Cough suppressants

Cough may be a symptom of an underlying disorder, such as asthma gastro-oesophageal reflux disease , or rhinitis which should be addressed before prescribing cough suppressants. Cough may be a side-effect of another drug, such as an ACE inhibitor or it can be associated with smoking or environmental pollutants. Cough can also have a significant habit component. When there is no identifiable cause, cough suppressants may be useful, for example if sleep is disturbed. They may cause sputum retention and this may be harmful in patients with chronic bronchitis and bronchiectasis.Codeine may be effective but it is constipating and can cause dependence; dextromethorphan and pholcodine have fewer side-effects. Sedating antihistamines are used as the cough suppressant component of many compound cough preparations on sale to the public; all tend to cause drowsiness which may reflect their main mode of action.

Children
The use of cough suppressants containing codeine or similar opioid analgesics is not generally recommended in children and should be avoided altogether in those under 1 year of age.
Sub-sections

CODEINE PHOSPHATE
Indications
dry or painful cough; diarrhoea ,pain
Cautions
asthma; hepatic impairment; renal impairment history of drug abuse

Contra-indications
liver disease, ventilatory failure
Side-effects
constipation, respiratory depression in sensitive patients or if given large doses

Phaeochromocytoma

Long-term management of phaeochromocytoma involves surgery. Alpha-blockers are used in the short-term management of hypertensive episodes in phaeochromocytoma. Once alpha blockade is established, tachycardia can be controlled by the cautious addition of a beta-blocker a cardioselective beta-blocker is preferred.
Phenoxybenzamine, a powerful alpha-blocker, is effective in the management of phaeochromocytoma but it has many side-effects. Phentolamine is a short-acting alpha-blocker used mainly during surgery of phaeochromocytoma; its use for the diagnosis of phaeochromocytoma has been superseded by measurement of catecholamines in blood and urine.
Metirosine inhibits the enzyme tyrosine hydroxylase, and hence the synthesis of catecholamines. It is rarely used in the pre-operative management of phaeochromocytoma, and long term in patients unsuitable for surgery; an alpha-adrenoceptor blocking drug may also be required. Metirosine should not be used to treat essential hypertension.

Myocardial infarction is part of the spectrum of acute coronary syndromes which includes unstable angina, and myocardial infarction with or without ST-segment elevation.
These notes give an overview of the initial and long-term management of myocardial infarction with ST-segment elevation. For advice on the management of non-ST-segment elevation myocardial infarction and unstable angina, see section 2.6. The aims of management of ST-segment elevation myocardial infarction are to provide supportive care and pain relief, to promote reperfusion and to reduce mortality. Oxygen, diamorphine and nitrates can provide initial support and pain relief; aspirin and percutaneous coronary intervention or thrombolytics promote reperfusion; long-term use of aspirin, beta-blockers, ACE inhibitors, and statins help to reduce mortality further.
Initial managementOxygen should be administered if there is evidence of hypoxia, pulmonary oedema, or continuing myocardial ischaemia; hyperoxia should be avoided and particular care is required in patients with chronic obstructive airways disease.
The pain (and anxiety) of myocardial infarction is managed with slow intravenous injection of diamorphine ; an antiemetic such as metoclopramide (or, if left ventricular function is not compromised, cyclizine) by intravenous injection should also be given
Aspirin (chewed or dispersed in water) is given for its antiplatelet effect ; a dose of 300 mg is suitable. If aspirin is given before arrival at hospital, a note saying that it has been given should be sent with the patient. Clopidogrel, in a dose of 300 mg, should also be given
Patency of the occluded artery can be restored by percutaneous coronary intervention or by giving a thrombolytic drug , unless contra-indicated. Percutaneous coronary intervention is the preferred method and patients should receive a glycoprotein IIb/IIIa inhibitor (section 2.9) to reduce the risk of immediate vascular occlusion. In patients who cannot be offered percutaneous coronary intervention within 90 minutes of diagnosis, a thrombolytic drug should be administered. A low molecular weight heparin or fondaparinux should also be given to all patients; anticoagulant treatment should be continued for up to 8 days, or until percutaneous coronary intervention, or hospital discharge.
Nitrates are used to relieve ischaemic pain. If sublingual glyceryl trinitrate is not effective, intravenous glyceryl trinitrate or isosorbide dinitrate is given.
Early administration of some beta-blockers has been shown to be of benefit and should be given to patients without contra-indications.
ACE inhibitors , and angiotensin-II receptor antagonists if an ACE inhibitor cannot be used, are also of benefit to patients who have no contra-indications; in hypertensive and normotensive patients treatment with an ACE inhibitor, or an angiotensin-II receptor antagonist, can be started within 24 hours of the myocardial infarction and continued for at least 5–6 weeks (see below for long-term treatment).
All patients should be closely monitored for hyperglycaemia; those with diabetes or raised blood-glucose concentration should receive insulin.
Long-term management

Long-term management involves the use of several drugs which should ideally be started before the patient is discharged from hospital.
Aspirin should be given to all patients, unless contra-indicated, at a dose of 75 mg daily. The addition of clopidogrel has been shown to reduce morbidity and mortality. For those intolerant of clopidogrel, and who are at low risk of bleeding, the combination of and aspirin should be considered. In those intolerant of both aspirin and clopidogrel, warfarin alone can be used. Warfarin should be continued for those who are already being treated for another indication, such as atrial fibrillation, with the addition of aspirin if there is a low risk of bleeding. The combination of aspirin with clopidogrel or warfarin increases the risk of bleeding.
Beta-blockers should be given to all patients in whom they are not contra-indicated. Acebutolol, metoprolol, propranolol, and timolol are suitable; for patients with left ventricular dysfunction, carvedilol, bisoprolol, or long-acting metoprolol may be appropriate
Diltiazem orverapamil can be considered if a beta-blocker cannot be used; however, they are contra-indicated in those with left ventricular dysfunction. Other calcium-channel blockers have no place in routine long-term management after a myocardial infarction.
An ACE inhibitor should be considered for all patients, especially those with evidence of left ventricular dysfunction. If an ACE inhibitor cannot be used, an angiotensin-II receptor antagonist may be used for patients with heart failure. A relatively high dose of either the ACE inhibitor or angiotensin-II receptor antagonist may be required to produce benefit.
Nitrates are used for patients with angina.
Eplerenone is licensed for use following a myocardial infarction in those with left ventricular dysfunction and evidence of heart failure.

Heart failure

Drug treatment of heart failure due to left ventricular systolic dysfunction is covered below; optimal management of heart failure with preserved left ventricular function is not established.
The treatment of chronic heart failure aims to relieve symptoms, improve exercise tolerance, reduce the incidence of acute exacerbations, and reduce mortality. An ACE inhibitor, titrated to a ‘target dose’ (or the maximum tolerated dose if lower), and a beta-blocker is recommended to achieve these aims. A diuretic is also necessary in most patients to reduce symptoms of fluid overload.
An ACE inhibitor is generally advised for patients with asymptomatic left ventricular dysfunction or symptomatic heart failure. An angiotensin-II receptor antagonist may be a useful alternative for patients who, because of side-effects such as cough, cannot tolerate ACE inhibitors; a relatively high dose of the angiotensin-II receptor antagonist may be required to produce benefit.
The beta-blockers bisoprolol and carvedilol are of value in any grade of stable heart failure and left-ventricular systolic dysfunction; nebivolol is licensed for stable mild to moderate heart failure in patients over 70 years. Beta-blocker treatment should be started by those experienced in the management of heart failure, at a very low dose and titrated very slowly over a period of weeks or months. Symptoms may deteriorate initially, calling for adjustment of concomitant therapy.
Patients with fluid overload should also receive either a loop or a thiazide diuretic (with salt or fluid restriction where appropriate). A thiazide diuretic may be of benefit in patients with mild heart failure and good renal function; however, thiazide diuretics are ineffective in patients with poor renal function (estimated creatinine clearance less than 30 mL/minute, see Appendix 3) and a loop diuretic is preferred. If diuresis with a single diuretic is insufficient, a combination of a loop diuretic and a thiazide diuretic may be tried; addition of metolazone may also be considered but the resulting diuresis may be profound and care is needed to avoid potentially dangerous electrolyte disturbances.
The aldosterone antagonist spironolactone can be considered for patients with moderate to severe heart failure who are already taking an ACE inhibitor and a beta-blocker; low doses of spironolactone (usually 25 mg daily) reduce symptoms and mortality in these patients. If spironolactone cannot be used, eplerenone may be considered for the management of heart failure after an acute myocardial infarction with evidence of left ventricular dysfunction. Close monitoring of serum creatinine and potassium is necessary with any change in treatment or in the patient’s condition.
Digoxin improves symptoms of heart failure and exercise tolerance and reduces hospitalisation due to acute exacerbations but it does not reduce mortality. Digoxin is reserved for patients with atrial fibrillation and also for selected patients in sinus rhythm who remain symptomatic despite treatment with an ACE inhibitor, a beta-blocker, and a diuretic.
Patients who cannot tolerate an ACE inhibitor or an angiotensin-II receptor antagonist, or in whom they are contra-indicated, may be given isosorbide dinitrate with hydralazine but this combination may be poorly tolerated. In African-American patients, the combination of isosorbide dinitrate and hydralazine may be considered in addition to standard therapy if necessary.

Management of arrhythmias

Management of an arrhythmia requires precise diagnosis of the type of arrhythmia, and electrocardiography is essential; underlying causes such as heart failure require appropriate treatment.
Ectopic beats
If ectopic beats are spontaneous and the patient has a normal heart, treatment is rarely required and reassurance to the patient will often suffice. If they are particularly troublesome, beta-blockers are sometimes effective and may be safer than other suppressant drugs.
Atrial fibrillation
Atrial fibrillation can be managed by either controlling the ventricular rate or by attempting to restore and maintain sinus rhythm.Ventricular rate can be controlled with a beta-blocker or diltiazem [unlicensed indication], or verapamil. If rate control is inadequate during normal activities, digoxin can be added; in those who require additional rate control during exercise, a combination of diltiazem or verapamil with digoxin should be used, but care is required if ventricular function is diminished. Digoxin is usually only effective for controlling ventricular rate at rest, therefore digoxin monotherapy should only be used in predominantly sedentary patients; digoxin is also used if atrial fibrillation is accompanied by congestive heart failure.
Sinus rhythm can be restored by electrical cardioversion, or pharmacological cardioversion with an intravenous anti-arrhythmic drug e.g. propafenone, flecainide, or amiodarone. If necessary, sotalol or amiodarone can be started 4 weeks before electrical cardioversion to increase success of the procedure. If drug treatment is required to maintain sinus rhythm, a beta-blocker is used. If a standard beta-blocker is not appropriate or is ineffective, an oral anti-arrhythmic drug such as sotalol flecainide, propafenone, or amiodarone, is required.
In symptomatic paroxysmal atrial fibrillation, ventricular rhythm is controlled with a beta-blocker. Alternatively, if symptoms persist or a beta-blocker is not appropriate, an oral anti-arrhythmic drug such as sotalol, flecainide, propafenone, or amiodarone can be given.
All haemodynamically unstable patients with acute-onset atrial fibrillation should undergo electrical cardioversion. Intravenous amiodarone, or alternatively flecainide, can be used in non-life-threatening cases where electrical cardioversion is delayed. If urgent ventricular rate control is required, a beta-blocker, verapamil, or amiodarone can be given intravenously.
All patients with atrial fibrillation should be assessed for their risk of stroke and the need for thromboprophylaxis. Anticoagulants are indicated for those with a history of ischaemic stroke, transient ischaemic attacks, or thromboembolic events, and those with valve disease, heart failure, or impaired left ventricular function; anticoagulants should be considered for those with cardiovascular disease, diabetes, hypertension, or thyrotoxicosis, and in the elderly. Anticoagulants are also indicated during cardioversion procedures. Aspirin is less effective than warfarin at preventing emboli, but may be appropriate if there are no other risk factors for stroke.
Atrial flutter
The ventricular rate at rest can sometimes be controlled with digoxin. Reversion to sinus rhythm (if indicated) may be achieved by cardiac pacing or appropriately synchronised d.c. shock. Alternatively, amiodarone may be used to restore sinus rhythm, and amiodarone or sotalol to maintain it. If the arrhythmia is long-standing a period of treatment with anticoagulants should be considered before cardioversion to avoid the complication of emboli.
Paroxysmal supraventricular tachycardia
In most patients this remits spontaneously or can be returned to sinus rhythm by reflex vagal stimulation with respiratory manoeuvres, prompt squatting, or pressure over one carotid sinus (important: pressure over carotid sinus should be restricted to monitored patients—it can be dangerous in recent ischaemia, digitalis toxicity, or the elderly).
If vagal stimulation fails, intravenous administration of adenosine is usually the treatment of choice. Intravenous administration of verapamil is useful for patients without myocardial or valvular disease For arrhythmias that are poorly tolerated, synchronised d.c. shock usually provides rapid relief.
In cases of paroxysmal supraventricular tachycardia with block, digitalis toxicity should be suspected. In addition to stopping administration of the cardiac glycoside and giving potassium supplements, intravenous administration of a beta-blocker may be useful. Specific digoxin antibody is available if the toxicity is considered life-threatening .
Arrhythmias after myocardial infarction
In patients with a paroxysmal tachycardia or rapid irregularity of the pulse it is best not to administer an antiarrhythmic until an ECG record has been obtained. Bradycardia, particularly if complicated by hypotension, should be treated with 500 micrograms of atropine sulphate given intravenously; the dose may be repeated every 3–5 minutes if necessary up to a maximum total dose of 3 mg. If there is a risk of asystole, or if the patient is unstable and has failed to respond to atropine, adrenaline should be given by intravenous infusion in a dose of 2–10 micrograms/minute, adjusted according to response. For further advice, refer to the most recent recommendations of the Resuscitation Council (UK) available at www.resus.org.uk.
Ventricular tachycardia
Drug treatment is used both for the treatment of ventricular tachycardia and for prophylaxis of recurrent attacks that merit suppression. Ventricular tachycardia requires treatment most commonly in the acute stage of myocardial infarction, but the likelihood of this and other life-threatening arrhythmias diminishes sharply over the first 24 hours after the attack, especially in patients without heart failure or shock. Lidocaine (lignocaine) is the preferred drug for emergency use. Other drugs are best administered under specialist supervision. Very rapid ventricular tachycardia causes profound circulatory collapse and should be treated urgently with d.c. shock.
Torsade de pointes is a form of ventricular tachycardia associated with a long QT syndrome (usually drug-induced, but other factors including hypokalaemia, severe bradycardia, and genetic predisposition are also implicated). Episodes are usually self-limiting, but are frequently recurrent and can cause impairment or loss of consciousness. If not controlled, the arrhythmia can progress to ventricular fibrillation and sometimes death. Intravenous infusion of magnesium sulphate is usually effective. A beta-blocker (but not sotalol) and atrial (or ventricular) pacing can be considered. Anti-arrhythmics can further prolong the QT interval, thus worsening the condition.

Management of acute severe asthma

Acute severe asthma can be fatal and must be treated promptly and energetically. All patients with acute severe asthma should be given high-flow oxygen (if available) and an inhaled short-acting beta2 agonist via a large-volume spacer or nebuliser; give 4–10 puffs of salbutamol 100 micrograms/metered inhalation, each puff inhaled separately via a large-volume spacer, and repeat at 10–20 minute intervals if necessary. If there are life-threatening features, give salbutamol or terbutaline via an oxygen-driven nebuliser every 15–30 minutes. In all cases, a systemic should be given. For adults, give prednisolone 40–50 mg by mouth for at least 5 days, or intravenous hydrocortisone 100 mg (preferably as sodium succinate) every 6 hours until conversion to oral prednisolone is possible. For children, give prednisolone 1–2 mg/kg by mouth (max. 40 mg) for 3–5 days or intravenous hydrocortisone (under 1 year 25 mg, 1–5 years 50 mg, 6–12 years 100 mg) (preferably as sodium succinate) every 6 hours until conversion to oral prednisolone is possible. If the child has been taking an oral corticosteroid for more than a few days, then give prednisolone 2 mg/kg (CHILD under 2 years max. 40 mg, over 2 years max. 50 mg). In life-threatening asthma, also consider initial treatment with ipratropium by nebuliser
Most patients do not require and do not benefit from the addition of intravenous aminophylline or of intravenous beta2 agonist; both cause more adverse effects than nebulised beta2 agonists. Nevertheless, an occasional patient who has not been taking theophylline may benefit from aminophylline infusion. Patients with severe asthma may be helped by magnesium sulphate [unlicensed indication] 1.2–2 g given by intravenous infusion over 20 minutes, but evidence of benefit is limited.
Treatment of acute severe asthma is safer in hospital where resuscitation facilities are immediately available. Treatment should never be delayed for investigations, patients should never be sedated, and the possibility of a pneumothorax should be considered.
If the patient’s condition deteriorates despite pharmacological treatment, intermittent positive pressure ventilation may be needed.

Dyspepsia

Dyspepsia covers pain, fullness, early satiety, bloating, and nausea. It can occur with gastric and duodenal ulceration and gastric cancer but most commonly it is of uncertain origin.
Urgent endoscopic investigation is required if dyspepsia is accompanied by ‘alarm features’ (e.g. bleeding, dysphagia, recurrent vomiting, or weight loss). Urgent investigation should also be considered for patients over 55 years with unexplained dyspepsia that has not responded to treatment.
Patients with dyspepsia should be advised about lifestyle changes (see Gastro-oesophageal reflux disease, below). Some medications may cause dyspepsia—these should be stopped, if possible. Antacids may provide some symptomatic relief.
If symptoms persist in uninvestigated dyspepsia, treatment involves a proton pump inhibitor for 4 weeks. A proton pump inhibitor can be used intermittently to control symptoms long-term. Patients with uninvestigated dyspepsia, who do not respond to an initial trial with a proton pump inhibitor, should be tested for Helicobacter pylori and given eradication therapy if H. pylori is present. Alternatively, particularly in populations where H. pylori infection is more likely, the ‘test and treat’ strategy for H. pylori can be used before a trial with a proton pump inhibitor.
If H. pylori is present in patients with functional (investigated, non-ulcer) dyspepsia, eradication therapy should be provided. However, most patients with functional dyspepsia do not benefit symptomatically from H. pylori eradication. If symptoms persist, treatment with either a proton pump inhibitor or a histamine H2-receptor antagonist can be given for 4 weeks. These antisecretory drugs can be used intermittently to control symptoms long-term.

Pharmaceutics

Pharmaceutics is the discipline of pharmacy that deals with all facets of the process of turning a new chemical entity (NCE) into a medication able to be safely and effectively used by patients in the community. Pharmaceutics is the science of dosage form design. There are many chemicals with known pharmacological properties but a raw chemical is of no use to a patient. Pharmaceutics deals with the formulation of a pure drug substance into a dosage form. Branches of pharmaceutics include:
Pharmacokinetics
Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion, the study of time dependency; sometimes abbreviated as “PK”) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. In practice, this discipline is applied mainly to drug substances, though in principle it concerns itself with all manner of compounds ingested or otherwise delivered externally to an organism, such as nutrients, metabolites, hormones, toxins, etc.
Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug. Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites of the drug
Pharmacodynamics
Pharmacodynamics is the study of the physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect.One dominant example is drug-receptor interactions as modeled by L=ligand (drug), R=receptor (attachment site), reaction dynamics that can be studied mathematically through tools such as free energy maps. Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug. Pharmacodynamics is sometimes abbreviated as "PD", and when referred to in conjunction with pharmacokinetics can be referred to as "PKPD".
Pharmacogenomics
Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimise drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs.