Dr Chris Danbury

• Consultant Intensivist
• Royal Berkshire Hospital
• Reading

Adverse effects Erythromycin is remarkably safe and may be used in pregnancy and in children osteoarthritis pain treatment guidelines buy sulfasalazine 500mg visa. Nausea treatment for shingles pain management sulfasalazine 500 mg cheap, vomiting pain treatment with laser cheap sulfasalazine 500mg without prescription, diarrhoea and abdominal cramps are the most common adverse effects reported pain solutions treatment center cheap 500 mg sulfasalazine, related to direct pharmacological actions rather than allergy pain treatment center fairbanks discount 500mg sulfasalazine fast delivery. Pharmacokinetics Tetracyclines are well absorbed orally when fasting pain treatment studies purchase 500 mg sulfasalazine fast delivery, but their absorption is reduced by food and antacids. The half-life varies between different members of the group, ranging from six to 12 hours. The shorter-acting drugs are given four times daily and the longer-acting ones once daily. Doxycycline is given once daily, can be taken with food and is not contraindicated in renal impairment. Drug interactions Erythromycin inhibits cytochrome P450 and causes accumulation of theophylline, warfarin and terfenadine. Azithromycin is less effective against Grampositive bacteria than erythromycin, but has a wider spectrum of activity against Gram-negative organisms. Clarithromycin is an erythromycin derivative with slightly greater activity than the parent compound; tissue concentrations are higher than with erythromycin. Azithromycin and clarithromycin are more expensive than erythromycin, but cause fewer gastro-intestinal side effects. Drug interactions Tetracyclines chelate calcium and iron in the stomach, and their absorption is reduced by the presence of antacids or food. It is normally used in conjunction with flucloxacillin for serious staphylococcal infections. They are used in atypical pneumonias and chlamydial and rickettsial infections, and remain useful in treating exacerbations of chronic bronchitis or community-acquired pneumonia. They are not used routinely for staphylococcal or streptococcal infections because of the development of resistance. Pharmacokinetics When administered either orally or intravenously, its half-life is four to six hours and it is excreted primarily via the liver. Uses and antibacterial spectrum Vancomycin is valuable in the treatment of resistant infections due to Staphylococcus pyogenes. Pharmacokinetics Metronidazole is well absorbed after oral or rectal administration, but is often administered by the relatively expensive intravenous route. Drug interactions Metronidazole interacts with alcohol because it inhibits aldehyde dehydrogenase and consequently causes a disulfiramlike reaction. There is now widespread resistance to sulphonamides, and they have been largely replaced by more active and less toxic antibacterial agents. Sulphonamides are generally well absorbed after oral administration and are widely distributed. Rarely, agranulocytosis, megaloblastic, aplastic or haemolytic anaemia and thrombocytopenia occur. Sulphonamides potentiate the action of sulphonylureas, oral anticoagulants, phenytoin and methotrexate due to inhibition of their metabolism. It is generally well tolerated, but occasionally causes gastro-intestinal disturbances, skin reactions and (rarely) bone marrow depression. Additionally, the high doses used in the management of Pneumocystis pneumonia in immunosuppressed patients cause vomiting (which can be improved by prophylactic anti-emetics), a higher incidence of serious skin reactions, hepatitis and thrombocytopenia. Pharmacokinetics Vancomycin is not absorbed from the gut and is usually given as an intravenous infusion (except for the treatment of pseudomembranous colitis). Because of its concentration-related toxicity, the dose is adjusted according to the results of plasma concentration monitoring. It is also active against several medically important protozoa and parasites (see Chapter 47). It is used to treat trichomonal infections, amoebic dysentery, giardiasis, gas gangrene, pseudomembranous colitis and various abdominal infections, lung abscesses and dental sepsis. Oral bioavailability is good and thus the 4-fluoroquinolones offer an oral alternative to parenteral aminoglycosides and antipseudomonal penicillins for treatment of Pseudomonas urinary and chest infections. Although the 4-fluoroquinolones have a very broad spectrum of activity, all of those currently available have very limited activity against streptococci. Most experience has been obtained with ciprofloxacin, which has the additional advantage of being available for intravenous use. In addition to Pseudomonas, it is particularly active against infection with Salmonella, Shigella, Campylobacter, Neisseria and Chlamydia. Ciprofloxacin is generally well tolerated, but should be avoided by epileptics (it rarely causes convulsions), children (it causes arthritis in growing animals) and individuals with glucose-6-phosphate dehydrogenase deficiency. Anaphylaxis, nephritis, vasculitis, dizziness, hepatic and renal damage have all been reported. If practicable, take specimens for microbiological analyses before starting antibacterial therapy. Consider patient factors, particularly allergies and potential drug interactions (see text). Monitor the response and alter the therapy and route of administration as appropriate. For most bacterial infections other than those involving bone, joint or heart valve tissue, five to seven days of treatment are sufficient. Case history While on holiday in Spain, a 66-year-old man develops a cough, fever and breathlessness at rest. He is started on a seven-day course of oral antibiotics by a local physician and stays in his hotel for the remainder of his ten-day holiday. Question What other tests should you do and what antibiotics would be most likely to cause this clinical scenario Answer the patient received a course of antibiotics for pneumonia and then developed what appears to be a haemolytic anaemia. This could be further confirmed by raised unconjugated bilirubin levels and low haptoglobin levels, and observation of target cells and poikilocytosis on the blood film. Mycoplasma pneumonia should be excluded by performing Mycoplasma titres, as this can itself be complicated by a haemolytic anaemia. Note that chloramphenicol is more commonly prescribed in certain countries on the European mainland. Aplastic anaemia (not the picture in this patient) is a major concern with the use of systemic chloramphenicol. Management involves stopping the drug, giving folic acid and monitoring recovery of the haemoglobin. Pharmacokinetics Approximately 80% of an oral dose of ciprofloxacin is systemically available. Ciprofloxacin is removed primarily by glomerular filtration and tubular secretion. Drug interactions Co-administration of ciprofloxacin and theophylline causes elevated blood theophylline concentrations due to inhibition of cytochrome P450. Although the spread of multi-resistant organisms can be minimized by judicious use of antibiotics and the instigation of tight infection-control measures, there is a continuing need for the development of well-tolerated, easily administered, broad-spectrum antibiotics. At present, their use is restricted and should be administered under close microbiological supervision. He complains of worsening shortness of breath, productive cough, fever and malaise. On examination, his sputum is viscous and green, his respiratory rate is 20 breaths per minute at rest but, in addition to wheezes, bronchial breathing is audible over the right lower lobe. Twenty-four hours later, the patient is brought to the local Accident and Emergency Department confused, cyanosed and with a respiratory rate of 30 breaths per minute. Question In addition to controlled oxygen and bronchodilators, which three antibacterial drugs would you prescribe and why The previously abnormal chest, the concurrent flu epidemic and the rapid deterioration suggest Staphylococcus, but Streptococcus pneumoniae and Legionella are also possible pathogens. Physical examination was normal and he was sent home with paracetamol and vitamins. Answer this young man has meningococcal meningitis and requires benzylpenicillin i. Infection with Mycobacterium tuberculosis usually occurs in the lungs, but may affect any organ, especially the lymph nodes, gut, meninges, bone, adrenal glands or urogenixtal tract. The British Thoracic Society now recommends standard therapy for pulmonary tuberculosis for six months. A combination of isoniazid, rifampicin, pyrazinamide and ethambutol (or streptomycin) is administered for the first two months, followed by rifampicin and isoniazid for a further four months. The initial four-drug combination therapy should also be used in all patients with non-tuberculous mycobacterial infection, which often involves organisms that are resistant to both isoniazid and pyrazinamide. Patients with open active tuberculosis are initially isolated to reduce the risk of spread, but may be considered non-infectious after 14 days of therapy. In cases where compliance with a daily regimen is a problem, the initial two months of triple or quadruple chemotherapy can be given on an intermittent supervised basis two or three times a week. At the end of the two-month period, the precise identification and sensitivities of the organism will be available. If they are fully sensitive, treatment will continue with daily rifampicin plus isoniazid for a further four months. After six months, treatment can usually be discontinued unless the sputum remains positive or the patient is immunocompromised or poorly compliant. If the initial drug sensitivities reveal isoniazid resistance, treatment with ethambutol plus rifampicin must be continued for a total of 12 months. The duration of chemotherapy will also need to be extended if either isoniazid, rifampicin or pyrazinamide has to be discontinued because of side effects. The treatment of tuberculosis which is resistant to multiple drugs is more difficult, and regimens have to be individualized according to drug sensitivity. Between 40 and 45% of people in European populations are rapid acetylators (Chapter 14). The t1/2 of isoniazid is less than 80 minutes in fast acetylators and more than 140 minutes in slow acetylators. Abnormally high and potentially toxic concentrations of isoniazid may occur in patients who are both slow acetylators and have renal impairment. It inhibits the metabolism of several anticonvulsants, including phenytoin and carbamazepine, causing toxic concentrations of these drugs in some patients. Uses Rifampicin is a derivative of rifamycin, which is produced by Amycolatopsis mediterranei (known as Streptomyces mediterranei). Because of its high lipophilicity, it diffuses easily through cell membranes to kill intracellular organisms, such as Mycobacterium tuberculosis. It is important to monitor hepatic transaminases, particularly in patients at high risk of liver dysfunction. It is metabolized by deacetylation and both the metabolite and parent compound are excreted in the bile and undergo enterohepatic circulation. Less than 10% appears unchanged in the urine and thus standard dosing is unaffected by renal failure. Because ethambutol is 80% excreted unchanged in the urine, it is contraindicated in renal failure. If the effect of such a drug is not closely monitored in the weeks following cessation of rifampicin treatment and the dose reduced accordingly, serious complications. It inhibits some strains of Mycobacterium tuberculosis, but other organisms are completely resistant. Resistance to ethambutol develops slowly and the drug often inhibits strains that are resistant to isoniazid or streptomycin. Because of its ability to kill bacteria in the acid intracellular environment of a macrophage, it exerts its main effects in the first two to three months of therapy. Pyrazinamide is most active against slowly or intermittently metabolizing organisms, but is inactive against atypical mycobacteria. Pyrazinamide should be avoided if there is a history of alcohol abuse, because of the occurrence of hepatitis (see below). Mechanism of action the enzyme pyrazinamidase in mycobacteria cleaves off the amide portion of the molecule, producing pyrazinoic acid which impairs mycolic acid synthesis by inhibiting the bacterial enzyme fatty acid synthase I. This then undergoes further metabolism by xanthine oxidase to hydroxypyrazinoic acid. Pyrazinamide and its metabolites are excreted via the kidney, and renal failure necessitates dose reduction.

Warfarin (anticoagulant) + Barbiturate (enzyme inducer) decreased anticoagulation joint pain treatment at home purchase generic sulfasalazine online. Penicillin (antibiotic) + Probenecid (antigout drug) Increases the duration of action of penicillin (Both drugs excreted through tubular secretion) pain medication for uti infection buy discount sulfasalazine online. Pharmacodynamic interactions: (i) Drug Synergism: When the therapeutic effect of two drugs are greater than the effect of individual drugs active pain treatment knoxville tn sulfasalazine 500 mg for sale, it is said to be drug synergism phoenix pain treatment center buy sulfasalazine 500 mg without a prescription. Trimethoprim+sulfamethoxazole 23 (iii) Drug Antagonism: the phenomenon of opposing actions of two drugs on the same physiological system is called drug antagonism sciatic pain treatment pregnancy purchase sulfasalazine online. Competitive antagonism can be overcome by increasing the concentration of the agonist at the receptor site hip pain treatment relief discount sulfasalazine 500mg with visa. Acetyl choline causes constriction where as adrenaline causes dilatation of pupil. Importance of drug antagonism (i) Correcting adverse effects of drugs (ii) Treating drug poisoning. Tachyphylaxis: Rapid development of tolerance on repeated administration is called tachyphylaxis. Ephedrine, amphetamine and nitroglycerine which produce tachyphylaxis on repeated administration. Placebo: It is a Latin word meaning" I shall please" and it is a tablet looking exactly like the active treatment but containing no active component. It refers originally to substances merely to please the patient when no specific treatment was available. Adverse drug reactions: the drugs that produce useful therapeutic effect may also produce unwanted or toxic effects. If is always an exaggeration of its pharmacological actions and some times it is predictable. The adverse effects are 1)Side effects 2)untoward effects 3)allergic reactions 4)idiosyncratic reactions and 5)teratogenic effects. They are undesirable and if very severe, may necessitate the cessation of treatment. When an individual has been sensitized to an antigen (allergen) further contact with that antigen can some times lead to tissue damaging reactions. With the increasing knowledge of pharmacogenetics, many idiosyncratic reactions have been found to be genetically determined. The best known example is thalidomide which results in early easily recognizable abnormalities such as absent or grossly abnormal limbs. Other drugs with teratogenic potential are androgens, steroids, anti convulsants, anti neoplastic drugs, cortisone, lithium, pencillamine, tricyclic antidepressants and warfarin. V) Development and evaluation of new drugs: the ultimate aim of pharmacological studies in animals is to find out a therapeutic agent suitable for clinical evaluation in man. The administration of biologically active agent to human beings is associated with an element of risk, which cannot be predicted by even the most careful and exhaustive animal experiments. Scientists all over the world are in a continuous effort to develop new drugs although drug development is an extremely technical and enormously expensive operation. Research and development of new drugs have been done under strict government regulations which have greatly increased over the past couple of decades. In this preclinical phase, varying drug doses are tested on animals and/or in vitro systems. If active compounds are found, then studies on animals are done which include pharmacodynamics, pharmacokinetics, toxicology and special toxicological studies (mutagenicity and carcinogenicity) have to be done. In this study single dose is used for acute toxicity and repeated doses for sub chronic and chronic toxicity studies. Most of the preclinical tests have to be conducted in accordance with the standards prescribed. The steps to be studied in this stage include: a) Pharmaceutical study b) Pharmacological study c) Clinical trial. With each phase, the safety and efficacy of the compound are tested progressively. Phase - I: this is the first exposure of the new drug on man which is usually conducted in healthy volunteers and which is designed to test the tolerable dose, duration of action. It involves randomised control trials on 250 to 2000 patients and is done in multiple centres. Reports about efficacy and toxicity are received from the medical practitioners and reviewed by the committee of review of medicines. Renewal or cancellation of the product license depends on the comment of the review committee. The peripheral nervous system includes the somatic and autonomic nervous systems which control voluntary and involuntary functions respectively. These include functions like circulation, respiration, digestion and the maintenance of body temperature. Autonomic nerves are actually composed of two neuron systems, termed preganglionic and postganglionic, based on anatomical location relative to the ganglia. The sympathetic nervous system arises from the thoracic and lumbar areas of the spinal cord and the preganglionic fibers for the parasympathetic nervous system arise from the cranial and sacral nerves. The postganglionic neurons send their axons directly to the effector organs (peripheral involuntary visceral organs). Autonomic innervation, irrespective of whether it belongs to the parasympathetic or the sympathetic nervous system, consists of a myelinated preganglionic fiber which forms a synapse with the cell body of a non-myelinated second neuron termed post-ganglionic fiber. The synapse is defined as a structure formed by the close apposition of a neuron either with another neuron or with effector cells. In contrast, the sympathetic nervous system is concerned with the expenditure of energy, i. To understand autonomic nervous system pharmacology, it is very important to know how the system works and clearly identify the mechanisms behind the functions, i. Acetylcholine is synthesized inside the cytoplasm of nerve fibers from acetyl coenzyme A and choline through the catalytic action of the enzyme choline acetyltransferase. Once synthesized, it is transported form the cytoplasm into the vesicles to be stored; when action potential reaches the terminal and the latter undergoes stimulation, acetylcholine is released to the synaptic cleft. After release from the presynaptic terminal the molecule binds to and activates an acetylcholine receptor (cholinergic receptor) located on effector cell. Finally, it is hydrolyzed into choline and acetate by acetyl cholinesterase enzyme and thereby the action of the transmitter is terminated. Cholinergic receptors are classified into muscarinic and nicotinic cholinergic receptors. The response of most autonomic effector cells in peripheral visceral organs is typically muscarinic, whereas the responses in parasympathetic and sympathetic ganglia, as well as responses of skeletal muscle are nicotinic. The effect of parasympathetic nervous system activity in an organ may be produced either by stimulation of a parasympathetic nerve fibers supplying the organ or by the application of acetylcholine or other parasympathomimetics to the effector cells. Noradrenaline is the neurotransmitter released by post ganglionic sympathetic nerves to elicit its effect on effectors cells. Sympathetic nerve activity may be demonstrated by sympathetic nerve stimulation or by application of noradrenaline or adrenaline or other sympathomimetics, i. Adrenergic neuron terminals synthesize noradrenaline, store it in vesicles and release it to effector cells upon stimulation of the nerve. The transmitter is synthesized from precursor tyrosine (amino acid) through several processes which are potential sites of drug action. Termination of noradrenergic transmission results from several processes such as reuptake into the nerve terminal (reuptake1), diffusion away from the synaptic cleft and subsequent reuptake into the perisynaptic glia or smooth muscle (reuptake2) or degradation by enzymes. Reuptake into the nerve terminal is the most important mechanism for termination of the effects of noradrenaline. Receptors that respond to adrenergic nerve transmitter are termed adrenergic receptors. These receptors are subdivided into alpha and beta adrenoreceptor types on the basis of both agonist and antagonist selectivity. These are synthesis, storage, release, activation of receptors and termination of the action of the transmitter. Drugs acting on the sympathetic nervous system a) Sympathomimetics or adrenergic drugs: are drugs that mimic the effects of sympathetic nerve stimulation. Drugs acting on the parasympathetic nervous system a) Parasympathomimetics or cholinergic drugs: are drugs which mimic acetylcholine or the effects of parasympathetic nerve stimulation. Administration of these drugs will result in an increase in the parasympathetic activities in the systems innervated by cholinergic nerves. Direct-acting: bind to and activate muscarinic or nicotinic receptors (mostly both) and include the following subgroups: a. Irreversible: Organophosphate compounds; echothiophate the actions of acetylcholine may be divided into two main groups: 1. Nicotinic actions- those produced by stimulation of all autonomic ganglia and the neuromuscular junction 2. It functions as a neurotransmitter at all cholinergic sites in the body; because of its unique pharmacokinetic properties, it has never been used in medical therapeutics; the discussion which follows is for academic exercise. Pharmacokinetics Acetylcholine is poorly absorbed from the gastric mucosa; therefore it is ineffective if given orally. In the blood it is rapidly hydrolyzed by the enzyme cholinesterase into acetic acid and choline; this makes its duration of action very short and unreliable for therapeutic purposes. Pharmacodynamics As mentioned earlier it has two types of actions: nicotinic and muscarinic; the muscarinic actions are of main interest and are discussed below. Cardiovascular system Heart slow heart rate 36 Blood vessels Blood pressure vasodilator falls because of the effect on the heart and blood revels i) Gastrointestinal tract It stimulates the tone and motility of the Gl tract but the sphincters will be relaxed ii) Urinary tract It stimulates the detrusor muscle and relaxes the internal urethral sphincter resulting in evacuation of bladder iii) Bronchioles It increase bronchial secretion and brings about bronchoconstriction iv) Eye- It has two effects- miosis and accommodation for near objects because of stimulation of the constrictor pupillae and ciliary muscles respectively. These are synthetic derivatives of choline and include metacholine, carbachol and betanechol. Bronchial asthma because they may induce bronchial constriction and increase bronchial secretions 2. Coronary insufficiency because the hypertension produced will further compromise coronary blood flow 5. Pharmacodynamics the drug directly stimulates the muscarinic receptors to bring about all the muscarinic effects of acetylcholine. Pharmacodynamics Inhibits the enzyme cholinesterase; therefore, it increases and prolongs the effect of endogenous acetylcholine at the different sites. Pharmacodynamics Just like physostigmine, it inhibits cholinesterase enzyme; but unlike physostigmine, it has a direct nicotinic action on skeletal muscles. Antinicotinics which include ganglion blockers such as hexamethonium, trimethaphan, etc. Antimuscarinics include tertiary amines such as atropine, scopolamine, tropicamide, etc, andquaternary amines such as propantheline, ipratropium, benztropine, etc. Pharmacokinetics Atropine is absorbed completely from all sites of administration except from the skin wall, where absorption is for limited extent; it has good distribution. Sweat Glands: - suppresses sweating 40 Clinical Indications Pre anesthetic medication -to reduce the amount of secretion and to prevent excessive vagal tone due to anesthesia. Better for preanesthetic medication because of strong antisecretory and antiemetic action and also brings about amnesia 4. Mydriatic atropine substitutes, this group of drugs have shorter duration of action than atropine and are used locally in the eye; drugs included: Homatropine, Eucatropine etc. Antiseccretory antispasmodic atropine substitutes: - Effective more localized to the Gl. Antiparkinsonian atropine substitute: - drugs like Benztropine, Trihexyphenidyl 4. Catecholamines have a direct action on sympathetic effectors cells through interactions with receptor sites on the cell membrane. The group includes adrenaline, noradrenaline, dopamine, isoprenaline, and dobutamine. They may directly act on the receptors or may indirectly release the physiologic catecholaminese. Indirect mode of action: their actions are dependent on the release of endogenous catecholamines. Blood Vessels and Blood pressure: constriction of blood vessels in the skin and mucous membranes 42 - Dilatation of skeletal muscle vessels - Adrenaline increases systolic and decreases diastolic blood pressure at low doses but increases both at higher doses - Noradrenaline increases both systolic and diastolic blood pressure 2. Bladder: relaxation of detrusor muscle; contraction of sphincter and trigone muscle 3. Eye: mydriasis; reduction of intraocular pressure in normal and glacucomatous eyes 4. Respiration: Bronchodilatation; relief of congestion; mild stimulation of respiration 5. Metabolic: Increased hepatic glycogenolysis; decreased peripheral glucose intake; increased free fatty acids in the blood (lipolysis) 6. Skeletal muscle: facilitation of neuromuscular transmission and vasodilatation Drugs Acting on the Adrenergic Receptor Subtypes 1 Agonist Phenylephrine Methoxamine Antagonist Prazosin Phentolamine 2 Clonidine Oxymetazoline Yohimbine Phentolamine 1 Dobutamine Isoproterenol Terbutaline Propranolol Pindolol Metoprolol Timolol Adrenaline stimulates all the four receptor subtypes. Noradrenaline stimulates both alpha receptors and beta1 but has very poor affinity for beta2 receptors. It is therefore ineffective when given orally and should be given intramuscularly or subcutaneous.

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They are pain medication for shingles nerves buy generic sulfasalazine, however pain management utica new york purchase sulfasalazine canada, useful in hypertensive patients with an additional complication such as ischaemic heart disease (Chapter 29) or heart failure (Chapter 31) back pain treatment videos order sulfasalazine 500 mg line. Used in the latter part of pregnancy Oxprenolol Non-selective Hepatic hydroxylation/glucuronidation Partial agonist mean pressure who pain treatment guidelines purchase sulfasalazine amex, but also to reduce the rate of rise of the arterial pressure wave pain management treatment plan order sulfasalazine without prescription. Classification of -adrenoceptor antagonists -Adrenoceptors are subdivided into 1-receptors (heart) spine diagnostic pain treatment center purchase 500 mg sulfasalazine free shipping, 2-receptors (blood vessels, bronchioles) and 3-receptors (some metabolic effects. There is little hard evidence supporting their superiority to antagonists for most indications although individual patients may find such a drug acceptable when they have failed to tolerate a pure antagonist. Pharmacokinetics -Adrenoceptor antagonists are well absorbed and are only given intravenously in emergencies. Slow-release preparation for hypertension, angina central nervous system side effects. Mechanism of action Calcium-channel blockers inhibit Ca2 influx through voltage-dependent L-type calcium channels. Calcium-channel blockers therefore relax arteriolar smooth muscle, reduce peripheral vascular resistance and lower arterial blood pressure. These formulations of nifedipine should be avoided in the treatment of hypertension and never used sublingually. There are three classes: dihydropyridines, benzothiazepines and phenylalkylamines. It is a good choice, especially in older patients and Afro-Caribbeans, although more expensive than chlortalidone. The daily dose can be increased if needed, Pharmacokinetics Calcium-channel antagonists are absorbed when given by mouth. Amlodipine is renally eliminated and has a half-life of two to three days and produces a persistent antihypertensive effect with once daily administration. However, adverse metabolic effects (see below) are dose related, so increasing the dose is seldom appropriate. Loop diuretics are useful in hypertensive patients with moderate or severe renal impairment, and in patients with hypertensive heart failure. Contraindications the effects of thiazide diuretics described above contraindicate their use in patients with severe renal impairment (in whom they are unlikely to be effective), and in patients with a history of gout. They should not be used in pre-eclampsia, which is associated with a contracted intravascular volume. It is prudent to discontinue diuretics temporarily in patients who develop intercurrent diarrhoea and/or vomiting, to avoid exacerbating fluid depletion. Mechanism of action Thiazide diuretics inhibit reabsorption of sodium and chloride ions in the proximal part of the distal convoluted tubule. Excessive salt intake or a low glomerular filtration rate interferes with their antihypertensive effect. Natriuresis is therefore probably important in determining their hypotensive action. However, it is not the whole story since although plasma volume falls when treatment is started, it returns to normal with continued treatment, despite a persistent effect on blood pressure. During chronic treatment, total peripheral vascular resistance falls slowly, suggesting an action on resistance vessels. Li is similar to Na in many respects, and is reabsorbed mainly in the proximal convoluted tubule (Chapter 20). Diuretics indirectly increase Li reabsorption in the proximal tubule, by causing volume contraction. Diuretic-induced hypokalaemia and hypomagnesaemia increase the toxicity of digoxin (Chapters 31 and 32). They may precipitate gout and worsen glucose tolerance or dyslipidaemia, but they reduce the risk of stroke and other vascular events. They are suitable first-line drugs, especially in black patients, who often have low circulating renin levels and respond well to salt restriction and diuretics. Beta-blockers reduce the risk of vascular events, but are contraindicated in patients with obstructive pulmonary disease. Heart failure, heart block or claudication can be exacerbated in predisposed patients. Other drugs that are useful in occasional patients with severe disease include minoxidil, hydralazine and nitroprusside. The main adverse effects are hyperkalaemia (especially in patients with renal impairment) and, with spironolactone, oestrogen-like effects of gynaecomastia, breast tenderness and menstrual disturbance. It is uniquely valuable in preparing patients with phaeochromocytoma for surgery, but has no place in the management of essential hypertension. Prazosin is a selective 1-blocker, but its use is limited by severe postural hypotension, especially following the first dose. Doxazosin is closely related to prazosin, but is longer lasting, permitting once daily use and causing fewer problems with first-dose hypotension. Doxazosin improves symptoms of bladder outflow tract obstruction (Chapter 36), and is useful in men with mild symptoms from benign prostatic hypertrophy. Retains a place in severe hypertension during pregnancy Headache; flushing; tachycardia; fluid retention. Long-term high-dose use causes systemic lupus-like syndrome in susceptible individuals -Methyldopa Taken up by noradrenergic nerve terminals and converted to -methylnoradrenaline, which is released as a false transmitter. This acts centrally as an 2-agonist and reduces sympathetic outflow Hypertension during pregnancy. This relaxes vascular smooth muscle, reducing peripheral vascular resistance and lowering blood pressure. It is a powerful vasodilator and is used in very severe hypertension unresponsive to other drugs, combined with a -adrenoceptor antagonist to block reflex tachycardia and a loop diuretic because of the severe fluid retention it causes. It increases hair growth (indeed the sulphate metabolite is licensed as a topical cream for male baldness) and coarsens facial features, so is unacceptable to most women. Large doses are associated with a lupuslike syndrome with positive antinuclear antibodies. It has been widely and safely used in pregnancy and retains a use for severe hypertension in this setting although nifedipine is now preferred by many obstetric physicians. Prolonged use is precluded by the development of cyanide toxicity and its use requires specialist expertise. Its mechanism is uptake into central neurones and metabolism to false transmitter (-methylnoradrenaline) which is an 2-adrenoceptor agonist. Moxonidine is another centrally acting drug: it acts on imidazoline receptors and is said to be better tolerated than methyldopa. She had had a small stroke two years previously, which was managed at home, and from which she made a complete recovery. She looks after her husband (who has mild dementia) and enjoys life, particularly visits from her grandchildren. Central imidazoline (I1) receptors as targets of centrally acting antihypertensives: moxonidine and rilmenidine. Comment Treating elderly patients with systolic hypertension reduces their excess risk of stroke and myocardial infarction. The absolute benefit of treatment is greatest in elderly people (in whom events are common). Treatment is particularly desirable as this patient made a good recovery from a stroke. She was strongly discouraged from smoking (by explaining that this would almost immediately reduce the risk of a further vascular event), but she was unable to stop. Continued smoking puts her at increased risk of stroke and she agreed to take bendroflumethiazide 2. Unstable angina may be a prelude to myocardial infarction, which can also occur unheralded. Both unstable angina and myocardial infarction occur as a result of fissuring of an atheromatous plaque in a coronary artery. Platelets adhere to the underlying subendothelium and white thrombus, consisting of platelet/fibrinogen/fibrin aggregates, extends into the lumen of the artery. In addition to mechanical obstruction caused by atheroma, with or without adherent thrombus, spasm of smooth muscle in the vascular media can contribute to ischaemia. The importance of such vascular spasm varies both among different patients and at different times in the same patient, and its contribution is often difficult to define clinically. Its importance or otherwise in the majority of patients with acute coronary syndromes is a matter of considerable debate. Treatment of patients with ischaemic heart disease is directed at the three pathophysiological elements identified above, namely atheroma, haemodynamics and thrombosis. New onset of chest pain at rest or crescendo symptoms should raise suspicion of unstable angina or myocardial infarction, and emergency referral to a hospital with coronary care unit. The object of defining these factors is to improve them in individual patients, thereby preventing progression (and hopefully causing regression) of coronary atheroma. However, in patients with chronic stable angina, pain usually resolves within a few minutes of stopping exercise even without treatment, so prophylaxis is usually more important than relief of an attack. Antithrombotic therapy with aspirin reduces the incidence of myocardial infarction; its use and mechanism of action as an antiplatelet agent are discussed further in Chapter 30. A dose is taken immediately before undertaking activity that usually brings on pain. Nicorandil combines nitrate-like with K -channel-activating properties and relaxes veins and arteries. It is used in acute and long-term prophylaxis of angina, usually as an add-on to nitrates, beta-blockers and/or calcium-channel blockers where these have been incompletely effective, poorly tolerated or contraindicated. Coronary artery disease is progressive and there are two roles for such interventions: 1. Those with significant disease in the left main coronary artery survive longer if they are operated on and so do patients with severe triple-vessel disease. Patients with strongly positive stress cardiograms have a relatively high incidence of such lesions, but unfortunately there is no foolproof method of making such anatomical diagnoses non-invasively, so the issue of which patients to subject to the low risks of invasive study remains one of clinical judgement and of cost. Surgical treatment consists of coronary artery grafting with saphenous vein or, preferably, internal mammary artery (and sometimes other artery segments. Aspirin is usually continued indefinitely and clopidogrel is usually continued for at least one month following the procedure. This is more urgent than in other patients with coronary artery disease, because of the acute pro-thrombotic effect of smoking. This antiplatelet/antithrombotic regime approximately halves the likelihood of myocardial infarction, and is the most effective known treatment for improving outcome in pre-infarction syndromes. If -blockers are contraindicated, a long-acting Ca2 -antagonist is a useful alternative. Diltiazem is often used as it does not cause reflex tachycardia and is less negatively inotropic than verapamil. Moreover, there is a theoretical risk of severe bradycardia or of precipitation of heart failure if -blockers are co-administered with these negatively chronotropic and inotropic drugs, especially so for verapamil; where concomitant -blockade and calcium-channel blockade is desired, it is probably safest to use a dihydropyridine calcium-channel blocker. Nicorandil is now often added as well, but again there is not much evidence of added benefit. Pain relief this usually requires an intravenous opiate (morphine or diamorphine; see Chapter 25) and concurrent treatment with an anti-emetic. Infarct limitation In centres where immediate access is available to the cardiac catheterization laboratory, the treatment of choice for limitation of infarct size and severity is generally considered to be primary angioplasty. However, at the present time, many hospitals do not have such immediate access available, and in such cases, since prevention of death and other serious complications is directly related to the speed with which opening of the infarct-related artery can be achieved, antithrombotic/ fibrinolytic treatment should be instituted. Early fears about toxicity of the combination proved unfounded, so they are used together. Heparin or, more commonly low-molecular-weight heparin administered subcutaneously, is needed to maintain patency of a vessel opened by aspirin plus thrombolysis when alteplase, reteplase or tenecteplase are used; this is not the case, however, for streptokinase. Recent evidence suggests that the additional use of clopidogrel in the early course of myocardial infarction improves outcome further, over and above the benefit seen with aspirin and thrombolysis or primary angioplasty. Haemodynamic treatment has less impact than opening of the infarct-related artery, but is also potentially important. The intravenous use of -blockers within the first few hours of infarction has a modest short-term benefit. This small absolute benefit was not maintained (there were more deaths in the atenolol group than in the control group at one year) and does not warrant routine use of -blockers for this indication (as opposed to their use in secondary prevention, five days or more after acute infarction, which is discussed below). Treatable complications these may occur early in the course of myocardial infarction, and are best recognized and managed with the patient in a coronary-care unit. Transfer from the admission room should therefore not be delayed by obtaining x-rays, as a portable film can be obtained on the unit if necessary. Complications include cardiogenic shock (Chapter 31) as well as acute tachyor brady-dysrhythmias (Chapter 32). Drugs are used prophylactically following recovery from myocardial infarction to prevent sudden death or recurrence of myocardial infarction.

They are used as potassium-sparing diuretics and to treat primary or secondary hyperaldosteronism in the contexts of hypertension and/or heart failure (Chapters 28 and 36) pain medication for dogs hydrocodone generic sulfasalazine 500 mg mastercard. It binds to the mineralocorticoid steroid receptor and mimics the action of aldosterone xiphisternum pain treatment effective 500 mg sulfasalazine. It undergoes significant presystemic metabolism pain treatment order sulfasalazine 500 mg line, but unlike aldosterone is active by mouth treatment guidelines for chronic pain discount sulfasalazine online mastercard. Uses Dexamethasone is powerfully anti-inflammatory pain medication for little dogs order generic sulfasalazine on line, but is virtually devoid of mineralocorticoid activity anterior knee pain treatment exercises generic 500 mg sulfasalazine. It has no glucocorticoid activity, but is about 1000 times more active than hydrocortisone as a mineralocorticoid. Aldosterone acts on the distal nephron, promoting Na /K exchange, causing sodium retention and urinary loss of potassium Adrenaline (epinephrine) is the main hormone produced by the adrenal medulla. It is used in emergency situations, such as cardiac arrest (Chapter 32), anaphylactic shock (Chapter 50) and other life-threatening disorders that require combined potent - and -agonist activity. It is used to prolong the action of local anaesthetics (via its vasoconstrictor action). Dipivefrine is a prodrug eye-drop formulation of adrenaline used to treat chronic open angle glaucoma (Chapter 52). Tumours of the adrenal medulla that secrete adrenaline and other pharmacologically active catecholamines (phaeochromocytoma) are treated surgically; in these patients preoperative blockade with phenoxybenzamine, a long-acting -blocker, followed by -blockade is essential. Glucocorticosteroids, primarily in the form of hydrocortisone (cortisol), are secreted in a diurnal pattern from the zona fasciculata. Case history A 32-year-old man presents after collapsing in the street complaining of severe lower abdominal pain. His relevant past medical history is that for 10 years he has had chronic asthma, which is normally controlled with 2-agonists and inhaled beclometasone 2000 g/day. Initial assessment shows that he has peritonitis, and emergency laparotomy reveals a perforated appendix and associated peritonitis. His immediate post-operative state is stable, but approximately 12 hours post-operatively he becomes hypotensive and oliguric. The hypotension does not respond well to intravenous dobutamine and dopamine and extending the spectrum of his antibiotics. By 16 hours post-operatively, he remains hypotensive on pressor agents (blood pressure 85/50 mmHg) and he becomes hypoglycaemic (blood glucose 2. Answer In a chronic asthmatic patient who is receiving high-dose inhaled steroids (and may have received oral glucocorticosteroids periodically), any severe stress. In this case, the development of refractory hypotension in a patient who is on antibiotics and pressors, and the subsequent hypoglycaemia, should alert one to the probability of adrenal insufficiency. This possibility is further supported by the low sodium, slightly increased potassium and elevated urea levels. The treatment consists of immediate administration of intravenous hydrocortisone and intravenous glucose. With improvement, the patient could then be given twice his normal dose of prednisolone or its parenteral equivalent for five to seven days. This unfortunate clinical scenario could have been avoided if parenteral hydrocortisone was given preoperatively and every eight hours for the first 24 hours postoperatively. Glucocorticosteroids should be continued at approximately twice their normal dose for the next two to three days post-operatively, before reverting to his usual dose (clinical state permitting). The main hormones secreted by the ovary are oestradiol17, oestrone, progesterone and androgens. Oestrogens influence the development of secondary sexual characteristics, including breast development and the female distribution of fat, as well as ovulation during the reproductive years. From the start of menses until the menopause, the primary oestrogen is oestradiol-17, whereas in post-menopausal women oestrone predominates. Ethinylestradiol, a synthetic oestrogen, is an alternative for many of the above indications. Oestrogens are no longer used to suppress lactation because of the risk of thromboembolism. Salt and water retention with oedema, hypertension and exacerbation of heart failure can occur with pharmacological doses. Oestrogens are carcinogenic in some animals and there is an increased incidence of endometrial carcinoma in women who have uninterrupted treatment with exogenous oestrogen unopposed by progestogens. Pharmacokinetics Oestrogens are absorbed by mouth and via the skin and mucous membranes. The most potent natural oestrogen is oestradiol-17 which is largely oxidized to oestrone and then hydrated to produce oestriol. All three oestrogens are metabolized in the liver and excreted as glucuronide and sulphate conjugates in the bile and urine. Ethinylestradiol has a prolonged action because of slow hepatic metabolism with a half-life of about 25 hours. Progesterone is the precursor of 17-hydroxyprogesterone which is converted to androstenedione which subsequently is converted to testosterone, oestrone and oestradiol. Progesterone is produced in the adrenal glands, by the corpus luteum, the brain and by the placenta. There are two main groups of progestogens, namely the naturally occurring hormone progesterone and its analogues, and the testosterone analogues, such as norethisterone and norgestrel. All progestogens have antioestrogenic and anti-gonadotrophic properties, and differ in their potency and their side effects. The newer progestogens, desogestrel, gestodene and norgestimate produce good cycle control and have a less marked adverse effect on plasma lipids; however, studies have shown that oral contraceptives containing desogestrel and gestodene are associated with an increase of around two-fold in the risk of venous thromboembolism compared to those containing other progestogens and should be avoided in women with risk factors for thromboembolic disease. Desogestrel, drospirenone (a derivative of spironolactone with anti-androgenic and anti-mineralocorticoid properties) and gestodene should be considered for women who have side effects, such as acne, headache, depression, weight gain, breast symptoms and breakthrough bleeding with other progestogens. The progestogen norelgestromin is combined with ethinylestradiol in a transdermal contraceptive patch. Mechanism of action Progestogens act on intracellular cytoplasmic receptors and initiate new protein formation. Their main contraceptive effect is via an action on cervical mucus which renders it impenetrable to sperm. Nortestosterone derivatives are partially metabolized oestrogenic metabolites which may account for some additional anti-ovulatory effect. A pseudodecidual change in the endometrium further discourages implantation of the zygote. Pharmacokinetics Progesterone is subject to presystemic hepatic metabolism and is most effective when injected intramuscularly or administered sublingually. Norethisterone, a synthetic progestogen used in many oral contraceptives, is rapidly absorbed orally, is subject to little presystemic hepatic metabolism and has a half-life of 7. It is the most consistently effective contraceptive method and allows sexual relations to proceed without interruption, but it lacks the advantage of protection against sexually transmitted disease that is afforded by condoms. Medroxyprogesterone acetate administered by depot injection is used when parenteral contraception is indicated. Progestogens currently used in combined oral contraceptives include desogestrel, gestodene and norgestimate. However, desogestrel and gestadene have been associated with an increased risk of venous thrombo-embolism. Jaundice similar to that of pregnancy cholestasis can occur, usually in the first few cycles. There is a decreased incidence of benign breast lesions and functional ovarian cysts. Amenorrhoea after stopping combined oral contraception is not unusual (about 5% of cases) but is rarely prolonged, and although there may be temporary impairment of fertility, permanent sterility is very uncommon. Users have an increased risk of venous thromboembolic disease, this risk being greatest in women over 35 years of age, especially if they smoke cigarettes, are obese and have used oral contraceptives for five years or more continuously. Progestogen-only pills may be appropriate in women at higher risk of thrombotic disease. Increased blood pressure is common with the pill, and is clinically significant in about 5% of patients. When medication is stopped, the blood pressure usually falls to the pretreatment value. In normotensive non-smoking women without other risk factors for vascular disease, there is no upper age limit on using the combined oral contraceptive, but it is prudent to use the lowest effective dose of oestrogen, especially in women aged 35 years or over. With regards to cervical cancer, there is a small increase after five years and a two-fold increase after ten years of treatment. The risk of ovarian cancer and endometrial cancer is halved and this benefit persists for ten years or more. Key point the main mechanism of action of the combined oral contraceptive is suppression of ovulation. Antihypertensive therapy may be adversely affected by oral contraceptives, at least partly because of increased circulating renin substrate. Oral contraceptive steroids undergo enterohepatic circulation, and conjugated steroid in the bile is broken down by bacteria in the gut to the parent steroid and subsequently reabsorbed. If vomiting occurs within three hours of ingestion, Uses Progestogen-only contraceptive pills. Contraceptive effectiveness is less than with the combined pill, as ovulation is suppressed in only approximately 40% of women and the major contraceptive effect is on the cervical mucus and endometrium. Pregnancy rates are of the same order as those with the intra-uterine contraceptive device or barrier methods (approximately 1. Progestogen-only pills are taken continuously throughout the menstrual cycle, which is convenient for some patients. A single intramuscular injection of medroxyprogesterone acetate provides contraception for ten weeks with a failure rate of 0. The side effects are essentially similar to those of oral progestogenonly preparations. Contraindications these include pregnancy, undiagnosed vaginal bleeding, severe arterial disease, liver adenoma and porphyria. A single oral dose of mifepristone is followed by gemeprost (a prostaglandin that ripens and softens the cervix), as a vaginal pessary unless abortion is already complete. Gemeprost can cause hypotension, so the blood pressure must be monitored for six hours after the drug has been administered. Subcutaneous and transdermal routes of administration are available and may be suitable for certain women. Subcutaneous implants can cause rebound vasomotor symptoms, as abnormally high plasma concentrations may occur. Hormone replacement therapy does not provide contraception and a woman is considered potentially fertile for two years after her last menstrual period if she is under 50 years of age, and for one year if she is over 50 years. Women under 50 years without any of the risk factors for venous or arterial disease may use a low-oestrogen combined oral contraceptive pill to gain both relief of menopausal symptoms and contraception. There is an increased risk of endometrial carcinoma after several years of use which can be countered by progestogen. For vaginal atrophy, oestrogen can be given as a local topical preparation for a few weeks at a time, repeated as necessary. However, the periods of treatment need to be limited, as again there is a risk of endometrial carcinoma. Vasomotor Pregnancy, oestrogen-dependent cancers, active thromboembolic disease, liver disease, undiagnosed vaginal bleeding and breast-feeding. The relative contraindications include migraine, history of breast nodules and fibrocystic disease, pre-existing uterine fibroids, endometriosis, risk factors for thrombo-embolic disease. Oestrogen receptor antagonists include tamoxifen which is licensed for breast cancer and anovulatory infertility, fulvestrant which is licensed for the treatment of oestrogen receptor-positive metastatic or locally advanced breast cancer in post-menopausal women, and toremifene which is licensed for hormone-dependent metastatic breast cancer in post-menopausal women. The aromatase inhibitors block the conversion of androgens to oestrogens in the peripheral tissues. They do not inhibit ovarian oestrogen synthesis and are not suitable for use in premenopausal women who will continue to secrete ovarian oestrogens. The gonadorelin analogue goserelin is licensed for the management of advanced breast cancer in premenopausal women. It acts by initially stimulating and then depressing luteinizing hormone released by the pituitary, which in turn reduces oestrogen production. Clomifene and tamoxifen are used in the treatment of female infertility due to oligomenorrhoea or secondary amenorrhoea (for example, that associated with polycystic ovarian disease).