VENOUS THROMOEMBOLISM

Venous thromboembolism (VTE) is an important medical problem that affects millions of patients each year. With appropriate prophylaxis, many of these thromboembolic events can be prevented. Although strong evidence supporting VTE prophylaxis spans several decades, several large American and global registries have documented very poor use of appropriate prophylaxis. Because of increasing regulatory requirements, hospitals nationwide are in the process of developing documentation of appropriate VTE prophylaxis programs for both surgical and medical patients. A wide range of clinicians must understand what constitutes appropriate VTE prophylaxis in various patient populations. With the existence of numerous pharmacologic agents, abundance of data from major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on appropriate VTE prophylaxis can be difficult for clinicians. Therefore, we provide a bibliography of key articles and guidelines related to the prevention of VTE in various patient groups. We hope this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients who may be at risk for VTE.
INTRODUCTION
Venous thromboembolism (VTE), which encompasses both deep vein thrombosis (DVT) and pulmonary embolism, is a significant health care problem, causing considerable morbidity, mortality, and resource utilization.[1] Every year in the United States, there are more than 1 million DVT events and more than 100,000 deaths from pulmonary embolism. These events occur in a wide range of patients in both surgical and medical populations. Among patients discharged from U.S. hospitals, VTE was the second leading cause of medical complications and prolonged length of stay, and third leading cause of preventable mortality and excessive hospital charges.[2] Clinicians must realize that many thromboembolic events can be prevented with appropriate VTE prophylaxis. Despite more than 30 years of demonstrated effectiveness and safety, VTE prophylaxis is substantially underutilized. This underutilization has led to the recent involvement of government and other regulatory agencies in an attempt to improve VTE prophylaxis in U.S. hospitals.
The Cardiology Practice and Research Network (PRN) of the American College of Clinical Pharmacy has taken the initiative to compile lists of key articles and guidelines in major focus areas of cardiology. From 2004-2006, five collections of annotative bibliographies were published on the topics of acute coronary syndromes, arrhythmias, hypertension, systolic heart failure, and dyslipidemias.[3-7] These documents are being updated and published in Pharmacotherapy.[8] Since the prevention of VTE is not only a cardiology issue, the Cardiology PRN joined with the Internal Medicine PRN and the Ambulatory Care PRN to compile this document that focuses on key articles and guidelines in the prevention of VTE. We collected guidelines and significant articles published in the area of VTE prevention and provide a summary of the results of the clinical trials, as well as clinical insights on the implications for clinical practice and research. This document will serve as an excellent review and resource for pharmacists, physicians, nurses, residents, and students, especially in this time of increased attention on VTE prevention.

Can Erythropoiesis-Stimulating Agents Increase Mortality in Patients With Cancer?

Bohlius J, Schmidlin K, Brillant C, et al
Lancet. 2009;373:1532-1542
SUMMARY
To determine the role of erythropoiesis-stimulating drugs, such as epoetin on patients with cancer, the study authors conducted a meta-analysis of 53 randomized trials involving almost 14,000 patients. The study included all common tumor types and patients of varying ages with varying degrees of anemia. The combined results showed that these drugs caused a 17% increase in overall mortality (P = .003) and a reduced survival (P = .046).The results appeared to be unchanged by different types of cancer therapy.
VIEWPOINT
One of the strengths of this study is that it was carried out on individual patient data from each trial, rather than on published results. Clinicians have used these compounds because they reduce patient fatigue and lesson the need for transfusions. However, this carefully conducted trial demonstrated that these improvements in quality of life must be balanced against the increased mortality and lower life expectancy.

TYPES OF EMULSIONS

An emulsion may be prepared from any two immiscible liquids but in pharmacy one phase is usually water.

Oil in water emulsions

These consist of oil droplets dispersed throughout an aqueous continuous phase.

Examples:

Medicinal emulsions mostly for oral use

Rubber latex

Egg yolk

Milk

Vanishing creams

Water in oil emulsions

These consist of water dispersed throughout a continuous oil phase

Examples:

Oily calamine lotion

Hydrous ointment

Cold creams

Multiple Emulsions

It is possible to prepare oil in water emulsion in which water globules are dispersed within the oil globules so that the system may be designated as water in oil in water

Medicinally used emulsions for oral administration are usually oil in water type and require oil in water emulsifying agent. These include synthetic non-ionic surface active agents, acacia, gelatin and tragacanth.

Externally applied emulsions may be oil in water or water in oil. Intravenous emulsions may be oil in water while intramuscular emulsions are water in oil or oil in water.

Water in oil emulsions are used almost exclusively for external application and may contain one or several of the following emulsifiers such as calcium palmitate, spans, cholesterol wool fat.

EMULSIONS

Definition:

An emulsion is a system of two immiscible phases, one of which is dispersed as fine globules throughout the other.

Emulsions may also be defined as a thermodynamically unstable system of at least two immiscible liquid phases, one of which is dispersed as globules in other liquid phase, stabilized by presence of emulsifying agent.

The liquid phase that is subdivided is termed the dispersed phase and the other liquid surrounding the globules is the continuous phase.

Emulsion is stabilized by adding emulsifying agent.

Dispersed phase or continuous phase may consist of mobile liquids or semisolids, so emulsified systems include lotions, creams ointments.

Particle of globules size may generally extend from about 0.1 to 10 micron.

DEFINITION OF pH

Definition of pH:

pH is defined as the negative log of the hydrogen ion concentration, or pH = -log [H+]. pH may be an abbreviation of power of hydrogen or more explicitly the power of hydrogen ion concentration The pH scale commonly ranges from 0 to 14, which denotes a measure of the alkalinity or acidity of a solution. The pH scale is equal to 7 numerically for the neutral value of pH. An increase in the numerical value above 7 denotes an increase in alkalinity, while a decrease in the value below 7 shows an increase in the acidity of the solution.

SULFONAMIDES MECHANISM OF ACTION

Bacteria cannot absorb Folic Acid from medium, which is required for growth and reproduction. In contrast, human cells obtain Folic Acid from diet as Vitamin.

So bacteria have to synthesize Folic Acid inside the cell using Para-amino benzoic acid with the help of certain enzymes.

Sulphonamides being structural analogs of PABA (Para Amino Benzoic Acid) inhibit the pathway of Folic Acid synthesis and growth of bacteria becomes arrested.

Sulfonamides inhibit the “Dihydropteroate Synthetase”, while Trimethoprim inhibits the “Dihydrofolate Reductase (DHFR)”. So a combination of these two drugs block the two successive steps of DNA synthesis and results into bactericidal action.

SULPHONAMIDES PHARMCOLOGY

CLINICAL USE

ORAL: Acute complicated urinary tract infections (UTIs).

Respiratory tract infections (RTIs).

TOPICAL: Burn sepsis, Wounds, Conjunctivitis, Colitis, Enteritis, Intestinal infections.

INTRAVENOUSLY: Patients, who are unable to take orally especially with meningitis.

ADVERSE EFFECTS

1. ALLERGIC REACTIONS: For example, rashes, fever, purpura, agranulocytosis, aplastic anemia, serum sickness.
2. Crystalluria:
3. G-6-PD DEFICIENCY:
4. OTHERS: Headache, GIT upsets, stomatitis.

CONTRA-INDICATIONS

1. HYPERSENSITIVITY
2. PREGNANCY
3. LACTATION
4. IMPAIRED RENAL FUNCTION
5. IMPAIRED HEPATIC FUNCTION

SULFONAMIDES STRUCTURE ACTIVITY RELATIONSHIP

The molecular modifications of “Sulfanilamide” have been resulted into about 10,000 compounds and only less than three-dozen of them have attained therapeutic significance.

The nitrogen of “Sulfanilamide” is designated as N₁ and that of aniline as N_4.

