The drug of choice for these organisms is vancomycin/linezolid prehypertension chart cheap hydrochlorothiazide 25mg with mastercard, but ciprofloxacin can also be used blood pressure medication names starting with t generic hydrochlorothiazide 12.5 mg amex. Haematuria pulse pressure 22 purchase 12.5mg hydrochlorothiazide, albuminuria and reversible interstitial nephritis are the specific adverse effects of methicillin blood pressure chart for child buy cheap hydrochlorothiazide 25 mg online. Activity against PnG sensitive organisms is weaker hypertension emergency treatment purchase hydrochlorothiazide 12.5 mg otc, and it should not be used as a substitute for PnG hypertension kidshealth 12.5 mg hydrochlorothiazide mastercard. Cloxacillin/dicloxacillin are incompletely but dependably absorbed from oral route blood pressure for elderly hydrochlorothiazide 25mg with mastercard, especially if taken in empty stomach heart attack 51 buy 25mg hydrochlorothiazide with mastercard. Oxacillin, Flucloxacillin (Floxacillin) are other isoxazolyl penicillins, similar to cloxacillin, but not marketed in India. Urinary tract infections: Ampicillin has been the drug of choice for most acute infections, but resistance has increased and fluoroquinolones/cotrimoxazole are now more commonly used for empirical therapy. Meningitis: Ampicillin has been a first line drug, but a significant number of meningococci, pneumococci and H. For empirical therapy, it is now used only in combination with a third generation cephalosporin with or without another antibiotic. Gonorrhoea: It is one of the first line drugs for oral treatment of nonpenicillinase producing gonococcal infections. Typhoid fever: Due to emergence of resistance, it is now rarely used, only when the organism is shown to be sensitive. Salmonella diarrhoeas should usually not be treated with antimicrobials, including ampicillin. Bacillary dysentery: due to Shigella often responds to ampicillin, but many strains are now resistant; quinolones are preferred. However, due to wide-spread use, many of these have developed resistance; usefulness of this antibiotic has decreased considerably. Pharmacokinetics Ampicillin is not degraded by gastric acid; oral absorption is incomplete but adequate. Cholecystitis: Ampicillin is a good drug because high concentrations are attained in bile. Septicaemias and mixed infections: Injected ampicillin may be combined with gentamicin or one of the third generation cephalosporins. Patients with a history of immediate type of hypersensitivity to PnG should not be given ampicillin as well. By inhibiting colonic flora, it may interfere with deconjugation and enterohepatic cycling of oral contraceptives failure of oral contraception. Bacampicillin It is an ester prodrug of ampicillin which is nearly completely absorbed from the g. Incidence of diarrhoea is claimed to be lower, because of lesser alteration in intestinal ecology. This combination is not synergistic since cloxacillin is not active against gram-negative bacteria, while ampicillin is not active against staphylococci. Since mixed staphylococcal and gramnegative bacillary infections are uncommon, for any given infection, one of the components is useless but adds to the cost and adverse effects. Since the amount of the drug which is actually going to act in any individual patient is halved (when the combination is used), efficacy is reduced and chances of selecting resistant strains are increased. Carboxypenicillins Carbenicillin the special feature of this penicillin congener is its activity against Pseudomonas aeruginosa and indole positive Proteus which are not inhibited by PnG or aminopenicillins. Pseudomonas strains less sensitive to carbenicillin have developed in some areas, especially when inadequate doses have been used. This appears to result from perturbation of agonist receptors on platelet surface. Amoxicillin It is a close congener of ampicillin (but not a prodrug); similar to it in all respects except: the indications for carbenicillin are-serious infections caused by Pseudomonas or Proteus, e. Ureidopenicillins Piperacillin this antipseudomonal penicillin is about 8 times more active than carbenicillin. It has good activity against Klebsiella, many Enterobacteriaceae and some Bacteroides. It is frequently employed for treating serious gramnegative infections in neutropenic/immunocompromised or burn patients. However, it is eliminated mainly by glomerular filtration and its excretion is not affected by probenecid. Moreover, it is largely hydrolysed and decarboxylated before excretion, while amoxicillin is primarily excreted unchanged by tubular secretion. Uses Addition of clavulanic acid re-establishes the activity of amoxicillin against -lactamase producing resistant Staph. Clavulanic acid does not potentiate the action of amoxicillin against strains that are already sensitive to it. Three inhibitors of this enzyme clavulanic acid, sulbactam and tazobactam are available for clinical use. Clavulanic acid Obtained from Streptomyces clavuligerus, it has a -lactam ring but no antibacterial activity of its own. It permeates the outer layers of the cell wall of gram-negative bacteria and inhibits the periplasmically located -lactamase. Sulbactam does not induce chromosomal -lactamases, while clavulanic acid can induce some of them. It has been combined with ampicillin for use against -lactamase producing resistant strains. Absorption of its complex salt with ampicillin- sultamicillin tosylate is better, which is given orally. They are chemically related to penicillins; the nucleus consists of a -lactam ring fused to a dihydrothiazine ring, (7-aminocephalosporanic acid). By addition of different side chains at position 7 of -lactam ring (altering spectrum of activity) and at position 3 of dihydrothiazine ring (affecting pharmacokinetics), a large number of semisynthetic compounds have been produced. This division has a chronological sequence of development, but more importantly, takes into consideration the overall antibacterial spectrum as well as potency. Its pharmacokinetics matches with piperacillin with which it has been combined for use in severe infections like peritonitis, pelvic/urinary/respiratory infections caused by -lactamase producing bacilli. However, the combination is not active against piperacillin-resistant Pseudomonas, because tazobactam (like clavulanic acid and sulbactam) does not inhibit inducible chromosomal lactamase produced by Enterobacteriaceae. It is also of no help against Pseudomonas that develop resistance by losing permeability to piperacillin. All cephalosporins are bactericidal and have the same mechanism of action as penicillin, i. Acquired resistance to cephalosporins could have the same basis as for penicillins, i. It is the preferred parenteral first generation cephalosporin, especially for surgical prophylaxis. Fourth generation cephalosporins (c) elaboration of -lactamases which destroy specific cephalosporins (cephalosporinases); the most common mechanism. Though the incidence is low, resistance has been developed by some organisms, even against the third generation compounds. Individual cephalosporins differ in their: (a) Antibacterial spectrum and relative potency against specific organisms. Cefazolin It is the prototype first generation cephalosporin that is active against most PnG sensitive organisms, i. Streptococci (pyogenes as well as viridans), gonococci, meningococci, Cephalexin It is the most commonly used orally effective first generation cephalosporin, similar in spectrum to cefazolin, but less active against penicillinase producing staphylococci and H. It is excreted unchanged in urine; the dose needs to be reduced only if creatinine clearance is < 50 ml/min. The antibacterial activity of cefadroxil and indications are similar to those of cephalexin. Cefotaxime It is the prototype of the third generation cephalosporins; exerts potent action on aerobic gram-negative as well as some grampositive bacteria, but is not active on anaerobes (particularly Bact. It is an alternative to ceftriaxone for typhoid fever, and can be utilized for single dose therapy (1 g i. Cefotaxime is deacetylated in the body; the metabolite exerts weaker but synergistic action with the parent drug. Cefaclor It retains significant activity by the oral route and is more active than the first generation compounds against H. Cefprozil this 2nd generation cephalosporin has good oral absorption (>90%) with augmented activity against Strep. Ceftizoxime It is similar in antibacterial activity and indications to cefotaxime, but inhibits B. Ceftriaxone has shown high efficacy in a wide range of serious infections including bacterial meningitis (especially in children), multiresistant typhoid fever, complicated urinary tract infections, abdominal sepsis and septicaemias. Ceftazidime the most prominent feature of this third generation cephalosporin is its high activity against Pseudomonas aeruginosa, and the specific indications are-febrile neutropenic patients with haematological malignancies, burn, etc. Its activity against Enterobacteriaceae is similar to that of cefotaxime, but it is less active on Staph. Neutropenia, thrombocytopenia, rise in plasma transaminases and blood urea have been reported. Cefpodoxime proxetil It is the orally active ester prodrug of 3rd generation cephalosporin cefpodoxime. In addition to being highly active against Enterobacteriaceae and streptococci, it inhibits Staph. Cefdinir this orally active 3rd generation cephalosporin has good activity against many lactamase producing organisms. Cefoperazone Like ceftazidime, it differs from other third generation compounds in having stronger activity on Pseudomonas and weaker activity on other organisms. The indications are-severe urinary, biliary, respiratory, skin-soft tissue infections, typhoid, meningitis and septicaemias. Ceftibuten Another oral 3rd generation cephalosporin, active against gram-positive and few gram-negative bacteria, but not Staph. Ceftamet pivoxil this ester prodrug of ceftamet, a 3rd generation cephalosporin has high activity against gram-negative bacteria, especially Enterobacteriaceae and N. Cefepime Developed in 1990s, this 4th generation cephalosporin has antibacterial spectrum similar to that of 3rd generation compounds, but is highly resistant to -lactamases, hence active against many bacteria resistant to the earlier drugs. Due to high potency and extended spectrum, it is effective in many serious infections like hospital-acquired pneumonia, febrile neutropenia, bacteraemia, septicaemia. Diarrhoea due to alteration of gut ecology or irritative effect is more common with orally administered compounds like cephalexin, cefixime and parenteral cefoperazone, which is largely excreted in bile. Hypersensitivity reactions are the most important adverse effects of cephalosporins. Rashes are the most frequent manifestation, but anaphylaxis, angioedema, asthma and urticaria have also occurred. About 10% patients allergic to penicillin show cross reactivity with cephalosporins. Those with a history of immediate type of reactions to penicillin should better not be given a cephalosporin. Nephrotoxicity Some cephalosporins have low-grade nephrotoxicity which may be accentuated by preexisting renal disease, concurrent administration of an aminoglycoside or loop diuretic. Bleeding occurs with cephalosporins having a methylthiotetrazole or similar substitution at position 3 (cefoperazone, ceftriaxone). This is due to hypoprothrombinaemia caused by the same mechanism as warfarin and is more common in patients with cancer, intra-abdominal infection or renal failure. Neutropenia and thrombocytopenia are rare adverse effects reported with ceftazidime and some others. Its zwitterion character permits better penetration through porin channels of gram-negative bacteria. It is resistant to many -lactamases; inhibits type 1 -lactamase producing Enterobacteriaceae and it is more potent against grampositive and some gram-negative bacteria than the 3rd generation compounds. Adverse effects Cephalosporins are generally well tolerated, but are more toxic than penicillin. Respiratory, urinary and soft tissue infections caused by gram-negative organisms, especially Klebsiella, Proteus, Enterobacter, Serratia. Cephalosporins preferred for these infections are cefuroxime, cefotaxime, ceftriaxone. Septicaemias caused by gram-negative organisms: an aminoglycoside may be combined with a cephalosporin. Ceftazidime + gentamicin is the most effective therapy for Pseudomonas meningitis. Gonorrhoea caused by penicillinase producing organisms: ceftriaxone is a first choice drug for single dose therapy of gonorrhoea if the penicillinase producing status of the organism is not known. For chancroid also, a single dose is as effective as erythromycin given for 7 days. They are preferred over fluoroquinolones (especially in children) for empirical therapy, since many S. Mixed aerobic-anaerobic infections in cancer patients, those undergoing colorectal surgery, obstetric complications: cefuroxime, cefaclor or one of the third generation compounds is used. Hospital acquired infections, especially respiratory and other infections in intensive care units, resistant to commonly used antibiotics: cefotaxime, ceftizoxime or a fourth generation drug may work. Prophylaxis and treatment of infections in neutropenic patients: ceftazidime or another third generation compound, alone or in combination with an aminoglycoside. Thus, it is a -lactam antibiotic with a spectrum resembling aminoglycosides, and is resistant to gram-negative -lactamases. The main indications of aztreonam are hospitalacquired infections originating from urinary, biliary, gastrointestinal and female genital tracts. Lack of cross sensitivity with other -lactam antibiotics except ceftazidime (which has chemical similarity to aztreonam) is the most prominent feature of aztreonam: permiting its use in patients allergic to penicillins or cephalosporins. It is resistant to most -lactamases; inhibits penicillinase producing staphylococci. A limiting feature of imipenem is its rapid hydrolysis by the enzyme dehydropeptidase I located on the brush border of renal tubular cells. Imipenem has propensity to induce seizures at higher doses and in predisposed patients. Diarrhoea, vomiting, skin rashes and other hypersensitivity reactions are the side effects. Meropenem is a reserve drug for the treatment of serious nosocomial infections like septicaemia, febrile neutropenia, intraabdominal and pelvic infections, etc. The adverse effects of meropenem are similar to imipenem, but it is less likely to cause seizures. Meropenem this newer carbapenem is not hydrolysed by renal peptidase; does not need to be protected by cilastatin. Like imipenem, it is active against both gram-positive and gram- Doripenem Introduced recently, this carbapenem has antimicrobial activity similar to meropenem, but is more active against some resistant Pseudomonas. Other properties, including nonsusceptibility to renal peptidase, as well as clinical indications are also similar to meropenem. Adverse effects are nausea, diarrhoea, superinfections and phlebitis of the injected vein. The boy also complains of abdominal pain, bloating, loose motions, loss of appetite, occasional vomiting, weakness, malaise and cough. A local doctor had given some tablets for the past 3 days, but the condition has worsened. He looks ill, mildly dehydrated with coated tongue; pulse is 70/min, abdomen is distended and tender on pressing. The first to be introduced was chlortetracycline in 1948 under the name aureomycin (because of the golden yellow colour of S. Oxytetracycline soon followed; others were produced later, either from mutant strains or semisynthetically. All tetracyclines are slightly bitter solids which are slightly water soluble, but their hydrochlorides are more soluble. The subsequently developed members have high lipid solubility, greater potency and some other differences. The tetracyclines still available in India for clinical use are: Tetracycline Doxycycline Oxytetracycline Minocycline Demeclocycline Glycylcycline: Tigecycline Many others like Chlortetracycline, Methacycline, Rolitetracycline, Lymecycline are no longer commercially available. The sensitive organisms have an energy dependent active transport process which concentrates tetracyclines intracellularly. The more lipid-soluble members (doxycycline, minocycline) enter by passive diffusion also (this is partly responsible for their higher potency). The carrier involved in active transport of tetracyclines is absent in the host cells. Moreover, protein synthesizing apparatus of host cells is less susceptible to tetracyclines. These two factors are responsible for the selective toxicity of tetracyclines for the microbes. However, promiscous and often indiscriminate use has gradually narrowed the field of their usefulness.
A pattern of insulin action almost similar to that of insulin glargine is obtained hypertension benign essential discount 25mg hydrochlorothiazide otc, but twice daily dosing may be needed 000 heart attack buy hydrochlorothiazide 12.5mg with amex. Insulin aspart: the proline at B 28 of human insulin is replaced by aspartic acid blood pressure chart time of day 12.5mg hydrochlorothiazide sale. This change reduces the tendency for self-aggregation arrhythmia or panic attack generic hydrochlorothiazide 12.5mg mastercard, and a time-action profile similar to insulin lispro is obtained pulse pressure is calculated by quizlet 25 mg hydrochlorothiazide free shipping. It more closely mimics the physiological insulin release pattern after a meal blood pressure is highest in the safe 25 mg hydrochlorothiazide, with the same advantages as above hypertension diet plan 12.5mg hydrochlorothiazide with visa. Insulin glulisine: Another rapidly acting insulin analogue with lysine replacing asparagine at B 23 and glutamic acid replacing lysine at B 29 arrhythmia kardiak order hydrochlorothiazide 25 mg with visa. Hypoglycaemia this is the most frequent and potentially the most serious reaction. Hypoglycaemia can occur in any diabetic following inadvertent injection of large dose, by missing a meal after injection or by performing vigorous exercise. Generally, the reflex sympathetic symptoms occur before the neuroglucopenic, but the warning symptoms of hypoglycaemia differ from patient to patient and also depend on the rate of fall in blood glucose level. Hypoglycaemic unawareness tends to develop in patients who experience frequent episodes of hypoglycaemia. Finally, when blood glucose falls further (to < 40 mg/dl) mental confusion, abnormal behaviour, seizures and coma occur. It remains soluble at pH4 of the formulation, but precipitates at neutral pH encountered on s. A depot is created from which monomeric insulin dissociates slowly to enter the circulation. Onset of action is delayed, but relatively low blood levels of insulin are maintained for upto 24 hours. Thus, it is suitable for once daily injection to provide background insulin action. Fasting and interdigestive blood glucose levels are effectively lowered irrespective of time of the day when injected or the site of s. Local reactions Swelling, erythema and stinging sometimes occur at the injected site, especially in the beginning. Lipodystrophy of the subcutaneous fat around the injection site may occur if the same site is injected repeatedly. Allergy this is due to contaminating proteins, and is very rare with human/highly purified insulins. Edema Some patients develop short-lived dependent edema (due to Na + retention) when insulin therapy is started. Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to raise blood sugar and reduce effectiveness of insulin. Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic glycogen. Lithium, high dose aspirin and theophylline may also accentuate hypoglycaemia by enhancing insulin secretion and peripheral glucose utilization. Many type 2 cases can be controlled by diet, reduction in body weight and appropriate exercise supplemented, if required, by oral hypoglycaemics. When instituted, insulin therapy has to be tailored according to the requirement and convenience of each patient. A tentative regimen is instituted and the insulin requirement is assessed by testing urine or blood glucose levels (glucose oxidase based spot tests and glucometers are available). Any satisfactory insulin regimen should provide basal control by inhibiting hepatic glucose output, lipolysis and protein breakdown, as well as supply extra amount to meet postprandial needs for disposal of absorbed glucose and amino acids. A single daily injection of any long/intermediate/ short-acting insulin or a mixture of these cannot fulfil both these requirements. Either multiple (2-4) injections daily of long and short acting insulins or a single injection daily of long-acting insulin supplemented by oral hypoglycaemics for meal time glycaemia is used. The advantage is that only two daily injections are required, but the post-lunch glycaemia may not be adequately covered (see Fig. Such intensive regimens more completely meet the objective of achieving round-the-clock euglycaemia, but are more demanding and expensive. Thus, the risk of microvascular disease appears to be related to the glycaemia control. However, regimens attempting near normoglycaemia are associated with higher incidence 267 Fig. Moreover, injected insulin fails to reproduce the normal pattern of increased insulin secretion in response to each meal, and liver is exposed to the same concentration of insulin as other tissues, while normally it receives much higher concentration through portal circulation. As such, the overall desirability and practicability of intensive insulin therapy has to be determined in individual patients. Intensive insulin therapy is best avoided in young children (risk of hypoglycaemic brain damage) and in the elderly (more prone to hypoglycaemia and its serious consequences). Diabetic ketoacidosis (Diabetic coma) Ketoacidosis of different grades generally occurs in insulin dependent diabetics. The most common precipitating cause is infection; others are trauma, stroke, pancreatitis, stressful conditions and inadequate doses of insulin. The principles of treatment remain the same, irrespective of severity, only the vigour with which therapy is instituted is varied. This is maintained till the patient becomes fully conscious and routine therapy with s. When insulin therapy is instituted ketosis subsides and K+ is driven back intracellularly- dangerous hypokalemia can occur. Antibiotics and other supportive measures and treatment of precipitating cause must be instituted simultaneously. Hyperosmolar (nonketotic hyperglycaemic) coma this usually occurs in elderly type 2 patients. Its cause is obscure, but appears to be precipitated by the same factors as ketoacidosis, especially those resulting in dehydration. The general principles of treatment are the same as for ketoacidotic coma, except that faster fluid replacement is to be instituted and alkali is usually not required. These patients are prone to thrombosis (due to hyperviscosity and sluggish circulation), prophylactic heparin therapy is recommended. Insulin resistance Insulin resistance refers to suboptimal response of body tissues, especially liver, skeletal muscle and fat to physiological amounts of insulin. Glucose entry into muscle and liver in response to insulin is deficient in individuals with large stores of body fat. However, in most type 2 diabetics the transducer mechanism linking insulin receptor to the response appears to be faulty, rather than the receptor itself. Exercise increases insulin sensitivity and lack of it contributes to insulin resistance. Pregnancy and oral contraceptives often induce relatively low grade and reversible insulin resistance. Hypertension is often accompanied with relative insulin resistance as part of metabolic syndrome. Acute insulin resistance this form of insulin resistance develops rapidly and is usually a short term problem. Causes are- (a) Infection, trauma, surgery, emotional stress induce release of corticosteroids and other hyperglycaemic hormones which oppose insulin action. Treatment is to overcome the precipitating cause and to give high doses of regular insulin. The insulin requirement comes back to normal once the condition has been controlled. Newer insulin delivery devices A number of innovations have been made to improve ease and accuracy of insulin administration as well as to achieve tight glycaemia control. Insulin syringes Prefilled disposible syringes contain specific types or mixtures of regular and modified insulins. Preset amounts (in 2 U increments) are propelled by pushing a plunger; convenient in carrying and injecting. Moreover, cost, strict adherence to diet, exercise, care of the device and cannula, risk of pump failure, site infection, are too demanding on the patient. Implantable pumps Consist of an electromechanical mechanism which regulates insulin delivery from a percutaneously refillable reservoir. Other routes of insulin delivery Intraperitoneal, oral (by complexing insulin into liposomes or coating it with impermeable polymer) and rectal routes are being tried. These have the advantage of providing higher concentrations in the portal circulation, which is more physiological. Taking this lead, the first clinically acceptable sulfonylurea tolbutamide was introduced in 1957. Clinically useful biguanide phenformin was produced parallel to sulfonylureas in 1957. All first generation compounds have been discontinued except tolbutamide which is infrequently used. Mechanism of action Sulfonylureas provoke a brisk release of insulin from pancreas, the mechanism of which is detailed in Fig. That they do not cause hypoglycaemia in pancreatectomised animals and in type 1 diabetics (presence of at least 30% functional cells is essential for their action), confirms their indirect action through pancreas. A minor action reducing glucagon secretion, probably by increasing insulin and somatostatin release has been demonstrated. In this phase, they sensitize the target tissues (especially liver) to the action of insulin. This is due to increase in number of insulin receptors and/or a postreceptor action-improving translation of receptor activation. It is hypothesized that long-term improvement in carbohydrate tolerance leads to overall lowering of circulating insulin concentration which reverses the down regulation of insulin receptors. As such, they should be used cautiously in patients with liver or kidney dysfunction. Hypoglycaemia It is the commonest problem, may occasionally be severe and rarely fatal. It is more common in elderly, liver and kidney disease patients and when potentiating drugs are added. Tolbutamide carries lowest risk due to its low potency and short duration of action. Treatment of hypoglycaemic episode is to give glucose, may be for a few days because hypoglycaemia may recur. Nausea, vomiting, flatulence, diarrhoea or constipation, headache and paresthesias are generally mild and infrequent. Hypersensitivity Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis. Gliclazide Weaker, shorter acting, flexible dosage, safer in elderly and in those prone to hypoglycaemia. Fast and shorter acting, higher daily dose to be devided, hypoglycaemia and weight gain less likely, preferable in elderly. Has antiplatelet action, generates only inactive metabolite, daily dose > 80mg to be divided. Stimulates 1st phase insulin secretion, less likely to cause delayed hypoglycaemia. Benefits noted are lowering of postprandial as well as fasting blood glucose, HbA1c and body weight. The most important side effect is nausea and vomiting occurring in ~ 50% recipients, but tolerance develops later. Repaglinide this meglitinide analogue oral hypoglycaemic is designed to normalise mealtime glucose excursions. It is administered before each major meal to control postprandial hyperglycaemia; the dose should be omitted if a meal is missed. Because of short lasting action it may have a lower risk of serious hypoglycaemia. Repaglinide is indicated only in selected type 2 diabetics who suffer pronounced post prandial hyperglycaemia, or to supplement metformin/long-acting insulin. Ingested 10 min before meal, it limits postprandial hyperglycaemia in type 2 diabetics without producing late phase hypoglycaemia. The inward flow of K+ ions is thereby restricted, intracellular K+ concentration falls and the membrane is partially depolarized augmenting Ca2+ channel opening as well as release of Ca2+ from intracellular stores. The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane and exocytotic release of insulin. Nausea and diarrhoea are the frequent side effects, but decrease in incidence over time. Use of liraglutide is attended by weight loss, and it is being evaluated as an antiobesity drug even for nondiabetics. However, sitagliptin monotherapy is recommended only when metformin cannot be used. Sitagliptin is well tolerated, side effects are nausea, loose stools, headache, rashes, allergic reactions and edema. Nasopharyngitis and cough occurs in some patients, which has been ascribed to prevention of substance P degradation. The tolerability of vildagliptin is similar to that of sitagliptin, but hepatotoxicity has been reported. Vildagliptin may require twice daily dosing; though single daily dose suffices in most cases when combined with another hypoglycaemic. Because of higher risk of lactic acidosis, phenformin was withdrawn and has been banned in India since 2003. Mechanism of action Biguanides do not cause insulin release, but presence of insulin is essential for their action. Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization through anaerobic glycolysis. Metformin also retards intestinal absorption of glucose, other hexoses, amino acids and Vit B12. Pharmacokinetics the important features of metformin pharmacokinetics are given in Table 19. Adverse effects Side effects with metformin are frequent, but generally not serious. Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea and tiredness are the usual complaints, which tend to subside with time. Lactic acidosis Small increase in blood lactate occurs with metformin, but lactic acidosis is rare (<1 per 10,000 patient years) because it is poorly concentrated in hepatic cells. Infertility: Metformin has been found to improve ovulation and fertility in some infertile women with polycystic ovary. It may be due to mitigation of insulin resistance and lowering of circulating insulin levels. Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue contributes to the insulin sensitizing action. In addition to general restrictions for use of oral hypoglycaemics (see below), metformin is contraindicated in hypotensive states, heart failure, severe respiratory, hepatic and renal disease, as well as in alcoholics because of increased risk of lactic acidosis. Drugs like cimetidine, furosemide may compete with metformin excretion and enhance its toxicity. Pioglitazone is well tolerated; adverse effects are plasma volume expansion, edema, weight gain, headache, myalgia and mild anaemia. About 25% patients may not respond (nonresponders), probably due to low baseline insulin levels. Glucosidase inhibitors Acarbose It is a complex oligosaccharide which reversibly inhibits -glucosidases, the final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. It slows down and decreases digestion and absorption of polysaccharides (starch, etc. Flatulence, abdominal discomfort and loose stool are produced in about 50% patients due to fermentation of unabsorbed carbohydrates. It has been used as an adjuvant to meal time insulin injection to suppress the glycaemic peak in both type 1 and type 2 diabetics. After single daily dose it produces round-the-clock glucosuria and lowers blood glucose levels. The concerns which appear inbuilt due to its mechanism of action are-glycosuria which can predispose to urinary and genital infections, electrolyte imbalance and increased urinary frequency. Metformin, however, could reduce macrovascular complications as well; it decreased risk of death and other diabetes related endpoints in overweight patients. All oral hypoglycaemics do however control symptoms that are due to hyperglycaemia and glycosuria, and are much more convenient than insulin. Oral hypoglycaemics are indicated only in type 2 diabetes, in addition to diet and exercise. Oral hypoglycaemics should be used to supplement dietary management and not to replace it.
But if inflammation is severe pulse pressure 46 cheap hydrochlorothiazide 25 mg on line, they may be applied in conjunction with an effective antibiotic pulse pressure tamponade discount hydrochlorothiazide 12.5mg without a prescription. Posterior segment afflictions like retinitis blood pressure 4 year old child cheap hydrochlorothiazide 25mg free shipping, optic neuritis prehypertension food hydrochlorothiazide 25 mg mastercard, uveitis require systemic steroid therapy just started blood pressure medication generic hydrochlorothiazide 12.5 mg online. Systemic therapy is needed (may be life-saving) in pemphigus vulgaris hypertensive emergency quality 12.5mg hydrochlorothiazide, exfoliative dermatitis blood pressure of 140 90 generic hydrochlorothiazide 25mg visa, Stevens-Johnson syndrome and other severe afflictions heart attack kidney damage discount hydrochlorothiazide 25 mg without prescription. Corticoids are indicated during acute phases- may be used orally or as retention enema (for colonic involvement). They are particularly valuable for patients with systemic manifestions, and are given in addition to sulfasalazine/ mesalazine + other measures (see Ch. Dexa-or betamethasone are preferred because they donot have Na+ retaining activity. Corticoids also afford symptomatic relief in other advanced malignancies by improving appetite and controlling secondary hypercalcaemia. For hypercalcaemia, however, bisphosphonates are more effective and have superseded corticosteroids. Organ transplantation and skin allograft High dose corticoids are given along with other immunosuppressants to prevent the rejection reaction. Low maintenance doses are generally continued over long term + maintenance doses of companion drugs. Septic shock High-dose corticosteroid therapy for septic shock has been abandoned, because it worsens the outcome. Recent studies have documented beneficial effects of low-dose (hydrocortisone 100 mg 8 hourly i. Thyroid storm Many patients in thyroid storm have concomitant adrenal insufficiency. To test pituitary-adrenal axis function Dexamethasone suppresses pituitary-adrenal axis at doses which do not contribute to steroid metabolites in urine. Responsiveness of the axis can be tested by measuring daily urinary steroid metabolite excretion after dosing with dexamethasone. Fragile skin, purple striae-typically on thighs and lower abdomen, easy bruising, telangiectasis, hirsutism. Muscular weakness: proximal (shoulder, arm, pelvis, thigh) muscles are primarily affected. Susceptibility to infection: this is nonspecific for all types of pathogenic organisms. Latent tuberculosis may flare; opportunistic infections with low grade pathogens (Candida, etc. Peptic ulceration: risk is doubled; bleeding and silent perforation of ulcers may occur. Compression fractures of vertebrae and spontaneous fracture of long bones can occur, especially in the elderly. Radiological evidence of osteoporosis is an indication for withdrawal of corticoid therapy. Corticosteroid induced osteoporosis can be prevented/arrested by calcium supplements + vit D, and by estrogen/raloxifene or androgen replacement therapy in females and males respectively. Avascular necrosis of head of femur, humerous, or knee joint is an occasional abrupt onset complication of high dose corticosteroid therapy. Posterior subcapsular cataract may develop after several years of use, especially in children. Growth retardation: in children occurs even with small doses if given for long periods. Foetal abnormalities: Cleft palate and other defects are produced in animals, but have not been encountered on clinical use in pregnant women. The risk of abortion, stillbirth or neonatal death is not increased, but intrauterine growth retardation can occur after prolonged therapy, and neurological/ behavioral disturbances in the offspring are feared. Prednisolone appears safer than dexa/ beta methasone, because it is metabolized by placenta, reducing foetal exposure. Prolonged corticosteroid therapy during pregnancy increases the risk of gestational diabetes, pregnancy induced hypertension and preeclampsia. Psychiatric disturbances: mild euphoria frequently accompanies high dose steroid treatment. In time, adrenal cortex atrophies and stoppage of exogenous steroid precipitates withdrawal syndrome consisting of malaise, fever, anorexia, nausea, postural hypotension, electrolyte imbalance, weakness, pain in muscles and joints and reactivation of the disease for which they were used. Subjected to stress, these patients may go into acute adrenal insufficiency leading to cardiovascular collapse. If a patient on steroid therapy develops an infection-the steroid should not be discontinued despite its propensity to weaken host defence and delay healing. Surgery is such a patient should be covered by intraoperative and postoperative i. Alternate-day therapy also resulted in less immunological suppression-lower risk of infection. Since corticosteroids may have to be used as a life-saving measure, all of these are relative contraindications in the presence of which these drugs are to be employed only under compelling circumstances and with due precautions. After 4 weeks, the symptoms subsided and prednisolone dose was tapered at the rate of 10 mg every 2 weeks. When she was taking 10 mg prednisolone/ day, she met with a road-side accident and suffered compound fracture of both bones of the right leg. Internal fixation of the fracture and suturing of wounds under general anaesthesia is planned. That testes are responsible for the male characters is known since prehistoric times. Testosterone was isolated as the testicular hormone, its structure was worked out and it was synthetically prepared by the year 1935. In women ovary produces small quantity of testosterone; this together with that derived indirectly from adrenals amounts to 0. Synthetic androgens Methyltestosterone and fluoxymesterone are 17-alkyl substituted derivatives of testosterone which are orally active because of resistance to first pass metabolism, but have submaximal androgenic efficacy and potential to cause cholestatic jaundice. Other orally active compounds are testosterone undecanoate which is administered as oily solution to be absorbed through lymphatics bypassing the liver, and mesterolone. A number of lipid-soluble esters of testosterone have been produced, suitable for injection in oily vehicle, from which they are absorbed slowly and exert prolonged action after deesterification in the body. Estrogens are more potent inhibitors of Gn secretion even in males, and it is believed that the small amount of estradiol produced by testes as well as that resulting from conversion of testosterone to estradiol in liver and fat plays a role in feedback inhibition. Sex organs and secondary sex characters (Androgenic) Testosterone is responsible for all the changes that occur in a boy at puberty: Growth of genitals-penis, scrotum, seminal vesicles, prostate. Growth of hair-pubic, axillary, beard, moustache, body hair and male pattern of its distribution. Thickening of skin which becomes greasy due to proliferation and increased activity of sebaceous glands-especially on the face. Behavioral effects are-increased physical vigour, aggressiveness, penile erections. Male libido appears to be activated by testosterone directly, and probably to a greater extent by estradiol produced from testosterone. Testosterone is also important for the intrauterine development of the male phenotype. Relatively large amounts of testosterone are produced by the foetal testes during the first half of intrauterine life. Testes Moderately large doses cause testicular atrophy by inhibiting Gn secretion from pituitary. High concentration of testosterone is attained locally in the spermatogenic tubules by diffusion from the neighbouring Leydig cells and stimulates spermatogenesis. Skeleton and skeletal muscles (Anabolic) Testosterone is responsible for the pubertal spurt of growth in boys and to a smaller extent in girls. Estradiol produced from testosterone, and not testosterone itself, is responsible for fusion of epiphyses in boys as well as in girls. There is accretion of nitrogen, minerals (Na, K, Ca, P, S) and water-body weight increases rapidly, more protoplasm is built. Testosterone given to patients prone to salt and water retention may develop edema. Erythropoiesis Testosterone accelerates erythropoiesis by increasing erythropoietin production and probably direct action on haeme synthesis. Mechanism of action Testosterone can largely be regarded as the circulating prohormone. The genital skin of both sexes and urogenital tract of male contains 5- reductase-2 which is more sensitive to inhibition by finasteride. Genetic deficiency of this isoenzyme causes male pseudohermaphroditism because of inability of male genitalia to produce the active hormone dihydrotestosterone from circulating testosterone. Therefore, slowly absorbed esters of testosterone are used by this route-are hydrolysed to the active free form. The major metabolic products of testosterone are androsterone and etiocholanolone which are excreted in urine, mostly as conjugates with glucuronic acid and sulfate. Small quantities of estradiol are also produced from testosterone by aromatization of A ring in extraglandular tissues (liver, fat, hypothalamus). By cutaneous delivery, testosterone/ dihydrotestosterone circumvent hepatic first pass metabolism; uniform blood levels are produced round the clock. A gel formulation has been marketed for once daily application which has become the preferred method of androgen replacement for hypogonadism and impotence. Fixed dose combinations of testosterone with yohimbine, strychnine and vitamins are banned in India. Frequent, sustained and often painful erections in males in the beginning of therapy; subside spontaneously after sometime. Oligozoospermia can occur with moderate doses given for a few weeks to men with normal testosterone levels. Precocious puberty, premature sexual behaviour, and stunting of stature due to early closure of epiphysis-if testosterone is given continuously to young boys for increasing stature. Salt retention and edema: especially when large doses are used in patients with heart or kidney disease. Cholestatic jaundice: occurs with methyltestosterone and other 17-alkyl substituted derivatives (fluoxymesterone and some anabolic steroids like oxymetholone, stanozolol) in a dose dependent manner, but not with parenterally used esters of testosterone. Hepatic carcinoma: incidence is higher in patients who have received long-term methyltestosterone or other oral androgens. Gynaecomastia: may occur, especially in children and in patients with liver disease. Dihydrotestosterone does not cause gynaecomastia because it is not converted to estradiol. Contraindications Androgens are contraindicated in carcinoma of prostate and male breast, liver and kidney disease and during pregnancy (masculinization of female foetus). Secondary testicular failure occurring later in life manifests mainly as loss of libido, muscle mass and energy, feminization, mild anaemia and impotence. However, impotence due to psychological and other factors, and not testosterone deficiency, does not respond. The attacks can be prevented by 17-alkylated androgens (methyltestosterone, stanozolol, danazol) but not by testosterone. Ageing Because testosterone levels decline in old age, it has been administered to elderly males to improve bone mineralization and muscle mass. However, safety of such therapy in terms of metabolic, cardiovascular and prostatic complications is not known. Occasionally small amount of androgen is added to postmenopausal hormone replacement. Idiopathic male infertility Since high intratesticular level of testosterone is essential for spermatogenesis, it is presumed that exogenous androgens will stimulate spermatogenesis or improve sperm maturation in epididymis. On the other hand, androgens can adversely affect spermatogenesis by suppressing Gn secretion. Since mesterolone causes less feedback inhibition of Gn (probably due to restricted entry into brain) it is believed that moderate doses will predominantly stimulate testis directly. A recent metaanalysis of 11 clinical trials has found that oral androgens (mesterolone and testosterone undecanoate) had no effect on sperm count or sperm motility as well as on subsequent pregnancy rate when given to oligoastheno-spermic subfertile men. The anabolic : androgenic activity ratio is determined by injecting the drug in castrated rats and measuring the increase in weight of levator ani muscles to that of ventral prostate. The anabolic : androgenic ratio of testosterone is considered as 1; the anabolic selectivity of these steroids is modest with ratios between 1 to 3 in the rat model, and probably still lower in man. The anabolic effects are similar to that of testosterone and are mediated through the same receptor as the androgenic effects. The 17-alkyl substituted compounds oxymetholone, stanozolol, can produce jaundice and worsen lipid profile. Anabolic steroids can reduce N2 loss over short periods, but long-term benefits are questionable. They may cause a transient response in the elderly, under-nourished or debilitated individuals, but controlled studies have failed to demonstrate a difference in the total weight gained. However, short-term use may be made during convalescence for the sense of wellbeing and improvement in appetite caused by such treatment. Osteoporosis In elderly males and that occurring due to prolonged immobilization may respond to anabolic steroids, but bisphosphonates are more effective and are the preferred drugs. Brief spurts in linear growth can be induced by anabolic steroids, but this probably does not make a difference in the final stature, except in hypogonadism. Use for more than 6 months is not recommended-premature closure of epiphyses and shortening of ultimate stature may result. To enhance physical ability in athletes When administered during the period of training androgens/anabolic steroids can increase the strength of exercised muscles. However, effects are mostly short-lived and the magnitude of improvement in performance is uncertain except in women. In addition, it suppresses gonadal function directly by inhibiting steroidogenic enzymes. In women endometrial atrophy occurs over few a weeks and amenorrhoea may supervene. Endometriosis Danazol causes improvement in ~75% cases by inhibiting ovarian function. Danazol is infrequently used now because of androgenic side effects and risk of liver damage. Hereditary angioneurotic edema Danazol is a 17 alkylated steroid: has prophylactic effect in this condition by inducing complement (C1) esterase inhibitor (see above). Androgenic side effects are acne, hirsutism, decreased breast size, deepening of voice, edema and weight gain. Cimetidine and spironolactone have weak antiandrogenic action which manifests as side effects. Given to boys in relatively higher doses, it prevents pubertal changes, while in adult men libido and androgenic anabolism are suppressed. Its clinical indications are- precocious puberty in boys, inappropriate sexual behaviour in men, acne and hirsutism in women (usually in combination with an estrogen). Its efficacy in metastatic prostate carcinoma is inferior to other forms of androgen deprivation. Side effects are hot flashes, chills, edema and loose stools, but it is better tolerated and less hepatotoxic than flutamide. Elevation of hepatic transaminase above twice normal is a signal for stopping the drug. It is relatively selective for 5 -reductase type 2 isoenzyme which predominates in male urogenital tract. The beneficial effects are typically delayed needing ~6 months for maximum symptomatic relief. Patients with large prostate (volume > 40 ml) obtain greater relief than those with smaller gland. Withdrawal of the drug results in regrowth of prostate, but with continued therapy benefit is maintained for 3 years or more. The relief of obstructive symptoms, however, is less marked compared to surgery and adrenergic 1 blockers (see p. It primarily reduces the static component of obstruction, while 1 blockers overcome the dynamic component. Finasteride has also been found effective in male pattern baldness, though hair follicles have primarily type 1 enzyme. Its active metabolite 2-hydroxyflutamide competitively blocks androgen action on accessory sex organs as well as on pituitary. Plasma testosterone levels increase in males which partially overcome the direct antiandrogenic action. Along with oral contraceptives it has been tried in female hirsutism, but its hepatotoxic potential may not justify such use. Though gynaecomastia and breast tenderness occur frequently, libido and potency are largely preserved during flutamide treatment.
