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Tolerability of Eto is poor; frequent adverse effects are- anorexia symptoms 24 hours before death order genuine duphalac line, nausea treatment 5th metatarsal shaft fracture purchase duphalac amex, vomiting treatment 3rd stage breast cancer order duphalac 100ml amex, salivation symptoms pinched nerve neck 100ml duphalac overnight delivery, metallic taste, epigastric discomfort, sulfurous belching and hepatitis. It also causes aches and pains, peripheral neuritis, behavioural changes, rashes, impotence, menstrual disturbances and goiter on prolonged use. Prothionamide (Pto) A close congener of Eto, to which it resembles in antimycobacterial property, mechanism of action, pharmacokinetics and adverse effects. Clinically it is cosidered interchangeable with Eto for use in MDR-TB, MAC infection, etc. Accordingly, it inhibits bacterial cell well synthesis by inactivating the enzymes which racemize L-alanine and link two D-alanine residues. Cs is tuberculostatic; in addition inhibits MAC as well as some other gram-positive bacteria, E. Resistance to Cs develops slowly; no cross resistance with any other anti-TB drugs occurs. Oral absorption of Cs is good; it diffuses all over the body; CSF concentration is equal to that in plasma. Adverse effects of Cs are primarily neurological; about half of the recipients experience neuropsychiatric symptoms, viz. Dose: Start with 250 mg BD, increase if tolerated to 750 mg/day for patients with body weight >45 kg. Terizidone It contains 2 molecules of cycloserine and has antibacterial properties as well as mechanism of action similar to it; but is believed to be less neurotoxic; reported incidence of adverse effects is lower. It is used as a substitute of Cs, especially in genitourinary TB, because it attains higher and longer lasting concentration in urine. Para-amino salicylic acid (PAS) Introduced in 1946, PAS is related to sulfonamides and acts probably by the same mechanism, i. It is not active against other bacteria, and this selectivity may be due to difference in the affinity for folate synthase of M. PAS is tuberculostatic and one of the least active drugs: does not add to the efficacy of more active drugs that are given with it; only delays development of resistance-probably by directly inhibiting episomal resistance transfer. It is used as the sodium salt (large doses that are needed may cause Na+ overload) or calcium salt (better gastric tolerance is claimed). PAS is absorbed completely by the oral route and distributed all over except in CSF. Patient acceptability of PAS is poor because of frequent anorexia, nausea and epigastric pain. Other adverse effects are rashes, fever, malaise, hypokalaemia, goiter, liver dysfunction and rarely blood dyscrasias. Thiacetazone (Thz) Its efficacy in TB is now considered uncertain, and it is not indicated, even as a reserve drug, in MDR-TB. Rifabutin It is related to rifampin in structure and mechanism of action, but is less active against M. The primary indication of rifabutin is for prophylaxis and treatment of MAC infection in HIV-AIDS patients. Gastrointestinal intolerance, rashes, granulocytopenia, myalgia and uveitis have been reported with rifabutin. Fixed dose combination of antitubercular drugs with vitamins (except INH + Vit B6) are banned in India. This has been possible due to better understanding of the biology of tubercular infection and the differential properties of the antitubercular drugs. In unfavourable conditions it grows only intermittently or remains dormant for prolonged periods. Several subpopulations of bacilli, each with a distinctive metabolic state, could exist in an infected patient. They are particularly vulnerable to Z, while H, R and E are less active, and S is inactive. The relative activity of the first line drugs in achieving these goals differs. On the other hand S is active only against rapidly multiplying extracellular bacilli. E is bacteriostatic-mainly serves to prevent resistance and may hasten sputum conversion. Drug combinations are selected to maximise the above actions together with considerations of cost, convenience and feasibility. The general principles of antitubercular chemotherapy are: Use of any single drug in tuberculosis results in the emergence of resistant organisms and relapse in almost 3/4th patients. Because an average patient of pulmonary tuberculosis harbours 108 to 1010 bacilli, the number of organisms that will not respond to a single drug is high and cannot be dealt by the host defence.