(A). ISOMERIC FORMS OF SULFANILAMIDE:

The ortho and meta isomers i.e. orthonilamide and metanilamide, as well as the corresponding isomers of N₁-heterocyclic derivatives are antibacterially inactive both in vivo and in vitro.

Some metanilamides have been proved effective as antimalarials e.g.

2-metanilamide-5-chloropyrimide is 16-times more active against plasmodium gallinaceum than quinine or Sulfadiazine.

(B). SUBSTITUTION OF BENZENE RING:

In general, any substitution of the nucleus of the sulfanilamides leads to loss of activity.

This effect is related to mechanism of action, which requires a basic amino group that should be free to conjugate with sulfamyl group.

For example, 3-carboxyhydrazide is active only against staphylococcus and pneumococcus in vitro.

(C). REPLACEMENT OF THE BENZENE RING:

The benzene nucleus can’t be replace by 5 or 6-membered heterocyclics because the aralkylation with PTERIDYLMETHYL moiety, in the PABA utilization process, would occur at the ring nitrogen and not at the amino group if it is nest to a heterocyclic ring nitrogen e.g. 3-aza analog is inactive.

(D). DERIVATION OR REPLACEMENT OF –SO₂

The antibacterial activity lies in –SO₂ group and any addition or removal at –SO₂ group or even –SO₃ will result in total loss of antibacterial activity.

(E). DERIVATION OR REPLACEMENT OF 4-AMINO GROUP:

1. Amino group at position-4 is responsible for the anti-microbial activity of sulphonamides. Any permanent substitution at N₄ results in loss of anti-microbial activity.

2. If alkyl or any other functional group is placed at N₄ removing hydrogen, activity is lost.

3. Pro-drugs can be formed by attaching a functional group at N_4, which, can be hydrolyzed in the body to resume free NH₂ state again, necessary for anti-bacterial activity. N₄ acetylation with dicarboxylic acids such as succinic acid or phthalic acid yields sulphonamides, which are not absorbed in small intestine but are hydrolyzed in large intestine to yield free active form of drug allowed to act locally.

Other examples are:

Sulfasalazine

N₄-phthalylsulfathiazole

Mafenide

(F). N₁ SUBSTITUTION DERIVATIVE:

Substituted sulphonamides are more active clinically when compared to sulphonamides e.g.

1. SULFANILAMIDE (SNM):

Very less soluble in water.

Should be given with NaHCO₃

More effective against skin infections.

2. SULFADIAZINE (SDZ):

10 times more potent than SNM.

More soluble in water than SNM but can

crystallize in kidney due to high acidic

level so should be given with NAHCO₃.

3. SULFAMERAZINE (SMZ):

5 times more active than SNM.

50% less active than SDZ due to addition

of –CH₃ group in pyrimidine (pyr) ring.

Water solubility is more than

SULFADIAZINE (SDZ).

4. SULFADIMIDINE:

Activity is comparable to

SULFANILAMIDE (SNM).

Very much soluble in water.

5. SULFAPYRIDINE:

Water solubility is 1:3500.

It is comparable to Sulfadiazine (SDZ)

in efficacy but is more toxic than

Sulfadiazine (SDZ) in terms of crystalluria.

6. SULFAMETHIAZOLE:

Oral absorption is adequate.

More potent than sulfanilamide (SNM).

7. SULFISOXAZOLE:

Also effective against

Gram-negative bacteria.

Very much soluble in water.

8. SULFAMETHOXAZOLE:

Oral absorption is less than Sulfisoxazole.

Efficacy is similar to Sulfisoxazole

with larger half-life.

9. SULFACETAMIDE:

Very much soluble in water.

Used for ophthalmic infections.

10. SULFAGUANIDINE:

Not well absorbed orally.

Used for GIT infections.

11. SULFATHIAZOLE:

Show moderate solubility in water.

Show relatively low toxicity.

Much more effective as compared

to sulfanilamide (SNM).

TRIMETHOPRIM (FOLATE REDUCTASE INHIBITOR)

Trimethoprim is not a sulphonamides but it shows anti-bacterial activity by inhibiting the Folate Reductase in Para Amino Benzoic Acid (PABA) metabolism. Trimethoprim is closely related to antimalarials but it does not show any sufficient activity against malaria.

It is being widely used in combination with sulphonamides and this combination exhibits bactericidal effect in contrast to parents, which are individually bacteriostatic

STRUCTURE-ACTIVITY RELATIONSHIP

When one of the primary amines is removed, activity is completely lost.

The removal of one or more methoxy groups results in loss of activity up-to varying degree.

USES

Can be safely used alone in sulphonamide hypersensitive people to eradicate Gram-negative infections.

It is especially used in UTIs (Urinary Tract Infections) and prostatic infections.

VOLATILE OILS ARE INFACT?

INTRODUCTION:

Volatile oils are odorous principles found in various plant parts. Because they evaporate when exposed to air at ordinary temperature they are called volatile oils, ethereal oils or essential oils. They are called essential oils as the essence or odoriferous constituents of the plants.

Volatile oils are colourless when fresh but darken in colour after prolong standing due to it s oxidation. To prevent this darkening, they should be stored in cool, dry place in tight stoppered preferably full (not half-emptied) amber glass container.

All volatile oils are complex mixtures of chemicals. They vary widely in chemical composition. They are generally a mixture of hydrocarbons and oxygenated compound derived from these hydrocarbons. The hydrocarbons are generally terpene derivatives formed via the acetate mevalonic acid pathway and often are liquid called ELEOPTENE.

The oxygenated hydrocarbon portions, which are derived from skikimic acid and often are called stearoptenes. The odour and taste of volatile oils are mainly determined by oxygenated stearoptene, which are usually soluble in water and alcohol.

VOLTILE OILS OCCURANCE

Volatile oils occur in special secretary cells. These secretary structures are glandular hair as in case of membranes of Piperaceae. Many of them occur in special oil tubes i.e. pericarp of the fruit e.g. vittae of Umbelliferae. Many of them occur in lysigenous or shizogenous cavities as in case of membranes of Pinaceae and Rutaceae.

In the individual plant they may occur in all the tissues i.e. in conifers or in petals of flowers i.e. rose, or in the bark i.e. cinnamon, or in fruit i.e. in coriander, or leaves i.e. mint and peppermint.

IMPORTANCE OF VOLATILE OILS

SIGNIFICANCE:

Volatile oils have great significance for both the plant and human beings. The exact role of volatile oils in plants is not known. They are produced as a result of metabolism in the plant, however they are said to be important for;

(i) Insect repellant due to their specific odour, thus preventing the destruction of flowers.

(ii) They also serve as insect attractant, thus helping in cross-fertilization in plants.

There are three main uses of volatile oils in human life.

(i) They are used therapeutically.

(ii) They are used as flavoring agents.

(iii) They are used perfumery and cosmetics.

Therapeutically:

1. They are used as irritant. When applied to skin it produces dose dependent irritation, which may reach the range of severe inflammation and sometimes blisters as well.

2. They improve local circulation and this property is applied in making lotions and linaments e.g. camphor and turpentine.

3. They act as carminative e.g. oils from coriander, fennel, and cardamom. They improve digestion and appetite is increased.

4. They act as local anesthetics e.g. clove oil (applied to teeth).

5. When given internally it reduces the secretions of lungs, particularly the cough in asthma e.g. menthol in ammonium chloride syrup.

6. Some of them are used as antiseptic, anti bacterial and fungicidal. Eucalyptol oil and thymol (1: 100) are used in the growth of bacteria in foods.

7. They are employed as antihermatic e.g. chenopodium oil. 

DIFFERENCE BETWEEN FIXED OILS AND VOLATILE OILS

(i) Volatile oils are volatile at room temperature and are usually obtained by distillation. On the other hand fixed oils are not volatile at room temp. so they can only be obtained by special extraction methods

(ii) Volatile oils when evaporated do not leave any spot while fixed oils leave spot after evaporation.

