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Blood agar and MacConkey agar at room temperature order generic grifulvin v online, if bubonic plague is suspected: • Inoculate the specimen • Incubate both pletes aerobically at room temperature far up to 48hours safe grifulvin v 125mg. Additional: Potassium hydroxide preparation discount grifulvin v 125mg otc, if ringworm or other superficial fungi infection is suspected discount 250mg grifulvin v with visa. For detection of ringworm: Giemsa techniques or wayson`s techniques,if bubonic plague is suspected. Ziel-Neelsenstained smear if buruli ulcer is suspected examine for acid fast bacilli. Dark-field microscope to detect treponemes - look for motile treponeme if yaws or pinta is suspected Examine and report the culture Blood agar and MacConkey agar cultures Look for: S. Pyogenes • Ureaplasma urealyticum • Chlamydia trachomatis and • Occassionally Trichomonas vaginalis Cervical swabs from non-puerperal women: • N. Collection and transport of urogenital specimen • Amies medium is the most efficient medium for transporting urethral, cervical and vaginal swabs. The pathogen is, therefore, more likely to be isolated from a cervical swab than from a vaginal swab. Gently massage the urethra from above downwards, and collect a sample of pus on a sterile cotton wool swab. Make a smear of the discharge on a slide for staining by the Gram technique and label the specimen. Pass a sterile cotton wool swab into the endocervical canal and gently rotate the swab to obtain a specimen. Suspected chanchroid 156 Look for Gram negative coccobacilli showing bipolar staining Additional culture Blood agar (aerobic and anaerobic), macCokey agar,and cooked meat medium, if puerperal sepsis or septic abortion is suspected Sabourand medium, if vaginal candidiasis is suspected and yeast cell not detected microscopically Serum culture, if chancroid is suspected ⇒H. Gemsa stained smear: If donovanosis is suspected Dark field preparation, if syphilis is suspected. Colleciton, transport and examination of cerebrospinal fluid Possible pathogens Gram positive S. Fungi: Cryptococcus neoformans Parasites: Trypanosoma species Naegleria fowleri Acanthamoeba species and rarely the larvae of Angiostrongylus cantonensis and Dirofilaira immitis Note: 1. Inflammation of the meninges (membranes that cover the brain and spinal cord) is called meningitis. Pathogens reach the meninges in the blood stream or occasionally by spreading from nearby sites such as the middle ear or nasal sinuses. This rare form of meningitis is caused by helminthes larvae such as Angiostrongylus cantonensis and Dirofilaria imitis • Meningitis of the newborn (neonatal meningitis) is caused mainly by E. Commensals No normal microbial flora Collection of Csf • It should be collected by medical officer in aspectic procedure • The fluid is usually collected from the arachnoid space. A sterile wide-bore needle is inserted th th between the 4 and 5 lumbar vertebrate and C. If typanosomes are present, they will not be found because they are rapidly lyzed once the C. The fluid should be handled with special care because it is collected by lumbar puncture and only a small amount can be withdrawn. This is because sample No 1 may contain blood (due to a traumatic lumbar puncture) which will affect the accuracy of the cell count and biochemical estimations. Yellow-red (after centrifuting) The fluid may also appear xanthromic if the patient is jaundiced or when there is spinal constriction. This should be transferred to a slide, pressed out, alcohol- fixed, and stained by the Ziel-Neelsen method I. Test the specimen biochemically - Glucose estimation ½ - 2/3 of that found in blood, i. Culture the specimen (sample No 1) It is necessary, if the fluid contains cells and, or, the protein concentration is abnormal. If a delay is unavoidable, the fluid should be 0 kept at 35-37 C (never refrigerated). Additional MacConkey and blood agar if the patiente is a newborn infant 0 incubate both plate at 35-37 C overnight - E. If capsulated yeast cells are seen in the microscopial preparations, 0 inoculate a plate of sabouraud agar. Incubate at 35-37 C for up to 72hours, cheeking for growth after overnight incubation. The term septicaemia refers to a severe and often fatal infection of the blood in which bacteria