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Dynamic shaping of cellular membranes by phospholipids and membrane-deforming proteins treatment neutropenia buy duphalac once a day. The effects of most drugs result from their interaction with macromolecular components of the organism medications used for bipolar disorder buy generic duphalac 100ml line. The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response medicine ball 100ml duphalac amex. Drugs commonly alter the rate or magnitude of an intrinsic cellular or physiological response rather than create new responses symptoms multiple myeloma 100ml duphalac for sale. Drug receptors are often located on the surface of cells but may also be located in specific intracellular compartments, such as the nucleus, or in the extracellular compartment, as in the case of drugs that target coagulation factors and inflammatory mediators. A large percentage of the new drugs approved in recent years are therapeutic biologics, including genetically engineered enzymes and monoclonal antibodies. Going far beyond the traditional concept of a drug are genetically modified viruses and microbes. One recently approved agent for treating melanoma is a genetically modified live oncolytic herpes virus that is injected into tumors that cannot be removed completely by surgery. Gene therapy products using viruses as vectors to replace genetic mutations that give rise to lethal and debilitating diseases have already been approved in China and Europe. These new agents will have pharmacological properties that are distinctly different from traditional small-molecule drugs. Agents that are only partially as effective as agonists are termed partial agonists. In the presence of a full agonist, partial and inverse agonists will behave as competitive antagonists. Specificity of Drug Responses the strength of the reversible interaction between a drug and its receptor, as measured by the dissociation constant, is defined as the affinity of one for the other. A drug that interacts with a single type of receptor that is expressed on only a limited number of differentiated cells will exhibit high specificity. Conversely, a drug acting on a receptor expressed ubiquitously throughout the body will exhibit widespread effects. Many clinically important drugs exhibit a broad (low) specificity because they interact with multiple receptors in different tissues. Such broad specificity might not only enhance the clinical utility of a drug but also contribute to a spectrum of adverse side effects because of off-target interactions. One example of a drug that interacts with multiple receptors is amiodarone, an agent used to treat cardiac arrhythmias. The stereoisomers can exhibit different pharmacodynamic as well as pharmacokinetic properties. For example, the antiarrhythmic drug sotalol is prescribed as a racemic mixture; the d- and l-enantiomers are equipotent as K+ channel blockers, but the l-enantiomer is a much more potent adrenergic antagonist (see Chapter 30). A drug may have Physiological Receptors Many drug receptors are proteins that normally serve as receptors for endogenous regulatory ligands. Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists. If the drug binds to the same recognition site as the endogenous agonist, the drug is said to be a primary agonist. Allosteric (or allotopic) agonists bind to a different region on the receptor, referred to as an allosteric or allotopic site. In this model, receptor R can exist in active (Ra) and inactive (Ri) conformations, and drugs binding to one, the other, or both states of R can influence the balance of the two forms of R and the net effect of receptor-controlled events. The ordinate is the activity of the receptor produced by Ra, the active receptor conformation. If the drug selectively binds to Ri, then the net influence and amount of Ra will be diminished. If L can bind to receptor in an active conformation Ra but also bind to inactive receptor Ri with lower affinity, the drug will produce a partial response; L will be a partial agonist. If there is sufficient Ra to produce an elevated basal response in the absence of ligand (agonist-independent constitutive activity), and L binds to Ri, then that basal activity will be inhibited; L will then be an inverse agonist. Inverse agonists selectively bind to the inactive form of the receptor and shift the conformational equilibrium toward the inactive state. In systems that are not constitutively active, inverse agonists will behave like competitive antagonists, which helps explain that the properties of inverse agonists and the number of such agents previously described as competitive antagonists were only recently appreciated. Receptors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine, bradykinin, and adenosine receptors. Chronic administration of a drug may cause a downregulation of receptors or desensitization of response that can require dose adjustments to maintain adequate therapy. Chronic administration of nitrovasodilators to treat angina results in the rapid development of complete tolerance, a process known as tachyphylaxis. For instance, aluminum and magnesium hydroxides [Al(OH)3 and Mg(OH)2] reduce gastric acid chemically, neutralizing H+ with OH+ and raising gastric pH. Mannitol acts osmotically to cause changes in the distribution of water to promote diuresis, catharsis, expansion of circulating volume in the vascular compartment, or reduction of cerebral edema (see Chapter 25). Anti-infective drugs such as antibiotics, antivirals, and antiparasitics achieve specificity by targeting receptors or cell processes that are critical for the growth or survival of the infective agent but are nonessential or lacking in the host organism.

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It has been approved for use in children 7 years or older for depression and OCD on the basis of similar efficacy and side effect profile as in adults medications like abilify purchase cheapest duphalac and duphalac, but should be given to children only when psychotherapy fails medications 24 buy discount duphalac 100 ml. Because of slower onset of antidepressant effect symptoms for pregnancy purchase duphalac with a visa, it is considered less suitable for patients needing rapid effect treatment glaucoma buy 100ml duphalac otc, but is more appropriate for poorly compliant patients. Relatively more nausea, dyspepsia, flatulence, nervousness and discontinuation reactions have been reported with fluvoxamine. Sertraline this SSRI has gained popularity, because in clinical trials fewer patients stopped sertraline due to side effects. Efficacy in juvenile depression has been demonstrated, and it is recommended for anxiety and post-traumatic stress disorder (PTSD) as well. Drug interactions due to inhibition of CYP isoenzymes are less likely to occur with this SSRI. Citalopram this SSRI shares with sertraline a lower propensity to cause drug interactions. However, few deaths due to overdose of citalopram are on record, because of which it is to be avoided in patients likely to attempt suicide. Escitalopram It is the active S(+) enantiomer of citalopram, effective at half the dose, with similar properties. Side effects are nausea, vomiting, loose motions, headache, dizziness and occasionally insomnia. Duloxetine is also indicated in panic attacks, diabetic neuropathic pain, fibromyalgia and stress urinary incontinence in women (because it increases urethral tone). Trazodone It is the first atypical antidepressant; less efficiently blocks 5-HT uptake and has prominent adrenergic and weak 5-HT2 antagonistic actions. The latter may contribute to its antidepressant effect, which nevertheless is modest. It is sedative but not anticholinergic, causes bradycardia rather than tachycardia, does not interfere with intracardiac conduction-less prone to cause arrhythmia and better suited for the elderly. Inappropriate, prolonged and painful penile erection (priapism) occurs in few recipients resulting in impotence in a fraction of these. The 1 adrenergic blocking property has been held responsible for this effect as well as for postural hypotension. Mianserin It is unique in not inhibiting either NA or 5-HT uptake; but blocks presynaptic 2 receptors thereby increasing release and turnover of NA in brain which may be responsible for the antidepressant effect. While anticholinergic and cardiac side effects are less prominent, it has caused seizures in overdose. The augmented NA further increases firing of Other uses of SSRIs the SSRIs are now 1st choice drugs for OCD, panic disorder, social phobia, eating disorders, premenstrual dysphoric disorder and PTSD. They are also being increasingly used for anxiety disorders, body dysmorphic disorder, compulsive buying, kleptomania and premature ejaculation. Elevation of mood and increased work capacity has been reported in postmyocardial infarction and other chronic somatic illness patients. Thus, SSRIs are being used to improve outlook on life and to feel good, even in apparently nondepressed patients. Venlafaxine A novel antidepressant referred to as SNRI, because it inhibits uptake of both NA and 5-HT but, in contrast to older TCAs, does not interact with cholinergic, adrenergic or histaminergic receptors or have sedative property. Trials have shown it to be as effective antidepressant as TCAs and may work in some resistant cases. Mood changes and hot flushes in menopausal syndrome, some anxiety and eating disorders are also benefited by venlafaxine. It does not produce the usual side effects of TCAs; tends to raise rather than depress BP and is safer in overdose. Prominent side effects are nausea, sweating, anxiety, dizziness, impotence and withdrawal reactions on discontinuation. Selective enhancement of antidepressive 5-HT1 receptor action is achieved by concurrent blockade of 5-HT2 and 5-HT3 receptors which are held responsible for some of the adverse effects of high serotonergic tone. Accordingly, it has been labelled as "noradrenergic and specific serotonergic antidepressant" (NaSSA). It is a H1 blocker and quite sedative, but not anticholinergic or antidopaminergic. Efficacy in mild as well as severe depression is reported to be comparable to TCAs, and given once daily at bed time, it is particularly suitable for those with insomnia. Bupropion this inhibitor of DA and NA uptake has excitant rather than sedative property. It is metabolized into an amphetamine like compound which can cause presynaptic release of DA and NA. In clinical trials it has been found to yield higher smoking abstinence and quitting rates than placebo and equivalent to nicotine replacement.

Discontinuation reaction consisting of paresthesias treatment brown recluse spider bite discount 100ml duphalac with mastercard, bodyache symptoms quitting weed purchase 100 ml duphalac visa, bowel upset medications every 8 hours buy duphalac once a day, agitation and sleep disturbances occurs in some patients treatment math definition cheap duphalac 100 ml with amex. However, risk of switching over to hypomania during treatment is less with SSRIs than with TCAs. Some authorities now consider SSRIs to be more effective antidepressants than TCAs. The converse is also true, and there is no way to predict which patient will respond to which drug. Because of freedom from psychomotor and cognitive impairment, SSRIs are preferred for prophylaxis of recurrent depression (should be combined with lithium/ valproate). Metaanalysis of comparative trials has shown no significant difference in efficacy among individual SSRIs, but there are pharmacokinetic differences and incidence of particular side effects differs somewhat. Fluoxetine A bicyclic compound, is the first SSRI to be introduced, and the longest acting. However, longterm efficacy is not known, and it can cause insomnia, agitation, dry mouth and nausea, but not sexual side effects. Seizures occur in over dose and in predisposed patients due to lowering of seizure threshold. Tianeptine this antidepressant is reported to increase rather than inhibit 5-HT uptake, and is neither sedative nor stimulant. It has shown efficacy in anxiodepressive states, particularly with psychosomatic symptoms, as well as in endogenous depression. Side effects are dry mouth, epigastric pain, flatulence, drowsiness/ insomnia, tremor and bodyache. Amineptine Like tianeptine it enhances 5-HT uptake, and has antidepressant property. It produces anticholinergic side effects including tachycardia, confusion and delirium. Postural hypotension, conduction disturbances and arrhythmias can occur, especially in patients with heart disease. Atomoxetine It is unrelated to tricyclic antidepressants, but is a selective NA reuptake inhibitor. It is approved only for treatment of attention deficit hyperactivity disorder (ADHD), and is described in Ch. Endogenous (major) depression: the aim is to relieve symptoms of depression and restore normal social behaviour. Choice of a particular drug for an individual patient depends on the secondary properties (sedative, anticholinergic, hypotensive, cardiotoxic, seizure precipitating, etc. The SSRIs are currently used as first choice for their better tolerability, safety and may be higher efficacy as well. The only antidepressants clearly shown to be effective in juvenile depression are fluoxetine and sertraline. The TCAs are mostly used as alternatives in non-responsive cases or in those not tolerating the second generation antidepressants. Substituting a drug with a different pattern of aminergic action often succeedes in nonresponsive cases. Moclobemide is a well tolerated option for mild to moderate depression, especially suited for elderly and cardiac patients. However, antidepressants are not the answer to every grief, loss, set back and other sad events that are part of life, but the less toxic and more patient-friendly SSRIs/SNRIs/atypical antidepressants are now more readily prescribed for depressive illness. ECT may be given in the severely depressed, especially initially while the effect of antidepressants is developing, because no antidepressant has been clearly demonstrated to act fast enough to prevent suicide. The TCAs or SSRIs must be combined with lithium/ valproate/lamotrigine for bipolar depression, and not used alone due to risk of switching over to mania. Combination of one of the SSRIs with an atypical antipsychotic (such as olanzapine, aripiprazole or quetiapine) is also accepted as a treatment option for bipolar depression. Obsessive-compulsive and phobic states: the SSRIs, particularly fluoxamine, are the drugs of choice due to better patient acceptability. TCAs, especially clomipramine, are highly effective in OCD and panic disorders: more than 25% improvement occurs in OCD rating scale and panic attacks are reduced in >75% patients. SSRIs and TCAs also reduce compulsive eating in bulimia, and help patients with body dysmorphic disorder, compulsive buying and kleptomania, though these habits may not completely die. Anxiety disorders: Antidepressants, especially SSRIs, exert a delayed but sustained beneficial effect in many patients of generalized anxiety disorder; may be used along with a short course of BZDs to cover exacerbations. SSRIs have also proven helpful in phobic disorders, sustained treatment of panic attacks and in posttraumatic stress disorder. Neuropathic pain: Amitriptyline and other TCAs afford considerable relief in diabetic and some other types of chronic pain. Duloxetine, a SNRI, is now a first line drug for diabetic neuropathy, fibromyalgia, etc. Combination of duloxetine + pregabalin may work if monotherapy is not satisfactory. Attention deficit-hyperactivity disorder (ADHD) in children: TCAs with less depressant properties like imipramine, nortriptyline and amoxapine are now first line drugs in this disorder, comparable in efficacy to amphetaminelike drugs, with the advantage of less fluctuating action and fewer behavioural side effects. Atomoxetine is a NA reuptake inhibitor unrelated to both TCAs as well as amphetamine, which is used specifically in ADHD. Premature ejaculation: It refers to repeated occurrences of ejaculation before or shortly after penetration, or with minimal sexual stimulation. It is a very common sexual complaint, which is often interpreted as sexual weakness; can cause considerable distress and dissatisfaction in the patient as well as in his partner. Sometimes the subject has unreasonable expectations about the optimal/desirable length of intercourse.

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