Jennifer L. Martin, PhD

• Research Health Scientist and Psychologist, VA Greater
• Los Angeles Healthcare System Sepulveda Ambulatory
• Care Center
• Assistant Research Professor, University
• of California, Los Angeles, CA, USA

It is similar to thiopentone asthma treatment 4 syphilis order singulair with a visa, 3 times more potent asthma ventilator singulair 4 mg amex, has a quicker and briefer (5­8 min) action asthma symptoms for a 2 year old 10 mg singulair order fast delivery. It is more rapidly metabolized (t½ 4 hr) than thiopentone: patient may be roadworthy more quickly asthma treatment with antibiotics generic 5 mg singulair free shipping. Elimination t½ (100 min) is much shorter than that of thiopentone due to rapid metabolism asthmatic bronchitis jaw buy singulair with a visa. Intermittent injection or continuous infusion of propofol is frequently used for total i. It lacks airway irritancy and is not likely to induce bronchospasm: preferred in asthmatics. It is particularly suited for outpatient surgery, because residual impairment is less marked and shorter-lasting. Incidence of postoperative nausea and vomiting is low; patient acceptability is very good. However, it is not approved for such use in children; prolonged sedation with higher doses has caused severe metabolic acidosis, lipaemia and heart failure even in adults. If no other anaesthetic or opioid is given, the patient becomes responsive in 1 hr or so due to redistribution of the drug (distribution t½ of diazepam is 15 min), but amnesia persists for 2­3 hr and sedation for 6 hr or more. Also used for sedation of intubated and mechanically ventilated patients and in other critical care anaesthesia as 0. Ketamine this unique anaesthetic is pharmacologically related to the hallucinogen phencyclidine. Respiration is not depressed, bronchi dilate, airway reflexes are maintained, muscle tone increases. Emergence delirium, hallucinations and involuntary movements occur in upto 50% patients during recovery; but the injection is not painful. Ketamine has been used for operations on the head and neck, in patients who have bled, in asthmatics (relieves bronchospasm), in those who do not want to lose consciousness and for short operations. Combined with diazepam, it has found use in angiographies, cardiac catheterization and trauma surgery. It may be dangerous for hypertensives, in ischaemic heart disease (increases cardiac work), in congestive heart failure and in those with raised intracranial pressure (ketamine increases cerebral blood flow and O2 consumption), but is good for hypovolemic patients. Respiratory depression is marked, but predictable; the patient may be encouraged to breathe and assistance may be provided. Tone of chest muscles and masseters may increase with rapid fentanyl injection: a muscle relaxant is then required to facilitate mechanical ventilation. Supplemental doses of fentanyl are needed every 30 min or so, but recovery is prolonged after repeated doses. The opioid antagonist naloxone can be used to counteract persisting respiratory depression and mental clouding. Fentanyl is also employed as adjunct to spinal and nerve block anaesthesia, and to relieve postoperative pain. Alfentanil, Sufentanil and remifentanil are still shorter acting analogues which can be used in place of fentanyl. Dexmedetomidine Activation of central 2 adrenergic receptors has been known to cause sedation and analgesia. Clonidine (a selective 2 agonist antihypertensive) given before surgery reduces anaesthetic requirement. Dexmedetomidine is a centrally active selective 2A agonist that has been introduced for sedating critically ill/ventilated patients in intensive care units. Analgesia and sedation are produced with little respiratory depression, amnesia or anaesthesia. It allows the operative procedure to be performed with minimal physiologic and psychologic stress. Fentanyl this highly lipophilic, short acting (30­50 min) potent opioid analgesic related to pethidine (see Ch. This permits use of lower anaesthetic concentrations with better haemodynamic stability. Further injection is stopped, after which this state lasts for about 1 hour and psychomotor impairment persists for 6­24 hours; an escort is needed to take the patient back to home. Oral diazepam administered 1 hr before is also used with the limitation that level of sedation cannot be titrated. Advantage is that level of sedation can be altered during the procedure and recovery is relatively quick, permitting early discharge of the patient. Nitrous oxide the patient is made to breathe 100% oxygen through a nose piece or hood and N2O is added in 10% increments (to a maximum of 50%, rarely 70%) till the desired level of sedation assessed by constant verbal contact is obtained. Cognitive defects: prolonged excess cognitive decline has been observed in some patients, especially the elderly, who have undergone general anaesthesia, particularly of long duration. Neuroleptics, opioids, clonidine and monoamine oxidase inhibitors potentiate anaesthetics. If a patient on corticosteroids is to be anaesthetized, give 100 mg hydrocortisone intraoperatively because anaesthesia is a stressful state-can precipitate adrenal insufficiency and cardiovascular collapse. Relief of anxiety and apprehension preoperatively and to facilitate smooth induction. Supplement analgesic action of anaesthetics and potentiate them so that less anaesthetic is needed. Decrease acidity and volume of gastric juice so that it is less damaging if aspirated. Sedative-antianxiety drugs Benzodiazepines like diazepam (5­10 mg oral) or lorazepam (2 mg oral or 0. Midazolam is a good amnesic with potent and shorter lasting action; it is also better suited for i. Other disadvantages are lack of amnesia, flushing, delayed gastric emptying and biliary spasm. Morphine particularly contributes to postoperative constipation, vomiting and urinary retention. The main aim of their use now is to prevent vagal bradycardia and hypotension (which occur reflexly due to certain surgical procedures), and prophylaxis of laryngospasm which is precipitated by respiratory secretions. Hyoscine, in addition, produces amnesia and antiemetic effect, but tends to delay recovery. Glycopyrrolate is twice as potent and longer acting quaternary antimuscarinic which does not produce central effects. Antisecretory action is more marked than atropine, while tachycardia is less marked, especially after i. Neuroleptics Chlorpromazine (25 mg), triflupromazine (10 mg) or haloperidol (2­4 mg) i. However, they potentiate respiratory depression and hypotension caused by the anaesthetics and delay recovery. Domperidone