Capítulo 7. Resultados
7.1. Análisis de las agendas temáticas presentes en los debates
49
Ta b l e 5 . 1 Examples of adverse drug reactions that may be predicted from the pharmacology of the drug class;
further information is given in the relevant chapters
Drug class Side effect Pharmacological
mechanism
Possible solutions
β Blockers Cold extremities Antagonism of
peripheral β2-adrenoceptors
• Choose a more cardioselective agent such as atenolol, which has less affinity for agent β2-adrenoceptors
• Choose a β blocker with vasodilator actions, e.g. nebivolol
β Blockers Bradycardia Antagonism of
chronotropic cardiac β1-adrenoceptors
• Withdraw β blockers gradually to prevent rebound tachycardia
β Blockers Bronchospasm Antagonism of bronchial
β2-adrenoceptors
•All β blockers are
contraindicated in asthma. A cardioselective one may be used with extreme caution under specialist supervision
Cardioselective β blockers should be used with caution in COPD α Blockers, diuretics,
ACE inhibitors
Postural hypotension Impairment of blood pressure regulation
• Caution on standing
• Take first dose of α blocker or ACE inhibitor on retiring to bed Thiazide and loop
diuretics
Hypokalaemia Activation of the renin–angiotensin–
aldosterone system See Chapter 15
Potassium levels should be monitored
Nitrates Flushing, headache Vasodilatation • Headache relieved by
paracetamol
• Sublingual tablets may be discarded by spitting them out Oral anticoagulants Increased bleeding Plasma concentration too
high or increased bleeding tendency
• Monitoring of INR required and dose adjustment may be required
Opioids Constipation Inhibition of lower GI
tract motility
• Use a laxative such as lactulose or senna such as dry mouth, blurred vision, constipation and urinary retention
Antagonism of muscarinic receptors
• Consider an SSRI for depression
• Choose a newer antihistamine with less muscarinic binding, e.g. loratadine
Sulphonylureas Hypoglycaemia Augmented
pharmacological effect
• Careful monitoring with dose adjustment
• Use short-acting agents
Continued
Type A: augmented response
This type of ADR can be explained or predicted on the basis of the drug’s pharmacology. Type A reactions are often dose dependent and may often be managed by dose reduction. If they are anticipated, measures may be taken to ameliorate or prevent the problem, e.g. the use of anti-emetics in patients receiving chemotherapy, or laxatives with opioid analgesics.
Type B: bizarre or idiosyncratic reactions
These ADRs are unrelated to the known pharma-cology of the drug, which makes them less common and unpredictable; they may also be severe. This group of ADRs is often related to genetics or immunology, which means that
certain individuals may be at a higher risk than others.
Risk factors for developing ADRs
When considering ADRs there are a number of risk factors that may predispose a patient to adverse responses:
• extremes of age
• gender
• concurrent drug usage
• concurrent disease, e.g. respiratory disease and β blockers
• pharmacokinetic variables, e.g. renal or hepatic function
• pharmaceutical factors, e.g. nature of dosage form or excipients
Ta b l e 5 . 1 (Continued)
Drug class Side effect Pharmacological
mechanism
Possible solutions
Broad-spectrum antibiotics
Diarrhoea Alterations of lower GI flora
• Caution: severe diarrhoea should alert one to the risk of pseudomembranous colitis.
Otherwise a short course of loperamide may be used with caution
NSAIDs Gastric damage Inhibition of the
production of cytoprotective prostaglandins
•Use a less irritant NSAID such as ibuprofen
•Consider a COX-2 inhibitor.
•Combine NSAID with misoprostol or a PPI
NSAIDs Bronchospasm Inhibition of the
production of prostaglandins, favouring the production of leukotrienes
•Avoid in patients with asthma who are sensitive to NSAIDs
Cytotoxic agents Myelosuppression Cytotoxic effects on bone marrow
• Prophylactic antibacterial and antifungal agents
• Use of transfusions or colony-stimulating factors to increase white blood cell counts
ACE, angiotensin-converting enzyme; COPD, chronic obstructive pulmonary disease; COX-2, cyclo-oxygenase 2; GI, gastrointestinal; INR, international normalized ratio; NSAIDs, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitor; SSRI, selective serotonin reuptake inhibitor.
• genetics, e.g. glucose-6-phosphate dehydroge-nase (G6PD) deficiency.
Mechanisms of adverse reactions
The effects of a drug may be enhanced by various pharmacodynamic or pharmacokinetic factors, leading to enhanced side effects or adverse reactions.
Pharmacological mechanisms
These represent the most straightforward examples that may be predicted from a sound knowledge of a drug’s pharmacology. The best example is β-adrenoceptor antagonists which, to varying degrees, will block β2-adrenoceptors on the bronchial smooth muscle, opposing the actions of circulating adrenaline (epinephrine), which may lead to bronchoconstriction, and it is for this reason that they are contraindicated in asthma. Other examples are given in Table 5.1.
These predictable responses are dose dependent and so increases in plasma concentration, which may occur as a consequence of pharmacokinetic mechanism (as outlined below) or drug inter-actions (see later), necessarily increase their like-lihood and impact.
Pharmacokinetic mechanisms
Pharmacokinetic ADRs result from impaired absorption, distribution, metabolism or excre-tion (ADME). The first potential site is absorpexcre-tion and this might be delayed if, for example, gastric emptying is slowed and the consequences might be retarded absorption, leading to failure of therapy, which is itself an ADR. Metabolism and elimination are far more important, e.g. a reduced rate of elimination, often due to im-paired renal function, is likely to increase plasma concentrations, leading to augmented effects.
These are common causes of ADRs and may often be prevented by careful prescribing and patient monitoring. Impaired renal function is common in elderly people and neonates, and should be measured so that drug doses or dosage intervals are adjusted as appropriate to prevent an ADR.
An important example of this is digoxin, which is predominantly (about two-thirds) cleared by
the kidneys, and in renally impaired patients the plasma concentration may reach toxic levels (Figure 5.1). Accordingly, when using digoxin the dose should be determined in relation to renal function.
The alternative strategy that is used with aminoglycosides such as gentamicin is to increase the dosage interval in renally impaired patients.
Important examples where serious toxicity may arise as a consequence of renal impairment are:
Differences in hepatic metabolism
Alterations in drug metabolism may also lead to increased plasma concentrations. Metabolism may be altered at the extremes of age, such that neonates conjugate drugs at a relatively slow rate, whereas microsomal enzyme activity in the liver by cytochrome P450 isoenzymes decreases variably with age. An example of this is the pro-longed half-life of diazepam with age, and hence the increased propensity to side effects, including oversedation. Hepatic metabolism may be impaired in liver disease and this may lead to the enhanced effects of drugs that are usually cleared by the liver.
Figure 5.1 A schematic graph illustrating the variation of plasma concentration of digoxin over time. In patients the ideal is to maintain the plasma concentration within the therapeutic window. However, in the renally impaired patient, without a dose reduction, the plasma concentration rises to toxic levels.
Genetic differences in the expression of cytochrome P450 isoenzymes may also contrib-ute to variations in metabolism. Approximately 10% of the population express a defective P450 isoenzyme, CYP2D6, which slows down the metabolism of a range of drugs including flecainide, metoclopramide and some anti-depressants. Accordingly, patients may vary in the way that they handle drugs.
Disorders of metabolism
These include a lack of G6PD in erythrocytes and porphyria. G6PD is an enzyme present in red blood cells, which provides reducing power, thereby maintaining glutathione in the reduced form. This prevents oxidative damage to the cells. The absence of G6PD therefore leads to fragile red blood cell membranes and haemoly-sis, resulting in anaemia. G6PD deficiency is prevalent in the Mediterranean population and patients are sensitive to the effects of oxidative drugs such as antimalarials, sulphonamides, quinolones, nalidixic acid, nitrofurantoin, sul-fasalazine and aspirin (refer to Section 9.1.5. of the British National Formulary), leading to oxida-tive damage with haemolysis and anaemia.
Individuals with porphyria lack one of the enzymes for haemoglobin synthesis and there is an accumulation of porphyrin precursors, leading to gastrointestinal (GI), neurological and behavioural disturbances. Cytochrome P450 inducers including barbiturates, carbamazepine, griseofulvin and hormonal contraceptives (refer to Section 9.8.2 of the British National Formulary) tend to provoke an attack by inducing amino laevulinic acid synthase, giving rise to por-phyrins.
Immunological responses
Drugs are foreign molecules and some may induce an immunological response. These reactions may be delayed and tend not to be dose related, occurring with the smallest doses of drug. They are usually reversible on cessation of the causative agent. Patients at risk of these responses tend to have a predisposition to allergic disorders and the responses may vary from simple skin rashes to life-threatening ana-phylaxis (see Chapter 20). Important examples of
causative agents are penicillins and streptoki-nase.
Penicillins couple to proteins, forming im-munogens, which may precipitate hypersensi-tivity reactions. Management includes stopping the drug and treating the patient with antihista-mines, adrenaline and/or parenteral steroids according to severity (see Chapter 20). In the case of penicillins, the allergic reaction is a class effect resulting from the presence of the β-lactam ring in the drug molecule and approximately 10% of penicillin-allergic patients are also sensitive to chemically similar cephalosporins. It is therefore appropriate that non-penicillin, non-cephalo-sporin antibiotics are chosen for patients with a history of penicillin allergy.
In the case of streptokinase, once patients have been treated with this agent for throm-bolysis they are likely to develop antibodies against it. This means that on a subsequent exposure the antibodies may either prevent it from acting or lead to an allergic reaction. It is for this reason that patients do not generally receive streptokinase a second time and usually receive an alternative clot-busting agent for a second heart attack.
The increasing use of monoclonal antibodies (e.g. in immunological diseases and anticancer chemotherapy) is also likely to be associated with increased instances of immunological responses.
These drugs are likely to be used in specialist settings and the patient should be observed for the period immediately after administration for hypersensitivity reactions, which might involve skin reactions, breathing problems and hypoten-sion. In some cases corticosteroids and anthista-mines are given prophylactically.
Withdrawal responses
The withdrawal of certain drugs may lead to predictable symptoms and patients should be counselled appropriately. This type of reaction tends to result from physiological adaptation during the course of treatment, e.g. chronic treat-ment with β blockers leads to receptor up-regulation, i.e. an increase in the number of β-adrenoceptors occurs in response to the blockade of existing receptors. Sudden with-drawal of β blockade may therefore result in
over-stimulation of β-adrenoceptors. In the heart this may predispose to arrhythmias and is associ-ated with increased mortality. Common examples of drugs where abrupt withdrawal may lead to adverse reactions are given below.
Alcohol
Delirium tremens and seizures occur after chronic excessive alcohol intake. Treatment includes short-term chlordiazepoxide or clome-thiazole (inpatients only) (British National Formu-lary, Section 4.10).
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs, particularly paroxetine), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) of 8 weeks’ use or more should be withdrawn gradu-ally over at least 4 weeks (up to 6 months after long-term maintenance). Monitor for withdrawal symptoms such as nausea, vomiting, anorexia, headache and panic anxiety (see Chapter 24 and the British National Formulary, Section 4.3).
Benzodiazepines
Withdrawal from benzodiazepines requires a gradual reduction of dose to prevent symptoms of confusion, toxic psychosis, convulsions or those similar to delirium tremens following alcohol withdrawal. These symptoms may take from a few hours to 3 weeks to develop with longer-acting agents. Milder symptoms include insomnia, loss of appetite, anxiety, weight loss, tremor, sweating, tinnitus and disturbances of perception. Patients are transferred to the equivalent dose of diazepam (British National Formulary, Section 4.1.1). The dose is then reduced by increments of approxi-mately one-eighth of the daily dose (or 2–2.5 mg) every 2 weeks, maintaining the new dose for a longer period if withdrawal symptoms occur. The time taken to withdraw completely from long-term benzodiazepine use can be from 4 weeks to a year or occasionally longer. Specialist coun-selling may benefit some patients, including education about the risks and benefits of with-drawing from these drugs.
It should be noted that antipsychotics aggra-vate the symptoms of benzodiazepine with-drawal and should not be used (see the British National Formulary, Section 4.1).
Anticonvulsants See Chapter 23.
Opioids
‘Cold turkey’ may be experienced after opioid addiction but is rare when opioids are prescribed for pain relief. Debilitating diarrhoea may occur;
this may be treated with loperamide.
Baclofen
There is a risk of serious withdrawal reactions.
The dose should be reduced gradually over at least 1–2 weeks, or longer if symptoms develop (British National Formulary, Section 10.2.2).
Corticosteroids
Prolonged use of corticosteroids results in the suppression of endogenous production and treat-ment should therefore be withdrawn gradually according to the recommendations of the Com-mittee on Safety of Medicines or CSM (British National Formulary Section 6.3.2; the CSM is now called the Commission for Human Medicines or CHM).
The gradual withdrawal is recommended for patients whose disease is unlikely to relapse and who have:
• recently received repeated courses
• taken a short course within 1 year of stopping long-term therapy
• other possible causes of adrenal suppression
• received more than 40 mg prednisolone (or equivalent) daily
• repeat doses given in the evening
• received more than 3 weeks’ treatment.
Sympathomimetics
Prolonged use of topical decongestant vasocon-strictors causes tolerance and rebound conges-tion, probably due in part to down-regulation of
␣-adrenoceptors.
Antipsychotics
Withdraw gradually after long-term therapy and monitor closely for acute withdrawal syndromes or rapid relapse (British National Formulary, Section 4.2.1).
Type A ADRs
In the simplest case, one may predict many common type A ADRs on the basis of the known pharmacology of the drugs. Some common examples are given in Table 5.1.
Gastrointestinal ADRs
ADRs can occur throughout the GI system and, as indicated above, NSAID-induced damage represents the most significant of all ADRs.
Oral problems
The mouth may be the site of ADRs leading to unpleasant side effects, e.g. drugs with significant antimuscarinic activity (e.g. tricyclic antidepres-sants, older antihistamines) may lead to a dry mouth, which is a minor problem and may be resolved by selecting an alternative (e.g. an SSRI for depression). Alternatively artificial saliva might be recommended. More significant problems include tooth discoloration with tetra-cycline (which should be avoided in pregnant patients and in children under 12 years) and gingival hyperplasia with phenytoin and calcium channel blockers.
Oesophageal disorders
These may be induced by the local effects of drugs such as aspirin, tetracycline, doxycycline and bisphosphonates on the oesophagus, leading to irritation, or by drug-induced relaxation of the gastro-oesophageal sphincter producing reflux (e.g. opioids, calcium channel antagonists, nitrates). Symptoms include dysphagia or odynophagia (difficult or painful swallowing, respectively), heartburn, substernal chest pain or the feeling of something lodged in the throat (see Chapter 7).
Bisphosphonates pose a significant risk of oesophagitis and, in the case of alendronic acid, ibandronic acid and risedronate sodium, patients should be counselled to take the tablets with a full tumbler of water in the sitting or standing position and not to lie down for 30 minutes
afterwards. These measures are to prevent the tablet becoming lodged in the oesophagus.
When a patient is affected then cessation of the particular drug may be appropriate or, in the case of ulceration and/or reflux, a proton pump inhibitor (PPI) might be prescribed.
NSAID gastrotoxicity
NSAID-induced gastrotoxicity represents the most important ADR and is discussed in Chapter 7.
Antiplatelet drugs and gastrotoxicity
The adenosine diphosphate (ADP) receptor antagonist clopidogrel is used as an alternative antiplatelet agent to low-dose aspirin for patients with aspirin sensitivity. Clopidogrel has been shown to exhibit comparable efficacy and fewer adverse GI effects when compared with low-dose aspirin but may cause GI bleeding in patients at risk and should not be used for patients at risk of GI bleeding (see Chapter 14; Harker et al 1999).
Diarrhoea
Drug-induced diarrhoea is discussed in Chapter 9.
Nausea and vomiting
Drug-induced nausea and vomiting are discussed in Chapter 8.
Constipation
Drug-induced constipation is discussed in Chapter 9.
Malabsorption
As the major role of the GI tract is the digestion and absorption of food, alterations in absorption can arise from adverse drug effects, e.g. the pan-creatic lipase inhibitor, orlistat, reduces the absorption of fat and consequently the absorp-tion of fat-soluble vitamins. In some cases it may be appropriate to give vitamin supplements (in particular vitamin D), which should be given at
least 2 hours after orlistat. Another example are the bile-binding agents such as colestyramine which also reduce the absorption of fat-soluble vitamins, and supplementation with vitamins A, D, E and K might be appropriate.
Hepatic ADRs
Liver function may be altered by drugs to varying degrees, ranging from mild, reversible and asymptomatic changes identified by routine liver function tests (LFTs) to severe damage, leading to hepatic failure. Drug types and classes associated with altered liver function through to liver failure include:
• clavulonic acid in co-amoxiclav.
Risk factors for developing drug-induced hepatic dysfunction:
• pre-existing liver disease
• female sex
• age
• genetic variations in the expression of cyto-chrome P450 isoenzymes
• concurrent treatment with enzyme inducers (see Drug interactions below)
• polypharmacy
• concurrent disease: diabetes mellitus pre-disposes patients to methotrexate-induced damage
• nutritional status: fasting patients lack gluta-thione required in the non-toxic pathway of paracetamol metabolism
• alcohol consumption.
Clinical features
The presentation of liver impairment may vary but key features that should raise the suspicion of liver dysfunction include anorexia, nausea, vomiting, jaundice, itching, pale stools and dark urine. Patients who are prescribed drugs that are
known to cause liver dysfunction should be counselled to report these symptoms if they occur. Diagnosis may be based on a drug history, clinical features, an LFT and a biopsy.
Paracetamol-induced hepatotoxicity and patient counselling
Paracetamol is the most common cause of drug-induced hepatotoxicity. This is partly due to a lack of awareness of the potential toxicity of paracetamol or its presence in different medi-cines taken together, leading to accidental ingestion of excessive doses (see Chapter 29).
Monitoring
The monitoring of liver function is discussed in Chapter 2. It should be noted that elevated LFTs are not always followed by hepatic injury.
Generally an increase of two to three times any baseline value would indicate possible drug-induced hepatotoxicity and the need to stop the drug.
Cardiovascular ADRs
Drug-induced cardiovascular disorders are common and often predictable type A reactions, particularly in patients with pre-existing heart disease. Additional risk factors include undis-closed self-medication with OTC drugs, electro-lyte disturbances and impaired renal function.
Drugs used to manage cardiovascular diseases may have predictable cardiovascular conse-quences, e.g. volume depletion with diuretics or inhibition of autonomic homeostatic mechan-isms (e.g. ␣ blockers) are very commonly associ-ated with orthostatic or postural hypotension.
This is especially prominent in elderly patients and associated with a high risk of falls. Obviously judicious prescribing might reduce this risk by choosing safer alternative agents and counselling patients to take care when changing posture. In the case of ACE inhibitors and ␣ blockers they also pose a risk of first-dose hypotension (especi-ally if the patient is already taking a diuretic) when the initiation of treatment may lead to a precipitous drop in blood pressure. When these
drugs are used the patient should be counselled
drugs are used the patient should be counselled