Showing papers in "Drugs in 1984"

Non-steroidal anti-inflammatory drugs. Current status and rational therapeutic use.

Abstract: Aspirin (acetylsalicylic acid), the first of the NSAIDs (introduced in 1899), was initially never referred to as an anti-inflammatory agent. It was the advent of cortisone in 1949 that demonstrated dramatically that corticosteroids had anti-inflammatory properties and the term ‘non-steroidal anti-inflammatory drug’ was first used when phenylbutazone was introduced 3 years later. Since then, the NSAIDs have proliferated. There is to date no good evidence that they halt progression of rheumatoid disease, but by easing pain and diminishing swelling they make life much easier in osteoarthrosis, rheumatoid arthritis and many other types of arthritis, and are the drugs of first choice in acute gout. Their mode (or modes) of action are obscure and though inhibition of cyclo-oxygenase (prostaglandin synthetase) is clearly important, other mechanisms are also involved. The assessment of the anti-inflammatory action of these agents has received considerable attention in clinical trials because, whatever their action may be in experimental animal models, their action in inflamed joints in human patients must be ascertained, since there may be little parallel between the two. Different experimental animal models give different results with various agents and often bear little relation to their therapeutic action in man. No attempt has been made here to review in depth all the NSAIDs that have appeared since 1952. All have anti-inflammatory and analgesic activity and all can cause gastrointestinal side effects, though effectiveness and toxicity vary from drug to drug and patient to patient, there being very great interpatient variability. Non-reactors, patients who apparently fail to respond to certain agents, need further study, for it seems that these subjects may metabolise these agents differently from others. Considerable ingenuity has been shown not only in evolving new NSAIDs but in finding new ways of administering them. The number and variety of NSAIDs in their various forms varies greatly from country to country, depending largely on the regulatory bodies of those countries. In the meantime, the search for a better, less toxic compound continues with the hope that one may be found which has a deeper and more basic action on the underlying disease process.

Midazolam. A review of its pharmacological properties and therapeutic use

Abstract: Midazolam is a short-acting water-soluble benzodiazepine (at pH less than 4), a member of a new class of imidazobenzodiazepine derivatives. At physiological pH the drug becomes much more lipid soluble. Water solubility minimises pain on injection and venous thrombosis compared with diazepam administered in organic solvent. Midazolam is a hypnotic-sedative drug with anxiolytic and marked amnestic properties. To date it has been used mostly by the intravenous route, for sedation in dentistry and endoscopic procedures and as an adjunct to local anaesthetic techniques. It has proved less reliable than thiopentone, but preferable to diazepam, as an intravenous induction agent and is unlikely to replace the other well established drugs. However, due to the cardiorespiratory stability following its administration, midazolam is useful for anaesthetic induction in poor-risk, elderly and cardiac patients. The short elimination half-life (1.5-3.5h) and the absence of clinically important long acting metabolites make midazolam suitable for long term infusion as a sedative and amnestic for intensive care, but clinical trials have yet to be completed. Thus, a combination of properties make midazolam a useful addition to the benzodiazepine group.

Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy.

Abstract: Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.

Flunarizine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use.

Abstract: Flunarizine is a 'selective' calcium entry blocker with a similar chemical structure and pharmacological profile to the related compound, cinnarizine. However, in contrast to cinnarizine it has a long plasma half-life and need only be given once a day. The majority of therapeutic trials in the prophylaxis of migraine, occlusive peripheral vascular disease and vertigo of central or peripheral origin have been placebo-controlled, and have shown that the drug produces significantly greater beneficial effects than placebo as evaluated by subjective and objective criteria. A small number of comparative studies have shown flunarizine to be at least as effective as pizotifen in migraine prophylaxis, and in a longer term study as effective as cinnarizine in vertigo of central origin. However, it has not been compared with other drugs which may be useful in these areas, such as methysergide in migraine prophylaxis, some antihistamines or phenothiazines in vertigo, or (understandably at this stage of its evolution) with surgical revascularisation in severe occlusive peripheral vascular disease. In preliminary placebo-controlled studies there was some evidence that flunarizine may improve impaired cognitive function in patients with cerebrovascular disorders, but such findings need further confirmation in additional carefully conducted studies. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimised by taking the daily dose in the evening. Thus, it appears that flunarizine will offer a useful alternative in some therapeutic areas that can be difficult to manage with previously available therapy. However, a definitive statement on its relative place in therapy of such conditions must await a few well-controlled comparative studies.

Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression.

Abstract: Alprazolam is a triazolobenzodiazepine which is related to diazepam and other 1,4-benzodiazepines, and has a similar pharmacological profile. Relative to the newer benzodiazepines, alprazolam has an intermediate half-life of 10 to 12 hours in healthy young subjects. In placebo-controlled and double-blind comparative trials in patients with anxiety, alprazolam was of comparable efficacy to diazepam and generally caused a lower incidence of drowsiness. Alprazolam has antidepressant activity and has been shown to be similar in efficacy to imipramine in the treatment of unipolar depression. Thus, alprazolam may be particularly useful in patients with mixed anxiety/depression. However, its general acceptance as an antidepressant awaits further studies.

