Clinical Pharmacology

Description

‘The very last thing a drug regulator wishes to be able to say is, like Lord Byron (1788-1824), on the publication of his poem Childe Harold’s Pilgrimage, ‘I awoke one morning and found myself famous.’ The twelfth edition of this long-established textbook of clinical pharmacology (first published in 1960) continues its fine tradition of balancing science and practice for improved evidence-based drug therapy and good prescribing in therapeutic settings increasingly complicated by intercurrent disease and polypharmacy. Coverage of all major therapeutic topics by body system. Introductory sections give brief chapter synopses. Case studies where relevant. Covers the needs of the developing world with a focus on practical prescribing and health technology assessment. Definition, tips, brief explanation boxes throughout. Interesting histories, etymologies and provenances of terms throughout. Entertaining footnotes throughout.Fully updated throughout. New co-editor: Fraz Mir, Addenbrooke’s Hospital and Department of Medicine, University of Cambridge. Now with free e-book on StudentConsult. Front Cover Inside Front Cover Half title page Dedication Clinical Pharmacology Copyright Page Table Of Contents Preface Contributors Acknowledgements 1 General 1 Clinical pharmacology Synopsis Guide to further reading 2 Topics in drug therapy Synopsis The therapeutic situation Some background Treating patients with drugs Drugs can do good Drugs can do harm Uses of drugs/medicines Cure Suppression Prevention Physician-induced (iatrogenic) disease Benefits and risks of medicines Unavoidable risks Reduction of risk Two broad categories of risk Elements of risk Three major grades of risk Whenever a drug is taken a risk is taken Public view of drugs and prescribers Criticisms of modern drugs Drug-induced injury (see also Ch. 9) Negligence and strict and no-fault liability Complementary, alternative and traditional medicine Homoeopathy Conclusion Placebo medicines Guidelines, ‘essential’ drugs and prescribing ‘Essential’ drugs Cost-containment Taking a drug history Repeat prescriptions Warnings and consent Legal hazards for prescribers Compliance Patient compliance Suggestions for doctors to enhance patient compliance/adherence Directly observed therapy Over-compliance. Evaluation of patient compliance. Doctor compliance Underdosing The clinical importance of missed dose(s) Pharmacoeconomics (see also Ch. 5) The economists’ objective Quality of life Guide to further reading Appendix: the prescription Example of a prescription for a patient with an annoying unproductive cough: Medicine containers. Unwanted medicines. Drugs liable to cause dependence Abbreviations Weights and measures Equivalents: Abbreviations: Home/domestic measures. Percentages, proportions, weight in volume 3 Discovery and development of drugs Synopsis Making a new medicine Techniques of discovery Molecular modelling and structural biology High throughput screening Fragments. Proteins as medicines: biotechnology. Antisense approaches. Gene therapy Stem cells. Immunopharmacology. Older approaches Drug quality Studies in animals Pharmacodynamics Pharmacokinetics Toxicology Genotoxicity Carcinogenicity Reproductive and developmental toxicity Local tolerance Biotechnology-derived pharmaceuticals Ethics and legislation Safety prediction Orphan drugs and diseases Guide to further reading 4 Evaluation of drugs in humans Synopsis Experimental therapeutics Research involving human subjects Ethics of research in humans The ethics of the randomised and placebo-controlled trial Injury to research subjects Payment of subjects in clinical trials Rational introduction of a new drug to humans Phases of clinical development Official regulatory guidelines and requirements Therapeutic investigations Therapeutic evaluation Need for statistics Concepts and terms Hypothesis of no difference A statistical significance test Confidence intervals. Types of error Type I error Type II error Types of therapeutic trial Dose–response trials. Superiority, equivalence and non-inferiority in clinical trials. Design of trials Techniques to avoid bias Randomisation Blinding. Some common design configurations Parallel group design Crossover design Factorial designs Multicentre trials N-of-1 trials Historical controls Size of trials Fixed sample size and sequential designs Sensitivity of trials Meta-analysis Results: implementation Relative and absolute risk Pharmacoepidemiology Observational cohort studies Case–control studies Surveillance systems: pharmacovigilance Voluntary reporting. Prescription event monitoring. Medical record linkage Population statistics, Strength of evidence In conclusion Guide to further reading 5 Health technology assessment Synopsis The scope Clinical effectiveness 1. Developing the protocol 2. Defining the methods 3. Analysing the data Qualitative synthesis Quantitative synthesis (meta-analysis) 4. Drawing conclusions Cost-effectiveness 1. Costs 2. Benefits Natural units Health utilities 3. Type of analysis Cost-effectiveness analysis Cost-utility analysis In conclusion Guide to further reading 6 Regulation of medicines Synopsis Basis for regulation Historical background Current medicines regulatory systems Rare diseases Requirements Authorisation for clinical trials in the UK Regulatory review of a new drug marketing application Regulatory review Post-licensing responsibilities Discussion Licensed medicines for unlicensed indications Unlicensed medicines and accelerated licensing Decision-taking Counterfeit drugs Complementary and alternative medicine Medicines regulation: the future Guide to further reading 7 Classification and naming of drugs Synopsis Classification Nomenclature (names) Non-proprietary names Clarity. Economy. Convenience. Proprietary names Confusing names. Guide to further reading 2 From pharmacology to toxicology 8 General pharmacology Synopsis Pharmacodynamics Pharmacokinetics Individual or biological variation Pharmacodynamics Qualitative aspects Mechanisms Receptors Agonists. Antagonists Partial agonists. Inverse agonists. Receptor binding Physiological (functional) antagonism Enzymes Selectivity Modification of drug structure. Selective delivery (drug targeting). Stereoselectivity. Quantitative aspects Dose–response relationships Potency and efficacy Potency Pharmacological efficacy Therapeutic efficacy Therapeutic index. Tolerance Bioassay and standardisation Pharmacokinetics Drug passage across cell membranes Passive diffusion Drugs that ionise according to environmental pH pH variation and drug kinetics. Drugs that are incapable of becoming ionised Permanently ionised drugs Brain and cerebrospinal fluid (CSF). Placenta. Filtration Carrier-mediated transport The order of reaction or process First-order (exponential) processes Zero-order processes (saturation kinetics) Alcohol An illustration. In practice. Order of reaction and t1/2. Zero-order absorption Time course of drug concentration and effect Plasma half-life and steady-state concentration Decrease in plasma concentration after an intravenous bolus injection Increase in plasma concentration with constant dosing Time to reach steady state Change in plasma concentration with change or cessation of dosing Biological effect t1/2 Therapeutic drug monitoring Plasma concentration may not be worth measuring Plasma concentration has no correlation with effect Plasma concentration may correlate poorly with effect. Plasma concentration may correlate well with effect. Interpreting plasma concentration measurements. Individual pharmacokinetic processes Absorption Absorption from the gastrointestinal tract Enterohepatic circulation Systemic availability and bioavailability Pharmaceutical factors Biological factors Presystemic (first-pass) elimination Advantages and disadvantages of enteral administration By swallowing For systemic effect. For effect in the gut. Sublingual or buccal for systemic effect Rectal administration For systemic effect (suppositories or solutions). For local effect, Advantages and disadvantages of parenteral administration Intravenous (bolus or infusion) Intramuscular injection Subcutaneous injection By inhalation As a gas, As an aerosol, As a powder, Topical application For local effect, For systemic effect. Distribution Distribution volume Selective distribution Plasma protein and tissue binding Albumin Disease Tissue binding. Metabolism Reducing lipid solubility Altering biological activity The metabolic processes Phase I Phase II Transporters. Enzyme induction Inducing substances Enzyme inhibition Elimination Renal elimination Glomerular filtration. Renal tubular transport. Renal tubular diffusion. Faecal elimination Biliary excretion. Pulmonary elimination Clearance Breast milk Drugs and breast feeding Drug dosage Dosing schedules To specify an initial dose To specify a maintenance dose: Dose calculation by body-weight and surface