is nearly as effective and does not produce extrapyramidal side effects. It is practically devoid of side effects and has become the antiemetic of choice in anaesthetic practice. H2 blockers/proton pump inhibitors Patients undergoing prolonged operations, caesarian section and obese patients are at increased risk of gastric regurgitation and aspiration pneumonia. Ranitidine (150 mg)/famotidine (20 mg) or omeprazole (20 mg)/pantoprazole (40 mg) given night before and in the morning benefit by raising pH of gastric juice and may also reduce its volume and thus chances of regurgitation. Pharmacology of alcohol is important for its presence in beverages (which have been used since recorded history), alcoholism and for alcohol intoxication, rather than as a medicinal substance. Though the alcohol content of these can vary from 40­55%, in India (and almost internationally) for all licenced brands it is standardized to 42. Rectified spirit 90% w/w ethyl alcohol produced from fermented mollases, by distillation. The major source of commercial alcohol is mollases, a byproduct of sugar industry. Malted liquors Obtained by fermentation of germinating cereals; are undistilled-alcohol content is low (3­6%). Wines Produced by fermentation of natural sugars as present in grapes and other fruits. Fortified wines Port, Sherry (alcohol 16­22%): distilled beverages are added from outside. Effervescent wines Champagne (12­16% alcohol): bottled before fermentation is complete. Local actions Ethanol is a mild rubefacient and counterirritant when rubbed on the skin. Applied to delicate skin (scrotum) or mucous membranes it produces irritation and burning sensation. Applied to the surface, alcohol is an astringent-precipitates surface proteins and hardens the skin. That 100% ethanol is more dehydrating but poorer antiseptic than 90% ethanol, shows that antibacterial action is not due to dehydration of bacterial protoplasm. Since the highest areas are most easily deranged and these are primarily inhibitory-apparent excitation and euphoria are experienced at lower plasma concentrations (30­60 mg/dl). With increasing concentration (80­ 150 mg/dl) mental clouding, disorganization of thought, impairment of attention, memory and other faculties, alteration of gait and perception and drowsiness supervene. Any measurable concentration of alcohol produces a measurable slowing of reflexes: driving is dangerous. Performance is impaired, fine discrimination and precise movements are obliterated; errors increase, except if fear of punishment and anxiety of failure has already impaired it. At any given blood alcohol level, central effects are more marked when the concentration is rising than when it is falling. Some individuals report poor quality of sleep and repeated or early morning awakening. Sleep architecture may be Alcohol: conscious Ether: conscious anaesthesia disorganized and sleep apnoea aggravated. Alcohol raises pain threshold and also alters reaction to it, but is not a dependable analgesic-severe pain can precipitate confusion and convulsions. During the time alcohol is acting on brain, it exerts anticonvulsant action, but this is followed by lowering of threshold: seizures may be precipitated in epileptics. The cortex and the reticular activating system are most sensitive to alcohol; other areas get depressed as concentration rises. However, lately specific effect on multiple receptor operated and voltage gated ion channels/ other critical proteins has been demonstrated at concentrations attained during moderate drinking. Some studies suggest that cerebral nicotinic cholinergic receptor (operating through Na+ channel) may also be one of the targets of alcohol action. Ethanol can indirectly reduce neurotransmitter release by inhibiting voltage sensitive neuronal Ca2+ channels. This is probably important in the pleasurable reinforcing effects of alcohol and in the genesis of alcohol dependence. Higher concentrations (above 20%) inhibit gastric secretion, cause vomiting, mucosal congestion and gastritis. Liver Neither brief alcohol intoxication nor chronic intake of small-to-moderate amounts cause significant liver damage, provided adequate nutrition is maintained. However, it does mobilize peripheral fat and increases fat synthesis in liver in a dose-dependent manner. Chronic alcoholism exposes liver to oxidative stress and causes cellular necrosis followed by fibrosis. Acetaldehyde produced during metabolism of alcohol appears to damage the hepatocytes and induce inflammation, especially on chronic ingestion of large amounts. These combined with vitamin and other nutritional deficiencies may be responsible for the so called alcoholic cirrhosis. Fatigue is allayed by small doses, but muscle work is increased or decreased depending on the predominating central effect. Small doses: produce only cutaneous (especially on the face) and gastric vasodilatation. Epidemiological studies have confirmed that chronic alcoholism contributes to hypertension and can lead to cardiomyopathy. Atrial fibrillation and other cardiac arrhythmias may occur due to conduction defects and Q-T prolongation. This may be responsible for the 15­35% lower incidence of coronary artery disease in such individuals. Risk reduction is greatest in high risk subjects and protection is lost if > 3 drinks are consumed daily. However, it is considered inapproptiate to advise nondrinkers to start drinking on this account, since other adverse consequences may more than nullify this benefit. Megaloblastic anaemia occurring in chronic alcoholism is due to interference with folate metabolism. It does produce a sense of warmth due to cutaneous and gastric vasodilatation, but heat loss is actually increased in cold surroundings. They irritate buccal and pharyngeal mucosa which may transiently stimulate respiration reflexly. However, it is better not to depend on this, because the direct action of alcohol on respiratory centre is only a depressant one. Chronic alcoholism can produce impotence, testicular atrophy, gynaecomastia and infertility in both men and women. Endocrine effects Moderate amounts of alcohol increase Adr release which can cause hyperglycaemia and other sympathetic effects. However, acute intoxication is often associated with hypoglycaemia and depletion of hepatic glycogen, because gluconeogenesis is inhibited. Glucagon, thus fails to reverse it and glucose must be given to counteract hypoglycaemia. Absorption of alcohol from skin of adults is minimal but may be significant in infants given alcohol sponges. Excretion of alcohol occurs through kidney and lungs, but neither is quantitatively significant.