Alpha- and beta-adrenergic receptor subtypes properties, distribution and regulation.

Abstract: The effects of catecholamines in the central and peripheral nervous systems appear to be mediated through interactions with 2 major classes of receptor: α-adrenoceptors and β-adrenoceptors. Subtypes of both α- and β-adrenoceptors exist. In the periphery, α1-receptors are located postsynaptically, mediating the excitatory effects of catecholamines at α-receptors. α2-Adrenoceptors, on the other hand, are autoreceptors involved in the regulation of noradrenaline (norepinephrine) release. In the central nervous system, both α1- and α2-receptors exist on postsynaptic cells; there are also 2 principal subtypes of β-adrenoceptors. β1-Receptors have a high affinity for both noradrenaline and adrenaline (epinephrine) and are found in the heart, brain, and adipose tissue. β2-Receptors have a low affinity for noradrenaline and are involved in mediation of relaxation of vascular and other smooth muscles and in many of the metabolic effects of catecholamines.

Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy

Abstract: Ursodeoxycholic acid is the 7 beta-hydroxy epimer of chenodeoxycholic acid and is normally present in only trace amounts in the bile. Oral administration of pharmacological doses markedly decreases biliary cholesterol saturation. Complete or partial dissolution of radiolucent gallstones located in a functioning gallbladder occurred in about 40 to 55% of patients treated with ursodeoxycholic acid in controlled studies of 6 months duration. Patients showing partial gallstone dissolution at that time are likely to continue improving possibly to complete gallstone dissolution with continued therapy. The success rate with ursodeoxycholic acid may be increased top about 80% if more stringent patient selection criteria are applied to include only those with non-calcified floating cholesterol stones of less than 10 to 15 mm diameter. Those with calcified stones or stones greater than 15 mm diameter or unlikely to respond to ursodeoxycholic acid therapy. The optimal dose in published studies was about 8 to 10 mg/kg/day, which is about half to two-thirds the dose of chenodeoxycholic acid (15 mg/kg/day) achieving approximately equivalent results. Ursodeoxycholic acid appears to be remarkably well tolerated, with diarrhoea occurring in only a very small proportion of patients. While surgery is clearly the preferred treatment in many patients with symptomatic gallstones, in a carefully selected subgroup of such patients gallstone dissolution therapy with ursodeoxycholic acid offers an important and worthwhile alternative.

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension.

Abstract: Indapamide is an orally active sulphonamide diuretic agent Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 25 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification

Budesonide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis.

Abstract: Budesonide is a non-halogenated glucocorticosteroid which has been shown to possess a high ratio of topical to systemic activity compared with a number of reference corticosteroids such as beclomethasone dipropionate, flunisolide, and triamcinolone acetonide. It appears to undergo extensive first-pass metabolism to metabolites of minimal activity which accounts for the low level of systemic activity. The majority of therapeutic trials in asthma have been of short term duration and have demonstrated that conventional doses of inhaled budesonide (200 to 800 micrograms/day) and beclomethasone dipropionate (400 to 800 micrograms/day) are of similar efficacy in both adults and children with moderate to severe asthma. Other studies have compared high doses of inhaled budesonide (400 to 3200 micrograms/day in 4 divided doses) with both alternate day (7.5 to 60 mg) and daily (7.5 to 40 mg) oral prednisone in patients with severe or unstable asthma. In the small number of such trials to date, inhaled budesonide was superior to prednisone with respect to the level of asthma control and the lesser influence on adrenal function. Long term open studies have similarly shown that inhaled budesonide can be gradually substituted for oral prednisone in steroid-dependent patients, often with a concomitant improvement in pulmonary function and asthma control. Intranasal budesonide (200 to 400 micrograms/day) relieves nasal symptoms in patients with seasonal allergic, perennial allergic and vasomotor rhinitis. In comparative studies in patients with seasonal rhinitis it has been shown to be of similar efficacy as intranasal flunisolide and intranasal beclomethasone dipropionate and superior to intranasal sodium cromoglycate (cromolyn sodium) and the antihistamine dexchlorpheniramine. Following inhalation, the most commonly reported side effects have been candidiasis, dysphonia and sore throat, while after intranasal administration the most frequent adverse reactions have been nasal stinging, throat irritation, dry nose and slight nasal bleeding. At usual dosages, both formulations of budesonide appear to have little or no effect on adrenal function. Thus, at this stage in its development budesonide has been shown to offer an effective alternative to oral or other inhaled corticosteroids in the management of asthma and rhinitis. However, its relative efficacy and tolerability during long term use, compared with beclomethasone dipropionate, remains to be clarified.

Bumetanide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use.