area Prolongation of drug action Sustained-release (oral) preparations Depot (injectable) preparations Reduction of absorption time Fixed-dose drug combinations Chronic pharmacology Interference with self-regulating systems Feedback systems. Regulation of receptors. Down-regulation, Up-regulation. The rebound phenomenon Abrupt withdrawal Resurgence Drug discontinuation syndromes, Other aspects of chronic drug use Metabolic changes Specific cell injury Drug holidays. Dangers of intercurrent illness Dangers of interactions with other drugs, herbs or food. Conclusions Individual or biological variation Prescribing for special risk groups Pharmacogenomics Introduction Sources of variability Identifying genetic variation. Examples of pharmacogenomic variation Drug efficacy Cancer therapy. Warfarin. Drug toxicity Immune-mediated adverse drug reactions. Statin myopathy. Summary Environmental and host influences Age The neonate, infant and child Distribution. Metabolism. Elimination. Pharmacodynamic responses. Dosage in the young. The elderly Absorption Distribution Metabolism Elimination. Pharmacodynamic Rules of prescribing for the elderly Pregnancy Absorption. Distribution. Hepatic metabolism Elimination. Placenta Disease Pharmacokinetic changes Absorption. Distribution. Metabolism. Elimination. Pharmacodynamic changes Food Drug interactions Clinical importance of drug interactions Pharmacological basis of drug interactions Antagonism Synergism Before administration. At the site of absorption. By direct chemical interaction in the gut. By altering gut motility. By altering gut flora. Interactions other than in the gut. During distribution. During metabolism. At receptor sites. Guide to further reading 9 Unwanted effects and adverse drug reactions Synopsis Background Definitions Toxicity Secondary effects Intolerance Idiosyncrasy Attribution and degrees of certainty Caution. Practicalities of detecting rare adverse reactions Pharmacovigilance and pharmacoepidemiology Drug-induced illness Drugs and skilled tasks Sources of adverse drug reactions Age Sex Genetic constitution The environment and social habits Allergy in response to drugs Type I reactions: immediate or anaphylactic type. Type II reactions: antibody-dependent cytotoxic type. Type III reactions: immune complex-mediated type. Type IV reactions: lymphocyte-mediated type. Cross-allergy Principal clinical manifestations and treatment 1. Urticarial rashes and angioedema (types I, III). 2a. Non-urticarial rashes (types I, II, IV). 2b. Diseases of the lymphoid system. 3. Anaphylactic shock (type I) Treatment is urgent. 4a. Pulmonary reactions: asthma (type I). 4b. Other types of pulmonary reaction (type III) 5. The serum sickness syndrome (type III). 6. Blood disorders 6a. Thrombocytopenia (type II, but also pseudo-allergic) 6b. Granulocytopenia (type II, but also pseudo-allergic), 6c. Aplastic anaemia (type II, but not always allergic). 6d. Haemolysis of all kinds 7. Fever 8. Collagen diseases (type II) 9. Hepatitis and cholestatic jaundice 10. Nephropathy Diagnosis of drug allergy Desensitisation Prevention of allergic reactions Pseudo-allergic reactions Miscellaneous adverse reactions Effects of prolonged administration: chronic organ toxicity Eye Nervous system. Lung. Kidney. Liver. Carcinogenesis: Adverse effects on reproduction Early pregnancy. Late pregnancy. Drugs given during labour. Detection of teratogens. Male reproductive function Guide to further reading 10 Poisoning, overdose, antidotes Synopsis Introduction Initial assessment Resuscitation Supportive treatment Preventing further absorption of the poison From the environment From the alimentary tract (‘gut decontamination’) Oral adsorbents. Whole-bowel irrigation Accelerating elimination of the poison Repeated doses of activated charcoal Alteration of urine pH and diuresis Haemodialysis Haemofiltration Peritoneal dialysis Specific antidotes Psychiatric and social assessment Poisoning by (non-drug) chemicals Heavy metal poisoning and use of chelating agents Dimercaprol Unithiol Sodium calcium edetate Dicobalt edetate. Penicillamine Desferrioxamine Cyanide Carbon monoxide (CO) Lead Methanol Ethylene glycol Hydrocarbons. Volatile solvent abuse. Herbicides and pesticides Organophosphorus pesticides Dinitro-compounds. Phenoxy herbicides Rodenticides Paraquat Diquat Incapacitating agents CS CN CR Poisoning by biological substances Specific measures. Guide to further reading 11 Drug dependence Synopsis Introduction Definitions Substance dependence Substance abuse Substance addiction Substance habituation Psychological dependence Physical (physiological) dependence Tolerance A discontinuation (withdrawal) syndrome Hard drugs Soft drugs Dependence/abuse liability Drug abuse use has two principal forms: Drives to drug abuse can be grouped as follows: General patterns of use Sites and mechanisms of action Route of administration and effect Prescribing for drug dependence Treatment of dependence Withdrawal of the drug. Maintenance and relapse. Severe pain in an opioid addict Mortality Escalation De-escalation Novel psychoactive substances Drugs and sport Performance enhancement Types of drug dependence Ethyl alcohol (ethanol) Pharmacokinetics Absorption. Distribution. Metabolism. Pharmacodynamics Chronic consumption Tolerance Car driving and alcohol Alcohol-dependence syndrome Withdrawal of alcohol Treatment of alcohol dependence Acamprosate Disulfiram Safe limits for chronic consumption Alcohol in pregnancy and breast feeding Fetal alcohol syndrome Lactation. Alcohol and other drugs Miscellaneous uses of alcohol Other cerebral depressants γ-Hydroxybutyrate Benzodiazepine Clomethiazole and barbiturate Tobacco Composition Tobacco dependence Acute effects of smoking tobacco Nicotine pharmacology Pharmacokinetics Pharmacodynamics Large doses. Doses from/with smoking. Metabolic rate. Tolerance Conclusion. Effects of chronic smoking Bronchogenic carcinoma Other cancers. Coronary heart disease (CHD). Chronic lung disease. Other effects. Interactions with drug therapy. Women and smoking Fertility. Complications of pregnancy The child Starting and stopping use Aids to giving up Nicotine Bupropion Electronic cigarettes Psychodysleptics or hallucinogens Experiences with psychodysleptics Lysergide (LSD) Mescaline Psilocybin Tenamfetamine Phencyclidine Ketamine Methylxanthines (xanthines) Pharmacokinetics. Pharmacodynamics. Actions on mental performance. Overdose Other effects Respiratory stimulation Sleep. Skeletal muscle. Cardiovascular system. Smooth muscle Kidney. Preparations and uses of caffeine and theophylline Aminophylline. Xanthine-containing drinks (see also above) Chronic overdose. Blood lipids. Cannabis Pharmacokinetics Pharmacodynamics Cannabinoids and skilled tasks, Uses Adverse effects Acute Chronic Management of adverse reactions to psychodysleptics Psychostimulants Cocaine Pharmacokinetics and pharmacodynamics. Route of administration. Mode of action. Overdose Amfetamines Pharmacokinetics. Mode of action. Dependence Acute poisoning Chronic overdose Khat Volatile substance abuse Guide to further reading 3 Infection and inflammation 12 Chemotherapy of infections Synopsis History Classification of antimicrobial drugs How antimicrobials act – sites of action The cell wall. The cytoplasmic membrane. Protein synthesis. Nucleic acid metabolism. Principles of antimicrobial chemotherapy Make a diagnosis Remove barriers to cure, Decide whether chemotherapy is really necessary. Select the best drug. Administer the drug Continue therapy Test for cure. Prophylactic chemotherapy Carriers of pathogenic or resistant organisms Use of antimicrobial drugs Choice Knowledge of the likely pathogens Rapid diagnostic tests. Route of administration. Combinations Chemoprophylaxis and pre-emptive suppressive therapy Chemoprophylaxis in surgery Antimicrobials should be selected Antimicrobials should be given Problems with antimicrobial drugs Resistance Mechanisms of resistance Limitation of resistance Superinfection Antibiotic-associated (or Clostridium difficile-associated) colitis Opportunistic infection Masking of infections Drugs of choice Guide to further reading 13 Antibacterial drugs Synopsis Classification Inhibition of cell wall synthesis β-lactams Inhibition of protein synthesis Aminoglycosides. Tetracyclines, Macrolides: Inhibition of nucleic acid synthesis Sulfonamides. Quinolones Azoles Inhibition of cell wall synthesis β-lactams Penicillins Mode of action. Pharmacokinetics. Adverse effects. Narrow-spectrum penicillins Benzylpenicillin Uses. Adverse effects Preparations and dosage for injection. Preparations and dosage for oral use. Antistaphylococcal penicillins Broad-spectrum penicillins Amoxicillin Ampicillin Co-amoxiclav Adverse effects. Mecillinam Temocillin Antipseudomonal penicillins Carboxypenicillins Ticarcillin Ureidopenicillins Piperacillin Cephalosporins Mode of action Pharmacokinetics. Classification