multiply and release toxins in to the blood stream. In typhoid, salmonella typhi can be detected in the blood of 75-90% of patients during the first 10 days of infection and in about 30% of patients during the third week. Collection and culture of Blood and Borne marrow 9 Blood and bone marrow require culturing immediately after collection, before clotting occurs. Choice of culture media 9 Because septicaemia is such a serious condition, it is essential to use media that will provide the fastest 167 growth and isolation of as wide a range of pathogens as possible. Because the bacteria can be seen growing on the slope, the need to subculture on a solid medium every few days is avoided, thus reducing the risk of contamination. It prevents clotting of the blood and neutralize the natural bactericidal substances in fresh blood. Aminobenzoic acid: This neutralizes the action of sulphonamides should these be present in the blood. Collect and culture the specimen Blood • It should be collected before antimicrobial treatement has been started and at the time the patient’s temperature is beginning to rise. Insert the needle through the rubber line of the bottle cap and dispense 5ml of blood into each culture bottle. Incubate the inoculated media: Thioglycollate broth 0 At 35-37 C for up to 2 weeks, examining and sub-culturing • Look for visible signs of bacterial growth such as turbidity above the red cell layer, colonies growing on top of the red cells (“cotton balls”), haemolysis, gas bubbles and clots. Synovitis means inflammation of the synovial membrane (living of a joint capsule). Arthritis may be caused by bacteria (infective arthritis), rheumatoid arthritis, gout and pseudogout, osteoatrhtitus 3. The term pleural effusion is used to describe a non-purulent serous effusion which sometimes forms in pneumonia, tuberculosis, malignante disease etc Empyema is used to describe a purulent pleural effusion when pus is found in the pleural space. Peritonitis means inflammation of the peritoneum, which is the serous membrane that lines the peritoneal cavity. Ascites refers to the accumulation of fluid in the pentional cary causing abdominal swelling. Commensales No microbial flora Collection is carried out by a medical officer - 2-3ml without anticogulent, to see whether clotting occurs. Staphylococcus warneri • Can readily grow in ordinary media under aerobic and micro- aerophilic conditions • grow most rapidly at 37 0c but form pigment best at room temperature of 20-25 oc • Colonies in solid media are round, smooth, raised and glistening. Peptidoglycan( Mucopeptide): Polysaccharide polymer which provide the rigid exoskeleton of the cell wall. It is important in the pathogenesis of infection like eliciting production of cytokines and opsonic antibodies; chemoattractant for polymorphs;and activate complement 2. Catalase- Produced by staphylococci Converts H202 into H20 and 02 175 Catalase test differentiates staphylococci(catalase-positive) from streptococci(catalase-negative). Coagulase may deposit fibrin on the surface of organism and alter ingestion by phagocytic cells. Clumping factor: A surface compound that is responsible for adherence of the organism to fibrinogen and fibrin Produced by Staphylococcus aureus Determines Invasive potential of the organism. Multiple (A-E, G-I, K-M) soluble heat-stable, gut enzyme resistant toxins which act on neural receptors 176 in the gut to stimulate vomiting center in the central nervous system. Epidermolytic toxin A: Chromosomal gene product and heat stable Epidermolytic toxin B: Plamid mediated and heat labile. Endocarditis and meningitis: Infection of heart tissue and leptomeninges respectively. Characterized by abrupt onset of high fever, vomiting, diarrhea, myalgia, scarlatiform rash,and hypotension with cardiac and renal failure in the most severe disease. Catalaseproducing Bacteria (Staphlococci) No active bubbling…………Non-catalase producing bacteria (streptococci) 2. Serologic specificity of the cell wall group specific substance and other cellwall capsular antigens 3. Partial Greenish discoloration Alpha(α) Viridans streptococci (reduced hemoglobin). None No change Gamma(δ) Enterococci Lancefield grouping of streptococci: Streptococci produce group specific carbohydrates(C carbohydrates) identified using group specific antiserum.