Abstract: Bumetanide is a potent 'loop' diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery. Bumetanide may be given orally, intravenously or intramuscularly and produces a rapid and marked diuresis, and increased urinary excretion of sodium, chloride and other electrolytes (within 30 minutes) which persists for 3 to 6 hours. Its principal site of action is on the ascending limb of the loop of Henle, with a secondary action on the proximal tubule. Pharmacologically, bumetanide is about 40-fold more potent than frusemide (furosemide), with the exception of its effects on urinary potassium excretion where its potency is lower. Studies in patients with oedema due to congestive heart failure, pulmonary oedema or hepatic disease show that oral or intravenous bumetanide 0.5 to 2 mg/day produces results comparable to those with frusemide 20 to 80 mg/day. In acute pulmonary oedema, intravenous bumetanide produces a very rapid diuresis. Higher doses of bumetanide may be required (up to 15 mg/day) in patients with chronic renal failure or nephrotic syndrome. In these patients muscle cramps are not uncommon with bumetanide, but glomerular filtration rates are unaffected. In most studies, diuretic effects were accompanied by decreased bodyweight, abdominal girth and improvements in a variety of haemodynamic parameters. Comparison of bumetanide with frusemide at a dose ratio of 1 : 40 reveals no significant differences in clinical response with the exception of renal disease, where patients with oedema appear to respond better to bumetanide. Combination with thiazide diuretics enhances the clinical response to bumetanide. Potassium supplements and spironolactone may be beneficial additions to bumetanide where patients at risk of hypokalaemia can be identified. Clinically important side effects are infrequent, with audiological impairment occurring to a lesser extent than with frusemide. Bumetanide thus offers an important alternative to frusemide when a 'loop' diuretic is indicated.

Magnesium, Electrolyte Transport and Coronary Vascular Tone

Abstract: Coronary heart diseases (CHD) have high indices of mortality and morbidity. A number of CHD and myocardial ischaemic syndromes such as unstable angina pectoris, sudden death ischaemic heart disease, acute myocardial infarction and ventricular arrhythmias have been associated with losses of myocardial magnesium and potassium. Mg++ ions are essential for regulation of Na+ and K+ transport across cell membranes, including those found in cardiac and vascular smooth muscle cells. Mg++ activates an Na+-K+-ATPase pump which in turn plays a major role in regulating Na+-K+ transport. Loss of cellular Mg++ results in loss of critically important phosphagens: MgATP and creatine phosphate. Thus, under conditions where cellular Mg++ is depleted (e.g. hypoxia, ischaemia, anoxia), the Na+-K+ pump and phosphagen stores will be compromised, leading to alterations in resting membrane potentials. Cellular Mg++ depletion has been found to result in concomitant depletion of K+ in a number of cells, including cardiac and vascular muscles. The consequences of these events are often production of cardiac arrhythmias. Myocardial and vascular injury lead to disturbances in electrolyte transport across cell membranes, whereby Na+ and Ca++ uptakes are enhanced and, just prior or concomitantly, Mg++ and K+ are lost. Such electrolyte disturbances often lead to necrotic foci. Considerable evidence has accumulated to indicate that the extracellular concentration of Mg++ is important in control of arterial tone and blood pressure via pressure via regulation of vascular membrane Mg++-Ca++ exchange sites. A reduction in the extracellular Mg++ concentration can produce hypertension, coronary vasospasm and potentiation of vasoconstrictor agents by allowing excess entry of Ca++; concomitantly, the potency of vasodilator agents is reduced. Alterations in vascular membrane Mg++ results in arterial and arteriolar membranes which are 'leaky', thus contributing to the cellular reduction in K+ and gain of Na+ and Ca+. Alterations in extracellular K+ or Na+ concentrations over physiological ranges, in the face of a Mg++ deficit, can exacerbate the coronary vasospasm noted with reduction in only extracellular Mg++. Since free Mg++ ions are necessary for maintaining Ca+ ions (both plasma membrane-bound and sarcoplasmic reticulum membrane-bound via Ca++ ATPases), intracellular free Mg++ would rise in conditions which result in cellular loss of Mg++, thereby exacerbating and contributing to elevation of blood pressure and coronary vasospasm.(ABSTRACT TRUNCATED AT 400 WORDS)

Isotretinoin. A review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders.

Abstract: Isotretinoin is a new orally active retinoic acid derivative for the treatment of severe refractory nodulocystic acne. The pharmacological profile of isotretinoin suggests that it acts primarily by reducing sebaceous gland size and sebum production, and as a result alters skin surface lipid composition. Bacterial skin microflora is reduced, probably as a result of altered sebaceous factors. Isotretinoin 1 to 2 mg/kg/day for 3 to 4 months produces 60 to 95% clearance of inflammatory lesions in patients with severe, recalcitrant nodulocystic acne, with evidence of continued healing and prolonged remissions in many patients after treatment withdrawal. Doses as low as 0.1 mg/kg/day have also proven successful in the clearance of lesions; however, with such low doses the duration of remission after discontinuation of therapy is usually shorter. Encouraging results have also been seen in small numbers of patients with rosacea, Gram-negative folliculitis, Darier's disease, ichthyosis and pityriasis rubra pilaris, the response in keratinising disorders resembling that with the related drug etretinate. While long term follow-up studies in these patients have not been reported, prolonged remission after withdrawal of isotretinoin in disorders of keratinisation is unlikely, as with other drugs used in these conditions. Isotretinoin is only partially effective in psoriasis, in contrast to etretinate which is very effective in psoriasis but ineffective in severe acne. Some encouraging results have also been reported with isotretinoin in patients with squamous and basal cell carcinomas, but isotretinoin has proven unsuccessful in non-squamous cell epithelial and non-epithelial cancer. Side effects affecting the mucocutaneous system occur in nearly all patients receiving isotretinoin, but rarely lead to drug withdrawal. Raised serum triglyceride levels are also commonly reported. The possibility of long term spinal or skeletal bone toxicity may restrict the use of isotretinoin in severe disorders of keratinisation requiring prolonged administration. Isotretinoin is strictly contraindicated in women of childbearing potential due to its severe teratogenic properties, unless an effective form of contraception is used. Thus, isotretinoin offers an effective advance on the treatment options available in a difficult therapeutic area - those patients with severe, nodulocystic acne not responding to 'traditional' therapy.

