Markers of Tuberculosis in Pleural Effusion :-
Interferon gamma > 140 IU
Adenosine deamylase > 40
PCR
Roth Spots :-
seen in the retina of Myeloproliferative, Lymphoproliferatie disorders and Infective endocarditis.
Spiral CT scan :-
for pulmonary embolism
Addison’s disease :-
The patients have microcardia (small heart).
Kikuchi’s disease :-
Mostly in Japan, in young girls, bilateral lymphadenopathy with high grade fever is seen in this disease.
The National Institute for Health and Clinical Excellence (NICE) and the National Collaborating Centre for Chronic Conditions, in conjunction with the British Hypertension Society (BHS) have today (Wednesday 28 June) launched the keenly awaited updated clinical guideline on the management of hypertension:-
The updated recommendations in the guideline include the following:
• In hypertensive patients aged 55 and over, or Black patients* of any age, first choice of initial therapy should be either a calcium channel blocker or a thiazide-type diuretic.
* Black patients are those of African or Caribbean descent, and not mixed race, Asian or Chinese patients
• In hypertensive patients younger than 55, first choice initial therapy should be an ACE inhibitor (or an Angiotensin receptor blocker if an ACE inhibitor is not tolerated).
• If initial therapy was with a calcium channel blocker or thiazide-type diuretic and a second drug is required, add an ACE inhibitor (or an Angiotensin receptor blocker if an ACE inhibitor is not tolerated). If initial therapy was with an ACE inhibitor, add a calcium channel blocker or a thiazide-type diuretic.
• If treatment with three drugs is required, the combination of ACE inhibitor (or an Angiotensin receptor blocker if an ACE inhibitor is not tolerated), calcium channel blocker and thiazide-type diuretic should be used.
The decision not to recommend Beta-blockers for first line therapy is based on evidence that suggests that they perform less well than other drugs, particularly in the elderly, and the increasing evidence that the most frequently used Beta-blockers at usual doses carries an unacceptable risk of provoking type 2 diabetes. The guideline also makes recommendations beyond a 3-drug combination, where, although the evidence is less certain, the GDG took into account existing guidelines and constructed recommendations most compatible with current good practice.
Hypertensive Crisis:-
Only HTN.
Hypertensive Emergency:-
With Complications.
Accelerated Hypertension:-
End Organ Damage.
The young patient with paroxysm of palpitations:-
at rest —-> mostly its paroxysmal svt
after exercise —-> rvot – vt.
Side effects of captopril:-
Angioedema.
Mechanical Valves induce haemolysis.
Regarding contraceptive when a male patient is on thalidomide , the answer is a single barrier method:-
Because of the known human teratogenicity of thalidomide, thalidomide is contraindicated in women who are or may become pregnant and who are not using the two required types of birth control or who are not continually abstaining from heterosexual sexual contact. If thalidomide is taken during pregnancy, it can cause severe birth defects or death to an unborn baby. Thalidomide should never be used by women who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman can cause birth defects. If pregnancy does occur during treatment, the drug should be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to THALOMID® (thalidomide) must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. The risk to the fetus from the semen of male patients taking thalidomide is unknown.
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Inducers of the P450 system include
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
Inhibitors of the P450 system include
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine, omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin
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Young people with septic arthritis – gonococcus; older people – Staph aureus
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Using Beta Blockers in Patients with Heart Failure
Compelling evidence now exists to support the safety and efficacy of beta-blocker therapy in patients with heart failure. Guidance on the implementation of beta-blocker therapy in these patients is provided in the following sections.
Beta-blocker therapy is appropriate in patients with New York Heart Association class II or class III symptoms resulting from left ventricular systolic dysfunction.Patient Selection
Beta blocker therapy is appropriate in patients with NYHA class II or class III symptoms resulting from left ventricular systolic dysfunction. Unless contraindicated, beta blockers should be considered a mainstay of therapy in these patients to improve symptoms and mortality and to decrease hospitalizations.
None of the trials described in this article tested the use of beta blockers in patients with NYHA class I disease. Many asymptomatic patients with left ventricular dysfunction have had a myocardial infarction sometime in the past. Data on the administration of beta blockers subsequent to myocardial infarction are compelling enough to justify the use of these agents, if tolerated, in patients with NYHA class I disease. Many of these patients have other comorbid conditions, such as hypertension or angina, for which beta blockers may also be indicated.
When beta blockers are used in patients with heart failure, they should be considered disease-modifying agents rather than “rescue” agents. Their utility lies in blocking the neurohormonal cascade that leads to progression of the disease, not in providing immediate symptomatic relief.
None of the published trials have included sufficient numbers of patients with NYHA class IV symptoms to justify the safety or efficacy of beta blockers in this group. BEST was designed to better address this issue, but the trial included relatively few patients with NYHA class IV symptoms and was stopped early. The COPERNICUS trial may provide guidance once data become available. Pending release of the COPERNICUS trial results or other data, beta blockers should not be used in patients with NYHA class IV symptoms; however, these agents may be started or resumed once NYHA class IV symptoms resolve and patients are hemodynamically stable.
When beta blockers are used in patients with heart failure, they should be considered disease-modifying agents rather than “rescue” agents. Their utility lies in blocking the neurohormonal cascade that leads to progression of the disease, not in providing immediate symptomatic relief. Thus, patients should be hemodynamically stable when beta-blocker therapy is initiated. This approach provides certain pragmatic difficulties in dealing with patients who may already be taking a number of medications and may be resistant to the thought of adding another medication at a time when they seem well. In this setting, however, the risks of polypharmacy seem to be justified when compared to the mortality benefit of beta-blocker therapy.
Beta blockers appear to be effective irrespective of the etiology of the heart failure. Similarly, no age-specific phenomena have been reported. Preliminary data from BEST imply that racial differences may exist in the response of patients with heart failure to beta blockers; however, conclusions about this issue must await release of the trial results.
Carvedilol is the only agent labeled by the FDA for use in patients with heart failure. It is also the only agent that is available in the appropriate starting dosage (3.125 mg twice daily). The starting dosages for metoprolol tartrate, metoprolol succinate and bisoprolol require that the tablet in the smallest available dose size be split into fourths, which may be a cumbersome task for some patients. In addition, dividing the metoprolol succinate tablet into fourths may disrupt the delivery system, although it is not known if tablet division would have an adverse clinical impact. Metoprolol tartrate and bisoprolol are the least expensive of these agents (Table 6).
Once the patient has tolerated the starting dosage of the selected beta blocker, the dosage should be doubled every two to four weeks as tolerated. While the dosage is being titrated, the patient should be monitored for signs of worsening heart failure, hypotension or bradycardia. If symptoms develop, the dosage may need to be held at the current level or decreased; in some patients, the drug may need to be stopped. Otherwise, the dosage should be increased until the target dosage is achieved or the patient is receiving the maximal tolerated dosage, if below the target level. Once the desired dosage has been reached, no further adjustments need to be made. Even if the patient’s symptoms stabilize or the ejection fraction normalizes, most experts recommend continuing beta-blocker therapy indefinitely.
Other Pharmacologic Therapy
In all of the published mortality trials, beta blockers were added to background therapy with ACE inhibitors, diuretics and, sometimes, digoxin (Lanoxin). All patients for whom beta-blocker therapy is indicated should also be taking an ACE inhibitor as tolerated, unless contraindications exist. Diuretics should be titrated as needed for symptoms of volume overload. Digoxin may be used to improve symptoms, but it has never been shown to improve mortality. Spironolactone (Aldactone) has recently been shown to improve mortality in heart failure and its use is indicated in patients with systolic dysfunction who have symptoms at rest or a recent history of symptoms at rest.13
The long list of potential medications poses challenges for both the physician and the patient. Close surveillance for volume, electrolyte and hemodynamic changes is essential. The frequency of office monitoring is based on the characteristics and needs of the individual patient.
Contraindications to Beta Blockers
Beta blockers should not be administered to patients with heart failure who have bradycardia, heart block or hemodynamic instability. Patients hospitalized for heart failure may receive beta blockers only after they have been stabilized. Patients with severe asthma should not be given beta blockers, although those with milder symptoms may be able to tolerate these medications.
Members of various medical faculties develop articles for “Practical Therapeutics.” This article is one in a series coordinated by the Department of Family Medicine at the University of Michigan Medical School, Ann Arbor. Guest editor of the series is Barbara S. Apgar, M.D., M.S., who is also an associate editor of AFP.
Long-term benefits of using Beta blowckers :-
• improved survival
• improved control of heart failure
• reduced need for hospitalisation
• improved quality of life
• improved left ventricular ejection fraction
Mechanism of action
The benefit of beta blockers almost certainly depends on blockade of beta-1 receptors. This action is consistent with the large body of data documenting high plasma catecholamines in severe heart failure, and more sophisticated studies demonstrating increased cardiac sympathetic activity and catecholamine release. Possible mechanisms for beta receptor blockade improving survival include:
• antiarrhythmic action
• anti-ischaemic action
• attenuation of catecholamine toxicity
• reduced cardiac remodelling.