Activity that increases can range from monitoring multidisci- the likelihood that a recovering patient in plinary staff members to direct manage- substance abuse treatment will relapse to ment of cases grifulvin v 125 mg otc, depending on the severity of substance use or contract a substance patientsí problems 125mg grifulvin v. Treatment of tion) in which addiction professionals and opioid addiction and related complications clinicians provide therapeutic services to that requires patient residency for some clients who live at home or in special resi- period in a hospital setting or outpatient dences order grifulvin v amex. Treatment is delivered in two to treatment in a hospital-linked facility to five regularly scheduled sessions per week ensure that necessary services and levels of totaling 6 to 24 hours per week order grifulvin v 125 mg line. The process of providing care macotherapy, usually during the acute to a patient or taking action to modify a phase of treatment, in which steady-state symptom, an effect, or a behavior. Types of -M - intervention can include crisis interven- tion, brief intervention, and long-term m aintenance dosage. Medication sons related to program operations, safety, used for ongoing treatment of opioid or treatment complianceófor example, addiction. An opioid ago- incident to withdrawal from the continuous nist medication derived from methadone or sustained use of opioid drugs. Type of fully or do not show an acceptable response addiction treatment, usually provided in to other addiction treatments. Program offering treatment services, including medical and the benefits of peer support to people who psychosocial services. Facility established as part Twelve-Step programs are one type of of, but geographically separate from, an mutual-help program. The most frequently used opioid displaces opioids from these receptors and agonist medication. Methadone is a synthet- can precipitate withdrawal, but it does not ic opioid that binds to mu opiate receptors activate the mu receptors, nor does it cause and produces a range of mu agonist effects the euphoria and other effects associated similar to those of short-acting opioids such with opioid drugs. Some pro- Dispensing of methadone at stable dosage grams use naloxone to evaluate an individ- levels for more than 21 days in the super- ualís level of opioid dependence. W ithdrawal comprehensive maintenance services (with symptoms evoked by naloxoneís antagonist medication and counseling in one or several interaction with opioids confirm an individ- mobile units) to more limited care, usually ualís current dependence. Other substances com- drawal from opioids to prevent drug monly used by people addicted to opioids relapse in selected, well-motivated patients. Some drugsóin particular, high-dose barbituratesóused in Glossary 289 -O- opioid agonist. Areas on cell surfaces in that normally are bound by opioid psy- the central nervous system that are activat- choactive substances and that blocks the ed by opioid molecules to produce the activity of opioids at these receptors with- effects associated with opioid use, such as out producing the physiologic activity pro- euphoria and analgesia. Drug that binds to, Mu and kappa opiate receptor groups prin- but incompletely activates, opiate receptors cipally are involved in this activity. Natural derivative of opium or syn- nist but, at increasing doses, does not pro- thetic psychoactive substance that has duce as great an agonist effect as do effects similar to morphine or is capable of increased doses of a full agonist. Opioid trexone, of individuals who are addicted to addiction is characterized by repeated self- opioids. Services may include medically supervised withdrawal and/or maintenance opioid addiction treatm ent. Dispensing treatment, along with various levels of of approved medication to prevent with- medical, psychiatric, psychosocial, and drawal and craving during the elimination other types of supportive care. Method of identify- and rehabilitation services or medication ing evidence of opioid and other psychoac- prescribed when necessary to alleviate the tive substance use and measuring the levels adverse medical, psychological, or physical of substances or medications in the body by effects. This term encompasses medically examining patient saliva for the presence supervised withdrawal, maintenance treat- and concentrations of identifiable drugs ment, comprehensive maintenance treat- and their metabolites. In most States, patient excep- withdrawal but not for ongoing mainte- tions are contingent on the approval of the nance pharmacotherapy. OxyContin is one of several as well as rights and responsibilities of prescription opioids increasingly obtained patients and treatment providers. Term applied to two lev- els of activity in addiction treatment: (1) a patient referral. Alternative to providing all social or political movement working for necessary treatment services and levels of changes in legislation, policy, and funding care at the program site by collaboratively to reflect patient concerns and protect their outsourcing some services to other settings rights (i. W hen a patient must obtain philosophy of substance abuse treatment comprehensive services in multiple settings, practice maintaining that patients should Glossary 291 treatment