Piroxicam. A reappraisal of its pharmacology and therapeutic efficacy.

Abstract: Piroxicam is a chemically different non-steroidal anti-inflammatory drug with a long half-life which enables it to be administered once daily. This member of the oxicam series of compounds is now well established in the treatment of rheumatoid arthritis and osteoarthritis and has been shown to be a suitable alternative to aspirin, indomethacin, naproxen, ibuprofen, ketoprofen, sulindac, phenylbutazone and diclofenac in the treatment of rheumatic diseases. Open trials in many thousands of patients in hospital clinics and in general practice have demonstrated its analgesic and anti-inflammatory efficacy in a wide cross-section of patients with rheumatic diseases, when administered once daily either at night or in the morning, and recent studies have demonstrated its usefulness in musculoskeletal disorders, dysmenorrhoea and postoperative pain. Such studies have also demonstrated the generally good tolerability of piroxicam 20mg daily. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. The frequency and severity of these effects are dose related. Thus, piroxicam is now well established in the treatment of rheumatic diseases and offers an alternative to other analgesics in various pain states.

Beclomethasone dipropionate. A reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis.

Abstract: Inhaled beclomethasone dipropionate is now well established in the management of asthma. Studies conducted over the last decade, and since the drug was previously reviewed in the Journal, have confirmed that inhaled beclomethasone dipropionate 400 to 800 micrograms daily can reduce the need for oral maintenance corticosteroids in the majority of asthmatic patients requiring such therapy, and that increasing the dosage to 2000 micrograms daily may provide additional clinical benefit in some patients unresponsive to usual therapeutic dosages. Follow-up over a period of several years has confirmed that the initial response to inhaled beclomethasone can be maintained in most patients. Recent studies indicate that beclomethasone dipropionate 400 micrograms daily is equally effective when administered in 2 or 4 divided doses in patients with stable asthma, but it is likely that the lower frequency of administration will be less effective when the asthma is unstable. Recent studies have established the usefulness and good tolerability of intranasal beclomethasone dipropionate in the treatment of perennial and seasonal rhinitis, where the drug has been shown to be more effective than intranasal sodium cromoglycate and similar in efficacy to flunisolide. Nasal polyps decrease in size during continuous treatment with intranasal beclomethasone dipropionate, but enlarge again during periods of respiratory infection. After a decade of treatment with inhaled and intranasal beclomethasone dipropionate, there is no evidence that the drug damages the tracheobronchial lining or the nasal mucosa. Thus, the initial promise of beclomethasone dipropionate has been fulfilled. It has had an important role in asthma therapy over the past decade, which will continue into the future.

Auranofin. A preliminary review of its pharmacological properties and therapeutic use in rheumatoid arthritis.

Abstract: Auranofin is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity. Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its effect on the occurrence or progression of erosive lesions. Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage, temporary or permanent withdrawal of auranofin may be necessary. Auranofin is clearly a useful addition to the limited list of agents with disease-modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.

Oral Hypoglycaemic Agents An Update

Abstract: Despite the availability of oral hypoglycaemic agents for nearly 30 years, their precise mode of action and role in the management of diabetes mellitus remains poorly defined and controversial. They are regarded by many, though not all, clinicians as helpful adjuncts in the treatment of patients with non-insulin-dependent diabetes who have failed to respond satisfactorily to an adequate programme of dietary treatment. Their initial effectiveness is greatest in those patients who have had diabetes for less than 5 years, are overweight at the time of initiation of therapy, and whose fasting blood glucose levels are not unduly raised (less than 200 mg/dl). If they are receiving treatment with insulin and a shift to oral compounds is contemplated, success in the changeover is more likely if the daily dose has been less than 20 to 30 units daily.

Intracellular Magnesium Loss After Diuretic Administration

Abstract: Diuretic agents influence the renal handling of magnesium, causing increased losses of the ion. Continuing magnesium losses may, in the long term, result in a magnesium deficiency. 296 patients with congestive heart failure or arterial hypertension receiving long term diuretic therapy were studied by skeletal muscle biopsies to assess their magnesium status. 65% of the congestive heart failure patients and 42% of the patients with arterial hypertension were found to have subnormal values for skeletal muscle magnesium. Studies with the potassium-sparing diuretics amiloride, spironolactone and triamterene demonstrate that these drugs significantly increase the muscle magnesium content in patients on long term diuretic treatment for congestive heart failure and/or arterial hypertension--in addition to their well known positive effect on potassium balance.

Gliclazide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in diabetes mellitus.

Abstract: Gliclazide is a 'second generation' oral hypoglycaemic agent. The particular interest with this drug is that it has shown certain effects on the blood for which it is hoped there may be some clinical benefit in diabetic angiopathies. Both in animal and human studies it has demonstrated a reduction in platelet adhesiveness and aggregation, whilst possible enhancement of platelet metabolism, reduction of coagulant factors, as well as increased fibrinolytic activity, are still being investigated. Initial trials have suggested that gliclazide therapy may reverse or at least slow down the progression of diabetic retinopathy. However, a few additional well-designed long term controlled studies are needed to confirm these findings, and to clarify whether any beneficial effect on diabetic retinopathy is unique to gliclazide or also occurs with other oral hypoglycaemic drugs. Both newly diagnosed maturity onset diabetics as well as those previously treated with sulphonylureas respond well to gliclazide therapy. In the small comparative studies which have been reported, gliclazide was of comparable efficacy to other oral hypoglycaemic agents.

An epidemiological perspective of sudden death. 26-year follow-up in the Framingham Study.

Abstract: Over 26 years of follow-up of 5209 Framingham subjects there were 147 sudden deaths in men and 50 in women. Half the sudden deaths in men and 70% in women occurred without prior coronary heart disease. The incidence doubled with each decade of age, with women lagging men by 20 years. At any age in either sex the risk varied widely in relation to their risk factor make-up. By incorporating systolic pressure, serum cholesterol, vital capacity, cigarette smoking, relative weight, heart rate and ECG abnormalities into a multivariate formulation, a composite estimate of risk was obtained over a wide range. The multivariate sudden death prediction was as efficient in women as in men, identifying 53% and 42% of the sudden deaths, respectively, in the upper decile of multivariate risk. At any level of multivariate risk, women had only a third of the sudden death incidence of men, suggesting a unique biological resistance to sudden death. Ventricular premature beats, associated with an excess sudden death incidence, often occurred concurrently with ECG evidence of left ventricular hypertrophy, intraventricular block, and nonspecific ECG abnormalities. These associated ECG abnormalities were more highly predictive of sudden death than ventricular premature beats. The key to prevention of sudden death would appear to be reduction of the risk of coronary attacks. Once overt coronary heart disease or cardiac failure appears, the risk of sudden death escalates 9-fold, and at this stage the standard coronary heart disease risk factors have little predictive value. Only ECG abnormalities, arrhythmia and poor cardiac function appear to be predictive.

Intravenous glyceryl trinitrate (nitroglycerin). A review of its pharmacological properties and therapeutic efficacy.

Abstract: The recently introduced preparation of intravenous glyceryl trinitrate (nitroglycerin) provides a rapid steady therapeutic blood concentration of nitrates during continuous infusion. Intravenous glyceryl trinitrate causes venodilation at low doses, but at higher doses dilates both arteries and veins. Its principal haemodynamic effects at therapeutic dosages include a decrease in blood pressure in preload (left ventricular filling pressure) and in determinants of afterload, and a decrease in myocardial oxygen demand. Human pharmacokinetic data are few and difficult to interpret due to wide interstudy and interindividual variation. There is no close correlation between infusion rate, blood concentration and haemodynamic effects. The nature of the patient population treated with intravenous glyceryl trinitrate has largely precluded the use of a placebo, but in open trials the drug has been used successfully in the treatment of unstable angina, left ventricular failure accompanying acute myocardial infarction and in the control of hypertension associated with cardiac surgery at dosages titrated to achieve a specific end-point. Favourable haemodynamic responses have been achieved in very short term studies in congestive heart failure, and preliminary studies suggest that institution of intravenous glyceryl trinitrate early after acute myocardial infarction may limit ischaemic damage. However, use of the drug in acute myocardial infarction remains controversial. Intravenous glyceryl trinitrate is generally well tolerated, although hypotension and headache occur occasionally, and sinus tachycardia and bradycardia less frequently. Careful titration of dosage is required (beginning at 5 micrograms/min), and if the infusion sets contain polyvinylchloride, the delivered dose is lower than that calculated, because of adsorption of glyceryl trinitrate onto the plastic tubing.

Sucralfate. A review of its pharmacodynamic properties and therapeutic use in peptic ulcer disease.

Abstract: Sucralfate is a basic aluminium salt of sulphated sucrose which is advocated for use in peptic ulcer disease. It is minimally absorbed after oral administration and is believed to act primarily at the ulcer site by protecting the ulcer from the effects of pepsin, acid and possibly bile salts. Controlled therapeutic trials have demonstrated that sucralfate 1g 4 times daily is effective in increasing the rate of healing of duodenal and gastric ulcer over a period of 4 to 8 weeks. Trials comparing sucralfate and cimetidine have not found any significant difference in efficacy between the drugs in small numbers of patients. A dosage of 2g daily given prophylactically decreases the rate of recurrence of duodenal ulcers, but the efficacy of sucralfate in preventing relapse of gastric ulcers has yet to be clearly demonstrated. Sucralfate is particularly well tolerated. Constipation, the most common side effect, occurs in 2% of patients. Thus, sucralfate offers an effective and well tolerated alternative for the management of peptic ulcer disease.

Pharmacology of Combined α-β-Blockade II

Abstract: The cardinal haemodynamic disturbance in established hypertension is an increased total peripheral resistance and a subnormal blood flow, particularly during exercise. The spontaneously occurring changes in central haemodynamics have been followed in young males with essential hypertension over a 17-year period: a gradual increase in total peripheral resistance and blood pressure, and a gradual fall in cardiac output and stroke volume, have been demonstrated. Labetalol is a unique antihypertensive agent which induces both α- and β-blockade. Numerous studies have shown that when labetalol is given intravenously to patients with mild to moderate essential hypertension, blood pressure falls within a few minutes — partly due to reduction in cardiac output and heart rate and partly due to reduction in total peripheral resistance. In most series the average reduction in blood pressure was 17 to 22%, the reduction in total peripheral resistance 11 to 14%, and the reduction in cardiac output 2 to 10%. Thus, the reduction in cardiac output with labetalol is less than that seen after single-dose injection of β-blockers without intrinsic sympathomimetic activity. After intravenous injection, the blood pressure-lowering effect is most marked in the upright position and during muscular exercise when cardiac output is usually significantly reduced. Labetalol reduces blood pressure in severe hypertension. Intravenous doses of 0.2 to 0.8 mg/kg bodyweight reduce blood pressure by approximately 20%. This hypotensive effect is partly due to a reduction in total peripheral resistance and partly due to a fall in cardiac index. When the reduction in blood pressure is gradual and moderate (< 20%), it is mainly produced by a reduction in total peripheral resistance. During long term use labetalol induces haemodynamic changes rather similar to those seen after bolus injection. However, during prolonged use there is a tendency to normalisation in cardiac output and stroke volume; the sustained decrease in blood pressure is mainly due to a reduction in total peripheral resistance. In a recent 6-year follow-up study where 15 patients were studied before treatment and after 1 and 6 years on long term labetalol treatment, a tendency to normalisation of central haemodynamics was found. Over the years total peripheral resistance was gradually reduced by 15 to 20% at rest as well as during exercise. Stroke volume gradually increased and after 6 years of treatment was approximately 10% higher than the pretreatment value. This compensated for the reduced heart rate and no significant reduction in cardiac output was seen either during exercise or at rest. Studies of the regional circulation have shown that labetalol reduces renal vascular resistance and forearm resistance. Coronary blood flow is slightly decreased but the reduction is less than that seen after conventional β-blockers. The effect on the pulmonary circulation is modest, and a significant reduction in pulmonary resistance is usually not seen. The responses to short and long term administration of labetalol differ from the responses to β-blockers, α-blockers and calcium antagonists. The long term responses resemble the effects of prolonged administration of prizidilol, a combined β-blocker and vasodilator. Prizidilol has been withdrawn from clinical trials and although several new compounds have been developed, labetalol is the only drug generally available for the treatment of hypertension which has both β-blocking and vasodilating or α-blocking properties. The haemodynamic effects of labetalol are well documented and would seem to make labetalol a particularly useful antihypertensive drug.

Ischaemic heart disease. An epidemiological perspective with special reference to electrolytes.

Abstract: Ischaemic heart disease (IHD) is a major public health problem in most industrialised countries. In the death rates from IHD, marked differences exist between various countries and also between different areas of individual countries. Unfavourable dietary factors appear to play an important role in the aetiology of IHD, and thus differences in dietary habits and the quality of food may be mainly responsible for the geographic differences in the prevalence of IHD.

Haemodynamic responses to specific renin-angiotensin inhibitors in hypertension and congestive heart failure: a review

Abstract: The renin-angiotensin system is an important regulator of vascular resistance in many patients with hypertension and congestive heart failure. To quantitatively evaluate this contribution requires correlation of markers of the renin-angiotensin system with haemodynamic parameters, notably blood pressure, cardiac output, and calculated systemic vascular resistance. In addition, to determine ventricular loading properties, assessment of cardiac filling pressures is also required. The availability of specific pharmacological inhibitors of the renin-angiotensin system greatly enhances such correlation, as the haemodynamic consequence of blocking the renin-angiotensin system can then more fully identify its contribution. In the last decade, highly specific pharmacological inhibitors have become available to serve such a purpose. Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin. However, this method of blockade is still at the early stages of investigation. More readily available are converting enzyme inhibitors which block the formation of angiotensin II, the potent vasoconstrictor which mediates increased systemic vascular resistance, and angiotensin II analogues which compete with endogenous angiotensin II for vascular and adrenal receptors. Although hypertension and chronic congestive heart failure are clinically distinct entities in many respects, their common bond is the fact that both pathological mechanisms are mediated by an increase of systemic vascular resistance. The implications of blocking the resulting vasoconstriction in both entities are therefore quite similar. This review summarises our present knowledge of the contribution of the renin-angiotensin system to the vasoconstriction of hypertension and congestive heart failure, and also summarises the haemodynamic consequences of such inhibition. The implications of the response to these specific pharmacological probes, as well as their limitations, are discussed. Their importance rests not only in their therapeutic application, but also in their contribution as probes for pathophysiological mechanisms of vasoconstriction in cardiovascular disease.

Anticonvulsant drugs. An update.

Abstract: A considerable amount of information is now available concerning the clinical pharmacology of the anticonvulsant drugs. Some of the more important data are reviewed in this article. In recent years, valproic acid (or sodium valproate) has found a place as a major anticonvulsant agent, while older drugs such as troxidone and sulthiame seem to be disappearing from use. Although much information is available, the essential mechanisms of action of the anticonvulsant drugs are still not understood, either at a molecular or at an electrophysiological level. The pharmacokinetics of the anticonvulsants in common use are now reasonably well documented, though some minor questions are still to be answered. Numerous interactions between anticonvulsants and endogenous substances or other drugs administered concurrently (including other anticonvulsants) have been recorded, but much work still needs to be done to elucidate the frequency and mechanisms of the various interactions. Many adverse effects of the anticonvulsants are known, but further unwanted effects of long-established drugs continue to emerge from time to time, including the still somewhat controversial matter of anticonvulsant-related dysmorphogenesis. The use of valproic acid and its sodium salt has been associated with a worrying incidence of serious liver and pancreatic toxicity. Adequate basic data are now available to put the clinical use of anticonvulsants on a rational basis, but much work remains to be done in this area. In particular, the question of ‘therapeutic ranges’ of plasma concentrations of the various drugs needs to be reinvestigated in a rigorous statistical fashion, and in relation to different clinical types of epilepsy. The usefulness of monitoring free rather than total drug concentrations also needs further investigation. The ultimate test of the validity of all background scientific pharmacological information about anticonvulsants is its usefulness in the treatment of patients with epilepsy.

New and experimental therapeutic roles for naloxone and related opioid antagonists

Abstract: Naloxone and related opioid antagonists have been shown to have therapeutic utility in a variety of conditions. The effects of opioid antagonists in either physiological or pathological processes are most clearly seen when there is excessive occupancy of opioid receptors, as in opiate overdose. Opioid antagonists are also able to reverse several types of cardiovascular shock, conditions in which endogenous opioids appear to be mobilised, resulting in increased opioid receptor occupation. There are also more controversial circumstances in which excessive occupation of opioid receptors may assume pathological significance, such as hypercapnia. Opioid antagonists could be useful in such a situation by re-sensitising the respiratory centres to carbon dioxide. There is some evidence that opioid antagonists may benefit some schizophrenic and manic-depressive patients, suggesting that an endogenous opioid ligand might cause disturbances in mental functioning. The diversity and complexity of opioid mechanisms in the central nervous system suggest that more specific opioid antagonists could be more selective in altering physiological or pathological functioning.

Coronary Thrombolysis for Evolving Myocardial Infarction

Abstract: An acute thrombus at the site of an atherosclerotic obstruction is the usual cause of myocardial infarction. Thrombolytic therapy is an exciting new therapy for reducing the extent of myocardial infarction by lysing intracoronary clots. Such therapy has now been widely applied by: prolonged intravenous infusion of streptokinase during the first 24 hours of infarction; intracoronary infusion of streptokinase, urokinase, or tissue plasminogen activator; early, high dose, brief duration intravenous infusion of streptokinase; or intravenous infusion of tissue plasminogen activator.

Malignant Arrhythmias in Acute Myocardial Infarction

Abstract: The risk of malignant arrhythmias during myocardial infarction is greatly increased in patients with diuretic-induced hypokalaemia. In our study an increased risk was seen also in hypokalaemic patients not treated with diuretics. This indicates that hypokalaemia as such could trigger malignant arrhythmias. The frequency of hypokalaemia was much higher (22.5%) in diuretic-treated infarct patients than in those not treated with diuretics (12.9%). Thus, hypokalaemia should be avoided in diuretic-treated patients with increased risk of myocardial infarction. The incidence of malignant arrhythmias in hypokalaemic patients was 13.2% in those treated with non-selective beta-blockers on admission versus 26.1% in those treated with selective beta-blockers; corresponding figures in infarctions with serum potassium concentrations above 3.6 mmol/L were 9.4% and 10.4%, respectively. Non-selective beta-blockers reduced the frequency of malignant arrhythmias in hypokalaemic infarctions. This was in contrast to selective beta-blockers, which had no favourable effect on the frequency of malignant arrhythmias in hypokalaemic infarctions. Non-selective beta-blockers did not completely counteract the hypokalaemia. Still, the risk of malignant arrhythmias decreased. Thus, our study indicates that apart from hypokalaemia, some additional mechanism specifically linked to adrenaline stimulation in important for the development of malignant arrhythmias in acute myocardial infarction.

Use of β-Adrenoceptor Blocking Drugs in Hyperthyroidism

Abstract: There is an increasing use and variety of β-adrenoceptor blocking agents (β-blockers) available for the treatment of hyperthyroidism. Recent comparative studies suggest that atenolol (200mg daily), metoprolol (200mg daily), acebutolol (400mg daily), oxprenolol (160mg daily), nadolol (80mg daily) and timolol (20mg daily) produce a beneficial clinical response equal to that seen with propranolol (160mg daily). Most β-blockers reduce resting heart rate by approximately 25 to 30 beats/min, although a lesser reduction is seen with those possessing intrinsic sympathomimetic activity such as oxprenolol and pindolol While earlier studies employing large doses of intravenous propranolol concluded that β-blockade reduced myocardial contractility, more recent non-invasive studies suggest that the predominant cardiac effect is on heart rate. In patients with cardiac failure, β-blockers may, however, produce a profound fall in cardiac output. Nevertheless, in combination with digoxin they may be useful in controlling the atrial fibrillation of thyrocardiac disease. β-Blockers improve nervousness and tremor (although to a lesser extent with cardioselective agents) and severe myopathy, and they also reduce the frequency of paralysis in patients with thyrotoxic periodic paralysis. There is often subjective improvement in sweating but usually no major effect on eye signs. Recent studies show a 10% reduction in oxygen consumption/basal metabolic rate with long term oral use of selective or nonselective β-blockers. In addition, many agents (propranolol, metoprolol, nadolol and sotalol but not acebutolol, atenolol or oxprenolol) reduce circulating tri-iodothyronine (T3) concentration by between 10 and 40%, although the clinical significance of this effect (if any) is not established. β-Blockers may also have endocrinological effects on gastrin, cyclic AMP, catecholamines and other hormone levels. Given in adequate dosage, propranolol has been shown to control thyrotoxic hypercalcaemia. Minor side effects (nausea, headaches, tiredness, etc.) are quite common but overall β-blockers are well tolerated by the thyrotoxic patient. The major use of these drugs is in symptomatic control while awaiting definitive diagnosis or treatment. As an adjunct to antithyroid drugs or radioactive iodine, β-blockers will produce a satisfactory clinical response in the weeks to months before these forms of therapy produce a euthyroid state. β-Blockers are more convenient than antithyroid drugs in the control of patients receiving therapeutic radioiodine, in that continuous therapy and assessment of biochemical response is possible. The long term use of β-blockers alone in the management of hyperthyroidism cannot be recommended except in mild and transient forms of the disorder such as postpartum thyrotoxicosis. There is increasing use of β-blockers to prepare patients for partial thyroidectomy. Given in adequate dosage and continued postoperatively, the clinical course is similar to conventional therapy but with a major reduction in the time to prepare patients, a greater flexibility in timing of surgery, and a decreased gland vascularity. However, this regimen, even with the addition of iodide, is not suitable for the more severely toxic patient. Of almost 1000 patients studied, approximately 3% showed exaggeration of toxic symptoms postoperatively. Cases of thyroid storm (crisis) have been associated with low dosage (160 mg/day propranolol or less), omission of critical postoperative doses, and a failure to objectively assess individual patient dosage requirements. A long acting β-blocker, nadolol, appears more convenient to use than propranolol in the perioperative setting, β-Blockers are now standard therapy in the management of thyroid storm but their use in pregnancy is somewhat controversial, as occasional cases of neonatal bradycardia have been reported. They may, however, be used for short term control as adjunctive therapy to antithyroid drugs or to prepare the patient for mid-trimester thyroidectomy. Added to conventional therapy, β-blockers have proved useful in some cases of neonatal thyrotoxicosis. The clearance of β-blockers that undergo extensive hepatic metabolism such as propranolol and metoprolol is increased in hyperthyroidism, while that of renally excreted agents such as atenolol and sotalol is unchanged. There is a wide interindividual variation in plasma concentrations in patients receiving the same dosage, particularly with propranolol where age and smoking habits are important determinants. Concentration-effect relationships for propranolol, metoprolol and nadolol are becoming apparent. Plasma propranolol concentrations are correlated with the degree of objective response (heart rate reduction, β-blockade, weight change and reduction in serum T3 concentrations) but not with the subjective response. Long-acting propranolol or nadolol given once daily appear to give adequate control. Where a cardioselective agent is indicated there is little to choose between atenolol and metoprolol. Otherwise, our long term experience with propranolol suggests that it is suitable for most situations. However, irrespective of which β-blocker is chosen, individualisation of dosage is necessary to produce a high degree of β-blockade.

Angiotensin converting enzyme inhibitors in the treatment of hypertension

Abstract: Inhibiting endogenous vasoconstrictor mechanisms or enhancing endogenous vasodilator substances is an alternative, more physiological approach to lowering high blood pressure. The renin angiotensin system is the most powerful and important hormonal system in the control of blood pressure and in the pathogenesis of hypertension. Investigators for many years have researched for methods of blocking this system. The advent of potent, orally active angiotensin converting enzyme (ACE) inhibitors has now made this approach a practical clinical reality.