A Textbook of Clinical Pharmacology and Therapeutics

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● Introduction: ocular anatomy, physiology and biochemistry 423 ● General pharmacokinetics of intra-ocular drug administration 423 ● Drugs used to dilate the pupil 423 ● Drugs used to constrict the pupil and to treat glaucoma 425 INTRODUCTION: OCULAR ANATOMY, PHYSIOLOGY AND BIOCHEMISTRY CHAPTER 52 DRUGS AND THE EYE The eye is protected by a series of barriers, namely the blood–retinal, blood–aqueous and blood–vitreous barriers, and so represents both an opportunity for localized drug administration and also a challenge to drug delivery. See Figure 52.1 for a cross-sectional view of the anatomy of the eye. The structures of the eye itself are divided into the anterior and posterior segments. The anterior segment includes the cornea, limbus, anterior and posterior chambers, trabecular meshwork, Schlemm’s canal, the iris, lens and the ciliary body. The posterior segment consists of the sclera, choroid, retina, vitreous and optic nerve. The anterior surface of the eye is covered by the conjunctiva. The ocular secretory system is composed of the main lacrimal gland located in the upper outer orbit, and accessory glands located in the conjunctiva. The lacrimal gland has both sympathetic and parasympathetic innervation. Parasympathetic innervation is relevant in that many drugs with anticholinergic side effects cause the symptom of dry eyes (see Table 52.1). Tear drainage starts through small puncta located in the medial aspects of the eyelids. Blinking causes tears to enter the puncta and drain through the canaliculi, lacrimal sac and nasolacrimal duct into the nose. The nose is lined with highly vascular epithelium which permits direct access of absorbed drugs to the systemic circulation. Consequently, even though the dose administered as eye drops is much smaller than the usual dose of the same drug (e.g. timolol) administered by mouth, the lack of first-pass metabolism may nonetheless lead to unwanted systemic effects. THE IRIS AND CILIARY BODY In the iris, dilator smooth muscle is orientated radially and innervated by the sympathetic system, which produces dilatation ● Drugs used to treat eye infections 427 ● Drugs used to treat inflammatory disorders in the eye 427 ● Drugs for age-related macular degeneration 428 ● Local anaesthetics and the eye 428 ● Adverse effects on the eye of systemic drug therapy 428 ● Contact lens wearers 429 (mydriasis). At the pupillary margin, the sphincter smooth muscle is organized in a circular orientation with parasympathetic innervation which, when stimulated, leads to pupillary constriction (miosis) (see Table 52.1 for a summary of the autonomic pharmacology of the eye). The ciliary body serves two specialized functions, namely secretion of the aqueous humour and accommodation. Parasympathetic stimulation contracts the ciliary muscle and allows the lens to become more convex, focusing on near objects. Contraction of this muscle also widens the spaces in the trabecular meshwork and this also explains, in part, the effect of parasympathomimetics in lowering intra-ocular pressure. GENERAL PHARMACOKINETICS OF INTRA-OCULAR DRUG ADMINISTRATION The bioavailability of intra-ocularly administered drugs depends on pH and other pharmaceutical properties of the vehicle. Most ophthalmic drugs in general use are delivered as drops, usually in aqueous solution. Formulations which prolong the time for which a drug remains in contact with the eye surface include gels, ointments, solid inserts, soft contact lenses and collagen shields. Drug penetration into the eye itself is approximately linearly related to the concentration of drug applied. Nasolachrymal drainage plays a key role in the systemic absorption of drugs administered to the eye, and drugs absorbed via this route circumvent hepatic first-pass metabolism. Thus ocular drugs such as β-adrenergic antagonists can cause wheezing in asthmatic patients. Figure 52.2 shows potential pathways for drug absorption in the eye. DRUGS USED TO DILATE THE PUPIL Mydriasis (pupillary dilatation) is often required for detailed examination of the retina. Two major groups of drugs are used
424 DRUGS AND THE EYE Posterior cavity (vitreous humour) Retinal arteries and veins Macula lutea Central fovea (II) nerve Optic disc (blind spot) Choroid Optic portion of retina Ciliary body Retina Choroid Sclera Suspensory ligaments of lens Lens Sclera Ciliary muscle Ciliary process Conjunctiva Ciliary body α-Iadrenoceptor Canal of Schlemm Carbonic anhydrase Posterior chamber Anterior chamber Iris Superior rectus muscle Conjunctiva Posterior chamber Anterior chamber Visual axis Light Pupil Iris Lens Cornea Sclera Inferior rectus muscle β- 2 - adrenoceptor Cornea Anterior cavity (aqueous humour) α- 2 adrenoceptor Ciliary blood supply Figure 52.1: The eye. (a) General features and the visual axis. (b) Enlargement to show features of the ciliary body and the circulation of aqueous humour, and high magnification area detailing the distribution of adrenergic receptors and carbonic anhydrase location. (Redrawn with permission from Clancy J, McVicar AJ. Physiology and anatomy. London: Edward Arnold, 1995). Table 52.1: Autonomic pharmacology/physiology of the eye and associated structures Tissue Adrenergic receptor Response Cholinergic receptor Response and subtype and subtype Iris radial muscle α 1 Mydriasis Iris sphincter muscle – – M 3 Miosis Ciliary epithelium α 2/β 2 Aqueous humour production Ciliary muscle β 2 Relaxation M 3 Accommodation Lacrimal gland α 1 Secretion M 2/M 3 Secretion
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A Textbook of Clinical Pharmacology
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A Textbook of Clinical Pharmacology
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This fifth edition is dedicated to
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FOREWORD viii PREFACE ix ACKNOWLEDG
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PREFACE Clinical pharmacology is th
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PART I GENERAL PRINCIPLES
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● Use of drugs 3 ● Adverse effe
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and acquired factors, notably disea
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100 Effect (%) 0 0 5 10 1 10 100 (a
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Dose ratio -1 100 50 The relationsh
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● Introduction 11 ● Constant-ra
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In reality, processes of eliminatio
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lood (from which samples are taken
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● Introduction 17 ● Bioavailabi
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ROUTES OF ADMINISTRATION ORAL ROUTE
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Transdermal absorption is sufficien
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FURTHER READING Fix JA. Strategies
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and thromboxanes are CYP450 enzymes
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and lorazepam. Some patients inheri
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Orally administered drug Parenteral
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● Introduction 31 ● Glomerular
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ACTIVE TUBULAR REABSORPTION This is
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DISTRIBUTION Drug distribution is a
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Detailed recommendations on dosage
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DIGOXIN Myxoedematous patients are
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● Introduction 41 ● Role of dru
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25 20 10 Life-threatening toxicity
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● Introduction 45 ● Harmful eff
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vagina in girls in their late teens
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an anti-analgesic effect when combi
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Case history A 20-year-old female m
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METABOLISM At birth, the hepatic mi
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lifelong effects as a result of tox
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DISTRIBUTION Ageing is associated w
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DIGOXIN Digoxin toxicity is common
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FURTHER READING Dhesi JK, Allain TJ
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Factors involved in the aetiology o
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analgesic. Following its release, t
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antibiotics, such as penicillin or
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predisposes to non-immune haemolysi
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● Introduction 71 ● Useful inte
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Response Therapeutic range Toxic ra
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Table 13.1: Interactions outside th
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Table 13.5: Competitive interaction
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● Introduction: ‘personalized m
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Table 14.2: Variations in drug resp
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lipoprotein (LDL) is impaired. LDL
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Key points • Genetic differences
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• Discovery • • Screening Pre
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Too many statistical comparisons pe
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ETHICS COMMITTEES Protocols for all
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Table 16.1: Recombinant proteins/en
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duration and benefit. Adenoviral ve
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● Introduction 97 ● Garlic 97
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A case report has suggested a possi
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including hypericin and pseudohyper
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PART II THE NERVOUS SYSTEM
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● Introduction 105 ● Sleep diff
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and daytime sleeping should be disc
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Key points • Insomnia and anxiety
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Box 19.1: Dopamine theory of schizo
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The Boston Collaborative Survey ind
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Oral medication, especially in liqu
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e.g. interpersonal difficulties or
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Partial response to first-line trea
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Key points Drug treatment of depres
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Case history A 45-year-old man with
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Levodopa PRINCIPLES OF TREATMENT IN
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• pulmonary, retroperitoneal and
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CHOREA The γ-aminobutyric acid con
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Cholinergic crisis Treatment of mya
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● Introduction 133 ● Mechanisms
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absolute arbiter. The availability
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Table 22.2: Metabolic interactions
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FURTHER ANTI-EPILEPTICS Other drugs
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Case history A 24-year-old woman wh
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Assessment of migraine severity and
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● General anaesthetics 145 ● In
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is the theoretical concern of a ‘
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• Respiratory system - apnoea fol
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Competitive antagonists (vecuronium
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have also proved useful in combinat
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● Introduction 155 ● Pathophysi
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ASPIRIN (ACETYLSALICYLATE) Use Anti
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Key points Drugs for mild pain •
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increases, correlating with the hig
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• If possible, use oral medicatio
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PART III THE MUSCULOSKELETAL SYSTEM
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● Introduction: inflammation 167
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Chapter 33). All NSAIDs cause wheez
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• Stomatitis suggests the possibi
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Pharmacokinetics Allopurinol is wel
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PART IV THE CARDIOVASCULAR SYSTEM
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esponsible for the strong predilect
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Ezetimibe Fat Muscle Dietary fat In
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educed). The risk of muscle damage
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Each of these classes of drug reduc
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AT 1 receptor) produce good 24-hour
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Table 28.2: Examples of calcium-cha
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Key points Drugs used in essential
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Case history A 72-year-old woman se
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Assess risk factors Investigations:
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Persistent ST segment elevation Thr
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Mechanism of action GTN works by re
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Because of the risks of haemorrhage
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Intrinsic pathway XIIa XIa the acti
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that the pharmacodynamic response i
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used with apparent benefit in acute
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The drugs that are most effective i
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therapeutic plasma concentration ca
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● Common dysrhythmias 217 ● Gen
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BASIC LIFE SUPPORT CARDIOPULMONARY
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arrest. The electrocardiogram is li
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should be given to insertion of an
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Drug interactions Amiodarone potent
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effect when treating sinus bradycar
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Case history A 24-year-old medical
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PART V THE RESPIRATORY SYSTEM
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CHAPTER 33 THERAPY OF ASTHMA, CHRON
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STEP 5: CONTINUOUS OR FREQUENT USE
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Adenylyl cyclase Table 33.1: Compar
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Drug interactions Although synergis
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use in asthma has declined consider
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α 1-antitrypsin deficiency, neutro
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PART VI THE ALIMENTARY SYSTEM
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● Peptic ulceration 247 ● Oesop
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PEPTIC ULCERATION 249 • With rega
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Ranitidine has a similar profile of
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Vestibular stimulation ? via cerebe
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cortical centres affecting vomiting
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• in hepatocellular failure to re
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Ciprofloxacin is occasionally used
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withdrawal), small doses of benzodi
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Table 34.7: Dose-independent hepato
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● Introduction 265 ● General ph
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dinucleotide (NAD) and nicotinamide
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Table 35.1: Common trace element de
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PART VII FLUIDS AND ELECTROLYTES
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● Introduction 273 ● Volume ove
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Key points Diuretics Diuretics are
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is sometimes caused by drugs, notab
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or with potassium-sparing diuretics
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Greger R, Lang F, Sebekova, Heidlan
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PART VIII THE ENDOCRINE SYSTEM
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in prefilled injection devices (‘
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Metformin should be withdrawn and i
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FURTHER READING American Diabetes A
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deficiency. Potassium iodide (3 mg
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fertility. It is contraindicated du
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● Introduction 297 ● Vitamin D
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effective in life-threatening hyper
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Further reading Block GA, Martin KJ
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Table 40.1: Actions of cortisol and
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injection may be useful, but if don
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CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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elease by the pituitary via negativ
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Treatment with depot progestogen in
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infusion using an infusion pump to
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significant proportion of men who r
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with symptoms caused by the release
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FURTHER READING Birnbaumer M. Vasop
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PART IX SELECTIVE TOXICITY
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● Principles of antibacterial che
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2. transfer of resistance between o
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Pharmacokinetics Absorption of thes
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Mechanism of action Macrolides bind
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asic quinolone structure dramatical
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Case history A 70-year-old man with
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PRINCIPLES OF MANAGEMENT OF MYCOBAC
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Pharmacokinetics Absorption from th
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MYCOBACTERIUM LEPRAE INFECTION Lepr
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POLYENES AMPHOTERICIN B Uses Amphot
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therapy is adequate though more fre
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NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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Table 45.3: Summary of available ac
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Uses Interferon-α when combined wi
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● Introduction 351 ● Immunopath
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Table 46.1: Examples of combination
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NON-NUCLEOSIDE ANALOGUE REVERSE TRA
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FUSION INHIBITORS Uses Currently, e
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salvage therapy include azithromyci
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● Malaria 361 ● Trypanosomal in
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Pharmacokinetics Chloroquine is rap
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Table 47.2: Drug therapy of non-mal
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Table 48.1: Classification of commo
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Polymorph count/mm 3 (a) (b) 10 000
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Page 386 and 387: Adverse effects Methotrexate Inhibi
Page 388 and 389: Table 48.7: Summary of clinical pha
Page 390 and 391: Table 48.9: Summary of the clinical
Page 392 and 393: Plasma membrane Signal transduction
Page 394 and 395: Table 48.10: Monoclonal antibodies
Page 396 and 397: INTERFERON-ALFA 2B Interferon-alfa
Page 398 and 399: PART X HAEMATOLOGY
Page 400 and 401: ● Haematinics - iron, vitamin B 1
Page 402 and 403: one marrow to produce red cells. Th
Page 404 and 405: EPO Erythroid precursors Erythrocyt
Page 406 and 407: Therapeutic principles The extent o
Page 408 and 409: PART XI IMMUNOPHARMACOLOGY
Page 410 and 411: ● Introduction 399 ● Immunity a
Page 412 and 413: Key points Antigen recognition Expr
Page 414 and 415: Table 50.1: Novel anti-proliferativ
Page 416 and 417: Key points Treatment of anaphylacti
Page 418 and 419: DRUGS THAT ENHANCE IMMUNE SYSTEM FU
Page 420 and 421: PART XII THE SKIN
Page 422 and 423: ● Introduction 411 ● Acne 411
Page 424 and 425: DERMATITIS (ECZEMA) PRINCIPLES OF T
Page 426 and 427: SPECIALISTS ONLY SPECIALISTS ONLY E
Page 428 and 429: TREATMENT OF OTHER SKIN INFECTIONS
Page 430 and 431: effect of too high a dose of UVB in
Page 432 and 433: PART XIII THE EYE
Page 436 and 437: to cause pupillary dilatation, name
Page 438 and 439: Table 52.3: Antibacterial agents us
Page 440 and 441: Table 52.6: Common drug-induced pro
Page 442 and 443: PART XIV CLINICAL TOXICOLOGY
Page 444 and 445: ● Introduction 433 ● Pathophysi
Page 446 and 447: Table 53.2: Central nervous system
Page 448 and 449: which provide anonymized data to th
Page 450 and 451: Peak plasma levels after smoking ci
Page 452 and 453: Key points Acute effects of alcohol
Page 454 and 455: FURTHER READING Goldman D, Oroszi G
Page 456 and 457: Table 54.2: Common indications for
Page 458 and 459: Table 54.5: Antidotes and other spe
Page 460 and 461: Commission on Human Medicines (CHM)
Page 462 and 463: Note: Page numbers in italics refer
Page 464 and 465: atrial fibrillation 217, 221 digoxi
Page 466 and 467: Cushing’s syndrome 302 cyclic ade
Page 468 and 469: 5-fluorouracil 375-6 fluoxetine, mo
Page 470 and 471: children 54 diazepam 108 iron prepa
Page 472 and 473: non-steroidal anti-inflammatory dru
Page 474 and 475: puberty (male), delay 314 puerperiu
Page 476: tolerance 9, 433 benzodiazepines 10
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A Textbook of Clinical Pharmacology and Therapeutics

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