.2 OVERVIEW OF COMBINATION FOR ANTIHYPERTENSIVE DRUG :

Today, the Pharmaceutical market is flooded with the multiple combination of drugs in various dosage forms. The multi-components formulations have gained a lot of importance nowadays due to greater patient acceptability, increased potency, multiple action, fewer side effects and quicker relief. The practice of combining agents that counteract different mechanisms is the most likely explanation for the fact that most available two-drug combinations have an agent that addresses renin secretion (beta-blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor blocker or direct renin inhibitor) and another one that is more effective in reninindependent hypertension (diuretic, dihydropyridine or non-dihydropyridine calcium channel blocker). Inclusion of a diuretic in the triple combination is based on the evidence that these agents are effective and cheap, enhance the effect of other antihypertensive agents, and add a specific effect to individuals with salt-sensitivity of blood pressure. The benefit of triple combination therapy with amlodipine, valsartan and hydrochlorothiazide over its dual component therapies has been demonstrated, and the use of a single pill will simplify therapy resulting in better blood pressure control. Based on these considerations, addition of hydrochlorothiazide to the combination of an antagonist of the renin-angiotensin system with a calcium channel blocker would constitute a logical approach.

Nowadays, it is postulated that hypertension must be considered a multifactorial disease, often requiring multiple drugs for its management, and the majority of hypertensive patients require two or more agents to reach a blood pressure goal. Particularly for those patients with stage 2 hypertension (or blood pressure > 20/10 mmHg above goal), it is recommended that treatment begins with a combination of two drugs from different classes. And for patients who do not respond to dual therapy, the addition of a third drug is usually necessary

M.Pharm (Pharmaceutical Analysis)

1.2 INTRODUCTION TO DRUGS 1.3.1 Drug profile for amlodipine besylate
Synonyms :

Introduction

1. Amlodipine Besilate 2.Amlodipine Besylate 3.Amlodipine Free Base 4.Amlodipino [Spanish] 5.Amlodipinum [Latin] 6.Amlodipine Benzenesulfonate

CAS registory no. 88150-42-9 (Chemical Abstracts Service) IUPAC NAME (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Physico-chemical properties Appearance : White powder

Chemical Formula : C20H25ClN2O5 Molecular weight: Melting point: Boiling point : 408.879 g/mol 199-201 C 527.2 C at 760 mmH

Dissociation constatnt (pka) 8.6

Category: Official status: Description :

long-acting calcium channel blocker (dihydropyridine class) official in BP

Dose: Amlodipine is available as 2.5 mg, 5 mg, and 10 mg tablets Solubilty: methanol slightly soluble in water and sparingly soluble in ethanol, freely soluble in

Storage : Store at room temperature away from light and moisture

PHARMACOLOGICAL PROFILE

Mechanism of Action : Amlodipine is a peripheral arterial vasodilator that acts directly on

vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. It is a dihydropyridine CCB that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle.

Counter regulation of CCB

PHARMACOKINETICS

Absorption : After oral administration of therapeutic doses of amlodipine

alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion Distribution : Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma protein Biotransformation:: Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites Elimination: Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine

Bioavailability: 64 to 90% Metabolism: Hepatic Protein Binding : 97.5% Excretion: Renal Half life: 30 to 50 hours Side effect

Palpitations; abdominal pain; nausea; sleepiness hot flushes

DRUG INTERACTIONS
Drug Interaction Diltiazem Diltiazem increases the effect and toxicity of amlodipine Quinupristin This combination presents an increased risk of toxicity In patients with severe coronary artery disease, amlodipine can increase the frequency and severity of angina or actually cause a heart attack on rare occasions. This phenomenon usually occurs when first starting amlodipine, or at the time of dosage increase.

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Introduction

Table Marketed Formulation Of Amlodipine Besylate

Sr. No. Brand name

1. 2. 3. 4. 5. 6. 7. 8. 9.

Agen Aken Amcard Lopin Amdepin Atecard-am Amdipin Amlodine Amlodine

Country Czech Republic Mexico Bangladesh Bangladesh India India Colombia Japan Philippines Thailand -

Name of Company Zentiva Kendrick Farmaceutica Apex Pharma Ltd Edruc Ltd Cadila pharmaceuticals Alembic Ltd Laboratorios Lafrancol Dainippon Sumitomo Pharmaceuticals Westfield Pharmaceuticals Berlin Pharmaceutical Industry Co Ltd Xeno Pharmaceuticals

10. Amlopine 11. Dailyvasc 12. Istin 13. Amlodipine

United Kingdom and Ireland -

North America, some Pfizer European countries, China, and Japan 14. Amlodipine,Perivasc Australia -

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1.3.2 Drug profile for Hydrochlorthiazide Synonyms : 1. Dihydrochlorothiazid 2. Dihydrochlorothiazide 3. Dihydrochlorothiazidum

Introduction

4. Dihydrochlorurit 5. Dihydrochlorurite 6. Dihydroxychlorothiazidum 7. HCTZ 8. HCZ 9. Hydrochlorothiazid 10. Hydrochlorthiazide

IUPAC NAME : 6-Chloro-7-sulfamoyl-3, 4-dihydro-2H-1,2,4-benzothiadiazine 1,1dioxide Physico-chemical properties CAS registory no. Appearance : Chemical Formula : Molecular weight: Melting point: Boiling point : 58-93-5 white crystalline powder C7H8ClN3O4S2 297.74 273-275 C 577C at 760mmHg

Dissociation constatnt (pka) :

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Category:
Antihypertensive Agents Diuretics Sodium Chloride Symporter Inhibitors

Introduction

Official status: Description : Dose: Solubilty:

official in BP, EP, USP and IP

Very slightly soluble in water; sparingly soluble in alcohol; soluble in acetone. Hydrochlorothiazide dissolves in dilute solutions of alkali hydroxides

Storage : Store in well-closed containers protected from light. Stabilty: Therapeutic considerations
Pregnancy category : B (D if used to treat pregnancy-induced hypertension) Legal status: Prescription only Routes : Oral (capsules, tablets, oral solution)

Pharmacological profile :

Mechanism of action : Hydrochlorothiazide belongs to the thiazide class of diuretics,

acting on the kidneys to reduce sodium (Na) reabsorption in the distal convoluted tubule. The major site of action in the nephron appears on an electroneutral Na+-Clco-transporter by competing for the chloride site on the transporter. By impairing Na transport in the distal convoluted tubule, hydrochlorothiazide induces a natriuresis and concomitant water loss. Thiazides increase the reabsorption of calcium in this segment in a manner unrelated to sodium transport. Absorption : Hydrochlorothiazide is variably but fairly rapidly absorbed from the gastrointestinal tract. Bio-availability of hydrochlorothiazide after oral administration is approximately 60 to 80 per cent. Peak plasma level occurs after 1 to 2 hours

 Distribution : Hydrochlorothiazide is widely distributed in body tissue and its

volume of distribution following oral administration corresponds to 0.83 L/Kg

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Introduction

Metabolism : - Hydrochlorothiazide is not modified by organic biochemical

processes. does not undergo significant metabolism (>95% excreted unchanged in urine) Half life : 5.6-14.8 h

Elimination : Elimination of hydrochlorothiazide is mainly due to renal

clearance that occurs in about 320 mg/min . It is excreted unchanged in the urine. Hydrochlorothiazide crosses the placental barrier and appears in breast milk . Total systemic clearance of drug from the plasma is 4.9 mL/min/kg , decreasing in patients with uremia or congestive heart failure.

Protein binding : 67.9%

Table Marketed Formulation Of Hydrochlorthiazide

Brand Name Apo-Hydro Chlorzide Cloredema Dichlotride Country Canada Foy, USA Spain Australia; Belgium; Norway UK Argentina Canada; USA USA Italy Brand Name Atenadon Clothia Delco-Retic Diclotride Country Italy Japan USA Italy Brand Name Catiazida Clorana Di-Chlotride Diidrotiazide Country Spain Brazil Germany Italy

Direma Hidrenox HydroDiuril Hydrozide Idrolisin

Diursana-H Hidrosaluretil HydroSaluric Hygroton Jen

Australia; Belgium Spain UK Brazil Diril

Esidrix Hydro-Alquil Hydro-Z Idrofluin Masquitt

Germany; USA Canada USA Italy Japan

M.Pharm (Pharmaceutical Analysis)

1.3.3 Drug Profile of Valsartan
SYNONYMS :

Introduction

Diovan; Valsartan

IUPAC NAME : (S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-

yl)phenyl]phenyl}methyl)pentanamido]butanoic acid
Physico-chemical properties CAS registory no. 137862-53-4 Appearance : a white to practically white fine powder Chemical Formula : C24H29N5O3 Molecular weight: 435.519 g/mol Melting point: Boiling point :

116-117 C 684.9 C at 760 mmHg

Dissociation constatnt (pka) : Category: Angiotensin II Receptor Antagonists

Official status: official in USP(2008) ,IP(2010) Description :

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Dose: Solubilty:

Introduction

Soluble in ethanol , methanol and slightly soluble in water.