and uses. Adverse effects. Ceftobiprole Other β-lactam antibacterials Monobactam Carbapenems Imipenem Adverse effects. Meropenem Ertapenem Penems Other inhibitors of cell wall synthesis and membrane function Vancomycin Uses. Adverse effects. Teicoplanin Daptomycin Oritavancin, dalbavancin and telavancin Inhibition of protein synthesis Aminoglycosides Mode of action. Pharmacokinetics. Antibacterial activity. Uses Adverse effects. Individual aminoglycosides Gentamicin Dose Tetracyclines and glycylcyclines Mode of action. Pharmacokinetics. Uses. Adverse reactions. Interactions. Individual tetracyclines Tetracycline Doxycycline Minocycline Tigecycline Macrolides and lincosamides Erythromycin Uses. Dose Adverse reactions. Interactions. Clarithromycin Azithromycin Telithromycin Clindamycin, Other inhibitors of protein synthesis Chloramphenicol Pharmacokinetics. Uses. Adverse effects. Sodium fusidate Uses. Adverse effects. Resistance to antimicrobials: linezolid, quinupristin-dalfopristin and fosfomycin Linezolid, Quinupristin-dalfopristin Fosfomycin, Inhibition of nucleic acid synthesis Sulfonamides and sulfonamide combinations Pharmacokinetics. Systemic use Sulfonamide-trimethoprim combination. Sulfadiazine Silver sulfadiazine Miscellaneous Sulfasalazine Adverse effects Allergic reactions Trimethoprim Adverse effects Nitrofurantoin Quinolones Pharmacokinetics. Uses Adverse effects Ciprofloxacin Norfloxacin Ofloxacin Nalidixic acid Others. Azoles Metronidazole Pharmacokinetics. Uses. Dose. Adverse effects Tinidazole Minor antimicrobials Mupirocin Retapamulin, Polypeptide (polymyxin) antibiotics Guide to further reading 14 Chemotherapy of bacterial infections Synopsis Infection of the blood Patients who have had a splenectomy or have hyposplenism Infection of paranasal sinuses and ears Sinusitis Otitis media Otitis externa Infection of the throat Chemoprophylaxis Adverse effects Other causes of pharyngitis Vincent’s infection Diphtheria Whooping cough Lemierre’s disease Infection of the bronchi, lungs and pleura Bronchitis In chronic bronchitis, For intermittent therapy, Pneumonias Pneumonia in previously healthy people (community acquired) Disease that is segmental or lobar Pneumonia following influenza ‘Atypical’ cases At an early stage (i.e. at 24–48 h), Pneumonia acquired in hospital Pneumonia is usually defined as being nosocomial Pneumonia in people with chronic lung disease Normal commensals Klebsiella pneumoniae Moraxella Pneumonia in immunocompromised patients Legionnaires’ disease Pneumonia due to anaerobic microorganisms Endocarditis Principles for treatment Dose regimens Prophylaxis Meningitis Drugs must be given i.v. in high dose. Initial therapy All ages older than 5 years Children younger than 5 years Neonates β-lactam anaphylaxis Subsequent therapy Neisseria meningitidis. Streptococcus pneumoniae. Haemophilus influenzae. Listeria monocytogenes. Chemoprophylaxis Meningococcal meningitis Haemophilus influenzae Pneumococcal meningitis Infection of the intestines Campylobacter spp. Shigella spp. Salmonella spp. Typhoid fever A carrier state Escherichia coli Vibrio cholerae. Selective decontamination Peritonitis Chemoprophylaxis in surgery. Antibiotic-associated colitis and Clostridium difficile diarrhoea. Traveller’s diarrhoea. Infection of the urinary tract Lower urinary tract infection (cystitis) Upper urinary tract infection Recurrent urinary tract infection Asymptomatic infection (‘asymptomatic bacteriuria’) Prostatitis Chemoprophylaxis Tuberculosis of the genitourinary tract Special drugs for urinary tract infections Nitrofurantoin, Nalidixic acid. Pivmecillinam Fosfomycin trometamol Genital tract infections Gonorrhoea Uncomplicated anogenital infections. Pharyngeal gonorrhoea Coexistent infection. Non-gonococcal urethritis Pelvic inflammatory disease Syphilis Results of treatment Chancroid Granuloma inguinale Bacterial vaginosis (bacterial vaginitis, anaerobic vaginosis) Candida vaginitis. Trichomonas vaginitis. Infection of bones and joints Septic arthritis Eye infections Superficial infections, Chlamydial conjunctivitis. Herpes keratitis. Fungal keratitis. Mycobacterial infections Pulmonary tuberculosis Principles of antituberculosis therapy Special problems Drug resistant organisms. Chemoprophylaxis Pregnancy. Extrapulmonary tuberculosis. Meningeal tuberculosis Bone and joint tuberculosis. Lymph node tuberculosis. Adrenal steroid and tuberculosis. Tuberculosis in the immunocompromised. Antituberculosis drugs Isoniazid Adverse effects. Rifampicin Adverse reactions. Interactions. Rifabutin Rifaximin Pyrazinamide Adverse effects Ethambutol Adverse effects. Antituberculosis drug-induced hepatitis Streptomycin Thiacetazone Adverse reactions Second-line antituberculosis drugs Kanamycin and amikacin Capreomycin Thioamides Ethionamide and prothionamide. Cycloserine and terizidone Fluoroquinolones Para-aminosalicylic acid (PAS) Bedaquiline. Delamanid. Clofazimine. Linezolid. Clarithromycin Leprosy Dapsone Rifampicin Clofazimine Other antileprotics Other non-tuberculous mycobacteria Mycobacterium abscessus Mycobacterium avium complex (MAC) Other bacterial infections Burns. Gas gangrene. Cellulitis Wounds. Bites Abscesses and infections in serous cavities Acne (see Ch. 17) Health care–associated infections (HCAIs) Actinomycosis. Leptospirosis. Lyme disease. Guide to further reading 15 Viral, fungal, protozoal and helminthic infections Synopsis Viral infections Herpes simplex and varicella zoster Aciclovir Indications. Adverse reactions. Valaciclovir. Famciclovir Idoxuridine. Human immunodeficiency virus (HIV) General comments Nucleoside and nucleotide reverse transcriptase inhibitors Zidovudine (AZT, Retrovir) Pharmacokinetics. Uses. Adverse reactions Didanosine Lamivudine and emtricitabine Emtricitabine Abacavir Tenofovir Stavudine Adefovir Protease inhibitors Adverse effects Interactions. Non-nucleoside reverse transcriptase inhibitors Efavirenz Nevirapine Etravirine Rilpivirine Entry inhibitors Enfuvirtide Adverse effects Maraviroc Integrase inhibitors Raltegravir Dolutegravir Fixed-dose combinations of antiretroviral drugs Influenza A Amantadine Adverse reactions Zanamivir (Relenza) Unwanted effects Oseltamivir (Tamiflu) Unwanted effects Peramivir Cytomegalovirus Ganciclovir Valganciclovir Adverse reactions Foscarnet Cidofovir Cidofovir Fomivirsen Respiratory syncytial virus (RSV) Ribavirin Palivizumab Drugs that modulate the host immune system Interferons. Adverse reactions Imiquimod Inosine pranobex Fungal infections Superficial mycoses Dermatophyte infections (ringworm, tinea) Candida infections Systemic mycoses Pneumocystosis, Drugs that disrupt the fungal cell membrane Polyenes Amphotericin (amphotericin B) Adverse reactions. Nystatin Azoles Ketoconazole Adverse reactions Interactions. Other imidazoles. Fluconazole Itraconazole Adverse effects Interactions. Voriconazole Adverse effects. Posaconazole Adverse effects Allylamine Terbinafine Drugs that disrupt the fungal cell wall Echinocandins Caspofungin Micafungin Anidulafungin Other antifungal drugs Griseofulvin Adverse reactions Flucytosine Protozoal infections Malaria Life cycle of the malaria parasite and sites of drug action Hepatic cycle Erythrocyte cycle Sexual forms In summary, Drug-resistant malaria Chemotherapy of an acute attack of malaria Falciparum (‘malignant’) malaria If the patient can swallow Seriously ill patients Non-falciparum (‘benign’) malarias Chemoprophylaxis of malaria General principles Examples of standard prophylactic regimens For ‘last minute’ travellers. Drug interactions. Antimalarial drugs and pregnancy Individual antimalarial drugs Chloroquine Adverse effects Acute overdose Halofantrine Lumefantrine Mefloquine Adverse effects Primaquine Adverse effects Proguanil (chloroguanide) Adverse effects. Pyrimethamine Adverse effects Pyrimethamine with sulfadoxine Adverse effects. Pyrimethamine with dapsone Quinine Adverse effects Quinidine, Artesunate and artemether Artemisinin-based combination therapies (ACTs) Riamet, Amoebiasis Dehydroemetine Notes on drugs for protozoal infections Helminthic infections Drugs for helminthic infections Guide to further reading 16 Drugs for inflammation and joint disease Synopsis Introduction Inflammation The adaptive immune response Pharmacological manipulation of inflammatory mediators Glucocorticoids Mode of action Non-steroidal anti-inflammatory drugs (NSAIDs) Mode of action Pharmacokinetics Uses Analgesia. Anti-inflammatory action. Antipyretic action. Antiplatelet action. Colorectal cancer. Adverse effects Gastrointestinal. Cardiovascular. Renal. Worsening of asthma. Other unwanted effects Principal interactions Paracetamol (acetaminophen) Mode of action and uses. Pharmacokinetics. Dose. Adverse effects. Acute overdose. Aspirin (acetylsalicylic acid) Mode of action. Uses. Pharmacokinetics. Dose. Adverse effects. Acute overdose. Colchicine Immunomodulatory drugs Methotrexate Mechanism of action. Prescription. Adverse effects. Interactions. Contraindications. Azathioprine Mechanism of action. Prescription. Adverse effects. Interactions. Contraindications. Mycophenolate mofetil Mechanism of action. Adverse effects. Leflunomide Adverse effects. Contraindications. Calcineurin inhibitors Adverse effects. Sirolimus Cyclophosphamide Prescription and adverse effects. Hydroxychloroquine Mechanism of action. Adverse effects. Contraindications. Sulfasalazine Mechanism of action. Adverse effects. Intravenous immunoglobulin Mechanism of action. Adverse effects. Thalidomide Dapsone Biologic agents Anti-TNFα therapies Infliximab Adalimumab Etanercept Adverse effects B-cell depletion Rituximab Belimumab Inhibition of T-cell activation Abatacept Other biologic anticytokine agents Other strategies Management of diseases affecting the joints Osteoarthritis Gout Allopurinol Febuxostat Sulfinpyrazone Rasburicase Rheumatoid arthritis Psoriatic arthritis Ankylosing spondylitis Systemic lupus erythematosus Polymyalgia rheumatica and giant cell arteritis Guide to further reading 17 Drugs and the skin Synopsis Dermal pharmacokinetics Vehicles for presenting drugs to the skin Liquid formulations Creams Oil-in-water creams, Water-in-oil creams, Ointments Water-soluble ointments Non-emulsifying ointments Collodions and gels Pastes Solid preparations Emollients and barrier preparations Emollients Barrier preparations. Topical analgesics Counterirritants and rubefacients Topical non-steroidal anti-inflammatory drugs (NSAIDs) Local anaesthetics. Antipruritics Generalised pruritus Localised pruritus Pruritus ani Adrenocortical steroids Actions. Uses. Choice. Adverse effects. Short-term use. Long-term use. Other effects include: Allergy. Sunscreens (sunburn and photosensitivity) Protection of the skin Absorbent sunscreens. Reflectant sunscreens. Uses. Drug photosensitivity Phototoxicity, Photoallergy, Systemic protection, Antimalarials Psoralens Miscellaneous compounds Keratolytics Tars Ichthammol Zinc oxide Urea Insect repellents, Benzyl benzoate Cutaneous drug reactions Drug-specific rashes Diagnosis Treatment Safety monitoring Individual disorders Psoriasis Topical adrenal corticosteroids Calcipotriol and tacalcitol Vitamin A UVB light Ciclosporin, Folic acid antagonists, Acne Urticaria Atopic dermatitis Skin infections Superficial bacterial infections, Deep bacterial infections, Fungal infections. Viral infections. Parasitic infection. Disinfection and cleansing of the skin. Guide to further reading 4 Nervous system 18 Pain and analgesics Synopsis Pain and analgesics Definition of pain Nociception Classification of clinical pain Acute pain, Chronic pain Neuropathic pain Cancer-related pain Evaluation of pain Pharmacotherapy Non-opioid analgesics NSAIDS (non-steroidal anti-inflammatory drugs) Mechanism of analgesia Clinical use Choice of NSAID and route of administration Adverse effects Acetaminophen (Paracetamol) Nefopam (3,4,5,6-tetrahydro-5-methyl-l-phenyl-1H-2.5-benoxazocine hydrochloride) Opioid analgesics Mechanism of action of opioids Classification of opioid drugs Opioid pharmacodynamics Systemic effects of opioid analgesics Central nervous system Cardiovascular system Gastrointestinal tract Urogenital tract Others Opioid pharmacokinetics Route of administration Pharmacology of individual opioids Opioid agonist drugs Morphine Diamorphine Codeine Dihydrocodeine Oxycodone Hydromorphone Methadone Fentanyl Alfentanil Remifentanil Papaveretum Partial agonist opioid analgesics Buprenorphine Meptazinol Mixed agonist-antagonist opioid analgesics Opioids with action on other systems Meperidine Tramadol Tapentadol Opioid antagonists Naloxone Choice of opioid analgesic Tolerance, dependence and addiction Tolerance Dependence Addiction Pain management in opioid addicts Co-analgesics Multipurpose adjuvant analgesics Corticosteroids Neuroleptics Benzodiazepines Adjuvant analgesics used in neuropathic pain Antidepressants Anticonvulsants Local anaesthetics Capsaicin Clonidine Cannabinoids Ziconotide Ketamine Adjuvants used for bone pain Bisphosphonates Pharmacotherapy of acute migraine headaches Management of migraine Abortive treatment of migraine Selective 5-HT1 agonists (triptans) Sumatriptan Ergotamine Preventive treatment for migraine Beta-adrenergic Blockers Valproic acid Topiramate Other drugs used in migraine prevention Guide to further reading 19 Anaesthesia and neuromuscular block Synopsis General anaesthesia Phases of general anaesthesia Before surgery, During surgery, After surgery, Before surgery (premedication) Anxiolysis and amnesia. Analgesia Timing. Gastric contents. During surgery. Induction Maintenance After surgery Relief of pain Postoperative nausea and vomiting Some special techniques Dissociative anaesthesia Sedation and amnesia Entonox, Methoxyflurane, Pharmacology of anaesthetics Mode of action Inhalation anaesthetics Pharmacokinetics (volatile liquids, gases) Nitrous oxide Advantages. Disadvantages. Uses. Dosage and administration. Contraindications. Precautions. Adverse effects. Halogenated anaesthetics Isoflurane Respiratory effects. Cardiovascular effects. Other effects. Sevoflurane Desflurane Halothane Oxygen in anaesthesia Intravenous anaesthetics Pharmacokinetics Propofol Central nervous system. Cardiovascular system. Respiratory system. Thiopental Central nervous system. Cardiovascular system. Respiratory system. Methohexitone Etomidate Ketamine Advantages. Disadvantages. Uses. Dosage and administration. Induction. Maintenance. Recovery Contraindications Use in pregnancy. Muscle relaxants Neuromuscular blocking drugs Mechanisms Competitive antagonists Atracurium Cisatracurium Vecuronium Rocuronium Mivacurium Pancuronium Tubocurarine Antagonism of competitive neuromuscular block Neostigmine Sugammadex Depolarising neuromuscular blocker Suxamethonium (succinylcholine) Uses of neuromuscular blocking drugs Other muscle relaxants Baclofen Dantrolene Anaphylaxis Local anaesthetics Desired properties Mode of action Pharmacokinetics Ester compounds Amide compounds Prolongation of action by vasoconstrictors Other effects Uses Regional anaesthesia Nerve block Intravenous. Extradural Subarachnoid (intrathecal) block (spinal anaesthesia). Opioid analgesics Adverse reactions Individual local anaesthetics Amides Lidocaine Prilocaine Bupivacaine Levobupivacaine Ropivacaine Esters Cocaine Obstetric analgesia and anaesthesia Pethidine Nitrous oxide and oxygen Epidural Spinal anaesthesia General anaesthesia Anaesthesia in patients already taking medication Drugs that affect anaesthesia Adrenal steroids. Antibiotics. Anticholinesterases Antiepilepsy drugs. Antihypertensives β-Adrenoceptor blocking drugs Diuretics. Oral contraceptives Psychotropic drugs. Antidepressants. Anaesthesia in the diseased, and in particular patient groups Respiratory disease and smoking Cardiac disease. Hepatic or renal disease Malignant hyperthermia Muscle diseases. Sickle cell disease. Atypical (deficient) pseudocholinesterase. Raised intracranial pressure The elderly Children Sedation in critical care units Diabetes mellitus. Thyroid disease. Porphyria. Guide to further reading 20 Psychotropic drugs Synopsis Diagnostic issues Drug therapy in relation to psychological treatment Antidepressant drugs Mechanism of action Pharmacokinetics Therapeutic efficacy Selection Mode of use Changing and stopping antidepressants Augmentation Other indications Adverse effects Selective serotonin reuptake inhibitors Serotonin syndrome SNRIs Venlafaxine Duloxetine Novel compounds Mirtazapine Trazodone Agomelatine Bupropion Vortioxetine Tricyclic antidepressants Overdose. Reboxetine Monoamine oxidase inhibitors Interactions Pharmacodynamic interactions Pharmacokinetic interactions Enzyme inhibition. Enzyme-inducing drugs, Monoamine oxidase inhibitors Hypertensive reactions. Symptoms The rational and effective treatment Patient education. Many simple remedies Foods MAOI interactions with other drugs. Antidepressants. Narcotic analgesics. Other drugs Overdose St John’s wort Adverse effects. Electroconvulsive therapy Repetitive Transcranial Magnetic Stimulation (rTMS) Ketamine Antipsychotics Classification Indications Mechanism of action Pharmacokinetics Efficacy Mode of use Alternative administration strategies in acute antipsychotic use Long-acting depot injections Rapid tranquillisation Adverse effects (see Table 20.5) Classical antipsychotics Extrapyramidal symptoms. Acute extrapyramidal symptoms. Akathisia Tardive dyskinesia Cardiovascular effects. Prolactin increase. Sedation. ‘Atypical’ antipsychotics Neuroleptic malignant syndrome Efficacy of conventional vs atypical antipsychotics Mood stabilisers Lithium The mode of action Pharmacokinetics. Indications and use. Pharmaceutics. Monitoring. Adverse effects Overdose. Interactions. Carbamazepine Valproate ‘Atypical’ antipsychotics Other drugs Drugs used in anxiety and sleep disorders Classification of anxiety disorders Panic disorder (PD) Treatment. Social anxiety disorder Treatment. Post-traumatic stress disorder (PTSD) Acute stress disorder/ adjustment disorder Treatment. Generalised anxiety disorder (GAD) Treatment. Simple phobia Obsessive–compulsive disorder (OCD) Drug treatments General comments about treating anxiety disorders (Table 20.7) Drugs for insomnia The GABAA–benzodiazepine receptor complex Benzodiazepines Pharmacokinetics. Uses. Doses. Tolerance Dependence. Withdrawal Adverse effects. Benzodiazepines in pregnancy. Interactions. Overdose. Benzodiazepine antagonist. Non-benzodiazepine hypnotics that act at the GABAA-benzodiazepine receptor Other drugs that act on the GABAA-benzodiazepine receptor Other drugs used in insomnia Hypersomnia Sleep-related breathing disorders Narcolepsy Parasomnias Nightmares Night terrors and sleep-walking REM behaviour disorder Other sleep disorders Drugs for Alzheimer’s disease (dementia) Doses Adverse effects Drugs in attention deficit/hyperactivity disorder Drugs for psychiatric illness in childhood Guide to further reading 21 Neurological disorders – epilepsy, Parkinson’s disease and multiple sclerosis Synopsis Epilepsy Definitions Pathology and seizure types Principles of management Practical guide to antiepilepsy drugs Dosage and administration Failure to respond Drug withdrawal Driving regulations and epilepsy Pregnancy and epilepsy Breast feeding Epilepsy and oral contraceptives Epilepsy in children Status epilepticus Pharmacology of individual drugs Modes of action (Fig. 21.1) Decreases electrical excitability. Decreases synaptic vesicle release. Enhancement of gamma-aminobutyric acid (GABA) transmission. Inhibition of excitatory neurotransmitters, e.g. glutamate. Other actions. Sodium channel blockers Carbamazepine Pharmacokinetics. Uses. Adverse effects Oxcarbazepine Eslicarbazepine Phenytoin Pharmacokinetics. Saturation kinetics. Enzyme induction and inhibition. Uses. Other uses. Adverse effects. Fosphenytoin Lamotrigine Lacosamide GABA-potentiators Sodium valproate Adverse effects. Barbiturates Benzodiazepines Vigabatrin Calcium channel blockers Gabapentin Pregabalin Ethosuximide Carbonic anhydrase inhibitors Topiramate Zonisamide Levetiracetam Perampanel Parkinson’s disease and parkinsonism Definitions Pathophysiology of Parkinson’s disease Objectives of therapy Enhancement of dopaminergic neurotransmission. Pre-empting and treating levodopa-induced motor complications. Use of cholinergic drugs. Treatment of non-motor symptoms of Parkinson’s disease. Recognition of conservative, surgical and co-morbidity therapies. Drugs for Parkinson’s disease Dopaminergic drugs Levodopa and dopa decarboxylase inhibitors Dose management. Adverse effects. Interactions. Dopamine agonists Ergot derivatives (cabergoline, pergolide, lisuride, bromocriptine). Bromocriptine Non-ergot dopamine agonists Apomorphine Inhibition of dopamine metabolism: MAO-inhibitors and COMT inhibitors Selegiline Rasagiline Entacapone Tolcapone Antimuscarinic (anticholinergic) drugs (see also p. 399) Other drugs Amantadine Adenosine A-2A receptor antagonists Neurosurgery Drug-induced parkinsonism Other movement disorders Essential tremor Drug-induced dystonic reactions are seen: Wilson’s disease. Chorea Dystonia. Spasticity Myotonia, Restless legs syndrome Botulinum toxin (Botox) Multiple sclerosis Traditional injectable disease-modifying drugs Interferon (IFN) β Glatiramer acetate Oral disease-modifying drugs Intravenous therapies Symptomatic therapies Corticosteroid Miscellaneous neurological disorders Peripheral neuropathies Motor neurone disease Tetanus Guide to further reading 5 Cardiorespiratory and renal systems 22 Cholinergic and antimuscarinic (anticholinergic) mechanisms and drugs Synopsis Cholinergic drugs (cholinomimetics) Classification Direct-acting (receptor agonists) Indirect-acting Sites of action (see Fig. 22.1) Pharmacology Autonomic nervous system Parasympathetic division. Sympathetic division. Neuromuscular (voluntary) junction Central nervous system Blood vessels Choline esters Acetylcholine Other choline esters Alkaloids with cholinergic effects Nicotine Pilocarpine, Arecoline Muscarine Anticholinesterases Physostigmine Neostigmine Pyridostigmine Distigmine Edrophonium Carbaryl Anticholinesterase poisoning Typical features Treatment. Poisoning Disorders of neuromuscular transmission Myasthenia gravis Pathogenesis. Diagnosis. Treatment Excessive dosing Lambert–Eaton syndrome Drug-induced disorders of neuromuscular transmission Antimicrobials. Cardiovascular drugs. Other drugs. Drugs that oppose acetylcholine Antimuscarinic drugs Atropine Exocrine glands. Smooth muscle Ocular effects. Cardiovascular system. Central nervous system. Antagonism to cholinergic drugs. Pharmacokinetics. Dose. Poisoning Other antimuscarinic drugs Hyoscine Hyoscine butylbromide Homatropine Tropicamide Ipratropium Tiotropium Flavoxate Oxybutynin Glycopyrronium Propantheline Dicyclomine Benzhexol Solifenacin, darifenacin Promethazine. Propiverine, Guide to further reading 23 Adrenergic mechanisms and drugs Synopsis Adrenergic mechanisms Classification of sympathomimetics By mode of action Tachyphylaxis Interactions of sympathomimetics History. Consequences of adrenoceptor activation Selectivity for adrenoceptors Adrenoceptor agonists (see Table 23.1) α + β effects, non-selective: α1 effects: α2 effects in the central nervous system: β effects, non-selective (i.e. β1 + β2): β1 effects, with some α effects: β1 effects: β2 effects, Adrenoceptor antagonists (blockers) Effects of a sympathomimetic Physiological note. Synthetic non-catecholamines Pharmacokinetics Catecholamines Adverse effects Sympathomimetics and plasma potassium. Overdose of sympathomimetics Individual sympathomimetics Catecholamines Adrenaline/epinephrine Adrenaline/epinephrine is used in anaphylactic shock Accidental overdose Noradrenaline/norepinephrine (chiefly α and β1 effects) Isoprenaline (isoproterenol) Dopamine Dobutamine Dopexamine Non-catecholamines Salbutamol (see also Asthma) Salmeterol Ephedrine Phenylephrine Mucosal decongestants Shock Definition. Treatment Types of shock In poisoning by a cerebral depressant In central circulatory failure Septic shock Choice of drug in shock Monitoring drug use Restoration of intravascular volume Dextran 70 Gelatin products Etherified starch. Chronic orthostatic hypotension Detrusor relaxation for urinary frequency, urgency and urge incontinence Guide to further reading 24 Arterial hypertension, angina pectoris, myocardial infarction and heart failure Synopsis Hypertension: how drugs act Angina pectoris: how drugs act Drugs used in hypertension and angina Diuretics (see also Ch. 27) Vasodilators Organic nitrates Pharmacokinetics. Tolerance Uses. Adverse effects. Interactions. Glyceryl trinitrate (see also above) For prophylaxis, Venepuncture. Isosorbide dinitrate Isosorbide mononitrate Pentaerithrityl tetranitrate Calcium channel blockers Vascular smooth muscle cells. Pharmacokinetics. Indications for use Adverse effects. Interactions Individual calcium channel blockers Nifedipine Amlodipine Verapamil Diltiazem Nimodipine Other members Angiotensin-converting enzyme (ACE) inhibitors, angiotensin (AT) II receptor blockers (ARBs) and renin inhibitors Uses Hypertension. Cardiac failure Diabetic nephropathy. Myocardial infarction (MI). Cautions Adverse effects ACE inhibitors: ARBs Interactions. Individual drugs Captopril Enalapril Other members Losartan Other ARBs Renin inhibitors Interactions. Individual drugs Aliskiren Other vasodilators Minoxidil Sodium nitroprusside Hydralazine Nicorandil Papaverine Alprostadil Vasodilators in heart failure Vasodilators in peripheral vascular disease Intermittent claudication. Raynaud’s phenomenon Adrenoceptor-blocking drugs α-Adrenoceptor–blocking drugs Adverse effects. Notes on individual drugs Prazosin Doxazosin Indoramin Phentolamine Phenoxybenzamine Moxisylyte Labetalol Chlorpromazine and amitriptyline, β-Adrenoceptor–blocking drugs Actions Intrinsic heart rate. Effects β-Adrenoceptor selectivity Pharmacokinetics Lipid-soluble Water-soluble Classification of β-adrenoceptor–blocking drugs Uses of β-adrenoceptor–blocking drugs Cardiovascular uses: Endocrine uses. Other uses: Adverse reactions due to β-adrenoceptor blockade Adverse reactions not certainly due to β-adrenoceptor blockade Overdose Interactions Pharmacokinetic. Pharmacodynamic. Pregnancy Notes on some individual β-adrenoceptor blockers Propranolol Atenolol Bisoprolol Nebivolol Combined β1- and α-adrenoceptor- blocking drug Labetalol Peripheral sympathetic nerve terminal Adrenergic neurone-blocking drugs Depletion of stored transmitter (noradrenaline/norepinephrine) Inhibition of synthesis of transmitter Autonomic ganglion-blocking drugs Hexamethonium Trimetaphan, Central nervous system α2-Adrenoceptor agonists Clonidine False transmitter Methyldopa Drug treatment of angina, myocardial infarction and hypertension Angina pectoris Antiangina drugs Summary of treatment For long-term prophylaxis: Newer therapies Ivabradine Myocardial infarction (MI) An overview Other antiplatelet agents. Unstable angina Secondary prevention Drugs for secondary prevention Arterial hypertension Aims of treatment Threshold and targets for treatment Principles of antihypertensive therapy Drug therapy Treating hypertension Treatment and severity Monitoring Diuretics and potassium. Compliance. Resistant hypertension Treatment of hypertensive emergencies Accelerated-phase hypertension Treatment. Pregnancy hypertension Unwanted interactions with antihypertensive drugs Alcohol intake Prostaglandin synthesis. Enzyme inhibition. Pharmacological antagonism. Surgical anaesthesia Sexual function and cardiovascular drugs Sexual intercourse and the cardiovascular system Pulmonary hypertension Idiopathic (primary) pulmonary arterial hypertension (PAH). Treatment of secondary hypertension Phaeochromocytoma Diagnosis Control of blood pressure Primary aldosteronism (Conn’s syndrome) Heart failure and its treatment Some physiology and pathophysiology Definition of chronic heart failure The Starling curve and heart failure Natural history of chronic heart failure Objectives of treatment Haemodynamic aims of drug therapy Classification of drugs Reduction of preload Diuretics Nitrates Reduction of afterload Reduction of preload and afterload ACE inhibitors and angiotensin receptor II blockers (ARBs) β-Adrenoceptor blockers. Spironolactone. Stimulation of the myocardium Digoxin Drug management of heart failure Chronic heart failure Acute left ventricular failure Surgery for heart failure Guide to further reading 25 Cardiac arrhythmia Synopsis Objectives of treatment Some physiology and pathophysiology Ionic movements into and out of cardiac cells Classification of antiarrhythmic drugs Classification of drugs Class I: sodium channel blockade. Class II: catecholamine blockade. Class III: lengthening of refractoriness Class IV: calcium channel blockade Principal drugs by class Class 1A (sodium channel blockade with lengthened refractoriness) Quinidine Pharmacokinetics. Adverse reactions. Disopyramide Pharmacokinetics. Adverse reactions. Class IB (sodium channel blockade with shortened refractoriness) Lidocaine Pharmacokinetics. Adverse reactions Mexiletine Adverse reactions, Class IC (sodium channel blockade with minimal effect on refractoriness) Flecainide Pharmacokinetics. Adverse reactions. Propafenone Pharmacokinetics. Adverse reactions Class II (catecholamine blockade) β-Adrenoceptor antagonists Pharmacokinetics. Adverse reactions. Interactions. Class III (lengthening of refractoriness due to potassium channel blockade) Amiodarone Pharmacokinetics. Adverse reactions. Interaction Dronedarone Pharmacokinetics. Contraindications. Unwanted effects. Class IV (calcium channel blockade) Calcium and cardiac cells Pacemaker Calcium channel blockers Verapamil Adverse effects Other arrhythmia modifying agents Digoxin and other cardiac glycosides Mode of action. Uses. Pharmacokinetics. Dose and therapeutic plasma concentration Adverse effects. Treatment of overdose. Interactions. Adenosine Adverse effects Cardiac effects of the autonomic nervous system The sympathetic division Isoprotenerol, The vagus nerve Proarrhythmic drug effects Choice between drugs and electroconversion Specific treatments Sinus bradycardia Atrial ectopic beats Paroxysmal supraventricular (AV re-entrant or atrial) tachycardia Atrial fibrillation (AF) What management options are available? Additional treatments in persistent atrial fibrillation. Atrial flutter Atrial tachycardia with variable AV block Heart block Pre-excitation (Wolff–Parkinson–White) syndromes Ventricular premature beats Ventricular tachycardia Ventricular fibrillation and cardiac arrest Long QT syndromes Guide to further reading 26 Hyperlipidaemias Synopsis Some physiology and pathophysiology Lipid disorders Primary inherited lipoprotein disorders Secondary lipoprotein disorders Sites of drug action Management Drugs used in treatment Statins Fibric acid derivatives (fibrates) Anion-exchange resins (bile acid sequestrants) Ezetimibe PCSK9 inhibitors Nicotinic acid and derivatives Other drugs Omega-3 marine triglycerides Orlistat, CETP inhibitors Lomitapide Mipomersen Volanesorsen Guide to further reading 27 Kidney and genitourinary tract Synopsis Diuretic drugs Definition. Sites and modes of action Proximal convoluted tubule Loop of Henle Distal convoluted tubule Collecting duct Classification High efficacy Furosemide Moderate efficacy The thiazide family, Low efficacy Triamterene, amiloride and spironolactone Osmotic diuretics, Individual diuretics High-efficacy (loop) diuretics Furosemide Pharmacokinetics. Uses. Adverse effects Moderate-efficacy diuretics Thiazides Uses. Pharmacokinetics. Adverse effects Bendroflumethiazide Diuretics related to the thiazides. Low-efficacy diuretics Spironolactone Adverse effects. Eplerenone Amiloride Triamterene Indications for diuretics Therapy Congestive cardiac failure Acute pulmonary oedema: left ventricular failure Renal oedema Hepatic ascites Adaptation to diuretic therapy Adverse effects characteristic of diuretics Potassium depletion Hyperkalaemia Hypovolaemia Urinary retention. Hyponatraemia Urate retention Magnesium deficiency. Carbohydrate intolerance Calcium homeostasis. Interactions Abuse of diuretics Osmotic diuretics Mannitol, Methylxanthines Carbonic anhydrase inhibitors Reduction of intraocular pressure. High-altitude (mountain) sickness Adverse effects. Cation-exchange compounds Cation-exchange resins Patiromer Alteration of urine pH Alkalinisation of urine: Acidification of urine: Drugs and the kidney Adverse effects Drug-induced renal disease Glomerular damage. Tubule damage. Tubule obstruction. Other drug-induced lesions Prescribing in renal disease Dose adjustment for patients with renal impairment General rules Nephrolithiasis Management. Pharmacological aspects of micturition Some physiology Functional abnormalities Drugs that may be used to alleviate abnormal micturition Antimuscarinic Tricyclic antidepressants. Oestrogens, Parasympathomimetic Benign prostatic hyperplasia (BPH) α-Adrenoceptor antagonists. Finasteride. Erectile dysfunction Sildenafil Adverse effects Interactions Alprostadil Papaverine, Guide to further reading 28 Respiratory system Synopsis Cough Sites of action for treatment Peripheral sites Central nervous system Cough suppression Antitussives that act peripherally Antitussives that act centrally Mucolytics and expectorants Mucolytics Expectorants Cough mixtures Respiratory stimulants Doxapram Adverse effects Aminophylline Uses Pulmonary surfactant Oxygen therapy Histamine, antihistamines and allergies Actions. Smooth muscle. Blood vessels. Skin. Gastric secretion. Metabolism. Histamine receptors. Histamine antagonism Actions. Pharmacokinetics. Uses. Individual H1-receptor antihistamines Non-sedative second-generation drugs including the ‘third-generation’ antihistamines Adverse effects. Sedative first-generation agents Adverse effects. Drug management of some allergic states Hay fever. Urticaria. Anaphylactic shock. Bronchial asthma Some pathophysiology Types of asthma Allergic asthma Late-onset eosinophilic asthma Neutrophilic asthma Obesity-related asthma Other types of asthma Exercise-induced asthma Aspirin-sensitive asthma Asthma associated with chronic obstructive pulmonary disease Approaches to treatment Prevention of exposure to allergen(s) Reduction of the bronchial inflammation and hyperreactivity Glucocorticoids Sodium cromoglicate Other drugs. Dilatation of narrowed bronchi β2-Adrenoceptor agonists. Theophylline, Adverse effects. Overdose Antimuscarinic bronchodilators. Leukotriene receptor antagonists, Drug therapy by inhalation Pressurised aerosol. Nebulisers Dry-powder inhalers. Drug treatment Constant and intermittent asthma An inhaled β2-adrenoceptor agonist Anti-inflammatory agents Inhaled glucocorticoids Oral prednisolone Chest infections in asthma Acute severe asthma (‘status asthmaticus’) Immediate treatment Subsequent management. Monitoring response to treatment Treatment in intensive care unit. Treatment at discharge from hospital. Warnings Overuse Chronic obstructive pulmonary disease (COPD) Drugs Long-term oxygen therapy Guide to further reading 6 Blood and neoplastic disease 29 Drugs and haemostasis Synopsis Introduction The coagulation system Procoagulant drugs Vitamin K Phytomenadione Menadiol Vitamin K is used to treat the following: Coagulation factor concentrates Use of coagulation factor concentrates Desmopressin (DDAVP) Adverse effects. Other agents Adrenaline/epinephrine Fibrin glue Sclerosing agents Anticoagulant drugs Oral vitamin K antagonists (VKA) Pharmacokinetics. Pharmacodynamics. Dose. Adverse effects. Withdrawal of oral anticoagulant therapy. Reversal of anticoagulation Drug interactions. Analgesics. Antimicrobials. Anticonvulsants. Antiarrhythmics. Antidepressants. Gastrointestinal drugs. Lipid-lowering drugs. Sex hormones and hormone antagonists. Sedatives and anxiolytics. Uses of oral VKA Surgery in patients receiving oral VKA Elective surgery. Emergency surgery. Dental extractions. Other vitamin K antagonists Oral direct thrombin and factor Xa inhibitors Dabigatran Rivaroxaban, apixaban and edoxaban Parenteral anticoagulants Heparin Pharmacokinetics. Pharmacodynamics. Monitoring heparin therapy. Adverse effects. Heparin reversal. Use of heparin Treatment of established venous thromboembolism. Prevention of venous thromboembolism. Cardiac disease. Peripheral arterial occlusion. Other anticoagulant drugs Anticoagulant drugs under development Fibrinolytic (thrombolytic) system Plasminogen activators Fibrinolysis inhibitors. Drugs that promote fibrinolysis Uses of thrombolytic drugs Vascular occlusion Adverse effects. Drugs that prevent fibrinolysis Tranexamic acid Aprotinin Platelet function Drugs that inhibit platelet activity (antiplatelet drugs) Aspirin Dipyridamole Clopidogrel Prasugrel Ticagrelor. Epoprostenol Glycoprotein (GP) IIb–IIIa antagonists Abciximab Eptifibatide Adverse effects. Uses of antiplatelet drugs Guide to further reading 30 Red blood cell disorders Synopsis Iron Iron deficiency Management of iron deficiency and prophylactic iron administration Oral iron preparations Liquid iron formulations Sustained or slow-release iron preparations Adverse effects Parenteral iron Adverse effects Drug interactions Anaemia of chronic disease Functional iron deficiency Chronic iron overload Parenteral iron chelator. Oral iron chelators. Deferiprone Deferasirox. Iron poisoning and acute overdose Vitamin B12 Vitamin B12 deficiency Management of vitamin B12 deficiency and prophylactic administration Contraindications to cobalamin Folic acid (pteroylglutamic acid) Folic acid deficiency Management of folic acid deficiency and prophylactic administration Haemolytic anaemia Autoimmune haemolytic anaemia Drug-induced haemolytic anaemia Glucose-6-phosphate dehydrogenase deficiency Haemoglobinopathies Sickle cell anaemia Thalassaemia Aplastic anaemia Polycythaemia vera Management of PV Haemopoietic growth factors Erythropoiesis-stimulating agents Clinical uses of ESAs Anaemia of chronic renal failure. Anaemia due to cancer chemotherapy. Other clinical uses of EPO. Adverse effects Granulocyte colony-stimulating factor Adverse effects Thrombopoietin receptor agonists Guide to further reading 31 Neoplastic disease and immunosuppression Synopsis Neoplastic disease Cancer treatments and outcomes Systemic cancer therapy Rationale for cytotoxic chemotherapy Classes of cytotoxic chemotherapy drugs Adverse effects of cytotoxic chemotherapy Nausea and vomiting Suppression of bone marrow and the lymphoreticular system. Opportunistic infection Diarrhoea and mouth ulcers Alopecia Urate nephropathy Local extravasation Hypersensitivity reactions Specific organ damage Delayed wound healing Germ cells and reproduction Carcinogenicity Classes of cytotoxic agents Alkylating agents Antimetabolites Anthracyclines and related compounds Topoisomerase inhibitors Spindle poisons Platinum drugs Miscellaneous agents Chemotherapy in clinical practice Drug use and tumour cell kinetics Cytotoxic drugs The selection of drugs Drug resistance Resistance Multiple drug resistance Improving efficacy of chemotherapy Hazards to staff handling cytotoxic agents A note of caution. Interactions of anticancer agents with other drugs Endocrine therapy Hormonal influence on cancer Hormonal agents Breast cancer Prostatic cancer Benign prostatic hypertrophy Adrenocortical steroids In general, Immunotherapy ATRA Development of anticancer drug therapy Targeted biological therapies Passive immunotherapy using monoclonal antibodies raised against specific tumour-associated antigens on the cell surface Radioimmunotherapy Chemo-immunotherapy Signal transduction inhibitors Targeting the cell cycle Protease inhibition Chemoprevention of cancer Viral immunisation and cancer prevention Immunosuppression Ciclosporin Pharmacokinetics. Uses. Adverse reactions. Interactions. Tacrolimus Antilymphocyte immunoglobulin Mycophenolate Hazards of immunosuppressive drugs Carcinogenicity Active immunisation during immunosuppressive therapy Guide to further reading 7 Gastrointestinal system 32 Oesophagus, stomach and duodenum Synopsis The oesophagus in health and disease Gastric acid secretion and mucosal protection Gastric acid secretion Gastrin Acetylcholine (ACh) Histamine Prostaglandins Mucosal protective mechanisms Helicobacter pylori (H. pylori): an occasionally silent killer NSAIDs: enemies of the gut Drugs affecting oesophageal motility and the lower oesophageal sphincter Drugs to reduce or neutralise gastric acid Proton pump inhibitors (PPIs) Pharmacology. Pharmacokinetics. Adverse reactions and interactions. H2-receptor antagonists (H2RAs) Pharmacology. Pharmacokinetics and dosage. Adverse effects and interactions. Antacids Individual antacids Other targets for acid suppression Drugs to enhance mucosal protection Sucralfate (SUCRose sulFATE and ALuminium hydroxide complex) Adverse effects and interactions. Bismuth chelate (tripotassium dicitratobismuthate, bismuth sub-citrate) Adverse effects. Misoprostol Adverse effects. Alginate Pharmacological management Gastro-oesophageal reflux Eosinophilic oesophagitis Oesophageal dysmotility Peptic ulceration (Fig. 32.2) Treatment of H. pylori Use of NSAIDs Other disorders of acid secretion Nausea and vomiting Drugs used in nausea and vomiting Antimuscarinics H1-receptor antagonists D2-receptor antagonists 5-HT3-receptor antagonists Corticosteroids Choice of antiemetic Non-ulcer dyspepsia and functional disorders Guide to further reading 33 Intestines Synopsis Diarrhoea Some physiology Mechanism of diarrhoea Osmotic diarrhoea Secretory diarrhoea Increased gut transit Motility patterns in the bowel Fluid and electrolyte treatment Oral rehydration therapy (ORT) Oral rehydration salts (ORSs). Antidiarrhoeal drugs Antimotility drugs Drugs that directly increase the viscosity of gut contents Infectious diarrhoea Diarrhoea due to Clostridium difficile (‘C. diff’) Drug-induced diarrhoea Secretory diarrhoea due to vasoactive peptides Bile acid malabsorption (BAM) Microscopic colitis Constipation Stool bulking agents Dietary fibre Individual preparations Bran Drugs to stimulate colonic motility Stimulant laxatives Bisacodyl Sodium picosulfate Glycerol The anthraquinone group Senna, Danthron Osmotic laxatives Some inorganic salts Lactulose Faecal softeners (emollients) Drastic purgatives Suppositories and enemas Contraindications Inflammatory bowel disease (IBD) Drugs to induce remission in UC Aminosalicylates Sulfasalazine Mesalazine. Other 5-ASAs. Corticosteroid Enemas and suppositories. Systemic corticosteroid. Ciclosporin Biological therapy Drugs to induce remission in Crohn’s disease 5-ASA Antibiotics Dietary therapy Corticosteroids Ciclosporin Biological therapies Maintenance of remission in IBD Corticosteroids Azathioprine Methotrexate, Biological therapies Maintenance of remission following surgery for Crohn’s disease Irritable bowel syndrome (IBS) Antimuscarinic drugs Direct smooth muscle relaxants Gastroparesis Diverticular disease Anal fissure Guide to further reading 34 Liver and biliary tract Synopsis Effects of liver disease Pharmacodynamic changes in liver disease Pharmacokinetic changes in liver disease Hepatic blood flow and metabolism Plasma protein binding of drug Other considerations Prescribing for patients with liver disease CNS depressants. Analgesics. Gastrointestinal system. Drug-induced liver damage Diagnosis and management of drug-induced liver injury Aspects of therapy Complications of cirrhosis Variceal bleeding Acute variceal haemorrhage Pharmacological reduction of portal pressure Prevention of variceal haemorrhage Pharmacological therapy Ascites Management of ascites Subacute bacterial peritonitis Hepatorenal syndrome Hepatic encephalopathy Hepatocellular carcinoma (HCC) Immune-mediated liver disease Autoimmune hepatitis (AIH) Primary biliary cholangitis (PBC) Primary sclerosing cholangitis (PSC) Alcohol-related hepatitis Metabolic disease Wilson’s disease Haemochromatosis Non-alcohol–related fatty liver disease Viral hepatitis Hepatitis A virus (HAV) Hepatitis B virus (HBV) Hepatitis B vaccination Hepatitis D virus (HDV) Hepatitis C virus (HCV) Gallstones Pancreas Digestive enzymes Acute pancreatitis Drugs and the pancreas Guide to further reading 8 Endocrine system, metabolic conditions 35 Adrenal corticosteroids, antagonists, corticotropin Synopsis Adrenal steroids and their synthetic analogues Mechanism of action On inorganic metabolism. On organic metabolism Individual adrenal steroids Hydrocortisone Prednisolone Methylprednisolone Fluorinated corticosteroids (triamcinolone, fludrocortisone) Triamcinolone Fludrocortisone Dexamethasone and betamethasone Aldosterone Spironolactone Beclometasone, budesonide, fluticasone, mometasone and ciclesonide Pharmacokinetics of corticosteroids Dosage schedules Adverse effects of systemic adrenal steroid pharmacotherapy Endocrine. Musculoskeletal. Immune. Gastrointestinal. Central nervous system. Ophthalmic effects Other effects Adrenal steroids and pregnancy Precautions during chronic adrenal steroid therapy Treatment of intercurrent illness Dosage and routes of administration Systemic commencing doses: Topical applications Contraindications Long-term use of adrenal steroids in children Uses of adrenocortical steroids Replacement therapy Acute adrenocortical insufficiency (Addisonian crisis) Chronic primary adrenocortical insufficiency (Addison’s disease) Chronic secondary adrenocortical insufficiency Iatrogenic adrenocortical insufficiency: abrupt withdrawal Pharmacotherapy Suppression of adrenocortical function Use in inflammation and for immunosuppression Further specific uses Use in diagnosis. Withdrawal of pharmacotherapy Inhibition of synthesis of adrenal and other steroid hormones Competitive antagonism of adrenal steroids Adrenocorticotrophic hormone (ACTH) (corticotropin) Natural corticotropin Synthetic corticotropins Actions The effects Uses. Diagnostic use Therapeutic use Preparations Guide to further reading 36 Diabetes mellitus, insulin, oral antidiabetes agents, obesity Synopsis Diabetes overview History of insulin therapy in diabetes Sources of insulin Insulin receptors Actions of insulin Uses Pharmacokinetics Preparations of insulin (Table 36.1) Notes for prescribing insulin Allergy Antibodies Compatibility. Intravenous insulin. The standard strength Choice of insulin regimen Dose and injection technique Adverse effects of insulin Hypoglycaemia Non-insulin antidiabetes drugs (i) Insulin secretagogues Meglitinides Incretin analogues and mimetics. Dipeptidyl peptidase-4 (DPP-4) inhibitors. (ii) Insulin sensitisers Biguanides Thiazolidinediones. (iii) Agents that increase urinary glucose excretion SGLT-2 inhibitors. (iv) Agents which reduce glucose absorption Acarbose Antidiabetics and cardiovascular outcome studies. Choice of oral antidiabetic drugs in type 2 diabetes Diet and diabetes Interactions with non-diabetes drugs Adrenal steroids, Growth hormone Oral contraceptives Thyroid hormone Drug-induced diabetes Diazoxide Pregnancy and diabetes Surgery in diabetic patients Principles of management Type 1 diabetes Elective major surgery Minor surgery/procedures Emergency surgery Type 2 diabetes Diabetic ketoacidosis Intravenous fluid. Soluble insulin Potassium. Bicarbonate Success in treatment Euglycaemic ketoacidosis Diabetic ketosis without acidosis. Ketosis-prone type 2 diabetes (“Flatbush diabetes”). Hyperosmolar Hyperglycaemic State (HHS) Preventing complications other than by glucose lowering Obesity and appetite control Orlistat Adverse effects Leptin Newer agents GLP-1 agonist Lorcaserin Obesity and diabetes Guide to further reading 37 Thyroid hormones, antithyroid drugs Synopsis Thyroid hormones Calcitonin. Physiology and pharmacokinetics T4 (levothyroxine). T3 (liothyronine) Pharmacodynamics Levothyroxine for hypothyroidism Treatment of hypothyroidism Levothyroxine tablets Liothyronine tabs. Subclinical hypothyroidism. Adverse effects In pregnancy Antithyroid drugs and hyperthyroidism Thionamides (thiourea derivatives) carbimazole, methimazole, propylthiouracil Mode of action (Fig. 37.1) Carbimazole and methimazole Propylthiouracil Immunosuppression Doses Use Adverse reactions Pregnancy. Control of antithyroid drug therapy β-Adrenergic blockade. Iodine (iodide and radioactive iodine) Effects Uses Potassium iodate As an antiseptic Bronchial secretions. Organic compounds Adverse reactions Symptoms of iodism Radioiodine (131I) Risks Radioisotope tests Preparation for surgery Thyroid storm Graves’ ophthalmopathy Treatment of subclinical hyperthyroidism Drugs that cause hypothyroidism Drugs causing either hyper- or hypothyroidism Amiodarone Biological therapies Miscellaneous Treatment of thyroiditis Calcitonin. Guide to further reading 38 Hypothalamic, pituitary and sex hormones Synopsis Hypothalamic and anterior pituitary hormones Corticotropin-releasing hormone (CRH) Adrenocorticotrophic hormone (ACTH) Thyrotrophin-releasing hormone (TRH) Thyroid-stimulating hormone (TSH) thyrotrophin, Sermorelin Octreotide Growth hormone, somatrophin Pegvisomant Gonadotrophin-releasing hormone (GnRH), Follicle-stimulating hormone (FSH) Chorionic gonadotrophin Prolactin Hypopituitarism Posterior pituitary hormones and analogues Vasopressin: antidiuretic hormone (ADH) Desmopressin Diabetes insipidus: vasopressin deficiency Desmopressin replacement therapy Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Emergency treatment of hyponatraemia Oxytocin. Sex (gonadal) hormones and antagonists: steroid hormones Steroid hormone receptors Selectivity. Pharmacokinetics. Androgens Indications for androgen therapy Preparations and choice of androgens Oral preparations Parenteral preparations Transdermal preparations Buccal preparations Testosterone implants Adverse effects Antiandrogens (androgen antagonists) Cyproterone Uses. Anabolic steroids Oestrogens Pharmacokinetics Preparations of oestrogens Choice of oestrogen Oestrogen formulations and routes of administration Oral. Transdermal Subcutaneous implants. Vaginal (ring, cream, tablet or pessary). Others. Indications for oestrogen therapy Replacement therapy in hypo-oestrogenaemia Post-menopausal hormone replacement therapy (HRT) Preparations used for HRT. Contraception. Adverse effects of HRT. Contraindications Anti-oestrogens Clomifene Cyclofenil Tamoxifen Progesterone and progestogens Uses Preparations Adverse effects Antiprogestogens Mifepristone Other progesterone derivatives Gestrinone Fertility regulation Infertility For women, For men, Polycystic ovary syndrome (PCOS) Contraception by drugs and hormones Hormonal contraception in women Combined contraceptives (the ‘pill’) Combined oestrogen–progestogen Important aspects Subsequent fertility. Effect on an existing pregnancy. Carcinomas The effect on menstruation Libido Cardiovascular complications. Major surgery Plasma lipoproteins Plasma proteins. Other adverse effects Absolute contraindications Relative contraindications Duration of use Benefits additional to contraception Formulations of oestrogen–progestogen combination Oestrogen: Progestogen Combined oral contraceptives Choice of oestrogen–progestogen combination Common problems Missed pill. Intercurrent gut upset. Changing of preparation. Breakthrough bleeding Progestogen-only contraception Postcoital (‘morning after pill’) and emergency contraception Progestogen-only treatment Drug interaction with steroid contraceptives Enzyme induction. Hypothalamic/pituitary hormone approach to contraception Other methods of contraception Copper intrauterine devices The intrauterine levonorgestrel system Vaginal preparations, Oil-based lubricants Risks of contraception in relation to benefit Menstrual disorders Amenorrhoea, Menorrhagia The timing of menstruation. Endometriosis. Dysmenorrhoea Premenstrual tension syndrome Cyclical breast pain Myometrium Oxytocics Oxytocin Ergometrine Prostaglandins Dinoprost Gemeprost Carboprost Induction of abortion Induction and augmentation of labour Prevention and treatment of uterine haemorrhage Uterine relaxants Guide to further reading 39 Vitamins, calcium, bone Synopsis Vitamin A: retinol Therapeutic uses Psoriasis Acne Acute promyelocytic leukaemia Vitamin A deficiency Adverse effects Teratogenicity. Vitamin B complex Thiamine (B1). Cobalamins (B12). Folic acid. Pyridoxine (B6) Niacin (nicotinic acid, B3) Vitamin C: ascorbic acid Indications Scurvy Methaemoglobinaemia Adverse effects Vitamin D, calcium, parathyroid hormone, calcitonin, bisphosphonates, bone Vitamin D Pharmacokinetics Actions Indications Vitamin D deficiency Osteoporosis Hypoparathyroidism Psoriasis Renal osteodystrophy Prevention of acute respiratory tract infections Adverse effects Treatment of calcium and bone disorders Hypocalcaemia Adverse effects Hypercalcaemia Temporary measures Longer-term treatment Sodium cellulose phosphate Inorganic phosphate, Hypercalciuria Parathyroid hormone Calcitonin Adverse effects Bisphosphonates Actions. Pharmacokinetics Indications Adverse effects Osteoporosis Pharmacotherapy Bisphosphonates Selective oestrogen receptor modulator. Parathyroid hormone. Oestrogen–progestogen. Selective oestrogen-receptor modulator (SERM). Calcitonin. Corticosteroid-induced osteoporosis. Chronic kidney disease – mineral bone disorder (CKD-MBD) Osteomalacia Paget’s disease of bone Bisphosphonates. Vitamin E: tocopherol Vitamin K Guide to further reading Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Inside Back Cover