Metoprolol and bisoprolol are both cardioselective beta blockers acting primarily on beta-1 receptors. By comparison, carvedilol is a non-selective beta blocker with additional alpha-receptor blocking and antioxidant properties. Based on the unequivocal treatment benefits seen in the CIBIS2 and MERIT3 studies, the principal mechanism by which these drugs improve outcome in heart failure is likely to be via their beta-1 receptor blocking action. We will not know if the additional properties of carvedilol are important, and whether carvedilol actually produces a larger benefit than standard beta blockers, until the results of current head-to-head comparisons are reported.
Indications other than systolic heart failure
There are two other types of heart failure where use of beta blockers provides clear benefits and little risk.
Atrial fibrillation
In some patients, atrial fibrillation with rapid ventricular response is a major factor which worsens the severity of their heart failure. In this situation, controlling the ventricular response alone can produce a major improvement in heart failure. Digoxin is usually effective in this situation. Beta blockers are also effective in slowing the ventricular rate, and rarely worsen the situation providing ventricular systolic function is reasonably well preserved.
Diastolic heart failure
Possibly as many as one third of patients with heart failure have normal ventricular systolic function. In these patients, the primary cardiac abnormality leading to heart failure is an abnormality of ventricular filling. They have so-called ‘diastolic heart failure’. In this situation, beta blockers can also produce improvement with little risk of the patient deteriorating. The drugs slow the heart rate and allow a longer period for diastolic filling, particularly if atrial fibrillation is also present. Patients with mitral stenosis are the best example. Beta blockers can also facilitate diastolic filling by improving abnormal myocardial relaxation, for example in patients with diastolic failure due to severe left ventricular hypertrophy. This is generally in patients with severe, long-standing, poorly-controlled hypertension.
Clinical trials in systolic heart failure
Patients with primarily systolic heart failure with low ejection fraction may deteriorate when given a beta blocker. Paradoxically, it is this very group of patients that had unequivocal long-term benefits in recent trials (see box).
Carvedilol trials
In the meta-analysis of beta blockade1, there were eight trials of carvedilol, with a total of 1657 patients. Carvedilol appeared to reduce total mortality by 49%. However, only one of the eight individual carvedilol trials produced a statistically significant reduction in total mortality. This trial markedly influences the overall estimate of the treatment benefit of carvedilol. The ANZ trial was the largest of the carvedilol trials (415 patients). Although it found a 27% reduction in total mortality and a 30% reduction in hospitalisation, neither result was statistically significant. None of the carvedilol trials were sufficiently powered to be able to detect a significant difference in these end-points.
It was pooled data from a number of relatively small trials of carvedilol which convinced the Therapeutic Goods Administration to approve carvedilol for systolic heart failure in 1998. Carvedilol requires an authority prescription under the Pharmaceutical Benefits Scheme.
CIBIS-II
CIBIS stands for Cardiac Insufficiency Bisoprolol Study.2 Bisoprolol is a beta-1 selective blocker not available in Australia. A total of 2647 patients, mostly in Class III heart failure, had either bisoprolol or a placebo added to optimal therapy. (Most patients were taking a loop diuretic and ACE inhibitor in reasonable doses, and 50% were taking digoxin.) The trial was stopped early because of an unequivocally statistically significant reduction in total mortality of 34%. There were also significant reductions in sudden death (44%) and in hospitalisation for congestive cardiac failure (20%).
MERIT-HF
MERIT-HF stands for Metoprolol Randomised Intervention Trial in Heart Failure.3 Metoprolol is a beta-1 selective blocker which has been available in Australia for many years. However, this trial used a slow-release formulation not currently available in Australia. A total of 3991 patients, with predominantly Class III heart failure, were randomised to have either a placebo or metoprolol, added to the optimal conventional therapy of a loop diuretic and ACE inhibitor. The trial was stopped early because of an unequivocally statistically significant reduction in total mortality of 34%. There was also a significant reduction in sudden death (41%).
COPERNICUS
This stands for Carvedilol Prospective Randomized Cumulative Survival Trial. This trial compared carvedilol with placebo in 2289 patients with severe Class III/IV heart failure and ejection fraction of less than 25%. Carvedilol or placebo was added to optimal conventional therapy for heart failure. The trial has been stopped prematurely because of a beneficial effect of carvedilol on the primary end-point of all cause mortality. The results have been presented at an international meeting, but have not yet been published. Carvedilol was associated with a 35% reduction in total mortality.