program staff members should psychotherapy. Treatment service provided arrange the referrals, monitor patient to patients in a comprehensive opioid treat- progress, and coordinate care. Process of and treats patients for diagnosed psychi- individualizing therapeutic resources to atric problems. Readmission usually is preceded by a (1) assessing, (2) selecting the most suitable review of the patientís records to determine treatment modality and site, and (3) identi- whether and how the individualís treatment fying the most appropriate services. Treatment of disease treatment medication continue to eliminate with prescribed medications. Breakdown or setback in a personís attempt to change or modify a particular prevalence. Number of cases of a disease in a behavior; an unfolding process in which the population, either at a point in time (point resumption of compulsive substance use is prevalence) or over a period (period the last event in a series of maladaptive prevalence). Prevalence rate is the fraction responses to internal or external stressors of people in a population who have a or stimuli. State in which a mental or physi- existing cases of the condition at a specified cal disorder has been overcome or a disease time and the denominator is the total process halted. Evaluation of within the context of a cooperative living program effectiveness based on compliance arrangement. A substance that affects combination of patient and program char- the mind, thoughts, feelings, and sometimes acteristics. Process of determining whether a assigned by the governor to exercise the prospective patient has a substance use dis- responsibility and authority within a State order before admission to treatment. Negative association attached to an observation of known presenting com- activity or condition; a cause of shame or plaints and symptoms that are indicators of embarrassment. Agent, drug, or medication that system sedating and tranquilizing proper- produces stimulation. An example is any of the benzodi- lant usually refers to drugs that stimulate azepines. Medically unsanctioned use referred to as substance abuse or of drugs by a person to relieve any of a dependence). Consequence (especially an or it can occur regularly and be associated adverse result) other than that for which a with medical and mental problems, often drug is usedóespecially the result pro- including tolerance and withdrawal. Process of provid- substances and continue on maintenance ing immediate assistance (as with an opioid medication while receiving other types of agonist) to eliminate withdrawal symptoms intervention as needed to resume primary and drug craving. Opioid addiction problems, language difficulties, ethnic and treatment medication dispensed to patients social attitudes, logistics (caring for chil- for unsupervised self-administration. Joining of patients and their treatment providers in an effec- treatm ent eligibility. Relative qualification tive collaboration to assess and treat of a prospective patient for admission to an patientsí substance use disorders. Consciously Federal guidelines are minimum require- designed social environment or residential ments and restrict admission to individuals treatment setting in which social and group who have been demonstrably dependent on processes are harnessed with treatment opioids for 1 year; however, certain high- intent. Treatment focuses on drug abstinence, coupled with social and treatm ent outcom es. Observable results of psychological change requiring a multidi- therapy, including decreased use of illicit mensional effort along with intensive mutu- psychoactive substances, improved physical al help and support. Combination of considered the best indicator of treatment amount of medication and frequency and program effectiveness. Therapeutic dosage levels that specifies the services to be provided should be determined by what each patient and their frequency and schedule (adapted needs to remain stable. Many addiction among the patient, program physician, and treatment programs use a 12-Step structure treatment providers. Originally used symptoms after abrupt discontinuation of as a measure of program effectiveness, or rapid decrease in use of a substance that urine testing now is used to make program- has been used consistently for a period. Fundam ental Ethical Principles Beneficence (Benefit) According to Beauchamp and Childress (2001), the medical principle of beneficence emphasizes that treatment providers should act for the benefit of patients by providing competent, timely care within the bounds of accepted treatment practice. The principle of beneficence is satisfied when treatment providers make proper diagnoses and offer evidence-based treatments, that is, treatments drawn from research that provides statistical data about outcomes or from consensus-based stan- dards of care. Beneficence is compromised when diagnoses are question- able or when outcome data do not validate a diagnosis or treatment. Autonom y Autonomy, like beneficence, springs from the ideal of promoting patientsí best interests. However, whereas beneficence emphasizes the application of provider knowledge and skills to improve patient health, autonomy emphasizes respect for patientsí rights to decide what treat- ment is in their best interests (Beauchamp and Childress 2001).

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Duration is from 4 to 10 hours buy grifulvin v 125 mg overnight delivery, with most drugs requiring multiple doses for continued anorexigenic effect buy cheap grifulvin v 125 mg line. Prevention Educate the patient concerning the misuse of caffeine and Amphetamines Prevent medically induced amphetamine addiction by: -Teaching the obese patient who is taking Amphetamines to report such symptoms as nervousness best order for grifulvin v, insomnia buy grifulvin v australia, and cardiac palpitations. Dextroamphetamine, in large doses, is more likely to cause fatigue, mental depression, increased blood pressure, cyanosis, respiratory failure, disorientation, hallucinations, convulsions, and coma. Respect the amphetamine addict as a human being, his motivation will be increased. Be firm in setting limits, but do not irritate or humiliate him unnecessarily when enforcing them. Make a special effort to establish a supportive relationship with the addicted patient during his withdrawal from Amphetamines. This critical stage of rehabilitation can have a favorable effect on the patient’s final recovery. Adolescents age 13 to 17, 18 mg orally extended release once daily in the morning. Adjust dosage by 18 mg at weekly intervals to a maximum of 72 mg orally not to exceed 2 mg/kg once daily in the morning. The peak range for the drug varies from 1½ to 8 hours, with a duration of from 8 to 14 hours. Monitor drug levels (or coagulation times if patient is also taking Warfarin (Coumadin – blood thinner). Drug may delay growth spurt, but children will attain normal height when drug is stopped. Not using enough water to swallow tablet may cause the tablet to swell and block the throat causing choking. Press firmly in place for about 30 seconds using the palm of your hand, being sure there is good contact with the skin – especially around the edges. Upon removal, fold patch in half so the sticky sides adhere to itself, then flush down toilet or dispose of in a lidded container. For patients who are taking Concerta/Ritalin, initially give half the current Concerta/Ritalin dosage, up to a maximum of 20 mg daily in divided doses. Adults – for patients who are not taking Focalin or Concerta, or who are on stimulants other than Concerta, give 10 mg, once daily in the morning. For patients who are now taking Concerta, initially give half the total dose of Concerta. Patients who are taking the immediate release form of Focalin may be switched to the same daily dose of extended release form. Children ages 6 and older: For patients who are not now taking Focalin or Concerta, or who are on stimulants other than Concerta, give 5 mg once daily in the morning to a maximum daily dose of 20 mg. For patients who are now taking Concerta, initially give half the total daily dose of Concerta. Patients who are now taking the immediate release form of Focalin may be switched to the same daily dose of extended release form. Available forms are the extended release in 5 mg, 10 mg, 258 and 20 mg and the tablets are available in 2. Nursing Considerations: Antacids, Acid Suppressants may altar the release of Extended release form. Also inform parents to watch for increased aggression or hostility and to report worsening behavior. Increase after at least 3 days to a total of 80 mg/day, as a single dose in the morning or two evenly divided doses in the morning and late afternoon or early evening. Adjust a dose – in patients with moderate hepatic impairment, reduce to 50% of the normal dose; in those with severe hepatic impairment, reduce to 25% of the normal dose. In children and adults who weigh more than 70 kg, start at 40 mg daily and increase to 80 mg daily if symptoms do not improve after 4 weeks and if first dose is still tolerated. Available form is capsules at 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg. Notify Physician at any sign of liver injury: yellowing of the skin or the sclera of the eyes, pruritus, dark urine, upper right sided tenderness or unexplained flulike symptoms. Because parasympathetic nerves innervate many organs, parasympatholytic action can be widespread. The effects of parasympatholytics are typically opposite those of parasympathetic