Till recently tamoxifen has been the standard hormonal treatment of breast cancer in both preand post-menopausal women pod asthma buy discount singulair 10 mg on-line, but aromatase inhibitors have now gained prominence asthma definition trust order singulair no prescription. In early cases tamoxifen is given as postmastectomy adjuvant therapy asthma treatment discount singulair 5 mg amex, while in advanced cases asthma young living essential oils cheap singulair online master card, it is a constituent of palliative treatment asthmatic bronchitis remedies order singulair 10 mg amex. Tamoxifen is the only drug approved for primary as well as metastatic breast carcinoma in premenopausal women. Recurrence rate in ipsilateral as well as contralateral breasts is reduced by tamoxifen, but benefits of prophylactic therapy beyond 5 years are not proven; outcomes may even be worse. Adjuvant therapy of breast carcinoma with tamoxifen when used in postmenopausal women is now generally replaced after 2 years by an aromatase inhibitor, while in premenopausal women, tamoxifen itself is continued till 5 years postmastectomy. Improvement in bone mass due to antiresorptive effect, and in lipid profile are the other benefits of tamoxifen therapy. However, endometrial thickening occurs and risk of endometrial carcinoma is increased 2­3 fold due to estrogenic action. Tamoxifen is effective orally; has a biphasic plasma t½ (10 hours and 7 days) and a long duration of action. Side effects Hot flushes, vomiting, vaginal bleeding, vaginal discharge, menstrual irregularities are the side effects. Increased risk of venous thromboembolism is due to estrogenic action on clotting mechanism. Dermatitis, anorexia, depression, mild leucopenia and ocular changes are infrequent. It is an estrogen partial agonist in bone and cardiovascular system, but an antagonist in endometrium and breast. Raloxifene does not stimulate endometrial proliferation and there is no increase in the risk of endometrial carcinoma. No relief of menopausal vasomotor symptoms occurs; rather hot flushes may be induced in some women. Raloxifene is absorbed orally but has low bioavailability due to extensive first pass glucuronidation. Side effects Hot flushes, leg cramps are generally mild; vaginal bleeding is occasional. The only serious concern is 3-fold increase in risk of deep vein thrombosis and pulmonary embolism. Use Raloxifene is a second line drug for prevention and treatment of osteoporosis in postmenopausal women; Ca 2+ and vit D supplements enhance the benefit. According to British guidelines, raloxifene is not recommended for primary prophylaxis of osteoporotic fractures in postmenopausal women, but is an alternative option for secondary prevention and treatment of vertebral fractures, i. In addition to the circulating hormone, locally produced estrogens appear to play an important role in the development of breast cancer. Letrozole It is an orally active nonsteroidal (type 2) compound that reversibly inhibits aromatization all over the body, including that within the breast cancer cells, resulting in nearly total estrogen deprivation. Proliferation of estrogen dependent breast carcinoma cells is suppressed to a greater extent than with tamoxifen. Letrozole is rapidly absorbed with 100% oral bioavailability, large volume of distribution, slow metabolism and a t½ of ~40 hours. Extended adjuvant therapy with letrozole beyond the standard 5 year tamoxifen treatment continues to afford protection, whereas continuation of tamoxifen is not useful. Greater delay in disease progression and greater survival advantage in palliative treatment of advanced/ metastatic breast Ca. Estrogen antagonist in breast and blood vessels, but agonist in uterus, bone, liver and pituitary. Less effective in delaying recurrence when used as adjuvant therapy after surgery. Less delay in disease progression and lower survival advantage in advanced/metastatic breast Ca. However, there is no endometrial hyperplasia or increased risk of endometrial carcinoma. Risk of venous thromboembolism is also not increased, and there is no deterioration of lipid profile. Though contraindicated in premenopausal women, letrozole was clandestinely promoted and tested as an ovulation inducing fertility drug. Use of letrozole for inducing ovulation in infertile women has been banned in India since Oct. Like letrozole, it is also a first line drug for early as well as advanced breast carcinoma in postmenopausal women. Side effects are hot flushes, vaginal dryness, vaginal bleeding, nausea, diarrhoea, thinning of hair. However, it does not predispose to endometrial carcinoma or to venous thromboembolism. Exemestane: this steroidal and irreversible (Type 1) inhibitor of aromatase acts like a suicide substrate by covalent binding to the enzyme. Exemestane has been found beneficial in early breast cancer by reducing the risk of disease progression when it was substituted for tamoxifen as adjuvant therapy. In advanced breast cancer, longer survival, increased time to disease progression and fewer treatment failures have been obtained with exemestane. At the turn of the last century it became apparent that ovaries secrete two hormones, and that corpus luteum was essential for maintenance of pregnancy. Progesterone was isolated in 1929, but its full therapeutic potential has been exploited only after the 1950s when a large number of orally active synthetic progestins were developed. Natural progestin Progesterone, a 21 carbon steroid, is the natural progestin and is derived from cholesterol. If the ovum gets fertilized and implants-the blastocyst immediately starts producing chorionic gonadotropin which is absorbed into maternal circulation and sustains the corpus luteum in early pregnancy. Placenta starts secreting lots of estrogens and progesterone from 2nd trimester till term. Men produce 1­ 5 mg progesterone per day from adrenals and testes; its role if any, in males is not known. The older 19-nortestosterone derivatives developed in the 1950-60s have additional weak estrogenic, androgenic, anabolic and potent antiovulatory action: are used primarily in combined contraceptive pills. In the 1980-90s a number of other gonane compounds were introduced, of which desogestrel has been marketed in India. In addition to being very potent progestins they have strong antiovulatory action (gestodene inhibits ovulation at as low as 40 µg/day dose), and little or no androgenic property. Therefore, they do not antagonise the beneficial action of estrogens on lipid profile and are preferable in women with hyperandrogenemia. High antiovulatory potency allows reduction of ethinylestradiol dose when these are combined in oral contraceptives. The newer 19-norprogesterone derivative nomegestrol has weak antiandrogenic property, is less antiovulatory, but has strong antiestrogenic effect on endometrium. Uterus Progesterone brings about secretory changes in the estrogen primed endometrium: hyperemia, tortuocity of glands and increased secretion occurs while epithelial proliferation is halted. It is lack of progestational support which causes mucosal shedding during menstruation. Continued action of progesterone (when pregnancy occurs) brings about decidual changes in endometrium-stroma enlarges and becomes spongy, glands atrophy, and sensitivity of myometrium to oxytocin is decreased. Cervix Progesterone converts the watery cervical secretion induced by estrogens to viscid, scanty and cellular secretion which is hostile to sperm penetration. Vagina Progesterone induces pregnancy like changes in the vaginal mucosa: leukocyte infiltration of cornified epithelium occurs. Cyclic epithelial proliferation and turnover occurs during luteal phase, but continuous exposure to progesterone during pregnancy halts mitotic activity and stabilizes mammary cells. Withdrawal of these hormones after delivery causes release of prolactin from pituitary and milk secretion starts. Respiration Progestins in relatively higher doses stimulate respiration, as occurs during pregnancy. Metabolism Prolonged use of oral contraceptives impairs glucose tolerance in some women. The two have differing activities, but because the ligand binding domain of both is identical, all agonists and antagonists display similar binding properties for them. Progesterone also acts on cell membrane receptors in certain tissues and produces rapid effects, like Ca2+ release from spermatozoa and oocyte maturation, but their physiological significance is not clear. Nearly complete degradation occurs in the liver- major product is pregnanediol which is excreted in urine as glucuronide and sulfate conjugates. A micronized formulation of progesterone has been developed for oral administration. Microfine particles of the drug are suspended in oil and dispensed in gelatin capsules. Most of the synthetic progestins are orally active and are metabolized slowly; have plasma t½ ranging from 8­24 hours. It has poor antiovulatory action: may be preferred when contraceptive effect is not required. Continued estrogenic action on endometrium (causing hyperplasia) without progesterone induction and withdrawal resulting in incomplete sloughing leads to irregular, often profuse bleeding. A progestin in relatively large doses (medroxyprogesterone acetate/norethindrone 10­20 mg/day or equivalent) promptly stops bleeding and keeps it in abeyance as long as given. Subsequently cyclic treatment at lower doses regularizes and normalizes menstrual flow. A progestin with inherent estrogenic action is preferred; often supplemental dose of estrogen is combined, or a combination oral contraceptive pill is given cyclically for 3­6 months. Endometriosis this condition results from presence of endometrium at ectopic sites. Continuous administration of progestin induces an anovulatory, hypoestrogenic state by suppressing Gn release. The direct action on endometrium prevents bleeding in the ectopic sites by suppressing menstruation. Progestin treatment of endometriosis is cheap and generally well tolerated, but not all cases respond and recurrences are frequent. Initial progestin therapy is often replaced by cyclic tratment with an estrogen-progestin contraceptive pill given for 3­6 months. Premenstrual syndrome/tension Some women develop headache, irritability, fluid retention, distention and breast tenderness a few days preceding menstruation. If severe, premenstrual syndrome requires suppression of ovulation by combined estrogen-progesterone treatment given cyclically. Threatened/habitual abortion In most such patients there is no progesterone deficiency; administration of excess hormone is of no benefit. Progestin therapy may be considered in those patients who have established deficiency. However, progestins are briskly promoted and almost routinely prescribed in India. There is some recent evidence of its efficacy in preventing premature delivery in high risk pregnancy. If such use is made-a pure progestin without estrogenic or androgenic activity should be employed. Endometrial carcinoma Progestins are palliative in about 50% cases of advanced/ metastatic endometrial carcinoma. Given during the follicular phase, its antiprogestin action results in attenuation of the midcycle Gn surge from pituitary slowing of follicular development and delay/failure of ovulation. If given during the luteal phase, it prevents secretory changes by blocking progesterone action on the endometrium. In the absence of progesterone (during anovulatory cycles or after menopause) it exerts weak progestational activity-induces predecidual changes. Termination of pregnancy of up to 7 weeks: 600 mg as single oral dose causes complete abortion in 60­85% cases. To improve the success rate, current recommendation is to follow it up 48 hours later by a single 400 mg oral dose of misoprostol. This achieves >90% success rate and is the accepted nonsurgical method of early first trimester abortion. In place of oral misoprostol, a 1 mg gemeprost pessary can be inserted intravaginally. Mifepristone administered within 10 days of a missed period results in an apparent late heavy period (with dislodged blastocyst) in upto 90% cases. This procedure is generally safe, but prolonged bleeding and failed abortion are the problems in some cases. Anorexia, nausea, tiredness, abdominal discomfort, uterine cramps, loose motions are the other side effects. Cervical ripening 24­30 hours before attempting surgical abortion or induction of labour, mifepristone 600 mg results in softening of cervix; the procedure is facilitated. Postcoital contraceptive Mifepristone 600 mg given within 72 hr of intercourse interferes with implantation and is a highly effective method of emergency contraception. Once-a-month contraceptive A single 200 mg dose of mifepristone given 2 days after midcycle each month prevents conception on most occasions. Administering mifepristone in late luteal phase to dislodge the embryo (if present) and to ensure menstruation irrespective of conception, has also been tried. These alternative methods of contraception, though attractive, may prolong/disrupt the next menstrual cycle, and thus cannot be used continuously. There is little experience and little justification to use these methods on regular basis. Induction of labour By blocking the relaxant action of progesterone on uterus of late pregnancy, mifepristone can promote labour. It may be tried in cases with intrauterine foetal death and to deliver abnormal foetuses. Other proposed uses are-in endometriosis, uterine fibroid, certain breast cancers and in meningioma.

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Benzoyl peroxide is a mild irritant of the skin-burning and stinging sensation is often felt initially asthmatic bronchitis guidelines buy singulair with amex, localized erythema may occur asthma related deaths buy singulair american express. Most patients gradually develop tolerance to these actions; if not asthmatic bronchitis icd 10 buy singulair 5 mg, use should be discontinued asthma and smoking order singulair amex. Adverse effects are excessive dryness of skin asthma winter cheap 5 mg singulair visa, marked scaling, erythema, edema and contact sensitization (in 1­2% patients). It is used as 5­10% cream, gel or lotion; duration and frequency of application is guided by the degree of irritation produced and tolerated; start with 15 min once daily. There is some evidence that they can prevent skin cancer and premature ageing of skin. Retinoic acid (all trans vitamin A acid, Tretinoin) It is a potent comedolytic: promotes lysis of keratinocytes, prevents horny cells from binding to each other, hence comedones, which are horny impactions in follicles, cannot form. Tretinoin has the potential to irritate the skin; start with the lower concentration applied once daily. Side effects are feeling of warmth, stinging, excessive redness, edema and crusting. Teratogenic risk with topical retinoic acid is minor because of low blood levels produced; but it should be used during pregnancy only if essential. Dry scaly surface, mottling, wrinkles, rough and leathery texture, sagging of loose skin that develop due to excessive exposure to sun are arrested and pigmented spots tend to fade. Topical antibiotics Clindamycin, erythromycin and tetracyclines are less effective against P. They are appropriate for cases with inflamed papules, rather than in non-inflamed comedones. Nadifloxacin is a newer topical quinolone broadspectrum antibiotic which has exerted therapeutic benefit in inflamed acne and folliculitis. Azelaic acid It is a natural product from Pityrosporum ovale that has been developed for topical treatment of acne. Azelaic acid reduces cutaneous bacterial density, free fatty acid content of skin surface lipids and proliferation of keratinocytes. Used as 10%, 20% cream, its efficacy in acne approaches that of benzoyl peroxide, but response is delayed. Systemic Therapy Systemic use of drugs in acne is indicated only in severe cases with cysts and pustules which are likely to form scars. Recently risk of intracranial hypertension after use of tetracyclines for > 2 months has been emphasized. Isotretinoin (13-cis retinoic acid) is an orally administered retinoid that reduces production of sebum (skin bacteria decrease secondarily), corrects abnormal keratinization of follicles and causes dramatic improvement. Adapalene It is a newer synthetic tretinoinlike drug which binds directly to the nuclear retinoic acid receptor and modulates keratinization and differentiation of follicular epithelial cells. Side effects are frequent-cheilitis, dryness of skin, eyes, nose and mouth, epistaxis, pruritus, conjunctivitis, paronychia, rise in serum lipids and intracranial tension, and musculoskeletal symptoms. It is contraindicated in women likely to become pregnant during therapy and one month after. The t½ of isotretinoin is ~18 hours, and it is not accumulated like other retinoids. Oral leucoplakia, actinic keratoses and other premalignant lesions can be treated, but benefitrisk ratio is not clear. Fluocinolone acetonide Fluocortolone Triamcinolone acetonide Moderately potent Fluocinolone acetonide Clobetasol butyrate Fluocortolone Mometasone Fluticasone propionate Prednicarbate Triamcinolone acetonide Hydrocortisone + urea 12% Hydrocortisone acetate Mild Hydrocortisone acetate 0. They benefit by virtue of their antiinflammatory, immunosuppressive, vasoconstrictor and antiproliferative (for scaling lesions) actions. The intensity of action depends on the extent of absorption to the deeper layers, thus lipophilicity of the compound determines potency to a great extent. The available preparations may be roughly graded as: Potent Beclomethasone dipropionate Betamethasone benzoate Betamethasone valerate Halcinonide Clobetasol propionate Dexamethasone sod. Areas of high penetration easily develop adverse effects-potent preparations should be avoided. Milder drugs should be used on acute lesions, stronger ones reserved for chronic lesions. Lotions and creams (to some extent) are better for exudative lesions-they allow evaporation, have a cooling, drying and antipruritic effect. Chronic, hypertrophied lesions may be occluded intermittently (12 hours at a time). Very potent preparations should be restricted to severe inflammatory conditions, unresponsive eczema, psoriasis, etc. A combination of steroid with an antimicrobial may be used for-impetigo, furunculosis, secondary infected dermatoses, napkin rash, otitis externa, intertriginous eruptions. Local adverse effects of topical steroids Thinning of epidermis Dermal changes-atrophy Telangiectasia, Striae Easy bruising Hypopigmentation Delayed wound healing Fungal and bacterial infections Related to the potency of preparation and duration of treatment; skin of face is more susceptible. Conventionally, agents used on living surfaces (skin, mouth) are called antiseptics while those used for inanimate objects (instruments, privies, water supply) are called disinfectants. A practical distinction between the two on the basis of a growth inhibiting versus direct lethal action is futile because these are often concentration dependent actions. While sterilization means complete killing of all forms of microorganisms, disinfection refers to reduction in the number of viable pathogenic microbes to a level that they do not pose a risk to individuals with normal host defence. The era of antiseptics and disinfectants was heralded by Semmelweiss (washing of hands in chlorinated lime) and Lister (antiseptic surgery by the use of phenol) in the 19th century. These germicides differ from systemically used antimicrobials by their low parasite selectivity-are too toxic for systemic use. However, many systemic antimicrobials are applied topically as well, and some antibiotics (bacitracin, neomycin) are restricted to topical use, but are generally not enumerated with the antiseptics. A disinfectant in addition should not corrode or rust instruments and be easily washable. An antiseptic in addition should be: Rapid in action and exert sustained protection. Spectrum of activity of majority of antisepticdisinfectants is wide, reflecting nonselectivity of action. Mechanisms of action of germicides are varied, but can be grouped into: (a) Oxidation of bacterial protoplasm. It is a general protoplasmic poison, injuring microbes and tissue cells alike- at higher concentrations causes skin burns and is a caustic. Organic matter diminishes its action slightly while alkalies and soaps do so profoundly (carbolic soaps are not more germicidal than soap itself). It is now seldom employed as an antiseptic, but being cheap, it is used to disinfect urine, faeces, pus, sputum of patients and is sometimes included in antipruritic preparations because of its mild local anaesthetic action. Cresol It is methyl-phenol; more active (3­10 times) and less damaging to tissues. Hexylresorcinol It is a more potent derivative of the phenolic compound resorcinol that is odourless and nonstaining; used as mouthwash, lozenge and as antifungal. Potency of a germicide is generally expressed by its phenol coefficient or Rideal Walker coefficient, which is the ratio of the minimum concentration of test drug required to kill a 24 hour culture of B. This test has only limited validity, particularly in relation to antiseptics which have to be tested on living surfaces. Therapeutic index of an antiseptic is defined by comparing the concentration at which it acts on microorganisms with that which produces local irritation, tissue damage or interference with healing. Phenol derivatives: Phenol, Cresol, Hexylresorcinol, Chloroxylenol, Hexachlorophene. Quaternary ammonium (Cationic): Cetrimide, Benzalkonium chloride, Dequalinium chloride. Metallic salts: Silver nitrate, Silver sulfadiazine, Mild silver protein, Zinc sulfate, Calamine, Zinc oxide. Chloroxylenol It has a phenol coefficient of 70; does not coagulate proteins, is noncorrosive, nonirritating to intact skin, but efficacy is reduced by organic matter. Hexachlorophene this chlorinated phenol acts by inhibiting bacterial enzymes and (in high concentration) causing bacterial lysis. The degerming action is slow but persistent due to deposition on the skin as a fine film that is not removed by rinsing with water. Use of a 3% solution for baby bath markedly reduced the incidence of staphylococcal infections, but produced brain damage (especially in premature neonates). The available oxygen and germicidal capacity is used up if much organic matter is present-the solution gets decolourised. The action is rather slow and higher concentrations cause burns and blistering-popularity therefore has declined. It has also been used to disinfect water (wells, ponds) and for stomach wash in alkaloidal poisoning (except atropine and cocaine which are not efficiently oxidized). Hydrogen peroxide It liberates nacent oxygen which oxidizes necrotic matter and bacteria. Catalase present in tissues speeds decomposition resulting in foaming-helps in loosening and removing slough, ear wax, etc. Solid iodine is corrosive, stronger solutions (> 5%) cause burning and blistering of skin. It is used on cuts, for degerming skin before surgery, and to treat ring worm, etc. Some individuals are sensitive to iodine-rashes and systemic manifestations occur in them. Iodophores these are soluble complexes of iodine with large molecular organic compounds that serve as carriers-release free iodine slowly. The most popular-Povidone (Polyvinylpyrrolidone) iodine: is nonirritating, nontoxic, nonstaining and exerts prolonged germicidal action. It is used on boils, furunculosis, burns, otitis externa, ulcers, tinea, monilial/trichomonal/ nonspecific vaginitis and for surgical scrubbing, disinfection of endoscopes and instruments. It is used as disinfectant for drinking water, swimming pools and sanitizer for privies, etc. It is a powerful disinfectant used in dairies for milk cans, other equipment and for infant feeding bottles. It is unstable and too irritant to be used as antiseptic, except for root canal therapy in dentistry. They act by altering permeability of cell membranes and denaturing of bacterial proteins. However, the germicidal action is rather slow and bacteria may thrive under a film formed by them on the skin. These disadvantages not withstanding, they are widely used as sanitizers, antiseptic and disinfectant for surgical instruments, gloves, etc, but should not be considered sterilizing. Used as 1­3% solution, it has good cleansing action, efficiently removing dirt, grease, tar and congealed blood from road side accident wounds. Alone or in combination with chlorhexidine, it is one of the most popular hospital antiseptic and disinfectant for surgical instruments, utensils, baths, etc. A 1:1000 solution is used for sterile storage of instruments and 1 in 5000 to 1 in 10,000 for douches, irrigation, etc. However, it may leave an unpleasant after taste, and repeated application causes brownish discolouration of teeth. The rapidity of action increases with concentration upto 70% and decreases above 90%. A cotton swab soaked in 70% ethanol rubbed on the skin kills 90% bacteria in 2 min. Low concentrations enhance the antiseptic activity of iodine and chlorhexidine when used as solvent for these. It is an irritant and should not be applied to mucous membranes or to delicate skin (scrotum), ulcers, etc. On open wounds it produces a burning sensation, injures the surface and forms a coagulum under which bacteria could grow. It is a poor disinfectant for instruments-does not kill spores and promotes rusting. A 37% aqueous solution called Formalin is diluted to 4% and used for hardening and preserving dead tissues. A broad-spectrum germicide, but use as antiseptic is restricted by its irritating nature and pungent odour. The urinary antiseptic methenamine acts by releasing formaldehyde in acidic urine (see p. Glutaraldehyde It is less volatile, less pungent, less irritating and better sterilizing agent than formalin, but needs to be activated by alkalinization of the solution. A 2% solution is used to disinfect surgical instruments and endoscopes, but prolonged contact is needed. The alkalinized solution has a short shelf life (2 weeks) unless stablilizing agents are added. But being nonirritating even to delicate structures, saturated aqueous solutions (4%) have been used for irrigating eyes, mouthwash, douche, etc. However, boric acid is not innocuous; systemic absorption causes vomiting, abdominal pain, diarrhoea, visual disturbances and kidney damage. Hence its use for irrigating bladder, large wounds, as ointment on extensive burnt areas, liberal use of powder for infants is not recommended. It is highly active against gonococci-1% solution is used for ophthalmia neonatorum. In addition to being mildly antiseptic, they are popular dermal protectives and adsorbants. Acriflavine and Proflavine these are orangeyellow acridine dyes active against gram-positive bacteria and gonococci. Their efficacy is not reduced by organic matter and is enhanced in alkaline medium. They are nonirritant and do not retard healing-particularly suitable for chronic ulcers and wounds.

Poor environmental sanitation and low socio-economic status are important factors in the spread of the disease asthma treatment dulera 5 mg singulair purchase free shipping, which occurs by faecal contamination of food and water asthma definition 5-by 4 mg singulair order amex. Amoebic cysts reaching the intestine transform into trophozoites which either live on the surface of colonic mucosa as commensals- form cysts that pass into the stools (luminal cycle) and serve to propagate the disease asthma triggers definition singulair 4 mg buy online, or invade the mucosa-form amoebic ulcers asthma symptoms later in life singulair 10 mg buy with visa. Occasionally the trophozoites pass into the bloodstream asthma definition history discount singulair online mastercard, reach the liver via portal vein and cause amoebic liver abscess. Other organs like lung, spleen, kidney and brain are rarely involved in extraintestinal amoebiasis. Tissue phase is always secondary to intestinal amoebiasis, which may be asymptomatic. In the colonic lumen, the Entamoebae live in symbiotic relationship with bacteria, and a reduction in colonic bacteria reduces the amoebic population. The pure alkaloid emetine obtained from it was found to be a potent antiamoebic in 1912. Emetine remained the most efficacious and commonly used drug for amoebiasis till 1960. Diloxanide furoate was a useful addition in 1960, covering mainly chronic intestinal forms of the disease. However, the most remarkable development was the demonstration of antiamoebic property of metronidazole in the early 1960s. This drug had been introduced a few years back as a well tolerated, orally effective agent for trichomonas vaginitis. Of the many congeners of metronidazole that were tested, tinidazole has emerged in the 1970s as a good alternative, and others have been added subsequently. Tissue amoebicides (a) For both intestinal and extraintestinal amoebiasis: Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole Alkaloids: Emetine, Dehydroemetine (b) For extraintestinal amoebiasis only: Chloroquine 2. It has broad-spectrum cidal activity against anaerobic protozoa, including Giardia lamblia in addition to the above two. Though, it does not directly inhibit the helminth Dracunculus medinensis, extraction of the worm from under the skin is facilitated. Metronidazole is selectively toxic to anaerobic and microaerophilic microorganisms. After entering the cell by diffusion, its nitro group is reduced by certain redox proteins operative only in anaerobic microbes to a highly reactive nitro radical which exerts cytotoxicity. Aerobic environment attenuates cytotoxicity of metronidazole by inhibiting its reductive activation. Moreover, O2 competes with the nitro radical of metronidazole for the free electrons generated during energy metabolism of anaerobes. Metronidazole, in addition, has been found to inhibit cell mediated immunity, to induce mutagenesis and to cause radiosensitization. Pharmacokinetics Metronidazole is almost completely absorbed from the small intestines; little unabsorbed drug reaches the colon. Metabolism occurs in liver primarily by oxidation and glucuronide conjugation followed by renal excretion. Adverse effects Side effects of metronidazole are relatively frequent and unpleasant, but mostly nonserious. Contraindications Metronidazole is contraindicated in neurological disease, blood dyscrasias, first trimester of pregnancy (though no teratogenic effect has yet been demonstrated, its mutagenic potential warrants caution). Interactions A disulfiram-like intolerance to alcohol occurs in some patients taking metronidazole. Alcohol-metronidazole interaction occurs only in some individuals, while majority of those taking it can consume alcohol without any reaction. There is no convincing evidence of disulfiram-like action of metronidazole, but manufactures advise caution in drinking during metronidazole therapy. Metronidazole is less effective than many luminal amoebicides in eradicating amoebic cysts from the colon, because it is nearly completely absorbed from the upper bowel. Repeated courses may be necessary in some patients, but should be given with gaps of 4­6 weeks. Anaerobic bacterial infections They occur mostly after colorectal or pelvic surgery, appendicectomy, etc. Metronidazole is an effective drug for these and is generally used in combination with gentamicin or cephalosporins (many are mixed infections). Prophylactic use in high risk situations (colorectal/biliary surgery) is recommended. Other drugs effective in anaerobic infections are clindamycin and chloramphenicol. Cimetidine can reduce metronidazole metabolism: its dose may need to be decreased. Amoebiasis: Metronidazole is a first line drug for all forms of amoebic infection. The response is rapid with disappearance of the spirochete-fusobacterium complex from the lesions and resolution of pain, bleeding, ulceration and bad breath within 2­3 days; but treatment must be continued for at least 5 days. Guinea worm infestation Niridazole is considered to be the drug of choice, but because it is not available in India, metronidazole is used. The local reaction to the worm may be suppressed by its antiinflammatory action, and extraction is facilitated. Anaerobic infections: prophylactic-2 g single dose before colorectal/biliary surgery; therapeutic-2 g followed by 0. Secnidazole A congener of metronidazole with the same spectrum of activity and potency. Absorption after oral administration is rapid and complete, but metabolism is slower resulting in a plasma t½ of 17­29 hours. In intestinal amoebiasis a single 2 g dose has been found to yield high cure rates. Dose: 2 g single dose (children 30 mg/kg) for mild intestinal amoebiasis, giardiasis, trichomonas vaginitis and nonspecific bacterial vaginosis. Ornidazole It has activity similar to metronidazole, but it is slowly metabolized-has longer t½ (12­14 hr). Dose and duration of regimens for amoebiasis, giardiasis, trichomoniasis, anaerobic infections and bacterial vaginosis resemble those for tinidazole. Emetine is a potent and directly acting amoebicide-kills trophozoites but has no effect on cysts. In acute dysentery the stool is rapidly cleared of the trophozoites and symptomatic relief occurs in 1­3 days (even faster than metronidazole), but it is not curative in the sense that the patient continues to pass cysts in the stool. Use Emetine is now rarely used for acute amoebic dysentery or for amoebic liver abscess, only in patients not tolerating metronidazole. A luminal amoebicide must always follow emetine to eradicate the cyst forming trophozoites. Dehydroemetine It is equally effective but less cumulative and less toxic to the heart. Because it is completely absorbed from the upper intestine and not so highly concentrated in the intestinal wall-it is neither effective in invasive dysentery nor in controlling the luminal cycle (cyst passers). Efficacy of chloroquine in amoebic liver abscess approaches that of emetine, but duration of treatment is longer and relapses are relatively more frequent, but amoebae do not develop resistance to chloroquine. A luminal amoebicide must always be given with or after chloroquine to abolish the luminal cycle. Dose for amoebic liver abscess: 600 mg (base) for two days followed by 300 mg daily for 2­3 weeks. It is employed only when metronidazole fails to clear the infection or is not tolerated. The furoate ester is hydrolysed in intestine and the released diloxanide is largely absorbed. It is less effective in invasive amoebic dysentery, because of poor tissue amoebicidal action. However, a single course produces high (80­90%) cure rate in mild intestinal amoebiasis and in asymptomatic cyst passers. It is a preferred drug for mild intestinal/asymptomatic amoebiasis, and is given after or along with any tissue amoebicide to eradicate cysts. Nitazoxanide this salicylamide congener of the anthelmintic niclosamide, introduced for the treatment of giardiasis and cryptosporidiosis is also active against many other protozoa and helminths including E. Tizoxanide generated from nitazoxanide is glucuronide conjugated and excreted in urine and bile. It is also indicated in giardiasis, and in amoebic dysentery as luminal amoebicide. Iodism (furunculosis, inflammation of mucous membranes) may occur due to chronic iodine overload. Individuals sensitive to iodine may experience acute reaction with chills, fever, angioedema and cutaneous haemorrhages. However, despite widespread use in the past, only sporadic and unconfirmed cases have been reported from India. These drugs have been banned in Japan and few other countries, but in India they are prohibited only for pediatric patients, because their use for chronic diarrhoeas in children has caused blindness. Their fixed dose combinations, except for external application, are banned in India, and a cautionary note is inserted that use of high doses for more than 14 days can cause neuritis and optic damage. They kill the cyst forming amoebic trophozoites in the intestine, but do not have tissue amoebicidal action. Like diloxanide furoate, they are not very effective in acute amoebic dysentery but afford relief in chronic intestinal amoebiasis. Their efficacy to eradicate cysts from asymptomatic carriers is rated lower than that of diloxanide furoate. The absorbed fraction is conjugated in liver with glucuronic acid and sulfate and excreted in urine; t½ ~12 hours. They may be employed in intestinal amoebiasis as alternative to diloxanide furoate. Other uses are-giardiasis; local treatment of monilial and trichomonas vaginitis, fungal and bacterial skin infections. In addition the older tetracyclines are incompletely absorbed in the small intestine, reach the colon in large amounts and inhibit the bacterial flora with which Entamoebae live symbiotically. Tetracyclines have an adjuvant role in the management of such cases, in conjunction with a more efficacious luminal amoebicide. They have also been added as the third drug along with a nitroimidazole + a luminal amoebicide in the treatment of amoebic dysentery, but have no role in hepatic amoebiasis. Dehydroemetine is rarely used in the most severe cases or when metronidazole produces severe allergic reaction or neurotoxicity. It should be discontinued as soon as acute symptoms are controlled (2­3 days) and metronidazole started. The above treatment should be followed by a course of luminal amoebicide to eradicate E. Mild intestinal amoebiasis/asymptomatic cyst passers Nitroimidazoles afford rapid symptomatic relief in mildly symptomatic intestinal amoebiasis as well, and are the first line drugs. However, they mostly fail to clear cysts, and the standard practice is to give diloxanide furoate or another luminal amoebicide, either concurrently or immediately after. Luminal amoebicides alone are generally slower in action, but avoid side effects of metronidazole. A tetracycline may be given concurrently with the luminal amoebicide in cases which fail to clear completely. Amoebic liver abscess It is a serious disease; complete eradication of trophozoites from the liver is essential to avoid relapses. Dehydroemetine is to be used only if metronidazole cannot be given for one reason or the other, and in patients not cured by metronidazole. Large abscesses usually take months to resolve, even if all trophozoites are killed. Distinctively, paromomycin is active against many protozoa like Emtamoeba, Giardia, Cryptosporidium, Trichomonas, Leishmania and some tape worms, in addition to having antibacterial spectrum like neomycin. In the 1960s an oral formulation of paromomycin was introduced as a luminal amoebicide and was briefly marketed in India as well. However, it was soon overshadowed by metronidazole, became commercially unviable and was discontinued. The mechanism of antiprotozoal action of paromomycin appears to be the same as its antibacterial action; viz. It is neither absorbed nor degraded in the intestines, and is eliminated unchanged in the faeces. Paromomycin can substitute for neomycin in hepatic coma and for preoperative preparation of bowel. Paromomycin is an efficacious luminal amoebicide, achieving similar or even better clearing of cysts from stools compared to diloxanide furoate in asymptomatic cyst passers. Good symptomatic relief and cyst clearance is obtained in chronic amoebic colitis. It can be given along with metronidazole in acute amoebic dysentery as well as in hepatic amoebiasis to eradicate the luminal cycle. Paromomycin is an alternative drug for giardiasis, especially during 1st trimester of pregnancy when metronidazole and other drugs are contraindicated. × 8­10 days Followed by/alternatively Chloroquine 600 mg (base) oral daily × 2 days, followed by 300 mg daily for 2­3 weeks. Alternative luminal amoebicides (as above, but no role of tetracycline) * In asymptomatic cases, a luminal amoebicide alone may be used (the nitroimidazole may be omitted).

References

• Bang JY, Ramesh J, Hasan M, et al. Endoscopic ultrasonography is no required for staging malignant esophageal strictures that preclude the passage of a diagnostic gastroscope. Dig Endosc. 2016;28:650-656.
• Elhilali MM, Badaan S, Ibrahim A, et al: Use of the Moses technology to improve holmium laser lithotripsy outcomes: a preclinical study, J Endourol 31(6):598-604, 2017.
• Body SC, Shernan SK: Genetic basis of cardiovascular disease and perioperative pain. In Van Aken H, editor: Clinical Anesthesiology, London, 2001, Bailliere Tindall. 565.
• Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-1585.
• Khan N, Brown A, Venkataraman ST. Predictors of extubation success and failure in mechanically ventilated infants and children. Crit Care Med 1996;24:1568-79.
• Talbott JH, Barrocas M. Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases. Semin Arthritis Rheum 1980;9:191-217.