In COPERNICUS, the annual mortality in the placebo group (18.6%) was higher than in either the MERIT (11.0%) or CIBIS (13.2%) studies. This reflects a generally sicker group of patients in COPERNICUS with more severe heart failure. As a result, the same relative risk reduction has resulted in a larger absolute mortality benefit and a smaller number needed to treat. However, the relative risk reduction was similar between the three studies.
Unresolved issues
Severity of heart failure
Both the CIBIS and MERIT trials enrolled predominantly patients with Class III heart failure. The number of patients with more severe Class IV heart failure was small (17% and 3% respectively) and the treatment benefit was not statistically significant in this sub-group. Nevertheless, on average, the magnitude of benefit was not different in the patients with more severe failure. The COPERNICUS study enrolled more patients with Class IV heart failure, yet produced virtually the same relative reduction in total mortality. It must be emphasised that patients with very severe heart failure are a much more difficult group in which to start beta blockers because of the risk of exacerbating their already severe heart failure.
Co-medication
Digoxin
Approximately 50% of patients in both the CIBIS and MERIT studies were taking digoxin. Randomisation was not performed in relation to digoxin, but there was no difference between the treatment benefit from beta blockade in those taking and those not taking digoxin. Given that there is no mortality benefit from digoxin4, it seems logical to recommend that patients in sinus rhythm should have a beta blocker added to optimal therapy before digoxin is introduced. However, this recommendation is not based on any definitive data.
Spironolactone
In the recently published RALES trial5 there was a highly significant 30% reduction in total mortality when a low dose of spironolactone (25 mg daily) was added to conventional therapy in patients with very severe heart failure. Only 10% of the patients were taking beta blockers. The patients in this study had much more severe heart failure than in most of the beta blocker studies. As a result of this trial, many physicians are now including low dose spironolactone as part of ‘optimal conventional therapy’ in patients with very severe heart failure before introducing a beta blocker.
Antiarrhythmics
There is no consensus on the role of conventional antiarrhythmics in severe heart failure. What is clear is that the beta blocker trials have shown a clear reduction in the very substantial risk of sudden death. This is assumed to be because they prevent ventricular tachyarrhythmias. It seems logical to recommend that, in the absence of documented sustained ventricular tachycardia, beta blockers should be used before any consideration of antiarrhythmic drug therapy.
Recommendations
A beta blocker should be considered for all patients with systolic heart failure who are stable on optimal doses of a diuretic and ACE inhibitor. If patients are not stable on optimal treatment, then digoxin and perhaps spironolactone should be added before a beta blocker.
Which beta blocker to use?
Both carvedilol and standard beta-1 blockers appear to be effective. There are currently multiple trials in progress of carvedilol in various different groups of heart failure patients. The results should tell us if carvedilol is more effective than standard beta-1 blockers. Carvedilol has the advantage of a lower dose formulation for starting treatment. However, carvedilol is also much more expensive than standard beta blockers (up to 10 times the cost of the standard form of metoprolol).
What dose for starting therapy?
Starting a beta blocker can make heart failure worse, so low doses are used. For most patients you can cautiously start with carvedilol 3.125 mg twice a day or metoprolol 12.5 mg twice a day. Patients with very severe heart failure should probably start on only a morning dose.
How rapidly can the dose be increased?
The dose can be doubled every 2-4 weeks providing the patient is stable. If the heart failure has deteriorated, the doses of diuretic, ACE inhibitor or digoxin should be adjusted first before any further increase in beta blocker. The dose of beta blocker may need to be reduced, particularly if there is undue bradycardia or worsening cardiac conduction.
What is the target dose?
For carvedilol, the target dose is 25 mg twice a day. For metoprolol it is 100 mg twice a day. Many patients will not reach these doses. Substantial benefits are almost certainly achieved with doses which are lower than these targets.
What about patients who are already taking a beta blocker?
Some patients who have been taking beta blockers long term for other indications such as angina or hypertension will develop heart failure. The clinician must first determine why the patient has developed heart failure (for example, new atrial fibrillation, silent myocardial infarction). Both the underlying cause and the heart failure must be treated appropriately. In many patients the degree of heart failure may not be too severe, and the beta blocker will be able to be continued. In other patients it may be necessary to either reduce the dose or even withdraw the beta blocker completely until the heart failure is under control. Once this has been achieved, the beta blocker should be cautiously reintroduced.
Who should manage the patient?
These patients are extremely fragile and difficult to treat. Occasional patients will deteriorate markedly after starting a beta blocker and may even require intensive or coronary care with intravenous beta agonist support. In Australia carvedilol can only be started in hospital patients. General practitioners should always consider involving a physician or cardiologist before starting or changing beta blocker therapy.
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