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AN OVERVIEW ON BUCCAL DRUG DELIVERY SYSTEM

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AN OVERVIEW ON BUCCAL DRUG DELIVERY SYSTEM

Surender Verma, Mahima Kaul*, Aruna Rawat and Sapna Saini

Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, Haryana, India


ABSTRACT

Buccal drug delivery has gained significant attention and momentum since it offers remarkable advantages. Over past few decades, buccal route for systemic drug delivery using mucoadhesive polymers to significantly improve the performance of many drugs has been of profound interest. This review article is an overview of buccal drug delivery systems encompassing a review of oral mucosa, formulation considerations for buccal drug delivery system, theories and mechanism of mucoadhesion, different mucoadhesive formulations for buccal drug delivery and active ingredients delivered via the buccal route. Additionally, commercial technologies and future prospects of this route of drug delivery are discussed


Keywords:Buccal drug delivery,

Mucoadhesion,

Polymers


INTRODUCTION: The pharmaceutical industry has engendered considerable interest making it a major participant in the healthcare industry. The advances and progress made by pharmaceutical industry have greatly contributed in terms of treatment of disease, thereby enhancing the quality of life 1. Over the time, scientists and researchers in the drug development industries are focusing on alternate routes of administration to add to the potential of approved drug products, or to overcome the drawbacks of the oral route.  Although oral route is preferred for administration of drugs, it is associated with some restrictions for example: hepatic first pass metabolism, local GI toxicity and enzymatic degradation within the GI tract.

One strategy that has been reasonably successful to circumvent such problems is to deliver drugs systemically via an alternate route of administration such as intranasal (IN), buccal/sublingual, pulmonary, or transdermal (TD) 2. Transmucosal routes of drug delivery which comprise of the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity offer excellent opportunities and potential advantages over peroral administration for systemic drug delivery. These advantages include possible bypass of first pass effect, avoidance of presystemic elimination within the GI tract and depending on the particular drug, a better enzymatic flora for drug absorption 3.

The sites of drug administration in the oral cavity include the floor of the mouth (sublingual), the inside of the cheeks (buccal) and the gums (gingival) 4. With the advances and progress in biotechnology, hydrophilic high molecular weight therapeutic agents such as proteins and peptides are readily available for therapeutic use.  However, when administered by the oral route, these agents suffer from problems such as degradation and poor absorption. To overcome these obstacles and for successful delivery of proteins and peptides, the buccal route of drug delivery has acquired significant attention 5.

In view of the systemic transmucosal drug delivery, the buccal mucosa is the preferred region as compared to the sublingual mucosa. One of the reasons is that buccal mucosa is less permeable and is thus not able to elicit a rapid onset of absorption and hence better suited for formulations that are intended for sustained release action.  Further, the buccal mucosa being relatively immobile mucosa and readily accessible, it makes it more advantageous for retentive systems used for oral transmucosal drug delivery.

Over the past few decades, the concept of use of bioadhesive polymers to prolong the contact time has gained remarkable attention in transmucosal drug delivery. Adhesion as a process is simply defined as the “fixing” of two surfaces to one another. Bioadhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods of time by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion 6.

Thorough and vast research over the past few years has resulted in profound advances in understanding the concepts and aspects of mucoadhesion.

To accomplish site-specific drug delivery, a lot of interest has been turned on to the concept of mucoadhesion, which encompasses a pharmaceutical formulation incorporating mucoadhesive hydrophilic polymers along with the active pharmaceutical ingredient (API). The rationale being that the formulation will be ‘held’ on a biological surface for localized drug delivery and the release of API will be close to the site of action leading to enhanced bioavailability 7.

In the early 1980’s, Professor Joseph R. Robinson at the University of Wisconsin pioneered the concept of mucoadhesion as a new strategy to prolong the residence time of various drugs on the ocular surface. Over the years, mucoadhesive polymers were shown to be able to adhere to various other mucosal membranes. The capability to adhere to the mucus gel layer which covers epithelial tissues makes such polymers very useful excipients in drug delivery 8.

Mucoadhesion is known to increase the intimacy and duration of contact between drug- containing polymer and a mucous surface. It is believed that the mucoadhesive nature of the device can increase the residence time of the drug in the body. The bioavailability of the drug is improved because of the combined effects of the direct drug absorption and the decrease in excretion rate. Increased residence time and adhesion may lead to lower API concentrations and lower administration frequency to achieve the desired therapeutic outcome 9.

Characteristics of an Ideal Buccoadhesive System 10-13: An ideal buccal adhesive system should possess the following characteristics:

  1. Quick adherence to the buccal mucosa and sufficient mechanical strength.
  2. Drug release in a controlled fashion.
  3. Facilitates the rate and extent of drug absorption.
  4. Should have good patient compliance.
  5. Should not hinder normal functions such as talking, eating and drinking.
  6. Should accomplish unidirectional release of drug towards the mucosa.
  7. Should not aid in development of secondary infections such as dental caries.
  8. Possess a wide margin of safety both locally and systemically.
  9. Should have good resistance to the flushing action of saliva.

Advantages of Buccal Drug Delivery System 7, 14-19: Drug administration via buccal mucosa offers several distinct advantages:

  1. The buccal mucosa is relatively permeable with a rich blood supply, robust in comparison to the other mucosal tissues.
  2. Bypass the first-pass effect and non-exposure of the drugs to the gastrointestinal fluids.
  3. Easy access to the membrane sites so that the delivery system can be applied, localized and removed easily.
  4. Improve the performance of many drugs, as they are having prolonged contact time with the mucosa.
  5. High patient acceptance compared to other non-oral routes of drug administration.
  6. Tolerance (in comparison with the nasal mucosa and skin) to potential sensitizers.
  7. Increased residence time combined with controlled API release may lead to lower administration frequency.
  8. Additionally significant cost reductions may be achieved and dose-related side effects may be reduced due to API localization at the disease site.
  9. As a result of adhesion and intimate contact, the formulation stays longer at the delivery site improving API bioavailability using lower API concentrations for disease treatment.
  10. Harsh environmental factors that exist in oral delivery of a drug are circumvented by buccal drug delivery.
  11. It offers a passive system of drug absorption and does not require any activation.
  12. The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal or transdermal routes.
  13. Provides an alternative route for the administration of various hormones, narcotic analgesics, steroids, enzymes, cardiovascular agents etc.
  14. It allows the local modification of tissue permeability, inhibition of protease activity and reduction in immunogenic response. Thus, delivery of therapeutic agents like peptides, proteins and ionized species can be done easily.

Disadvantages of Buccal Drug Delivery System 5, 20: The main challenges of buccal administration are:

  1. Limited absorption area- the total surface area of the membranes of the oral cavity available for drug absorption is 170 cm2 of which ~50 cm2 represents non-keratinized tissues, including buccal membrane.
  2. Barrier properties of the mucosa.
  3. The continuous secretion of the saliva (0.5-2 l/day) leads to subsequent dilution of the drug.
  4. The hazard of choking by involuntarily swallowing the delivery system is a concern.
  5. Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug and ultimately the involuntary removal of the dosage form.

Overview of the Oral Mucosa:

  • Anatomy of the oral mucosa 20: Light microscopy reveals several distinct patterns of maturation in the epithelium of the human oral mucosa based on various regions of the oral cavity. Three distinctive layers of the oral mucosa are the epithelium, basement membrane, and connective tissues. The oral cavity is lined with the epithelium, below which lies the supporting basement membrane. The basement membrane is, in turn, supported by connective tissues ( 1).

FIGURE 1: ANATOMY OF THE ORAL MUCOSA

The epithelium, as a protective layer for the tissues beneath, is divided into (a) non-keratinized surface in the mucosal lining of the soft palate, the ventral surface of the tongue, the floor of the mouth, alveolar mucosa, vestibule, lips, and cheeks, and (b) keratinized epithelium which is found in the hard palate and non-flexible regions of the oral cavity. The epithelial cells, originating from the basal cells, mature, change their shape, and increase in size while moving towards the surface. The thickness of buccal epithelium in humans, dogs, and rabbits has been determined to be approximately 500–800 µm.

The basement membrane forms a distinctive layer between the connective tissues and the epithelium. It provides the required adherence between the epithelium and the underlying connective tissues, and functions as a mechanical support for the epithelium. The underlying connective tissues provide many of the mechanical properties of oral mucosa.

The buccal epithelium is classified as a non-keratinized tissue. It is penetrated by tall and conical-shaped connective tissues. These tissues, which are also referred to as the lamina propria, consist of collagen fibers, a supporting layer of connective tissues, blood vessels, and smooth muscles. The rich arterial blood supply to the oral mucosa is derived from the external carotid artery. The buccal artery, some terminal branches of the facial artery, the posterior alveolar artery, and the infra-orbital artery are the major sources of blood supply to the lining of the cheek in the buccal cavity.

A gel-like secretion known as mucus, which contains mostly water-insoluble glycoproteins, covers the entire oral cavity. Mucus is bound to the apical cell surface and acts as a protective layer to the cells below. It is also a visco-elastic hydrogel, and primarily consists of 1-5% of the above-mentioned water insoluble glycoproteins, 95-99% water, and several other components in small quantities, such as proteins, enzymes, electrolytes, and nucleic acids. This composition can vary based on the origin of the mucus secretion in the body.

  • Drug permeability through buccal mucosa 21: There are two possible routes of drug absorption through the squamous stratified epithelium of the oral mucosa:
    • Transcellular (intracellular, passing through the cell) and;
    • Paracellular (intercellular, passing around the cell).

Permeation across the buccal mucosa has been reported to be mainly by the paracellular route through the intercellular lipids produced by membrane-coating granules (fig. 2).

FIG. 2: THE PARACELLULAR AND TRANSCELLULAR ROUTES OF TRANSPORT HAVE BEEN DESIGNATED TO THE BUCCAL MUCOSA

  • Barriers to penetration across buccal mucosa 10: The barriers such as saliva, mucus, membrane coating granules, basement membrane etc., retard the rate and extent of drug absorption through the buccal mucosa. The main penetration barrier exists in the outermost quarter to one third of the epithelium.

Membrane Coating Granules or Cored Granules: In non keratinized epithelia, the accumulation of lipids and cytokeratins in the keratinocytes is less evident and the change in morphology is far less marked than in keratinized epithelia. The mature cells in the outer portion of non-keratinized epithelia become large and flat retain nuclei and other organelles and the cytokeratins do not aggregate to form bundles of filaments as seen in keratinizing epithelia.

As cells reach the upper third to quarter of the epithelium, membrane-coating granules become evident at the superficial aspect of the cells and appear to fuse with the plasma membrane so as to extrude their contents into the intercellular space. The membrane-coating granules found in non-keratinizing epithelia are spherical in shape, membrane-bounded and measure about 0.2 μm in diameter. Such granules have been observed in a variety of other human non keratinized epithelia, including uterine cervix and esophagus.

However, current studies employing ruthenium tetroxide as a post-fixative indicate that in addition to cored granules, a small proportion of the granules in non-keratinized epithelium do contain lamellae, which may be the source of short stacks of lamellar lipid scattered throughout the intercellular spaces in the outer portion of the epithelium. In contrast to the intercellular spaces of stratum corneum, those of the superficial layer of non-keratinizing epithelia contain electron lucent material, which may represent non-lamellar phase lipid, with only occasional short stacks of lipid lamellae.

Basement Membrane: Although the superficial layers of the oral epithelium represent the primary barrier to the entry of substances from the exterior, it is evident that the basement membrane also plays a role in limiting the passage of materials across the junction between epithelium and connective tissue. A similar mechanism appears to operate in the opposite direction. The charge on the constituents of the basal lamina may limit the rate of penetration of lipophilic compounds that can traverse the superficial epithelial barrier relatively easily.

Mucus: The epithelial cells of buccal mucosa are surrounded by the intercellular ground substance called mucus with the thickness varies from 40 μm to 300 μm .Though the sublingual glands and minor salivary glands contribute only about 10% of all saliva, together they produce the majority of mucus and are critical in maintaining the mucin layer over the oral mucosa. It serves as an effective delivery vehicle by acting as a lubricant allowing cells to move relative to one another and is believed to play a major role in adhesion of mucoadhesive drug delivery systems.

At buccal pH, mucus can form a strongly cohesive gel structure that binds to the epithelial cell surface as a gelatinous layer. Mucus molecules are able to join together to make polymers or an extended three-dimensional network. Different types of mucus are produced, for example G, L, S, P and F mucus, which form different network of gels. Other substances such as ions, protein chains, and enzymes are also able to modify the interaction of the mucus molecules and, as a consequence, their biophysical properties.

Mucus is composed chiefly of mucins and inorganic salts suspended in water. Mucins are a family of large, heavily glycosylated proteins composed of oligosaccharide chains attached to a protein core. Three quarters of the protein core are heavily glycosylated and impart a gel like characteristic to mucus. The dense sugar coating of mucins gives them considerable water-holding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers.

  1. Khanvilkar et al., have studied various methods for mucous permeability. They concluded that the tertiary conformation of the glycoproteins and their resulting interactions with water and with other mucins determines the mucus gel’s structural characteristics. The observed variability in experimental data regarding the barrier properties of mucus suggests that the macromolecular structure of mucus is extremely sensitive to its environment. Changes in pH, ionic strength, and the presence of other agents (i.e., drugs) can all affect the self-association of mucin macromolecules 24.

A thorough understanding of the glycoprotein mucin component is very important with regard to understanding the properties of mucus (Fig. 3). Mucin glycoproteins may be described as consisting of a basic unit made from a single-chain polypeptide backbone with two distinct regions 24.

FIG. 3: THE COMPOSITION AND INTERACTION OF GLYCOPROTEIN CHAINS WITHIN MUCUS

  • A heavy glycosylated central protein core to which many large carbohydrate side chains are attached, predominantly via O-glycosidic linkages.
  • One or two terminal peptide regions where there is little glycosylation. These regions are often referred to as ‘naked protein regions’.

Mucins are secreted as massive aggregates by prostaglandins with molecular masses of roughly 1 to 10 million Da. Within these aggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular disulphide bonds also play a role in this process. Oligosaccharide side chains contain an average of about 8–10 monosaccharide residues of five different types namely L-fucose, D-galactose, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine and sialic acid. Amino acids present are serine, threonine and proline. Because of the presence of sialic acids and ester sulfates, mucus is negatively charged at physiological salivary pH of 5.8–7.4.

Saliva: The mucosal surface has a salivary coating estimated to be 70 μm thick, which act as unstirred layer. Within the saliva there is a high molecular weight mucin named MG1 that can bind to the surface of the oral mucosa so as to maintain hydration, provide lubrication, concentrate protective molecules such as secretory immunoglobulins, and limit the attachment of microorganisms. Several independent lines of evidence suggest that saliva and salivary mucin contribute to the barrier properties of oral mucosa.

The major salivary glands consist of lobules of cells that secrete saliva; parotids through salivary ducts near the upper teeth, submandibular under the tongue, and the sublingual through many ducts in the floor of the mouth. Besides these glands, there are 600–1000 tiny glands called minor salivary glands located in the lips, inner cheek area (buccal mucosa), and extensively in other linings of the mouth and throat. Total output from the major and minor salivary glands is termed as whole saliva, which at normal conditions has flow rate of 1–2 ml/min. Greater salivary output avoids potential harm to acid-sensitive tooth enamel by bathing the mouth in copious neutralizing fluid. With stimulation of salivary secretion, oxygen is consumed and vasodilator substances are produced; and the glandular blood flow increases, due to increased glandular metabolism.

Saliva is composed of 99.5% water in addition to proteins, glycoproteins and electrolytes. It is high in potassium (7×plasma), bicarbonate (3×plasma), calcium, phosphorous, chloride, thiocyanate and urea and low in Na (1/10×plasma). The normal pH of saliva is 5.6–7. Saliva contains enzymes namely α-amylase (breaks 1–4 glycosidic bonds), lysozyme (protective, digests bacterial cell walls) and lingual lipase (break down the fats).

Saliva serves multiple important functions:

  • It moistens the mouth, initiates digestion and protects the teeth from decay.
  • It also controls bacterial flora of the oral cavity.
  • Because saliva is high in calcium and phosphate, it plays a role in mineralization of new teeth repair and precarious enamel lesions.
  • It protects the teeth by forming “protective pellicle”. This signifies a saliva protein coat on the teeth, which contains antibacterial compounds.

Thus, problems with the salivary glands generally result in rampant dental caries. Lysozyme, secretory IgA, and salivary peroxidase play important roles in saliva's antibacterial actions. Lysozyme agglutinates bacteria and activates autolysins. Ig A interferes with the adherence of microorganisms to host tissue. Peroxidase breaks down salivary thiocyanate, which in turn, oxidizes the enzymes involved in bacterial glycolysis. However, salivary flow rate may play role in oral hygiene. Intraoral complications of salivary hypofunction may cause candidiasis, oral lichen planus, burning mouth syndrome, recurrent aphthous ulcers and dental caries.

A constant flowing down of saliva within the oral cavity makes it very difficult for drugs to be retained for a significant amount of time in order to facilitate absorption in this site. The other important factor of great concern is the role of saliva in development of dental caries. Salivary enzymes act on natural polysaccharidic polymers that hasten the growth of mutants of streptococci and other plaque bacteria leading to development of dental caries.

Permeabilities between different regions of the oral cavity vary greatly because of the diverse structures and functions. In general, the permeability is based on the relative thickness and degree of keratinization of these tissues in the order of sublingual>buccal> palatal. The permeability of the buccal mucosa was estimated to be 4–4000 times greater than that of the skin.

Formulation Considerations: For buccal drug delivery, it is cardinal to prolong and augment the contact between API and mucosa to obtain the desired therapeutic effect. Buccal adhesive drug delivery systems with the size 1-3 cm2 and a daily dose of 25 mg or less are preferable. The maximal duration of buccal delivery is approximately 4-6 h 25. To comply with the therapeutic requirements, the excipients or functional agents used in formulation for buccal drug delivery are mentioned below as per their categories. Also the excipients used in the formulation should be GRAS-listed i.e., Generally Recognized as Safe.

  • Mucoadhesive polymers: Polymer is a generic term used to describe a very long molecule consisting of structural units and repeating units connected by covalent chemical bonds. The term is derived from the Greek words: polys meaning many and more meaning parts 26. Mucoadhesives are synthetic or natural polymers that interact with the mucus layer covering the mucosal epithelial surface and main molecules constituting a major part of mucus. The concept of mucoadhesives has alerted many investigators to the possibility that these polymers can be used to overcome physiological barriers in long-term drug delivery27. The development of Orahesive® followed, leading to trials of Orabase® in 1959. Orabase® was formulated from natural gums and represented the first purposely developed mucoadhesive. Orabase® product (Adcortyl in Orabase®) provides local relief of mouth ulcers via a twofold mechanism: barrier function and an anti-inflammatory function (due to triamcinolone acetonide) 7.

Classification: In general, adhesive polymers can be classified as synthetic vs. natural, water-soluble vs. water insoluble, and charged vs. uncharged polymers. Table 1 summarizes the mucoadhesive polymers used in buccal drug delivery 20.

TABLE 1:  MUCOADHESIVE POLYMERS USED IN BUCCAL DELIVERY

CriteriaCategoriesExamples
SourceSemi-natural/naturalAgarose, chitosan, gelatin, Hyaluronic acid, Various gums (guar, hakea, xanthan, gellan, carrageenan , pectin, and sodium alginate)
SyntheticCellulose derivatives[CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC, methylhydroxyethylcellulose]
Poly(acrylic acid)-based polymers[CP, PC, PAA, polyacrylates, poly(methylvinylether-co-methacrylic acid), poly(2-hydroxyethyl methacrylate), poly(acrylic acid-co-ethylhexylacrylate), poly(methacrylate), poly(alkylcyanoacrylate), poly(isohexylcyanoacrylate), poly(isobutylcyanoacrylate), copolymer of acrylic acid and PEG]
OthersPoly(N-2-hydroxypropyl methacrylamide) (PHPMAm), polyoxyethylene, PVA, PVP, thiolated polymers
Aqueous solubilityWater-solubleCP, HEC, HPC (water < 38oC), HPMC (cold water), PAA, sodium CMC, sodium alginate
Water-insolubleChitosan (soluble in dilute aqueous acids), EC, PC
ChargeCationicAminodextran, chitosan, dimethylaminoethyl (DEAE)-dextran, trimethylated chitosan
AnionicChitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan gum
Non-ionicHydroxyethyl starch, HPC, poly(ethylene oxide), PVA, PVP, scleroglucan
Potential bioadhesive forcesCovalentCyanoacrylate
Hydrogen bondAcrylates [hydroxylated methacrylate, poly(methacrylic acid)], CP, PC, PVA
Electrostatic interactionChitosan

 

The polymers most commonly used in buccal dry or partially hydrated dosage forms include polyacrylic acid (PAA), polyvinyl alcohol (PVA), sodium carboxy methylcellulose (NaCMC), hydroxypropylmethyl cellulose (HPMC), hydroxyethylcellulose (HEC), hydroxy propylcellulose (HPC) and sodium alginate 28-34.

New generation of mucoadhesive polymers (with the exception of thiolated polymers) can adhere directly to the cell surface, rather than to the mucus. They interact with the cell surface by means of specific receptors or covalent bonding instead of non-specific mechanisms, which are characteristic of the previous polymers. Examples of such are the incorporation of L-cysteine into thiolated polymers and the target-specific, lectin-mediated adhesive polymers. These classes of polymers hold promise for the delivery of a wide variety of new drug molecules, particularly macromolecules, and create new possibilities for more specific drug-receptor interactions and improved targeted drug delivery 20.

Thiolated polymers or designated thiomers are mucoadhesive basis polymers, which display thiol bearing side chains 35. These polymers are obtained by addition of conjugated sulfidryl groups 36. Thiolated polymers are a type of second-generation mucoadhesive polymer derived from hydrophilic polymers such as polyacrylates, chitosan or deacetylated gellan gum.

Table 2 lists typical hydrophilic polymers that have been thiolated and the subsequent effect on mucoadhesive bond strength. The presence of thiol groups allows the formation of covalent bonds with cysteine-rich sub domains of the mucus gel layer, leading to increased residence time and improved bioavailability 7.

TABLE 2: AN EXAMPLE OF THIOLATED POLYMERS AND THE EFFECT ON MEASURED MUCOADHESION

PolymerMucoadhesive bond strength
Chitosan iminothiolane250-fold improved mucoadhesive properties.
Poly(acrylic acid)-cysteine100-fold improved mucoadhesive properties.
Poly(acrylic acid)- homocysteineApproximately 20-fold improved mucoadhesive properties
Chitosan-thioglycolic acidTenfold improved mucoadhesive properties
Chitosan-thioethylamidineninefold improved mucoadhesive properties
Alginate-cysteinefourfold improved mucoadhesive properties
Poly(methacrylic acid)-cysteineImproved cohesive and mucoadhesive properties
Sodium carboxymethylcellulose-cysteineImproved mucoadhesive properties

In recent years, lectins have been studied as specific bioadhesives for drug delivery in the oral cavity 37. Their peculiarity lies in the mucoadhesion mechanism: such substances are able to recognize and bind some specific sugar residues on mucosal surface without altering the structure of the recognized ligand 38. Recently, lamellar and cubic liquid crystalline phases of glyceryl monooleate (GMO) have shown mucoadhesive properties and feasibility to be used as carriers for buccal drug delivery 39.

Mechanism of Mucoadhesion 40: The mechanism of adhesion of certain macro­molecules to the surface of a mucous tissue is not well understood yet. The mucoadhesive must spread over the substrate to initiate close contact and hence increase surface contact, promoting the diffusion of its chains within the mucus. Attraction and repulsion forces arise and, for a mucoadhesive to be successful, the attraction forces must dominate. Each step can be facilitated by the nature of the dosage form and how it is administered.

Thus, the mechanism of mucoadhesion is generally divided in two steps:

  • The contact stage, and
  • The consolida­tion stage

The first stage or the contact stage (Figure 4) is characterized by the contact between the mucoadhesive and the mucous membrane, with spreading and swelling of the formu­lation, initiating its deep contact with the mucus layer. In the consolidation step (Figure 4), the mucoadhe­sive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the mucoadhe­sive molecules to break free and to link up by weak van der Waals and hydrogen bonds.

FIG. 4: THE TWO STEPS OF THE MUCOADHESION PROCESS

Theories of mucoadhesion 41: Although the chemical and physical basis of muco­adhesion are not yet well understood, there are six classi­cal theories adapted from studies on the performance of several materials and polymer-polymer adhesion which explain the phenomenon. The predominant theories on mucoadhesion are briefly described here in table 3.

 TABLE 3: THEORIES OF MUCOADHESION

TheoryMechanism of bioadhesionComments
Electronic theoryAttractive electrostatic forces between glycoprotein mucin network and the bioadhesive material.Electrons transfer occurs between the two forming a double layer of electric charge at the Surface.
Wetting theoryAbility of bioadhesive polymer to spread and develop intimate contact with the mucous membrane.Spreading coefficient of polymers must be positive. Contact angle between polymer and cells must be near to zero.
Adsorption theorySurface force resulting in chemical bonding.Strong primary force: covalent bonds. Weak secondary forces: hydrogen bonds and van der Waal’s forces.
Diffusion theoryPhysical entanglement of mucin strands and flexible polymer chains.For maximum diffusion and best adhesive strength, solubility parameters of the bioadhesive polymer and the mucus glycoproteins must be similar.
Mechanical theoryAdhesion arises from an interlocking of liquid adhesive into irregularities on the rough surface.Rough surfaces provide an increased surface area available for interaction along with an enhanced viscoelastic and plastic dissipation of energy during joint failure, which are more important in the adhesion process than a mechanical effect.
Fracture theoryAnalyses the maximum tensile stress developed during attachment of the transmucosal DDS from the mucosal surface.Does not require physical entanglement of bioadhesive polymer chains and mucous strands, hence it is appropriate to study the bioadhesion of hard polymers which lack flexible chains.

Penetration enhancers: Penetration enhancers are the substances, which increase the buccal mucosal membrane permeation rate. Although most penetration enhancers were originally designed for purposes other than absorption enhancement, a systemic search for safe and effective penetration enhancers must be a priority in drug delivery 42. With the rapid development of biotechnology, more and more protein, peptide, and nucleotide drugs are becoming available, most of which have low membrane-absorption characteristics including:

  • A large size with high molecular weight,
  • Domains of different hydrophobicity,
  • Irregular shapes, and
  • Delicate structures easily inactivated.

These drugs are unable to cross membrane barriers in therapeutic amounts and thus research into penetration enhancers becomes ever more important 43.

Classification 43:

TABLE 4: CLASSIFICATION OF PENETRATION ENHANCERS

Surfactantsa) IonicSodium  lauryl sulfate

Sodium  laurate

Polyoxyethylene-20-cetyl ether

Laureth-9

Sodium dodecyl sulfate(SDS)

Dioctyl Sodium sulfosuccinate

b) NonionicPolyoxyethylene-9-lauryl ether (PLE) (nonionic)

Tween 80(nonionic)

Nonylphenoxypolyoxyethylene(NP-POE)(nonionic)

Polysorbates

Sodium glycocholate

Bile salts and derivativesSodium deoxycholateSodium taurocholate

Sodium taurodihydrofusidate(STDHF)

Sodium glycodihydrofusidate

Sodium glycocholate

Sodium deoxycholate

Fatty acids and derivativesOleic acidCaprylic acid

Mono(di)glycerides

Lauric acid

Linoleic acid

Acylcholines

Acylcarnitine

Sodium caprate

Oleic acid

Chelating agentsEDTACitric acid

Salicylates

SulfoxidesDimethyl sulfoxide(DMSO)Decylmethyl sulfoxide
PolyolsPropylene glycolPolyethylene glycol

Glycerol

Propanediol

Monohydric alcoholsEthanolIsopropanol
Others (non-surfactants)Urea and derivativeUnsaturated cyclic urea

Azone(1-dodecylazacycloheptan-2-one)    (laurocapram)

Cyclodextrin

Enamine derivatives

Terpenes

Liposomes

Acyl carnitines and cholines

A new absorption promoter for buccal delivery named lysalbinic acid has been studied using hamster cheek mucosa as a simple animal model for the initial evaluation of absorption promoters. It was shown that co-administration of lysalbinic acid with relatively small proteins (6-16 kDa), such as α-inteferon and insulin, can significantly increase their absorption via the buccal epithelium. Thus, lysalbinic acid has been shown to increase significantly permeability of the hamster oral mucosa for peptide compounds of low-to middle-molecular weight 44.

Mechanism of buccal permeation enhancers 45: Table 5 provides an overview of some of the proposed mechanisms of action of penetration enhancers.

TABLE 5: MUCOSAL PENETRATION ENHANCERS AND MECHANISMS OF ACTION

ClassificationExamplesMechanism
SurfactantsAnionic: sodium lauryl sulfate, Sodium laurateCationic: cetylpyridinium chloride

Nonionic: poloxamer, Brij, Span, Myrj, Tween

Bile salts: sodium glycodeoxy cholate, sodium glycocholate, sodium taurodeoxycholate, sodium taurocholate, Azone®

Perturbation of intercellular lipids, protein domain integrity
Fatty acidsOleic acid, caprylic acidIncrease fluidity of phospholipids domains
Cyclodextrinsα-, β, γ-cyclodextrin, methylated β-cyclodextrinsInclusion of membrane compounds
ChelatorsEDTA, sodium citrate PolyacrylatesInterfere with Ca2+
Positively charged polymers, Cationic compoundsChitosan, trimethyl chitosan, Poly-L-arginine, L-lysineIonic interaction with negative charge on the mucosal surface

Enzyme Inhibitors: The co-administration of a drug with enzyme inhibitors is another strategy for improving the buccal absorption of drugs, particularly peptides. Enzyme inhibitors, such as aprotinin, bestatin, puromycin and some bile salts stabilize protein drugs by different mechanisms, including affecting the activities of the enzymes, altering the conformation of the peptides or proteins and/or rendering the drug less accessible to enzymatic degradation 25, 46, 47.

It has been shown that some mucoadhesive polymers can act as an enzyme inhibitor. The particular importance of this finding lies in delivering therapeutic compounds that are specifically prone to extensive enzymatic degradation, such as proteins and polypeptide drugs. Investigations have demonstrated that polymers, such as poly(acrylic acid), operate through a competitive mechanism with proteolytic enzymes.

This stems from their strong affinity to divalent cations (Ca2+, Zn2+). These cations are essential cofactors for the metalloproteinases, such as trypsin. Circular dichroism studies suggest that Ca2+  depletion, mediated by the presence of some mucoadhesive polymers, causes the secondary structure of trypsin to change, and initiates a further autodegradation of the enzyme48, 49.

Buccal Dosage Forms: Over the past few years, different dosage forms intended for buccal drug delivery have been developed. Table 6 lists the active ingredients delivered via the buccal route 21.

Buccal mucoadhesive dosage forms can be categorized into three types based on their geometry illustrated in the following fig. 5.

TABLE 6: ACTIVE INGREDIENTS DELIVERED VIA THE BUCCAL ROUTE

Active IngredientsActive Ingredients
AcitretinMetronidazole
AcyclovirMelatonin
ArecolineMetoprolol tartrate
BuprenorpineMorphine sulphate
CarbamazepineNalbuphine
Cetyl Pyridinium chlorideNicotine
Chlorhexidine diacetateNifedipine
ChitosanOmeprazole
Chlorpheniramine maleateOxytocin
CyanocobalaminPentazocine
DanazolProtirelin
DenbufyllinePindolol
Diclofenac sodiumPiroxicam
Diltiazem HydrochloridePropranolol
Ergotamine tartratePropolis
FlurideRecombinant human epidermal growth factor (Rh EFG)
FlurbiprofenSalmon calcitonin
Glucagon-like peptide (GLP)-1Sodium fluoride
Hydrocortisone acetateTestosterone
InsulinTerbutaline  sulphate
LactoferrinTheophylline
LignocaineThyotropin releasing hormone
Leu-enkephalinTriamcinolone acetate
Luteinizing hormone releasingHormone (LHRH)Zinc sulphate

 

FIGURE 5: DESIGN OF BUCCAL MUCOADHESIVE DOSAGE FORMS

Buccal Mucoadhesive Dosage: 3 types;

Type І:  It is a single layer device with multidirectional drug release. This type of dosage form suffers from significant drug loss due to swallowing.

 Type ІІ: In this type, an impermeable backing layer is superimposed on top of the drug loaded bioadhesive layer, creating a double-layered device and preventing drug loss from the top surface of the dosage form into the oral cavity.

Type ІІІ: This is a unidirectional release device, from which drug loss is minimal, since the drug is released only from the side adjacent to the buccal mucosa. This can be achieved by coating every face of the dosage form, except the one that is in contact with the buccal mucosa.

Buccal dosage forms can also be classified as either a “reservoir” or “matrix” type. In the reservoir type, an excessive amount of the drug is present in the reservoir surrounded by a polymeric membrane, which controls the drug’s release rate. In the matrix type systems, the drug is uniformly dispersed in the polymer matrix, and drug release is controlled by diffusion through the polymer network.

A number of relevant buccal mucoadhesive dosage forms have been developed for a variety of drugs. Several peptides, including thyrotropin-releasing hormone (TRH), insulin, protirelin, buserelin and oxytocin, have been delivered via the buccal route, albeit with relatively low bioavailability (0.1–5%)47 owing to their hydrophilicity and large molecular weight, as well as the inherent permeation and enzymatic barriers of the buccal mucosa.

Buccal dosage forms can be used to treat both local and systemic conditions. A promising example of buccal mucoadhesive formulations for systemic use is the buccal delivery of salmon calcitonin (sCT) using thin-film composite containing 40 μg of sCT (200 IU) 50.

The in vivo studies in female New Zealand white rabbits demonstrated a relative bioavailability of 43.8±10.9%, and the reduction in plasma calcium level after the buccal administration of sCT was comparable to that observed when sCT was administered by the intravenous route. These results indicate that therapeutically effective amounts of salmon calcitonin can be delivered to the systemic circulation via the buccal mucosa.

Table 7 summarizes various buccal dosage forms described in the literature 5.

Table 7: Summary of the different buccal dosage forms described in the literature

Dosage formsStructuresReleaseEffectActive ingredients
Matrix tabletsMonolithic matrixSustained/bidirectionalLocal/systemicLocal administration: metronidazole.Systemic administration: propanolol, timolol, metoclopramide, morphine sulphate, nitroglycerin, codein, insulin, calcitonin, glucagone-like peptide
Coating matrix (coated on the outer side or on all but one faces)MonodirectionalSystemic
Two-layer matrix,BidirectionalLocal (mainly)
Two-layer matrix coated with impermeable layerMonodirectionalSystemic
PatchesLaminated film with coating layerMonodirectionalLocal/systemicLocal administration: diclofenac, tannic acid, boric acid.Systemic administration: thyrotropin-releasing hormone, octreotide, oxytocin, buserelin, calcitonin, leuenkephalin
Lipophilic gelsCubic and lamellar liquid crystalline phases of glyceryl monooleateSystemicSystemic administration: (D-Ala2, D-Leu5) enkephalin
TransfersomesPhospholipid deformable vesiclesSystemicSystemic administration: insulin

Buccal Tablets: Tablets have been the most commonly investigated dosage form for buccal drug delivery. Buccal tablets are small, flat, and oval shaped dosage form and unlike conventional tablets allow for drinking and speaking without major discomfort. They soften, adhere to the mucosa and are retained in position until dissolution and/or release is complete 17. List of investigated buccal mucoadhesive tablets is given in the following table 8.

TABLE 8: LIST OF INVESTIGATED BUCCAL MUCOADHESIVE TABLETS

Active ingredientPolymers usedInvestigators [Ref.]
BaclofenNaMC, Na alginate and Methocel K15MBasani et al.51
CarvedilolHPMC K4M and CP 934PPandey et al.52
CarvedilolHPMC K4M, HPMC K15M and CP 934Yamsani et al.53
Chlorhexidine diacetateChitosan and Na alginateGiunchedi et al.54
Chlorpheniramine maleateHakea gum from Hakea gibbosaAlur et al.55
DiltiazemNaCMC, HPMC, Na alginate and guar gum.Manivannan et al.56
FlurbiprofenHPMC K15M, HEC, CP971 and Carbomer 940Perioli et al.57
ItraconazoleEudragit 100M, HPMC K4M and CP 934PMadgulkar et al.58
Miconazole nitrateCP 934, HPMC K4M and PVP K30Madgulkar et al.59
Morphine sulfateHPMC K100M, CP 910 and Eudragit RSPMAnlar et al.60
NicotineCP 934 and HPCPark and Munday 61
NifedipineCMC, CP 934P, HPMC, PVP K30 and PVAVarshosaz et al.62
OmeprazoleNa alginate, HPMCChoi and Kim63
OndansetronHPMC 15 cps, CP 934, Na alginate and NaCMC.Hassan et al.64
OxytocinMucilage of Diospyros peregrina fruitMetia et al.65
PiroxicamHPMC K4M and CP934Velmurugan et al.66
Pravastatin NaPVP K-30 and Pluronic F127and ECShidhaye et al.67
PrednisoloneHPMC, CP 934 and NaCMCSamani et al.68
Propranolol HClNa alginate, CP 971P and PVP K30Derle et al.69
Propranolol HClHPMC K4M,  Xanthan gum, EC and acrypol 934PShukla et al.70
Salbutamol sulphateHPMC K4M and ECArya et al.71
Tizanidine HClCP 934, HPMC K4M, HPMC K15M and NaCMC and ECShivanand et al.72
Verapamil HClCP934 P, HPMC K4M, HEC and NaCMCChandira et al.73

 

Monolithic and two-layered matrix tablets have been designed for buccal drug delivery. In Fig. 6, a schematic representation of several kinds of matrix tablets is given 5.

Bioadhesive tablets may be prepared using different methods such as direct compression or wet granulation technique. For buccal drug delivery, the tablets which are inserted into the buccal pouch may dissolve or erode; therefore, they must be formulated and compressed with sufficient pressure only to give a hard tablet. To enable or to achieve unidirectional release of drug, water impermeable materials, such as ethylcellulose, hydrogenated castor oil, etc. may be used either by compression or by spray coating to coat every face of the tablet except the one that is in contact with the buccal mucosa.

If necessary, the drug may be formulated in certain physical states, such as microspheres, prior to direct compression in order to achieve some desirable properties, e.g. enhanced activity and prolonged drug release 54.

Buccal patches: Buccal patches are described as laminates which comprise of an impermeable backing layer, a drug-containing reservoir layer which releases the drug in a controlled manner, and a bioadhesive surface for mucosal attachment. Two methods, namely, solvent casting method and direct milling are used to prepare adhesive patches. In the solvent casting method, the intermediate sheet from which patches are punched is prepared by casting the solution of the drug and polymer(s) onto a backing layer sheet, and subsequently allowing the solvent(s) to evaporate.

FIG. 6: SCHEMATIC REPRESENTATION OF DIFFERENT MATRIX TABLETS FOR BUCCAL DELIVERY. ARROWS INDICATE THE DIRECTION OF DRUG RELEASE

In the direct milling method, formulation constituents are homogeneously mixed and compressed to the desired thickness, and patches of predetermined size and shape are then cut or punched out.

Also to control the direction of drug release, prevent drug loss, and minimize deformation and disintegration of the device during the application period, an impermeable backing layer may be applied. The drugs and polymers that have been used to develop buccal patches are listed in table 9 as given below.

Buccal films: In recent times, a number of mucoadhesive dosage forms for buccal drug delivery have been developed such as tablet, films, patches, discs, ointments and gels 74-75 and 90-97. However, buccal films are preferable over mucoadhesive discs and tablets in terms of patient comfort and flexibility and they ensure more accurate drug dosing and longer residence time compared to gels and ointments. Buccal films also reduce pain by protecting the wound surface and hence increase the treatment effectiveness 98.

An ideal buccal film should be flexible, elastic, and soft yet strong enough to withstand breakage due to stress from activities in the mouth. Moreover, it should also possess good mucoadhesive strength so that it is retained in the mouth for the desired duration 99.

The drugs and polymers that have been used to develop buccal mucoadhesive films are listed in table 10.

TABLE 9: LIST OF INVESTIGATED BUCCAL MUCOADHESIVE PATCHES

Active ingredientPolymers usedInvestigators [Ref.]
AceclofenacGelatin, Poly Na CMC and PVA.Khairnar et al.74
AtenololCP 934P, HPMC and NaCMCAdhikari et al.75
CarvedilolHPMC, CP934, Eudragit RS 100, and ECThimmasetty et al.76
CarvedilolHPMC E15 and HPC JFVishnu et al.77
Cetylpyridium chloridePVA, HEC, or chitosanNafee et al.30
HydrochlorothiazideEC and HPMCAttama et al. 78
IbuprofenNaCMC and PVPPerioli et al.79
InsulinNaCMC-DVPSahni et al.80
MethotrexateHPMC K4M, Na alginate, NaCMC, CP 934, PVA and PVP K-30Bhanja et al.81
Metoprolol tartrateEudragit NE40D with HPMC, Na CMC or CPWong et al.82
MiconazoleHPMC, NaCMC, Chitosan, HECand PVA.Nafee et al.31
PentazocineCMC, HPMC K4M, CP 974P and PVAAgarwal et al.83
ProchlorperazineHPMC E15Kolli et al.84
Propranolol HClChitosan and PVP K-30Patel et al.85
Salbutamol sulphateChitosan,PVA and PVPK30Patel et al.86
Tizanidine HClNaCMC and CP 934Giradkar et al.87
Triamcinolone acetonideHPMC, Polaxamer 407 and CP971Chun et al.88
Verapamil HClChitosan and PVP K-30Deshmane et al.89

TABLE 10: LIST OF INVESTIGATED BUCCAL MUCOADHESIVE FILMS

Active ingredientPolymers usedInvestigators [Ref.]
AtenololNa alginate, CP 934P and ECSatishbabu et al.100
CarvedilolHPMC K15,Eudragit RL100, CP-934P, NaCMC and PVPViram J et al.101
Chlorhexidine diacetateChitosan, HPMC, Na alginateJuliano et al.102
Ciprofloxacin HClHPMC K4M, PVAChoudhury et al.103
FamotidineHPMC, NaCMC and PVAKumar et al.104
FentanylEudragit RS, PVP K30 and PVP K90Consuelo et al.105
Flufenamic acidChitosan and  KollicoatIR®Mura et al.106
GlibenclamideHPC, PVP and ECGoudanavar et al.107
GlipizideHPMC E-15, NaCMC, Eudrait RL-100 and CP 934PSemalty et al. 108
Isosorbide DinitrateEudragit RL 100, CP 93P and PVPDoijad et al.109
Isoxsuprine HClHPMC, PVP K-30 and HECPillai et al.110
KetorolacHPMC, CP 934P, NaCMC, HPC and ECAlanazi et al.111
LycopeneHPMC E15, PVP K30 and CP 934Shah et al.112
Metoprolol  tartrateCP934 P, Eudragit RL100, PVP, HPMC K15M and Na CMCNagaich et al.113
MontelukastHPMC K4M, HPMC 50cps, HPMC 5cps, Eudragit RL-100 and PVP K30Rao et al.114
RanitidineHPMC 15 cps and PVPAlagusundaram et al.115
Terbutaline sulphateHPMC K4M, HPMCP, Chitosan, CP 934PKumar et al.116

Buccal gels and ointments: These are semisolid dosage forms having the advantage of easy dispersion throughout the oral mucosa. The problem of poor retention of gels at the application site has been overcome by using bioadhesive formulations. Certain bioadhesive polymers for example, sodium carboxymethylcellulose82 undergo a phase change from a liquid to a semisolid. This change enhances or improves the viscosity, resulting in sustained or controlled release of drugs.

The drugs and polymers used for buccal mucoadhesive gels are listed in table 11.

TABLE 11: LIST OF INVESTIGATED BUCCAL MUCOADHESIVE GELS

Active ingredientPolymers usedInvestigators [Ref.]
InsulinPluronic F-127gel, oleic acid, eicosapentaenoic acid and docosahexaenoic acid.Morishita et al. 96
Itraconazole2-ethylmethyl-2 pyrrolidone, Polaxamer 188 and CP 934Kumar.K et al.117
NystatinChitosanRasool et al.118
Triamcinolone acetonidePolaxamer 407 and CP 934Shin et al. 97

Innovative Drug Delivery Systems: Innovative drug delivery systems comprise use of lipophilic gel, buccal spray and phospholipid vesicles to deliver peptides via the buccal route. The use of cubic and lamellar liquid crystalline phases of glyceryl monooleate as buccal drug carrier for peptide drugs has also been proposed.

A novel liquid aerosol formulation (Oralin, Generex Biotechnology) 119 has been recently developed, and it is now in clinical phase III trials. This system allows precise insulin dose delivery via a metered dose inhaler in the form of fine aerosolized droplets directed into the mouth. Levels of drug in the mouth are dramatically increased compared with conventional technology. This oral aerosol formulation is rapidly absorbed through the buccal mucosal epithelium, and it provides the plasma insulin levels necessary to control postprandial glucose rise in diabetic patients. This novel, pain-free, oral insulin formulation has a number of advantages including rapid absorption, a simple (user-friendly) administration technique, precise dosing control (comparable to injection within one unit) and bolus delivery of drug.

Phospholipid deformable vesicles, transfersomes, have been recently devised for the delivery of insulin in the buccal cavity 120. They are morphologically similar to liposomes but differ on account of function. Transferomes respond to external stresses by rapid shape transformations requiring low energy. This high deformability allows them to deliver drugs across epithelial barriers. To prepare these vesicles, surfactants, such as sodium cholate or sodium dehoxycholate are incorporated into the vesicular membrane. The insulin administration in rabbits surpasses that seen with traditional liposomes: compared with subcutaneous administration of insulin solution, the bioavailability of deformable vesicles was significantly greater than that of the conventional vesicles.

Commercial Technologies and Marketed Products: Marketed formulations or formulations under research in clinical trials for buccal drug delivery are listed in table 125.

 

TABLE 12: MARKETED AND UNDER RESEARCH FORMULATIONS

Brand nameActive ingredientBioadhesive polymerDosage formCompany
AphtachTriamcinolone acetonideHPC, PAATabletTeijin Ltd
BuccastemProchlorperazineXanthan gum, Povidone, Locust bean gumTabletReckitt  Benkiser Plc
Oralin–GenerexInsulinUnknownsolutionGenerex Biotechnology(Phase III trials)
LauriadMiconazoleUnknownTabletBioAlliance Pharma(Phase III trials)
Striant SRTestosteroneCarbomer 934P, Hypromellose, PCTabletArdana Bioscience Ltd
SuscardGlyceryl trinitrateHypromelloseTabletForest Laboratories

CONCLUSION: In the past few decades, research in buccal drug delivery has revealed remarkable growth and advances. The transmucosal route is becoming more and more popular because it does have significant advantages like avoidance of first pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract. Buccal drug delivery holds a great promise for systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules.

Despite the advantages of delivering drugs through buccal mucosa, this route is still very challenging, with the main obstacles being the limited absorption area and the barrier properties of the mucosa. The strategies studied to overcome such obstacles include use of materials that combine mucoadhesive, enzyme inhibitory and penetration enhancer properties and the design of novel formulations, which besides improving patient compliance favor an intimate and prolonged contact of the drug with the absorption mucosa.

New and unforeseen challenges are expected in the use of mucoadhesives for the delivery of new drugs and in the search of ideal mucoadhesives. Efforts have to be made to develop standardized in vitro and ex vivo biological models that allow one to characterize and compare different material and formulation in terms of their capability to promote drug absorption via the buccal route.

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Article Information

1

1303-1321

1020

3467

49

English

IJPSR

Surender Verma, Mahima Kaul*, Aruna Rawat and Sapna Saini

Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, Haryana, India

mahimak88@gmail.com

11 March, 2011

11 April, 2011

16 May, 2011

http://dx.doi.org/10.13040/IJPSR.0975-8232.2(6).1303-21

01 June, 2011

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In this essay we will discuss about the drugs used for treating the diseases of endocrine system.

Essay # 1. Insulin and Oral Antidiabetic Drugs:

Insulin is a protein hormone produced by the beta cells of the islets of Langerhans of the pancreas gland. It plays a key role in the regulation of carbohydrate, fat and protein metabolism. Lack of insulin or resistance to its action causes diabetes mellitus.

There are two types of diabetes:

Type 1 Diabetes:

This is known as insulin-dependent diabetes mellitus (IDDM) in which there is no circulating insulin in the plasma due to autoimmune destruction of pancreatic beta cells. Insulin deficiency leads to a rapid rise in the blood glucose concentration with subsequent loss of glucose with water and salt in the urine.

Fats in the body are broken down releasing ketone bodies in blood, which cause acidosis. Protein breakdown releases amino acids in the blood, which are converted to pyruvate, glucose, and urea in the liver. The excess urea produced is excreted in urine resulting in negative nitrogen balance and weight loss may be marked. If not treated with insulin, patient will lapse into coma (hyperglycemic ketoacidosis).

Type 2 Diabetes:

This is known as non-insulin dependent diabetes mellitus (NIDDM), which is due to reduced secretion of insulin or due to peripheral resistance to the action of insulin. The blood glucose concentration is raised with glycosuria, but ketoacidosis is not common and the symptoms are often those of late complications of diabetes.

These complications occur with both type of diabetes and are due to micro-vascular diseases including myocardial infarction, retinopathy, renal failure, and serious interference with the circulation to the legs sometimes requiring amputation and neuropathy. Type 2 diabetes may be controlled on diet alone, but many require administration of oral anti-diabetic drugs or insulin to maintain optimal glycaemic control.

Insulin:

Insulin lowers the concentration of glucose in the blood mainly by:

a. Facilitating glucose transport across cell membrane resulting in increased uptake of glucose by the tissues.

b. Facilitating glycogen synthesis from glucose in liver, muscles and fat.

c. Inhibiting gluconeogenesis (from protein) in liver and lipolysis in adipose tissue with increased production of fat and protein.

Sources of Insulin:

There are three sources of insulin, bovine, porcine and human. Bovine insulin extracted from beef pancreas is immunogenic and is rarely used. Porcine insulin extracted from pork pancreas is very similar to human insulin.

Nonhuman insulin can stimulate the production of anti-insulin antibodies (AIA), which occasionally give rise to local and systemic allergic reactions, but immunological resistance to insulin action is uncommon. Human insulin is prepared semisynthetically by enzymatic modification of porcine insulin or biosynthetically by recombinant DNA technology using Escherichia coli. Virtually all insulin now used is human insulin.

Mechanism of Action:

Insulin interacts with a highly specific receptor located on the cell membrane of practically all cells, particularly liver and fat cells. Glucose is transported from the blood into the cells across the cell membranes by so called glucose transporters, and insulin increases the activity of the glucose transporters.

Pharmacokinetics:

Insulin is inactivated by GIT enzymes and must therefore be given by injection. The subcutaneous route is ideal for self- administration. A different site should be used each time to minimize fat hypertrophy. Liver and kidney are of primary importance in the degradation of insulin by a proteolytic enzyme.

Insulin Administration:

Insulin Syringes:

Most diabetic patients use disposable plastic insulin syringe available in 0.5 ml (up to 50 units) and 1 ml (up to 100 units) sizes for subcutaneous injection.

Pen Devices:

Insulin pen devices contain a cartridge of insulin that is auto­matically injected. A wide range of insulin is available in cartridges and is more convenient for the patient.

Jet Injection:

Jet injection is high-pressure devices that eject insulin through a fine nozzle without a needle being used. Jet injections have not become popular because of delayed pain, greater bleeding and possibility of increased immunogenicity.

Syringe Pumps:

For intensive insulin requirements, soluble insulin can be given by subcutaneous infusion using a syringe pump. The rate of infusion can be modified to the patient’s needs and produce an accurate control of the diabetes. However, this technique has a limited place since it requires regular monitoring of blood glucose by patients themselves with an access to expert advice at all times.

Insulin Preparations:

Short-Acting Insulins:

These include soluble insulin, insulin lispro and insulin aspart. Soluble insulin is used by intravenous route for the treatment of diabetic coma (ketoacidosis), and for diabetic patients undergoing surgical operations. Soluble insulin is also used subcutaneously in combination with longer acting insulin in the long-term control of diabetes.

Insulin lispro and insulin aspart are modified forms of human insulin, which are very rapidly mobilized from the injection site, and their onset of action is even more rapid than subcutaneous soluble insulin. They are generally given before a meal for controlling the rise in blood sugar and their action mimics more closely to the response of the normal pancreas.

Intermediate-Acting Insulins:

These include NPH (isophane), lente (zinc) and glargine (Lantus). The insulin is released slowly from injection sites and act for varying periods. They are usually given once or twice daily and may be combined with soluble insulin. NPH (isophane) insulin consists of insulin complexes with protamine. This is mixed with soluble insulin to produce an intermediate effect. The most commonly used preparation is Human mixtard 30/70 (30% soluble and 70% isophane insulin).

Lente insulin is a mixture of amorphous and crystalline forms of insulin zinc suspension. Amorphous form contains small particles and has a rapid and short lived action, while crystalline form of insulin zinc suspension contain larger particles with a prolonged duration of action. The commonly used preparation is Human monotard (30% amorphous, 70% crystalline).

Insulin glargine (Lantus) is bioengineered human insulin analog that is given subcutaneously once daily at bedtime. It forms micro- crystals of insulin under the skin, which dissolve slowly and release insulin into the bloodstream. Insulin glargine produces no significant insulin peaks (peakless) in the bloodstream.

Insulin glargine has been claimed to produce less nocturnal hypoglycaemia, but may cause allergic reactions.

Long-Acting Insulins:

These include protamine zinc insulin and ultralente insulin. They are absorbed more slowly than the intermediate- acting preparations. Long-acting insulin’s provide a steady “basal” supply of circulating insulin. Protamine zinc insulin (PZI) is produced by adding protamine and zinc to bovine insulin. It may give rise to skin rashes and painful lumps at the site of injection. Ulralente is the crystalline form of human insulin zinc suspension (Human Ultratard).

After subcutaneous injection, there is an individual variation in the duration and peak activity of insulin preparations.

Choice of Insulin:

Human insulin is the least immunogenic and is preferred insulin for treatment. It does not give rise to allergic reaction, does not cause local reaction and does not lead to antibody production. Human insulin does not contain impurities and is preferred in pregnancy, because impurities in insulin from animal sources can cross the placenta and damage the islet tissue of the fetus.

Factors Altering Insulin Requirements:

Insulin requirement may be increased by infection, stress, accidental or surgical trauma, puberty, during second and third trimester of pregnancy, obesity and certain hormones (glucagon, adrenaline and growth hormones). Insulin requirements may be decreased in patients with renal or hepatic impairment and in those with some endocrine disorders (e.g. Addison’s disease, hypopituitarism) or coeliac disease.

Insulin Regimens:

In normal subjects insulin is secreted at two rates:

a. A basal rate during fasting to exert an inhibitory control on the catabolic processes of glycogenolysis, gluconeogenesis, lipolysis and the breakdown of proteins.

b. A rapid rate and response to meals to promote the storage of absorbed fuels. Insulin requirement regimens should mimic this pattern to achieve good control.

Insulin-Dependent Diabetes Mellitus (IDDM or Type I Diabetes):

In type I diabetes there is no circulating insulin due to autoimmune destruction of pancreatic beta cells. The insulin regimen used is a combination of short and intermediate acting insulin injected twice a day before breakfast and before the evening meal to mimic the normal insulin blood concentration. Alternatively soluble insulin three times a day may provide a good glycemic control.

Non-Insulin Dependent Diabetes Mellitus (NIDDM or Type II Diabetes):

Insulin requirement for patients with dominant insulin deficiency do not differ from those used for type I subjects and twice daily biphasic isophane insulin remains the choice.

Adverse Effects:

a. Hypoglycemia is a potential problem and is more likely to occur with human insulin. Alcohol and beta blockers may aggravate it. Warning signs of hypoglycemia such as faintness, dizziness, tremors, sweating and abnormal behavior are thought to be brought about by the compensatory secretion of adrenaline. It can be relieved by giving sugar or parenteral glucagon, if required. Failure of treatment may lead to convulsions, come and death. β blockers mask the symptoms of hypoglycemia in patients of diabetes receiving insulin.

b. Local reaction- Irritation at the site of injection can lead to fat hypertrophy, which can be minimized by rotating the injection sites. Local allergic reaction and infection may occur due to impurities.

c. Immunogenic response- Non-human insulin can stimulate the production of anti-insulin antibodies (AIA), which may lead to hypersensitivity reaction and to insulin resistance.

d. Growth promoting properties of insulin may be a factor in the micro-vascular complications of diabetes including micro-angiopathy, nephropathy, neuropathy, retinopathy and atherosclerosis.

e. Weight gain is an undesirable effect of intensive insulin therapy.

Diabetic Ketoacidosis (Diabetic Coma):

Patients with type I diabetes who are not treated or who develop infection during treatment, may rapidly pass into a diabetic coma, which is a potentially fatal complication. It is less likely to occur in type 2 diabetes.

Diabetic coma gives rise to prominent GI symptoms, dehydration, respiratory distress, shock, and coma and is due to very high blood and urinary glucose levels, production of large quantities of ketone bodies leading to acidosis (ketoacidosis), and severe diuresis resulting in depletion of sodium, potassium and water.

The aim of the treatment is fluid replacement, adequate insulin administration, and maintenance of normal plasma potassium levels, which constitutes a first-line management of diabetic ketoacidosis. Bicarbonate, phosphate, magnesium, antimicrobials or anticoagulants therapies may be required as part of specific therapy, once the patient has been stabilized.

Fluid replacement would restore the circulating blood volume, replenish total body water deficits and ensure its maintenance. This is achieved by giving infusion of normal saline at a speed depending on degree of dehydration and cardiac and renal status.

Insulin therapy- Sufficient insulin requires to be administered to turn off ketoacidosis and correct hyperglycemia. Soluble human insulin is given intravenously by an infusion pump and the dose is adjusted to produce a decrease in blood glucose of 50-75 mg/dl/ hour. Once oral intake resumes, insulin can be administered by subcutaneous injection.

Potassium supplements- Potassium should be added routinely to IV fluids, regardless of plasma levels on admission, because insulin therapy causes a rapid shift of potassium into the intracellular compartment. The goal is to maintain plasma potassium in the normal range and thereby prevent the potentially fatal cardiac effects of hypokalemia.

Potassium supplements are contraindicated in patients with hyperkalemia (ECG evidence), renal failure or oliguria confirmed by bladder catheterisation.

Bicarbonate therapy is not necessary routinely, but is indicated in patients who develop shock or coma, severe acidosis; acidosis- induced cardiac or respiratory dysfunction and severe hyperkalemia.

Restoration of electrolyte and water balance is usually sufficient and the kidneys will correct the acidosis by excreting acid urine.

Frequent examination of the urine for sugar and ketones, of the blood sugar hourly and of the electrolytes is important in controlling the treatment.

IV antimicrobial therapy for any possible bacterial or fungal infections and prophylactic subcutaneous heparin to prevent common deep vein thrombosis is indicated.

Essay # 2. Oral Anti-Diabetic Drugs:

Oral anti-diabetic drugs are used to supplement dietary control and exercise in the treatment of non-insulin dependent (type 2) diabetes.

Type 2 diabetes is characterized by three major pathophysiologic abnormalities, namely impaired insulin secretion leading to relative insulin deficiency, insulin resistance and increased hepatic glucose output (due to hepatic insulin resistance).

Oral anti-diabetic drugs include:

i. Insulin secretagogues

ii. Metformin

iii. Alpha-glucosidase inhibitors

iv. Thiazolidinedione

Essay # 3. Insulin Secretagogues (Sulphonylureas):

Mechanism of Action:

This group of drugs lowers blood glucose by augmenting insulin secretion. They may also increase the sensitivity of the tissues to insulin.

Pharmacokinetics:

There are several drugs in this group, which differ in duration of action, route of elimination and side effects (Table 8.2). Except for gliclazide, the hypoglycemic effect of all the second-generation drugs, though metabolized by liver, is potentiated in patients with renal failure.

Sulphonylureas are well absorbed orally. They are highly bound to plasma protein. The binding sites on albumin are different for second generation drugs and displacement interaction with drugs (e.g. warfarin, NSAIDs), which increase the hypoglycemic response to tolbutamide and chlorpropamide may perhaps be less with second generation drugs.

Therapeutic Uses:

Sulphonylureas are used in patients with NIDDM, who are usually middle-aged or elderly and obese. They should be taken 30-60 minutes before food and should not be administered to fasting patients. Gliclazide is the most commonly used; its action lasts up to 24 hours and it rarely causes hypoglycemic episodes. The first generation sulphonylureas are generally not used. Tolbutamide is safe and may be used the treatment of elderly patients because the risk of hypoglycemia is reduced due to its short duration of action (about 6 hours).

Adverse Effects:

Hypoglycemia and weight gain are notable adverse effects of sulphonylurea. Fluid retention, blood dyscrasias and skin rashes are other occasional side effects.

Drug Interactions:

ACE inhibitors, NSAIDs, antibacterial drugs, warfarin, MAOIs, antidepressants, β blockers, and cimetidine enhance hypoglycemic effects. Phenthiozine antidepressants, corticosteroids, diuretics (thiazide and loop) and oral contraceptives reduce the hypoglycemic effects of sulphonylureas.

Essay # 4. Prandial Glucose Regulators:

These are unique in that they act postprandially, i.e. they deal with the rise in circulating glucose that occurs immediately after a meal. Repaglinide augments food-stimulated insulin secretion with a similar glucose-lowering effect as suphonylureas, but in contrast to the latter it does not promote insulin release in the absence of glucose. Adverse effects include hypoglycemia and weight gain.

Nateglinide acts directly on the pancreatic β cells to stimulate early insulin secretion. The drug is well tolerated and the risk of hypoglycemia appears minimal. Both drugs are taken before a meal and are omitted if the meal is missed. METFORMIN, the only available biguanide, is an effective drug that requires the presence of insulin for its action. It does not stimulate insulin secretion.

Mechanism of Action:

There are multiple factors involved in its hypoglycemic action, which include:

i. Reduction of glucose absorption from GIT

ii. Inhibition of hepatic glucose output

iii. Stimulation of glucose uptake by peripheral tissues

iv. Inhibition of gluconeogenesis (biosynthesis of glucose from non-carbohydrate sources i.e. amino acids).

Pharmacokinetics:

Metformin is absorbed orally, though absorption is slow and variable. It has duration of action of 6-12 hours. Metformin is not appreciably metabolized and is rapidly eliminated via the kidneys by glomerular filtration and active tubular secretion.

Therapeutic Uses:

Metformin (in doses 500 mg daily, increased slowly every 1-2 weeks up to 2000 mg/day) is the drug of first choice in the treatment of non-insulin dependent diabetes in obese patients in whom dietary control has failed to control diabetes.

Metformin has the advantage of having some anorexic properties, which tend to lead to weight reduction. Metformin does not stimulate insulin secretion and hence does not cause hypoglycemia. It inhibits plasma LDL cholesterol and therefore reduces the danger of atheroma. It may be combined with insulin or sulphonylurea, if necessary.

Adverse Effects:

Metformin in doses of up to 2 g/day in 2-3 divided doses with meals causes mild GIT discomfort, nausea and anorexia. Lactic acidosis is the most serious adverse effect of metformin which though rare, may be fatal. Metformin is contraindicated in situations which predispose to lactic acidosis, e.g. severe dehydration, infection, shock, liver, renal, cardiac and pulmonary dysfunction, conditions associated with hypoxia or tissue ischemia, alcohol dependency, use of X- ray contrast media, major surgery, pregnancy and breast feeding.

Essay # 5. Alpha-Glucosidase Inhibitors:

Acarbose and miglitol inhibit the enzyme intestinal α-glucosidasr. This enzyme is part of the gastrointestinal metabolism for converting carbohydrate to glucose. Thus, they block carbohydrate digestion and decrease postprandial hyperglycemia when administered with food.

Monotherapy with these drugs seldom gives satisfactory results, but their addition to other drugs improves glycemic control. Dose related side effects are due to symptoms of carbohydrate malabsorption and include diarrhea, bloating, and abdominal cramps. The role of these drugs in diabetes is not yet determined, but they may be a useful adjunct to treatment of NIDDM.

Essay # 6. Thiazolidinediones(TZDs):

Pioglitazone and rosiglitazone are the available TDZs for clinical use. They act by increasing insulin sensitivity in muscle, adipose tissue and liver, thus lower tissue resistance to insulin. They are used alone as an adjunct to diet and exercise or in combination with either metformin or sulphonylureas. Pioglitazone can also be used with insulin.

Anorexia and nausea are troublesome and may require discontinuation of the treatment with these drugs. Hepatotoxicity, increased plasma volume leading to edema and cytopenia, precipitation of congestive heart failure especially in alcoholics, liver, renal and cardiac failure are more serious and rare complications. These drugs are contraindicated in pregnancy, breast-feeding, liver and cardiovascular diseases.

Essay # 7. Glucagon:

Glucagon is a polypeptide hormone produced by the alpha cells of the islets of Langerhans. It increases blood glucose by several mechanisms which include- breakdown of glycogen to glucose in the liver, stimulation of gluconeogenesis, inhibition of glycogen synthesis, inhibition of glucose oxidation, lipolysis in fat, and increase release of insulin.

It has the advantage of administration by intravenous, intramuscular or subcutaneous routes and is an effective initial therapy for severe hypoglycemia in patients who are unable to take glucose orally or in whom IV route is not easily accessible. The dose is 0.5-1.0 unit. Side effects are GIT disorders, hyperkalemia and rarely hypersensitivity reactions.

Essay # 8. Anti-Obesity Drugs:

Obesity is a serious health hazard, associated with many health problems including CVS diseases, diabetes mellitus, gall stones and osteoarthritis. Anti-obesity drugs should be avoided and the treatment should consist of a balanced diet, exercise and changes in life style. Appetite suppressants such as amphetamines, tobacco and thyroid hormones should not be used in the treatment of obesity.

Essay # 9. Orlistat:

Orlistat is a pancreatic lipase inhibitor and has been used in obesity. It inhibits the action of lipase in the intestine and reduces fat absorption. It may impair the absorption of fat soluble vitamins. The main drawback of orlistat is steatorrhea. Orlistat is contraindicated in chronic malabsorption syndrome, cholestasis, and pregnancy and breast-feeding.

Essay # 10. Thyroid Drugs:

Thyroxine (T4) and tri-iodothyronine (T3) are the two hormones stored in the thyroid gland as thyroglobulin. Thyroid hormones are important for normal growth and development and for energy metabolism. T4 in the tissues is converted to T3, which is the active hormone and T4 is generally regarded as a prohormone.

Thyroid hormone increases the metabolism of lipids, carbohydrates and proteins and this calorigenic effect is manifested as an increase in basal metabolic rate. It has a very important action on normal growth, partly by a direct action on cells and partly indirectly by stimulating the normal secretion of growth hormone. It is essential for the maturation of the CNS.

Therapeutic Uses:

Thyroid hormone is used in hypothyroidism and the treatment is usually continued for the rest of patient’s life. In infants, congenital absence or incomplete development of the thyroid results in cretinism, which is characterized by stunted development of the baby, causing dwarfism, mental retardation, and coarsened facial features and skin. It is also called congenital hypothyroidism.

In adults thyroid deficiency may be due to different causes which include:

i. Primary hypothyroidism (due to disease of the thyroid itself) accounts for more than 90% of cases.

ii. Insufficient iodine in the diet; this is called simple or nontoxic goiter.

iii. Chronic lymphocytic thyroiditis (Hashimoto’s disease), which is the most common and is an immunological disorder, when the body reacts against the protein thyroglobulin, which is the mechanism for storing T3 and T4 in the thyroid gland.

iv. Iatrogenic hypothyroidism due to thyroidectomy or radioactive iodine (131I) therapy.

v. Secondary hypothyroidism due to TSH is uncommon but may occur in disorders of the pituitary or hypothalamus.

vi. Drugs that may cause hypothyroidism include lithium, interferon-alpha, interleukin-2, thalidomide, NSAIDs, glucocorticoids, X-ray contrast agents, sympatholytics, sulphonylureas and tranquillizers.

When thyroid deficiency is severe it causes a condition called myxedema, which is mainly characterized by symptoms like, mental impairment, slow or slurred speech and hoarseness, bradycardia, fatigue, myalgias, constipation, cold intolerance, facial and periorbital edema, dry skin and non-pitting edema.

Thyroxine sodium (T4, levothyroxine sodium) is the drug of choice for maintenance therapy. The treatment is started with small doses, which are increased until the desired effects are produced. It is desirable to monitor the therapy with occasional T4 and TSH estimations to ensure the correct dose. Liothyronine (T3, Triiodothyronine) has actions similar to thyroxine but are much more rapid in onset. It is not so useful in the treatment of myxedema but is the treatment of choice in myxedema coma, when given intravenously.

Adverse Effects:

Excessive doses of thyroid hormones lead to cardiovascular disorders (anginal pain, arrhythmia, and tachycardia), muscle cramps, GIT disorders (especially constipation), muscle weakness and loss of weight. Hypnotics should be avoided for insomnia.

Essay # 11. Anti-Thyroid Drugs:

Anti-thyroid drugs are used for hyperthyroidism, either to prepare patients for surgical excision of the thyroid gland, or for its regular treatment. The common types of hyperthyroidism are diffuse toxic goiter (also called thyrotoxicosis or Grave’s disease) and toxic nodular goiter. The treatment of choice for diffuse toxic goiter is by drugs whereas for toxic nodular goiter is surgery. Anti-thyroid drugs used for the treatment of thyrotoxicosis are aqueous iodine solution (Lugol’s solution), radioiodine (radioactive iodine; 131I) and thionamides.

i. Aqueous Iodine Solution:

It is also called Lugol’s solution and is only indicated (1-2 drops orally given 12 hourly) to inhibit thyroid hormone secretion release as part of the treatment of thyroid crisis and also as premedication before thyroid surgery to make the thyroid gland less vascular. Its actions are temporary and after 10 days or so, the beneficial actions start wearing off. It is likely to give rise to allergic reactions.

ii. Radioiodine:

Radio-iodine (radioactive iodine; 131I) is the treatment of choice for almost all patients of Grave’s disease except during pregnancy. It is a radioactive isotope of iodine that is taken selectively by thyroid gland, where it emits powerful rays that kill cells.

It is a rare example of a “magic bullet”- i.e. a drug that targets the thyroid gland, because of its selective property of trapping the circulating iodine in the blood. A single dose permanently controls hyperthyroidism in 90% of patients. Radioiodine emits both β-particles and y-rays and has a short half-life of about 8 days.

Radioiodine does not increase the risk of malignancy, since its cytotoxic effects are mainly confined to thyroid gland because of relative short path of β-particles, which destroys quickly the thyroid tissue and the radio activity decays away completely because of its short half-life.

The common side effect is hypothyroidism, which occurs in more than half of patients within the first year and continues to develop at a rate of approximately 3% /year. Hypothyroidism is easily treated by administration of thyroxine.

iii. Thionamides:

Carbimazole, methimazole and propylthiouracil are thiourea derivatives that act primarily by interfering with the synthesis of thyroid hormone.

Mechanism of Action:

These drugs inhibit thyroid hormone synthesis, possibly by preventing the oxidation of iodide to iodine. Propylthouracil also blocks the conversion of T4 to T3 in target tissues. They do not have any permanent action on thyroid function and the symptoms recur, if the therapy is stopped.

Pharmacokinetics:

Thionamides are well absorbed orally. Carbimazole is a prodrug and is rapidly metabolized in the blood to methimazole. They are distributed throughout the extracellular water and have a short half-life. Though, not concentrated in thyroid, they have a prolonged effect on the thyroid and need only to be given once daily. These drugs are metabolized in the liver. Carbimazole should be used with care during pregnancy, as excessive doses may suppress the fetal thyroid. It is also excreted in maternal milk and may cause goiter and hypothyroidism in the newborn.

Therapeutic Uses:

Methimazole and propylthiouracil are commonly used. They act quickly to block the oxidation of iodide, but the beneficial effects are delayed because the circulating T3 and T4 have a long half-life and the thyroid has large stores of the hormones in the colloid. Propylthiouracil has a more rapid onset of action because of its extra-thyroidal (conversion of T4 to T3) inhibiting action. In the majority of patients with Graves’ disease, hypothyroidism recurs within 6 months after therapy is stopped. Spontaneous remission is likely to occur in mild, recent-onset hyperthyroidism and if the goiter is small.

Adverse Effects:

Minor side effects include rashes, joint pains, enlarged lymph nodes and transient depression of the white cell counts. Life- threatening side effects include agranulocytosis, hepatitis, vasculitis and drug-induced lupus erythematosus. Drug should be discontinued if jaundice or symptoms of agranulocytosis (e.g. fever, chills, and sore throat) develop.

Symptomatic Therapy:

β blockers reduce those symptoms of thyrotoxicosis that are due to over activity of the sympathetic system, such as palpitation, tremor, sweating and anxiety until hyperthyroidism is controlled by specific therapy. Verapamil can be used to control tachycardia in lieu of β blockers, if the latter is contraindicated.

Essay # 12. Corticosteroids:

The adrenal cortex produces a number of hormones which belong to three main groups:

i. Mineralocorticoid Hormone:

Aldosterone is the principal mineralocorticoid that causes retention of Na+, phosphate, Ca+ and bicarbonate and reduction of serum K+. It acts on Na+ and K+ transport in the distal tubule of the kidney to enhance Na+ reabsorption. Its secretion is governed by the renin mechanism and its main function is to ensure maintenance of constant body fluid volume. It is not used as a drug.

ii. Sex Corticoid Hormones:

These are secreted in small amounts and are of no pharmacological importance.

iii. Glucocorticoid Hormones:

Cortisol or hydrocortisone is the main glucocorticoid hormone released from the adrenal cortex. Its main physiological role is concerned with metabolism of carbohydrate, fat and protein, maintenance of cardiovascular and skeletal muscle functions, a feeling of wellbeing and modification of the responses of body in conditions of stress. In addition to Cortisol, there are a number of synthetic hormones with similar actions and the whole group is called the corticosteroid or steroid hormones.

The pharmacological actions of glucocorticoids generally fall under three main groups:

(a) General metabolic and systemic effects,

(b) Negative feedback effects on the anterior pituitary and hypothalamus and

(c) Suppression of disease process.

General Metabolic and Systemic Effects:

Carbohydrate and Protein Metabolism:

Glucocorticoids tend to cause hyperglycemia due to a decrease utilization of glucose by peripheral tissues, an increase in gluconeogenesis, an increase production of glucose from protein and decrease sensitivity to insulin. Prolonged treatment may rarely give rise to diabetes mellitus. Glucocorticoids decrease protein synthesis and increase protein breakdown, particularly in muscles. This catabolic action may result in muscle wasting (proximal myopathy) and thinning of the skin, which becomes susceptible to bruising. They increase uric acid secretion.

Fat Metabolism:

Glucocorticoids promote lipolysis. The peripheral tissues loose fat which is deposited over face, neck and shoulders giving rise to round “moon-like” face with a picture similar to that of Cushing’s disease.

Bone:

Glucocorticoids inhibit osteoblast formation as well as intestinal absorption of calcium. They stimulate the secretion of parathyroid hormone that mobilizes calcium from bone. The bone production is thus reduced resulting in osteoporosis, which may cause osteoporotic fractures of the hip or vertebrae in the elderly. High doses are associated with avascular necrosis of the femoral head.

Stomach:

Glucocorticoids increase secretion of gastric acid and pepsin and may exacerbate peptic ulcer. Their anti-inflammatory action may mask the symptoms of perforation of peptic ulcer.

Central Nervous System:

Glucocorticoids usually produce a feeling of wellbeing (euphoria). In patients with mental disorders, they may cause serious mental disease, a serious paranoid state or depression with risk of suicidal tendency.

Miscellaneous Effects:

In children, administration of glucocorticoids results in suppression of growth.

Negative Feedback Effects:

Glucocorticoid administration depresses the secretion of corticotrophin releasing hormone from the hypothalamus and adrenocorticotropic hormone from the anterior pituitary with a resultant decrease in secretion of endogenous glucocorticoids and atrophy of adrenal cortex. Adrenal atrophy can persist for years after stopping prolonged corticosteroid therapy and any illness or surgical emergency may require corticosteroid therapy to compensate for lack of sufficient adrenocortical response.

Suppression of Disease Processes:

Glucocorticoids have potent anti-inflammatory and immunosuppressive effects. The anti-inflammatory action may be due to the synthesis of a new protein, lipocortin, which inhibits the production of prostaglandins, leukotriene’s and platelet activating factor by inflammatory cells.

In certain disease antibody producing system may become deranged and produce antibodies against various body tissues. Diseases, which arise in this way, are called “autoimmune” and steroids, by suppressing the antibody system, can be useful in the management of such autoimmune disorders. Anti-inflammatory and immunosuppressive effect constitutes the main uses of glucocorticoids and their other pharmacological actions are responsible for the adverse effects seen in therapy.

Glucocorticoids have marked antitumor effects in acute leukemia and lymphomas. They have anti-lymphocyte action. They enhance appetite and produce a sense of wellbeing in the management of symptomatic end-stage malignant disease. In cerebral tumors, they help in reducing edema.

Pharmacokinetics:

Glucocorticoids are readily absorbed from GIT. Almost 90% of the drug is bound to plasma proteins. They are metabolized in the liver. Inhaled corticosteroids using spacer devices have high topical potency due to increased airway deposition and a low systemic bioavailability due to reduced oropharyngeal deposition.

Preparations:

Hydrocortisone and cortisone, the natural hormones exhibit some mineralocorticoid activity. Large number of semisynthetic analogues of the natural hormones does not possess mineralo­corticoid activity and can be given in anti-inflammatory (pharmacological) doses without the adverse effect of sodium retention.

Hydrocortisone:

The relative high mineralocorticoid activity makes it unsuitable for disease suppression on a long- term basis. It is used on a short-term basis by intravenous injection for emergency conditions.

Prednisolone:

It has predominant glucocorticoid activity and is the steroid most commonly used for long-term disease suppression.

Deflazacort:

It is derived from prednisolone and has a high glucocorticoid activity.

Triamcinolone: 

It causes marked muscle wasting which may result in proximal myopathy. It is not indicated for chronic therapy. Methylprednisolone, betamethasone and dexamethasone.Lack significant mineralocorticoid activity, which make them particularly suitable for high dose therapy in cerebral edema, where water retention would be a disadvantage.

Corticosteroid Inhalations:

Inhaled corticosteroids are useful adjunct to β2 stimulants in the management of asthma. Beclometasone, budesonide and fluticasone are highly lipophilic and employed.

Therapeutic Uses:

a. Suppression of Disease Processes:

Corticosteroids can save or prolong life by suppressing the effects of the disease process, but do not cure the under lying condition, although remission may occur.

b. Inflammatory Conditions:

The anti-inflammatory effect of steroids is used for treatment of systemic lupus, polyarteritis nodosa, nephrotic syndrome and related diseases. In rheumatoid arthritis, steroids although very effective, are rarely used over long periods because of high incidence of adverse effects.

c. Autoimmune Diseases:

Steroids are useful in idiopathic thrombocytopenic purpura, certain hemolytic anemia’s, acute chronic hepatitis and prevention and rejection of organ transplant rejection.

d. Allergic Conditions:

Hydrocortisone (100-300 mg IV) is life-saving in acute hypersensitivity reaction when used as an adjunct to adrenaline and septic shock.

e. Bronchial Asthma:

Inhaled steroids are the drugs of choice for prophylaxis of bronchial asthma. Oral or IV steroids are required with beta blockers in life threatening attacks.

f. Malignant Diseases:

Steroids are used for acute lymphoblastic leukemia, Hodgkin’s disease, lymphomas and cerebral tumors.

g. Intestinal Diseases:

Topical (by enema) and systemic (oral or IV) steroids are used for ulcerative colitis and Crohn’s disease.

h. Skin Diseases:

Inflammatory conditions of skin, such as eczematous disorders and psoriasis respond to topical steroids. Prolonged application to the skin can produce atrophy of the skin and a tendency to bacterial or fungal infections.

i. Eye:

Steroids may be used for short-term local treatment (eye drops or ointment or sub-conjunctival injection) of anterior segment inflammation. Steroid cataract, glaucoma and infection are dangerous hazard to indiscriminate use.

j. Replacement Therapy:

Small (physiological) doses of steroids are needed in adrenal insufficiency, which may arise in Addison’s disease, hypo­pituitarism, or adrenalectomy. A combination of hydrocortisone and fludrocortisone is indicated since hydrocortisone alone does not provide sufficient mineralocorticoid activity for complete requirements.

Adverse Effects:

Mineralocorticoid side effects include hypertension, edema and potassium loss.

Glucocorticoid side effects may be dangerous, when given in high suppressive (pharmacological) doses and include:

Diabetes especially in the elderly patients.

Osteoporosis with resultant fracture of the hip or vertebrae and high doses may cause avascular necrosis of femoral head.

Mental disturbances- Serious paranoid state or depression with risk of suicide may be induced, particularly in patients with history of mental disorder.

Muscle wasting,

Peptic ulcer may rarely occur.

Modification of tissue reactions may result in spread and masking of clinical signs of infection. Serious infection, e.g. septicemia and tuberculosis may reach an advance stage before being recognized. Chicken pox, herpes zoster and measles may become life threatening in patients taking steroids, if they have no immunity from a previous attack.

Cushing’s syndrome, growth suppression, glaucoma or cataract and adrenal cortical atrophy are other possible side effects. Side effects are minimized by using lowest effective dose for minimum possible period. Steroids are contraindicated in systemic infections unless specific antibacterial therapy is given and with live virus vaccines.

Essay # 13. Drugs Used to Cure Female Infertility:

i. Gonadotropins:

Follicular stimulating hormone and luteinizing hormone are the gonadotropins secreted by anterior pituitary, which act in concert to release female sex hormones responsible for the fertility and maintenance of pregnancy or menstruation. Follicular stimulating hormone (FSH) causes ripening of the ovarian follicle, which releases estrogen.

In males, it is necessary for the production of spermatozoa. Luteinizing hormone (LH) helps in the development of corpus luteum, which produces the hormone progesterone. In males, it stimulates the interstitial cells of the testis to produce androgens.

Follicular stimulating hormone (urofollitropin or follitropin alpha and beta) and luteinizing hormone (chorionic gonado­tropin) or a combination of FSH and LH (human menopausal gonadotrophins) are used in female infertility due to lack of normally secreted gonadotrophins.

ii. Clomifene:

Clomifene releases gonadotrophins from the anterior pituitary and is used in the treatment of female infertility due to failure of ovulation. It has the advantage of oral administration and a high success rate. It should not be used for longer than 6 cycles (5 days early in the menstrual cycle) because of the risk of ovarian cancer. Adverse effects include hot flushes, abdominal discomfort, menorrhagia, endometriosis, weight gain and visual disturbances.

iii. Gonadorelin Analogues:

Buserelin and goserelin produce an initial phase of stimulation, followed by a reduction in the secretion of gonadotrophins, which in turn leads to inhibition of androgen and estrogen production. They are used in the treatment of endometriosis and carcinoma of prostate.

iv. Gonadotrophin Inhibitors:

Danazol and gestrinone inhibit both gonadotrophin-releasing hormone and gonadotrophin release and are used to treat endometriosis and various benign breast disorders. They combine androgenic activity with antiestrogenic and antiprogestrogenic activity. Adverse effects are due to androgenic activity, which include abnormal hair growth, greasy skin, acne, fluid retention, weight gain and nausea.

v. Estrogens:

Estrogens are necessary for the development of female secondary characteristics. The important actions of estrogens are myometrial hypertrophy and endometrial hyperplasia, sensitisation of uterine muscle to certain stimulating agents, increase in the duct tissue in the breast and inhibition of production of prolactin by pituitary.

Estrogen used therapeutically belongs to three groups:

a. Natural Estrogens:

Estradiol, estrone and estriol

b. Synthetic Estrogens:

Ethinylestradiol, mestranol and dienestrol+

c. Conjugated Estrogen:

Premarin- +Used topically in the vagina

Therapeutic Uses:

Estrogens are used for hormone replacement therapy (HRT), rarely in neoplastic diseases, oral contraception and atrophic vaginitis (as a cream).

Hormone Replacement Therapy:

Natural and conjugated estrogens have a more appropriate profile for hormone replacement therapy (HRT) than synthetic estrogens. They are used during and after menopause to relieve vasomotor symptoms, and hot flushes. They are very effective in preventing osteoporosis, which is a serious problem in postmenopausal women. Progestogen is combined with estrogen to prevent the risk of carcinoma of the uterus.

Estrogen can be given by different routes. Topical estrogen can be used in atrophic vaginitis. Oral preparations of estrogens are subject to first pass metabolism, therefore, subcutaneous or transdermal administration is more akin to endogenous hormone activity.

Tibolone is a synthetic hormone that combines estrogenic and progestogenic activity with weak androgenic activity. It is used to control postmenopausal symptoms. Raloxifene blocks the action of estrogen on the breast and uterus. It prevents vertebral fractures in postmenopausal women at increased risk of osteoporosis. It does not reduce menopausal vasomotor symptoms and does not cause menstrual bleeding.

Side effects of HRT are nausea, weight gain, headache, fluid retention and risk of breast cancer and venous thrombosis. HRT is contraindicated in thromboembolic disorders, breast or endometrial cancer, undiagnosed uterine bleeding and liver diseases.

Neoplastic Diseases:

i. Prostate Cancer:

Diethylstilbesterol suppresses the production of androgens that stimulate the neoplasm. Toxicity is common and the standard treatment of metastatic cancer of the prostate includes cyproterone, which directly blocks the action of androgens on the prostate or orchidectomy or gonadorelin analogue, which reduce androgen secretion.

ii. Breast Cancer:

Estrogens are more usually associated with a worsening of breast cancer, but have been used with some success for the treatment of advanced breast cancer. Estrogens are occasionally used in advanced metastatic breast cancer in postmenopausal women, who obtain temporary but sometimes striking remissions of their disease.

iii. Atrophic Vaginitis:

Dienestrol cream is applied daily in the vagina for 1 week and then reduced in atrophic vaginitis, which occurs in postmenopausal women due to estrogen deficiency.

vi. Progestogens:

Progesterone is the natural progestogen and is mainly produced by the ovary. It is concerned in the maintenance of the pregnancy by thickening and development of the secretary phase in the endometrium and by damping down the excitability of the uterine muscle.

Progestogens used therapeutically belong to two groups:

a. Progesterone and Its Analogue:

Progesterone, dyhydro- gesterone, hydroxyprogesterone and medroxyprogesterone.

b. Testosterone Analogues:

Norethisterone, norgestrel, levonorgestrel, norgestimate, desogestrel and gestodene. Progesterone and its analogues are less androgenic and do not cause virilisation, However, they have adverse effects on plasma lipids and increase the possibility of vascular diseases. Testosterone analogues have no adverse effects on lipids and are commonly used.

Therapeutic Uses:

Progestogens have a very limited place in therapeutics, except for oral contraception where used either alone or in combination with estrogens. Progestogens prevent the development of intrauterine cancer by causing cyclical shedding of the endometrium. The other uses of progestogens are endometriosis, menstrual disorders and neoplastic diseases such as breast, endometrial and renal cell carcinoma.

Adverse Effects:

GIT disorders, fluid retention, weight gain, breast discomfort, acne, urticaria and menstrual disturbances are common side effects. They may cause CNS symptoms, alopecia and rarely jaundice. Progestogens are contraindicated in undiagnosed vaginal bleeding, severe arterial disease, breast or genital tract carcinoma and active liver disease.

vii. Oral Contraception:

There are two main types of oral contraceptive pill (the Pill):

a. The combined oral contraceptive pill

b. The progestogen only pill

a. Combined Oral Contraception pill:

The combined oral contraceptive pill containing estrogen and progestogen is the most effective method of fertility control.

It prevents conception by following mechanisms:

i. The estrogen inhibits the release of FSH by a negative feedback effect, thus inhibiting follicular development.

ii. The progestogen inhibits the release of LH, so that ovulation cannot occur. Together, estrogen and progestogen render the endrometrium hostile to implantation.

iii. Both estrogen and progestogen may upset the coordinated contractions of the fallopian tubes, uterus and cervix.

The oral combined contraceptive pill usually contains ethinylestradiol (30-50 microgram) and progestogens (norethisterone or levonorestrel or desogestrel or gestodene). The combined pill preparations are available in low strength (ethinylestradiol 20 microgram), standard strength (ethinylestradiol 30 microgram) and high strength (ethinylestradiol 50 microgram). The choice depends on the age and presence of risk factors for venous and arterial thrombosis such as obesity, diabetes, hypertension, migraine, varicose veins, etc.

Adverse Effects of the Combined Pill:

Thromboembolic Complications:

Though combined contraceptive pills may reduce the risk or incidence of menstrual disorders and benign breast disease and cancer of the ovary and uterus, there is now clear evidence that women, who are heavy smokers and are in the 40-44 age group run the risk of developing thromboembolic complications and therefore should not use combined contraceptive pills.

Thrombosis is believed to be due to the estrogen in the Pill and for this reason the estrogen content of these preparations is kept as low as possible. Progestogen fraction of the Pill has been associated with the arterial disease, which is due to alteration in blood lipids.

The new progestogens desogestrel and gestodene are less likely to cause changes in plasma lipids with consequent lesser risk of vascular disease (e.g. coronary thrombosis and strokes), but may actually increase the incidence of venous thrombosis in the legs and, thus, the risk of pulmonary embolism and therefore it is advisable to avoid contraceptives containing new progestogens in women, who are overweight, immobile or have a history of thrombosis.

Cancer:

There has been conflicting reports about the causation of cancer of breast and cervix with the use of combined Pill. However, a recent study suggests that current or former use of oral contraceptives is not associated with an increased risk of breast cancer. The incidence of cancer of the cervix has been found to be more common in those taking oral contraceptives, and it is advisable that women who have taken oral contraceptives for than 5 years should have an annual cervical smear checkup.

Other Effects:

Other side-effects like weight gain, GI upsets, acne, flushing, dizziness, irritability, depression, and gallstones have been reported, but they are of no significance and as a matter of fact many women feel better while taking these preparations.

b. Progestogen-Only Pill:

Use of preparations which only contain progestogens only prevent ovulation in about half the menstrual cycles and thus are less efficient as contraceptives. Progestogen Pill, which inhibits the ovulation and changes the character of the cervical mucus, is less safe contraceptive than the combined pill, but has virtually no risk of thrombotic disease and may be preferred in older women or those at special risk from thrombosis.

Progestogen preparations are available as oral pills, depot injections and intrauterine progestogen coil. The intrauterine coil releases a progestogen, levonorgestrel, directly into the uterine cavity, and is used as a contraceptive and to treat primary menorrhagia. It acts by causing thickening of cervical mucus and preventing endometrial proliferation. The main adverse effects of the progestogen-only Pill are amenorrhea, spotting, vomiting, breast discomfort, depression, and weight changes.

Contraindications of Oral Contraceptives:

The oral contraceptives should not be used in thromboembolic disease, carcinoma of breast and cervix, undiagnosed vaginal bleeding, severe liver disease, hypertension, migraine, depression and epilepsy. Drugs, which induce hepatic enzyme activity, decrease the efficacy of the contraceptive pill. The most important drug in this respect is rifampicin but anti-epileptics, isoniazid, griseofulvin, and broad spectrum antibiotics also reduce the efficacy of the Pill.

Postcoital Contraception (Yuzpe Method):

Oral contraceptive pills, progestogen alone or combined pill, if taken within 72 hours of unprotected intercourse are effective in reducing the risk of pregnancy. Centchroman (Saheli) is a non-steroidal estrogen antagonist developed by CDRI, India and is used as oral contraceptive. Its exact mode of action is not known. It is claimed to prevent implantation of the ovum and to be free of the side effects of contraceptive pill.

Essay # 8. Drugs Used to Cure Male Fertility:

Testosterone, the natural androgen, is produced by the interstitial cells of testis. It is responsible for the secondary male sex characteristics including distribution of hair, deepening of the voice and the growth of genitals. The luteinizing hormone (LH) of the pituitary controls its release from the testis. Testosterone also has an anabolic action.

Therapeutic Uses:

Testicular Hormone Deficiency:

Testosterone is used in testicular hormone deficiency due to hypopituitarism. It is given orally, as an implant or skin patches. Esters of testosterone (Sustanon) can be given intramuscularly every 3 weeks and is released slowly from the injection site. Mesterolone is similar to testosterone and is given orally. Unlike testosterone it does not cause jaundice or depress spermatogenesis.

Carcinoma of the Breast:

Testosterone is effective in about 30% of postmenopausal patients with advanced carcinoma of the breast for relieving symptoms and causing temporary regression of secondary deposits. It does, however, has virilising effects and causes the growth of facial hair, deepening of the voice and acne.

Adverse Effects:

Testosterone may lead to prostate abnormalities, prostate cancer and cholestasis jaundice. It may also cause electrolyte disturbances including sodium retention with edema and hypercalcemia, increased bone growth and virilism in women. Testosterone is contraindicated in breast cancer in men, prostate cancer, liver tumors, hypercalcemia and pregnancy.

Anti-Androgens:

Cyproterone acetate and flutamide block the action of testo­sterone at the cell receptors. They inhibit spermatogenesis and produce reversible infertility. Anti-androgens are used in various endocrine disorders, where there is overproduction of male hormone causing hirsutism in the female (when it is combined with estrogen) and severe hyper-sexuality and sexual deviations in the male. They are also used in patients with metastatic prostate cancer refractory to gonadorelin analogue therapy. Anti-androgens are hepatotoxic and are mainly indicated to palliate symptoms of advanced prostate cancer.

Finasteride is a specific inhibitor of testosterone metabolism and interferes with its action on the prostate gland. The size of the prostate gland is reduced and the obstructive symptoms of enlarged prostate are relieved. Its use is limited to benign prostatic hyperplasia, where it improves the urinary flow rate. The other drugs used for benign prostatic hyperplasia are selective alpha-blockers such as prazosin.

Anabolic Steroids:

These are the derivatives of male sex hormones that have less virilisation effects in women, but have significant anabolic action (protein building property). Their protein building property is thought to be useful to hasten convalescence and in senile osteoporosis (a condition due to lack of protein in bone), but clinically their effectiveness is not proven. Their use as body builders or tonics is quite unjustified. They are abused by athletes. The use of anabolic steroids is only limited in the treatment of some aplastic anemias.

Drugs for Impotence:

Male erectile dysfunction is commonly due to psychological factors, but endocrine abnormalities and certain drugs (e.g. alcohol, tricyclic antidepressants, neuroleptics, anti-hypertensives, and cimetidine) may also result in a failure to produce a satisfactory erection. Erection depends on the relaxation of the penile smooth muscle, with subsequent engorgement with blood following necessary stimulus.

Prostaglandin E1 (alprostadil) or papaverine given by intra-cavernosal injection relaxes smooth muscle and produces a satisfactory erection. The procedure is not only cumbersome, but leads to multiple penile problems. Erection lasting for longer than 4 hours (priapism) is an emergency requiring penile aspiration, intra-carvernosal injection of sympathomimetic vasoconstrictors or even surgical intervention.

Sildenafil (viagra) inhibits the phosphodiesterase 5 in the blood vessels of penis leading to vasodilatation and enhanced erection, when taken an hour or two before intercourse. It has the advantage of oral administration and being highly effective.

Common side effects of sildenafil are dyspepsia, headache, flushing, dizziness, visual disturbances and increased intraocular pressure. Sildenafil is contraindicated in recent stroke or myocardial infarction, hypotension (it should not be used in patients receiving nitrates) and hereditary degenerative retinal disorders. Antibiotics (erythromycin), antifungal, antiviral and ulcer healing (cimetidine) drugs increase the plasma sildenafil concentration and may cause priapism.

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