Ciprofloxacin is occasionally used for prophylaxis against travellers’ diarrhoea, but routine use is not recommended due to consequent encouragement of bacterial resistance. Lactobacillus preparations have not been shown to be effective. Early treatment of diarrhoea with ciprofloxacin will control the great majority of cases and this, together with oral replacement of salts and water, is the currently preferred approach. PSEUDOMEMBRANOUS COLITIS Broad-spectrum antibacterial drug therapy is sometimes associated with superinfection of the intestine with toxin-producing Clostridium difficile. Debilitated and immunosuppressed patients are at particular risk. The infection can be transmitted from person to person. Withdrawal of the antibacterial drug and the introduction of oral metronidazole or vancomycin should be instituted. IRRITABLE BOWEL SYNDROME This motility disorder of the gut affects approximately 10% of the population. Although the symptoms are mostly colonic, patients with the syndrome have abnormal motility throughout the gut and this may be precipitated by dietary items, such as alcohol or wheat flour. The important management principles are first to exclude a serious cause for the symptoms and then to determine whether exclusion of certain foods or alcohol would be worthwhile. An increase in dietary fibre over the course of several weeks may also reduce the symptoms. Psychological factors may be important precipitants and counselling may be helpful. Drug treatment is symptomatic and often disappointing. • Anticholinergic drugs, such as hyoscine, have been used for many years, although evidence of their efficacy is lacking. The oral use of better absorbed anticholinergics, such as atropine, is limited by their side effects. • Mebeverine (135 mg before meals three times daily) directly relaxes intestinal smooth muscle without anticholinergic effects. Its efficacy is marginal. • Peppermint oil relaxes intestinal smooth muscle and is given in an enteric-coated capsule which releases its contents in the distal small bowel. It is given before meals three times daily. • Antidiarrhoeal drugs, such as loperamide, reduce associated diarrhoea. • Psychotropic drugs, such as antipsychotics and antidepressants with anticholinergic properties, have also been effective in some patients. In general, however, they should be avoided for such a chronic and benign condition because of their serious adverse effects (see Chapters 19 and 20). PANCREATIC INSUFFICIENCY PANCREATIC INSUFFICIENCY 259 It is important to remember that, amongst the many causes of pancreatitis, certain drugs can very occasionally be an aetiological factor (Table 34.5). Exocrine pancreatic insufficiency is an important cause of steatorrhoea. The pancreas has a large functional reserve and malabsorption does not usually occur until enzyme output is reduced to 10% or less of normal. This type of malabsorption is usually treated by replacement therapy with pancreatic extracts (usually of porcine origin). Unfortunately, although useful, these preparations rarely abolish steatorrhoea. A number of preparations are available, but the enzyme activity varies between preparations – one with a high lipase activity is most likely to reduce steatorrhoea. Unfortunately, less than 10% of the lipase activity and 25% of the tryptic activity is recoverable from the duodenum regardless of the dose schedule. This limited effectiveness of oral enzymes is partly due to acid–peptic inactivation in the stomach and duodenum. H 2-antagonists decrease both acidity and volume of secretion and retard the inactivation of exogenous pancreatic enzymes. They are given as an adjunct to these preparations. Supplements of pancreatin are given to compensate for reduced or absent exocrine secretion in cystic fibrosis, pancreatectomy, total gastrectomy and chronic pancreatitis. Pancreatin is inactivated by gastric acid and therefore preparations are best taken with or immediately before or after food. Gastric acid secretion can be reduced by giving an H 2-blocker about one hour beforehand, or antacids may be given concurrently to reduce acidity. Pancreatin is inactivated by heat and, if mixed with liquids or food, excessive heat should be avoided. The dose is adjusted according to size, number and consistency of stools such that the patient thrives. Pancreatin can irritate the perioral skin and buccal mucosa if it is retained in the mouth and excessive doses can cause perianal irritation. The most frequent side effects are gastrointestinal ones including nausea, vomiting and abdominal discomfort. Hyperuricaemia and hyperuricuria have been associated with very high doses of the drug. Table 34.5: Drugs that are associated with pancreatitis (this is uncommon) Asparaginase Oestrogens Azathioprine Pentamidine Corticosteroids Sodium valporate Dideoxyinosine (DDI) Sulphonamides and Ethanol sulfasalazine Tetracycline Thiazides
260 ALIMENTARY SYSTEM AND LIVER LIVER DISEASE PRINCIPLES UNDERLYING DRUG TREATMENT OF HEPATIC ENCEPHALOPATHY AND LIVER FAILURE In severe liver dysfunction, neuropsychiatric changes occur and can progress to coma. The mechanism which produces these changes is not established, but it is known that in hepatic coma and pre-coma, the blood ammonia concentration increases. In many patients, the time-course of encephalopathy parallels the rise in blood ammonia concentrations. Orally administered nitrogenous compounds (e.g. protein, amino acids, ammonium chloride) yield ammonia in the gut, raise blood ammonia concentrations and provoke encephalopathy. The liver is the only organ that extracts ammonia from the blood and converts it to urea. Bacterial degradation products of nitrogenous material within the gut enter the systemic circulation because of a failure of first-pass hepatic extraction (due to hepatocellular damage), or due to bypass of the hepatocytes by collateral circulation or intrahepatic shunting. Another source is urea, which undergoes enterohepatic circulation and yields approximately 3.5 g/day of ammonia (see Figure 34.3). Ammonia diffuses into the blood across the large intestine epithelium, where it is trapped by becoming ionized due to the lower pH of blood compared to colonic contents. Ammonia is not the only toxin involved, as perhaps 20% of patients with encephalopathy have normal blood ammonia concentrations, and methionine can provoke encephalopathy without causing a significant rise in blood ammonia concentration. Furthermore, ammonia toxicity affects the cortex but not the brainstem, which is also involved in encephalopathy. Other toxins of potential relevance include the following: • Intestinal bacterial decarboxylation produces hydroxyphenyl amines, such as octopamine (from tyramine), which could replace normal transmitters at nerve endings in the central and peripheral nervous systems, thus acting as ‘false transmitters’ and changing the balance of inhibition and excitation at central synapses. Other nitrogenous substrates LIVER Systemic circulation Hepatic portal vein Urea Urine Protein Ammonia • Changes in fatty acid metabolism increase plasma free fatty acids, some of which have anaesthetic properties. In addition, these determine the availability of tryptophan to the brain and hence have an effect on 5-hydroxytryptamine synthesis. Glutathione synthesis is impaired in severe liver disease. Cellular damage due to free radical excess can produce multiorgan dysfunction. Intravenous administration of acetylcysteine is used prophylactically in some centres to enhance glutathione synthesis and thereby reduce oxidant (free radical) stresses by scavenging these reactive entities. Treatment of hepatic encephalopathy includes the following measures: • dietary protein restriction to as little as 20 g/day, while ensuring an adequate intake of essential amino acids; • emptying the lower bowel by means of enemas and purgatives to reduce the bacterial production of ammonia; • oral or rectal administration of non-absorbable antibiotics, such as neomycin, to reduce the bacterial population of the large bowel. Neomycin, 1–2 g four times daily, is often used. It should be remembered, if the patient also has renal impairment, that neomycin may accumulate and produce toxicity; • oral lactulose improves encephalopathy. This disaccharide is not a normal dietary constituent and humans do not possess a lactulase enzyme, so lactulose is neither digested nor absorbed but reaches the colon unchanged, where the bacterial flora breaks it down to form lactate, acetate and other acid products. These trap ammonia and other toxins within the intestinal lumen by reducing its pH, and in addition they act as a cathartic and reduce ammonia absorption by reducing the colonic transit time; • bleeding may occur due to interference with clotting factor synthesis or thrombocytopenia. Vitamin K is given and fresh frozen plasma or platelets are used as required. H 2 antagonists (e.g. ranitidine) or proton-pump inhibitors (e.g. omeprazole) are often used to prevent gastric erosions and bleeding; • sedatives should be avoided as patients with liver disease are extremely sensitive to such drugs. If sedation is essential (e.g. because of agitation due to alcohol Gut bacteria Bacterial urease Urea GUT Figure 34.3: Enterohepatic circulation of urea and ammonia.
A Textbook of Clinical Pharmacology
A Textbook of Clinical Pharmacology
This fifth edition is dedicated to
FOREWORD viii PREFACE ix ACKNOWLEDG
PREFACE Clinical pharmacology is th
PART I GENERAL PRINCIPLES
● Use of drugs 3 ● Adverse effe
and acquired factors, notably disea
100 Effect (%) 0 0 5 10 1 10 100 (a
Dose ratio -1 100 50 The relationsh
● Introduction 11 ● Constant-ra
In reality, processes of eliminatio
lood (from which samples are taken
● Introduction 17 ● Bioavailabi
ROUTES OF ADMINISTRATION ORAL ROUTE
Transdermal absorption is sufficien
FURTHER READING Fix JA. Strategies
and thromboxanes are CYP450 enzymes
and lorazepam. Some patients inheri
Orally administered drug Parenteral
● Introduction 31 ● Glomerular
ACTIVE TUBULAR REABSORPTION This is
DISTRIBUTION Drug distribution is a
Detailed recommendations on dosage
DIGOXIN Myxoedematous patients are
● Introduction 41 ● Role of dru
25 20 10 Life-threatening toxicity
● Introduction 45 ● Harmful eff
vagina in girls in their late teens
an anti-analgesic effect when combi
Case history A 20-year-old female m
METABOLISM At birth, the hepatic mi
lifelong effects as a result of tox
DISTRIBUTION Ageing is associated w
DIGOXIN Digoxin toxicity is common
FURTHER READING Dhesi JK, Allain TJ
Factors involved in the aetiology o
analgesic. Following its release, t
antibiotics, such as penicillin or
predisposes to non-immune haemolysi
● Introduction 71 ● Useful inte
Response Therapeutic range Toxic ra
Table 13.1: Interactions outside th
Table 13.5: Competitive interaction
● Introduction: ‘personalized m
Table 14.2: Variations in drug resp
lipoprotein (LDL) is impaired. LDL
Key points • Genetic differences
• Discovery • • Screening Pre
Too many statistical comparisons pe
ETHICS COMMITTEES Protocols for all
Table 16.1: Recombinant proteins/en
duration and benefit. Adenoviral ve
● Introduction 97 ● Garlic 97
A case report has suggested a possi
including hypericin and pseudohyper
PART II THE NERVOUS SYSTEM
● Introduction 105 ● Sleep diff
and daytime sleeping should be disc
Key points • Insomnia and anxiety
Box 19.1: Dopamine theory of schizo
The Boston Collaborative Survey ind
Oral medication, especially in liqu
e.g. interpersonal difficulties or
Partial response to first-line trea
Key points Drug treatment of depres
Case history A 45-year-old man with
Levodopa PRINCIPLES OF TREATMENT IN
• pulmonary, retroperitoneal and
CHOREA The γ-aminobutyric acid con
Cholinergic crisis Treatment of mya
● Introduction 133 ● Mechanisms
absolute arbiter. The availability
Table 22.2: Metabolic interactions
FURTHER ANTI-EPILEPTICS Other drugs
Case history A 24-year-old woman wh
Assessment of migraine severity and
● General anaesthetics 145 ● In
is the theoretical concern of a ‘
• Respiratory system - apnoea fol
Competitive antagonists (vecuronium
have also proved useful in combinat
● Introduction 155 ● Pathophysi
ASPIRIN (ACETYLSALICYLATE) Use Anti
Key points Drugs for mild pain •
increases, correlating with the hig
• If possible, use oral medicatio
PART III THE MUSCULOSKELETAL SYSTEM
● Introduction: inflammation 167
Chapter 33). All NSAIDs cause wheez
• Stomatitis suggests the possibi
Pharmacokinetics Allopurinol is wel
PART IV THE CARDIOVASCULAR SYSTEM
● Introduction 177 ● Pathophysi
esponsible for the strong predilect
Ezetimibe Fat Muscle Dietary fat In
educed). The risk of muscle damage
● Introduction 185 ● Pathophysi
Each of these classes of drug reduc
AT 1 receptor) produce good 24-hour
Table 28.2: Examples of calcium-cha
Key points Drugs used in essential
Case history A 72-year-old woman se
Assess risk factors Investigations:
Persistent ST segment elevation Thr
Mechanism of action GTN works by re
Because of the risks of haemorrhage
Intrinsic pathway XIIa XIa the acti
that the pharmacodynamic response i
elease by the pituitary via negativ
Treatment with depot progestogen in
infusion using an infusion pump to
significant proportion of men who r
with symptoms caused by the release
FURTHER READING Birnbaumer M. Vasop
PART IX SELECTIVE TOXICITY
● Principles of antibacterial che
2. transfer of resistance between o
Pharmacokinetics Absorption of thes
Mechanism of action Macrolides bind
asic quinolone structure dramatical
Case history A 70-year-old man with
PRINCIPLES OF MANAGEMENT OF MYCOBAC
Pharmacokinetics Absorption from th
MYCOBACTERIUM LEPRAE INFECTION Lepr
POLYENES AMPHOTERICIN B Uses Amphot
therapy is adequate though more fre
NUCLEOSIDE ANALOGUES ACICLOVIR Uses
Table 45.3: Summary of available ac
Uses Interferon-α when combined wi
● Introduction 351 ● Immunopath
Table 46.1: Examples of combination
NON-NUCLEOSIDE ANALOGUE REVERSE TRA
FUSION INHIBITORS Uses Currently, e
salvage therapy include azithromyci
● Malaria 361 ● Trypanosomal in
Pharmacokinetics Chloroquine is rap
Table 47.2: Drug therapy of non-mal
● Introduction 367 ● Pathophysi
Table 48.1: Classification of commo
Polymorph count/mm 3 (a) (b) 10 000
doses are used to prepare patients
Adverse effects Methotrexate Inhibi
Table 48.7: Summary of clinical pha
Table 48.9: Summary of the clinical
Plasma membrane Signal transduction
Table 48.10: Monoclonal antibodies
INTERFERON-ALFA 2B Interferon-alfa
PART X HAEMATOLOGY
● Haematinics - iron, vitamin B 1
one marrow to produce red cells. Th
EPO Erythroid precursors Erythrocyt
Therapeutic principles The extent o
PART XI IMMUNOPHARMACOLOGY
● Introduction 399 ● Immunity a
Key points Antigen recognition Expr
Table 50.1: Novel anti-proliferativ
Key points Treatment of anaphylacti
DRUGS THAT ENHANCE IMMUNE SYSTEM FU
PART XII THE SKIN
● Introduction 411 ● Acne 411
DERMATITIS (ECZEMA) PRINCIPLES OF T
SPECIALISTS ONLY SPECIALISTS ONLY E
TREATMENT OF OTHER SKIN INFECTIONS
effect of too high a dose of UVB in
PART XIII THE EYE
● Introduction: ocular anatomy, p
to cause pupillary dilatation, name
Table 52.3: Antibacterial agents us
Table 52.6: Common drug-induced pro
PART XIV CLINICAL TOXICOLOGY
● Introduction 433 ● Pathophysi
Table 53.2: Central nervous system
which provide anonymized data to th
Peak plasma levels after smoking ci
Key points Acute effects of alcohol
FURTHER READING Goldman D, Oroszi G
Table 54.2: Common indications for
Table 54.5: Antidotes and other spe
Commission on Human Medicines (CHM)
Note: Page numbers in italics refer
atrial fibrillation 217, 221 digoxi
Cushing’s syndrome 302 cyclic ade
5-fluorouracil 375-6 fluoxetine, mo
children 54 diazepam 108 iron prepa
non-steroidal anti-inflammatory dru
puberty (male), delay 314 puerperiu
tolerance 9, 433 benzodiazepines 10
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Magazine: A Textbook of Clinical Pharmacology and Therapeutics