stimulation. For example, parasympathetic (vagal) stimulation of the heart decreases heart rate, whereas Atropine, a parasympathetic drug, increases heart rate. Several of these drugs (for example, Benztropine (Cogentin) and Trihexyphenidyl – antidyskinetic drug) can enter the brain, where they antagonize the actions of cerebral acetylcholine. The cholinergic blockers help to control the clinical effects of Parkinsonism (a disease partly attributable to over activity of certain cholinergic pathways in the brain) and dyskinesias associated with the use of major Tranquilizers. The administration of Atropine to reverse severe bradycardia, for example, can dry oral and respiratory secretions. Likewise, the use of Benztropine (Cogentin) for Parkinsonism can produce urinary retention, especially in men with prostatic hypertrophy. Major Uses Atropine may be used for poisoning due to organic phosphate insecticides and certain mushrooms. Atropine and Scopolamine, as preanesthetic medications, are used to reduce salivary and respiratory secretions. Benztropine (Cogentin), Biperiden (Akineton – antiparkinsonism), Cycrimine (Pagitane – relief of spasms), Procyclidine (Kemadrin – antiparkinsonism), and Trihexyphenidyl (antidyskinetic) are used to treat Parkinsonism and extrapyramidal reactions associated with the use of Neuroleptics. They are widely distributed to body organs innervated by the parasympathetic nervous system and excreted unchanged in the urine. As a result, local muscle paralysis occurs, which leads to muscle atrophy and reinnervation due to development of new acetylcholines receptors. Dosage ranges from 198 units to 300 units to relax skeletal muscles and reduce severity of abnormal head position and neck pain associated with cervical dystonia. Nursing Considerations: Some doctors use Artane (antiparkinson) for drooling, but it is a systemic drug, where as Botox is a local injection. Ketoconazole (Nizoral - antifungal) may interfere with Nizoral (antifungal) absorption. Diminishes the volume and free acidity of gastric secretion and controls excessive pharyngeal, tracheal, and bronchial secretions. Watch closely for adverse reactions, especially in geriatric and debilitated patients. May affect neural pathways originating in the inner ear to inhibit nausea and vomiting. Transderm Scop is effective if applied 2 or 3 hours before experiencing motion but is more effective if applied 12 hours before. Tell patient to discard patch after removing it and to wash application site thoroughly. Used in patients lacking such digestive substances as bile salts, gastric acid, or pancreatic enzymes, they can provide replacement therapy in specific deficiencies. The most widely used digestants are bile salts, hydrochloric acid, and pancreatic enzymes. Major Uses Bile salts are used to treat uncomplicated constipation and to help maintain normal cholesterol solubility in the bile. Dehydrochloric and ketochloric acids (synthetic bile salts) increase the solubility of cholesterol, preventing its buildup in recurring biliary calculi or strictures, recurring noncalculous cholangitis, biliary dyskinesia, and chronic partial obstruction of the common bile duct, prolonged drainage from biliary fistulas or drainage of infected bile duct through a T tube, and sclerosing choledochitis. Glutamic acid hydrochloride and dilute hydrochloric acid (gastric acidifiers) are used to treat hypochlorhydria and achlorhydria. Pancreatin and pancrelipase (enzymes) supplement or replace exocrine pancreatic secretions, which are lacking in such disorders as cystic fibrosis. Mechanism of Action Bile salts, dehydrocholic acid, and ketocholanic acid stimulate bile flow from the liver, promoting normal digestion and absorption of fats, fat soluble vitamins, and cholesterol. Pancreatin and pancrelipase replace endogenous exocrine pancreatic enzymes and aid intestinal digestion of starches, fats, and proteins. Absorption, Distribution, Metabolism and Excretion About 80% to 90% of bile salts are reabsorbed primarily in the ileum. As natural body substances, the rest of these digestants assume the normal physiology of the body. A progestin that inhibits hormone dependent tumor growth by inhibiting pituitary and adrenal steroidogenesis.

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The construction of the membrane from amphipathic lipid molecules forms a highly impermeable barrier to most polar and charged molecules buy grifulvin v 125 mg cheap, thereby preventing the loss of most water-soluble contents of the cell order 125 mg grifulvin v mastercard. This selective permeability presents a physical barrier to drug absorption grifulvin v 250mg with visa, limiting absorption to specific routes and mechanisms order grifulvin v toronto, as described below (see Section 1. A further important feature of epithelia for drug delivery is that the epithelial cells are bound together by several types of plasma membrane specializations, including desmosomes, gap junctions and junctional complexes (Figure 1. Desmosomes (macula adherens) are the commonest type of cell junction and are found at many intercellular sites, including cardiac muscle, skin epithelium and the neck of the uterus. At the desmosome, the opposing plasma membranes are separated by a gap in which many fine, transverse filaments are present. Desmosomes provide strong points of cohesion between cells and act as anchorage points for the cytoskeleton of each cell. Gap junctions (nexus) are broad areas of closely opposed plasma membranes, but there is no fusion of the plasma membranes and a narrow gap, of about 2 to 3 nm wide, remains. The “gap” is crossed by cytoplasmic filaments, which allow intracellular cytoplasm to transfer between cells. This type of cell junction not only functions as an adherent zone, but also permits the passage of ions and other small molecules (sugars, amino acids, nucleotides and vitamins). Junctional complexes comprise intercellular membrane specializations which encircle the cells, preventing access of luminal contents to the intercellular spaces. They are found between the cells of simple cuboidal (for example in the lungs) and simple columnar (for example in the gastrointestinal tract) epithelia, and lie immediately below the luminal surface. They are made up of three components: (i) tight junctions (zonula occludentes), which consist of small areas where the outer lamina of opposing plasma membranes are fused with one another, via specific proteins which make direct contact across the intercellular space. A fine mat of filamentous material is present on the cytoplasmic aspect of these junctions. Biochemical barriers 9 In addition to a physical barrier, the epithelia also present a biochemical barrier to drug absorption, in the form of degradative enzymes. For example, the gastrointestinal tract contains a wide array of enzymes, which are present in a variety of locations: • the lumen; • adsorbed to the mucus layer; • the brush-border (microvilli) of the enterocytes; • intra-cellular (free within the cell cytoplasm and within cellular lysosomes); • the colon (colonic microflora). Enzymes in the gut lumen include proteases, glycosidases and lipases, which are highly efficient at breaking down proteins, carbohydrates and fats from foodstuffs, so that they can be absorbed to make energy available to the body. However, these enzymes (and the enzymes present in the other locations in the gastrointestinal tract) can also degrade drug molecules, deactivating them prior to absorption. For example, the metabolizing enzyme cytochrome P450 on the microvillus tip is associated with a significant loss of drugs. Drugs that are orally absorbed must also first pass through the liver, via the portal circulation, prior to reaching the systemic circulation. The loss of drug activity due to metabolism in the gut wall and liver prior to reaching systemic circulation is termed the “first-pass” effect. In some cases this pre-systemic metabolism accounts for a significant, or even total, loss of drug activity. Thus the gastrointestinal tract poses a formidable challenge to the delivery of enzymatically labile drugs, such as therapeutic peptides and proteins. The extremely high metabolic activity of the gastrointestinal tract has been a major impetus in the exploration of alternative routes for systemic drug delivery. In comparison to the oral route, much less is known about the nature of the enzymatic barrier presented by the buccal, nasal, pulmonary, dermal and vaginal routes. However, it is generally accepted that such routes have a lower enzymatic activity, particularly towards drugs such as peptides and proteins. Furthermore, such routes also offer the advantage of avoiding first-pass metabolism by the liver. Efflux systems In recent years, it has been found that the barrier function of the intestinal epithelium cannot be adequately described by a combination of metabolic and physical barriers alone. Apically polarized efflux systems are known to be present in cancer cells and represent a major barrier to the uptake of a wide variety of chemotherapeutic agents (i. Efflux systems have also now been identified in normal intestinal and colonic cells, and also at other epithelial sites. Some of these efflux systems seem to involve P-glycoprotein, the principal component of multidrug resistance in a variety of cell types. As these efflux systems are located on the apical surface of the plasma membrane, it can be assumed that their physiological role is to restrict transcellular flux of some molecules. The rate of passive diffusion follows Fick’s Law, which is described in detail below. Passive diffusion is driven by a concentration gradient and is inversely related to molecular weight. This route is therefore not suitable for large molecular weight drugs, which are too large to cross between cell junctions. One approach to enhancing drug absorption via this route is to temporarily damage the integrity of the tight junctions using certain types of penetration enhancers. Obviously this approach has considerable toxicological implications, both directly, by damaging the epithelial interface and also indirectly, by increasing the permeability of the epithelium, thereby increasing the possibility of entry of potentially harmful substances. Transcellular passive diffusion Low molecular weight and lipophilic drug molecules are usually absorbed transcellularly, by passive diffusion across the epithelial cells. With respect to passive diffusion, the outer membrane of the epithelial cell may be regarded as a layer of lipid, surrounded on both sides by water (Figure 1. Thus for transport through the apical membrane, there are three barriers to be circumvented: • the external water-lipid interface; • the lipid membrane; • the internal lipid-water interface. In the process of passive diffusion: • lipid-soluble substances move into the lipid membrane according to their lipid/water partition coefficient; • molecules then diffuse across the lipid phase according to the concentration gradient established between the apical and basolateral sides of the membrane; • the molecules distribute out at the other side of the membrane, according to their lipid/water partition coefficient. The rate of diffusion through the membrane follows Fick’s Law, which states that the rate of diffusion across a membrane is proportional to the difference in concentration on each side of the membrane: (Equation 1. C –C where C and C denote the drug concentrations on the outsideo i o i and the inside of themembrane, respectively. Thus a drug molecule, driven by the concentration gradient, diffuses through the apical cell membrane and gains access to the inside of the cell. The molecule then diffuses through the epithelial cell and subsequently diffuses out through the basolateral membrane, to be absorbed by the underlying blood capillaries (Figure 1. Another possibility is that certain drugs, of appropriate partition coefficients, would preferentially remain within the lipid bilayer of the plasma membrane, rather than partitioning out into the cell cytoplasm. Such moieties could thus diffuse along the lipid bilayer of the membrane, down the side of the cell (rather than through it), emerging finally at the basolateral surface of the cell. However this scenario is limited by the fact that the lipid membrane constitutes a minute proportion of the available surface area of the cell; also cell junctions can act as diffusion barriers within the lipid bilayer of the plasma membrane. In some cases, for example in stratified epithelia such as that found in the skin and buccal mucosa, the epithelial barrier comprises a number of cell layers rather than a single epithelial cell. Thus the effective barrier to drug absorption is not diffusion across a single membrane as described above, but diffusion across the entire epithelial and endothelial barrier, which may comprise several membranes and cells in series. The driving force for absorption is, again, the concentration gradient and the process is governed by Fick’s Law. However, in this case, the concentration gradient driving absorption comprises the gradient established across the entire effective barrier, from the epithelial surface to the circulating blood. It should be noted, however, that even though the barrier to drug absorption may actually comprise several membranes and cells in series, it would appear that, generally, it is ultimately the apical plasma membrane which is rate-limiting for drug absorption. Thus in transcellular passive diffusion, the epithelium is assumed to act as a simple lipophilic barrier through which drugs diffuse and the rate of diffusion correlates with the lipid solubility of the drug. The circulating concentration of the drug is reduced by one or more of the following factors: • distribution into body tissue and other fluids of distribution; • binding to plasma proteins; • metabolism and excretion. As a consequence, the concentration of drug in systemic circulation is negligible in comparison to the drug concentration at the absorption surface. When sink conditions occur, it ensures that a large concentration gradient is maintained throughout the absorption phase, thereby enhancing the driving-force for absorption. In active absorption, carriers may transport substrates against a concentration gradient, in an energy- consuming process. This form of transport may occur through “dynamic pores”, consisting of proteins or protein systems which span the plasma membrane.

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