Storage : Store at room temperature away from light and moisture Stabilty

Pharmacokinetic data
Mechanism of action : Valsartan blocks the vasoconstrictor and aldosteronesecreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues muscle and the adrenal gland.

Absorption Distribution : The steady state volume of distribution of valsartan after intravenous
administration is small (17 L), indicating that valsartan does not distribute into tissues

extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

INDICATIONS

Hypertension - Valsartan is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Heart Failure - Valsartan is indicated for the treatment of heart failure. In a controlled clinical trial, Valsartan significantly reduced hospitalizations for heart failure. Post-Myocardial Infarction- In clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, Valsartan is indicated to reduce cardiovascular mortalit
hydroxy valsartan. The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes.

Metabolism . The primary metabolite, accounting for about 9% of dose, is valeryl 4-

Half life : 6 hours Bioavailabilty : 25% Excretion : Renal 30%, biliary 70% Elimination : when administered as an oral solution, is primarily recovered in feces
(about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).

Protein binding : 95%

Table Marketed Formulation of Valssartan

Sr.no. 1. 2. 3. 4. Brand name Diovan Angiotan Valtan Valtan Country US Pakistan India Company Novartis Efroze Cipla Torrent Pharmaceuticals

M.Pharm (Pharmaceutical Analysis)

1.3. RATIONAL FOR COMBINATION

Introduction

A potential advantage of fixed dose combination therapy is improved patient compliance by reducing the multiple pill load and simplifying the treatment regimen, although the clinical relevance of this assumed benefit has been clearly established. The currently presented triple combination of valsartan, an angiotensin receptor blocker (ARB), amlodipine, a calcium channel blocker (CCB), and hydrochlorothiazide, a thiazide diuretic, could be an appropriate choice for management of some forms of hypertension as the mechanisms of action of the three drugs are complementary. Hydrochlorothiazide is a diuretic that produces smooth muscle cell relaxation and volume depletion. Hypokalaemia is a known side effect of thiazide diuretic therapy. The addition of an ARB to a thiazide diuretic has a potentially synergistic effect on blood pressure reduction by blocking the actions of angiotensin II at the AT1 receptor and also attenuates diuretic-induced hypokalaemia. The addition of a dihydropyridine calcium channel blocker, which is an arterial vasodilator, reduces blood pressure further. Apart from this, the ARB has the potential to diminish the peripheral oedema known to occur with dihydropyridine CCBs by providing both arterial and venous vasodilatation.

The Committee for Medicinal Products for Human Use (CHMP) noted that patients already taking the three active substances would be more likely to comply with their treatment if prescribed Exforge HCT which combines the three substances in a single tablet. The main study showed the benefit of the highest strength of Exforge HCT in lowering the blood pressure. For all doses, Exforge HCT also met requirements to prove that it was comparable to the combinations of the individual active substances taken seperately. The CHMP therefore decided that Exforge HCTs benefits are greater than its risks for the treatment of essential hypertension in adults whose blood pressure is already adequately controlled with a combination of amlodipine, valsartan and hydrochlorothiazide

The combination of the three active substances has an additive effect, reducing the blood pressure more than the individual medicines alone. By lowering the

blood pressure, the risks associated with high blood pressure, such as having a stroke, are reduced.

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Introduction

Synonyms Fluvin Brand Name: Exforge HCT Generic Name - amlodipine, hydrochlorothiazide, and valsartan Pronunciation: am LOE di peen, HYE droe klor oh THYE a zide, val SAR tan Physicochemical Properties Appearance - Film-coated tablet (tablet) slightly soluble in water and sparingly Solubility soluble in ethanol. Storage -.Store at room temperature between 59F to 86F (15C to 30C).Keep in dry (protect it from moisture). Category DIHYDROPYRIDINES Use Treatment of hypertension Pharmacokinetic data Shelf life 18 months Therapeutic considerations Pregnancy category Legal status Routes
Pregnancy Category D

Rx only oral

Exforge HCT available forms, composition, doses: DOSAGE ROUTE Tablet; Oral Tablet; Oral Tablet; Oral Tablet; Oral FORM AND Amlodipine 5 mg 5 mg 10 mg 10 mg Hydrochlorothiazide 12.5 mg 25 mg 12.5 mg 25 mg Valsartan 160 mg 160 mg 160 mg 160 mg

Tablet; Oral

10 mg

25 mg

320 mg

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Introduction

Table marketed formulation for combination of amlodipine besylate ,hydrochlorthiazide and valsartan
Novartis Europharm Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom

BRAND NAMES

Dafiro HCT 5 mg/160 mg/12.5 mg film-coated tablets