(iii) Volatile oils can not be saponified i.e. can not be turned into soap while fixed oil can be saponified.

(iv) Volatile oils are mixtures of cleoptenes and stearoptenes while fixed oils are esters of higher fatty acids with glycerin.

METHODS EMPLOYED TO OBTAIN VOLATILE OILS

Volatile oils are usually obtained by following different methods, depending upon the conditions of the plant material.

1. DISTILLATION:

a. Water distillation.

b. Water steam distillation.

c. Steam distillation.

2. Expression:

3. Enfleurage method.

4. Enzymatic hydrolysis.

5. Solvent extraction.

6. Destructive distillation.

1. DISTILLATION:

a. Water distillation:

This method is applied to plant material where there is no chance of injuries by boiling. Turpentine oil is obtained by this method. The material is placed in distillation chamber along with water and subjected to heat until volatile matter, both water and oil is condensed in the condensing chamber. This is a special type of receiver having two outlets; one at the bottom and other at the top. If volatile oil is heavier than water, it is separated from below. If it’s lighter than water, it is separated from upper outlet.

b. Water and steam distillation:

This method is employed when there is chance of destruction of volatile oil by boiling, or it is obtained from dry of fresh substance.

In case of dried material e.g. cinnamon or clove, the drug is ground and then covered with a layer of water. Steam is passed through the macerated mixture. Because the oil could be impaired by direct heating, the steam is generated else where and us piped into the container holding the drug.

The oily layer of the condensed distillate is separated from the aqueous layer.

c. Direct steam distillation:

This method is applied to fresh plants drugs e.g. peppermint or spearmint etc. The crop is cut and placed directly into a metal distillation tank on a truck bed. The truck is driven to distilling tank. The plant material is still green and contains considerable natural moisture, therefore maceration is necessary.

Steam is forced through the fresh herb which carries the droplets through a vapour pipe attached at the top of the tank to the condensing chamber.

During steam distillation certain components of a volatile oil tends to hydrolyze, where as other constituents the high temperature decomposes. In order to avoid it, the diffusion rate of steam and water through plant membrane should be highest as to keep the hydrolysis and decomposition at a minimum.

d. Destructive distillation:

Destructive distillation is a mean of obtaining empyreumatic oils.

When the wood or resin of membrane of the Pinaceae is heated without access of air, decomposition takes place and a no of volatile components are driven off. The resultant mass is charcoal. The condensed volatile matter usually separated into two layers.

An aqueous layer containing wood naphtha (methyl alcohol) and pyroligenous acid (crude acetic).

Other layer is tarry liquid in the form of pine tar, Juniper tar, or other tars depending upon the wood introduced.

This dry distillation is usually conducted in retorts and if the wood is chipped or coarsely ground and the heat applied rapidly the yield of tar represents about 10% of the wood used.

2. EXPRESSION AND ECUELLE METHOD:

Mostly the citrus oil is obtained by this method. This is a mechanical method in which fruits are rolled over a trough lined with sharp projections just long enough to penetrate the oil glands present in the fruits.

The droplets are collected in trough and finally separated. This method is used avoid the decomposition of volatile oils, which will necessarily take place by any other distillation method.

3. ENZYMATIC HYDROLYSIS:

Glycosidic volatile oils like bitter almond, mustard oil is obtained by enzymatic hydrolysis of glycosides. In bitter almond seeds amygdalin is acted upon by enzyme emulsin resulting in a mixture of constituents from which the volatile oil may be distilled with steam. In black mustard seeds the glycoside, sinigrin is hydrolysed by the enzyme myrosin with the product of volatile mustard oil.

4. ENFLEURAGE:

This method is especially used for those volatile oils, which are present in such a part which is very small and also liable to decomposition on distillation. In this case odourless and bland fixed oil or fat is spread in a thin layer on glass plates. The part of plant from which V.O has to be extracted say for example flower petal is placed in the fat or fixed oil for some time until its fragrance is removed as the oil or fat will absorb it. Then the petal is removed from the fixed oil or fat and is subjected to extraction with alcohol. This method not in practice as it is tedious and time consuming.

5. EXTRACTION BY SOLVENT:

This is very costly method and is mostly used in perfume industry. The parts containing volatile oil are extracted directly by one of the organic solvents and they are then separated.

CLASSIFICATION OF VOLATILE OILS ON CHEMICAL BASIS

1. Hemiterpenes:

Hemiterpenes are the compounds having 5-carbon atoms i.e.

a. Isoamyl alcohol:

Found in mentha spp.

b. Isovaler aldehyde:

Found in eucalyptus.

2. Monoterpenes:

These are composed of two isoprene units and have the formula C₁₀H₁₆. Monoterpenes are further classified as

a. Open chain or Acylic hydrocarbons.

b. Monocyclic hydrocarbons.

c. Dicyclic hydrocarbons.

d. Tricyclic monoterpenes.

3. Sesquiterpenes:

These contain three isoprene units having the molecular formula C₁₅H₂₄. Sesquiterpenes may be;

a. Acyclic or open chain e.g. Farnesol.

b. Monocyclic e.g. Zingeberene.

c. Dicyclic e.g. Cadinine.

4. Diterpenes:

Diterpenes have four isoprene units and have the molecular formula C₂₀H₃₂. Diterpenoid compounds include such resin acids as + and – pimaric acid and their isomer, the abietic acid of pine resin. Many diterpenoids (e.g. vit A and gibberellic acid) do not belong to the volatile oil-resin group.

Acyclic Diterpenes :

Phytol is an unsaturated alcohol, a component of the chlorophyll molecule. Phytol has following formula.

Monocyclic Diterpenes:

a-camphorene

Dicyclic Diterpenes:

e.g. Agathic acid found in Agathis alba

Tricyclic Diterpenes.

e.g. Abietic acid and Pimaric acid

Tetracyclic Diterpenes.

e.g. Phylleladene

5. Triterpenes:

These are abundant in nature particularly in resins and may occur as either esters or glycosides. They may be aliphatic e.g. squalene, tetracyclic or pentacyclic. Tetracyclic’s examples are Limonoids, sterols and pentacyclics examples are b-amyrin, 4,4-dimethyl sterol.

6.Tetraterpenes: (C= 40)

These are mainly cartenoids pigments. The important pigments are orange red and yellow. These are found along with chlorophyll in photosynthetic tissues and are located in chloroplast lamella.

The colour of red tomato and the orange are due to the lycopene.

Polyterpenoids:

These are compounds of many isoprene units e.g. rubber.

Rubber is a polyterpenoid product in latex of about 300 genera of angiosperm but only Hevea brasiliensis is used. Rubber is manufactured in Malaysia and Indonesia. This rubber is a cis-polymer containing 3000-6000 units.

Mixed Terpenoids:

Mixed Terpenoids compounds consist of terpenoid and non-terpenoid components other than sugar and fatty acids e.g. Terpenoid glycosides and terpenoid esters.

Stereopenes:

Another major group of volatile oils is stereopenes or phenyl propanoids. These compounds contain C=6 Phenyl ring with an attached c=3 propane side chain. Many of the phenyl propanoids found in volatile oils are phenols or phenol esters. Some of the famous examples are Cinnamaldehyde, anethole, eugenol, and phenyl ethyl alcohol, anisaldehyde and methyl salicylate.

These compounds form of oil in some spp. While in other spp. The hydrocarbon liquid portion predominates. The odour and the taste of ess. Oil is mainly determined by the oxygenated components which are usually soluble in water but more soluble in alcohol. They can further be classified as.

1. Open chain or Acentric.

2. Monocyclic.

3- Dicyclic: