Hypertension is defined as a sustained increase in blood pressure ≥140/90 mm Hg, a criterion that characterizes a group of patients whose risk of hypertension-related cardiovascular disease is high enough to merit medical attention. Actually, the risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic blood pressures of less than 120 mm Hg and diastolic BP less than 80 mm Hg. These risks increase progressively with higher systolic and diastolic blood pressures.
At very high blood pressures (systolic ≥210 and/or diastolic≤120 mm Hg), a subset of patients develops fulminant arteriopathy characterized by endothelial injury and a marked proliferation of cells in the intima leading to intimal thickening and ultimately to arteriolar occlusion. This is the pathological basis of the syndrome of immediately life-threatening hypertension, which is associated with rapidly progressive micro vascular occlusive disease in the kidney (with renal failure), brain (hypertensive encephalopathy), congestive heart failure, and pulmonary edema. These patients typically require in-hospital management on an emergency basis for prompt lowering of blood pressure.
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The heart muscles thicken to make up for increased blood pressure.
The force of the heart muscle contractions weakens over time, and the muscles have difficulty relaxing. This prevents the normal filling of the heart with blood.
The risk of cardiovascular disease, disability, and death in hypertensive patients also is increased markedly by concomitant cigarette smoking, diabetes or elevated low-density lipoprotein. The coexistence of hypertension with these risk factors increases cardiovascular morbidity and mortality to a degree that is compounded by each additional risk factor. Since the purpose of treating hypertension is to decrease cardiovascular risk, other dietary and pharmacological interventions may be required.
Pharmacological treatment of patients with hypertension associated with elevated diastolic pressures reduces morbidity and mortality from cardiovascular disease. Effective antihypertensive therapy markedly reduces the risk of strokes, cardiac failure, and renal insufficiency due to hypertension.
Principles of Antihypertensive Therapy
Arterial pressure is the product of cardiac output and peripheral vascular resistance. Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both. Drugs may reduce the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can reduce peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels (e.g., the sympathetic nervous system).
Classification of Antihypertensive Drugs by Primary Site or Mechanism of action
Thiazides and related agents (Hydrochlorothiazide, Chlorthalidone, etc.)
Loop diuretics (Furosemide, Bumetanide, Torsemide, Ethacrynic acid)
K+-sparing diuretics (Amiloride, Triamterene, Spironolactone)
Adrenergic antagonists (Metoprolol, Atenolol, etc.)
Adrenergic antagonists (Prazosin,Terazosin,Doxazosin,Phenoxybenzamine,Phentolamine)
Mixed adrenergic antagonists (Labetalol, Carvedilol)
Centrally acting agents (Methyldopa, Clonidine, Guanabenz, Guanfacine)
Adrenergic neuron blocking agents (Guanadrel, Reserpine)
Ca++ channel blockers
Verapamil, Diltiazem, Nimodipine, Felodipine, Nicardipine, Isradipine,Amlodipine
Angiotensin converting enzyme inhibitors
Moexipril,Perindopril, Trandolapril ,Captopril, Enalapril, Lisinopril, Quinapril, Benazepril, Fosinopril Ramipril,
Angiotensin II-receptor antagonists
Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan, Eprosartan
Arterial (Hydralazine, Minoxidil, Diazoxide, Fenoldopam))
Arterial and venous (Nitroprusside)
The homodynamic consequences of long-term treatment with antihypertensive agents provide a rationale for potential complementary effects of concurrent therapy with two or more drugs. The simultaneous use of drugs with similar mechanisms of action and hemodynamic effects often produces little additional benefit. However, concurrent use of drugs from different classes is a strategy for achieving effective control of blood pressure while minimizing dose-related adverse effects.
Bi-layer tablets are prepared with one layer of drug for immediate release while second layer designed to release drug, later, either as second dose or in an extended release manner. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose 2.
Advantages of Bilayer tablets
Bilayer tablet is suitable for preventing direct contact of two drugs and thus to maximize the efficacy of combination of two drugs.
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Patient convenience is improved because fewer daily doses are required compared to traditional delivery systems.
Patient compliance is enhanced leading to improved drug regimen efficacy.
Beta-blocker and Amlodipine Besilate combination exerts a superior effect on blood pressure, blood pressure variability, and end-organ damage.
Bilayer tablets can be designed in such a manner as to modify releases as either of the layers can be kept as extended and the other as immediate release.
Fixed low-dose combinations are very useful tools for treating hypertensive patients3.
The U S Food and Drug Administration (USFDA) defines an extended release dosage form as one that allows a reduction in dosing frequency from that necessitated by a conventional dosage form such as solution or an immediate release form. Soon after a single dose administration, the extended release dosage form helps to maintain therapeutic drug levels for 8-12 hours.
Some drugs are inherently long lasting and require only once a day oral dosing. They sustain adequate drug blood levels and provide the desired therapeutic effect. These drugs are formulated in the conventional manner as immediate release dosage forms. However several other drugs are not inherently long lasting and require multiple daily dosing to achieve the desired therapeutic results. Extended release formulation is a controlled release formulation designed to produce even and consistent release of active ingredient4.
Drug candidates for extended release dosage form
To be a successful extended release product the drug must be released from the dosage form at a predetermined rate, dissolve in the gastrointestinal fluids, maintain sufficient gastrointestinal residence time and be absorbed at a rate that will replace the amount of drug being metabolized and excreted.
The drugs best suited for incorporation into an extended release product must have the following characteristics
They exhibit neither very slow nor very fast rates of absorption and excretion.
They are uniformly absorbed from the gastro intestinal tract.
They are administered neither in very small doses (less than 10mg) nor in large single doses( greater than 500mg)
They are used in the treatment of chronic rather than acute conditions.
They posses a good margin of safety4.
Advantages of extended release drug delivery
It improves patient compliance
It may improve the patho-physiology of the disease
It minimizes or eliminates local side effects.
It minimizes or eliminates systemic side effects
It obtains less potentiation or reduction in drug activity with chronic use
It minimizes drug accumulation with chronic dosing
It improves the efficiency in treatment
It cure or controls the condition more promptly
It improves the control of condition i.e. reduces fluctuation in the drug level
It improves bioavailability of some drugs
Make use of special effects e.g. sustained release aspirin for morning relief of arthritis by dosing before bedtimes
Sustained blood level- the dosage form provided uniform drug availability or blood levels unlike peak and valley pattern obtained by intermittent administration.
Attenuation of adverse effects- the incidence and intensity of undesirable side effects caused by excessively high peak drug concentration resulting from the administration of conventional dosage forms is reduced5.
EXTENDED-RELEASE TECHNOLOGY FOR ORAL DOSAGE FORMS 4
For orally administered dosage forms extended drug action is achieved by affecting the rate at which the drug is released from the dosage form and or by slowing the transit time of the dosage form through the gastro intestinal tract.
1) Coated Beads, Granules and Micro spheres
In these systems the drug is distributed onto beads, pellets, granules or other particulate systems using pan coating or air suspension coating of a solution of drug substance on to small inert spheres of nonpareil seeds or beads made of sugar and starch or micro crystalline cellulose. If the dose of drug is large, the starting granules of materials may be composed of drug itself with a part of these granules may be composed of the drug itself a second part of the granules may remain uncoated to provide immediate drug release, the third part of the granules receive various coats of lipid material like beeswax, carnauba wax, glyceryl state etc.,
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2) Multi tablet System
Small spheroid compressed tablets, 3 to 4 mm in diameter, are prepared with varying drug release characteristics. They then may be placed in capsule shells to provide the desired pattern of drug release. Each capsule may contain 8 to 10 mm tablets, some uncoated for immediate release and others coated for Extended drug release.
3) Microencapsulated Drug
Micro-encapsulation is a process by which solids, liquids or gases may be enclosed in microscopic particles by formation of thin coating of wall materials around the substance. Gelatin, polyvinyl alcohol, polyvinyl chloride, nylon, acrylic polymers, polystyrene and a number of other polymers may be used. The dose of drug is subdivided into small units that are spread over a large area of gastrointestinal tract, which may improve absorption by diminishing local drug concentration.
4) Embedding Drug in Slowly Eroding Hydrophilic Matrix System
The drug is made into granules with an Excipients that slowly erodes in body fluids, progressively releasing the drug for absorption. When these granules are mixed with granules of drug prepared without Excipients, the uncombined granules provide the immediate effect, and the drug Excipients granules provide extended action. The granule mix may be formulated as tablets or capsules for oral delivery.
5) Embedding Drug in Inert Plastic Matrix
The drug is granulated with polyvinyl alcohol, polyvinyl chloride, nylon, acrylic polymers, polystyrene and other polymers and the granulation is compressed into tablets. The drug is slowly eroded from plastic matrix by erosion.
6) Complex Formation
Some drug substances when chemically combined with other chemical agents, form complexes that may be only soluble in body fluids depending on the pH of the environment. This slow dissolution provides extended release of drug.
TYPES OF EXTENDED-RELEASE PRODUCTS6
1) Diffusion-controlled product
In these systems, there is a water-insoluble polymer which controls the flow of water and the subsequent egress of dissolved drug from the dosage form. Both diffusion and dissolution processes are involved here.
a) Reservoir Devices
Reservoir devices are characterized by a core of drug, the reservoir, surrounded by a polymeric membrane. The nature of the membrane determines the rate of release of drug from the system. The release of drug from a reservoir device is governed by Fick's first law of diffusion which is given as
J = - D dc/dx
Where, J = flux in units of amount / area - time,
D = diffusion coefficient,
dc/dx = change in concentration C relative to distance X in the Membrane.
b) Matrix devices
A matrix device consists of drug dispersed homogeneously throughout a polymer matrix. In this model, drug in the outer layer, exposed to the bathing solution, dissolves first and later diffuses out of the matrix. This process continues with the interface between the bathing solution and the solid drug moving toward the interior. Derivation of the mathematical model to describe this system involves the following assumption. (a) a pseudo-steady state is maintained during drug release, (b) the diameter of the drug particles is less than the average distance of drug diffusion through the matrix, (c) the bathing solution provides sink conditions at all times. (d)The diffusion coefficient of drug in the matrix remains constant.
2) Dissolution-controlled products
In these products, the rate of dissolution of the drug is controlled by slowly soluble polymers or by micro encapsulation. Once the coating is dissolved, the drug becomes available for dissolution. By varying the thicknesses of the coat and its composition, the rate of drug release can be controlled. Some preparations contain a fraction of the total dose as an immediate-release component to provide a pulse dose soon after administration. The pellet dosage forms of diffusion- or dissolution-controlled products can be encapsulated or prepared as a tablet.
3) Erosion products
The release of drug from these products is controlled by the erosion of a carrier matrix. The rate of release is determined by the rate of erosion.
4) Osmotic pump systems
The rate of release of drug in these products is determined by the constant inflow of water across a semi permeable membrane into a reservoir which contains an osmotic agent. The drug is either mixed with the agent or is located in a reservoir. The dosage form contains a small hole from which dissolved drug is pumped at a rate determined by the rate of entrance of water due to osmotic pressure. The rate of release is constant and can be controlled within time limits yielding relatively constant blood levels.
5) Ion exchange resin
Some drugs can be bound to ion exchange resins and, when ingested, the release of drug is determined by the ionic environment within the gastrointestinal tract. This system incorporates a polymer barrier coating and bead technology in addition to ion exchange mechanism. The release extends over 12 hours 7.
One of the simplest approaches to the manufacture of extended release dosage forms involvers the direct compression of blends of drug, dissolution retardant material and additives to form a tablet in which drug is embedded in a matrix of the retardant. Alternately, retardant drug blends may be granulated prior to compression.
There are three different types of matrix tablets, hydrophilic matrices, fat-wax materials and plastic matrices6.
a) Hydrophilic Matrix Tablets:
Sodium carboxy methyl cellulose, Methylcellulose, Hydroxyl Propyl Cellulose, Hydroxyl Ethyl Cellulose, Poly Ethylene oxide, Poly Vinyl Pyrolidone, Polyvinyl Acetate, Carboxy Poly Ethylene, Alginic Acid, Gelatin and natural gums are be used as matrix materials.
The matrix may be tableted by direct compression of the blend of active ingredient and certain hydrophilic carriers (or) form a wet granulation containing the drug and hydrophilic matrix materials. The hydrophilic matrix requires water to activate the release mechanism. Upon immersion in water, the hydrophilic matrix quickly forms a gel around the tablet. Drug release is controlled by a gel diffusion barrier that is formed and / or tablet erosion.
Ease of manufacture and uniformity of matrix tablets.
b). Fat-wax Matrix Tablets
The primary constituents of a fat-wax matrix are fatty acids and / or fatty esters.
The drug can be incorporated into fat-wax granulations by spray congealing in air, blend congealing in an aqueous media with or without the aid of surfactants and spray drying techniques. The mixture of active ingredients, waxy materials and fillers can be converted into granules by compacting with a roller compactor, heating in a suitable mixer such as fluidized bed and steam jacketed blender or granulating with a solution of waxy materials or other binders.
The drug embedded into a melt of fats and waxes is released by leaching and / or hydrolysis as well as dissolution of fats under the influence of enzymes and pH changes in the gastro intestinal tract.
Fatty acids are more soluble in an alkaline rather than acidic medium. Fatty esters are more susceptible to alkali catalyzed hydrolysis than to acid catalyzed hydrolysis. Polyethylene, ethyl cellulose and glycerin esters of hydrogenated resins have been added to modify release pattern.
c). Plastic Matrix Tablets
Commonly used plastic matrix materials are polyvinyl chloride, polyethylene, vinyl acetate / vinyl chloride co-polymer, vinylidene chloride, acrylonitile co-polymer, acrylate / methyl methacrylate co-polymer, ethyl cellulose, cellulose acetate and polystyrene.
Plastic matrix tablets can be prepared by direct compression of drug with plastic materials provided the plastic material can be comminuted or granulated to desired particle size to facilitate mixing with drug particle.
The process may be accomplished by
Mixing the solid drug, and the plastic powder and kneading with a solution of the same plastic material or other binding agent in an organic solvent and then granulating.
Dissolving the drug and the plastic in a common organic solvent and then a granulating upon evaporation of the solvent.
Using latex or pseudo latex as granulation fluid to granulate the drug and plastic masses.
MATERIAL USED AS RETARDANTS IN MATRIX TABLET FORMULATION
Hydrophilic : Methylcellulose (400CPs, 4000CPs),Hydroxy ethyl cellulose, Hydroxy propyl methyl cellulose (60HG,90HG,25 CPs,40000 CPs,150000 CPs),Sodium carboxy methylcellulose, Carboxy poly methylene, Galactomannose , Sodium alginate.
Insoluble inert : Polyethylene, Polyvinyl chloride, Methyl acrylate-methacrylate copolymer, Ethyl cellulose.
Insoluble Erodable : Carnauba wax, Stearyl alcohol, Stearic acid, Polyethylene glycol monostearate, Triglycerides, Castor wax.