Chapter 12 the target site so that the antimicrobial binds less effectively. More is becoming known of the complex molecular systems which control expression of antimicrobial resistance, and this knowledge should soon lead to novel compounds that inhibit resistance mechanisms at the genetic and phenotypic levels (see Stix13 for an example). Performing ward rounds on areas of the hospital with high rates of antibiotic use. Constant monitoring of resistance patterns in a hospital or community (changing recommended antibiotics used for empirical treatment when the prevalence of resistance becomes high), and good infection control in hospitals. Avoiding transmission of multiply resistant bacteria among patients and staff in hospital, by health-care workers performing careful hand hygiene between each patient contact, and through identification and isolation of carriers. Some bacteria are innately resistant to certain classes of antimicrobial agent. Facultatively anaerobic bacteria (such as Escherichia coli) lack the ability to reduce the nitro group of metronidazole which therefore remains in an inactive form. Spontaneous mutation brings about organisms with novel antibiotic resistance mechanisms. If these cells are viable, in the presence of the antimicrobial agent selective multiplication of the resistant strain occurs so that it eventually dominates. Transmission of genes from other organisms is the commonest and most important mechanism. Alternatively, genetic transfer may occur through bacteriophages (viruses which infect bacteria), particularly in the case of staphylococci. Other mechanisms include decreasing the passage into or increasing the efflux of drug from the bacterial cell. But careful clinical assessment of the patient is essential, as the mere presence of such organisms in diagnostic specimens taken from a site in which they may be present as commensals does not necessarily mean they are causing disease. Doctors are encouraged to avoid use of antimicrobial agents whenever possible, and international efforts are being made to educate the general public not to expect an antibiotic prescription for minor ailments such as coughs and colds (see, for example. Evidence is accumulating that resistance rates do not rise inevitably and irreversibly (see page 169). In this case, use of any of these antibiotics will select for increased resistance via all the mechanisms carried by the plasmid. Antibiotic-associated (or Clostridium difficileassociated) colitis is an example of a superinfection. It is caused by alteration of the normal bowel flora, which allows multiplication of Clostridium difficile which releases several toxins that damage the mucosa of the bowel and promote excretion of fluid. Almost any antimicrobial may initiate this condition, but the drugs most commonly reported today are cephalosporins and quinolones. It takes the form of an acute colitis (pseudomembranous colitis) with diarrhoeal stools containing blood or mucus, abdominal pain, leucocytosis and dehydration. A history of antibiotic use in the previous 3 weeks, even if the drug therapy has been stopped, should alert the physician to the diagnosis which is confirmed by detection of C. Some strains have been associated with particularly severe disease and have caused large outbreaks in hospitals combined therapy with oral vancomycin and parenteral metronidazole plus intensive care support is required for the most serious cases. Other therapeutic and preventative measures of unproven efficacy include intracolonic instillation of vancomycin, intravenous immunoglobulin and oral probiotics. Diarrhoea in some cases can be intractable, and desperate measures have included instillation of microbiologically screened donor faeces in an attempt to restore a normal balance of the gut flora in some cases with surprisingly good response rates of over 80% in therapeutic trials. Antimicrobial agents used instead that seem to carry a lower risk of causing colitis have included co-amoxiclav and piperacillin-tazobactam. Often, this causes no ill effects, but sometimes a drug-resistant organism, freed from Garborg K, Waagsb B, Stallemo A et al 2010 Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhoea. Such infections may involve organisms that rarely or never cause clinical disease in normal hosts. Treatment of possible infections in such patients should be prompt, initiated before the results of bacteriological tests are known, and usually involve combinations of bactericidal drugs administered parenterally. Local defences may also be compromised and allow opportunistic infection with lowly pathogens even in otherwise healthy hosts: the best example is Staphylococcus epidermidis infection of intravenous catheters. Detailed guidance, intended for use by primary care physicians in England and including evidence-based recommendations on antibiotic choice for particular infections and extensive reference lists, is available via the Health Protection Agency website. We also recommend section 5 of the Electronic British National Formulary bnf. Masking of infections Masking of infections by chemotherapy is an important possibility.
The illness often initially affects people during late adolescence or early adulthood and is a chronic and disabling disorder. Schizophrenia has a strong genetic component and probably reflects some fundamental biochemical abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neurons. Neuroleptic Drugs the neuroleptic drugs represent several diverse, heterocyclic structures with markedly different potencies. Furthermore, these more potent traditional drugs are no more effective than chlorpromazine. Dopamine receptorв"blocking activity in the brain: All of the older and most of the newer neuroleptic drugs block dopamine receptors in the brain and the periphery (Figure 13. D1 and D5 receptors activate adenylyl cyclase, often exciting neurons, whereas D2, D3 and D4 receptors inhibit adenylyl cyclase, or mediate membrane K+ channel opening leading to neuronal hyperpolarization. However, the clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain. Actions the antipsychotic actions of neuroleptic drugs appear to reflect a blockade at dopamine and/or serotonin receptors. However, many of these agents also block cholinergic, adrenergic, and histaminergic receptors (Figure 13. It is unknown what role, if any, these actions have in alleviating the symptoms of psychosis. The undesirable side effects of these agents, however, are often a result of actions at these other receptors. Antipsychotic actions: All of the neuroleptic drugs can reduce the hallucinations and delusions associated with schizophrenia (the so-called P. The вoenegativeв symptoms, such as blunted affect, anhedonia (not getting pleasure from normally pleasurable stimuli), apathy, and impaired attention, as well as cognitive impairment are not as responsive to therapy, particularly with the typical neuroleptics. Many atypical agents, such as clozapine, ameliorate the negative symptoms to some extent. All of the drugs also have a calming effect and reduce spontaneous physical movement. The antipsychotic effects usually take several days to weeks to occur, suggesting that the therapeutic effects are related to secondary changes in the corticostriatal pathways. Extrapyramidal effects: Dystonias (sustained contraction of muscles leading to twisting distorted postures), parkinson-like symptoms, akathisia (motor restlessness), and tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs) occur with chronic treatment. Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted movement symptoms. Other effects: Blockade of О±-adrenergic receptors causes orthostatic hypotension and light-headedness. The neuroleptics also alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment). In the pituitary, neuroleptics block D2 receptors, leading to an increase in prolactin release. Sedation occurs with those drugs that are potent antagonists of the H1-histamine receptor, including chlorpromazine, olanzapine, quetiapine, and clozapine. Sexual dysfunction may also occur with the antipsychotics due to various receptorbinding characteristics. Treatment of schizophrenia: the neuroleptics are considered to be the only efficacious treatment for schizophrenia. Not all patients respond, and complete normalization of behavior is seldom achieved. The traditional neuroleptics are most effective in treating positive symptoms of schizophrenia (delusions, hallucinations, thought processing, and agitation). However, even the atypical antipsychotics do not consistently improve the negative symptoms of schizophrenia more than the older agents. Prevention of severe nausea and vomiting: the older neuroleptics (most commonly prochlorperazine) are useful in the treatment of drug-induced nausea (see p. Nausea arising from motion should be treated with sedatives, antihistamines, and anticholinergics, however, rather than with the powerful neuroleptic drugs. Other uses: the neuroleptic drugs can be used as tranquilizers to manage agitated and disruptive behavior secondary to other disorders. Neuroleptics are used in combination with narcotic analgesics for treatment of chronic pain with severe anxiety. However, risperidone and haloperidol are also commonly prescribed for this tic disorder.
They thus inhibit the synthesis of bacterial dihydrofolic acid and, thereby, the formation of its essential cofactor forms. Antibacterial spectrum Sulfa drugs are active against selected enterobacteria in the urinary tract and nocardia. Resistance Only organisms that synthesize their folate requirements de novo are sensitive to the sulfonamides. Thus, humans, who synthesize critical folate cofactors from dietary folic acid, are not affected, and bacteria that can obtain folates from their environment are naturally resistant to these drugs. Administration: After oral administration, most sulfa drugs are well absorbed via the small intestine (Figure 33. Absorption of the sulfapyridine can lead to toxicity in patients who are slow acetylators (see below). Furthermore, mafenide can be absorbed in burn patients, causing an increased risk of acid-base imbalance. The product is devoid of antimicrobial activity but retains the toxic potential to precipitate at neutral or acidic pH. This causes crystalluria (вoestone formationв; see below) and, therefore, potential damage to the kidney. Therefore, depressed kidney function causes accumulation of both the parent compounds and their metabolites. Adequate hydration and alkalinization of urine prevent the problem by reducing the concentration of drug and promoting its ionization. Hypersensitivity: Hypersensitivity reactions, such as rashes, angioedema, and Stevens-Johnson syndrome, are fairly common. Hemopoietic disturbances: Hemolytic anemia is encountered in patients with glucose 6-phosphate dehydrogenase deficiency. Kernicterus: this disorder may occur in newborns, because sulfa drugs displace bilirubin from binding sites on serum albumin. Drug potentiation: Transient potentiation of the hypoglycemic effect of tolbutamide or the anticoagulant effect of warfarin results from their displacement from binding sites on serum albumin. Contraindications: Due to the danger of kernicterus, sulfa drugs should be avoided in newborns and infants less than 2 months of age as well as in pregnant women at term. Trimethoprim is most often compounded with sulfamethoxazole, producing the combination called cotrimoxazole. Mechanism of action the active form of folate is the tetrahydro-derivative that is formed through reduction of dihydrofolic acid by dihydrofolate reductase. Antibacterial spectrum the antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. Resistance Resistance in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has a lower affinity for trimethoprim. Overproduction of the enzyme may also lead to resistance, because this can decrease drug permeability. Pharmacokinetics the half-life of trimethoprim is similar to that of sulfamethoxazole. However, because the drug is a weak base, higher concentrations of trimethoprim are achieved in the relatively acidic prostatic and vaginal fluids. Trimethoprim undergoes some O-demethylation, but most of it is excreted unchanged through the kidney. These blood disorders can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria. The combination was selected because of the similarity in the half-lives of the two drugs. Antibacterial spectrum Cotrimoxazole has a broader spectrum of antibacterial action than the sulfa drugs (Figure 33. Resistance Resistance to the trimethoprim-sulfamethoxazole combination is less frequently encountered than resistance to either of the drugs alone, because it would require that the bacterium have simultaneous resistance to both drugs. Pharmacokinetics Trimethoprim is more lipid soluble than sulfamethoxazole and has a greater volume of distribution. Administration of one part trimethoprim to five parts of the sulfa drug produces a ratio of the drugs in the plasma of twenty parts sulfamethoxazole to one part trimethoprim. An exception involves intravenous administration to patients with severe pneumonia caused by P. Dermatologic: Reactions involving the skin are very common and may be severe in the elderly (Figure 33.
Adenovirus infections have a greater severity of illness in the immunocompromised. Hierholzer (1992) report a case-fatality rate of 53% for adenovirus infection in people with reduced immune function due to cancer treatment. This suggests that the enteric adenoviruses may survive for prolonged periods in water, representing a potential route of transmission (Enriquez and Gerba 1995). Epidemics of pharyngoconjunctival fever are associated with waterborne transmission of some adenovirus types. These are generally recorded from inadequately chlorinated swimming pools (Heinz et al. Most surveillance studies of adenovirus infections have been conducted in developed countries. Although the virus could not be isolated from the pool water, the author speculated that faecal contamination of the unchlorinated water could have been the source of the contamination. Viral culture of conjunctival and throat swabs of eight cases were positive for adenovirus type 7. Adenovirus type 4 was the causative agent of an outbreak of pharyngoconjunctivitis in users of a private swimming pool in Georgia, United States in the summer of 1977. Among members the attack rate was significantly higher in those who had used the pool (P<0. The virus was detected in samples of pool water and isolated from 20 of 26 swab specimens. At least 54 cases were identified with symptoms such as sore throat, fever, headache and anorexia. The outbreak coincided with a temporary defect in the pool filter system and inadequate maintenance of the chlorine levels. A telephone survey indicated that persons who swum at the community swimming pool were more likely to be ill than those that did not. Those who swallowed water were more likely to be ill than those that did not (relative risk 2. An outbreak of pharyngoconjunctival fever at a summer camp in North Carolina, United States was reported in July 1991 (Anonymous 1992). An epidemiological investigation identified the cause as pharyngoconjunctival fever associated with infection with adenovirus type 3. Approximately 700 persons swam every day in a one-acre man-made pond into which well water was continuously pumped. The attack rate for campers who swam daily (48%) did not differ significantly from that for campers who swam less than once per week (65%; relative risk 0. The attack rate for staff who swam was higher than that for staff who did not swim (77% versus 54%; relative risk 1. Of the 221 campers and staff members interviewed, 75 reported they had shared a towel with another person. Towel sharing increased the risk for illness (11 of 12 who shared versus 31 of 63 who did not; relative risk 1. A concentrated sample of pond water drawn approximately six feet below the surface yielded adenovirus serotype 3. An outbreak of pharyngoconjunctivitis amongst competitive swimmers in southern Greece caused by adenovirus is reported by Papapetropoulou and Vantarakis (1998). At least 80 persons showed symptoms of fever, sore throat, conjunctivitis, headache and abdominal pain. There was a strong correlation between the development of symptoms and having been swimming on a recent school camp. Although adenovirus could not be isolated from the swimming pool water from the camp, it was found that the swimming pool was not adequately chlorinated or maintained and it was concluded that it was probable that adenovirus infection was transmitted via the swimming pool water. Adenovirus infections are generally mild; however, there are a number of fatal cases of infection reported in the literature. Transmission of adenovirus in recreational 198 Water Recreation and Disease waters, primarily inadequately chlorinated swimming pools, has been documented via faecally-contaminated water and through droplets, although no fatal cases attributable to recreational waters have been documented in the literature. There are 23 serotypes of coxsackie A viruses and at least six serotypes of coxsackie B virus (King et al.
The hypothesis about the pathophysiology is still a subject for debate, and the most accepted is a vascular mechanism secondary to ischemic lesions (9). The clinical symptoms often include transverse myelitis with severe motor and sensory dysfunction. Moreover, it has been found that the central high-signal spinal lesion in T2 sequences, oc- a b Figure 17. Forty-four-year old patient with demyelinating disease and proven neurological decline. Granados A; Garcнa L; Ortega C; Lуpez A review articles cupying two-thirds of the spinal cord in axial sections, extends over three or four segments and shows variable gadolinium enhancement (22,25). Angiotensin-converting enzyme elevation is suggestive of the diagnosis but is not specific. A satisfactory response to empirical steroid treatment, during months or even years, suggests the diagnosis (6). Post-radiation or electric damage Neurotoxicity is a known complication of high-dose radiation. The deep white matter is the most affected since it comprises the cortex and the subcortical arcuate fibers. There are three forms of lesions: acute (weeks or months), early late and late (six months to two years). The latter may be irreversible, progressive and, on occasions, fatal; however, it may resolve spontaneously in some cases (52,53). It is a rare cause of acute myelopathy, accounting for only 2% of complications, and it is suggested in cases where there is a history of exposure to head and neck a b Figure 18. It may have an early manifestation ten to sixteen weeks into radiotherapy, or a late manifestation, and may resolve spontaneously between two and nine months after onset (9). In the early stages, there is evidence of edema or spinal enhancement and, in late cases, spinal atrophy is observed (8). The transient sensory loss gives an electric-shock sensation when the neck is flexed forward (Lhermitte sign) and it resolves within two and thirty-six weeks. In chronic progressive myelopathy, it presents like a Brown Sйquard syndrome lasting between three months and five years. After this time, the signal intensity is normal and there is severe atrophy, with or without persistent enhancement that diminishes after 24 months (22) (Figure 19). Patient with a history of radiotherapy due to esophageal cancer who complains of paresthesias and discreet loss of strength in the lower limbs, and Lhermitte sign. Subacute combined degeneration Combined subacute degeneration is a complication of vitamin B12 deficiency, associated with pernicious anemia. This deficiency may be related to parietal-cell autoantibodies or the intrinsic factor required for vitamin B12 binding. There is a genetic deficiency of transcobalamin 2 (cobalamin transporter protein). The complete transcobalamin 2 deficiency is a recessive autosomal condition characterized by normal concentrations of vitamin B12 with severe infantile megaloblastic anemia associated with neurologic damage (54). The clinical picture presents as a slowly-progressing spastic paraparesis with distal proprioceptive loss and symmetrical dysesthesias (54). The absence of anemia with or without macrocytosis does not rule out a vitamin B12 deficiency diagnosis. The mean time to diagnosis since the onset of neurological symptoms due to vitamin B12 deficiency is approximately on year, with a range that extends to four years (54) (Figure 20). Acute paraneoplastic or necrotizing myelitis Paraneoplastic myelopathy is a rare disease. The lesion often involves the thoracic spinal cord that shows a high-intensity signal in T2 sequences and gadolinium enhancement. Low concentrations of vitamin B12 were found, pointing to the diagnosis of myelopathy due to vitamin B12 deficiency. A prospective survey of the causes of non-traumatic spastic paraparesis and tetraparesis in 585 patients. Increased signal intensity of the spinal cord on magnetic resonance images in cervical compressive myelopathy. Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients.
Halfway houses provided by the state are considered extensions of the hospitals, and the rates are the same. We have also investigated social camps and have been quoted rates of as much as $1000 per month. If a community mental health center is nearby, the patient can frequently be treated at home after the diagnosis is established. The public health nurse may also be able to give relatives valuable advice in regard to local treatment facilities. In New Jersey, under the Beadleson Act, the homebound patient is entitled to continued schooling. The sedation was produced by hot baths or packs, paraldehyde, sodium amytal, or morphine-scopolamine. Every means was needed to keep the patient from dying of acute psychotic exhaustion. In spite of rotating methods of sedative therapy, tube feeding, and hot packs, many patients died. Odegard, in a study involving Norwegian hospitals, says: "This was the period of mental hygiene: prevention was stressed, because the prognosis was so bad for fully fledged mental disorders. The high hopes of a prevention have hardly been fulfilled even today, whereas the dramatic improvement in therapeutic results was quite unexpected. Starting from 1935, the discharge rate was doubled in five years, and in ten years it was trebled. The real change was in the severe schizophrenics who might otherwise have remained hospitalized for years or their lifetime. They found that a single convulsion could be safely produced by the application of an alternating current to the head. Both of these therapies shortened hospitalization or produced complete remission of the disease in some patients. When given in moderation, no more often than every other day to the nondominant side of the brain (the right side in right-handed and the left side in left-handed patients), the treatment may be well tolerated but it can also get out of hand. We know from treating epileptics that the seizures of epilepsy will decorticate (produce a vegetable) a young patient by the age of six years. The goal in epilepsy is to reduce the harmful seizures to no more than one a week. Electrically-induced seizures are just as debilitating to the brain as is grand mal epilepsy, and so should be limited. It is indeed sad that the middle-class, insurance paying, employed patients with allergies and depression are getting a dubious quick fix rather than adequate diagnosis and treatment. Instead of receiving gentle drug treatments, these five patients had five points taken off their I. Today we know that many psychotic patients are merely that way due to biochemical imbalances. Today, one must adopt a philosophy of treatment wherein all therapeutic measures are used in a progressive fashion to either prevent hospitalization or restore a hospitalized patient to community living. The first move should be talking therapy of a supportive nature, reduction of environmental stress, and mega-nutrient therapy. Only after these have been tried, should antipsychotic drugs be included alongside the nutrients. Is the patient taking basic nutrients at doses that will combat environmental stress? Only if none of these alternative diagnoses prove positive, and severe suicidal depression or severe psychotic symptoms remain, should electroconvulsive therapy begin. In such cases, it may be the only treatment available and then may be ineffective! For some time they were described as the "major" tranquilizers to distinguish them from the "minors" of the antianxiety type.
Our study analyzed the additional risk factors which could move the patients to elevated or higher risks in spite being normolipidemic. It was found that there are additional risks which are missed out or not evaluated in normal routine follow up in patients. Additionally it was found that there is interplay of oxidants and anti-oxidants and balance between these two components were disrupted leading to higher levels of conjugated dienes, malondialdehyde and lower levels of antioxidants namely uric acid, bilirubin, superoxide dismutase, glutathione peroxidase and catalase [5]. Research studies have also linked adiponectin levels with insulin resistance, dyslipidemia, abdominal 2 this article is available from: In a tertiary health care setup, apart from analyzing lipid parameters, one should look for additional risk factor analysis which could be feasible and cost effective for patients so that the risk stratification can be evaluated well in advance and proper advice can be conveyed to the patients. In order to overcome the risk of cardiovascular disease, we need to change the life style which is an important area to look upon. We must incorporate more of folic acid and vitamin B12 and B6 which can breakdown or decrease homocysteine levels in circulation. In order to prevent the heavy cost incurred in Intensive coronary care unit and the agony of death in family members, we can take precautionary measures and improve our quality of life style. Cardiovascular Risk Factors in Elderly Normolipidemic Acute Myocardial Infarct patients. Cardiovascular risk factor trends and potential for reducing coronary heart disease mortality in the United States of America. Oxidative Stress, Endogenous Antioxidant and Ischemia-modified Albumin in Normolipidemic Acute Myocardial Infarction Patients. Serum Caeruloplasmin as a Coronary Risk Factor in Patients with Acute Myocardial Infarction with Normal Lipid Profile. Emerging Biomarkers for Evaluating Cardiovascular Risk in the Chronic Kidney Disease Patient: How Do New Pieces Fit into the Uremic Puzzle? Scope of this journal includes: Biochemistry, Biomedical sciences, Biotechnology, Microbiology, Molecular biology and Genetics. Secondary research including narrative reviews, systematic reviews, evidencebased articles, meta-analysis, practice guidelines will also be considered for publication. From time to time invited articles, editorials and review of selected topics will be published. Conclusions · As a specialty, we address all aspects of vascular disease · Can create the career you want! No part of this publication may be reproduced or transmitted, in any form or by any means, electronic, photocopying or otherwise without prior permission of the publishers. Health professionals and teachers may make photocopies for educational purposes only, provided that no charge or profit is made for any course or event for which they are used. The mission of the European Heart Network is to play a leading role in the prevention and reduction of cardiovascular diseases, in particular heart disease and stroke, through advocacy, networking, education and patient support, so that they are no longer a major cause of premature death and disability throughout Europe. It comprises 6 Associations, 5 Councils, 18 Working Groups covering a wide variety of sub-specialities as well as 55 National Cardiac Societies in European and Mediterranean countries, all involved in the advancement of knowledge of diseases of the heart and circulation. This fourth edition is published jointly by the European Heart Network, the European Society of Cardiology and the British Heart Foundation Health Promotion Research Group, Department of Public Health, University of Oxford. The differences are greatest between Northern, Southern and Western European countries and Central and Eastern European Countries. However, policy makers need to consider the differences and take a close look at risk factor prevalence and trends. Differences between Southern and Western European countries may persist but they are narrowing. The data presented in the fourth edition of European Cardiovascular Disease Statistics show that our efforts to reduce mortality from cardiovascular diseases have been successful. A read through the chapters of the European Cardiovascular Disease Statistics confirms that Europe suffers badly from lack of data and, particularly, lack of comparable data. This is true for prevalence and incidence rates, rates of surgical procedures as well as for diets. The European Union has an important task in developing standard methods for collecting information or agreed procedures for calibration of locally appropriate methods and questionnaires, to ensure effective service planning and quality of care for patients across the European Union.
Individual pharmacokinetic processes Drug absorption into, distribution around, metabolism by and elimination from the body are reviewed. Plasma concentration monitoring has proved useful: · As a guide to the effectiveness of therapy. To reduce the risk of adverse drug effects when therapeutic doses are close to toxic doses (low therapeutic index). When the desired effect is suppression of infrequent sporadic events such as epileptic seizures or episodes of cardiac arrhythmia. To check patient compliance on a drug regimen, when there is failure of therapeutic effect at a known effective dose. Digoxin is both a treatment for, and sometimes the cause of, cardiac supraventricular tachycardia; a plasma digoxin measurement will help to distinguish whether an arrhythmia is due to too little or too much digoxin. Usually these are: · · · · · · Enteral: by mouth (swallowed) or by sublingual or buccal absorption; by rectum. Recommended plasma concentrations for drugs appear throughout this book where these are relevant but the following points ought to be kept in mind: Absorption from the gastrointestinal tract the small intestine is the principal site for absorption of nutrients and it is also where most orally administered drugs enter the body. This part of the gut has an enormous surface area due to the intestinal villi, and an epithelium through · the target therapeutic concentration range for a drug is a guide to optimise dosing together with other clinical indicators of progress. Factors influencing systemic availability present in three main ways, as described below. Additionally, it is becoming apparent that uptake and efflux transporters in enterocytes (see p. Absorption of ionisable drugs from the buccal mucosa responds to the prevailing pH, which is 6. Lipidsoluble drugs are rapidly effective by this route because blood flow through the mucosa is abundant; these drugs enter directly into the systemic circulation, avoiding the possibility of first-pass (presystemic) inactivation by the liver and gut (see below). The stomach does not play a major role in absorbing drugs, even those that are acidic and thus un-ionised and lipid soluble at gastric pH, because its surface area is much smaller than that of the small intestine and gastric emptying is speedy (tЅ 30 min). Pharmaceutical factors7 the amount of drug released from a dose form (and so becoming available for absorption) is referred to as its bioavailability. With tablets, for example, particle size (surface area exposed to solution), diluting substances, tablet size and pressure used in the tabletting process can affect disintegration and dissolution and so the bioavailability of the drug. Manufacturers must test their products to ensure that their formulations release the same amount of drug at the same speed from whatever manufactured batch or brand the patient may be taking. Differences in bioavailability are prone to occur with modified-release (m/r) formulations, i. Modified-release preparations from different manufacturers may differ in their bioavailability profiles despite containing the same amount of drug, i. Physicians tend to ignore pharmaceutical formulation as a factor in variable or unexpected responses because they do not understand it and feel entitled to rely on reputable manufacturers and official regulatory authorities to ensure provision of reliable formulations. Good pharmaceutical companies reasonably point out that, having a reputation to lose, they take much trouble to make their preparations consistently reliable. This is a matter of great importance when dosage must be precise (anticoagulants, antidiabetics, adrenal corticosteroids). Tablet: a solid dose form in which the drug is compressed or moulded with pharmacologically inert substances (excipients); variants include sustained-release and coated tablets. Suppository: a solid dose form shaped for insertion into rectum (or vagina, when it may be called a pessary); it may be designed to dissolve or it may melt at body temperature (in which case there is a storage problem in countries where the environmental temperature may exceed 37 C); the vehicle in which the drug is carried may be fat, glycerol with gelatin, or macrogols (polycondensation products of ethylene oxide) with gelatin. Several drugs form conjugates with glucuronic acid in the liver and enter the bile. Too polar (ionised) to be reabsorbed, the glucuronides remain in the gut, are hydrolysed by intestinal enzymes and bacteria, and the parent drug, thus released, is reabsorbed and reconjugated in the liver. Enterohepatic recycling appears to help sustain the plasma concentration and so the effect of sulindac, pentaerithrityl tetranitrate and ethinylestradiol (in many oral contraceptives). Systemic availability and bioavailability A drug injected intravenously enters the systemic circulation and thence gains access to the tissues and to receptors, i. If the same quantity of the drug is swallowed, it does not follow that the entire amount will reach first the portal blood and then the systemic blood, i. The anticipated response to a drug must take account of its availability to the systemic circulation.
References:
